Eye Gaze Technology as a Form of Augmentative and Alternative Communication for Individuals with Rett Syndrome: Experiences of Families in The Netherlands.
This paper provides a brief report on families' experiences of eye gaze technology as one form of augmentative and alternative communication (AAC) for individuals with Rett syndrome (RTT), and the advice, training and support they receive in relation to this. An online survey exploring communication and AAC was circulated to 190 Dutch families; of the 67 questionnaires that were returned, 63 had answered questions relating to eye gaze technology. These 63 were analysed according to parameters including: experiences during trial periods and longer-term use; expert knowledge, advice and support; funding; communicative progress; and family satisfaction. 20 respondents were using or had previous experience of using an eye gaze system at the time of the survey, 28 of those with no prior experience wanted to try a system in the future. Following a trial period, 11 systems had been funded through health insurance for long-term use and two families had decided a system was not appropriate for them. Levels of support during trials and following long-term provision varied. Despite frustrations with the technology, satisfaction with the systems was higher than satisfaction with the support. The majority of families reported progress in their child's skills with longer term use. These findings suggest that although eye gaze technologies offer potential to individuals with RTT and their families, greater input from suppliers and knowledgeable AAC professionals is essential for individuals and families to benefit maximally. Higher levels of training and support should be part of the 'package' when an eye gaze system is provided.


Two-step mechanism of photodamage to photosystem II: step 1 occurs at the oxygen-evolving complex and step 2 occurs at the photochemical reaction center.
Under strong light, photosystem II (PSII) of oxygenic photosynthetic organisms is inactivated, and this phenomenon is called photoinhibition. In a widely accepted model, photoinhibition is induced by excess light energy, which is absorbed by chlorophyll but not utilized in photosynthesis. Using monochromatic light from the Okazaki Large Spectrograph and thylakoid membranes from Thermosynechococcus elongatus, we observed that UV and blue light inactivated the oxygen-evolving complex much faster than the photochemical reaction center of PSII. These observations suggested that the light-induced damage was associated with a UV- and blue light-absorbing center in the oxygen-evolving complex of PSII. The action spectrum of the primary event in photodamage to PSII revealed the strong effects of UV and blue light and differed considerably from the absorption spectra of chlorophyll and thylakoid membranes. By contrast to the photoinduced inactivation of the oxygen-evolving complex in untreated thylakoid membranes, red light efficiently induced inactivation of the PSII reaction center in Tris-treated thylakoid membranes, and the action spectrum resembled the absorption spectrum of chlorophyll. Our observations suggest that photodamage to PSII occurs in two steps. Step 1 is the light-induced inactivation of the oxygen-evolving complex. Step 2, occurring after step 1 is complete, is the inactivation of the PSII reaction center by light absorbed by chlorophyll. We confirmed our model by illumination of untreated thylakoid membranes with blue and UV light, which inactivated the oxygen-evolving complex, and then with red light, which inactivated the photochemical reaction center.


Environmental health specialists' self-reported foodborne illness outbreak investigation practices.
To collect qualitative data on the investigation practices of environmental health specialists with respect to foodborne illness outbreaks, the authors convened six focus groups of randomly selected specialists working in public health agencies in eight states. Participants discussed their investigation activities, methods used to identify contributing factors, success in identifying contributing factors, and the difficulties they faced when conducting investigations. Findings revealed substantial variability in the type of activities in which participants engaged during investigations, and the amount and nature of the collaboration between epidemiologists and environmental health specialists during investigations. Many participants indicated that during investigations they often did not identify contributing factors associated with an outbreak. Participants also identified several difficulties associated with outbreak investigations, including difficulties associated with restaurant employees, restaurant customers, and environmental health organizations.


Identification and analysis of CYP450 and UGT supergene family members from the transcriptome of Aralia elata (Miq.) seem reveal candidate genes for triterpenoid saponin biosynthesis.
Members of the cytochrome P450 (CYP450) and UDP-glycosyltransferase (UGT) gene superfamily have been shown to play essential roles in regulating secondary metabolite biosynthesis. However, the systematic identification of CYP450s and UGTs has not been reported in Aralia elata (Miq.) Seem, a highly valued medicinal plant. In the present study, we conducted the RNA-sequencing (RNA-seq) analysis of the leaves, stems, and roots of A. elata, yielding 66,713 total unigenes. Following annotation and KEGG pathway analysis, we were able to identify 64 unigenes related to triterpenoid skeleton biosynthesis, 254 CYP450s and 122 UGTs, respectively. A total of 150 CYP450s and 92 UGTs encoding > 300 amino acid proteins were utilized for phylogenetic and tissue-specific expression analyses. This allowed us to cluster 150 CYP450s into 9 clans and 40 families, and then these CYP450 proteins were further grouped into two primary branches: A-type (53%) and non-A-type (47%). A phylogenetic analysis of 92 UGTs and other plant UGTs led to clustering into 16 groups (A-P). We further assessed the expression patterns of these CYP450 and UGT genes across A. elata tissues, with 23 CYP450 and 16 UGT members being selected for qRT-PCR validation, respectively. From these data, we identified CYP716A295 and CYP716A296 as the candidate genes most likely to be associated with oleanolic acid synthesis, while CYP72A763 and CYP72A776 were identified as being the most likely to play roles in hederagenin biosynthesis. We also selected five unigenes as the best candidates for oleanolic acid 3-O-glucosyltransferase. Finally, we assessed the subcellular localization of three CYP450 proteins within Arabidopsis protoplasts, highlighting the fact that they localize to the endoplasmic reticulum. This study presents a systematic analysis of the CYP450 and UGT gene family in A. elata and provides a foundation for further functional characterization of these two multigene families.


The Professionalism Assessment of Clinical Teachers (PACT): the reliability and validity of a novel tool to evaluate professional and clinical teaching behaviors.
Physicians function as clinicians, teachers, and role models within the clinical environment. Negative learning environments have been shown to be due to many factors, including the presence of unprofessional behaviors among clinical teachers. Reliable and valid assessments of clinical teacher performance, including professional behaviors, may provide a foundation for evidence-based feedback to clinical teachers, enable targeted remediation or recognition, and help to improve the learning environment. However, few tools exist for the evaluation of clinical teachers that include a focus on both professional and clinical teaching behaviors. The Professionalism Assessment of Clinical Teachers (PACT) was developed and implemented at one Canadian institution and was assessed for evidence of reliability and validity. Following each clerkship rotation, students in the 2009-2010 third-year undergraduate clerkship cohort (n = 178) anonymously evaluated a minimum of two clinical teachers using the PACT. 4,715 forms on 567 faculty members were completed. Reliability, validity, and free text comments (present in 45 % of the forms) were examined. An average of 8.6 PACT forms were completed per faculty (range 1-60), with a reliability of 0.31 for 2.9 forms (harmonic mean); 12 forms were necessary for a reliability of 0.65. Global evaluations of teachers aligned with ratings of free-text comments (r = 0.77, p < 0.001). Comment length related negatively with overall rating (r = -0.19, p < 0.001). Mean performance related negatively with variability of performance (r = -0.72, p < 0.001), although this may be related to a ceiling effect. Most faculty members were rated highly; however 'provided constructive feedback' was the least well-rated item. Respectful interactions with students appeared to be the most influential item in the global rating of faculty performance. The PACT is a moderately reliable tool for the assessment of professional behaviors of clinical teachers, with evidence supporting its validity.


Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers.
Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to (R)-methadone. Whole-cell patch-clamp experiments using cells expressing hERG showed that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s (half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 microM). As CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)-methadone, electrocardiograms, CYP2B6 genotypes, and (R)- and (S)-methadone plasma concentrations were obtained for 179 patients receiving (R,S)-methadone. The mean heart-rate-corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 439+/-25 ms; n=11) than in extensive metabolizers (non *6/*6; 421+/-25 ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2-17.7; P=0.03). This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. This risk could be reduced by the administration of (R)-methadone.


Jejunal Inflammation in Crohn's Disease: Comparison between Diffusion Weighted Magnetic Resonance Imaging and Video Capsule Endoscopy.
Jejunal disease is associated with worse prognosis in Crohn's disease. The added value of diffusion weighted imaging for evaluating jejunal inflammation related to Crohn's Disease is scarce. To compare diffusion weighted imaging, video capsule endoscopy, and inflammatory biomarkers in the assessment of Crohn's disease involving the jejunum. Crohn's disease patients in clinical remission were prospectively recruited and underwent magnetic resonance (MR)-enterography and video capsule endoscopy. C-reactive protein and fecal-calprotectin levels were obtained. MR-enterography images were evaluated for restricted diffusion, and apparent diffusion coefficient values were measured. The video capsule endoscopy-based Lewis score was calculated. Associations between diffusion weighted imaging, apparent diffusion coefficient, Lewis score, and inflammatory biomarkers were evaluated. The study included 51 patients, and 27/51 (52.9%) with video capsule endoscopies showed jejunal mucosal inflammation. Sensitivity and specificity of restricted diffusion for video capsule endoscopy mucosal inflammation were 59.3% and 37.5% for the first reader, and 66.7% and 37.5% for the second reader, respectively. Diffusion weighted imaging was not statistically associated with jejunal video capsule endoscopy inflammation (P = 0.813). Diffusion weighted imaging was not an effective test for evaluation of jejunal inflammation as seen by video capsule endoscopy in patients with quiescent Crohn's disease.


Treatment-dependent loss of polyfunctional CD8+ T-cell responses in HIV-infected kidney transplant recipients is associated with herpesvirus reactivation.
Antiretroviral-therapy has dramatically changed the course of HIV infection and HIV-infected (HIV(+)) individuals are becoming more frequently eligible for solid-organ transplantation. However, only scarce data are available on how immunosuppressive (IS) strategies relate to transplantation outcome and immune function. We determined the impact of transplantation and immune-depleting treatment on CD4+ T-cell counts, HIV-, EBV-, and Cytomegalovirus (CMV)-viral loads and virus-specific T-cell immunity in a 1-year prospective cohort of 27 HIV(+) kidney transplant recipients. While the results show an increasing breadth and magnitude of the herpesvirus-specific cytotoxic T-cell (CTL) response over-time, they also revealed a significant depletion of polyfunctional virus-specific CTL in individuals receiving thymoglobulin as a lymphocyte-depleting treatment. The disappearance of polyfunctional CTL was accompanied by virologic EBV-reactivation events, directly linking the absence of specific polyfunctional CTL to viral reactivation. The data provide first insights into the immune-reserve in HIV+ infected transplant recipients and highlight new immunological effects of thymoglobulin treatment. Long-term studies will be needed to assess the clinical risk associated with thymoglobulin treatment, in particular with regards to EBV-associated lymphoproliferative diseases.


Modulation of Cerebellar Cortical Plasticity Using Low-Intensity Focused Ultrasound for Poststroke Sensorimotor Function Recovery.
Stroke affects widespread brain regions through interhemispheric connections by influencing bilateral motor activity. Several noninvasive brain stimulation techniques have proved their capacity to compensate the functional loss by manipulating the neural activity of alternative pathways. Over the past few decades, brain stimulation therapies have been tailored within the theoretical framework of modulation of cortical excitability to enhance adaptive plasticity after stroke. However, considering the vast difference between animal and human cerebral cortical structures, it is important to approach specific neuronal target starting from the higher order brain structure for human translation. The present study focuses on stimulating the lateral cerebellar nucleus (LCN), which sends major cerebellar output to extensive cortical regions. In this study, in vivo stroke mouse LCN was exposed to low-intensity focused ultrasound (LIFU). After the LIFU exposure, animals underwent 4 weeks of rehabilitative training. During the cerebellar LIFU session, motor-evoked potentials (MEPs) were generated in both forelimbs accompanying excitatory sonication parameter. LCN stimulation group on day 1 after stroke significantly enhanced sensorimotor recovery compared with the group without stimulation. The recovery has maintained for a 4-week period in 2 behavior tests. Furthermore, we observed a significantly decreased level of brain edema and tissue swelling in the affected hemisphere 3 days after the stroke. This study provides the first evidence showing that LIFU-induced cerebellar modulation could be an important strategy for poststroke recovery. A longer follow-up study is, however, necessary in order to fully confirm the effects of LIFU on poststroke recovery.


Clinical and psychological features of normal-weight women with subthreshold anorexia nervosa: a pilot case-control observational study.
Weight preoccupations have been frequently reported in normal-weight subjects. Subthreshold anorexia nervosa (s-AN, all DSM IV TR criteria except amenorrhea or underweight) is a form of eating disorder not otherwise specified that has received scarce scientific attention. Under a case-control design we compared the general characteristics, body composition, and psychopathological features of normal-weight patients with s-AN with those of BMI- and sex-matched controls. Participants in this pilot study included 9 normal-weight women who met the DSM IV TR criteria for s-AN and 18 BMI-matched normal-weight controls. The general characteristics of the study participants were collected by questionnaire. Body composition was measured by bioelectrical impedance. Behavioral and psychological measures included the standardized symptom checklist (SCL-90-R) and the eating disorder inventory (EDI-2). There were no differences in age, education, employment status, marital status, and history of previous slimming treatment in the two study groups. In addition, anthropometric measures and body composition of s-AN patients and BMI-matched normal weight controls were not significantly different. In the s-AN subgroup, we found a significant relationship between waist circumference and the SCL-90-R obsessivity-compulsivity scale (n=9, r=-0.69, p<0.05). After multiple regression analysis, the SCL-90-R obsessivity-compulsivity scale (beta = 0.61, t=2.7, p=0.017) was the only independent predictor of the presence s-AN in our study cohort. These pilot results suggest that psychopathological criteria (particularly related to the obsessivity-compulsivity dimension) may be more useful than anthropometric measures for screening of s-AN in normal-weight women.


Causal relationship between microbial ecology dynamics and proteolysis during manufacture and ripening of protected designation of origin (PDO) cheese Canestrato Pugliese.
Pyrosequencing of the 16S rRNA gene, community-level physiological profiles determined by the use of Biolog EcoPlates, and proteolysis analyses were used to characterize Canestrato Pugliese Protected Designation of Origin (PDO) cheese. The number of presumptive mesophilic lactococci in raw ewes' milk was higher than that of presumptive mesophilic lactobacilli. The numbers of these microbial groups increased during ripening, showing temporal and numerical differences. Urea-PAGE showed limited primary proteolysis, whereas the analysis of the pH 4.6-soluble fraction of the cheese revealed that secondary proteolysis increased mainly from 45 to 75 days of ripening. This agreed with the concentration of free amino acids. Raw ewes' milk was contaminated by several bacterial phyla: Proteobacteria (68%; mainly Pseudomonas), Firmicutes (30%; mainly Carnobacterium and Lactococcus), Bacteroidetes (0.05%), and Actinobacteria (0.02%). Almost the same microbial composition persisted in the curd after molding. From day 1 of ripening onwards, the phylum Firmicutes dominated. Lactococcus dominated throughout ripening, and most of the Lactobacillus species appeared only at 7 or 15 days. At 90 days, Lactococcus (87.2%), Lactobacillus (4.8%; mainly Lactobacillus plantarum and Lactobacillus sakei), and Leuconostoc (3.9%) dominated. The relative utilization of carbon sources by the bacterial community reflected the succession. This study identified strategic phases that characterized the manufacture and ripening of Canestrato Pugliese cheese and established a causal relationship between mesophilic lactobacilli and proteolysis.


Potential therapeutic application of the association of vitamins C and K3 in cancer treatment.
The decision of stressed cells to die or to survive is made by integrating signals at different levels through multiple check points. However, initiation and continued progression toward cell death by apoptosis in cancer cells may be blocked by mutation of the tumor suppressor p53 or overexpression of members of the bcl-2 family of proteins. The existence of such mechanisms indicates that cancer cells lose the controls regulating their cell cycle. Therefore, the activation of their programmed cell death appears as a major therapeutic target. Oxidative stress can stimulate growth, trigger apoptosis, or cause necrosis depending upon the dose and the exposure time of the oxidizing agent. A large body of evidence supports the idea that oxidative stress induced by redox cycling of vitamins C and K(3) in association surpasses cancer cellular defense systems and results in cell death. The molecular mechanisms underlying such a process are, however, still unknown. Indeed, several types of cell death may be produced, namely autoschizis, apoptosis and necrosis. Combined vitamin C and K(3) administration in vitro and in vivo produced tumor growth inhibition and increased the life-span of tumor-bearing mice. CK(3)-treatment selectively potentiated tumor chemotherapy, produced sensitization of tumors resistant to some drugs, potentiated cancer radiotherapy and caused inhibition of the development of cancer metastases without inducing toxicity in the host. We propose the association of vitamins C and K(3) as an adjuvant cancer therapy which may be introduced into human cancer therapy without any change in the classical anticancer protocols, and without any supplementary risk for patients.


Heavy chain myosin 9-related disease (MYH9 -RD): neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder.
MYH9-related disease ( MYH9-RD) is an autosomal dominant thrombocytopenia with giant platelets variably associated with young-adult onset of progressive sensorineural hearing loss, presenile cataract, and renal damage. MYH9-RD is caused by mutations of MYH9 , the gene encoding for non-muscle heavy-chain myosin-9. Wild-type and mutant myosin-9 aggregate as cytoplasmic inclusions in patients' leukocytes, the identification of which by immunofluorescence has been proposed as a suitable tool for the diagnosis of MYH9-RD. Since the predictive value of this assay, in terms of sensitivity and specificity, is unknown, we investigated 118 consecutive unrelated patients with a clinical presentation strongly consistent with MYH9-RD. All patients prospectively underwent both the immunofluorescence assay for myosin-9 aggregate detection and molecular genetic analysis of the MYH9 gene. Myosin-9 aggregates were identified in 82 patients, 80 of which (98%) had also a MYH9 mutation. In the remaining 36 patients neither myosin-9 aggregates nor MYH9 mutations were found. Sensitivity and specificity of the immunofluorescence assay was evaluated to be 100% and 95%, respectively. Except for the presence of aggregates, we did not find any other significant difference between patients with or without aggregates, demonstrating that the myosin-9 inclusions in neutrophils are a pathognomonic sign of the disease. However, the identification of the specific MYH9 mutation is still of importance for prognostic aspects of MYH9-RD.


An interaction map of circulating metabolites, immune gene networks, and their genetic regulation.
Immunometabolism plays a central role in many cardiometabolic diseases. However, a robust map of immune-related gene networks in circulating human cells, their interactions with metabolites, and their genetic control is still lacking. Here, we integrate blood transcriptomic, metabolomic, and genomic profiles from two population-based cohorts (total N = 2168), including a subset of individuals with matched multi-omic data at 7-year follow-up. We identify topologically replicable gene networks enriched for diverse immune functions including cytotoxicity, viral response, B cell, platelet, neutrophil, and mast cell/basophil activity. These immune gene modules show complex patterns of association with 158 circulating metabolites, including lipoprotein subclasses, lipids, fatty acids, amino acids, small molecules, and CRP. Genome-wide scans for module expression quantitative trait loci (mQTLs) reveal five modules with mQTLs that have both cis and trans effects. The strongest mQTL is in ARHGEF3 (rs1354034) and affects a module enriched for platelet function, independent of platelet counts. Modules of mast cell/basophil and neutrophil function show temporally stable metabolite associations over 7-year follow-up, providing evidence that these modules and their constituent gene products may play central roles in metabolic inflammation. Furthermore, the strongest mQTL in ARHGEF3 also displays clear temporal stability, supporting widespread trans effects at this locus. This study provides a detailed map of natural variation at the blood immunometabolic interface and its genetic basis, and may facilitate subsequent studies to explain inter-individual variation in cardiometabolic disease.


Differential Transmission of Two Isolates of Wheat streak mosaic virus by Five Wheat Curl Mite Populations.
Wheat streak mosaic virus (WSMV), type member of the genus Tritimovirus in the family Potyviridae, is an economically important virus causing annual average yield losses of approximately 2 to 3% in winter wheat across the Great Plains. The wheat curl mite (WCM), Aceria tosichella, transmits WSMV along with two other viruses found throughout the Great Plains of the United States. Two common genotypes of WSMV (Sidney 81 and Type) in the United States share 97.6% nucleotide sequence identity but their transmission relationships with the WCM are unknown. The objective of this study was to determine transmission of these two isolates of WSMV by five WCM populations ('Nebraska', 'Montana', 'South Dakota', 'Type 1', and 'Type 2'). Nonviruliferous mites from each population were reared on wheat source plants mechanically inoculated with either Sidney 81 or Type WSMV isolates. For each source plant, individual mites were transferred to 10 separate test plants and virus transmission was determined by a double-antibody sandwich enzyme-linked immunosorbent assay. Source plants were replicated nine times for each treatment (90 individual mite transfers). Results indicate that three mite populations transmitted Sidney 81 at higher rates compared with Type. Two mite populations (Nebraska and Type 2) transmitted Sidney 81 and Type at higher rates compared with the other three populations. Results from this study demonstrate that interactions between virus isolates and mite populations influence the epidemiology of WSMV.


Transposition Pattern of the Maize Element Ac from the Bz-M2(ac) Allele.
The pattern of transposition of Ac from the mutable allele bz-m2(Ac) has been investigated. Stable (bz-s) and finely spotted (bz-m(F)) exceptions were selected from coarsely spotted bz-m2(Ac) ears. The presence or absence of a transposed Ac (trAc) in the genome was determined and, when present, the location of the trAc was mapped relative to the flanking markers sh and wx. The salient general features of Ac transposition to sites linked to bz are that the receptor sites tend to be clustered on either side of the bz donor site and that transposition is bidirectional and nonpolar. Thus, the symmetrical clustering in the distribution of receptor sites adjacent to bz differs from the asymmetrical clustering reported in 1984 for the P locus by I. M. GREENBLATT. Though Ac tends to transpose preferentially to closely linked sites, an appreciable fraction of Ac transpositions from bz-m2(Ac) is to unlinked sites: 41% among bz-s derivatives and 59% among bz-m(F) derivatives. Many transposition events among the bz-m(F) selections result in kernels carrying a genetically noncorresponding embryo. These can be interpreted as twin sectors arising at one of the megagametophytic mitoses. The bz locus data fit the earlier (1962) model of I. M. GREENBLATT and R. A. BRINK in which transposition takes place from a replicated donor site to either an unreplicated or replicated receptor site.


Outcome of elective prostatectomy.
To determine the symptomatic and urodynamic outcome of elective prostatectomy and to establish whether the outcome is influenced or can be predicted by preoperative urodynamic measurements. Prospective non-randomised study with follow up at a mean of 11 months after operation. Most men were assessed jointly by a urologist and a general practitioner. Department of urology in a teaching hospital serving a large district population. 253 Men listed for elective prostatectomy because of symptoms and low urinary flow rates (less than 15 ml/s) and excluding those already on a waiting list or with acute urinary retention, clinically apparent prostatic cancer, and neurological or cerebrovascular disease; 217 (86%) were followed up. Elective prostatectomy. Classification on the basis of relief of symptoms assessed by patients and urologist and general practitioner and of symptom scores obtained by questionnaire. Of the 217 men followed up, 171 (79%) had a satisfactory subjective review and 155 (72%) had a satisfactory review and also low symptom scores. An unsatisfactory outcome was associated with preoperative symptoms of urge incontinence, small prostatic size and resected weight, low voiding pressures, and low urethral resistance. Preoperative maximum urinary flow rates did not predict outcome. Men with poor outcome could be classified into two groups: those with irritative symptoms who were more likely before operation to have had urge incontinence and detrusor instability and men with symptoms of poor urinary flow who were more likely before operation to have had a small prostate, low voiding pressures, and low urethral resistance. In patients in the second group flow rates or voiding pressures improved little after operation. Men with stable detrusors and either low urethral resistance or low voiding pressures were less likely to do well after prostatectomy, but despite these associations preoperative urodynamic measurements were unable to predict outcome accurately. Prostatectomy was satisfactory in relieving symptoms and improving urodynamic measurements in most men, but even in those with classic symptoms and low urinary flow rates a substantial minority experienced little improvement afterwards and urodynamic measurements did not accurately predict outcome in individual patients.


The association of betaine, homocysteine and related metabolites with cognitive function in Dutch elderly people.
The importance of the one-carbon metabolites, choline and homocysteine, to brain function is well known. However, the associations between the one-carbon metabolites choline, betaine, methionine and dimethylglycine with cognition in elderly are unclear. We therefore examined the associations of these metabolites with cognition in a double-blind, placebo-controlled trial. Individuals (n 195) were randomized to receive daily oral capsules with either 1000 microg cobalamin (vitamin B12), or 1000 microg cobalamin plus 400 microg folic acid, or placebo for 24 weeks. Concentrations of homocysteine, methionine, choline, betaine and dimethylglycine were assessed before and after 12 and 24 weeks of treatment. Cognitive function, including domains of attention, construction, sensomotor speed, memory and executive function, was assessed before and after 24 weeks of treatment. At baseline, elevated plasma homocysteine was associated with lower performance of attention, construction, sensomotor speed and executive function. In addition, betaine was positively associated with better performance of construction, sensomotor speed and executive function, whereas elevated concentrations of methionine were positively associated with sensomotor speed. Daily combined supplementation with cobalamin plus folic acid decreased total homocysteine concentrations by 36%, and increased betaine concentrations by 38%. Participants with the largest increases in betaine concentrations showed a borderline significant (P = 0.07) higher memory performance compared to those without it. Although this trial observed associations of homocysteine and betaine with cognitive domains prior to supplementation, decreased concentrations of homocysteine were not related to improved cognitive performance. There was a tendency of participants with the largest increases in betaine concentrations to show the greatest improvement in memory function.


Silent cerebral infarcts in sickle cell anemia: a risk factor analysis. The Cooperative Study of Sickle Cell Disease.
Silent infarcts have been reported in 17% of young patients with sickle cell disease and are associated with impaired performance on standardized psychometric tests. Risk factors for the development of these lesions have not been identified. Investigators in the Cooperative Study of Sickle Cell Disease performed a brain magnetic resonance imaging scan on sickle cell anemia patients age 5.9 years and older who had been followed according to the protocols of the Cooperative Study since birth. Individuals with a known history of cerebrovascular accident were excluded from this analysis. Patients with and without silent infarctions were compared with regard to clinical and laboratory parameters. The study sample included 42 patients (18.3%) with silent infarcts. Patients who had silent infarcts were significantly more likely to have a clinical history of seizure and a lower painful event rate. Lower hemoglobin level, increased leukocyte count, elevated pocked red blood cell count, and SEN betaS globin gene haplotype were associated also with the presence of silent infarcts. There was no relationship between silent infarcts and platelet count, fetal hemoglobin level, reticulocyte percentage, serum aspartate aminotransferase level, total bilirubin concentration, blood pressure, growth parameters, or presence of alpha-thalassemia. A multivariate model for silent infarction identified the following as risk factors: low pain event rate, history of seizure, leukocyte count >/=11.8 x 10(9)/L, and the SEN betaS globin gene haplotype. Patients with risk factors for silent infarcts should be evaluated for cerebrovascular disease. If evidence of infarction is found, consideration must be given to therapeutic intervention. At present, the appropriate treatment has not been determined.


Comparisons of Objective Sleep Quality Between Elderly Individuals With and Without Cataract Surgery: A Cross-Sectional Study of the HEIJO-KYO Cohort.
Cataract surgery (CS) drastically increases the capacity for light reception to the retina. Several previous studies have suggested the beneficial effect of CS on subjectively measured sleep quality; however, the association between CS and objectively measured sleep quality remains uncertain. To evaluate the association between CS and objectively measured sleep quality in home settings, we conducted a cross-sectional study in 1037 elderly individuals (mean age, 71.9 years). We evaluated actigraphically measured sleep quality, urinary 6-sulfatoxymelatonin excretion, and ambulatory light levels, in addition to CS status. The CS group (n = 174) showed significantly higher sleep efficiency and shorter wake after sleep onset than the no CS group (n = 863), even after adjustment for age, gender, body mass index, current smoking status, alcohol consumption, hypertension, diabetes, sleep medication, bedtime, rising time, daytime physical activity, daytime and nighttime light exposure, and urinary 6-sulfatoxymelatonin excretion (sleep efficiency: 85.8% in the CS group vs 84.4% in the no CS group, P = 0.042; wake after sleep onset: 45.7 min vs 50.6 min, respectively, P = 0.033). In contrast, urinary 6-sulfatoxymelatonin excretion, sleep onset latency, total sleep time, and sleep-mid time did not differ significantly between the CS and no CS groups. Among a community-dwelling elderly population, CS is significantly associated with objectively measured sleep quality, but urinary levels of melatonin metabolite do not differ between individuals with and without CS. These associations are independent of daily light exposure profiles.


Dominance of an invasive fruit fly species, Bactrocera invadens, along an altitudinal transect in Morogoro, Eastern Central Tanzania.
Bactrocera invadens, a fruit fly from Asia, is an invasive pest species across Africa. It appears to continue spreading, not only in latitude but also in altitude. To assess its capacity to infest a large variety of hosts and its competition with other fruit fly species, a study along an altitudinal gradient was conducted. At low altitudes, the high abundance in the field and high infestation of B. invadens in different fruit species make it a serious pest. At high altitudes, colonization has started and B. invadens occurs in low numbers by reproducing successfully in high altitude fruits. Overall the abundance and infestation of B. invadens is influenced by its direct competitor Ceratitis rosa and the presence of its preferred host species. C. rosa is still the dominant species in temperate fruits grown at high altitude. Ceratitis cosyra, however, is negatively affected by B. invadens, this species seems to have shifted hosts to avoid competition. The broad host range and competitive potential of B. invadens increase the risk for further spread not only to higher areas, but also to subtropical regions.


A breeding program for balanced improvement of performance and health in broilers.
To illustrate the consequences of including health related traits in a sustainable broiler breeding program, two scenarios were simulated using the SelAction program. In the first scenario (economic), selection was only for production traits and Gait Score (GS) and Heart Failure (HF) were ignored in the breeding goal. In the second scenario (sustainable), GS and HF as well as production traits were included in the breeding goal. Economic values of GS and HF were determined using desired-gain approach to obtain a zero response in GS and HF. The results indicate that, despite improved responses for production traits in the economic scenario, there was an unfavorable reduction in GS of about 0.13 points and an unfavorable increase in HF of about 0.025 points. In the sustainable scenario, the deterioration of GS and HF was stopped. In the economic scenario with zero economic values for GS and HF, the total monetary response was higher (0.104 euros) than sustainable scenario (0.097 euros). Due to negative correlations between health and production traits, increased emphasis on health traits in the sustainable scenario resulted in a reduction in the total monetary response. In conclusion to stop the increased incidence of diseases, health traits should be included in the breeding goal and assigned appropriate values.


Linkage and the maintenance of heritable variation by mutation-selection balance.
The role of linkage in influencing heritable variation maintained through a balance between mutation and stabilizing selection is investigated for two different models. In both cases one trait is considered and the interactions within and between loci are assumed to be additive. Contrary to most earlier investigations of this problem no a priori assumptions on the distribution of genotypic values are imposed. For a deterministic two-locus two-allele model with recombination and mutation, related to the symmetric viability model, a complete nonlinear analysis is performed. It is shown that, depending on the recombination rate, multiple stable equilibria may coexist. The equilibrium genetic and genic variances are calculated. For a polygenic trait in a finite population with a possible continuum of allelic effects a simulation study is performed. In both models the equilibrium genetic and genic variances are roughly equal to the house-of-cards prediction or its finite population counterpart as long as the recombination rate is not extremely low. However, negative linkage disequilibrium builds up. If the loci are very closely linked the equilibrium additive genetic variance is slightly lower than the house-of-cards prediction, but the genic variance is much higher. Depending on whether the parameters are in favor of the house-of-cards or the Gaussian approximation, different behavior of the genetic system occurs with respect to linkage.


Mesothelioma in Cyprus.
For many years, the main source of asbestos in Cyprus was thought to be the chrysotile mine in the central mountains. When a woman, who had no connection with the mine, developed mesothelioma, it was surprising to discover tremolite asbestos bodies within her lung. However, further studies have shown that tremolite occurs as a contaminant within the chrysotile ore body. In this study we have shown that both chrysotile and tremolite can be found in domestic and environmental samples throughout the mountain region; in particular, numerous fine fibres of both materials are present in stucco. Preliminary radiological studies have shown pleural disease in the village population and 5 out of 13 known cases of mesothelioma have arisen in persons unconnected with the mine. This suggests an environmental contribution to asbestos-related disease on the island.


Systemic Delivery of a Brain-Penetrant TrkB Antagonist Reduces Cocaine Self-Administration and Normalizes TrkB Signaling in the Nucleus Accumbens and Prefrontal Cortex.
Cocaine exposure alters brain-derived neurotrophic factor (BDNF) expression in the brain. BDNF signaling through TrkB receptors differentially modulates cocaine self-administration, depending on the brain regions involved. In the present study, we determined how brain-wide inhibition of TrkB signaling affects cocaine intake, the motivation for the drug, and reinstatement of drug taking after extinction. To overcome the inability of TrkB ligands to cross the blood-brain barrier, the TrkB antagonist cyclotraxin-B was fused to the nontoxic transduction domain of the tat protein from human immunodeficiency virus type 1 (tat-cyclotraxin-B). Intravenous injection of tat-cyclotraxin-B dose-dependently reduced cocaine intake, motivation for cocaine (as measured under a progressive ratio schedule of reinforcement), and reinstatement of cocaine taking in rats allowed either short or long access to cocaine self-administration. In contrast, the treatment did not affect operant responding for a highly palatable sweet solution, demonstrating that the effects of tat-cyclotraxin-B are specific for cocaine reinforcement. Cocaine self-administration increased TrkB signaling and activated the downstream Akt pathway in the nucleus accumbens, and had opposite effects in the prefrontal cortex. Pretreatment with tat-cyclotraxin-B normalized protein levels in these two dopamine-innervated brain regions. Cocaine self-administration also increased TrkB signaling in the ventral tegmental area, where the dopaminergic projections originate, but pretreatment with tat-cyclotraxin-B did not alter this effect. Altogether, our data show that systemic administration of a brain-penetrant TrkB antagonist leads to brain region-specific effects and may be a potential pharmacological strategy for the treatment of cocaine addiction. Brain-derived neurotrophic factor (BDNF) signaling through TrkB receptors plays a well established role in cocaine reinforcement. However, local manipulation of BDNF signaling yields divergent effects, depending on the brain region, thereby questioning the viability of systemic TrkB targeting for the treatment of cocaine use disorders. Our study provides first-time evidence that systemic administration of a brain-penetrant TrkB antagonist (tat-cyclotraxin-B) reduces several behavioral measures of cocaine dependence, without altering motor performance or reinforcement by a sweet palatable solution. In addition, although cocaine self-administration produced opposite effects on TrkB signaling in the nucleus accumbens and prefrontal cortex, tat-cyclotraxin-B administration normalized these cocaine-induced changes in both brain regions.


Study of the oxygen vacancy influence on magnetic properties of Fe- and Co-doped SnO2 diluted alloys.
Transition-metal (TM)-doped diluted magnetic oxides (DMOs) have attracted attention from both experimental and theoretical points of view due to their potential use in spintronics towards new nanostructured devices and new technologies. In the present work, we study the magnetic properties of Sn0.96TM0.04O2 and Sn0.96TM0.04O1.98(VO)0.02, where TM = Fe and Co, focusing in particular in the role played by the presence of O vacancies nearby the TM. The calculated total energy as a function of the total magnetic moment per cell shows a magnetic metastability, corresponding to a ground state, respectively, with 2 and 1 μB/cell, for Fe and Co. Two metastable states, with 0 and 4 μB/cell were found for Fe, and a single value, 3 μB/cell, for Co. The spin-crossover energies (ES) were calculated. The values are ES0/2 = 107 meV and ES4/2 = 25 meV for Fe. For Co, ES3/1 = 36 meV. By creating O vacancies close to the TM site, we show that the metastablity and ES change. For iron, a new state appears, and the state with zero magnetic moment disappears. The ground state is 4 μB/cell instead of 2 μB/cell, and the energy ES2/4 is 30 meV. For cobalt, the ground state is then found with 3 μB/cell and the metastable state with 1 μB/cell. The spin-crossover energy ES1/3 is 21 meV. Our results suggest that these materials may be used in devices for spintronic applications that require different magnetization states.


TP53 genomic status regulates sensitivity of gastric cancer cells to the histone methylation inhibitor 3-deazaneplanocin A (DZNep).
DZNep (3-deazaneplanocin A) depletes EZH2, a critical component of polycomb repressive complex 2 (PRC2), which is frequently deregulated in cancer. Despite exhibiting promising anticancer activity, the specific genetic determinants underlying DZNep responsiveness in cancer cells remain largely unknown. We sought to determine molecular factors influencing DZNep response in gastric cancer. Phenotypic effects of DZNep were evaluated in a panel of gastric cancer cell lines. Sensitive lines were molecularly interrogated to identify potential predictors of DZNep responsiveness. The functional importance of candidate predictors was evaluated using short hairpin RNA (shRNA) and siRNA technologies. DZNep depleted PRC2 pathway components in almost all gastric cancer lines, however, only a subset of lines exhibited growth inhibition upon treatment. TP53 genomic status was significantly associated with DZNep cellular responsiveness, with TP53 wild-type (WT) lines being more sensitive (P < 0.001). In TP53-WT lines, DZNep stabilized p53 by reducing ubiquitin conjugation through USP10 upregulation, resulting in activation of canonical p53 target genes. TP53 knockdown in TP53-WT lines attenuated DZNep sensitivity and p53 target activation, showing the functional importance of an intact p53 pathway in regulating DZNep cellular sensitivity. In primary human gastric cancers, EZH2 expression was negatively correlated with p53 pathway activation, suggesting that higher levels of EZH2 may repress p53 activity. Our results highlight an important role for TP53 genomic status in influencing DZNep response in gastric cancer. Clinical trials evaluating EZH2-targeting agents such as DZNep should consider stratifying patients with gastric cancer by their TP53 genomic status.


Weak Epistasis Generally Stabilizes Phenotypes in a Mouse Intercross.
The extent and strength of epistasis is commonly unresolved in genetic studies, and observed epistasis is often difficult to interpret in terms of biological consequences or overall genetic architecture. We investigated the prevalence and consequences of epistasis by analyzing four body composition phenotypes--body weight, body fat percentage, femoral density, and femoral circumference--in a large F2 intercross of B6-lit/lit and C3.B6-lit/lit mice. We used Combined Analysis of Pleiotropy and Epistasis (CAPE) to examine interactions for the four phenotypes simultaneously, which revealed an extensive directed network of genetic loci interacting with each other, circulating IGF1, and sex to influence these phenotypes. The majority of epistatic interactions had small effects relative to additive effects of individual loci, and tended to stabilize phenotypes towards the mean of the population rather than extremes. Interactive effects of two alleles inherited from one parental strain commonly resulted in phenotypes closer to the population mean than the additive effects from the two loci, and often much closer to the mean than either single-locus model. Alternatively, combinations of alleles inherited from different parent strains contribute to more extreme phenotypes not observed in either parental strain. This class of phenotype-stabilizing interactions has effects that are close to additive and are thus difficult to detect except in very large intercrosses. Nevertheless, we found these interactions to be useful in generating hypotheses for functional relationships between genetic loci. Our findings suggest that while epistasis is often weak and unlikely to account for a large proportion of heritable variance, even small-effect genetic interactions can facilitate hypotheses of underlying biology in well-powered studies.


Pilot study of oral silibinin, a putative chemopreventive agent, in colorectal cancer patients: silibinin levels in plasma, colorectum, and liver and their pharmacodynamic consequences.
Silibinin, a flavonolignan from milk thistle, has intestinal cancer chemopreventive efficacy in rodents. It is a strong antioxidant and modulates the insulin-like growth factor (IGF) system by increasing circulating levels of IGF-binding protein 3 (IGFBP-3) and decreasing levels of IGF-I. Here, the hypothesis was tested that administration of oral silibinin generates agent levels in human blood and colorectal and hepatic tissues consistent with pharmacologic activity. Patients with confirmed colorectal adenocarcinoma received silibinin formulated with phosphatidylcholine (silipide) at dosages of 360, 720, or 1,440 mg silibinin daily for 7 days. Blood and biopsy samples of normal and malignant colorectum or liver were obtained before dosing, and blood and colorectal or hepatic tissues were collected at resection surgery after the final silipide dose. Levels of silibinin were quantified by high-pressure liquid chromatography-UV, and plasma metabolites were identified by liquid chromatography-mass spectrometry. Blood levels of IGFBP-3, IGF-I, and the oxidative DNA damage pyrimidopurinone adduct of deoxyguanosine (M1dG) were determined. Repeated administration of silipide was safe and achieved levels of silibinin of 0.3 to 4 micromol/L in the plasma, 0.3 to 2.5 nmol/g tissue in the liver, and 20 to 141 nmol/g tissue in colorectal tissue. Silibinin monoglucuronide, silibinin diglucuronide, silibinin monosulfate, and silibinin glucuronide sulfate were identified in the plasma. Intervention with silipide did not affect circulating levels of IGFBP-3, IGF-I, or M1dG. The high silibinin levels achieved in the human colorectal mucosa after consumption of safe silibinin doses support its further exploration as a potential human colorectal cancer chemopreventive agent.


Measuring aqueous solubility in the presence of small cosolvent volume fractions by passive dosing.
A new passive dosing method was developed to determine aqueous solubility of hydrophobic chemicals. In the passive dosing method, chemical crystals were loaded to a polydimethylsiloxane (PDMS) phase to maintain the maximum chemical activity and to prevent direct contact of chemical crystals with the aqueous solution. Eight polycyclic aromatic hydrocarbons (PAHs) were chosen covering their literature aqueous solubility from 0.001 to 30 mg L(-1). Values of the aqueous solubility for less hydrophobic PAHs (naphthalene, 2-methylnaphthalene, and fluorene) were measured by an Organization for Economic Co-ordination and Development (OECD)-recommended generator column method and those for more hydrophobic PAHs (anthracene, chrysene, and benzo(a)pyrene) were measured by the passive dosing method. For phenanthrene and pyrene, both methods were used for comparison. The results obtained by the passive dosing method were very close to those obtained by the generator column method. Aqueous solubilities in deionized water for more hydrophobic PAHs obtained using the passive dosing method agreed very well with values reported in the literature, suggesting the utility of the passive dosing method for the determination of aqueous solubility for highly hydrophobic chemicals. Because hydrophobic chemicals are often introduced in aqueous solutions by using a cosolvent, the solubility enhancement for PAHs at low cosolvent volume fractions was also evaluated. Three cosolvents (dimethyl sulfoxide, ethanol, and acetone) were chosen and their volume fractions in water were between 0.2% and 2%. The enhancement of the aqueous solubility could be well explained quantitatively by using a log-linear cosolvency model. The measured values of cosolvency power at the range of volume fraction investigated (σ(0.02)) correlated very well with log K(ow) of the PAHs. The combination of the log-linear model and semiempirical relationships between σ(0.02) and log K(ow) would be useful for the prediction of the solubility enhancement of hydrophobic chemicals.


From vulnerable plaque to vulnerable patient--Part III: Executive summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force report.
Screening for early-stage asymptomatic cancers (eg, cancers of breast and colon) to prevent late-stage malignancies has been widely accepted. However, although atherosclerotic cardiovascular disease (eg, heart attack and stroke) accounts for more death and disability than all cancers combined, there are no national screening guidelines for asymptomatic (subclinical) atherosclerosis, and there is no government- or healthcare-sponsored reimbursement for atherosclerosis screening. Part I and Part II of this consensus statement elaborated on new discoveries in the field of atherosclerosis that led to the concept of the "vulnerable patient." These landmark discoveries, along with new diagnostic and therapeutic options, have set the stage for the next step: translation of this knowledge into a new practice of preventive cardiology. The identification and treatment of the vulnerable patient are the focuses of this consensus statement. In this report, the Screening for Heart Attack Prevention and Education (SHAPE) Task Force presents a new practice guideline for cardiovascular screening in the asymptomatic at-risk population. In summary, the SHAPE Guideline calls for noninvasive screening of all asymptomatic men 45-75 years of age and asymptomatic women 55-75 years of age (except those defined as very low risk) to detect and treat those with subclinical atherosclerosis. A variety of screening tests are available, and the cost-effectiveness of their use in a comprehensive strategy must be validated. Some of these screening tests, such as measurement of coronary artery calcification by computed tomography scanning and carotid artery intima-media thickness and plaque by ultrasonography, have been available longer than others and are capable of providing direct evidence for the presence and extent of atherosclerosis. Both of these imaging methods provide prognostic information of proven value regarding the future risk of heart attack and stroke. Careful and responsible implementation of these tests as part of a comprehensive risk assessment and reduction approach is warranted and outlined by this report. Other tests for the detection of atherosclerosis and abnormal arterial structure and function, such as magnetic resonance imaging of the great arteries, studies of small and large artery stiffness, and assessment of systemic endothelial dysfunction, are emerging and must be further validated. The screening results (severity of subclinical arterial disease) combined with risk factor assessment are used for risk stratification to identify the vulnerable patient and initiate appropriate therapy. The higher the risk, the more vulnerable an individual is to a near-term adverse event. Because <10% of the population who test positive for atherosclerosis will experience a near-term event, additional risk stratification based on reliable markers of disease activity is needed and is expected to further focus the search for the vulnerable patient in the future. All individuals with asymptomatic atherosclerosis should be counseled and treated to prevent progression to overt clinical disease. The aggressiveness of the treatment should be proportional to the level of risk. Individuals with no evidence of subclinical disease may be reassured of the low risk of a future near-term event, yet encouraged to adhere to a healthy lifestyle and maintain appropriate risk factor levels. Early heart attack care education is urged for all individuals with a positive test for atherosclerosis. The SHAPE Task Force reinforces existing guidelines for the screening and treatment of risk factors in younger populations. Cardiovascular healthcare professionals and policymakers are urged to adopt the SHAPE proposal and its attendant cost-effectiveness as a new strategy to contain the epidemic of atherosclerotic cardiovascular disease and the rising cost of therapies associated with this epidemic.


Translating Prevention Research for Evidence-Based Policymaking: Results from the Research-to-Policy Collaboration Pilot.
The importance of basing public policy on sound scientific evidence is increasingly being recognized, yet many barriers continue to slow the translation of prevention research into legislative action. This work reports on the feasibility of a model for overcoming these barriers-known as the Research-to-Policy Collaboration (RPC). The RPC employs strategic legislative needs assessments and a rapid response researcher network to accelerate the translation of research findings into usable knowledge for policymakers. Evaluation findings revealed that this model can successfully mobilize prevention scientists, engage legislative offices, connect policymakers and experts in prevention, and elicit congressional requests for evidence on effective prevention strategies. On average, the RPC model costs $3510 to implement per legislative office. The RPC can elicit requests for evidence at an average cost of $444 per request. The implications of this work, opportunities for optimizing project elements, and plans for future work are discussed. Ultimately, this project signals that the use of scientific knowledge of prevention in policymaking can be greatly augmented through strategic investment in translational efforts.


Identifying Critical Points of Trajectories of Depressive Symptoms from Childhood to Young Adulthood.
Depression is a common mental illness and research has focused on late childhood and adolescence in an attempt to prevent or reduce later psychopathology and/or social impairments. It is important to establish and study population-averaged trajectories of depressive symptoms across adolescence as this could characterise specific changes in populations and help identify critical points to intervene with treatment. Multilevel growth-curve models were used to explore adolescent trajectories of depressive symptoms in 9301 individuals (57% female) from the Avon Longitudinal Study of Parents and Children, a UK based pregnancy cohort. Trajectories of depressive symptoms were constructed for males and females using the short mood and feelings questionnaire over 8 occasions, between 10 and 22 years old. Critical points of development such as age of peak velocity for depressive symptoms (the age at which depressive symptoms increase most rapidly) and the age of maximum depressive symptoms were also derived. The results suggested that from similar initial levels of depressive symptoms at age 11, females on average experienced steeper increases in depressive symptoms than males over their teenage and adolescent years until around the age of 20 when levels of depressive symptoms plateaued and started to decrease for both sexes. Females on average also had an earlier age of peak velocity of depressive symptoms that occurred at 13.5 years, compared to males who on average had an age of peak velocity at 16 years old. Evidence was less clear for a difference between the ages of maximum depressive symptoms which were on average 19.6 years for females and 20.4 for males. Identifying critical periods for different population subgroups may provide useful knowledge for treating and preventing depression and could be tailored to be time specific for certain groups. Possible explanations and recommendations are discussed.


Values and preferences for oral antithrombotic therapy in patients with atrial fibrillation: physician and patient perspectives.
Exploration of values and preferences in the context of anticoagulation therapy for atrial fibrillation (AF) remains limited. To better characterize the distribution of patient and physician values and preferences relevant to decisions regarding anticoagulation in patients with AF, we conducted interviews with patients at risk of developing AF and physicians who manage patients with AF. We interviewed 96 outpatients and 96 physicians in a multicenter study and elicited the maximal increased risk of bleeding (threshold risk) that respondents would tolerate with warfarin vs. aspirin to achieve a reduction in three strokes in 100 patients over a 2-year period. We used the probabilistic version of the threshold technique. The median threshold risk for both patients and physicians was 10 additional bleeds (10 P = 0.7). In both groups, we observed large variability in the threshold number of bleeds, with wider variability in patients than clinicians [patient range: 0-100, physician range: 0-50]. We observed one cluster of patients and physicians who would tolerate <10 bleeds and another cluster of patients, but not physicians, who would accept more than 35. Our findings suggest wide variability in patient and physician values and preferences regarding the trade-off between strokes and bleeds. Results suggest that in individual decision making, physician and patient values and preferences will often be discordant; this mandates tailoring treatment to the individual patient's preferences.


Atrial fibrillation in endurance-trained athletes.
Endurance exercise training produces multiple cardiac adaptations including changes in electrophysiological function that may make endurance-trained athletes more vulnerable to atrial fibrillation (AF). This possible association is not recognised by many practising cardiologists and sports physicians. Consequently, we performed a literature review to examine the relationship between atrial fibrillation and endurance exercise training among athletes. PubMed was searched from January 1960 through December 2008 to identify articles examining the relationship between endurance exercise training and AF. Evidence suggests that athletes are at increased risk for development of AF. Possible factors increasing AF in this population include increased parasympathetic tone, reduced sympathetic tone, increased atrial size and increased inflammation. Suggested management of AF in athletes should follow similar principles to those used to manage AF in the general population.


Electronic structure of M(BH4)4, M = Zr, Hf, and U, by variable photon-energy photoelectron spectroscopy and density functional calculations.
Photoelectron (PE) spectra have been obtained for the M(BH(4))(4) (M = Zr, Hf and U) molecules in the 20-60 eV photon-energy range, and for M = U, also in the 90-120 eV region. Derived branching ratios (BR) and relative partial-photoionization cross sections (RPPICS) of the valence bands are used to confirm band assignment and demonstrate d-orbital covalency for all three compounds and f-orbital covalency for U(BH(4))(4). Core ionizations are identified and used to confirm resonance features in the RPPICS. The absorption spectrum of Zr(BH(4))(4) between 20 and 60 eV shows 4p absorption at 35.5 eV, coincident with the 4p-4d resonance in the RPPICS of the 1e and 2t(2) ionization bands of Zr(BH(4))(4). Less intense absorption bands at 32.5 and 33.8 eV correspond with shape resonance features in the 1a(1) and 1t(2) PE bands. The RPPICS of the f band of U(BH(4))(4) shows two strong resonant features between 95 and 120 eV. Direct photoemission of the 5f electrons from U(BH(4))(4) results only in the observation of the (2)F(5/2) ion state of [U(BH(4))(4)](+), but in the 5d-5f resonant region, a weak band corresponding to the (2)F(7/2) ion state is also observed. The splitting of the 1t(2) band of U(BH(4))(4) is attributed to a small contribution of U 6p semi-core electrons to this MO. Density functional calculations give a good estimate of the pattern of ionization energies, although the calculated absolute values are lower than the experimental values, the first IE by 0.5 eV for Zr(BH(4))(4) and Hf(BH(4))(4) and 1.0 eV for U(BH(4))(4). The MO compositions are in very good agreement with the deductions made from the BR and RPPICS analyses.


The first single responders in Sweden - Evaluation of a pre-hospital single staffed unit.
Single responder (SR) systems have been implemented in several countries. When the very first SR system in Sweden was planned, it was criticised because of concerns about sending single emergency nurses out on alerts. In the present study, the first Swedish SR unit was studied in order to register waiting times and assess the working environment. Quantitative data were collected from the ambulance dispatch register. Data on the working environment were collected using a questionnaire sent to the SR staff. The SR system reduced the average patient waiting time from 26 to 13min. It also reduced the number of ambulance transports by 35% following triage of patient(s) priority determined by the SR. The staff perceived the working environment to be adequate. The SR unit was successful in that it reduced waiting times to prehospital health care. Contrary to expectations, it proved to be an adequate working environment. There is good reason to believe that SR systems will spread throughout the country. In order to enhance in depth the statistical analysis, additional should be collected over a longer time period and from more than one SR unit.


Effect of provincial spending on social services and health care on health outcomes in Canada: an observational longitudinal study.
Escalating health care spending is a concern in Western countries, given the lack of evidence of a direct connection between spending and improvements in health. We aimed to determine the association between spending on health care and social programs and health outcomes in Canada. We used retrospective data from Canadian provincial expenditure reports, for the period 1981 to 2011, to model the effects of social and health spending (as a ratio, social/health) on potentially avoidable mortality, infant mortality and life expectancy. We used linear regressions, accounting for provincial fixed effects and time, and controlling for confounding variables at the provincial level. A 1-cent increase in social spending per dollar spent on health was associated with a 0.1% (95% confidence interval [CI] 0.04% to 0.16%) decrease in potentially avoidable mortality and a 0.01% (95% CI 0.01% to 0.02%) increase in life expectancy. The ratio had a statistically nonsignificant relationship with infant mortality (p = 0.2). Population-level health outcomes could benefit from a reallocation of government dollars from health to social spending, even if total government spending were left unchanged. This result is consistent with other findings from Canada and the United States.


The Anti-Cancer Effect of Quercetin: Molecular Implications in Cancer Metabolism.
Cancer is a problem with worldwide importance and is the second leading cause of death globally. Cancer cells reprogram their metabolism to support their uncontrolled expansion by increasing biomass (anabolic metabolism-glycolysis) at the expense of their energy (bioenergetics- mitochondrial function) requirements. In this aspect, metabolic reprogramming stands out as a key biological process in understanding the conversion of a normal cell into a neoplastic precursor. Quercetin is the major representative of the flavonoid subclass of flavonols. Quercetin is ubiquitously present in fruits and vegetables, being one of the most common dietary flavonols in the western diet. The anti-cancer effects of quercetin include its ability to promote the loss of cell viability, apoptosis and autophagy through the modulation of PI3K/Akt/mTOR, Wnt/-catenin, and MAPK/ERK1/2 pathways. In this review, we discuss the role of quercetin in cancer metabolism, addressing specifically its ability to target molecular pathways involved in glucose metabolism and mitochondrial function.


Prevalence and diagnostic spectrum of generalized retinal dystrophy in Danish children.
The aim of the present population-based cross-sectional study was to examine the prevalence and diagnostic spectrum of generalized retinal dystrophy in Danish children. The Danish Registry for the Blind and Partially Sighted Children comprises all visually impaired children residing in Denmark aged 0-17 years. Among registered children, the primary diagnosis of generalized retinal dystrophy was assessed by chart review, including fundus photographs and electroretinograms. Age-specific data for live children in Denmark were retrieved from Statistics Denmark. Of the 1,204,235 Danish children aged 0-17 years on 1 October 2011, 2017 children were registered as visually impaired. Of these, 153 cases were attributed to generalized retinal dystrophy, corresponding to a prevalence of 13 per 100,000 children. The age-specific prevalence increased prominently with increasing age. In 43% of the children the eye condition was part of a syndrome, while the remaining 57% had eye disease only. The most common hereditary pattern was autosomal recessive (99 children, 66%). This epidemiological survey demonstrates that the prevalence of generalized retinal dystrophy in Danish children is 13 per 100,000, which is a considerable increase compared to the 9.8 per 100,000 reported by Rosenberg in 1988. The prevalence of Leber congenital amaurosis, Usher syndrome, and Bardet-Biedl syndrome doubled, which may be explained by a documented history of consanguinity in more than one third of the children. Many of the dystrophies are the subject of clinical intervention trials, and nation-wide epidemiological data can help assess the future need for treatment.


Disruption of the actin network enhances MAP-2c and Fyn-induced process outgrowth.
We investigated the interaction of MAP-2c and Fyn in the initiation of process outgrowth in COS7 cells. Single transfections of Fyn and MAP-2c resulted in a dramatic decrease in flat, rounded COS7 cells, and a significant increase in both the number of cells with multiple short, spike-like processes, and cells with longer processes. Co-transfection of Fyn and MAP-2c resulted in an additive increase in the number of cells with more than two processes and discrete sites of co-localization within processes. When single or double transfected cells were treated with cytochalasin D or lantrunculin there was a dramatic increase in the number of cells with more than two processes. In addition, there was an increase in the length of the processes, both in single and double transfected cells, suggesting that the actin meshwork provides a barrier for MT-based process extension. When co-transfected cells were post-treated with nocodazole, Fyn was not associated with MAP-2c and acetylated, stable tubulin. Although some Fyn/MAP-2c co-localization was retained, punctate staining of MAP-2c and Fyn were observed at the cell periphery, in areas devoid of stable MTs. Mutations in either tyrosine 67 (Tyr67), a site on human MAP-2c phosphorylated by Fyn, or a second tyrosine residue (Tyr50), did not alter the ability of MAP-2c and Fyn to induce process outgrowth. These studies suggest that independent of one another MAP-2c and Fyn are able to induce process outgrowth and in concert can initiate and enhance process outgrowth in an additive manner.


Influence of optic disc size on the diagnostic performance of macular ganglion cell complex and peripapillary retinal nerve fiber layer analyses in glaucoma.
To evaluate the influence of optic disc size on the diagnostic accuracy of macular ganglion cell complex (GCC) and conventional peripapillary retinal nerve fiber layer (pRNFL) analyses provided by spectral domain optical coherence tomography (SD-OCT) in glaucoma. Eighty-two glaucoma patients and 30 healthy subjects were included. All patients underwent GCC (7 × 7 mm macular grid, consisting of RNFL, ganglion cell and inner plexiform layers) and pRNFL thickness measurement (3.45 mm circular scan) by SD-OCT. One eye was randomly selected for analysis. Initially, receiver operating characteristic (ROC) curves were generated for different GCC and pRNFL parameters. The effect of disc area on the diagnostic accuracy of these parameters was evaluated using a logistic ROC regression model. Subsequently, 1.5, 2.0, and 2.5 mm(2) disc sizes were arbitrarily chosen (based on data distribution) and the predicted areas under the ROC curves (AUCs) and sensitivities were compared at fixed specificities for each. Average mean deviation index for glaucomatous eyes was -5.3 ± 5.2 dB. Similar AUCs were found for the best pRNFL (average thickness = 0.872) and GCC parameters (average thickness = 0.824; P = 0.19). The coefficient representing disc area in the ROC regression model was not statistically significant for average pRNFL thickness (-0.176) or average GCC thickness (0.088; P ≥ 0.56). AUCs for fixed disc areas (1.5, 2.0, and 2.5 mm(2)) were 0.904, 0.891, and 0.875 for average pRNFL thickness and 0.834, 0.842, and 0.851 for average GCC thickness, respectively. The highest sensitivities - at 80% specificity for average pRNFL (84.5%) and GCC thicknesses (74.5%) - were found with disc sizes fixed at 1.5 mm(2) and 2.5 mm(2). Diagnostic accuracy was similar between pRNFL and GCC thickness parameters. Although not statistically significant, there was a trend for a better diagnostic accuracy of pRNFL thickness measurement in cases of smaller discs. For GCC analysis, an inverse effect was observed.


Improved urethral fluorescence during low rectal surgery: a new dye and a new method.
The aim of this study was to demonstrate highlighting of the urethra during surgery through the use of two different methods: a new near-infrared fluorophore IRDye800BK, and indocyanine green (ICG) mixed with silicone. Male cadavers from the department of anatomy at the University of Oxford were used to visualise the urethra during near-infrared fluorescence excitation. To assess IRDye800BK, a perineal incision was utilised after infiltrating the urethra directly with an IRDye800BK solution mixed with Instillagel. ICG-silicone was assessed when the urethra was purposely exposed as part of a simulated transanal total mesorectal dissection. ICG was previously mixed with ethanol and silicone and left to set in a Foley catheter. Fluorescence was visualised using an in-house manufactured fluorescence-enabled laparoscopic system. IRDye800BK demonstrated excellent penetration and visualisation of the urethra under fluorescence at an estimated tissue depth of 2 cm. An ICG-silicone catheter demonstrated excellent fluorescence without leaving any residual solution behind in the urethra after its removal. The newly described ICG-silicone method opens up the possibility of new technologies in this area of fluorescence guided surgery. IRDye800BK is a promising alternative to ICG in visualising the urethra using fluorescence imaging. Its greater depth of penetration may allow earlier detection of the urethra during surgery and prevent wrong plane surgery sooner.


Relationship between generalized and upper body obesity to insulin resistance in Asian Indian men.
It has been proposed that excessive insulin resistance in Asian Indians living in urban areas or migrated to western countries is responsible for the higher incidence of type 2 diabetes and coronary heart disease observed in this population. To evaluate whether Asian Indians are more insulin resistant than Caucasians and to define the role of generalized and truncal adiposity, we performed hydrodensitometry, skinfold measurements, and euglycemic-hyperinsulinemic clamps in 21 healthy Asian Indian men and 23 Caucasian men of similar age and body fat content. The glucose disposal rate (Rd) was significantly lower in the Asian Indians than in the Caucasians (3.7+/-1.3 vs. 5.3+/-2.0 mg/min x kg lean body mass, respectively; P = 0.003). Despite similar total body fat content, Asian Indians had higher truncal adiposity than Caucasians (sum of truncal skinfolds, 117+/-37 and 92.4+/-38 mm, respectively). In both Asian Indians and Caucasians, the insulin sensitivity index (Rd/plasma insulin concentrations) was inversely correlated with both total body fat (r = -0.49; P<0.03 and r = -0.67; P<0.001, respectively) and sum of truncal skinfold thickness (r = -0.55; P<0.001 and r = -0.61; P<0.002, respectively). After adjustment for total body fat and truncal skinfold thickness, Asian Indians still had a significantly lower glucose disposal rate (P = 0.04). These results show that Asian Indian men are more insulin resistant than Caucasian men independently of generalized or truncal adiposity. The excessive insulin resistance in Asian Indians is probably a primary metabolic defect and may account for the excessive morbidity and mortality from diabetes and coronary heart disease in this population.


Relation between gastric cancer and previous peptic ulcer disease.
It is presently not well understood to what extent peptic ulcer and gastric cancer represent related diseases. The objective of this study was to assess past occurrence of gastric and duodenal ulcers in patients with cancer of the gastric cardia or other parts of the stomach. The association between peptic ulcer and gastric cancer was studied among patients followed up at hospitals of the US Department of Veterans Affairs. Two populations of 1069 subjects with cancer of the cardia and 3078 subjects with cancer of other parts of the stomach were compared with a control population of 89082 subjects without gastric cancer. In multivariate logistic regressions, presence or absence of cancer served as the outcome variable, while age, sex, race, previous histories of gastric ulcer, duodenal ulcer, peptic ulcer site unspecified, gastric resection, or vagotomy served as modifier variables. Old age, non-white ethnicity, and male sex proved strong and independent risk factors for non-cardiac gastric cancer. A previous history of gastric, but not duodenal ulcer was associated with a significantly raised odd ratio of 1.53 (95% confidence interval: 1.24 to 1.87). Cancer of the cardia affected predominantly whites, and was relatively more common in men than non-cardiac gastric cancer. Past gastric ulcers exerted no significant influence (1.02, 0.67 to 1.56), while duodenal ulcers and peptic ulcer site unspecified were protective (duodenal ulcer: 0.68, 0.47 to 0.95; peptic ulcer disease: 0.66, 0.47 to 1.00). Partial gastrectomy was a risk factor for non-cardiac gastric cancer (1.86, 1.32 to 2.63), but not for cancer of the cardia (1.09, 0.54 to 2.20). These epidemiological patterns might stem from underlying differences in the influences of gastritis and acid secretion on the development of the two cancer types.


Abnormal inhibition of return in mild cognitive impairment: is it specific to the presence of prodromal dementia?
Although there is some evidence that amnestic mild cognitive impairment (aMCI) can be characterized by significant deficits in visuospatial function, the cross-sectional design of the majority of these studies renders it impossible to determine whether such deficits occur in aMCI as a result of, or accompany, amnestic dysfunction per se or whether they are the result of disproportionately poorer performance in a sub-group of patients for whom aMCI represents prodromal dementia. Similarly, whether the absence of aMCI-related functional deficit stems from the masking of dementia-specific abnormality by the preserved performance of those with a different cause of aMCI cannot be ascertained. Here we report the outcome of a cross-sectional and 2.5-year longitudinal evaluation follow-up, computer-based study of visuospatial attention, specifically attentional disengagement and inhibition of return and the mean (RTSPEED) and intra-individual variability (IIVRT) of their component reaction times, in 45 patients with aMCI and 31 cognitively healthy older adults. Reduced inhibition of return (p = 0.01 and p = 0.037 in response to 400 and 800 ms cue to target interval conditions), slowed RTSPEED (p = 0.038 and p = 0.03 in response to 400 and 800 ms cue), and raised IIVRT at baseline testing (p = 0.003, p = 0.026, p = 0.013 in response to 200, 400 and 800 ms cue) were associated with the development of dementia within the 2.5-year follow-up period, whereas the performance of patients with aMCI who did not develop dementia did not differ significantly from that of the cognitively healthy controls. Attentional disengagement appeared insensitive to the presence of prodromal dementia or amnestic dysfunction per se. The results indicate that those patients for whom aMCI represents prodromal dementia may experience, in addition to amnestic dysfunction, a decline in the functional integrity of some fundamental aspects of visual information processing, an effect potentially capable of increasing disease burden and reducing quality of life.


Prognostic Value of Stress Dynamic Myocardial Perfusion CT in a Multicenter Population With Known or Suspected Coronary Artery Disease.
The purpose of this study was to determine the prognostic value of myocardial perfusion CT for major adverse cardiac events (MACE). Data from six centers in Asia, Europe, and North America on 144 patients with known or suspected coronary artery disease who had undergone coronary CT angiography (CCTA) and dynamic myocardial perfusion CT with a dual-source CT system were analyzed. CCTA studies were acquired at rest. Dynamic myocardial perfusion CT was performed under vasodilator stress. CCTA data were evaluated for the presence of coronary artery stenosis (≥ 50% luminal narrowing) on a per-vessel basis. Myocardial perfusion CT data were qualitatively evaluated for perfusion defects in each vessel territory. Patient follow-up was performed 6, 12, and 18 months after imaging. The prognostic value of CT findings was assessed with Kaplan-Meier statistics and the multivariate Cox proportional hazards regression model. According to the CCTA findings, 62 of 144 patients (43.1%) had at least one 50% or greater stenosis. According to the myocardial perfusion CT findings, 51 patients (35.4%) had one or more perfusion defects. Patients with at least one perfusion defect at myocardial perfusion CT were at increased risk of MACE (hazard ratio, 2.50; 95% CI, 1.34-4.65; p = 0.0040). This association remained significant after adjustment for age, sex, and clinical risk factors (hazard ratio, 2.41; 95% CI, 1.28-4.51; p = 0.0064) and after further adjustment for CCTA findings (hazard ratio, 2.03; 95% CI, 1.04-3.97; p = 0.0390). The number of territories with perfusion defects was strongly predictive of MACE with adjusted hazard ratios of 1.41, 3.44, and 4.76 for one, two, and three affected territories. In assessment for future MACE, myocardial perfusion CT has incremental predictive value over clinical risk factors and detection of coronary artery stenosis with CCTA.


Mediterranean diet for type 2 diabetes: cardiometabolic benefits.
Dietary patterns influence various cardiometabolic risk factors, including body weight, lipoprotein concentrations, and function, blood pressure, glucose-insulin homeostasis, oxidative stress, inflammation, and endothelial health. The Mediterranean diet can be described as a dietary pattern characterized by the high consumption of plant-based foods, olive oil as the main source of fat, low-to-moderate consumption of fish, dairy products and poultry, low consumption of red and processed meat, and low-to-moderate consumption of wine with meals. The American Diabetes Association and the American Heart Association recommend Mediterranean diet for improving glycemic control and cardiovascular risk factors in type 2 diabetes. Prospective studies show that higher adherence to the Mediterranean diet is associated with a 20-23 % reduced risk of developing type 2 diabetes, while the results of randomized controlled trials show that Mediterranean diet reduces glycosylated hemoglobin levels by 0.30-0.47 %, and is also associated with a 28-30 % reduced risk for cardiovascular events. The mechanisms by which Mediterranean diet produces its cardiometabolic benefits in type 2 diabetes are, for the most, anti-inflammatory and antioxidative: increased consumption of high-quality foods may cool down the activation of the innate immune system, by reducing the production of proinflammatory cytokines while increasing that of anti-inflammatory cytokines. This may favor the generation of an anti-inflammatory milieu, which in turn may improve insulin sensitivity in the peripheral tissues and endothelial function at the vascular level and ultimately act as a barrier to the metabolic syndrome, type 2 diabetes and development of atherosclerosis.


An evaluation of a self-management package for people with diabetes at risk of chronic kidney disease.
The overall purpose was to develop, test and evaluate an educational package to help people with diabetes self-manage their risk of developing chronic kidney disease (CKD), one of the main complications of diabetes. Management of people in primary care who have both CKD and diabetes can be controlled by strict blood pressure (BP) and blood sugar control and advice on lifestyle changes, such as smoking cessation. However, there is little evidence to support the assertion that self-management can slow the rate of kidney disease progression. A mixed-method longitudinal study. Development of the self-management package was informed by the findings of a case study in six GP Practices and also through interviews with 15 patients. Testing of the self-management package was undertaken in the same six Practices, with one additional control Practice. Patients with Type 1 or Type 2 diabetes at risk of kidney disease were included. Outcomes in patients in the participating surgeries who did receive a pack (n = 116) were compared with patients in the control group (n = 60) over 6 time points. At the end of the study (time point 6), the intervention group had a mean systolic BP of 4.1 mmHg lower and mean diastolic BP of 2.7 mmHg lower than in the control group. Self-management techniques such as understanding of, and subsequent concordance with, prescribed BP medication may contribute to a reduction in BP, which in turn will reduce cardiovascular risk. This study contributes to the evidence base for self-management of early kidney disease. Although the exact reason for reduced BP in the intervention group is unclear, the importance of practitioner understanding of kidney disease management and patient understanding of BP medication are likely to be the contributing factors.


Do accurate HIV and antiretroviral therapy knowledge, and previous testing experiences increase the uptake of HIV voluntary counselling and testing? Results from a cohort study in rural Tanzania.
Despite the introduction of free antiretroviral therapy (ART), the use of voluntary counselling and testing (VCT) services remains persistently low in many African countries. This study investigates how prior experience of HIV and VCT, and knowledge about HIV and ART influence VCT use in rural Tanzania. In 2006-7, VCT was offered to study participants during the fifth survey round of an HIV community cohort study that includes HIV testing for research purposes without results disclosure, and a questionnaire covering knowledge, attitudes and practices around HIV infection and HIV services. Categorical variables were created for HIV knowledge and ART knowledge, with "good" HIV and ART knowledge defined as correctly answering at least 4/6 and 5/7 questions about HIV and ART respectively. Experience of HIV was defined as knowing people living with HIV, or having died from AIDS. Logistic regression methods were used to assess how HIV and ART knowledge, and prior experiences of HIV and VCT were associated with VCT uptake, with adjustment for HIV status and socio-demographic confounders. 2,695/3,886 (69%) men and 2,708/5,575 women (49%) had "good" HIV knowledge, while 613/3,886 (16%) men and 585/5575 (10%) women had "good" ART knowledge. Misconceptions about HIV transmission were common, including through kissing (55% of women, 43% of men), or mosquito bites (42% of women, 34% of men).19% of men and 16% of women used VCT during the survey. After controlling for HIV status and socio-demographic factors, the odds of VCT use were lower among those with poor HIV knowledge (aOR = 0.5; p = 0.01 for men and aOR = 0.6; p < 0.01 for women) and poor ART knowledge (aOR = 0.8; p = 0.06 for men, aOR = 0.8; p < 0.01 for women), and higher among those with HIV experience (aOR = 1.3 for men and aOR = 1.6 for women, p < 0.01) and positive prior VCT experience (aOR = 2.0 for all men and aOR = 2.0 for HIV-negative women only, p < 0.001). Two years after the introduction of free ART in this setting, misconceptions regarding HIV transmission remain rife and knowledge regarding treatment is worryingly poor, especially among women and HIV-positive people. Further HIV-related information, education and communication activities are urgently needed to improve VCT uptake in rural Tanzania.


Scaling theory for information networks.
Networks distribute energy, materials and information to the components of a variety of natural and human-engineered systems, including organisms, brains, the Internet and microprocessors. Distribution networks enable the integrated and coordinated functioning of these systems, and they also constrain their design. The similar hierarchical branching networks observed in organisms and microprocessors are striking, given that the structure of organisms has evolved via natural selection, while microprocessors are designed by engineers. Metabolic scaling theory (MST) shows that the rate at which networks deliver energy to an organism is proportional to its mass raised to the 3/4 power. We show that computational systems are also characterized by nonlinear network scaling and use MST principles to characterize how information networks scale, focusing on how MST predicts properties of clock distribution networks in microprocessors. The MST equations are modified to account for variation in the size and density of transistors and terminal wires in microprocessors. Based on the scaling of the clock distribution network, we predict a set of trade-offs and performance properties that scale with chip size and the number of transistors. However, there are systematic deviations between power requirements on microprocessors and predictions derived directly from MST. These deviations are addressed by augmenting the model to account for decentralized flow in some microprocessor networks (e.g. in logic networks). More generally, we hypothesize a set of constraints between the size, power and performance of networked information systems including transistors on chips, hosts on the Internet and neurons in the brain.


CDC-42 and RAC-1 regulate opposite chemotropisms in Neurospora crassa.
Cell polarization and fusion are crucial developmental processes that occur in response to intracellular and extracellular signals. Asexual spores (conidia) of the mold Neurospora crassa differentiate two types of polarized cell protrusions, germ tubes and conidial anastomosis tubes (CATs), which exhibit negative and positive chemotropism, respectively. We provide the first evidence that shared and separate functions of the Rho-type GTPases CDC-42 and RAC-1 regulate these opposite chemotropisms. We demonstrate that RAC-1 is essential for CAT formation and cell fusion, whereas CDC-42 is necessary and sufficient for normal germ tube development. Cdc42-Rac-interactive-binding (CRIB) reporters were constructed to exclusively label locally activated GTP-bound GTPases. Time course analyses showed that repositioning of these activated GTPase clusters within germ tube and CAT tip apices controls directional growth in the absence of a tip-localized vesicle supply center (Spitzenkörper). We propose a model in which the local assembly of a plasma-membrane-associated GTPase-PAK-MAPK signaling platform regulates chemoattractant perception and secretion in order to synchronize oscillatory cell-cell communication and directional CAT tip growth.


Drug-resistance mechanisms of three mutations in anaplastic lymphoma kinase against two inhibitors based on MM/PBSA combined with interaction entropy.
As a promising drug target in the treatment of lung cancer, anaplastic lymphoma kinase (ALK) and its mutations have been studied widely through the development of multiple generations of inhibitors. Experiments have found that compared with the wild-type, the L1198F and C1156Y/L1198F mutations resulted in resistance to 5P8 inhibitors, and the C1156Y mutation resulted in resistance to VGH inhibitors. In this study, the newly developed interaction entropy (IE) method combined with the polarized protein-specific charge (PPC) force field was utilized to explore the origin of the resistance mechanism of the ALK mutant system. The calculated binding free energy was consistent with the experimental results. Per-residue binding free energy decomposition showed that the predicted hot-spot residues (LEU1122, LEU/PHE1198, MET1199, GLY1202 and LEU1256) were almost identical across systems. Especially, the GLU1197 residue played an important role in inducing drug-resistance for both inhibitors. The electrostatic interaction of GLU1197, PHE1198 and MET1199 mainly resulted in the resistances of the L1198F and C1156Y/L1198F mutations to 5P8. And the van der Waals interaction energy of LEU1256 residue, and electrostatic energy and entropy change of GLU1197 resulted in the resistances of the C1156Y mutations to VGH. The indicated origins of the drug-resistance in the ALK systems provide a theoretical foundation for the design of potent inhibitors.


Identification of a thyroxine-containing self-epitope of thyroglobulin which triggers thyroid autoreactive T cells.
Although thyroglobulin (Tg), the thyroid prohormone, is well known as a T cell dependent autoantigen in human and experimental autoimmune thyroid disease, very little is known about the molecular basis of Tg recognition by T cells. In this paper, we have characterized the epitopes recognized by two clonotypically distinct, murine Tg autoreactive T cell hybridomas, CH9 and ADA2. In vitro iodination of a Tg preparation which was deficient in in vivo organified iodine was first used to confirm our previous observation that these T cells recognize iodination-related epitopes in the Tg molecule. Affinity chromatography of tryptic peptides derived from normally iodinated human Tg revealed that these epitopes were exclusively located in thyroxine (T4) containing peptides. Through the use of synthetic T4-containing peptides, representing the four major hormonogenic sites in Tg, we demonstrated that both CH9 and ADA2 recognize an epitope containing the T4 at position 2553 in human Tg. Sets of overlapping 5mer to 12mer peptides around this T4 showed that the most potent peptide was a 9mer beginning at Asp 2551. The T4 was shown to be a critical residue, since its replacement with any of the 20 naturally occurring amino acids produced only nonstimulatory peptides. Since the T cell hybridomas could also be stimulated by major histocompatibility complex class II positive (interferon-gamma-treated) thyroid epithelial cells in vitro, and their parent T cell lines can induce thyroiditis on adoptive transfer, the T4-containing Tg sequence described here is implicated as a pathogenic epitope in murine thyroid autoimmunity.


Adolescent obesity increases significantly in second and third generation U.S. immigrants: the National Longitudinal Study of Adolescent Health.
Little is known concerning obesity patterns of ethnic subpopulations in the U.S. and the effects of acculturation on these patterns. Adolescent obesity, a major public health problem, has important health, social and economic consequences for the adolescent. The National Longitudinal Study of Adolescent Health survey is unique in the size of the adolescent sample and in its ability to provide large representative samples of Anglo, African-American, Hispanic and Asian-American adolescents. A nationally representative sample of 13,783 adolescents was studied. Measurements of weight and height collected in the second wave of the survey were used to study adolescent obesity. Multivariate logit techniques were used to provide an understanding of the ethnic, age, gender and intergenerational patterns of adolescent obesity. Comparisons are presented between the NHANES III results and those from the Adolescent Health Survey. The smoothed version of the NHANES I 85th percentile cut-off was used for the measure of obesity in this paper. For the total sample, 26.5% were obese. The rates were as follows: white non-Hispanics, 24.2%; black non-Hispanics, 30.9%; all Hispanics, 30.4%; and all Asian-Americans, 20.6%. Important variations within the Hispanic and Asian-American subpopulations are presented. The Chinese (15.3%) and Filipino (18.5%) samples showed substantially lower obesity than non-Hispanic whites. All groups showed more obesity among males than among females, except for blacks (27.4% for males and 34.0% for females). Asian-American and Hispanic adolescents born in the U.S. are more than twice as likely to be obese as are first generation residents of the 50 states.