Efficacy and safety of liposomal cytarabine in lymphoma patients with central nervous system involvement from lymphoma.
: Standard intrathecal chemotherapy for lymphomatous meningitis (LM) is limited by the short cerebrospinal half-lives of the agents used, necessitating frequent administration. Liposomal cytarabine (DepoCyte) has an extended half-life that permits administration at 2- to 4-weekly intervals. : Patients with LM who underwent treatment with liposomal cytarabine at treatment centers in Spain between 2004 and 2007 were identified. Data on demographics, treatment, and outcomes were extracted from medical notes and entered, retrospectively, into a database for analysis. : Data on 55 patients with lymphoma (mainly stage IV) and LM were entered into the database. Most patients (n = 36) had diffuse large B-cell lymphoma. The median number of cycles of liposomal cytarabine received was 4 (range, 1-10), and the median follow-up period was 124 days. Complete and partial neurologic responses were achieved in 27 and 12 patients, respectively (overall response rate, 72%), all of whom also showed a cytological response, except for 5 with initially negative cytology. Median time to neurologic progression among responders was 105.5 days. Liposomal cytarabine was generally well tolerated; headache was the most commonly reported adverse effect (n = 17). : Liposomal cytarabine is effective and well tolerated in the treatment of LM, and should be considered as an agent of choice for the treatment of this complication. Cancer 2009. (c) 2009 American Cancer Society.


Neurophysiological basis of penile erection.
Penile erection involves a complex interaction between the central nervous system and local factors. It is a neurovascular event modulated by psychological and hormonal factors. The discovery of nitric oxide (NO) as an intercellular messenger or neurotransmitter paved the way for identifying important mechanisms underlying physiological and pathophysiological events in the penis, in addition to providing the knowledge for the development of new therapeutics based on a novel concept of molecule and cell interaction. Despite the fact that sinusoidal endothelial cells also produce and release NO in response to chemical and possibly physical stimuli, roles of neurogenic NO in penile erection appear to be more attractive and convincing, since the pharmacological neuromodulation represents an essential step to attaining penile erection. Erectile dysfunction (ED) is caused by a variety of pathogenic factors, particularly impaired formation and action of NO. Hence, a thorough knowledge of the physiology of erection is essential for future pharmacological innovations in the field of male ED, particularly targeting NO or intracellular cyclic GMP, which represent the most promising therapeutic approach to treat patients with ED.


Adaptive randomized study of idarubicin and cytarabine versus troxacitabine and cytarabine versus troxacitabine and idarubicin in untreated patients 50 years or older with adverse karyotype acute myeloid leukemia.
Troxacitabine has activity in refractory myeloid leukemia, either as a single agent or when combined with cytarabine (ara-C) or with idarubicin. A prospective, randomized study was conducted in patients aged 50 years or older with untreated, adverse karyotype, acute myeloid leukemia (AML) to assess troxacitabine-based regimes as induction therapy. Patients were randomized to receive idarubicin and ara-C (IA) versus troxacitabine and ara-C (TA) versus troxacitabine and idarubicin (TI). A Bayesian design was used to adaptively randomly assign patients to treatment. Thus, although there was initially an equal chance for randomization to IA, TA, or TI, treatment arms with a higher success rate progressively received a greater proportion of patients. Thirty-four patients were treated. Randomization to TI stopped after five patients and randomization to TA stopped after 11 patients. Defining success as complete remission (CR) that occurred within 49 days of starting treatment, success rates were 55% (10 of 18 patients) with IA, 27% (three of 11 patients) with TA, and 0% (zero of five patients) with TI. Because three CRs occurred after day 49, final CR rates were 55% (10 of 18 patients) with IA, 45% (five of 11 patients) with TA, and 20% (one of five patients) with TI. The probability that TA was inferior to IA was 70%, with a 5% probability that TA would have a 20% higher CR rate than IA. Survival was equivalent with all three regimens. Neither troxacitabine combination was superior to IA in elderly patients with previously untreated adverse karyotype AML.


Evaluating the contributions of purifying selection and progeny-skew in dictating within-host Mycobacterium tuberculosis evolution.
The within-host evolutionary dynamics of tuberculosis (TB) remain unclear, and underlying biological characteristics render standard population genetic approaches based upon the Wright-Fisher model largely inappropriate. In addition, the compact genome combined with an absence of recombination is expected to result in strong purifying selection effects. Thus, it is imperative to establish a biologically relevant evolutionary framework incorporating these factors in order to enable an accurate study of this important human pathogen. Further, such a model is critical for inferring fundamental evolutionary parameters related to patient treatment, including mutation rates and the severity of infection bottlenecks. We here implement such a model and infer the underlying evolutionary parameters governing within-patient evolutionary dynamics. Results demonstrate that the progeny skew associated with the clonal nature of TB severely reduces genetic diversity and that the neglect of this parameter in previous studies has led to significant mis-inference of mutation rates. As such, our results suggest an underlying de novo mutation rate that is considerably faster than previously inferred, and a progeny distribution differing significantly from Wright-Fisher assumptions. This inference represents a more appropriate evolutionary null model, against which the periodic effects of positive selection, associated with drug-resistance for example, may be better assessed.


Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames.
All species continuously evolve short open reading frames (sORFs) that can be templated for protein synthesis and may provide raw materials for evolutionary adaptation. We analyzed the evolutionary origins of 7,264 recently cataloged human sORFs and found that most were evolutionarily young and had emerged de novo. We additionally identified 221 previously missed sORFs potentially translated into peptides of up to 15 amino acids-all of which are smaller than the smallest human microprotein annotated to date. To investigate the bioactivity of sORF-encoded small peptides and young microproteins, we subjected 266 candidates to a mass-spectrometry-based interactome screen with motif resolution. Based on these interactomes and additional cellular assays, we can associate several candidates with mRNA splicing, translational regulation, and endocytosis. Our work provides insights into the evolutionary origins and interaction potential of young and small proteins, thereby helping to elucidate this underexplored territory of the human proteome.


Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects.
Chronic stressful life events are risk factors for developing major depression, the pathophysiology of which is strongly linked to impairments in serotonin (5-HT) neurotransmission. Exposure to chronic unpredictable stress (CUS) has been found to induce depressive-like behaviours, including passive behavioural coping and anhedonia in animal models, along with many other affective, cognitive, and behavioural symptoms. The heterogeneity of these symptoms represents the plurality of corticolimbic structures involved in mood regulation that are adversely affected in the disorder. Chronic stress has also been shown to negatively regulate adult hippocampal neurogenesis, a phenomenon that is involved in antidepressant effects and regulates subsequent stress responses. Although there exists an enormous body of data on stress-induced alterations of 5-HT activity, there has not been extensive exploration of 5-HT adaptations occurring presynaptically or at the level of the raphe nuclei after exposure to CUS. Similarly, although hippocampal neurogenesis is known to be negatively regulated by stress and positively regulated by antidepressant treatment, the role of neurogenesis in mediating affective behaviour in the context of stress remains an active area of investigation. The goal of this review is to link the serotonergic and neurogenic hypotheses of depression and antidepressant effects in the context of stress. Specifically, chronic stress significantly attenuates 5-HT neurotransmission and 5-HT1A autoreceptor sensitivity, and this effect could represent an endophenotypic hallmark for mood disorders. In addition, by decreasing neurogenesis, CUS decreases hippocampal inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, exacerbating stress axis overactivity. Similarly, we discuss the possibility that adult hippocampal neurogenesis mediates antidepressant effects via the ventral (in rodents; anterior in humans) hippocampus' influence on the HPA axis, and mechanisms by which antidepressants may reverse chronic stress-induced 5-HT and neurogenic changes. Although data are as yet equivocal, antidepressant modulation of 5-HT neurotransmission may well serve as one of the factors that could drive neurogenesis-dependent antidepressant effects through these stress regulation-related mechanisms.


Effectiveness of Various Remineralizing Agents on White Spot Lesions after Orthodontic Treatment: A Comparative Study.
To evaluate and compare the ability of three commercially available remineralizing agents on the surface microhardness (SMH) of enamel after induction of white spot lesions (WSLs) by demineralization. About 80 sound mandibular human premolars that were later removed as a part of orthodontic treatment were employed in this research under the inclusion criteria. After cleaning and disinfecting the teeth, their crowns were mounted in acrylic resin and painted with nail varnish, not including a 3 mm × 3 mm window in the middle of the buccal surface. Each tooth was soaked in 15 mL of a demineralizing solution at a pH of 4.5 that was prepared for this study and left in a place for 10 subsequent days to permit the formation of WSLs after which the SMH was again assessed. The premolar teeth were then randomly allocated and equally divided into one of the four groups of 20 each depending on the treatment they received as Group 1: control group, Group 2: Colgate sensitive Pro-Relief toothpaste group, Group 3: Amflor group, and Group 4: Enafix group. After 15 days, the microhardness of all samples was estimated and alterations in the same were noted. Scanning electron microscopy (SEM) was used to evaluate the surface morphology. Enhanced and highest mean SMH was present in the Colgate sensitive Pro-Relief group (53.26 ± 0.10) followed by Enafix group (47.72 ± 0.21), Amflor group (44.84 ± 0.66), and control group (39.52 ± 0.32), respectively after application of remineralizing agents. Except for Group 3 vs Group 4, statistically significant differences (p < 0.05) were noted in all the groups. All the three agents employed in this study, that is, Colgate sensitive Pro-Relief toothpaste, Amflor, and Enafix improved the SMH of teeth after the therapy given over 15 days compared to the microhardness following demineralization. White spot lesions often occur on labial surfaces of teeth after orthodontic treatment. Hence, these lesions pose esthetic challenges thereby affecting treatment satisfaction perceived by the patient. As esthetics and appearance are of foremost significance after orthodontic treatment, elimination protocols for remineralization of WSLs are of utmost importance employing economic means. How to cite this article: Nalawade VA, Jeri SY, Dash BP, et al. Effectiveness of Various Remineralizing Agents on White Spot Lesions after Orthodontic Treatment: A Comparative Study. J Contemp Dent Pract 2021;22(5):545-548.


Can closeness, conflict, and dependency be used to characterize students' perceptions of the affective relationship with their teacher? Testing a new child measure in middle childhood.
The constructs of closeness, conflict, and dependency, which are derived from attachment theory, are widely used to qualify teachers' perceptions of relationships with individual children. Our main aim was to reveal whether similar and reliable dimensions could be identified in middle childhood with a newly developed student measure Student Perception of Affective Relationship with Teacher Scale (SPARTS). Additional validity support was sought by examining gender differences and associations with (1) teacher relationship perceptions and (2) problem and prosocial behaviours in children. Factor structure was determined in a sample of 586 children (46.5% boys) from 26 regular elementary Dutch classrooms (grade 4-6). Associations with teacher relationship reports (n = 82) and child behaviours (n = 64) were analysed in random subsamples. Students' relationship perceptions were assessed with the SPARTS; teachers' relationship perceptions with the Student-Teacher Relationship Scale (STRS; closeness, conflict, and dependency); and problem and prosocial behaviours in children with the teacher-reported Strengths and Difficulties Questionnaire. Exploratory factor analysis and confirmatory factor analysis supported a 3-factor model of conflict, closeness, and a third factor, unexpectedly reflecting negative expectations of the student instead of dependency. Satisfactory internal consistency was found for all three scales. Additional validity evidence included the following: Substantial student-teacher agreement for conflict and closeness; meaningful associations with problem and prosocial behaviours in children; and expected gender differences showing that, compared to boys, girls share more favourable relationships (more closeness and less conflict) with teachers. The 3-dimensional SPARTS comes close to the attachment-derived teacher STRS, as far as conflict and closeness are concerned. The third dimension, negative expectations, represents a new and relevant attachment-related dimension reflecting a lack of confidence of students in the relationship with their teacher.


Tandem mass spectrometry in vitamin E analysis.
Tandem mass spectrometry is applied to the tocopherols and representative tocotrienols of the vitamin E family. The collision-induced dissociation/mass analysed ion kinetic energy spectra generated from three ions in the electron impact ionization spectra of 5,7,8-trimethyltocol, 5,7,8-trimethyltocotrienol, 5,7-, 5,8- and 7,8-dimethyltocol and 7,8-dimethyltocotrienol are described. The technique allowed direct physical characterization of each class of tocochromanol, and in the case of monomethyltocols differentiation of 5-methyltocol from the 7- and 8-methyltocol isomers, and its value in analysis of biological tissue extracts is established.


Identification, Verification and Pathway Enrichment Analysis of Prognosis-Related Immune Genes in Patients With Hepatocellular Carcinoma.
Hepatocellular carcinoma is a common malignant tumor with poor prognosis, poor treatment effect, and lack of effective biomarkers. In this study, bioinformatics analysis of immune-related genes of hepatocellular carcinoma was used to construct a multi-gene combined marker that can predict the prognosis of patients. The RNA expression data of hepatocellular carcinoma were downloaded from The Cancer Genome Atlas (TCGA) database, and immune-related genes were obtained from the IMMPORT database. Differential analysis was performed by Wilcox test to obtain differentially expressed genes. Univariate Cox regression analysis, lasso regression analysis and multivariate Cox regression analysis were performed to establish a prognostic model of immune genes, a total of 5 genes (HDAC1, BIRC5, SPP1, STC2, NR6A1) were identified to construct the models. The expression levels of 5 genes in HCC tissues were significantly different from those in paracancerous tissues. The Kaplan-Meier survival curve showed that the risk score calculated according to the prognostic model was significantly related to the overall survival (OS) of HCC. The receiver operating characteristic (ROC) curve confirmed that the prognostic model had high accuracy. Independent prognostic analysis was performed to prove that the risk value can be used as an independent prognostic factor. Then, the gene expression data of hepatocellular carcinoma in the ICGC database was used as a validation data set for the verification of the above steps. In addition, we used the CIBERSORT software and TIMER database to conduct immune infiltration research, and the results showed that the five genes of the model and the risk score have a certain correlation with the content of immune cells. Moreover, through Gene Set Enrichment Analysis (GSEA) and the construction of protein interaction networks, we found that the p53-mediated signal transduction pathway is a potentially important signal pathway for hepatocellular carcinoma and is positively regulated by certain genes in the prognostic model. In conclusion, this study provides potential targets for predicting the prognosis and treatment of hepatocellular carcinoma patients, and also provides new ideas about the correlation between immune genes and potential pathways of hepatocellular carcinoma.


Association of the Polygenic Scores for Personality Traits and Response to Selective Serotonin Reuptake Inhibitors in Patients with Major Depressive Disorder.
Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD). Moreover, personality traits are thought to be associated with response to antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs) derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs). In addition, we performed meta-analyses of genome-wide association studies (GWASs) on these traits to identify genetic variants underpinning the cross-trait polygenic association. The PGS analysis was performed using data from two cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS, n = 529) and the International SSRI Pharmacogenomics Consortium (ISPC, n = 865). The cross-trait GWAS meta-analyses were conducted by combining GWAS summary statistics on SSRIs treatment outcome and on the personality traits. The results showed that the PGS for openness and neuroticism were associated with SSRIs treatment outcomes at p < 0.05 across PT thresholds in both cohorts. A significant association was also found between the PGS for conscientiousness and SSRIs treatment response in the PGRN-AMPS sample. In the cross-trait GWAS meta-analyses, we identified eight loci associated with (a) SSRIs response and conscientiousness near YEATS4 gene and (b) SSRI remission and neuroticism eight loci near PRAG1, MSRA, XKR6, ELAVL2, PLXNC1, PLEKHM1, and BRUNOL4 genes. An assessment of a polygenic load for personality traits may assist in conjunction with clinical data to predict whether MDD patients might respond favorably to SSRIs.


Retinal and optical adaptations for nocturnal vision in the halictid bee Megalopta genalis.
The apposition compound eye of a nocturnal bee, the halictid Megalopta genalis, is described for the first time. Compared to the compound eye of the worker honeybee Apis mellifera and the diurnal halictid bee Lasioglossum leucozonium, the eye of M. genalis shows specific retinal and optical adaptations for vision in dim light. The major anatomical adaptations within the eye of the nocturnal bee are (1) nearly twofold larger ommatidial facets and (2) a 4-5 times wider rhabdom diameter than found in the diurnal bees studied. Optically, the apposition eye of M. genalis is 27 times more sensitive to light than the eyes of the diurnal bees. This increased optical sensitivity represents a clear optical adaptation to low light intensities. Although this unique nocturnal apposition eye has a greatly improved ability to catch light, a 27-fold increase in sensitivity alone cannot account for nocturnal vision at light intensities that are 8 log units dimmer than during daytime. New evidence suggests that additional neuronal spatial summation within the first optic ganglion, the lamina, is involved.


The relationship between forests and freshwater fish consumption in rural Nigeria.
Nigerians depend on fish for maintaining diverse and healthy diets. Fish are a key source of protein and micronutrients, both of which are important for healthy diets. Some research has shown that forests provide important ecosystem functions that support the productive capacity and sustainability of inland fisheries. Our study aims to empirically assess the relationship between forest cover around rivers and fish consumption. We use data from the Living Standards Measurement Survey (LSMS) and spatially merge household and village data with forest cover and river maps. We estimate the relationship between forest cover around rivers and average village fresh fish consumption, while also accounting for other socio-economic and geographical determinants. We find that that the density of forest cover around rivers is positively and significantly correlated with village consumption of fresh fish. Our results suggest that forests influence the consumption of fresh fish by improving the productivity of inland fisheries and increasing the availability of fish. Aquatic habitats tend to be overlooked in debates on land use and food production, and yet can be critically important sources of nutrient-rich foods that are limited in rural diets in developing countries, particularly for the poor. Clearing forests for agriculture in order to produce more agricultural crops might have the unintended consequence of reducing another important food source.


Predicting high-risk versus higher-risk substance use during late adolescence from early adolescent risk factors using Latent Class Analysis.
Much of the existing risk factor literature focuses on identifying predictors of low-levels of substance use versus higher-levels of substance use. In this paper, we explore more nuanced patterns of alcohol, tobacco, and other drug (ATOD) use during late adolescence. Our aims were to: 1) identify subgroups of youth with qualitatively different patterns of ATOD use; and 2) explore whether membership among qualitatively distinct, high-risk classes could be predicted based on early adolescent risk factors. Data came from a selected subsample of the National Longitudinal Survey of Youth (n = 1,689). Predictors were measured when youth were about 12 years old; ATOD use was assessed when youth were aged 17 years. Results showed that adolescent ATOD use is not a homogenous behavior. Four distinct classes of adolescent ATOD users were derived. Each class had a qualitatively distinct and discriminable pattern of ATOD use. Ecological predictors were shown to differentiate between latent classes, with peer factors playing a particularly important role in differentiating between high-risk and higher-risk users. Implications for prevention and limitations are discussed.


Activity and impact on antibiotic use and costs of a dedicated infectious diseases consultant on a septic orthopaedic unit.
The Orthopaedic Service of the Geneva University Hospitals engages dedicated infectious disease (ID) specialists to assist in the treatment of infected patients. We investigated the daily clinical activity and the impact on antibiotic costs in the Septic Unit since 2000. Retrospective analysis of various databases. Prospective survey of clinical activity from January 2008 to March 2008. According to the survey, the ID specialist performed 265 first-time and 1420 follow-up consultations (average of 11.4 consultations per working day). In 88% of cases the antibiotic regimen initiated by the surgeons was approved. When the ID specialist had to change antibiotic treatment, it was for de-escalation in 43.7%, discontinuance in 32.4%, and initiation in 24.4% of cases. From April 2007 to March 2008, the ID specialist decreased total antibiotic use by 43 DDD/100 patients-days (p=0.0006) in the Septic Unit. Direct antibiotic costs decreased by US$64,380 over the same period, equal to the annual salary of the ID specialist. There was no change in the number of recurrent infections. The main antibiotic-related activity of the dedicated orthopaedic ID specialist in Geneva our institution was to discontinue or adjust a pre-existing antimicrobial therapy. This activity significantly reduced antibiotic use and related costs on a septic orthopaedic unit.


Did cooling oceans trigger Ordovician biodiversification? Evidence from conodont thermometry.
The Ordovician Period, long considered a supergreenhouse state, saw one of the greatest radiations of life in Earth's history. Previous temperature estimates of up to approximately 70 degrees C have spawned controversial speculation that the oxygen isotopic composition of seawater must have evolved over geological time. We present a very different global climate record determined by ion microprobe oxygen isotope analyses of Early Ordovician-Silurian conodonts. This record shows a steady cooling trend through the Early Ordovician reaching modern equatorial temperatures that were sustained throughout the Middle and Late Ordovician. This favorable climate regime implies not only that the oxygen isotopic composition of Ordovician seawater was similar to that of today, but also that climate played an overarching role in promoting the unprecedented increases in biodiversity that characterized this period.


Tai Chi as an adjunct physical activity for adults aged 45 years and older enrolled in phase III cardiac rehabilitation.
Cardiac rehabilitation improves physical, cognitive and psychosocial functioning, yet services are greatly underutilized with increasing patterns of attrition over time. Tai Chi has been suggested as a possible adjunct to cardiac rehabilitation exercise training. To describe differences in physical, cognitive and psychosocial functioning among adults ≥ 45 years old attending phase III cardiac rehabilitation, who have or have not self-selected Tai Chi exercise as an adjunct physical activity. A cross-sectional design compared subjects attending group-based Wu style Tai Chi classes plus cardiac rehabilitation, with cardiac rehabilitation only. Subjects had a battery of physical and cognitive functioning tests administered to examine aerobic endurance, balance, strength, and flexibility, verbal retrieval/recall, attention, concentration and tracking. Subjects completed a health survey to ascertain cardiac event information, medical history, and psychosocial functioning (i.e. health-related quality of life, stress, depressive symptoms, social support, and Tai Chi self-efficacy). A total of 51 subjects (75% married, 84% college-educated, 96% White/European-American) participated. Subjects were on average 70 (± 8) years old and had attended cardiac rehabilitation for 45 (± 37) months. Approximately 45% (n = 23) attended Tai Chi classes plus cardiac rehabilitation, while 55% (n = 28) attended cardiac rehabilitation only. Subjects attending Tai Chi plus cardiac rehabilitation had better balance, perceived physical health, and Tai Chi self-efficacy compared to those attending cardiac rehabilitation only (p ≤ 0.03). Tai Chi can be easily implemented in any community/cardiac rehabilitation facility, and may offer adults additional options after a cardiac event.


Metabolic risk factors, physical activity and physical fitness in Azorean adolescents: a cross-sectional study.
The prevalence of metabolic syndrome has increased over the last few decades in adolescents and has become an important health challenge worldwide. This study analyzed the relationships between metabolic risk factors (MRF) and physical activity (PA) and physical fitness (PF) in a sample of Azorean adolescents. A cross-sectional school-based study was conducted on 417 adolescents (243 girls) aged 15-18 from the Azorean Islands, Portugal. Height, weight, waist circumference, fasting glucose, HDL-cholesterol, triglycerides, and blood pressure were measured. A sum of MRF was computed, and adolescents were classified into three groups: no MRF, one MRF and two or more MRF. PA was assessed by a sealed pedometer. PF was assessed using five tests from the Fitnessgram Test Battery. Dietary intake was obtained using a semi-quantitative food frequency questionnaire. Mean daily steps for girls and boys were 7427 ± 2725 and 7916 ± 3936, respectively. Fifty-nine percent of the adolescents showed at least one MRF and 57.6% were under the healthy zone in the 20 m Shuttle Run Test. Ordinal logistic regression analysis showed that after adjusting for sex, body mass index, socio-economic status and adherence to a Mediterranean diet, adolescents who were in the highest quartile of the pedometer step/counts (≥9423 steps/day) and those who achieved the healthy zone in five tests were less likely to have one or more MRF (OR = 0.56;95%CI:0.33-0.95; OR = 0.55;95%CI:0.31-0.98, respectively). Daily step counts and PF levels were negatively associated with having one or more MRF among Azorean adolescents. Our findings emphasize the importance of promoting and increasing regular PA and PF to reduce the public health burden of chronic diseases associated with a sedentary lifestyle.


Heterozygosity-fitness correlations revealed by neutral and candidate gene markers in roe deer from a long-term study.
Heterozygosity-fitness correlations (HFCs) are increasingly reported but the underlying mechanisms causing HFCs are generally poorly understood. Here, we test for HFCs in roe deer (Capreolus capreolus) using 22 neutral microsatellites widely distributed in the genome and four microsatellites in genes that are potentially under selection. Juvenile survival was used as a proxy for individual fitness in a population that has been intensively studied for 30 years in northeastern France. For 222 juveniles, we computed two measures of genetic diversity: individual heterozygosity (H), and mean d(2) (relatedness of parental genomes). We found a relationship between genetic diversity and fitness both for the 22 neutral markers and two candidate genes: IGF1 (Insulin-like Growth Factor I) and NRAMP (natural resistance-associated macrophage protein). Statistical evidence and the size of genetic effects on juvenile survival were comparable to those reported for early development and cohort variation, suggesting a substantial influence of genetic components on fitness in this roe deer population. For the 22 neutral microsatellites, a correlation with fitness was revealed for mean d(2), but not for H, suggesting a possible outbreeding advantage. This heterosis effect could have been favored by introduction of genetically distant (Hungarian) roe deer to the population in recent times and, possibly, by the structuring of the population into distinct clans. The locus-specific correlations with fitness may be driven by growth rate advantages and resistance to diseases known to exist in the studied population. Our analyses of neutral and candidate gene markers both suggest that the observed HFCs are likely mainly due to linkage with dominant or overdominant loci that affect fitness ("local" effect) rather than to a genome-wide relationship with homozygosity due to inbreeding ("general" effect).


Evaluating performance of neural codes in model neural communication networks.
Information needs to be appropriately encoded to be reliably transmitted over physical media. Similarly, neurons have their own codes to convey information in the brain. Even though it is well-known that neurons exchange information using a pool of several protocols of spatio-temporal encodings, the suitability of each code and their performance as a function of network parameters and external stimuli is still one of the great mysteries in neuroscience. This paper sheds light on this by modeling small-size networks of chemically and electrically coupled Hindmarsh-Rose spiking neurons. We focus on a class of temporal and firing-rate codes that result from neurons' membrane-potentials and phases, and quantify numerically their performance estimating the Mutual Information Rate, aka the rate of information exchange. Our results suggest that the firing-rate and interspike-intervals codes are more robust to additive Gaussian white noise. In a network of four interconnected neurons and in the absence of such noise, pairs of neurons that have the largest rate of information exchange using the interspike-intervals and firing-rate codes are not adjacent in the network, whereas spike-timings and phase codes (temporal) promote large rate of information exchange for adjacent neurons. If that result would have been possible to extend to larger neural networks, it would suggest that small microcircuits would preferably exchange information using temporal codes (spike-timings and phase codes), whereas on the macroscopic scale, where there would be typically pairs of neurons not directly connected due to the brain's sparsity, firing-rate and interspike-intervals codes would be the most efficient codes.


Data-driven human rights: using the electronic health record to promote human rights in jail.
The electronic health record (EHR) is a commonplace innovation designed to promote efficiency, quality, and continuity of health services. In the New York City jail system, we implemented an EHR across 12 jails between 2008 and 2011. During the same time, our work increasingly focused on the importance of human rights as an essential element to the provision of medical and mental health care for our patients. Consequently, we made major modifications to the EHR to allow for better surveillance of vulnerable populations and enable reporting and analysis of patterns of abuse, neglect, and other patient concerns related to human rights. These modifications have improved our ability to find and care for patients injured in jail and those with mental health exacerbations. More work is needed, however, to optimize the potential of the EHR as a tool to promote human rights among patients in jail.


Feasible Cluster Model Method for Simulating the Redox Potentials of Laccase CueO and Its Variant.
Laccases are regarded as versatile green biocatalysts, and recent scientific research has focused on improving their redox potential for broader industrial and environmental applications. The density functional theory (DFT) quantum mechanics approach, sufficiently rigorous and efficient for the calculation of electronic structures, is conducted to better comprehend the connection between the redox potential and the atomic structural feature of laccases. According to the crystal structure of wild type laccase CueO and its variant, a truncated miniature cluster model method was established in this research. On the basic of thermodynamic cycle, the overall Gibbs free energy variations before and after the one-electron reduction were calculated. It turned out that the trends of redox potentials to increase after variant predicted by the theoretical calculations correlated well with those obtained by experiments, thereby validating the feasibility of this cluster model method for simulating the redox potentials of laccases.


Effect of beta-adrenergic blockade on exercise performance in patients with chronic atrial fibrillation.
Beta-adrenergic blocking agents are commonly used in combination with digitalis to control excessive heart rate during exercise in patients with chronic atrial fibrillation. However, little is known about the effect of beta-adrenergic blockade on exercise capacity in these patients. Accordingly, a randomized, double-blind, cross-over placebo-controlled study was performed to assess the efficacy of celiprolol, a new cardioselective beta-blocker with partial intrinsic sympathomimetic activity, on exercise performance in nine men with chronic atrial fibrillation. All but one patient was receiving maintenance digitalis during the study. Heart rate, blood pressure and gas exchange variables were measured at rest and during treadmill exercise testing while the patients were receiving maintenance celiprolol or placebo. Significant reductions in heart rate and systolic blood pressure compared with control values were observed at submaximal exercise, at the gas exchange anaerobic threshold and at maximal exertion while the patients were taking celiprolol. However, oxygen uptake at the gas exchange anaerobic threshold during celiprolol therapy was 12.3 versus 14.0 ml oxygen/kg per min during placebo administration (a 12% difference, p less than 0.01). Similarly, oxygen uptake at maximal exertion during celiprolol therapy was 17.6 versus 21.0 ml/kg per min during placebo administration (a 16% difference, p less than 0.01). Treadmill time was also reduced during the celiprolol phase compared with placebo (11.3 versus 10.3 minutes; a 19% difference, p less than 0.01). These results indicate that in patients with atrial fibrillation the major beneficial effects of beta-adrenergic blockade--reduced submaximal and maximal exercise heart rate and blood pressure--must be weighed against the decrease in exercise capacity.


Oral delivery of bioencapsulated exendin-4 expressed in chloroplasts lowers blood glucose level in mice and stimulates insulin secretion in beta-TC6 cells.
Glucagon-like peptide (GLP-1) increases insulin secretion but is rapidly degraded (half-life: 2 min in circulation). GLP-1 analogue, exenatide (Byetta) has a longer half-life (3.3-4 h) with potent insulinotropic effects but requires cold storage, daily abdominal injections with short shelf life. Because patients with diabetes take >60 000 injections in their life time, alternative delivery methods are highly desired. Exenatide is ideal for oral delivery because insulinotropism is glucose dependent, with reduced risk of hypoglycaemia even at higher doses. Therefore, exendin-4 (EX4) was expressed as a cholera toxin B subunit (CTB)-fusion protein in tobacco chloroplasts to facilitate bioencapsulation within plant cells and transmucosal delivery in the gut via GM1 receptors present in the intestinal epithelium. The transgene integration was confirmed by PCR and Southern blot analysis. Expression level of CTB-EX4 reached up to 14.3% of total leaf protein (TLP). Lyophilization of leaf material increased therapeutic protein concentration by 12- to 24-fold, extended their shelf life up to 15 months when stored at room temperature and eliminated microbes present in fresh leaves. The pentameric structure, disulphide bonds and functionality of CTB-EX4 were well preserved in lyophilized materials. Chloroplast-derived CTB-EX4 showed increased insulin secretion similar to the commercial EX4 in beta-TC6, a mouse pancreatic cell line. Even when 5000-fold excess dose of CTB-EX4 was orally delivered, it stimulated insulin secretion similar to the intraperitoneal injection of commercial EX4 but did not cause hypoglycaemia in mice. Oral delivery of the bioencapsulated EX4 should eliminate injections, increase patient compliance/convenience and significantly lower their cost.


Oocyte-specific ablation of N- and O-glycans alters cumulus cell signalling and extracellular matrix composition.
Cumulus-oocyte complex (COC) expansion is essential for ovulation and fertilisation and is linked to oocyte quality. Hyaluronan (HA), the major matrix constituent, is cross-linked via inter-α-inhibitor heavy chains (HCs), pentraxin 3 (PTX3) and tumour necrosis factor-stimulated gene 6 (TSG-6). All except HCs are secreted by cumulus cells in response to oocyte-secreted factors, which signal via SMAD pathways. The double mutant (DM) mouse generates oocytes lacking complex N- and O-glycans due to oocyte-specific deletion of core 1 β1,3-galactosyltransferase (C1galt1) and N-acetylglucosaminyltransferase I (Mgat1) and has modified cumulus expansion. We compared COCs before expansion (48 h-post-pregnant mare serum gonadotrophin (PMSG)) and at late-stage expansion (9 h-post-human chorionic gonadotrophin (hCG); control n=3 mice, DM n=3 per group). Using histochemistry the levels of HA, HCs, PTX3, TSG-6 and phosphorylated-SMAD1/5/8 and -SMAD2 (12-25 COCs per group) were assessed. DM COCs did not differ from Controls in cumulus size or cell density at 9 h-post-hCG; however, HA and HC levels and phosphorylated-SMAD1/5/8 were reduced. Furthermore, no correlations were found between the levels of matrix molecules and cumulus area in DM or Control samples. These data suggest that HA and HCs can support cumulus expansion provided that they are present above minimum threshold levels. We propose that oocyte-specific ablation of C1galt1 and Mgat1 may affect bone morphogenetic protein 15 synthesis or bioactivity, thereby reducing SMAD1/5/8 phosphorylation and HA production.


The phenomenon of micronutrient deficiency among children in China: a systematic review of the literature.
The present study aimed to review the literature on micronutrient deficiency and other factors influencing a deficiency status among children living in China. A systematic review was performed to analyse the literature. Studies were identified through a search of PubMed and secondary references. Children living in China aged less than 18 years. Sixty-one articles were included. The prevalence of vitamin A deficiency decreased to approximately 10 % in 1995-2009. It increased with age but no significant difference was found between genders. The prevalence of thiamin and vitamin B12 deficiency was 10·5 % in Yunnan and 4·5 % in Chongqing provinces, respectively. Higher vitamin D deficiency rates were seen in spring and winter. The incidence of bleeding due to vitamin K deficiency was 3·3 % in 1998-2001 and more prevalent in rural areas. Both iodine deficiency and excess iodine intake were observed. Goitre rates were reported in Tibet, Jiangxi, Gansu and Hong Kong (3·5-46 %). Anaemia rates ranged from 20 % to 40 % in 2007-2011. High Se deficiency rates were found in Tibet, Shaanxi and Jiangsu. High Zn deficiency rates were also found (50-70 %) in 1995-2006. Few studies reported Ca deficiency rates (19·6-34·3 %). The degrees of deficiency for vitamin A, vitamin B12, Fe and Zn were more substantial in rural areas compared with urban areas. The prevalence of micronutrient deficiency rates varied. Socio-economic status, environmental factors and the Chinese diet may influence micronutrient deficiency. Public health policies should consider implementing programmes of supplementation, food fortification and nutrition education to address these deficiencies among Chinese children.


Metatranscriptomics Supports the Mechanism for Biocathode Electroautotrophy by "Candidatus Tenderia electrophaga".
Biocathodes provide a stable electron source to drive reduction reactions in electrotrophic microbial electrochemical systems. Electroautotrophic biocathode communities may be more robust than monocultures in environmentally relevant settings, but some members are not easily cultivated outside the electrode environment. We previously used metagenomics and metaproteomics to propose a pathway for coupling extracellular electron transfer (EET) to carbon fixation in "Candidatus Tenderia electrophaga," an uncultivated but dominant member of an electroautotrophic biocathode community. Here we validate and refine this proposed pathway using metatranscriptomics of replicate aerobic biocathodes poised at the growth potential level of 310 mV and the suboptimal 470 mV (versus the standard hydrogen electrode). At both potentials, transcripts were more abundant from "Ca. Tenderia electrophaga" than from any other constituent, and its relative activity was positively correlated with current. Several genes encoding key components of the proposed "Ca. Tenderia electrophaga" EET pathway were more highly expressed at 470 mV, consistent with a need for cells to acquire more electrons to obtain the same amount of energy as at 310 mV. These included cyc2, encoding a homolog of a protein known to be involved in iron oxidation. Mean expression of all CO2 fixation-related genes is 0.27 log2-fold higher at 310 mV, indicating that reduced energy availability at 470 mV decreased CO2 fixation. Our results substantiate the claim that "Ca. Tenderia electrophaga" is the key electroautotroph, which will help guide further development of this community for microbial electrosynthesis. IMPORTANCE Bacteria that directly use electrodes as metabolic electron donors (biocathodes) have been proposed for applications ranging from microbial electrosynthesis to advanced bioelectronics for cellular communication with machines. However, just as we understand very little about oxidation of analogous natural insoluble electron donors, such as iron oxide, the organisms and extracellular electron transfer (EET) pathways underlying the electrode-cell direct electron transfer processes are almost completely unknown. Biocathodes are a stable biofilm cultivation platform to interrogate both the rate and mechanism of EET using electrochemistry and to study the electroautotrophic organisms that catalyze these reactions. Here we provide new evidence supporting the hypothesis that the uncultured bacterium "Candidatus Tenderia electrophaga" directly couples extracellular electron transfer to CO2 fixation. Our results provide insight into developing biocathode technology, such as microbial electrosynthesis, as well as advancing our understanding of chemolithoautotrophy.


Mechanisms of pollution-induced airway disease: in vitro studies in the upper and lower airways.
Evidence from both epidemiological and laboratory-based studies suggests that increased exposure to liquid petroleum and gas-derived air pollutants [nitrogen dioxide (NO2), ozone, and respirable particulate matter] may play a role in the clinical manifestation of both allergic and non-allergic airway disease. The mechanisms and cell types involved in pollutant-mediated effects in the airways, however, are not clear. In vitro studies have suggested that human fibroblasts, B-lymphocytes, alveolar macrophages, and epithelial cells/cell lines may be involved. Studies of fibroblasts and macrophages have demonstrated that exposure to ozone results in decreased cell viability and increased release of pro-inflammatory mediators from macrophages. Similarly, studies of B-lymphocytes have demonstrated that exposure to diesel exhaust particles (DEP) enhances the synthesis of immunoglobulin E by these cells. The airway epithelial cells have received the greatest attention in mechanistic studies of air pollution-induced airway disease and suggest that these cells are likely to play a pivotal role in the pathogenesis of airways disease. Various studies have demonstrated that exposure of nasal or bronchial epithelial cells to NO2, ozone, and DEP results in significant synthesis and release of pro-inflammatory mediators, including eicosanoids, cytokines, and adhesion molecules. Additionally, evidence suggests that epithelial cells of atopic individuals release significantly greater amounts of cytokines such as granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-6 (IL-6), IL-8, and regulated on activation, normal T-cell expressed and secreted (RANTES), on exposure to NO2 and ozone. Studies investigating the biological relevance of epithelial cell-derived pro-inflammatory mediators have shown that these enhance eosinophil chemotaxis and eosinophil adherence to endothelial cells, suggesting that pollution-induced inflammation of the airways is likely to be influenced by modulation of epithelial synthesis and release of these mediators.


Renal Replacement Therapy in Eritrea.
Historically, communicable diseases in addition to maternal, perinatal, and malnutrition have accounted for the greatest burden of morbidity and mortality in many developing countries. This spectrum however has recently begun to shift toward chronic noncommunicable diseases, including diabetes and hypertension. Although great strides have been made in the diagnosis and care of chronic kidney disease in the industrialized world, the availability of renal replacement therapy and kidney transplantation is unequivocally lower in Africa than in any other region of the world. Here, we provide a critical assessment of the growing prevalence of kidney disease and current treatments in Eritrea, a young, developing country located in Northeast Africa.


Comparative 11A structure of two molluscan hemocyanins from 3D cryo-electron microscopy.
Hemocyanins are giant extracellular proteins that transport oxygen in the hemolymph of many molluscs. Molluscan hemocyanins are cylindrical decamers or didecamers of a 350-400 kDa subunit that contains seven or eight different covalently linked globular functional units (FUs), arranged in a linear manner. Each FU carries a single copper active site and reversibly binds one dioxygen molecule. As a consequence, the decamer can carry up to 70 or 80 O(2) molecules. Although complete sequence information is now available from several molluscan hemocyanins, many details of the quaternary structure are still unclear, including the topology of the 10 subunits within the decamer. Here we show 3D reconstructions from cryo-electron micrographs of the hemocyanin decamer of Nautilus pompilius (Cephalopoda) and Haliotis tuberculata (Gastropoda) at a resolution of 11A (FSC(1/2-bit) criterion). The wall structure of both hemocyanins is very similar and shows, as in previous reconstructions, three tiers with 20 functional units each that encircle the cylinder wall, and the 10 oblique minor and major wall grooves. However, the six types of wall FUs of the polypeptide subunit, termed a-b-c-d-e-f, are now for the first time individually discernable by their specific orientation, shape, and connections. Also, the internal collar complex of the decamers shows superior resolution which, in this case, reveals striking differences between the two hemocyanins. The five arcs (FU-g pairs) of the central collar (in both hemocyanins) and the five slabs (FU-h pairs) of the peripheral collar (only present in Haliotis hemocyanin), as well as their connections to the wall and to each other are now more clearly defined. The arc is attached to the wall through a feature termed the anchor, a previously undescribed structural element of the hemocyanin wall.


National bioethical legislation and guidelines for biomedical research in the Islamic Republic of Iran.
Rapid advances in biomedical science and technology, which have revolutionized medicine and health-care services in different societies, have been associated with inevitable ethical challenges. Undoubtedly, these innovations could lead to irreversible disasters if they are not limited by appropriate regulations. Substantial attempts have been made in the Islamic Republic of Iran to establish a structured approach for identifying, analysing and resolving ethical issues in clinical practice. Given the consensus of religious and scientific scholars, some laws recently approved by the parliament include the Deceased and Brain-Dead Patients Organ Transplantation Act (2000), Embryo Donation to Infertile Spouses Act (2003) and the Therapeutic Abortion Act (2005). National guidelines for ethical assessment and supervision of research proposals have also been compiled by the authorities. This paper reviews the main endeavours made in bioethics legislation in the Islamic Republic of Iran.


Association between Hypertension and the Prevalence of Low Back Pain and Osteoarthritis in Koreans: A Cross-Sectional Study.
Hypertension and musculoskeletal disorders are highly prevalent in adult populations. The objective of this study was to investigate the association between hypertension and prevalence of low back pain (LBP) and osteoarthritis in Koreans. A total 17,128 participants (age ≥20 years) who answered low back pain and osteoarthritis items in the 4th Korean National Health and Nutrition Examination Survey (2007-2009) were analyzed. Odds ratios were calculated using logistic regression and were adjusted for age, sex, income level, education, occupation, BMI, smoking status, alcohol consumption, and physical activity. Lifetime prevalence of LBP in hypertensive subjects was 34.4%, and that of osteoarthritis 26.2%. LBP prevalence was significantly lower in hypertensives (fully adjusted OR 0.79; 95% CI 0.70-0.90), and both LBP and osteoarthritis prevalence was significantly lower in participants with systolic blood pressure ≥140mmHg than those with <120mmHg (fully adjusted OR 0.81; 95% CI 0.70-0.94, and 0.81; 95% CI 0.68-0.96, respectively). Prevalence of LBP in subjects with diastolic blood pressure ≥90mmHg was also significantly lower than those with <80mmHg (fully adjusted OR 0.73; 95% CI 0.63-0.85). LBP and osteoarthritis prevalence did not differ by systolic or diastolic blood pressure interval in respondents taking antihypertensive medication. LBP and osteoarthritis prevalence increased with longer hypertension duration (fully adjusted p for trend 0.028, and 0.0008, respectively). Hypertension showed an inverse relationship with LBP and osteoarthritis prevalence, which may be ascribed to hypertension-associated hypalgesia, and antihypertensive medication intake and longer hypertension duration attenuated this association.


ASH: an Automatic pipeline to generate realistic and individualized chronic Stroke volume conduction Head models.
Objective.Large structural brain changes, such as chronic stroke lesions, alter the current pathways throughout the patients' head and therefore have to be taken into account when performing transcranial direct current stimulation simulations.Approach.We implement, test and distribute the first MATLAB pipeline that automatically generates realistic and individualized volume conduction head models of chronic stroke patients, by combining the already existing software SimNIBS, for the mesh generation, and lesion identification with neighborhood data analysis, for the lesion identification. To highlight the impact of our pipeline, we investigated the sensitivity of the electric field distribution to the lesion location and lesion conductivity in 16 stroke patients' datasets.Main results.Our pipeline automatically generates 1 mm-resolution tetrahedral meshes including the lesion compartment in less than three hours. Moreover, for large lesions, we found a high sensitivity of the electric field distribution to the lesion conductivity value and location.Significance.This work facilitates optimizing electrode configurations with the goal to obtain more focal brain stimulations of the target volumes in rehabilitation for chronic stroke patients.


Diet and kidney disease in high-risk individuals with type 2 diabetes mellitus.
Type 2 diabetes mellitus and associated chronic kidney disease (CKD) have become major public health problems. Little is known about the influence of diet on the incidence or progression of CKD among individuals with type 2 diabetes. To examine the association between (healthy) diet, alcohol, protein, and sodium intake, and incidence or progression of CKD among individuals with type 2 diabetes. All 6213 individuals with type 2 diabetes without macroalbuminuria from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) were included in this observational study. Recruitment spanned from January 2002 to July 2003, with prospective follow-up through January 2008. Chronic kidney disease was defined as new microalbuminuria or macroalbuminuria or glomerular filtration rate decline of more than 5% per year at 5.5 years of follow-up. We assessed diet using the modified Alternate Healthy Eating Index (mAHEI). The analyses were adjusted for known risk factors, and competing risk of death was considered. After 5.5 years of follow-up, 31.7% of participants had developed CKD and 8.3% had died. Compared with participants in the least healthy tertile of mAHEI score, participants in the healthiest tertile had a lower risk of CKD (adjusted odds ratio [OR], 0.74; 95% CI, 0.64-0.84) and lower risk of mortality (OR, 0.61; 95% CI, 0.48-0.78). Participants consuming more than 3 servings of fruits per week had a lower risk of CKD compared with participants consuming these food items less frequently. Participants in the lowest tertile of total and animal protein intake had an increased risk of CKD compared with participants in the highest tertile (total protein OR, 1.16; 95% CI, 1.05-1.30). Sodium intake was not associated with CKD. Moderate alcohol intake reduced the risk of CKD (OR, 0.75; 95% CI, 0.65-0.87) and mortality (OR, 0.69; 95% CI, 0.53-0.89). A healthy diet and moderate intake of alcohol may decrease the incidence or progression of CKD among individuals with type 2 diabetes. Sodium intake, within a wide range, and normal protein intake are not associated with CKD. clinicaltrials.gov Identifier: NCT00153101.


Vaginitis: diagnosis and management.
Vaginitis is one of the most common ambulatory problems to occur in women. It is a disorder responsible for > 10% of visits made to providers of women's health care. Although vaginal infections are the most common cause, other considerations include cervicitis, a normal vaginal discharge, foreign-body vaginitis, contact vaginitis, atrophic vaginitis, and desquamative inflammatory vaginitis. The medical history and examination are an important source of clues to the underlying diagnosis. However, making a definitive diagnosis requires skillful performance of office laboratory procedures, including the vaginal pool wet mount examination, determination of the vaginal pH, and the whiff test. Vaginal and cervical cultures, nucleic acid tests, and point-of-care tests are available and may be required in selected patients. Once a specific diagnosis is made, effective therapy can be prescribed. Candida vaginitis is generally treated with either the vaginal administration of an imidazole or triazole antifungal agent or the prescription of oral fluconazole. Oral nitroimidazole agents, metronidazole or tinidazole, are the only effective treatments for trichomoniasis in the United States. Bacterial vaginosis, which has been linked to important gynecologic and pregnancy complications, can be treated with an available oral or topical agent containing either a nitroimidazole or clindamycin.


Mg-doped congruent LiTaO3 crystal for large-aperture quasi-phase matching device.
Mg-doped congruent composition LiTaO(3) (MgLT) crystal, which can be grown by a conventional Czochralski method, has improved properties such as transparent range, thermal conductivity, and coercive field compared to conventional undoped congruent LiTaO(3). In this paper, various properties of MgLT including Mg-doping dependence are characterized, and also compared to that of undoped congruent LiTaO(3), LiNbO(3), and Mg-doped congruent LiNbO(3), as a material of high power quasi-phase matching (QPM) device. Up to 3-mm-thick periodically poled MgLT crystal is shown to demonstrate the possibility of large-aperture QPM-MgLT devices. Subsequently, optical parametric oscillation experiments by using periodically poled MgLT are demonstrated to discuss an efficient QPM condition.


Appropriateness of endoscopic surveillance recommendations in organised colorectal cancer screening programmes based on the faecal immunochemical test.
To assess the appropriateness of recommendations for endoscopic surveillance in organised colorectal cancer (CRC) screening programmes based on the faecal immunochemical test (FIT). 74 Italian CRC screening programmes provided aggregated data on the recommendations given after FIT-positive colonoscopies in 2011 and 2013. Index colonoscopies were divided into negative/no adenoma and low- risk, intermediate-risk and high-risk adenomas. Postcolonoscopy recommendations included a return to screening (FIT after 2 years or 5 years), an endoscopic surveillance after 6 months or after 1 year, 3 years or 5 years, surgery or other. We assessed the deviation from the postcolonoscopy recommendations of the European Guidelines in 2011 and 2013 and the correlation between overuse of endoscopic surveillance in 2011 and the process indicators associated with the endoscopic workload in 2013. 49 704 postcolonoscopy recommendations were analysed. High-risk, intermediate-risk and low-risk adenomas, and no adenomas were reported in 5.9%, 19.3%, 15.3% and 51.5% of the cases, respectively. Endoscopic surveillance was inappropriately recommended in 67.4% and 7%, respectively, of cases with low-risk and no adenoma. Overall, 37% of all endoscopic surveillance recommendations were inappropriate (6696/17 860). Overuse of endoscopic surveillance was positively correlated with the extension of invitations (correlation coefficient (cc) 0.29; p value 0.03) and with compliance with post-FIT+ colonoscopy (cc 0.25; p value 0.05), while it was negatively correlated with total colonoscopy waiting times longer than 60 days (cc -0.26; p value 0.05). In organised screening programmes, a high rate of inappropriate recommendations for patients with low risk or no adenomas occurs, affecting the demand for endoscopic surveillance by a third.


Hepatocyte nuclear factor 4α is required for cell differentiation and homeostasis in the adult mouse gastric epithelium.
We have previously shown that the sequential transcription factors Xbp1→Mist1 (Bhlha15) govern the ultrastructural maturation of the secretory apparatus in enzyme-secreting zymogenic chief cells (ZCs) in the gastric unit. Here we sought to identify transcriptional regulators upstream of X-box binding protein 1 (XBP1) and MIST1. We used immunohistochemistry to characterize Hnf4α(flox/flox) adult mouse stomachs after tamoxifen-induced deletion of Hnf4α We used qRT-PCR, Western blotting, and chromatin immunoprecipitation to define the molecular interaction between hepatocyte nuclear factor 4 alpha (HNF4α) and Xbp1 in mouse stomach and human gastric cells. We show that HNF4α protein is expressed in pit (foveolar) cells, mucous neck cells, and zymogenic chief cells (ZCs) of the corpus gastric unit. Loss of HNF4α in adult mouse stomach led to reduced ZC size and ER content, phenocopying previously characterized effects of Xbp1 deletion. However, HNF4α(Δ/Δ) stomachs also exhibited additional phenotypes including increased proliferation in the isthmal stem cell zone and altered mucous neck cell migration, indicating a role of HNF4α in progenitor cells as well as in ZCs. HNF4α directly occupies the Xbp1 promoter locus in mouse stomach, and forced HNF4α expression increased abundance of XBP1 mRNA in human gastric cancer cells. Finally, as expected, loss of HNF4α caused decreased Xbp1 and Mist1 expression in mouse stomachs. We show that HNF4α regulates homeostatic proliferation in the gastric epithelium and is both necessary and sufficient for the upstream regulation of the Xbp1→Mist1 axis in maintenance of ZC secretory architecture.


Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase-A/5-Hydroxytryptamine/5-Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis.
Serotonin (5HT) is a neuroendocrine hormone synthetized in the central nervous system (CNS) as well as enterochromaffin cells of the gastrointestinal tract. Tryptophan hydroxylase (TPH1) and monoamine oxidase (MAO-A) are the key enzymes for the synthesis and catabolism of 5HT, respectively. Previous studies demonstrated that 5-hydroxytryptamine receptor (5HTR)1A/1B receptor agonists inhibit biliary hyperplasia in bile-duct ligated (BDL) rats, whereas 5HTR2B receptor antagonists attenuate liver fibrosis (LF) in mice. Our aim was to evaluate the role of 5HTR2A/2B/2C agonists/antagonists in cholestatic models. While in vivo studies were performed in BDL rats and the multidrug resistance gene 2 knockout (Mdr2-/- ) mouse model of PSC, in vitro studies were performed in cell lines of cholangiocytes and hepatic stellate cells (HSCs). 5HTR2A/2B/2C and MAO-A/TPH1 are expressed in cholangiocytes and HSCs from BDL rats and Mdr2-/- - mice. Ductular reaction, LF, as well as the mRNA expression of proinflammatory genes increased in normal, BDL rats, and Mdr2-/- - mice following treatment 5HTR2A/2B/2C agonists, but decreased when BDL rats and Mdr2-/- mice were treated with 5HTR2A/2B/2C antagonists compared to BDL rats and Mdr2-/- mice, respectively. 5HT levels increase in Mdr2-/- mice and in PSC human patients compared to their controls and decrease in serum of Mdr2-/- mice treated with 5HTR2A/2B/2C antagonists compared to untreated Mdr2-/- mice. In vitro, cell lines of murine cholangiocytes and human HSCs express 5HTR2A/2B/2C and MAO-A/TPH1; treatment of these cell lines with 5HTR2A/2B/2C antagonists or TPH1 inhibitor decreased 5HT levels as well as expression of fibrosis and inflammation genes compared to controls. Modulation of the TPH1/MAO-A/5HT/5HTR2A/2B/2C axis may represent a therapeutic approach for management of cholangiopathies, including PSC.


Pregnancy dose Tdap and postpartum cocooning to prevent infant pertussis: a decision analysis.
Infants <2 months of age are at highest risk of pertussis morbidity and mortality. Until recently, the US Advisory Committee on Immunization Practices (ACIP) recommended protecting young infants by "cocooning" or vaccination of postpartum mothers and other close contacts with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, adsorbed (Tdap) booster vaccine. ACIP recommends pregnancy vaccination as a preferred and safe alternative to postpartum vaccination. The ACIP cocooning recommendation has not changed. We used a cohort model reflecting US 2009 births and the diphtheria-tetanus-acellular pertussis schedule to simulate a decision and cost-effectiveness analysis of Tdap vaccination during pregnancy compared with postpartum vaccination with or without vaccination of other close contacts (ie, cocooning). We analyzed infant pertussis cases, hospitalizations, and deaths, as well as direct disease, indirect, and public health costs for infants in the first year of life. All costs were updated to 2011 US dollars. Pregnancy vaccination could reduce annual infant pertussis incidence by more than postpartum vaccination, reducing cases by 33% versus 20%, hospitalizations by 38% versus 19%, and deaths by 49% versus 16%. Additional cocooning doses in a father and 1 grandparent could avert an additional 16% of cases but at higher cost. The cost per quality-adjusted life-year saved for pregnancy vaccination was substantially less than postpartum vaccination ($414 523 vs $1 172 825). Tdap vaccination during pregnancy could avert more infant cases and deaths at lower cost than postpartum vaccination, even when postpartum vaccination is combined with additional cocooning doses. Pregnancy dose vaccination is the preferred alternative to postpartum vaccination for preventing infant pertussis.


Racist appearance standards and the enhancements that love them: Norman Daniels and skin-lightening cosmetics.
Darker skin correlates with reduced opportunities and negative health outcomes. Recent discoveries related to the genes associated with skin tone, and the historical use of cosmetics to conform to racist appearance standards, suggest effective skin-lightening products may soon become available. This article examines whether medical interventions of this sort should be permitted, subsidized, or restricted, using Norman Daniels's framework for determining what justice requires in terms of protecting health. I argue that Daniels's expansive view of the requirements of justice in meeting health needs offers some support for recognizing a societal obligation to provide this kind of 'enhancement,' in light of the strong connections between skin tone and health outcomes. On balance, however, Daniels's framework offers compelling reasons to reject insurance coverage for skin-lightening medical interventions, including the likely ineffectiveness of such technologies in mitigating racial health disparities, and the danger that covering skin-lightening enhancements would undermine public support for cooperative schemes that protect health. In fact, justice may require limiting access to these technologies because of their potential to exacerbate the negative effects of racism.


Evaluation of iodine-benzoflavone and ruthenium tetroxide spray reagents for the detection of latent fingermarks at the crime scene.
The performance of two spray reagents, iodine-benzoflavone and ruthenium tetroxide (RTX), was evaluated and compared with the conventional technique currently used at the crime scene, that is, powdering. Neither the spray techniques nor powdering were shown to be suitable for all surfaces and ages of marks tested. On some surfaces such as glass and treated wood, powdering was still the superior technique, whereas the spray techniques produced better development on wallpaper, vinyl, and brick. Sequencing work showed that RTX was incompatible with powdering and cyanoacrylate (with a rhodamine 6G stain). Iodine-benzoflavone can be used successfully either before or after powdering in a sequence; however, it was incompatible with cyanoacrylate. Two non-CFC formulations of iodine-benzoflavone using HFC4310mee and HFE7100 solvents were tested and shown not to be as effective as the original Arklone (CFC-113) formulation; however, the HFC4310mee solvent is recommended as the most suitable replacement solvent. Due to the expense of the commercial RTX spray, attempts at formulating a more cost-effective version were also carried out. A formulation was developed that gave comparable development to the commercial version but at a much cheaper cost, and with a shelf life of up to two months. Recommendations are presented for which techniques are suitable for different surfaces and ages of marks. Powdering was shown to be the best technique on all ages of marks tested on treated wood, glass, and also on marks aged three days and older on paint. Iodine-benzoflavone was the best technique on wallpaper, vinyl, brick, and raw wood. RTX was the best detection technique for fresh marks and marks aged up to one day on wallpaper and paint.


Macrophage bridging conduit trafficking of HIV-1 through the endoplasmic reticulum and Golgi network.
Bridging conduits (BC) are tubular protrusions that facilitate cytoplasm and membrane exchanges between tethered cells. We now report that the human immunodeficiency virus type I (HIV-1) exploits these conduits to accelerate its spread and to shield it from immune surveillance. Endosome transport through BC drives HIV-1 intercellular transfers. How this occurs was studied in human monocyte-derived macrophages using proteomic, biochemical, and imaging techniques. Endosome, endoplasmic reticulum (ER), Golgi markers, and HIV-1 proteins were identified by proteomic assays in isolated conduits. Both the ER and Golgi showed elongated and tubular morphologies that extended into the conduits of polarized macrophages. Env and Gag antigen and fluorescent HIV-1 tracking demonstrated that these viral constituents were sequestered into endocytic and ER-Golgi organelles. Sequestered infectious viral components targeted the Golgi and ER by retrograde transport from early and Rab9 late endosomes. Disruption of the ER-Golgi network impaired HIV-1 trafficking in the conduit endosomes. This study provides, for the first time, mechanisms for how BC Golgi and ER direct cell-cell viral transfer.


Improvement of adult Still's disease with granulocyte and monocyte adsorption apheresis.
Adult Still's disease is characterized by a high spiking fever, transient skin rash, and polyarthralgia. Joint pain is one of the major complaints and is often intractable. We assessed the efficacy of granulocyte and monocyte adsorption apheresis (GCAP) therapy for treating arthralgia in adult Still's disease. A 33-year-old woman with adult Still's disease who suffered from recalcitrant arthralgia resistant to systemic corticosteroids was treated with GCAP therapy. She underwent five GCAP treatments at 5-day intervals. Her joint pain responded dramatically to the GCAP therapy, suggesting that GCAP may be useful for treating adult Still's disease. We present a detailed description of the patient and this novel therapy.


How place matters: unpacking technology and power in health and social care.
The devolution of care into nontraditional community-based settings has led to a proliferation of sites for health and social care. Despite recent (re)formulations of 'evidence-based' approaches that stress the importance of optimizing interventions to best practice by taking into account the uniqueness of place, there is relatively little guidance in the literature and few attempts to systematically 'unpack' key dimensions of settings most relevant to policy, practice and research. In this paper, we explore how place matters for health and social care. In effect, we propose making place the lens through which to view practice, and not simply an interesting sideline focus. We focus specifically on (a) the emplacement of power relations in health and social care in and across settings; and (b) the pervasive (and often unrecognised) influence of technology on and in place (both 'mundane' and more visible 'high' technologies) as arguably among the most significant and pervasive (and often overlooked) dimensions of place pertinent to health and social care in both traditional (institutional) and nontraditional (community) settings. Drawing on diverse disciplinary literatures, we seek to make visible certain issues and bodies of work that health professionals may not be aware of, and which often remain inaccessible to practitioners and applied researchers on account of their density, complexity, and specialised terminology. In particular, drawing on the rich tradition of cultural studies, we advance the culture of place as a rubric for understanding the complex interrelationship between power, technology, culture, and place. Several fruitful avenues for place-sensitive research of health and social care practice (and its effects) are suggested.


A therapeutic confirmatory study to assess the safety and efficacy of Zydena (udenafil) for the treatment of erectile dysfunction in male patients with diabetes mellitus.
Patients with diabetes mellitus (DM) are reported to experience more severe erectile dysfunction (ED) symptoms and respond less to ED treatments compared with patients with ED of other etiologies. This study was undertaken to evaluate the safety and efficacy of udenafil for the treatment of ED in a larger number of patients with DM. A placebo-controlled, randomized, double-blind, double-dummy, parallel-group design multicenter study, fixed-dose trial was conducted. The trial involved seven study sites in Korea, with 174 ED patients with DM. The subjects, treated with placebo, 100 mg, or 200 mg of udenafil for 12 weeks, were asked to complete the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment Question (GAQ) during the study period. The primary efficacy parameter was the change in the erectile function domain (EFD) score of IIEF from baseline. Secondary parameters were IIEF questions 3 (Q3) and Q4, SEP Q2 and Q3, rate of achieving normal erectile function (EFD ≥ 26), and the response to GAQ. Compared with the placebo, patients receiving both doses of udenafil showed statistically significant improvements in the IIEF-EFD score, respectively. However, statistically significant difference was not observed between the udenafil 100 mg and the udenafil 200 mg groups. Similar results were observed in the comparison of Q3 and Q4 of IIEF, SEP diary, and GAQ. The percentages of subjects experiencing at least one adverse event related to the study drugs were 3.6%, 15.8%, and 22.4% for the placebo, udenafil 100 mg, and udenafil 200 mg groups, respectively. However, these events were all mild in severity. Major adverse events were flushing, headache, nausea, and conjunctival hyperemia. Udenafil was significantly effective for the treatment of ED, demonstrating statistically significant improvement in erectile function in patients with DM. The incidence of adverse events was relatively low and well tolerated in patients with DM.


Effects of resident duty hour reform on surgical and procedural patient safety indicators among hospitalized Veterans Health Administration and Medicare patients.
Improving patient safety was a strong motivation behind duty hour regulations implemented by Accreditation Council for Graduate Medical Education on July 1, 2003. We investigated whether rates of patient safety indicators (PSIs) changed after these reforms. Observational study of patients admitted to Veterans Health Administration (VA) (N = 826,047) and Medicare (N = 13,367,273) acute-care hospitals from July 1, 2000 to June 30, 2005. We examined changes in patient safety events in more versus less teaching-intensive hospitals before (2000-2003) and after (2003-2005) duty hour reform, using conditional logistic regression, adjusting for patient age, gender, comorbidities, secular trends, baseline severity, and hospital site. Ten PSIs were aggregated into 3 composite measures based on factor analyses: "Continuity of Care," "Technical Care," and "Other" composites. Continuity of Care composite rates showed no significant changes postreform in hospitals of different teaching intensity in either VA or Medicare. In the VA, there were no significant changes postreform for the technical care composite. In Medicare, the odds of a Technical Care PSI event in more versus less teaching-intensive hospitals in postreform year 1 were 1.12 (95% CI; 1.01-1.25); there were no significant relative changes in postreform year 2. Other composite rates increased in VA in postreform year 2 in more versus less teaching-intensive hospitals (odds ratio, 1.63; 95% CI; 1.10-2.41), but not in Medicare in either postreform year. Duty hour reform had no systematic impact on PSI rates. In the few cases where there were statistically significant increases in the relative odds of developing a PSI, the magnitude of the absolute increases were too small to be clinically meaningful.


Crystal structure of KsgA, a universally conserved rRNA adenine dimethyltransferase in Escherichia coli.
The bacterial enzyme KsgA catalyzes the transfer of a total of four methyl groups from S-adenosyl-l-methionine (S-AdoMet) to two adjacent adenosine bases in 16S rRNA. This enzyme and the resulting modified adenosine bases appear to be conserved in all species of eubacteria, eukaryotes, and archaebacteria, and in eukaryotic organelles. Bacterial resistance to the aminoglycoside antibiotic kasugamycin involves inactivation of KsgA and resulting loss of the dimethylations, with modest consequences to the overall fitness of the organism. In contrast, the yeast ortholog, Dim1, is essential. In yeast, and presumably in other eukaryotes, the enzyme performs a vital role in pre-rRNA processing in addition to its methylating activity. Another ortholog has been discovered recently, h-mtTFB in human mitochondria, which has a second function; this enzyme is a nuclear-encoded mitochondrial transcription factor. The KsgA enzymes are homologous to another family of RNA methyltransferases, the Erm enzymes, which methylate a single adenosine base in 23S rRNA and confer resistance to the MLS-B group of antibiotics. Despite their sequence similarity, the two enzyme families have strikingly different levels of regulation that remain to be elucidated. We have crystallized KsgA from Escherichia coli and solved its structure to a resolution of 2.1A. The structure bears a strong similarity to the crystal structure of ErmC' from Bacillus stearothermophilus and a lesser similarity to sc-mtTFB, the Saccharomyces cerevisiae version of h-mtTFB. Comparison of the three crystal structures and further study of the KsgA protein will provide insight into this interesting group of enzymes.


Malondialdehyde modification of myelin oligodendrocyte glycoprotein leads to increased immunogenicity and encephalitogenicity.
Self proteins may become autoantigenic through structural modification. We studied malondialdehydation of recombinant rat (rr) myelin oligodendrocyte glycoprotein (MOG), an autoantigen in multiple sclerosis. Malondialdehyde (MDA) modification changed protein weight and charge, the location of these adducts being mapped by Fourier transform ion cyclotron resonance. Molecular modelling revealed significant differences in the MDA-rrMOG three-dimensional structure. DBA/1 mice immunised with MDA-rrMOG developed greater proliferative responses and more severe experimental autoimmune encephalomyelitis than mice immunised with unmodified rrMOG. MDA-rrMOG was taken up more effectively by antigen-presenting cells (APC), at least partially through scavenger receptors. Exposure to MDA-rrMOG led to increased expression of IL-23, IL-12 and IL-12R, indicating a role not only for increased antigen uptake but also for activation of APC. We thus provide biochemical, structural, immunological and clinical data that suggest that the post-translationally modified form of this myelin autoantigen is a more relevant form of the molecule.


The secondary structure of RNA under tension.
We study the force-induced unfolding of random disordered RNA or single-stranded DNA polymers. The system undergoes a second-order phase transition from a collapsed globular phase at low forces to an extensive necklace phase with a macroscopic end-to-end distance at high forces. At low temperatures, the sequence inhomogeneities modify the critical behaviour. We provide numerical evidence for the universality of the critical exponents which, by extrapolation of the scaling laws to zero force, contain useful information on the ground-state (f = 0) properties. This provides a good method for quantitative studies of scaling exponents characterizing the collapsed globule. In order to get rid of the blurring effect of thermal fluctuations, we restrict ourselves to the ground state at fixed external force. We analyze the statistics of rearrangements, in particular below the critical force, and point out its implications for force-extension experiments on single molecules.


Kafka, Borges, and the creation of consciousness, Part I: Kafka--dark ironies of the "gift" of consciousness.
The ways in which Franz Kafka and Jorge Luis Borges struggled with the creation of consciousness in their lives and in their literary works are explored in this two-part essay. In Part I, the author juxtaposes a biographical sketch of Kafka with a close reading of his story "A Hunger Artist" (1924), in which a character (whose personality holds much in common with that of Kafka) spends his life in a quasi-delusional state starving himself in public performances. The hunger artist's self-awareness (of having lived a life devoid of the experience of love and mutual recognition) is achieved in the context of an interpersonal experience in which he has, in fact, found/created "the food [he] liked," that is, an experience of loving and being loved, of seeing and being seen, of being aware of and alive to his own imminent death. This fragile, paradoxical state of consciousness is sustained for only a moment before it is attacked, but not entirely destroyed.


Heart and brain interaction in patients with heart failure: overview and proposal for a taxonomy. A position paper from the Study Group on Heart and Brain Interaction of the Heart Failure Association.
Heart failure (HF) is a complex clinical syndrome with multiple interactions between the failing myocardium and cerebral (dys-)functions. Bi-directional feedback interactions between the heart and the brain are inherent in the pathophysiology of HF: (i) the impaired cardiac function affects cerebral structure and functional capacity, and (ii) neuronal signals impact on the cardiovascular continuum. These interactions contribute to the symptomatic presentation of HF patients and affect many co-morbidities of HF. Moreover, neuro-cardiac feedback signals significantly promote aggravation and further progression of HF and are causal in the poor prognosis of HF. The diversity and complexity of heart and brain interactions make it difficult to develop a comprehensive overview. In this paper a systematic approach is proposed to develop a comprehensive atlas of related conditions, signals and disease mechanisms of the interactions between the heart and the brain in HF. The proposed taxonomy is based on pathophysiological principles. Impaired perfusion of the brain may represent one major category, with acute (cardio-embolic) or chronic (haemodynamic failure) low perfusion being sub-categories with mostly different consequences (i.e. ischaemic stroke or cognitive impairment, respectively). Further categories include impairment of higher cortical function (mood, cognition), of brain stem function (sympathetic over-activation, neuro-cardiac reflexes). Treatment-related interactions could be categorized as medical, interventional and device-related interactions. Also interactions due to specific diseases are categorized. A methodical approach to categorize the interdependency of heart and brain may help to integrate individual research areas into an overall picture.


Individual piglets' contribution to the development of tail biting.
Conflicting hypotheses exist about the contribution of individual pigs to the development of a tail-biting outbreak, but there is limited quantitative information to support or dismiss them. This study aims to quantify the development of tail-biting behaviour at pen and individual piglet level, before and after the first visible tail damage. Video recordings of 14 pens with tail-biting outbreaks and individually marked weaned piglets were used to observe tail-biting incidents (TBIs; piglet biting a penmate's tail). When visible tail damage was first observed in a pen (i.e. day of tail biting outbreak; D0), the video recordings of the previous 6 (till D-6) and the following 6 days (till D6) were analysed every other day for TBIs and the identities of the biter and bitten piglet were recorded. The average TBIs per individual piglet (within each pen) per observation day were analysed to quantify the development of tail-biting behaviour and to identify pronounced biters and/or bitten piglets. The (absence of) coherence for TBIs in a pen was used to test whether biters preferred a specific penmate. There was an exponential increase in the intensity (linear on log scale) of the TBIs from an average of 0.7 bites/h at D-6 to 2.3 bites/h at D6. An additional negative quadratic component suggests that a plateau for tail-biting behaviour was reached by the end of the observation period. Before any visible tail damage was observed (i.e. before D0), 82% of the piglets performed and 96% of them received tail bites. After D0, the figures were 99% and 100%, respectively. One or a few pronounced biters could be identified in almost all pens. These biters already showed more tail biting at D-6 than their penmates. Furthermore, these biters showed a greater increase in tail-biting behaviour during the observation period than the average scores of their penmates. In contrast, there was no apparent increase in the receipt of bites among the piglets that had already been bitten more than their penmates at D-6. Finally, there was no significant coherence between biters and bitten piglets, indicating that biters showed no preference for biting particular penmates, even when some of them had a damaged tail. These results show that, by using observations of TBIs, possible biters or bitten piglets can already be identified 6 days before tail damage is first apparent in a pen.


Visual detection of transposition of the maize element activator (ac) in tobacco seedlings.
A bacterial streptomycin resistance gene (SPT) was engineered to make it possible to detect visually the transposition of the maize transposon Activator (Ac) in tobacco. In the presence of streptomycin, transgenic seedlings carrying the SPT gene appear green, whereas those carrying an SPT:: Ac construct display clones of green cells on a white background. Fully green seedlings arise in the progeny of SPT:: Ac transformants as a result of excision of Ac before fertilization. About half of these germinal revertants carry a transposed Ac element. Therefore, SPT:: Ac constitutes an efficient marker for selecting plants that have undergone transposition. In maize, there is a negative effect of increasing Ac dosage on the frequency and timing of Ac transposition. This negative effect is not observed in tobacco with the streptomycin variegation assay.


The causality analysis of climate change and large-scale human crisis.
Recent studies have shown strong temporal correlations between past climate changes and societal crises. However, the specific causal mechanisms underlying this relation have not been addressed. We explored quantitative responses of 14 fine-grained agro-ecological, socioeconomic, and demographic variables to climate fluctuations from A.D. 1500-1800 in Europe. Results show that cooling from A.D. 1560-1660 caused successive agro-ecological, socioeconomic, and demographic catastrophes, leading to the General Crisis of the Seventeenth Century. We identified a set of causal linkages between climate change and human crisis. Using temperature data and climate-driven economic variables, we simulated the alternation of defined "golden" and "dark" ages in Europe and the Northern Hemisphere during the past millennium. Our findings indicate that climate change was the ultimate cause, and climate-driven economic downturn was the direct cause, of large-scale human crises in preindustrial Europe and the Northern Hemisphere.


Larval ecology of Anopheles coluzzii in Cape Coast, Ghana: water quality, nature of habitat and implication for larval control.
There is a growing interest in larval control intervention to supplement existing malaria control strategies, particularly in urban areas. However, effective implementation requires a good understanding of habitat ecology of Anopheles mosquitoes. Clean water bodies have long been reported by several studies as a preferred breeding habitat for Anopheles gambiae. Other studies have also reported the breeding of An. gambiae in polluted water bodies. However, the term clean or polluted is mostly based on visual examination and is not well defined. This study was conducted with the aim of assessing water quality in Anopheles breeding habitats and the practicability of larval control in Cape Coast, Ghana. A larval survey was conducted for 15 months in Cape Coast. In individual breeding habitats, habitat characteristics, physicochemical parameters and bacterial fauna were measured in both Anopheles positive breeding (APL) habitats and habitats colonized by only Culex species. The sibling species of An. gambiae were identified using PCR assay. Anopheles coluzzii dominated in almost all the APL habitats found in this study. The habitats had high levels of salinity and ammonium ions. However, ammonium ions were significantly higher (p = 0.001) in habitats colonized by only Culex larvae compared to APL habitats. About 47 % of the habitats that were colonized by only Culex larvae had no measurable dissolved oxygen while An. coluzzii was absent in such habitats. High concentration of faecal bacteria confirmed faecal contamination in both groups of breeding habitats. From the results, it was evident that larval stages of An. coluzzii have tolerance to high levels of salinity and organic pollution in breeding habitats. However, its level of tolerance to organic pollution is probably lower than Culex larvae. The nature of breeding habitats found in the city demonstrates the opportunistic behaviour of An. coluzzii and how its breeding requirements are so intimately intertwined with the haphazard and uncontrolled human activities in the urban area. Considering the nature of APL habitats, larval control intervention could greatly reduce Anopheles population. However, improving basic hygiene and sanitation in the city could even make larval control intervention more practical and cost effective.


Expression of lysosome-related proteins and genes in the skeletal muscles of inclusion body myositis.
Despite the unknown etiology and pathogenesis of sporadic inclusion body myositis (s-IBM), investigators have speculated that the lysosome system in muscle fiber plays a central role in rimmed vacuole formation, a hallmark of s-IBM. We explored the role of receptor-mediated intracellular transport and autophagy in the lysosomal system in the abnormal accumulation of rimmed vacuoles in s-IBM. Expressions of mannose 6-phosphate receptor (M6PR), clathrin and hApg5 and hApg12 were analyzed in muscle biopsy specimens from patients with s-IBM, amyotrophic lateral sclerosis (ALS) or peripheral neuropathy and in normal human muscle specimens by means of immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Most muscle fibers in control specimens showed little or no immunoreactivity for clathrin and M6PR, which are involved in the receptor-mediated intracellular transport. Abnormal increases in both proteins were observed mainly in the sarcoplasm of atrophic fibers in all diseased specimens. In s-IBM muscles in particular, clathrin and M6PR were often observed inside rimmed vacuoles and in the sarcoplasm of vacuolated or non-vacuolated fibers. mRNA levels of hApg5 and hApg12, which are involved in autophagic vacuole formation, as well as of M6PR and clathrin were significantly increased in s-IBM muscles in comparison to levels in normal and ALS/peripheral neuropathy muscles. Our results suggest that the transport of newly synthesized lysosomal enzymes from the secretory pathway via the trans-Golgi network of the Golgi apparatus and autophagic vacuole formation (i.e., autophagy) in the lysosome system are activated in s-IBM muscles. Remarkable accumulation of rimmed vacuoles is thought to occur because of abnormal lysosome function, especially the formation or turnover of autolysosomes after the fusion of autophagic vacuoles with the early endosomes or because of the increase in the rate of muscle fiber breakdown.


Visible skin colouration predicts perception of male facial age, health and attractiveness.
Although there is evidence that perception of facial age, health and attractiveness is informed by shape characteristics as well as by visible skin condition, studies on the latter have focused almost exclusively on female skin. Recent research, however, suggests that a decrease in skin colour homogeneity leads to older, less healthy and less attractive ratings of facial skin in both women and men. Here, we elaborate on the significance of the homogeneity of visible skin colouration in men by testing the hypothesis that perception of age, health and attractiveness of (non-contextual) digitally isolated fields of cheek skin only can predict that of whole facial images. Facial digital images of 160 British men (all Caucasian) aged between 10 and 70 were blind-rated for age, health and attractiveness by a total of 147 men and 154 women (mean age = 22.95, SD = 4.26), and these ratings were related to those of corresponding images of cheek skin reported by Fink et al. (J. Eur. Acad. Dermatol. Venereol. in press). Linear regression analysis showed that age, health and attractiveness perception of men's faces could be predicted by the ratings of cheek skin only, such that older men were viewed as older, less healthy and less attractive. This result underlines once again the potent signalling role of skin in its own right, independent of shape or other factors and suggests strongly that visible skin condition, and skin colour homogeneity in particular, plays a significant role in the perception of men's faces.


Distinct v-SNAREs regulate direct and indirect apical delivery in polarized epithelial cells.
SNARE [soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor] proteins control the membrane-fusion events of eukaryotic membrane-trafficking pathways. Specific vesicular and target SNAREs operate in specific trafficking routes, but the degree of specificity of SNARE functions is still elusive. Apical fusion requires the polarized distribution at the apical surface of the t-SNARE syntaxin 3, and several v-SNAREs including TI-VAMP and VAMP8 operate at the apical plasma membrane in polarized epithelial cells. It is not known, however, whether specific v-SNAREs are involved in direct and indirect routes to the apical surface. Here, we used RNAi to assess the role of two tetanus-neurotoxin-insensitive v-SNAREs, TI-VAMP/VAMP7 and VAMP8, in the sorting of raft- and non-raft-associated apical markers that follow either a direct or a transcytotic delivery, respectively, in FRT or Caco2 cells. We show that TI-VAMP mediates the direct apical delivery of both raft- and non-raft-associated proteins. By contrast, sorting by means of the transcytotic pathway is not affected by TI-VAMP knockdown but does appear to be regulated by VAMP8. Together with the specific role of VAMP3 in basolateral transport, our results demonstrate a high degree of specificity in v-SNARE function in polarized cells.