Nutritional status of young children in Mumbai slums: a follow-up anthropometric study.
Chronic childhood malnutrition remains common in India. As part of an initiative to improve maternal and child health in urban slums, we collected anthropometric data from a sample of children followed up from birth. We described the proportions of underweight, stunting, and wasting in young children, and examined their relationships with age. We used two linked datasets: one based on institutional birth weight records for 17 318 infants, collected prospectively, and one based on follow-up of a subsample of 1941 children under five, collected in early 2010. Mean birth weight was 2736 g (SD 530 g), with a low birth weight (<2500 g) proportion of 22%. 21% of infants had low weight for age standard deviation (z) scores at birth (<-2 SD). At follow-up, 35% of young children had low weight for age, 17% low weight for height, and 47% low height for age. Downward change in weight for age was greater in children who had been born with higher z scores. Our data support the idea that much of growth faltering was explained by faltering in height for age, rather than by wasting. Stunting appeared to be established early and the subsequent decline in height for age was limited. Our findings suggest a focus on a younger age-group than the children over the age of three who are prioritized by existing support systems. The trial during which the birth weight data were collected was funded by the ICICI Foundation for Inclusive Growth (Centre for Child Health and Nutrition), and The Wellcome Trust (081052/Z/06/Z). Subsequent collection, analysis and development of the manuscript was funded by a Wellcome Trust Strategic Award: Population Science of Maternal and Child Survival (085417ma/Z/08/Z). D Osrin is funded by The Wellcome Trust (091561/Z/10/Z).


Postnatal neurodevelopmental expression and glutamate-dependent regulation of the ZNF804A rodent homologue.
The zinc finger protein ZNF804A rs1344706 variant is a replicated genome-wide significant risk variant for schizophrenia and bipolar disorder. While its association with altered brain structure and cognition in patients and healthy risk allele carriers is well documented, the characteristics and function of the gene in the brain remains poorly understood. Here, we used in situ hybridization to determine mRNA expression levels of the ZNF804A rodent homologue, Zfp804a, across multiple postnatal neurodevelopmental time points in the rat brain. We found changes in Zfp804a expression in the rat hippocampus, frontal cortex, and thalamus across postnatal neurodevelopment. Zfp804a mRNA peaked at postnatal day (P) 21 in hippocampal CA1 and DG regions and was highest in the lower cortical layers of frontal cortex at P1, possibly highlighting a role in developmental migration. Using immunofluorescence, we found that Zfp804a mRNA and ZFP804A co-localized with neurons and not astrocytes. In primary cultured cortical neurons, we found that Zfp804a expression was significantly increased when neurons were exposed to glutamate [20μM], but this increase was blocked by the N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801. Expression of Comt, Pde4b, and Drd2, genes previously shown to be regulated by ZNF804A overexpression, was also significantly changed in an NMDA-dependent manner. Our results describe, for the first time, the unique postnatal neurodevelopmental expression of Zfp804a in the rodent brain and demonstrate that glutamate potentially plays an important role in the regulation of this psychiatric susceptibility gene. These are critical steps toward understanding the biological function of ZNF804A in the mammalian brain.


Statistical assessment of the learning curves of health technologies.
(1) To describe systematically studies that directly assessed the learning curve effect of health technologies. (2) Systematically to identify 'novel' statistical techniques applied to learning curve data in other fields, such as psychology and manufacturing. (3) To test these statistical techniques in data sets from studies of varying designs to assess health technologies in which learning curve effects are known to exist. METHODS - STUDY SELECTION (HEALTH TECHNOLOGY ASSESSMENT LITERATURE REVIEW): For a study to be included, it had to include a formal analysis of the learning curve of a health technology using a graphical, tabular or statistical technique. METHODS - STUDY SELECTION (NON-HEALTH TECHNOLOGY ASSESSMENT LITERATURE SEARCH): For a study to be included, it had to include a formal assessment of a learning curve using a statistical technique that had not been identified in the previous search. METHODS - DATA SOURCES: Six clinical and 16 non-clinical biomedical databases were searched. A limited amount of handsearching and scanning of reference lists was also undertaken. METHODS - DATA EXTRACTION (HEALTH TECHNOLOGY ASSESSMENT LITERATURE REVIEW): A number of study characteristics were abstracted from the papers such as study design, study size, number of operators and the statistical method used. METHODS - DATA EXTRACTION (NON-HEALTH TECHNOLOGY ASSESSMENT LITERATURE SEARCH): The new statistical techniques identified were categorised into four subgroups of increasing complexity: exploratory data analysis; simple series data analysis; complex data structure analysis, generic techniques. METHODS - TESTING OF STATISTICAL METHODS: Some of the statistical methods identified in the systematic searches for single (simple) operator series data and for multiple (complex) operator series data were illustrated and explored using three data sets. The first was a case series of 190 consecutive laparoscopic fundoplication procedures performed by a single surgeon; the second was a case series of consecutive laparoscopic cholecystectomy procedures performed by ten surgeons; the third was randomised trial data derived from the laparoscopic procedure arm of a multicentre trial of groin hernia repair, supplemented by data from non-randomised operations performed during the trial. RESULTS - HEALTH TECHNOLOGY ASSESSMENT LITERATURE REVIEW: Of 4571 abstracts identified, 272 (6%) were later included in the study after review of the full paper. Some 51% of studies assessed a surgical minimal access technique and 95% were case series. The statistical method used most often (60%) was splitting the data into consecutive parts (such as halves or thirds), with only 14% attempting a more formal statistical analysis. The reporting of the studies was poor, with 31% giving no details of data collection methods. RESULTS - NON-HEALTH TECHNOLOGY ASSESSMENT LITERATURE SEARCH: Of 9431 abstracts assessed, 115 (1%) were deemed appropriate for further investigation and, of these, 18 were included in the study. All of the methods for complex data sets were identified in the non-clinical literature. These were discriminant analysis, two-stage estimation of learning rates, generalised estimating equations, multilevel models, latent curve models, time series models and stochastic parameter models. In addition, eight new shapes of learning curves were identified. RESULTS - TESTING OF STATISTICAL METHODS: No one particular shape of learning curve performed significantly better than another. The performance of 'operation time' as a proxy for learning differed between the three procedures. Multilevel modelling using the laparoscopic cholecystectomy data demonstrated and measured surgeon-specific and confounding effects. The inclusion of non-randomised cases, despite the possible limitations of the method, enhanced the interpretation of learning effects. CONCLUSIONS - HEALTH TECHNOLOGY ASSESSMENT LITERATURE REVIEW: The statistical methods used for assessing learning effects in health technology assessment have been crude and the reporting of studies poor. CONCLUSIONS - NON-HEALTH TECHNOLOGY ASSESSMENT LITERATURE SEARCH: A number of statistical methods for assessing learning effects were identified that had not hitherto been used in health technology assessment. There was a hierarchy of methods for the identification and measurement of learning, and the more sophisticated methods for both have had little if any use in health technology assessment. This demonstrated the value of considering fields outside clinical research when addressing methodological issues in health technology assessment. CONCLUSIONS - TESTING OF STATISTICAL METHODS: It has been demonstrated that the portfolio of techniques identified can enhance investigations of learning curve effects. (ABSTRACT TRUNCATED)


Assessing the empirical validity of alternative multi-attribute utility measures in the maternity context.
Multi-attribute utility measures are preference-based health-related quality of life measures that have been developed to inform economic evaluations of health care interventions. The objective of this study was to compare the empirical validity of two multi-attribute utility measures (EQ-5D and SF-6D) based on hypothetical preferences in a large maternity population in England. Women who participated in a randomised controlled trial of additional postnatal support provided by trained community support workers represented the study population for this investigation. The women were asked to complete the EQ-5D descriptive system (which defines health-related quality of life in terms of five dimensions: mobility, self care, usual activities, pain/discomfort and anxiety/depression) and the SF-36 (which defines health-related quality of life, using 36 items, across eight dimensions: physical functioning, role limitations (physical), social functioning, bodily pain, general health, mental health, vitality and role limitations (emotional)) at six months postpartum. Their responses were converted into utility scores using the York A1 tariff set and the SF-6D utility algorithm, respectively. One-way analysis of variance was used to test the hypothetically-constructed preference rule that each set of utility scores differs significantly by self-reported health status (categorised as excellent, very good, good, fair or poor). The degree to which EQ-5D and SF-6D utility scores reflected alternative dichotomous configurations of self-reported health status and the Edinburgh Postnatal Depression Scale score was tested using the relative efficiency statistic and receiver operating characteristic (ROC) curves. The mean utility score for the EQ-5D was 0.861 (95% CI: 0.844, 0.877), whilst the mean utility score for the SF-6D was 0.809 (95% CI: 0.796, 0.822), representing a mean difference in utility score of 0.052 (95% CI: 0.040, 0.064; p < 0.001). Both measures demonstrated statistically significant differences between subjects who described their health status as excellent, very good, good, fair or poor (p < 0.001), as well as monotonically decreasing utility scores (test for linear trend: p < 0.001). The SF-6D was between 29.1% and 423.6% more efficient than the EQ-5D at detecting differences in self-reported health status, and between 129.8% and 161.7% more efficient at detecting differences in the Edinburgh Postnatal Depression Scale score. In addition, the SF-6D generated higher area under the curve (AUC) scores generated by the ROC curves than the EQ-5D, indicating greater discriminatory power, although in all but one analysis the differences in AUC scores between the measures were not statistically significant. This study provides evidence that the SF-6D is an empirically valid and efficient alternative multi-attribute utility measure to the EQ-5D, and is capable of discriminating between external indicators of maternal health.


Predictors of smoking among male college students in Saudi Arabia.
Identifying the predictors of smoking in one of the top cigarette-consuming countries in the world is a vital step in smoking prevention. A cross-sectional study assessed the predictors of smoking in a cohort of male students in 3 universities in Saudi Arabia. A pre-tested, validated questionnaire was used to determine sociodemographic characteristics, academic performance, peers' smoking, and presence of a smoker within the family. Of the 337 participants, 30.9% were current smokers (smoked 1 or more cigarettes within the last 30 days). Lower academic performance (OR = 2.29, 95% CI: 1.02-5.17), peer smoking (OR = 4.14, 95% CI: 1.53-11.3) and presence of other smokers in the family (OR = 2.77, 95% CI: 1.37-5.64) were the significant predictors of smoking status identified using multiple logistic regression analysis. These findings highlight the influence of family and peer pressure in initiating cigarette use among the youth of Saudi Arabia.


Trauma recidivism at an emergency department of a Swedish medical center.
To inform targeted prevention, we studied patterns of trauma recidivism and whether a first injury predicts the risk for a recurrent injury. In a population-based study of 98,502 adult injury events 1999-2012, at the emergency department of Umeå University Hospital, Sweden, we compared non-recidivists with recidivists in terms of patients' sex, age, type of injury and severity of the injury. Thirty-six percent of all patients suffered recurrent injuries, which were associated with a higher proportion of inpatient care and more hospital days. Young men and elderly women were at the highest risk for trauma recidivism. At 20 to 24 years, men had a 2.4 (CI 95 % 2.3-2.5) higher risk than women, a 90 years old woman had almost a 10-fold higher risk for another moderate/severe injury than a 20 years old one. A fracture were associated with a hazard ratio of 1.28 (CI 95 % 1.15-1.42) among men younger than 65 years and 1.31 (CI 95 % 1.12-1.54) for men older than 65 years for a subsequent moderate/severe injury. For women younger than 65 years a fracture was associated with a hazard ratio of 1.44 (CI 95 % 1.28-1.62) for a subsequent moderate/severe injury. A sprain carries a higher risk for a new moderate/severe injury for both men and women and in both age groups; the hazard ratio was 1.13 (CI 95 % 1.00-1.26) for men younger than 65 years, 1.42 (CI 95 % 1.01-1.99) for men older than 65 years, 1.19 (CI 95 % 1.05-1.35) for women younger than 65 years and 1.26 (CI 95 % 1.02-1.56) for women older than 65 years. A higher degree of injury severity was associated with a higher risk for a new moderate/severe injury. Trauma recidivism is common and represents a large proportion of all injured. Age and sex are associated with the risk for new injury. Injury types and severity, also have implications for future injury.


OsNAC3 regulates seed germination involving abscisic acid pathway and cell elongation in rice.
Seed germination is a critical trait for the success of direct seeding in rice cultivation. However, the underlying mechanism determining seed germination is largely unknown in rice. Here, we report that NAC transcription factor OsNAC3 positively regulates seed germination of rice. OsNAC3 regulates seed germination involving abscisic acid (ABA) pathway and cell elongation. OsNAC3 can directly bind to the promoter of ABA catabolic gene OsABA8ox1 and cell expansion gene OsEXP4, which consequently activates their expressions during seed germination. We also find that the expression of OsEXP4 is reduced by ABA during seed germination in rice. OsNAC3 regulates seed germination by influencing cell elongation of the embryo through directly affecting OsEXP4 expression and indirectly ABA-medicated OsEXP4 expression. The OsNAC3 elite haplotype is useful for genetic improvement of seed germination, and overexpression of OsNAC3 can significantly increase seed germination. We therefore propose that OsNAC3 is a potential target in breeding of rice varieties with high seed germination for direct seeding cultivation.


Statins Improve Long Term Patency of Arteriovenous Fistula for Hemodialysis.
The protective effects of statins against stenosis for permanent hemodialysis access have been repeatedly demonstrated in animal studies, but remain controversial in human studies. This study aims to evaluate the association between statin use and permanent hemodialysis access patency using a nationwide hemodialysis cohort. A total of 9862 pairs of statin users and non-users, matched by age and gender, were selected for investigation from 75404 new hemodialysis patients during 2000-2008. The effect of statins on permanent hemodialysis access patency was evaluated using Cox proportional hazards models. Compared with non-users, statin users had an overall 18% risk reduction in the composite endpoint in which angioplasty and recreation were combined (adjusted hazard ratio = 0.82 [95%CI, 0.78-0.87]) and 21% in recreation of permanent hemodialysis access (adjusted hazard ratio = 0.79 [95%CI, 0.69-0.80]). Specifically, the protective effect was found for arteriovenous fistula (adjusted hazard ratio = 0.78[95% CI, 0.73-0.82] for composite endpoint and 0.74 [95% CI, 0.69-0.80] for vascular recreation), but not for arteriovenous grafts (adjusted hazard ratio = 1.10 [95% CI, 0.98-1.24] and 0.94 [95% CI, 0.83-1.07]). Statins possess a protective effect for arteriovenous fistula against the recreation of permanent hemodialysis access. The results provide a pharmaco-epidemiologic link between basic research and clinical evidence.


Ovarian senescence increases liver fibrosis in humans and zebrafish with steatosis.
Contrasting data exist on the effect of gender and menopause on the susceptibility, development and liver damage progression in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether menopause is associated with the severity of liver fibrosis in individuals with NAFLD and to explore the issue of ovarian senescence in experimental liver steatosis in zebrafish. In 244 females and age-matched males with biopsy-proven NAFLD, we assessed anthropometric, biochemical and metabolic features, including menopausal status (self-reported); liver biopsy was scored according to 'The Pathology Committee of the NASH Clinical Research Network'. Young and old male and female zebrafish were fed for 24 weeks with a high-calorie diet. Weekly body mass index (BMI), histopathological examination and quantitative real-time PCR analysis on genes involved in lipid metabolism, inflammation and fibrosis were performed. In the entire cohort, at multivariate logistic regression, male gender [odds ratio (OR): 1.408, 95% confidence interval (95% CI): 0.779-2.542, P=0.25] vs women at reproductive age was not associated with F2-F4 fibrosis, whereas a trend was observed for menopause (OR: 1.752, 95% CI: 0.956-3.208, P=0.06). In women, menopause (OR: 2.717, 95% CI: 1.020-7.237, P=0.04) was independently associated with F2-F4 fibrosis. Similarly, in overfed zebrafish, old female fish with failing ovarian function [as demonstrated by extremely low circulating estradiol levels (1.4±0.1 pg/µl) and prevailing presence of atretic follicles in the ovaries] developed massive steatosis and substantial fibrosis (comparable with that occurring in males), whereas young female fish developed less steatosis and were totally protected from the development of fibrosis. Ovarian senescence significantly increases the risk of fibrosis severity both in humans with NAFLD and in zebrafish with experimental steatosis.


[The Chagas Disease Control Program of the São Paulo State: the contribution of serology to the epidemiological investigation of triatomine-infested domiciliary units during the 1990s].
The Chagas Disease Control Program in São Paulo State, Brazil, now in the entomological surveillance phase, includes a serological examination of individuals residing in domiciliary units infested with vector triatomines infected with Trypanosoma cruzi. From 1990 to 1999, this action included area in which triatomine searches were conducted either as a routine procedure, according to their levels of intra- or peridomiciliary infestation, or at the request of local residents. Among residents of the 1,415 UDs inspected, we collected 5,587 blood samples for serological examination, 87 of which (1.56%) tested positive, seven of which from individuals under 29 years of age. The species most frequently captured were Panstrongylus megistus, Triatoma sordida, and Triatoma tibiamaculata in the adult stage. No association was found between presence of seropositive residents and triatomines infected with Tr. cruzi (OR = 1.498; 0.875 < OR < 2.564, 95% C.I.). Our purpose was to use serological testing to investigate the situation of areas identifiable as being at risk of Chagas disease transmission and to compare the results with extant data about Tr. cruzi infection both in humans and vector triatomines.


Neural and behavioural correlates of autobiographical memory retrieval in patients with major depressive disorder and a history of trauma exposure.
Alterations in autobiographical memory (AM) performance have been identified in major depressive disorder (MDD) and in trauma-related disorders, however, the neural and behavioural correlates of AM retrieval in patients with MDD and a co-morbid history of trauma remain unexplored. Here, we used behavioural and neuroimaging techniques to investigate AM in this patient group and in matched healthy comparison subjects (HCs). Twenty patients with MDD and trauma exposure and 20 HCs underwent fMRI scanning while recalling positive, negative, and neutral events. Participants were subsequently administered the Autobiographical Interview (Levine et al., 2002), allowing for separation of episodic and non-episodic details of memories. Key clinical variables, including illness severity, dissociative (e.g., depersonalization, derealization) symptoms, and history of parental bonding, were assessed. Compared to controls, patients showed reduced activation in the left parahippocampus and left anterior insula during retrieval of positive memories. Among patients, greater specificity of positive AM recall on the Autobiographical Interview was related to reduced activation of the left anterior insula during retrieval of positive memories. Moreover, increased left parahippocampal activation during negative memory recall was related to heightened levels of paternal care among the patient group. Taken together, these findings point towards potential alterations in key neural processes (e.g., episodic vividness and embodiment) associated with AM retrieval among MDD patients with a history of co-morbid trauma exposure. These alterations appear unrelated to illness severity, but instead are associated with parental bonding.


Quantifying the potential for dose reduction with visual grading regression.
Objectives To propose a method to study the effect of exposure settings on image quality and to estimate the potential for dose reduction when introducing dose-reducing measures. Methods Using the framework of visual grading regression (VGR), a log(mAs) term is included in the ordinal logistic regression equation, so that the effect of reducing the dose can be quantitatively related to the effect of adding post-processing. In the ordinal logistic regression, patient and observer identity are treated as random effects using generalised linear latent and mixed models. The potential dose reduction is then estimated from the regression coefficients. The method was applied in a single-image study of coronary CT angiography (CTA) to evaluate two-dimensional (2D) adaptive filters, and in an image-pair study of abdominal CT to evaluate 2D and three-dimensional (3D) adaptive filters. Results For five image quality criteria in coronary CTA, dose reductions of 16-26% were predicted when adding 2D filtering. Using five image quality criteria for abdominal CT, it was estimated that 2D filtering permits doses were reduced by 32-41%, and 3D filtering by 42-51%. Conclusions VGR including a log(mAs) term can be used for predictions of potential dose reduction that may be useful for guiding researchers in designing subsequent studies evaluating diagnostic value. With appropriate statistical analysis, it is possible to obtain direct numerical estimates of the dose-reducing potential of novel acquisition, reconstruction or post-processing techniques.


Molecular characterization of the cytotoxic mechanism of multiwall carbon nanotubes and nano-onions on human skin fibroblast.
The increasing use of nanotechnology in consumer products and medical applications underlies the importance of understanding its potential toxic effects to people and the environment. Although both fullerene and carbon nanotubes have been demonstrated to accumulate to cytotoxic levels within organs of various animal models and cell types and carbon nanomaterials have been exploited for cancer therapies, the molecular and cellular mechanisms for cytotoxicity of this class of nanomaterial are not yet fully apparent. To address this question, we have performed whole genome expression array analysis and high content image analysis based phenotypic measurements on human skin fibroblast cell populations exposed to multiwall carbon nano-onions (MWCNOs) and multiwall carbon nanotubes (MWCNTs). Here we demonstrate that exposing cells to MWCNOs and MWCNTs at cytotoxic doses induces cell cycle arrest and increases apoptosis/necrosis. Expression array analysis indicates that multiple cellular pathways are perturbed after exposure to these nanomaterials at these doses, with material-specific toxigenomic profiles observed. Moreover, there are also distinct qualitative and quantitative differences in gene expression profiles, with each material at different dosage levels (6 and 0.6 microg/mL for MWCNO and 0.6 and 0.06 microg/mL for MWCNT). MWCNO and MWCNT exposure activates genes involved in cellular transport, metabolism, cell cycle regulation, and stress response. MWCNTs induce genes indicative of a strong immune and inflammatory response within skin fibroblasts, while MWCNO changes are concentrated in genes induced in response to external stimuli. Promoter analysis of the microarray results demonstrate that interferon and p38/ERK-MAPK cascades are critical pathway components in the induced signal transduction contributing to the more adverse effects observed upon exposure to MWCNTs as compared to MWCNOs.


Next-generation sequencing in understanding complex neurological disease.
Next-generation sequencing techniques have made vast quantities of data on human genomes and transcriptomes available to researchers. Huge progress has been made towards understanding the basis of many Mendelian neurological conditions, but progress has been considerably slower in complex neurological diseases (multiple sclerosis, migraine, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and so on). The authors review current next-generation sequencing methodologies and present selected studies illustrating how these have been used to cast light on the genetic etiology of complex neurological diseases with specific focus on multiple sclerosis. The authors highlight particular pitfalls in next-generation sequencing experiments and speculate on both clinical and research applications of these sequencing platforms for complex neurological disorders in the future.


Effect of fixed-dose subcutaneous reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid-dependent asthma: results from two phase 3, randomised, double-blind, placebo-controlled trials.
Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2). Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per μL or more (including no more than 30% patients with an eosinophil count <400 cells/μL), and at least a medium dose of inhaled corticosteroids with one or more additional asthma controllers. Patients in study 2 had severe asthma, a blood eosinophil count of 300 cells per μL or more, daily maintenance oral corticosteroid (prednisone 5-40 mg, or equivalent), and high-dose inhaled corticosteroids plus another controller. Patients were randomly assigned (1:1) to subcutaneous reslizumab (110 mg) or placebo once every 4 weeks for 52 weeks in study 1 and 24 weeks in study 2. Patients and investigators were masked to treatment assignment. Primary efficacy outcomes were frequency of exacerbations during 52 weeks in study 1 and categorised percentage reduction in daily oral corticosteroid dose from baseline to weeks 20-24 in study 2. Primary efficacy analyses were by intention to treat, and safety analyses included all patients who received at least one dose of study treatment. These studies are registered with ClinicalTrials.gov, NCT02452190 (study 1) and NCT02501629 (study 2). Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56-1·12; p=0·19). Subcutaneous reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per μL or more (0·64, 95% CI 0·43-0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the reslizumab group vs the placebo group, 1·23, 95% CI 0·70-2·16; p=0·47). The frequency of adverse events and serious adverse events with reslizumab were similar to those with placebo in both studies. Fixed-dose (110 mg) subcutaneous reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/μL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous reslizumab are required to achieve maximal efficacy. Teva Branded Pharmaceutical Products R&D.


Ab initio Modeling of the Vibrational Sum-Frequency Generation Spectrum of Interfacial Water.
Understanding the structural and dynamical features of interfacial water is of greatest interest in physics, chemistry, biology, and materials science. Vibrational sum-frequency generation (SFG) spectroscopy, which is sensitive to the molecular orientation and dynamics on the surfaces or at the interfaces, allows one to study a wide variety of interfacial systems. The structural and dynamical features of interfacial water at the air/water interface have been extensively investigated by SFG spectroscopy. However, the interpretations of the spectroscopic features have been under intense debate. Here, we report a simulated SFG spectrum of the air/water interface based on ab initio molecular dynamics simulations, which covers the OH stretching, bending, and libration modes of interfacial water. Quantitative agreement between our present simulations and the most recent experimental studies ensures that ab initio simulations predict unbiased structural features and electrical properties of interfacial systems. By utilizing the kinetic energy spectral density (KESD) analysis to decompose the simulated spectra, the spectroscopic features can then be assigned to specific hydrogen-bonding configurations of interfacial water molecules.


Supervisor-subordinate age dissimilarity and performance ratings: the buffering effects of supervisory relationship and practice.
Using 394 pairs of employees and their immediate supervisors working in the Information and Communication Technology (ICT) sector in three northern European countries, this study examined the effect of workplace moderators on the link between relational demography and supervisor ratings of performance. Directional age differences between superior and subordinate (i.e., status incongruence caused when the supervisor is older or younger than his/her subordinate) and non-directional age differences were used as predictors of supervisor ratings of occupational expertise. The quality of the supervisor-subordinate relationship and the existence of positive age-related supervisory practices were examined as moderators of this relationship. The results provide no support for a relationship between directional age differences and age-related stereotyping by supervisors in ratings of performance, neither for the effects of age-related supervisory practices. However, high quality supervisor-subordinate relationships did moderate the effects of age dissimilarity on supervisory ratings. The implications of these findings for performance appraisal methodologies and recommendations for further research are discussed.


Dependence of surface enhanced Raman scattering on the plasmonic template periodicity.
Surface enhanced Raman scattering has been investigated from rhodamine 6G molecules embedded in polymethyl methacrylate (R6G+PMMA) and coated on one-dimensional and two-dimensional gold-dielectric gratings fabricated by laser interference lithographically. The Raman signals from these plasmonic templates are 200 to 400 times larger than the signal from R6G+PMMA coated on plain gold films. The enhancement of the Raman signal varies almost periodically with the period of the grating. Finite-difference time-domain simulations show that large electromagnetic near fields occur at the metallic edges due to the resonant excitation of localized surface plasmon of the gold patches by the pump laser. These give rise to large enhancements of the Raman signal. The dependence on period is due to the combined effects of the localized surface plasmon and the periodic grating that couples the pump laser to the surface plasmon polariton.


Lamellar MoSe2 nanosheets embedded with MoO2 nanoparticles: novel hybrid nanostructures promoted excellent performances for lithium ion batteries.
A carbon-free nanocomposite consisting of MoO2 nanoparticles embedded between MoSe2 nanosheets, named MoO2@MoSe2, has been synthesized and demonstrated excellent electrochemical properties for lithium ion batteries. In such a composite, MoSe2 nanosheets provide a flexible substrate for MoO2 nanoparticles; while MoO2 nanoparticles act as spacers to retain the desired active surface to electrolyte and also introduce metallic conduction. In addition, the heterojunctions at the interface between MoSe2 and MoO2 introduce a self-built electric field to promote the lithiation/delithiation process. As a result, such lamellar composite has a long cycling stability with a reversible capacity of 520.4 mA h g-1 at a current density of 2000 mA g-1 after 400 cycles and excellent rate performance, which are attributed to the synergistic combination of the two components in nanoscale.


Physiological determinants of time to exhaustion during intermittent treadmill running at vV(.-)O(2max).
Previous studies have reported large between-subject variations in the time to exhaustion during intermittent running at the velocity at V(.-)O (2max) (vV(.-)O (2max)). This study aimed to determine which physiological factors contribute to this variability. Thirteen male runners (age 38.9 +/- 8.7 years) each completed five treadmill running tests; two incremental tests to determine V(.-)O (2max), vV(.-)O (2max), the lactate threshold velocity (vLT) and the running velocity--V(.-)O (2) relationship; the third test to determine the time to exhaustion during continuous running at vV(.-)O (2max) (t (lim)cont); the fourth to determine the maximal accumulated oxygen deficit (MAOD); the fifth to determine the time to exhaustion during intermittent running at vV(.-)O (2max) (t (lim)int). Relief intervals during the intermittent test were run at 70 % vV(.-)O (2max). The vLT-vV(.-)O (2max) difference was significantly correlated with t (lim)int (r = - 0.70; p = 0.007). The correlation coefficient increased to r = - 0.83 (p < 0.001) when the difference between the relief interval velocity and the vLT was deducted from the vLT-vV(.-)O (2max) difference (theoretically representing the net depletion of the MAOD during each work/relief interval cycle). The main finding of this study was that 49 % of the variance in t (lim)int was explained by the vLT-vV(.-)O (2max) difference, compared to 74 % for t (lim)cont. However, a further 20 % of unique variance in t (lim)int could be explained with the inclusion of the relief interval velocity-vLT difference. Theoretically, runners with the largest relief interval velocity-vLT difference will replete their anaerobic capacity to a greater extent during each relief interval, thereby increasing time to exhaustion.


A 5-Year Follow-up Study on the Relationship between Obstructive Sleep Apnea and Parkinson Disease.
Sleep disturbances are among the most common nonmotor symptoms of Parkinson disease. However, no large epidemiological data regarding the association between obstructive sleep apnea (OSA) and Parkinson disease have been reported. The goal of this study was to investigate the risk for Parkinson disease during a 5-y follow-up period after a diagnosis of OSA using a population-based dataset. The data for this retrospective longitudinal cohort study were retrieved from the Taiwan Longitudinal Health Insurance Database 2000. We identified 1,532 patients with OSA as the study cohort and randomly selected 7,660 patients as the comparison cohort. Each subject was individually followed up for a 5-y period to identify those in whom Parkinson disease subsequently developed. Stratified Cox proportional hazard regressions were performed as a means of comparing the 5-y risk of subsequent Parkinson disease between the study cohort and comparison cohort. Of the 9,192 total patients, Parkinson disease developed in 0.73% during the 5-y follow-up period: 1.24% and 0.63% in the OSA and control cohorts, respectively. After censoring patients who died during the follow-up period and adjusting for socio-demographic characteristics, the hazard ratio (HR) of Parkinson disease during the 5-y follow-up period for patients with OSA was 2.26 (95% confidence interval [CI] = 1.32-3.88) compared with comparison patients. In addition, among females, the adjusted HR of Parkinson disease was 3.54 (95% CI = 1.50-8.34) for patients with OSA compared to patients without OSA. However, among males, there was no significantly increased hazard of Parkinson disease for patients with OSA compared to those without OSA. Female patients with OSA were found to be at a significant risk of subsequent Parkinson disease during a 5-y follow-up period.


Report from the 19th annual Western Canadian Gastrointestinal Cancer Consensus Conference; Winnipeg, Manitoba; 29-30 September 2017.
The 19th annual Western Canadian Gastrointestinal Cancer Consensus Conference (wcgccc) was held in Winnipeg, Manitoba, 29-30 September 2017. The wcgccc is an interactive multidisciplinary conference attended by health care professionals from across Western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) who are involved in the care of patients with gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; radiologists; and allied health care professionals participated in presentation and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of colorectal cancer.


How can the operating environment for nutrition research be improved in sub-Saharan Africa? The views of African researchers.
Optimal nutrition is critical for human development and economic growth. Sub-Saharan Africa is facing high levels of food insecurity and only few sub-Saharan African countries are on track to eradicate extreme poverty and hunger by 2015. Effective research capacity is crucial for addressing emerging challenges and designing appropriate mitigation strategies in sub-Saharan Africa. A clear understanding of the operating environment for nutrition research in sub-Saharan Africa is a much needed prerequisite. We collected data on the barriers and requirements for conducting nutrition research in sub-Saharan Africa through semi-structured interviews with 144 participants involved in nutrition research in 35 countries in sub-Saharan Africa. A total of 133 interviews were retained for coding. The main barriers identified for effective nutrition research were the lack of funding due to poor recognition by policymakers of the importance of nutrition research and under-utilisation of research findings for developing policy, as well as an absence of research priority setting from within Africa. Current research topics were perceived to be mainly determined by funding bodies from outside Africa. Nutrition researchers argued for more commitment from policymakers at national level. The low capacity for nutrition research was mainly seen as a consequence of insufficient numbers of nutrition researchers, limited skills and a poor research infrastructure. In conclusion, African nutrition researchers argued how research priorities need to be identified by African stakeholders, accompanied by consensus building to enable creating a problem-driven national research agenda. In addition, it was considered necessary to promote interactions among researchers, and between researchers and policymakers. Multidisciplinary research and international and cross-African collaboration were seen as crucial to build capacity in sub-Saharan nutrition research.


Germ cell transplantation into mouse testes procedure.
To illustrate the step-by-step protocol followed to assay germ cell transplantation into the seminiferous epithelium of mouse testes. Video presentation of an animal model for research in reproductive and regenerative medicine. Research laboratory. Male nude mice (NU-Foxn1(nu)). Mice were chemically sterilized with alkylant compounds (busulfan) followed by gonadal microsurgery to inject donor germ cells. Donor cells should be labeled with reporter genes, such as green fluorescent protein (GFP), lactose operon (LacZ), or alternatively design an effective strategy with specific antibodies to track them within the recipient testes. Sperm detection in the ejaculate can also be used as a read out. However, in this case detection of the donor genotype in the sperm is mandatory to elucidate their origin. In the present study we describe the complete protocol for germ cell transplant by efferent duct injection, including the preparation of recipient mice, surgery for the germ cell transplant, and analysis of recipient testes. The main strength of this technique is that it constitutes the gold standard for a functional test of the germ cell potential as only spermatogonial stem cells are able to properly colonize the seminal lumen. Both fresh and frozen/thawed testicular cells are suitable for this technique as donor germ cells. Also, enrichment of living spermatogonial stem cells, previous to the transplant, seems to improve the efficiency of colonization. For proper colonization of germ cells, the niche should be available and thus mouse strains that lack endogenous spermatogenesis such as W/W(v) mutant mice are usually used. In the case of nonmatched donor cells, seminiferous epithelium of immune-suppressed recipient mice should be germ cell depleted before the transplant. One limitation of this technique is that the procedure can take up to 3 months. Also, in contrast to the full recovery of spermatogenesis in mouse-to-mouse transplants, xenotransplantation of germ cells from phylogenetically distant species, such as humans into mouse recipients, results in colonization of donor cells and spermatogonial expansion, but fail in their spermatogenic progression due to evolutive incompatibilities with the recipient niche. Xenografting of pieces of donor testis tissue under the skin of mouse hosts is an alternative approach that is currently being investigated to try to solve this limitation. Transplantation of spermatogonial stem cells into the seminal lumen of mouse testes is a functional assay that defines this cellular subpopulation by its ability to colonize it. This technique can be used as a model to elucidate the insights of spermatogonial stem cells, to produce transgenic animals by genetically manipulating donor cells before transplantation, but also it has potential applications in fertility preservation in cattle and humans as it is feasible in large animals, as recent reports have demonstrated with rhesus monkeys, that recovered spermatogenesis after allogenic transplantation, and even from human cadaver testes. Therefore spermatogonial stem cells isolated from prepuberal boys, who are treated with alkylant chemotherapy, could be returned to their testis to regenerate spermatogenesis in the future.


[Health needs in marginalized urban areas in Mexico].
To understand the health needs of the population living in Mexico's marginalized urban areas. A population-based survey of families residing in poor, urban neighborhoods, in five geographic areas in Mexico (northern, central, southern, south-east, and Mexico City), selected through multistage sampling. Interviews were conducted and anthropometric measurements were taken in the home, and included all members of the participating family. Analysis was carried out on positive health factors, nutrition, reproductive health, health problems, and mental health, and results were disaggregated by age and sex. In all, 24,707 individuals participated. The interviewees were found to have minimal schooling (6 years or less). Only 46.8% had health care coverage, be it public or private. Among the children, 19.8% were malnourished; overweight was prevalent from adolescence onwards. Of adolescents 12-19 years of age, 15.7% were sexually active, but only 57.7% of the males and 41.9% of the females in this age group were using some method of contraception. Of the adults, 5.9% suffered from diabetes and 11.5%, from high blood pressure. In the sample of adolescents, adults, and elderly adults, tobacco use was 21.2%; alcohol consumption, 36.0%; illicit drug use, 9.5%; and depression, 20.2%. The health needs of people living in Mexico's marginalized urban areas proliferate in the context of a young population with weak ties and little support from family and health services. They face crisis and disease--infant malnutrition, high-risk pregnancy, and addictions--the byproducts of disparities in social progress. The rate of chronic conditions was similar to that of the general population of Mexico.


Causal Estimation with Functional Confounders.
Causal inference relies on two fundamental assumptions: ignorability and positivity. We study causal inference when the true confounder value can be expressed as a function of the observed data; we call this setting estimation with functional confounders (EFC). In this setting ignorability is satisfied, however positivity is violated, and causal inference is impossible in general. We consider two scenarios where causal effects are estimable. First, we discuss interventions on a part of the treatment called functional interventions and a sufficient condition for effect estimation of these interventions called functional positivity. Second, we develop conditions for nonparametric effect estimation based on the gradient fields of the functional confounder and the true outcome function. To estimate effects under these conditions, we develop Level-set Orthogonal Descent Estimation (LODE). Further, we prove error bounds on LODE's effect estimates, evaluate our methods on simulated and real data, and empirically demonstrate the value of EFC.


The domains of apoptosis: a genomics perspective.
Apoptosis plays important roles in many facets of normal physiology in animal species, including programmed cell death associated with fetal development or metamorphosis, tissue homeostasis, immune cell education, and some aspects of aging. Defects in the regulation of apoptosis contribute to multiple diseases associated with either inappropriate cell loss or pathological cell accumulation. Host-pathogen interactions have additionally provided evolutionary pressure for apoptosis as a defense mechanism against viruses and microbes, sometimes linking apoptosis mechanisms with inflammatory responses. To a large extent, the apoptosis machinery can be viewed as a network, with different nodes connected by physical interactions of evolutionarily conserved domains. These domains can serve as signatures for identification of proteins involved in the network. In particular, the caspase recruitment domains (CARDs); death effector domains (DEDs); death domains (DDs); BIR (baculovirus IAP repeat) domains of inhibitor of apoptosis proteins (IAPs); Bcl-2 family proteins; caspase protease domains; and endonuclease-associated CIDE (cell death-inducing DFF45-like effector) domains are found in common in proteins involved in apoptosis. In the genomes of mammals, genes encoding proteins that carry one or more of these signature domains are often present in multiple copies, making up diverse gene families that permit tissue-specific and highly regulated control of cell life and death decisions through combinations of stimulus-specific gene expression and complex protein interaction networks. In this Review, we organize the repertoire of apoptosis proteins of humans into domain families, drawing comparisons with homologs in other vertebrate and invertebrate animal species, and discuss some of the functional implications of these findings.


Conversion of metaplastic Barrett's epithelium into post-mitotic goblet cells by gamma-secretase inhibition.
Barrett's esophagus (BE) affects approximately 2% of the Western population and progresses to esophageal adenocarcinoma (EAC) in 0.5% of these patients each year. In BE, the stratified epithelium is replaced by an intestinal-type epithelium owing to chronic gastroduodenal reflux. Since self-renewal of intestinal crypts is driven by Notch signaling, we investigated whether this pathway was active in the proliferative crypts of BE. Immunohistochemistry confirmed the presence of an intact and activated Notch signaling pathway in metaplastic BE epithelium, but not in the normal human esophagus. Similar observations were made in two well-known human Barrett's-derived EAC cell lines, OE33 and SKGT-5. We then sought to investigate the effects of Notch inhibition by systemic treatment with a gamma-secretase inhibitor in a well-validated rodent model for BE. As we have shown previously in normal intestinal epithelium, Notch inhibition converted the proliferative Barrett's epithelial cells into terminally differentiated goblet cells, whereas the squamous epithelium remained intact. These data imply that local application of gamma-secretase inhibitors may present a simple therapeutic strategy for this increasingly common pre-malignant condition.


Synthetic Prion Selection and Adaptation.
Prion pathologies are characterized by the conformational conversion of the cellular prion protein (PrPC) into a pathological infectious isoform, known as PrPSc. The latter acquires different abnormal conformations, which are associated with specific pathological phenotypes. Recent evidence suggests that prions adapt their conformation to changes in the context of replication. This phenomenon is known as either prion selection or adaptation, where distinct conformations of PrPSc with higher propensity to propagate in the new environment prevail over the others. Here, we show that a synthetically generated prion isolate, previously subjected to protein misfolding cyclic amplification (PMCA) and then injected in animals, is able to change its biochemical and biophysical properties according to the context of replication. In particular, in second transmission passage in vivo, two different prion isolates were found: one characterized by a predominance of the monoglycosylated band (PrPSc-M) and the other characterized by a predominance of the diglycosylated one (PrPSc-D). Neuropathological, biochemical, and biophysical assays confirmed that these PrPSc possess distinctive characteristics. Finally, PMCA analysis of PrPSc-M and PrPSc-D generated PrPSc (PrPSc-PMCA) whose biophysical properties were different from those of both inocula, suggesting that PMCA selectively amplified a third PrPSc isolate. Taken together, these results indicate that the context of replication plays a pivotal role in either prion selection or adaptation. By exploiting the ability of PMCA to mimic the process of prion replication in vitro, it might be possible to assess how changes in the replication environment influence the phenomenon of prion selection and adaptation.


Probing Heavy Majorana Neutrinos and the Weinberg Operator through Vector Boson Fusion Processes in Proton-Proton Collisions at sqrt[s]=13 TeV.
The first search exploiting the vector boson fusion process to probe heavy Majorana neutrinos and the Weinberg operator at the LHC is presented. The search is performed in the same-sign dimuon final state using a proton-proton collision dataset recorded at sqrt[s]=13 TeV, collected with the CMS detector and corresponding to a total integrated luminosity of 138 fb^{-1}. The results are found to agree with the predictions of the standard model. For heavy Majorana neutrinos, constraints on the squared mixing element between the muon and the heavy neutrino are derived in the heavy neutrino mass range 50 GeV-25 TeV; for masses above 650 GeV these are the most stringent constraints from searches at the LHC to date. A first test of the Weinberg operator at colliders provides an observed upper limit at 95% confidence level on the effective μμ Majorana neutrino mass of 10.8 GeV.


Strong dynamical effects during stick-slip adhesive peeling.
We consider the classical problem of the stick-slip dynamics observed when peeling a roller adhesive tape at a constant velocity. From fast imaging recordings, we extract the dependence of the stick and slip phase durations on the imposed peeling velocity and peeled ribbon length. Predictions of Maugis and Barquins [in Adhesion 12, edited by K. W. Allen, Elsevier ASP, London, 1988, pp. 205-222] based on a quasistatic assumption succeed to describe quantitatively our measurements of the stick phase duration. Such a model however fails to predict the full stick-slip cycle duration, revealing strong dynamical effects during the slip phase.


Pulmonary artery distensibility in chronic obstructive pulmonary disease.
Pulmonary hypertension (PH) is an important complication in the natural history of chronic obstructive pulmonary disease (COPD) and is caused by the remodeling of pulmonary arteries impairing the distensibility and stiffness of the major pulmonary arteries. To evaluate the pulmonary artery distensibility by transthoracic echocardiography in patients with COPD. We prospectively investigated COPD male patients and compared with healthy controls. In addition to right ventricle (RV) conventional echocardiographic parameters, right pulmonary artery fractional shortening(RPA-FS) and new pulmonary artery stiffness (PAS) parameters were compared. Fifty-four COPD patients participated in the study and compared with a control group consisting of 24, all men, healthy, nonsmoking subjects. Six patients were excluded from study due to poor quality of echocardiographic recordings. The distensibility of PA evaluated by the RPA-FS parameter was found to be significantly lower in patients with COPD than it was in normal subjects (13.3 ± 8.1 vs. 27.6 ± 4.9,P :< 0.001) and correlated positively with tricuspid annular systolic excursion (TAPSE) (r = 0.566, P < 0.001) and pulmonary acceleration time (r = 0.607, P < 0.001) and correlated inversely with pulmonary artery systolic pressure (r = -0.587, P < 0.001), PAS(r = -0.479, P < 0.001) and functional capacity (r = -0.586, P < 0.001). Similar to this, PAS found to be impaired in COPD patients (29.5 ± 13.6 vs. 15.7 ± 4.1, P < 0.001) and correlated inversely RPA-FS (r = -0.479, P < 0.001). There were statistically significant difference for pulmonary artery distensibility (RPA-FS) and PAS parameters among the COPD subgroups with regard to NYHA functional capacity (P < 0.001). In this study, we found that PAS and distensibility were worsened in COPD patients and correlated with decreased functional capacity.


'SASA! is the medicine that treats violence'. Qualitative findings on how a community mobilisation intervention to prevent violence against women created change in Kampala, Uganda.
Intimate partner violence (IPV) violates women's human rights and is a serious public health concern. Historically strategies to prevent IPV have focussed on individuals and their relationships without addressing the context under which IPV occurs. Primary prevention of IPV is a relatively new focus of international efforts and what SASA!, a phased community mobilisation intervention, seeks to achieve. Conducted in Kampala, Uganda, between 2007 and 2012, the SASA! Study is a cluster randomised controlled trial to assess the community-level impact of SASA! This nested qualitative study explores pathways of individual- and community-level change as a result of SASA! Forty in-depth interviews with community members (20 women, 20 men) were conducted at follow-up, audio recorded, transcribed verbatim and analysed using thematic analysis complemented by constant comparative methods. SASA! influenced the dynamics of relationships and broader community norms. At the relationship level, SASA! is helping partners to explore the benefits of mutually supportive gender roles; improve communication on a variety of issues; increase levels of joint decision-making and highlight non-violent ways to deal with anger or disagreement. Not all relationships experienced the same breadth and depth of change. At the community level, SASA! has helped foster a climate of non-tolerance of violence by reducing the acceptability of violence against women and increasing individuals' skills, willingness, and sense of responsibility to act to prevent it. It has also developed and strengthened community-based structures to catalyse and support on-going activism to prevent IPV. This paper provides evidence of the ways in which community-based violence prevention interventions may reduce IPV in low-income settings. It offers important implications for community mobilisation approaches and for prevention of IPV against women. This research has demonstrated the potential of social norm change interventions at the community level to achieve meaningful impact within project timeframes.


Nitrate-nitrogen, land use/land cover, and soil drainage associations at multiple spatial scales.
Managing non-point-source pollution of water requires knowledge of land use/land cover (LULC) influences at altering watershed scales. To gain improved understanding of relationships among LULC, soil drainage, and dissolved nitrate-N dynamics within the Calapooia River Basin in western Oregon, we selected 44 watersheds ranging in size between 3 and 33 km(2) for monthly synoptic sampling of surface water quality between October 2003 and September 2004. Seasonal associations were examined between dissolved nitrate-N and proportion of woody vegetation or poorly drained soils at differing scales (10, 20, 30, 60, 90, 150, 300 m, and entire watershed), which we defined as influence zones (IZs), surrounding stream networks. Correlations between nitrate-N and proportion woody vegetation or poorly drained soil at each IZ were analyzed for differences using the Hotelling-Williams test. We observed negative correlations (r = -0.81 to -0.94) between nitrate-N and proportion of woody vegetation during winter and spring. Poorly drained soils had positive correlations (r = 0.63-0.87) with nitrate-N. Altering the scale of analysis significantly changed correlations between nitrate-N and woody vegetation, with IZs <150 m being stronger than the watershed scale during winter. However, absolute differences in correlation values were small, indicating minimal ecological consequence for significant differences among scales. In contrast, nitrate-N correlations with poorly drained soil were stronger at the watershed scale than the 10- through 90-m IZs during winter and spring, and absolute differences were sufficient to suggest that scale is ecologically important when determining associations between dissolved nitrate-N and poorly drained soils.


Tobacco and nicotine product testing.
Tobacco product testing is a critical component of the Family Smoking Prevention and Tobacco Control Act (FSPTCA), which grants the Food and Drug Administration the authority to regulate tobacco products. The availability of methods and measures that can provide accurate data on the relative health risks across types of tobacco products, brands, and subbrands of tobacco products on the validity of any health claims associated with a product, and on how consumers perceive information on products toxicity or risks is crucial for making decisions on the product's potential impact on public health. These tools are also necessary for making assessments of the impact of new indications for medicinal products (other than cessation) but more importantly of tobacco products that may in the future be marketed as cessation tools. To identify research opportunities to develop empirically based and comprehensive methods and measures for testing tobacco and other nicotine-containing products so that the best science is available when decisions are made about products or policies. Literature was reviewed to address sections of the FSPTCA relevant to tobacco product evaluation; research questions were generated and then reviewed by a committee of research experts. A research agenda was developed for tobacco product evaluation in the general areas of toxicity and health risks, abuse liability, consumer perception, and population effects. A cohesive, systematic, and comprehensive assessment of tobacco products is important and will require building consensus and addressing some crucial research questions.


Expression of CDKN1C in the bone marrow of patients with myelodysplastic syndrome and secondary acute myeloid leukemia is associated with poor survival after conventional chemotherapy.
We tested the hypothesis that proliferative activity of hematopoietic stem cells has impact on survival in newly diagnosed patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML). RNA expression profiles of CD34(+) cells were analyzed in 125 MDS patients and compared to healthy controls. Prognostic impact on overall survival (OS) of mRNA proliferation signatures established for solid tumor cells was analyzed retrospectively. For validation on the protein level, immunofluorescence and immunohistochemistry analyses in bone marrow (BM) biopsies were performed, and an independent cohort of 223 MDS and secondary AML patients was investigated. Lower proliferative activity correlated with the expression of cyclin-dependent kinase inhibitor 1C (CDKN1C) and with shorter OS (p < 0.001). In multivariable analysis, higher CDKN1C expression was associated with worse OS (p = 0.02). On the BM level, a total of 84 (38%) patients showed CDKN1C protein expression before start of treatment. Patient, disease and treatment characteristics did not differ between CDKN1C-positive and -negative patients. Positive CDKN1C BM status was associated with shorter OS in multivariable analysis (HR 1.54, p = 0.04). There was an interaction between CDKN1C BM status and subsequent treatment with negative impact on OS being most pronounced in patients receiving conventional cytotoxic chemotherapy (n = 83, 2-year OS 30% versus 58%, p = 0.002). In conclusion, low-proliferative phenotype and CDKN1C expression were associated with shorter OS. CDKN1C protein expression in the BM of newly diagnosed, treatment-naïve MDS and secondary AML patients was identified as a prognostic factor for poor survival in patients treated with antiproliferative chemotherapy.


Enhanced fitness conferred by naturally occurring variation in the circadian clock.
Natural variation in clock parameters is necessary for the circadian clock to contribute to organismal fitness over a broad geographic range. Considerable variation is evident in the period, phase, and amplitude of 150 Arabidopsis accessions, and the period length is correlated with the day length at the latitude of origin, implying the adaptive significance of correctly regulated circadian timing. Quantitative trait loci analysis of recombinant inbred lines indicates that multiple loci interact to determine period, phase, and amplitude. The loss-of-function analysis of each member of the ARABIDOPSIS PSEUDO-RESPONSE REGULATOR family suggests that they are candidates for clock quantitative trait loci.


Transbilayer Colocalization of Lipid Domains Explained via Measurement of Strong Coupling Parameters.
When micron-scale compositional heterogeneity develops in membranes, the distribution of lipids on one face of the membrane strongly affects the distribution on the other. Specifically, when lipid membranes phase separate into coexisting liquid phases, domains in each monolayer leaflet of the membrane are colocalized with domains in the opposite leaflet. Colocalized domains have never been observed to spontaneously move out of registry. This result indicates that the lipid compositions in one leaflet are strongly coupled to compositions in the opposing leaflet. Predictions of the interleaflet coupling parameter, Λ, vary by a factor of 50. We measure the value of Λ by applying high shear forces to supported lipid bilayers. This causes the upper leaflet to slide over the lower leaflet, moving domains out of registry. We find that the threshold shear stress required to deregister domains in the upper and lower leaflets increases with the inverse length of domains. We derive a simple, closed-form expression relating the threshold shear to Λ, and find Λ = 0.016 ± 0.004 kBT/nm2.


An optimization study of the ultra-short period for HRV analysis at rest and post-exercise.
Ultra-short-term heart rate variability (HRV) analysis (< 5 min) has been extensively growing in the field of exercise performance for autonomic assessment. However, the validation of ultra-short-term HRV was unclear in the recovery period of exercise. This study aimed to elucidate the agreement between ultra-short-term HRV (0-30 s, 0-1 min, 0-2 min, 0-3 min, 0-4 min) and standard short-term HRV (5 min) and to explore the optimal recording duration under rest and post-exercise conditions. 69 participants were recruited to perform physical exercise on a treadmill with an intensity of 6 km/h, 9 km/h and 12 km/h, independently. The standard deviation of RR-interval (SDNN) and root mean square of successive differences of RR-intervals (RMSSD) were calculated by using ultra-short periods and standard period at rest condition (Pre-E) and three post-exercise trials, i.e., Post-E1, Post-E2 and Post-E3, respectively. One-way ANOVA with repeated-measures and Cohen's d statistics were conducted, and Bland-Altman analysis and interclass correlation coefficients (ICC) were used to assess the levels of agreement. For SDNN and RMSSD, the results of agreement analysis at rest condition were different from those at post-exercise. At Pre-E, SDNN and RMSSD were reliable for ultra-short-term HRV analysis at all ultra-short periods, i.e., 0-30 s, 0-1 min, 0-2 min, 0-3 min and 0-4 min, with most ICCs greater than 0.9 and Cohen's d showing trivial differences (Cohen's d = 0.024-0.117). However, at post-exercise, SDNN0-30s, SDNN0-1min, RMSSD0-30s and RMSSD0-1min showed significant differences with SDNN5min and RMSSD5min, respectively (p < 0.01), and the ICCs was not perfect (< 0.9). HRV analysis with time duration longer than 2 min showed nearly perfect reliability in all post-exercise trials, with trivial differences (Cohen's d = -0.003-0.110) and perfect ICCs (ICCs = 0.916-0.998). Furthermore, the limits of the agreement became tighter as the period duration increased in Bland-Altman plots. This study demonstrated that ultra-short-term HRV analysis was a good surrogate of standard HRV time-domain measures to reflect the autonomic regulation at rest and post-exercise. Specifically, ultra-short-term HRV0-30s or HRV0-1min was recommended at rest condition, whereas longer than 2 min recording period was reliable to obtain SDNN and RMSSD for the accuracy of HRV analysis.


Behavioral adaptations to heat stress and water scarcity in white-faced capuchins (Cebus capucinus) in Santa Rosa National Park, Costa Rica.
We examined thermoregulatory behaviors in a wild population of white-faced capuchins (Cebus capucinus) inhabiting a highly seasonal dry forest in Santa Rosa National Park (SRNP), Costa Rica. The dry season in SRNP lasts approximately 5 months and is characterized by high ambient temperatures regularly exceeding 37 degrees C, low relative humidity, and the near absence of precipitation. This study demonstrates that capuchins rest more and travel shorter distances during the hottest and driest hours of the day, and suggests that they extend their tongues to lower body temperature via evaporative cooling. Seasonal weather patterns and group movement data reported here are based on 940 h of observations on three social groups of capuchins (wet season: 370 h, dry season: 570 h). In the dry season, the proportion of time spent resting increased at higher temperatures whereas the proportion of time spent traveling decreased. Distance traveled between location points taken at half-hour intervals decreased significantly as temperature increased, although the correlation was not strong. Capuchins exposed their tongues during hot, dry, windy conditions, and this behavior was much more frequent in the dry season. Temperature was significantly higher and humidity significantly lower for "tongue-out" events than expected for a random event in the dry season. Finally, as surface water became scarce, home-range areas of heavy use became increasingly centered on the remaining permanent water sources. These results suggest that heat stress and water scarcity are significant influences on the behavior of capuchins in hot, dry conditions.


Efficacy and safety of recombinant C1 inhibitor for the treatment of hereditary angioedema attacks: a North American open-label study.
The efficacy of recombinant human C1 inhibitor (rhC1INH) for the treatment of patients with acute hereditary angioedema (HAE) attacks has been demonstrated in 2 randomized, double-blind, placebo-controlled studies. To assess the safety and efficacy of rhC1INH for repeated treatment of acute attacks of HAE. In this open-label extension study, patients with eligible HAE attacks were treated with an intravenous 50-U/kg dose of rhC1INH with an option for an additional dose of 50 U/kg based on clinical response. Time to beginning of relief was assessed by patients using a 100-mm visual analogue scale (VAS). Safety evaluation was based on the clinical laboratory results and adverse events. Sixty-two patients were treated for 168 attacks (range, 1-8 attacks per patient). A total of 90% of the attacks were treated with a single 50-U/kg dose of rhC1INH. Median times to beginning of symptom relief for the first 5 attacks were 37 to 67 minutes. More than 90% of attacks responded within 4 hours after treatment with rhC1INH. There was no requirement for increased dosing with successive treatments. Thirty-nine patients (63%) reported at least 1 treatment-emergent adverse event, with most events rated mild to moderate. Seven severe treatment-emergent adverse events were reported, and all were considered to be unrelated to treatment with rhC1INH. The results of this open-label extension support continued efficacy of rhC1INH after repeated treatments for subsequent HAE attacks. There was no increase in adverse event reporting after repeated exposure to rhC1INH.


Aromatase excess syndrome: a rare autosomal dominant disorder leading to pre- or peri-pubertal onset gynecomastia.
Overexpression of CYP19A1 encoding aromatase results in a rare genetic disorder referred to as aromatase excess syndrome (AEXS). Male patients with AEXS manifest pre- or peri-pubertal onset gynecomastia, gonadotropin deficiency, and advanced bone age, while female patients are mostly asymptomatic. To date, 30 male patients with molecularly confirmed AEXS have been reported. A total of 12 types of submicroscopic rearrangements, i.e., two simple duplications, four simple deletions, two simple inversions, and four complex rearrangements, have been implicated in AEXS. Clinical severity of AEXS primarily depends on the types of the rearrangements. AEXS appears to account for a small number of cases of pre- or peri-pubertal onset gynecomastia, and should be suspected particularly when gynecomastia is associated with an autosomal dominant inheritance pattern, characteristic hormone abnormalities and/or advanced bone age. Treatment with an aromatase inhibitor appears to benefit patients with AEXS, although long-term safety of this class of drugs remains unknown.


C-CAM expression in odontogenesis and tooth eruption.
The distribution of the cell adhesion molecule C-CAM was analyzed during tooth development, eruption and formation of the junctional epithelium in rat molars by immunohistochemistry and in situ hybridization. C-CAM could not be detected during odontogenesis until the late bell stage; then only the mRNA was demonstrated in the odontoblasts and ameloblasts. Prior to eruption, a local increase in C-CAM (mRNA and protein) was observed in the reduced enamel epithelium. During eruption, high C-CAM levels were seen in the fusion zone between the oral epithelium and the reduced enamel epithelium. In the adult rat, C-CAM remained strongly expressed in the junctional epithelium. Our study indicates that C-CAM may play a role in odontogenesis and during formation of the epithelial structures involved in tooth eruption and formation of the junctional epithelium.


Approximate performance of the nonlinear joint transform correlator in signallike noise.
We present a statistical-analysis technique for a nonlinear joint transform correlator (JTC) based on two assumptions: the noise and the signal spectra are identical, and the signal energy is small relative to the noise energy. The first assumption, while admittedly convenient, is also defensible in that it is a worst case and in that image and scene noise can be similar in texture. The second is also reasonable, given that even a clearly visible signal may have small energy compared with the scene noise if it is of limited extent; in any case, the results appear moderately faithful even for the case that signal and noise energies are equal. We discover that the optimal Fourier-plane transformation is spatially variant and tends to remove the Fourier amplitudes of the input image, and indeed functions in a way very similar to the spatially variant binary JTC. We also see that the classic (or spatially invariant linear) JTC is a very inferior technique for signallike noise, that the best spatially variant binary JTC uses a threshold proportional to the noise power spectrum, and that, if a spatially invariant binary-thresholded JTC is desired, then the median Fourier-plane value is an excellent choice of threshold. The performance predictions are verified by simulation and appear to be reasonable even for the highly nonlinear binary schemes.


Organ-targeted mutagenicity of nitrofurantoin in Big Blue transgenic mice.
Nitrofurans are widely used in human medicine, as nitrofurantoin and nifuroxazide, still prescribed for long-term antimicrobial prophylaxis of urinary tract and gastrointestinal infection in humans respectively. Recent experiments in mammals, as well as reports mentioning toxic effects in humans associated with a long-term use, specially in the case of nitrofurantoin, raised the need for reevaluating their genotoxicity. The objective of this study was to determine whether these two compounds induce a mutagenic effect in the Big Blue transgenic mouse mutation assay. Mice were orally treated either with nitrofurantoin or nifuroxazide for five consecutive days and sacrificed 3 weeks later. In order to optimize the genotoxic response, the doses used for each compound were 25-fold higher as the posology in humans. They corresponded to 50% of the highest doses tolerated by mice. The mutant frequency was determined from kidney, lung, bladder, caecum, colon, small intestine, spleen and stomach. A weak mutagenic response of nitrofurantoin-treated mice specifically in the kidney was observed. As in the case of other nitrofuran compounds, the mutation spectra determined from treated samples exhibited slightly more GC-->TA transversions as compared with untreated conditions. These data are relevant to the targeted action of nitrofurantoin as a urinary antimicrobial agent. No significant increase of mutants was detected in the case of nifuroxazide-treated mice whatever the organs analysed.


Analysis of the current care model of the COPD patient: a health outcomes assessment and economic evaluation.
Because chronic obstructive pulmonary disease (COPD) is a common but serious illness affecting millions worldwide, we present an overview of the disease and discuss its underdiagnosis and treatment options. COPD, a disease encompassing emphysema and chronic bronchitis, is associated with cigarette smoking, chronic exposure to environmental pollutants, and, occasionally, genetic conditions. The disease is severely underdiagnosed and underrecognized. The economic costs of COPD, which accounted for about 14 million office visits and 3.5 million hospital days in 1993, are estimated at more than $7 billion, and another $8 billion worth of productivity was lost to morbidity and mortality in the same year.1 The death rate from COPD is rising, principally among women. Uniform diagnosis and treatment standards are now being realized. The American Thoracic Society and European Respiratory Society recommend treatment, based on worsening symptoms, with bronchodilators and, in more advanced cases, inhaled corticosteroids. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) treatment algorithm also uses a step-care approach. The GOLD guidelines recommend a management program that prevents disease progression, relieves symptoms, improves exercise tolerance and health status, and prevents and treats complications and exacerbations, thereby reducing mortality. The GOLD guidelines recommend avoiding risk factors, using short- or long-acting bronchodilators, and adding rehabilitation and inhaled glucocorticoids. In severe cases, the GOLD guidelines recommend long-term oxygen administration and even surgery. Decisions in managing COPD require a consideration of multiple outcomes measures. Although spirometry remains the foundation for diagnosis and demonstration of efficacy, the patients and their families may be more concerned with symptoms, quality of life, and prevention of exacerbations. In patients with COPD, bronchodilators such as tiotropium produce significant improvements in all of these outcomes measures. COPD is a common disease that substantially affects patients, health care systems, and society. With increasing awareness of the disease, improved diagnostic guidelines, and newer cost-effective pharmacologic regimens, this chronic progressive disorder can be effectively recognized and treated, helping to improve patients. overall health and quality of life.


[General and family medicine: a gratifying choice].
The problematic discussion of speciality choice have been largely studied in other countries, where we can see the same setting of the announced crises of Primary Care and the so called decline of Family Medicine. In Portugal, many authors have shown an increasing concern in the way of getting more attention by the political policies/entities for the reduction of the number of family doctors. The decline of the interest of the medical students for Family Medicine is a complex and multifactorial problem that exists at international level, as in other generalist specialities, without technical procedures and technological investment. The importance of human values in medical education, by the new challenges that we have in the XXI century medicine, puts us the question about the students we are graduating today in our schools. The educational and health system reform, and the medical schools support, may influence the choices of medical graduates and motivate them for this speciality, developing a more real and more close medical care that responds to the interests and the needs of the population.


Purification and activation of the double-stranded RNA-dependent eIF-2 kinase DAI.
The double-stranded RNA (dsRNA)-dependent protein kinase DAI (also termed dsI and P1) possesses two kinase activities; one is an autophosphorylation activity, and the other phosphorylates initiation factor eIF-2. We purified the enzyme, in a latent form, to near homogeneity from interferon-treated human 293 cells. The purified enzyme consisted of a single polypeptide subunit of approximately 70,000 daltons, retained its dependence on dsRNA for activation, and was sensitive to inhibition by adenovirus VA RNAI. Autophosphorylation required a suitable concentration of dsRNA and was second order with respect to DAI concentration, which suggests an intermolecular mechanism in which one DAI molecule phosphorylates a neighboring molecule. Once autophosphorylated, the enzyme could phosphorylate eIF-2 but seemed unable to phosphorylate other DAI molecules, which implies a change in substrate specificity upon activation. VA RNAI blocked autophosphorylation and activation but permitted the activated enzyme to phosphorylate eIF-2. VA RNAI also blocked the binding of dsRNA to the enzyme. The data are consistent with a model in which activation requires the interaction of two molecules of DAI with dsRNA, followed by intermolecular autophosphorylation of the latent enzyme. VA RNAI would block activation by preventing the interaction between DAI and dsRNA.


A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene.
Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer's disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known. Using genotyping from 1313 individuals with sporadic Alzheimer's disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer's disease. The same OAS1 locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer's disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression. Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer's disease and COVID-19 patients, we identify co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases. In human induced pluripotent stem cell-derived microglia with lowered OAS1 expression, we show exaggerated production of TNF-α with IFN-γ stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells. Collectively, our data support a link between genetic risk for Alzheimer's disease and susceptibility to critical illness with COVID-19 centred on OAS1, a finding with potential implications for future treatments of Alzheimer's disease and COVID-19, and development of biomarkers to track disease progression.


Gene expression profile of the aging process in rat liver: normalizing effects of growth hormone replacement.
The mechanisms that control life span and age-related phenotypes are not well understood. It has been suggested that aging or at least some of its symptoms are related to a physiological decline in GH levels with age. To test this hypothesis, and to improve our understanding of the cellular and molecular mechanisms behind the aging process, we have analyzed age-induced changes in gene expression patterns through the application of DNA chip technology. In the present study, the aging process was analyzed in rat liver in the presence or absence of GH replacement. Out of 3,000 genes printed on the microarrays, approximately 1,000 were detected in the rat liver. Among these, 47 unique transcripts were affected by the aging process in male rat livers. The largest groups of age-regulated transcripts encoded proteins involved in intermediary metabolism, mitochondrial respiration, and drug metabolism. Approximately 40% of the differentially expressed gene products were normalized after GH treatment. The majority of those transcripts have previously not been shown to be under GH control. The list of gene products that showed normalized expression levels in GH-treated old rats may shed further insight on the action and mechanism behind the positive effects of GH on, for example, fuel metabolism and body composition observed in different animal and human studies.


Semantic layers for illustrative volume rendering.
Direct volume rendering techniques map volumetric attributes (e.g., density, gradient magnitude, etc.) to visual styles. Commonly this mapping is specified by a transfer function. The specification of transfer functions is a complex task and requires expert knowledge about the underlying rendering technique. In the case of multiple volumetric attributes and multiple visual styles the specification of the multi-dimensional transfer function becomes more challenging and non-intuitive. We present a novel methodology for the specification of a mapping from several volumetric attributes to multiple illustrative visual styles. We introduce semantic layers that allow a domain expert to specify the mapping in the natural language of the domain. A semantic layer defines the mapping of volumetric attributes to one visual style. Volumetric attributes and visual styles are represented as fuzzy sets. The mapping is specified by rules that are evaluated with fuzzy logic arithmetics. The user specifies the fuzzy sets and the rules without special knowledge about the underlying rendering technique. Semantic layers allow for a linguistic specification of the mapping from attributes to visual styles replacing the traditional transfer function specification.


A draft sequence of the rice genome (Oryza sativa L. ssp. indica).
We have produced a draft sequence of the rice genome for the most widely cultivated subspecies in China, Oryza sativa L. ssp. indica, by whole-genome shotgun sequencing. The genome was 466 megabases in size, with an estimated 46,022 to 55,615 genes. Functional coverage in the assembled sequences was 92.0%. About 42.2% of the genome was in exact 20-nucleotide oligomer repeats, and most of the transposons were in the intergenic regions between genes. Although 80.6% of predicted Arabidopsis thaliana genes had a homolog in rice, only 49.4% of predicted rice genes had a homolog in A. thaliana. The large proportion of rice genes with no recognizable homologs is due to a gradient in the GC content of rice coding sequences.


Intravenous ferumoxytol allows noninvasive MR imaging monitoring of macrophage migration into stem cell transplants.
To develop a clinically applicable imaging technique for monitoring differential migration of macrophages into viable and apoptotic matrix-associated stem cell implants (MASIs) in arthritic knee joints. With institutional animal care and use committee approval, six athymic rats were injected with intravenous ferumoxytol (0.5 mmol iron per kilogram of body weight) to preload macrophages of the reticuloendothelial system with iron oxide nanoparticles. Forty-eight hours later, all animals received MASIs of viable adipose-derived stem cells (ADSCs) in an osteochondral defect of the right femur and mitomycin-pretreated apoptotic ADSCs in an osteochondral defect of the left femur. One additional control animal each received intravenous ferumoxytol and bilateral scaffold-only implants (without cells) or bilateral MASIs without prior ferumoxytol injection. All knees were imaged with a 7.0-T magnetic resonance (MR) imaging unit with T2-weighted fast spin-echo sequences immediately after, as well as 2 and 4 weeks after, matrix-associated stem cell implantation. Signal-to-noise ratios (SNRs) of viable and apoptotic MASIs were compared by using a linear mixed-effects model. MR imaging data were correlated with histopathologic findings. All ADSC implants showed a slowly decreasing T2 signal over 4 weeks after matrix-associated stem cell implantation. SNRs decreased significantly over time for the apoptotic implants (SNRs on the day of matrix-associated stem cell implantation, 2 weeks after the procedure, and 4 weeks after the procedure were 16.9, 10.9, and 6.7, respectively; P = .0004) but not for the viable implants (SNRs on the day of matrix-associated stem cell implantation, 2 weeks after the procedure, and 4 weeks after the procedure were 17.7, 16.2, and 15.7, respectively; P = .2218). At 4 weeks after matrix-associated stem cell implantation, SNRs of apoptotic ADSCs were significantly lower than those of viable ADSCs (mean, 6.7 vs 15.7; P = .0013). This corresponded to differential migration of iron-loaded macrophages into MASIs. Iron oxide loading of macrophages in the reticuloendothelial system by means of intravenous ferumoxytol injection can be utilized to monitor differential migration of bone marrow macrophages into viable and apoptotic MASIs in a rat model.


Clinical and molecular characterization of patients with heterozygous mutations in wilms tumor suppressor gene 1.
The Wilms tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of WT1 mutations with renal function and proteinuria have been observed in world-wide cohorts with nephrotic syndrome or Wilms tumor (WT). This study analyzed mid-European patients with known constitutional heterozygous mutations in WT1, including patients without proteinuria or WT. Retrospective analysis of genotype, phenotype, and treatment of 53 patients with WT1 mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012. Median age was 12.4 (interquartile range [IQR], 6-19) years. Forty-four of 53 (83%) patients had an exon mutation (36 missense, eight truncating), and nine of 53 (17%) had an intronic lysine-threonine-serine (KTS) splice site mutation. Fifty of 53 patients (94%) had proteinuria, which occurred at an earlier age in patients with missense mutations (0.6 [IQR, 0.1-1.5] years) than in those with truncating (9.7 [IQR, 5.7-11.9]; P<0.001) and splice site (4.0 [IQR, 2.6-6.6]; P=0.004) mutations. Thirteen of 50 (26%) were treated with steroids and remained irresponsive, while three of five partially responded to cyclosporine A. Seventy-three percent of all patients required RRT, those with missense mutations significantly earlier (at 1.1 [IQR, 0.01-9.3] years) than those with truncating mutations (16.5 [IQR, 16.5-16.8]; P<0.001) and splice site mutations (12.3 [IQR, 7.9-18.2]; P=0.002). Diffuse mesangial sclerosis was restricted to patients with missense mutations, while focal segmental sclerosis occurred in all groups. WT occurred only in patients with exon mutations (n=19). Fifty of 53 (94%) patients were karyotyped: Thirty-one (62%) had XY and 19 (38%) had XX chromosomes, and 96% of male karyotypes had urogenital malformations. Type and location of WT1 mutations have predictive value for the development of proteinuria, renal insufficiency, and WT. XY karyotype was more frequent and associated with urogenital malformations in most cases.


The effects of glucocorticoids and progesterone on hormone-responsive human breast cancer in long-term tissue culture.
Glucocorticoids, at physiological concentration, inhibit cell division and thymidine incorporation in three lines of human breast cancer maintained in long-term tissue culture. At steroid concentrations sufficient to inhibit thymidine incorporation 50%, little or no effect is seen on protein synthesis 48 hr after hormone addition. All three of these lines are shown to have glucocorticoid receptors demonstrable by competitive protein binding assays. Receptors are extensively characterized in one line by sucrose density gradient analysis and binding specificity studies. Good correlation between receptor-binding specificity and biological activity is found except for progesterone, which binds to glucocorticoid receptor but is noninhibitory. Cross-competition and quantification studies demonstrate a separate receptor for progesterone. This receptor has limited binding specificities restricted largely to progestational agents, whereas the glucocorticoid receptor bound both glucocorticoids and progesterone. Two other human breast cancer lines neither contain glucocorticoid receptor nor are inhibited by glucocorticoids. It is concluded that in some cases glucocorticoids can directly limit growth in human breast cancer in vitro without requiring alterations in other trophic hormones.


Communication is key: extracellular vesicles as mediators of infection and defence during host-microbe interactions in animals and plants.
Extracellular vesicles (EVs) are now understood to be ubiquitous mediators of cellular communication. In this review, we suggest that EVs have evolved into a highly regulated system of communication with complex functions including export of wastes, toxins and nutrients, targeted delivery of immune effectors and vectors of RNA silencing. Eukaryotic EVs come in different shapes and sizes and have been classified according to their biogenesis and size distributions. Small EVs (or exosomes) are released through fusion of endosome-derived multivesicular bodies with the plasma membrane. Medium EVs (or microvesicles) bud off the plasma membrane as a form of exocytosis. Finally, large EVs (or apoptotic bodies) are produced as a result of the apoptotic process. This review considers EV secretion and uptake in four eukaryotic kingdoms, three of which produce cell walls. The impacts cell walls have on EVs in plants and fungi are discussed, as are roles of fungal EVs in virulence. Contributions of plant EVs to development and innate immunity are presented. Compelling cases are sporophytic self-incompatibility and cellular invasion by haustorium-forming filamentous pathogens. The involvement of EVs in all of these eukaryotic processes is reconciled considering their evolutionary history.


Pantoea stewartii subsp. stewartii produces an endoglucanase that is required for full virulence in sweet corn.
Pantoea stewartii subsp. stewartii, a xylem-dwelling bacterium, is the causal agent of Stewart's wilt and blight of sweet corn. The goal of this study was to characterize the only gene in the P. stewartii subsp. stewartii genome predicted to encode an endoglucanase (EGase); this gene was designated engY. Culture supernatants from P. stewartii subsp. stewartii and Escherichia coli expressing recombinant EngY protein possessed both EGase and xylanase activities. Deletion of engY abolished EGase and xylanase activity, demonstrating that EngY appears to be the major EGase or xylanase produced by P. stewartii subsp. stewartii. Most importantly, our results show that EngY contributes to movement in the xylem and disease severity during the wilting phase of Stewart's wilt but is not required for water-soaked lesion formation.


Spectral descriptors for bulk metallic glasses based on the thermodynamics of competing crystalline phases.
Metallic glasses attract considerable interest due to their unique combination of superb properties and processability. Predicting their formation from known alloy parameters remains the major hindrance to the discovery of new systems. Here, we propose a descriptor based on the heuristics that structural and energetic 'confusion' obstructs crystalline growth, and demonstrate its validity by experiments on two well-known glass-forming alloy systems. We then develop a robust model for predicting glass formation ability based on the geometrical and energetic features of crystalline phases calculated ab initio in the AFLOW framework. Our findings indicate that the formation of metallic glass phases could be much more common than currently thought, with more than 17% of binary alloy systems potential glass formers. Our approach pinpoints favourable compositions and demonstrates that smart descriptors, based solely on alloy properties available in online repositories, offer the sought-after key for accelerated discovery of metallic glasses.


Module map of stem cell genes guides creation of epithelial cancer stem cells.
Self-renewal is a hallmark of stem cells and cancer, but existence of a shared stemness program remains controversial. Here, we construct a gene module map to systematically relate transcriptional programs in embryonic stem cells (ESCs), adult tissue stem cells, and human cancers. This map reveals two predominant gene modules that distinguish ESCs and adult tissue stem cells. The ESC-like transcriptional program is activated in diverse human epithelial cancers and strongly predicts metastasis and death. c-Myc, but not other oncogenes, is sufficient to reactivate the ESC-like program in normal and cancer cells. In primary human keratinocytes transformed by Ras and I kappa B alpha, c-Myc increases the fraction of tumor-initiating cells by 150-fold, enabling tumor formation and serial propagation with as few as 500 cells. c-Myc-enhanced tumor initiation is cell-autonomous and independent of genomic instability. Thus, activation of an ESC-like transcriptional program in differentiated adult cells may induce pathologic self-renewal characteristic of cancer stem cells.