Disability levels and correlates among older mobile home dwellers, an NHATS analysis.
Although remarkably understudied, manufactured or mobile homes are the housing choice for nearly 20 million Americans and little is known about the health of older persons living in mobile homes. We sought to investigate disability levels and other health correlates among older adults living in mobile or manufactured homes compared to their counterparts living in other types of homes. We sampled non-institutional adults aged 65 years or older (n = 7609), of whom 344 lived in mobile homes, from the 2011 National Health and Aging Trends Study (NHATS). Respondents living in mobile homes (average age = 75.1 years; SD = 0.5) had lower education and income and medical insurance than older adults living in other types of community residence (average age = 77.5 years; SD = 0.2). They were more likely to smoke, have lung and heart disease, and report fair or poor general health status. Mobile home dwellers reported more difficulty or inability in performing the following activities of daily living when compared to their counterparts: stooping and kneeling (64.9% vs 60.8%, p = 0.007), walking 6 blocks (46.5% vs 41.5%, p = 0.001), walking 3 blocks (37.7% vs 33.5%, p = 0.002), and climbing up to 20 stairs (39.2% vs 34.8%, p = 0.02). Among those reporting disability, mobile home dwellers had fewer bathroom safety modifications. There is higher prevalence of chronic conditions, functional and cognitive impairment in older mobile home dwellers compared to older adults living in other types of housing.


Self-help educational booklets for the prevention of smoking relapse following smoking cessation treatment: a randomized controlled trial.
Most people who quit smoking for a short term will return to smoking again in 12 months. We tested whether self-help booklets can reduce relapse in short-term quitters after receiving behavioural and pharmacological cessation treatment. A parallel-arm, pragmatic individually randomized controlled trial. Smoking cessation clinics in England. Participants People who stopped smoking for 4 weeks after receiving cessation treatment in stop smoking clinics. Participants in the experimental group (n=703) were mailed eight booklets, each of which taught readers how to resist urges to smoke. Participants in the control group (n=704) received a leaflet currently used in practice. The primary outcome was prolonged, carbon monoxide-verified abstinence from months 4 to 12. The secondary outcomes included 7-day self-reported abstinence at 3 and 12 months. Mixed-effects logistic regression was used to estimate treatment effects and to investigate possible effect modifying variables. There were no statistically significant differences between the groups in prolonged abstinence from months 4 to 12 (36.9% versus 38.6%; odds ratio 0.93, 95% confidence interval 0.75-1.16; P=0.524). In addition, there were no significant differences between the groups in any secondary outcomes. However, people who reported knowing risky situations for relapse and using strategies to handle urges to smoke were less likely to relapse. In people who stop smoking successfully with behavioural support, a comprehensive self-help educational programme to teach people skills to identify and respond to high-risk situations for return to smoking did not reduce relapse.


Ancient Duplications and Expression Divergence in the Globin Gene Superfamily of Vertebrates: Insights from the Elephant Shark Genome and Transcriptome.
Comparative analyses of vertebrate genomes continue to uncover a surprising diversity of genes in the globin gene superfamily, some of which have very restricted phyletic distributions despite their antiquity. Genomic analysis of the globin gene repertoire of cartilaginous fish (Chondrichthyes) should be especially informative about the duplicative origins and ancestral functions of vertebrate globins, as divergence between Chondrichthyes and bony vertebrates represents the most basal split within the jawed vertebrates. Here, we report a comparative genomic analysis of the vertebrate globin gene family that includes the complete globin gene repertoire of the elephant shark (Callorhinchus milii). Using genomic sequence data from representatives of all major vertebrate classes, integrated analyses of conserved synteny and phylogenetic relationships revealed that the last common ancestor of vertebrates possessed a repertoire of at least seven globin genes: single copies of androglobin and neuroglobin, four paralogous copies of globin X, and the single-copy progenitor of the entire set of vertebrate-specific globins. Combined with expression data, the genomic inventory of elephant shark globins yielded four especially surprising findings: 1) there is no trace of the neuroglobin gene (a highly conserved gene that is present in all other jawed vertebrates that have been examined to date), 2) myoglobin is highly expressed in heart, but not in skeletal muscle (reflecting a possible ancestral condition in vertebrates with single-circuit circulatory systems), 3) elephant shark possesses two highly divergent globin X paralogs, one of which is preferentially expressed in gonads, and 4) elephant shark possesses two structurally distinct α-globin paralogs, one of which is preferentially expressed in the brain. Expression profiles of elephant shark globin genes reveal distinct specializations of function relative to orthologs in bony vertebrates and suggest hypotheses about ancestral functions of vertebrate globins.


Withdrawal of voluntary inhibition unravels the off state of the spontaneous blink generator.
Involuntary movements such as spontaneous eye blinks can be successfully inhibited at will. Little do we know how the voluntary motor circuits countermand spontaneous blinks. Do the voluntary inhibitory commands act to pause or to turn off the endogenous blink generator, or does inhibition intersect and counter the generator׳s excitatory outputs? In theory, the time taken for the system to generate an after-inhibition blink will reflect onto the form of inhibition. For instance, if voluntary commands were to turn the blink generator off then the after-blink latency would be fixed to the inhibition offset and reflect the time it takes for the generator to rebound and turn on. In this study we measured the after-blink latency from the offset of voluntary inhibition. Volunteers inhibited their blinks in response to sound tones of randomly varying durations. At the offset volunteers withdrew the inhibition and relaxed. Interestingly, the spontaneous after-blinks were fixed to the offset of the inhibition as if the generator rebounded from an off state. The after-blink latency was not related to the duration of the inhibition, and inhibiting even for a small fraction of the mean inter-blink interval generated an after-blink time-locked to the inhibition offset. Interestingly, the insertion of voluntary blinks after inhibition further altered the blink generator by delaying the spontaneous after-blinks. We propose that the inhibition of spontaneous blinks at the level of the generator allows for highly effective voluntary countermanding. Nevertheless, the withdrawal of such inhibition was strongly associated with motor excitation.


Relationship between gelatin concentrations in silk fibroin-based composite scaffolds and adhesion and proliferation of mouse embryo fibroblasts.
Porous scaffolds of silk fibroin and composite porous scaffolds with 10, 20, 30, 40, and 50% gelatin were made by the freezing-thawing method. The relationship between adhesion and proliferation rate mouse embryo fibroblast and the scaffold composition was studied by laser confocal scanning microscopy. Addition of gelatin to the scaffold structure stimulated adhesion and proliferation of mouse embryo fibroblasts; the optimal content of gelatin was 30%.


Making the case: married versus separate models of alphaherpes virus anterograde transport in axons.
Alphaherpesvirus virions infect neurons and are transported in axons for long distance spread within the host nervous system. The assembly state of newly made herpesvirus particles during anterograde transport in axons is an essential question in alphaherpesvirus biology. The structure of the particle has remained both elusive and controversial for the past two decades, with conflicting evidence from EM, immunofluorescence, and live cell imaging studies. Two opposing models have been proposed-the Married and Separate Models. Under the Married Model, infectious virions are assembled in the neuronal cell body before sorting into axons and then traffic inside a transport vesicle. Conversely, the Separate Model postulates that vesicles containing viral membrane proteins are sorted into axons independent of capsids, with final assembly of mature virions occurring at a distant egress site. Recently, a complementary series of studies employing high-resolution EM and live cell fluorescence microscopy have provided evidence consistent with the Married Model, whereas other studies offer evidence supporting the Separate Model. In this review, we compare and discuss the published data and attempt to reconcile divergent findings and interpretations as they relate to these models.


A continuous labour supply model in microsimulation: a life-cycle modelling approach with heterogeneity and uncertainty extension.
This paper advances a structural inter-temporal model of labour supply that is able to simulate the dynamics of labour supply in a continuous setting and addresses two main drawbacks of most existing models. The first limitation is the inability to incorporate individual heterogeneity as every agent is sharing the same parameters of the utility function. The second one is the strong assumption that individuals make decisions in a world of perfect certainty. Essentially, this paper offers an extension of marginal-utility-of-wealth-constant labour supply functions known as "Frisch functions" under certainty and uncertainty with homogenous and heterogeneous preferences. The lifetime models based on the fixed effect vector decomposition yield the most stable simulation results, under both certain and uncertain future wage assumptions. Due to its improved accuracy and stability, this lifetime labour supply model is particularly suitable for enhancing the performance of the life cycle simulation models, thus providing a better reference for policymaking.


Associations among body size dissatisfaction, perceived dietary control, and diet history in African American and European American women.
European American (EA) women report greater body dissatisfaction and less dietary control than do African American (AA) women. This study investigated whether ethnic differences in dieting history contributed to differences in body dissatisfaction and dietary control, or to differential changes that may occur during weight loss and regain. Eighty-nine EA and AA women underwent dual-energy X-ray absorptiometry to measure body composition and completed questionnaires to assess body dissatisfaction and dietary control before, after, and one year following, a controlled weight-loss intervention. While EA women reported a more extensive dieting history than AA women, this difference did not contribute to ethnic differences in body dissatisfaction and perceived dietary control. During weight loss, body satisfaction improved more for AA women, and during weight regain, dietary self-efficacy worsened to a greater degree for EA women. Ethnic differences in dieting history did not contribute significantly to these differential changes. Although ethnic differences in body image and dietary control are evident prior to weight loss, and some change differentially by ethnic group during weight loss and regain, differences in dieting history do not contribute significantly to ethnic differences in body image and dietary control.


Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant.
p53-germline mutations located in the core DNA-binding domain have been associated with a more dominant tumor penetrance especially for breast cancer and brain tumors. We previously reported an unusual accumulation of CNS tumors associated with a unique p53 germline mutation, Y236delta (deletion of codon 236). To test whether this tissue-specific tumor predisposition reflects a gain-of-function activity of Y236delta, we generated transgenic mice expressing Y236delta in astrocytes using the regulatory elements of the glial fibrillary acidic protein (GFAP) gene. After transplacental exposure to N-ethyl-N-nitrosourea (25 mg/kg BW) brain tumors developed in 18% (7/39) of GFAP-Y236delta transgenic p53-/- mice, while in p53+/- mice the incidence was 28% (11/40) (P>0.3). However, the mean tumor latency for GFAP-Y236delta/p53+/- mice was significantly shorter than for p53+/- mice, with 19.9 weeks vs 31.6 weeks (P=0.039), respectively. Taken together, cell specific expression of Y236delta results in an acceleration of tumor progression but does not confer a higher tumor penetrance. Conceivably, the transdominant effect of Y236delta provided a growth advantage early in the progression of neoplastic cells, since the endogenous p53 wild-type allele was lost in all brain tumors independent of the genotype. This reflects well observations from human astrocytic neoplasms with p53 mutations.


High-resolution imaging of the immunological synapse and T-cell receptor microclustering through microfabricated substrates.
T-cell activation via antigen presentation is associated with the formation of a macromolecular membrane assembly termed the immunological synapse (IS). The genesis of the IS and the onset of juxtacrine signalling is characterized by the formation of cell membrane microclusters and the organization of such into segregated microdomains. A central zone rich in T-cell receptor (TCR)-major histocompatibility complex microclusters termed the central supramolecular activation cluster (cSMAC) forms the bullseye of this structure, while the cellular interface surrounding the cSMAC is characterized by regions enriched in adhesion and co-stimulatory molecules. In vitro, the study of dynamic TCR microcluster coalescence and IS genesis in T-cell populations is hampered by cell migration within the culture system and resolution constraints resulting from lateral cell-cell contact. Here, we detail a novel system describing the fabrication of micropit arrays designed to sequester single T-cell-antigen presenting cell (APC) conjugates and promote IS formation in the horizontal imaging plane for high-resolution studies of microcluster dynamics. We subsequently use this system to describe the formation of the cSMAC in T-cell populations and to investigate the morphology of the interfacial APC membrane.


Myoelectric Control for Adaptable Biomechanical Energy Harvesting.
We have designed and tested a myoelectric controller that automatically adapts energy harvesting from the motion of leg joints to match the power available in different walking conditions. To assist muscles in performing negative mechanical work, the controller engages power generation only when estimated joint mechanical power is negative. When engaged, the controller scales its resistive torque in proportion to estimated joint torque, thereby automatically scaling electrical power generation in proportion to the available mechanical power. To produce real-time estimates of joint torque and mechanical power, the controller leverages a simple model that predicts these variables from measured muscle activity and joint angular velocity. We first tested the model using available literature data for a range of walking speeds and found that estimates of knee joint torque and power well match the corresponding literature profiles (torque R(2): 0.73-0.92; power R(2): 0.60-0.94). We then used human subject experiments to test the performance of the entire controller. Over a range of steady state walking speeds and inclines, as well as a number of non-steady state walking conditions, the myoelectric controller accurately identified when the knee generated negative mechanical power, and automatically adjusted the magnitude of electrical power generation.


A web-based team-oriented medical error communication assessment tool: development, preliminary reliability, validity, and user ratings.
Multiple-choice exams are not well suited for assessing communication skills. Standardized patient assessments are costly and patient and peer assessments are often biased. Web-based assessment using video content offers the possibility of reliable, valid, and cost-efficient means for measuring complex communication skills, including interprofessional communication. We report development of the Web-based Team-Oriented Medical Error Communication Assessment Tool, which uses videotaped cases for assessing skills in error disclosure and team communication. Steps in development included (a) defining communication behaviors, (b) creating scenarios, (c) developing scripts, (d) filming video with professional actors, and (e) writing assessment questions targeting team communication during planning and error disclosure. Using valid data from 78 participants in the intervention group, coefficient alpha estimates of internal consistency were calculated based on the Likert-scale questions and ranged from α=.79 to α=.89 for each set of 7 Likert-type discussion/planning items and from α=.70 to α=.86 for each set of 8 Likert-type disclosure items. The preliminary test-retest Pearson correlation based on the scores of the intervention group was r=.59 for discussion/planning and r=.25 for error disclosure sections, respectively. Content validity was established through reliance on empirically driven published principles of effective disclosure as well as integration of expert views across all aspects of the development process. In addition, data from 122 medicine and surgical physicians and nurses showed high ratings for video quality (4.3 of 5.0), acting (4.3), and case content (4.5). Web assessment of communication skills appears promising. Physicians and nurses across specialties respond favorably to the tool.


Rapid Naming and Phonemic Awareness in Children With Reading Disabilities and/or Specific Language Impairment: Differentiating Processes?
The objective of this study was to assess and compare the predictive values of group membership for rapid automatized naming (RAN) and phonemic awareness (PA) in Dutch school children with and without reading disabilities (RD) or specific language impairment (SLI). A composite word reading index and a formal SLI diagnosis were used to classify a total of 1,267 children aged 8 to 13 years old either as RD-only (n = 126), SLI-only (n = 21), comorbid (RD+SLI; n = 30), or typically developing (n = 1,090). RAN and PA were assessed with 4 standardized subtests. The clinical subgroups were compared to each other and contrasted with the control group. For each subgroup, results indicate substantial effect sizes of RAN and PA. However, the RD-only group seems to be more affected by poor RAN than the SLI-only group, whereas the 2 groups perform equally poorly on PA. The comorbid group was revealed as most severely impaired on all measurements. In studying RD and SLI, this research indicates that it is important to distinguish between RD-only, SLI-only, and comorbid groups. The comorbid group shows additive effects of both disorders.


Association between frequency of dairy product consumption and hypertension: a cross-sectional study in Zhejiang Province, China.
Hypertension, a well-known risk factor, contributes to millions of deaths from cardiovascular and renal diseases worldwide. However, evidence on the association between frequency of dairy product consumption and hypertension is inconsistent. The data for the present study are from the Tongxiang baseline dataset of the China Kadoorie Biobank prospective study. A total of 53,916 participants aged 30-79 years were included in the final analysis. Multivariable logistic regression was utilized to evaluate the association of dairy product consumption with hypertension, and multiple linear regression was conducted to assess the association of dairy product consumption with systolic and diastolic blood pressure. Of the 53,916 participants, 2.6% reported consuming dairy products weekly, and 44.4% had prevalent hypertension. After adjusting for socio-demographic status, lifestyle factors, BMI, waist circumference, sleep duration and snoring, when compared with participants who never consumed dairy products, the odds ratios (95% CI) for hypertension among those consuming dairy products less than once per week, and ≥ 1 time per week were 0.85 (0.77-0.95) and 0.74 (0.65-0.84), respectively. The corresponding odds ratios (95% CI) for men were 0.85 (0.71-1.02) and 0.75 (0.61-0.92), respectively (Ptrend = 0.001), and for women were 0.88 (0.76-1.01) and 0.77 (0.65-0.91), respectively. (Ptrend < 0.001). In this large epidemiological study, higher frequency of dairy product consumption is associated with significantly lower odds of hypertension among Chinese adults.


Isolation of an actin-binding protein from membranes of Dictyostelium discoideum.
We prepared a probe of radiolabeled, glutaraldehyde cross-linked filamentous actin (F-actin) to study binding of actin to membranes of Dictyostelium discoideum. The probe bound to membranes or detergent extracts of membranes with a high affinity and in a saturable manner. The binding could be reduced by boiling of either the actin probe or the membranes, or by addition of excess native F-actin, but not by addition of an equivalent amount of bovine serum albumin, to the assay. The probe labeled several proteins when used to overlay sodium dodecyl sulfate gels of Dictyostelium membranes. One of these labeled proteins was a 24,000-mol-wt protein (p24), which was soluble only in the presence of a high concentration of sodium deoxycholate (5%, wt/vol) at room temperature or above. The p24 was purified by selective detergent extraction and column chromatography. When tested in a novel two-phase binding assay, p24 bound both native monomeric actin (G-actin) and F-actin in a specific manner. In this assay, G-actin bound p24 with a submicromolar affinity.


Effect of admixed high-density polyethylene (HDPE) spheres on contraction stress and properties of experimental composites.
Additives that provide stress relief may be incorporated into dental composites to reduce contraction stress (CS). This study attempted to test the hypothesis that conventional fillers could be replaced by high-density polyethylene (HDPE) spheres in hybrid and nanofill composites to reduce CS, but with minimal effect on mechanical properties. Nanofill and hybrid composites were made from a Bis-GMA/TEGDMA resin having either all silica nanofiller or 75 wt.% strontium glass + 5 wt.% silica and replacing some of the nanofiller or the glass with 0%, 5% (hybrid only), 10% or 20 wt.% HDPE. The surface of the HDPE was either left untreated or had a reactive gas surface treatment (RGST). Contraction stress (CS) was monitored for 10 min in a tensilometer (n = 5) after light curing for 60 s at 390 mW/cm(2). Other specimens (n = 5) were light cured 40 s from two sides in a light-curing unit and aged 1 d in water before testing fracture toughness (K(Ic)), flexure strength (FS), and modulus (E). Results were analyzed by ANOVA with Tukey's multiple comparison test at p < 0.05. There was no difference between composites with RGST and untreated HDPE except for FS-10% HDPE hybrid (RGST higher). An increased level of HDPE reduced contraction stress for both types of composites. Flexure strength, modulus (hybrid only), and fracture toughness were also reduced as the concentration of HDPE increased. SEM showed evidence for HDPE debonding and plastic deformation during fracture of the hybrid composites. In conclusion, the addition of HDPE spheres reduces contraction stress in composites, either through stress relief or a reduction in elastic modulus.


The influence of Ras pathway signaling on tumor radiosensitivity.
Radiotherapy is used to treat approximately 60% of solid tumors in the US. The relative radiosensitivity of these tumors can have a significant impact upon local control. One factor that has been shown to contribute to the increased survival of tumor cells is the activation of signaling pathways in which oncogene products play a central role. The Ras oncoprotein family, comprised of H-, K-, and N-Ras are frequently activated by mutation in certain tumors such as pancreatic and non-small cell lung cancers and are activated by receptor tyrosine kinase activity in an even wider range of tumor types. The role of ras mutation and more recently Ras signaling has been an area of intense study in both radiobiology and tumor biology in general. In this review, we focus on findings from our lab and others that led to the current hypotheses relating to the role of Ras signaling in tumor radiation survival and the strategies used to block Ras activation. We will also point out new means of studying the contribution of Ras and Ras pathway components that could contribute to defining new targets for inhibition in the context of radiation therapy.


An integrative assessment of the diversity, phylogeny, distribution, and conservation of the terrestrial reptiles (Sauropsida, Squamata) of the United Arab Emirates.
In the present study we use an unprecedented database of 5,535 distributional records to infer the diversity, ecological preferences and spatial distribution of the 60 species of terrestrial reptiles of the United Arab Emirates (UAE), and use the 57 native species to test the effectiveness of the protected areas' network in conserving this unique vertebrate fauna. We infer a time-calibrated phylogeny with 146 species of squamates and 15 genes including all UAE terrestrial reptile species to determine the phylogenetic diversity (PD) and evolutionary distinctiveness (ED) of the native species and to compare it with the distribution of the hotspots of native species richness. The results of this study indicate that the sampling effort is remarkable, covering 75% of the country's territory representing nearly the entire climatic space of the UAE defined by the mean annual temperature and the total annual precipitation, as well as the multivariate climatic space defined by a principal component analysis (PCA). Species richness is highest in the northeast of the country, in a transitional area from sandy desert to the mountainous terrain of the Hajar Mountains. The highest PD of a single square cell of 10 arc-minutes grid is of 2,430 million years (my) of accumulated evolutionary history and the strong correlation between PD and species richness suggests that the raw number of species is a good surrogate to quantify the evolutionary history (i.e., PD). The species with the highest values of ED are those in families represented by only one species in the UAE. Finally, the assessment of the UAE protected areas shows that, despite their relevance in protecting the terrestrial reptiles, they do not offer adequate protection for some threatened species. Therefore, a reassessment of some of the protected areas or the creation of species specific conservation action plans are recommended in order to ensure the preservation of the unique diversity of UAE terrestrial reptiles.


Amelioration of age-related brain function decline by Bruton's tyrosine kinase inhibition.
One of the hallmarks of aging is the progressive accumulation of senescent cells in organisms, which has been proposed to be a contributing factor to age-dependent organ dysfunction. We recently reported that Bruton's tyrosine kinase (BTK) is an upstream component of the p53 responses to DNA damage. BTK binds to and phosphorylates p53 and MDM2, which results in increased p53 activity. Consistent with this, blocking BTK impairs p53-induced senescence. This suggests that sustained BTK inhibition could have an effect on organismal aging by reducing the presence of senescent cells in tissues. Here, we show that ibrutinib, a clinically approved covalent inhibitor of BTK, prolonged the maximum lifespan of a Zmpste24-/- progeroid mice, which also showed a reduction in general age-related fitness loss. Importantly, we found that certain brain functions were preserved, as seen by reduced anxiety-like behaviour and better long-term spatial memory. This was concomitant to a decrease in the expression of specific markers of senescence in the brain, which confirms a lower accumulation of senescent cells after BTK inhibition. Our data show that blocking BTK has a modest increase in lifespan in Zmpste24-/- mice and protects them from a decline in brain performance. This suggests that specific inhibitors could be used in humans to treat progeroid syndromes and prevent the age-related degeneration of organs such as the brain.


Prevalence of symptomatic knee, hand, and hip osteoarthritis in Greece. The ESORDIG study.
To assess the prevalence of symptomatic knee, hand, and hip osteoarthritis (OA) in the general adult population of Greece. This cross-sectional population based study was conducted on the total adult population of 7 communities (8547 subjects) and on 2100 out of 5686 randomly selected subjects in an additional 2 communities. Sixteen rheumatologists visited the target population at their homes; an interview based on a standardized questionnaire was conducted and clinical evaluation and laboratory investigations were done, when necessary. ACR classification criteria were used for diagnosing symptomatic OA. Of the final target population of 10,647 subjects, 8740 (82.1%) participated in the study. The age and sex adjusted prevalence of symptomatic knee, hand, and hip OA was 6.0% (95% CI 5.6-6.4), 2% (1.8-2.2), and 0.9% (0.7-1.1), respectively. Symptomatic knee, hand, and hip OA prevalence was significantly higher among women than men and increased significantly with age. Symptomatic knee OA was significantly more common in the rural compared to urban and suburban populations. Logistic regression analysis showed a significant association of female sex and age > or = 50 years with all sites of OA, of obesity with knee and hip OA, and of a low level of education with knee OA. Symptomatic knee, hand, and hip OA is common in the general adult population of Greece, showing a female preponderance and a prevalence increasing with age. Female sex and age are risk factors for all sites of OA, obesity for knee and hip OA, and a low level of education for knee OA.


Tendon transfer surgery in upper-extremity cerebral palsy is more effective than botulinum toxin injections or regular, ongoing therapy.
For children with upper-extremity cerebral palsy (CP) who meet standard indications for tendon transfer surgery, we hypothesized that surgical treatment would result in greater functional improvement than treatment with botulinum toxin injections or regular, ongoing therapy. Thirty-nine children with upper-extremity CP, who were four to sixteen years of age and surgical candidates for the transfer of the flexor carpi ulnaris to the extensor carpi radialis brevis, pronator teres release, and extensor pollicis longus rerouting with adductor pollicis release, were prospectively assigned, either randomly (twenty-nine patients) or by patient/family preference (ten patients), to one of three treatment groups: surgical treatment (Group 1); botulinum toxin injections (Group 2); or regular, ongoing therapy (Group 3). Seven centers participated. Assessment measurements included active range of motion, pinch and grip strength, stereognosis, and scores as measured with eight additional functional or patient-oriented outcome instruments. Thirty-four patients (twenty-five randomized and nine from the patient-preference arm) were evaluated twelve months post-treatment as the study cohort. For the primary outcome of the Shriners Hospital Upper Extremity Evaluation (SHUEE) dynamic positional analysis (DPA), significantly greater improvement was seen in Group 1 than in the other two groups (p < 0.001). Improvements in SHUEE DPA reflected improved supination and wrist extension during functional activities after surgical treatment. Group 1 showed more improvement in the Pediatric Quality of Life Inventory (PedsQL) CP module domain of movement and in the Canadian Occupational Performance Measure (COPM) score for satisfaction than Groups 2 and 3. Both Groups 1 and 3 showed more improvement in pinch strength than did Group 2. For children with upper-extremity CP who were candidates for standard tendon transfer, surgical treatment was demonstrated to provide greater improvement, of modest magnitude, than botulinum toxin injections or regular, ongoing therapy at twelve months of follow-up for the SHUEE DPA, the PedsQL CP module domain of movement, and COPM satisfaction.


GEF-H1 functions in apical constriction and cell intercalations and is essential for vertebrate neural tube closure.
Rho family GTPases regulate many morphogenetic processes during vertebrate development including neural tube closure. Here we report a function for GEF-H1/Lfc/ArhGEF2, a RhoA-specific guanine nucleotide exchange factor that functions in neurulation in Xenopus embryos. Morpholino-mediated depletion of GEF-H1 resulted in severe neural tube defects, which were rescued by GEF-H1 RNA. Lineage tracing of GEF-H1 morphants at different developmental stages revealed abnormal cell intercalation and apical constriction, suggesting that GEF-H1 regulates these cell behaviors. Molecular marker analysis documented defects in myosin II light chain (MLC) phosphorylation, Rab11 and F-actin accumulation in GEF-H1-depleted cells. In gain-of-function studies, overexpressed GEF-H1 induced Rho-associated kinase-dependent ectopic apical constriction - marked by apical accumulation of phosphorylated MLC, γ-tubulin and F-actin in superficial ectoderm - and stimulated apical protrusive activity of deep ectoderm cells. Taken together, our observations newly identify functions of GEF-H1 in morphogenetic movements that lead to neural tube closure.


Deep sequencing discovery of novel and conserved microRNAs in trifoliate orange (Citrus trifoliata).
MicroRNAs (miRNAs) play a critical role in post-transcriptional gene regulation and have been shown to control many genes involved in various biological and metabolic processes. There have been extensive studies to discover miRNAs and analyze their functions in model plant species, such as Arabidopsis and rice. Deep sequencing technologies have facilitated identification of species-specific or lowly expressed as well as conserved or highly expressed miRNAs in plants. In this research, we used Solexa sequencing to discover new microRNAs in trifoliate orange (Citrus trifoliata) which is an important rootstock of citrus. A total of 13,106,753 reads representing 4,876,395 distinct sequences were obtained from a short RNA library generated from small RNA extracted from C. trifoliata flower and fruit tissues. Based on sequence similarity and hairpin structure prediction, we found that 156,639 reads representing 63 sequences from 42 highly conserved miRNA families, have perfect matches to known miRNAs. We also identified 10 novel miRNA candidates whose precursors were all potentially generated from citrus ESTs. In addition, five miRNA* sequences were also sequenced. These sequences had not been earlier described in other plant species and accumulation of the 10 novel miRNAs were confirmed by qRT-PCR analysis. Potential target genes were predicted for most conserved and novel miRNAs. Moreover, four target genes including one encoding IRX12 copper ion binding/oxidoreductase and three genes encoding NB-LRR disease resistance protein have been experimentally verified by detection of the miRNA-mediated mRNA cleavage in C. trifoliata. Deep sequencing of short RNAs from C. trifoliata flowers and fruits identified 10 new potential miRNAs and 42 highly conserved miRNA families, indicating that specific miRNAs exist in C. trifoliata. These results show that regulatory miRNAs exist in agronomically important trifoliate orange and may play an important role in citrus growth, development, and response to disease.


The mTOR regulated RNA-binding protein LARP1 requires PABPC1 for guided mRNA interaction.
The mammalian target of rapamycin (mTOR) is a critical regulator of cell growth, integrating multiple signalling cues and pathways. Key among the downstream activities of mTOR is the control of the protein synthesis machinery. This is achieved, in part, via the co-ordinated regulation of mRNAs that contain a terminal oligopyrimidine tract (TOP) at their 5'ends, although the mechanisms by which this occurs downstream of mTOR signalling are still unclear. We used RNA-binding protein (RBP) capture to identify changes in the protein-RNA interaction landscape following mTOR inhibition. Upon mTOR inhibition, the binding of LARP1 to a number of mRNAs, including TOP-containing mRNAs, increased. Importantly, non-TOP-containing mRNAs bound by LARP1 are in a translationally-repressed state, even under control conditions. The mRNA interactome of the LARP1-associated protein PABPC1 was found to have a high degree of overlap with that of LARP1 and our data show that PABPC1 is required for the association of LARP1 with its specific mRNA targets. Finally, we demonstrate that mRNAs, including those encoding proteins critical for cell growth and survival, are translationally repressed when bound by both LARP1 and PABPC1.


Boundary layer transition modeling on leading edge inflatable kite airfoils.
We present a computational fluid dynamic analysis of boundary layer transition on leading edge inflatable kite airfoils used for airborne wind energy generation. Because of the operation in pumping cycles, the airfoil is generally subject to a wide range of Reynolds numbers. The analysis is based on the combination of the shear stress transport turbulence model with the γ - R ˜ e θ t transition model, which can handle the laminar boundary layer and its transition to turbulence. The implementation of both models in OpenFOAM is described. We show a validation of the method for a sailwing (ie, a wing with a membrane) airfoil and an application to a leading edge inflatable kite airfoil. For the sailwing airfoil, the results computed with transition model agree well with the existing low Reynolds number experiment over the whole range of angles of attack. For the leading edge inflatable kite airfoil, the transition modeling has both favorable and unfavorable effects on the aerodynamics. On the one hand, the aerodynamics suffer from the laminar separation. But, on the other hand, the laminar boundary layer thickens slower than the turbulent counterpart, which, in combination with transition, delays the separation. The results also indicate that the aerodynamics of the kite airfoil could be improved by delaying the boundary layer transition during the traction phase and tripping the transition in the retraction phase.


Intercellular communication and human hepatocellular carcinoma.
We have previously reported that gap junction-mediated intercellular communication (GJIC) can be restored in junctionally deficient human prostate epithelial cells, also suggesting that GJIC activity is regulated by estrogen. In the present work, we report studies on sex steroid regulation of GJIC and proliferative activity in both nontumoral (Chang liver, CL) and malignant (HepG2, Huh7) human liver cells. Junctional activity and liver cell growth were measured using the scrape-loading/dye-transfer (SL/DT) and the MTS assay, respectively. Using the SL/DT, only Huh7 cells exhibited a moderate degree of junctional activity in basic conditions, while neither CL nor HepG2 cells showed functional GJIC. Under exactly the same experimental approach used for prostate studies, we observed that, once again, both estrogen (either estradiol or estrone) and FK induce a significant increase of GJIC in Huh7 cells, while exposure of HepG2 cells to FK produces only a limited rise of junctional activity in this cell line. However, estrogen induced a significant increase and reduction of the proliferative activity of CL and Huh7 cells, respectively, while growth of HepG2 cells was not affected. While the above evidence suggests that estrogens are primarily implicated in growth regulation and communication of both prostate and liver epithelial cells, it also implies that compounds able to restore GJIC in junctionally deficient cells or prevent its disruption in junctionally proficient cells may be used for development of new strategies in the prevention and/or treatment of several human malignancies, including hepatocellular carcinoma (HCC).


Association between trans fatty acid intake and cardiovascular risk factors in Europe: the TRANSFAIR study.
High intakes of trans fatty acids (TFA) have been found to exert an undesirable effect on serum lipid profiles, and thus may increase the risk for cardiovascular disease. Investigation of the association between TFA intake and serum lipids. Cross-sectional study in eight European countries (Finland, France, Greece, Iceland, The Netherlands, Portugal, Spain, Sweden) among 327 men and 299 women (50-65 y). Using a dietary history method, food consumption was assessed and TFA intake was calculated with recent figures on TFA levels of foods, collected in the TRANSFAIR study. Mean (+/-s.d.) TFA intake was 2.40+/-1.53 g/day for men and 1.98+/-1.49 g/day for women (0.87+/-0.48% and 0. 95+/-0.55% of energy, respectively), with the highest consumption in Iceland and the lowest in the Mediterranean countries. No associations were found between total TFA intake and LDL, HDL or LDL/HDL ratio after adjustment for cardiovascular risk factors. Additional adjustment for other fatty acid clusters resulted in a significant inverse trend between total TFA intake and total cholesterol (Ptrend<0.03). The most abundantly occurring TFA isomer, C18:1 t, contributed substantially to this inverse association. The TFA isomers C14:1 t9, C16:1 t9 and C22:1 t were not associated or were positively associated with LDL or total cholesterol. From this study we conclude that at the current European intake levels of trans fatty acids they are not associated with an unfavourable serum lipid profile. Unilever Research Laboratorium, the Dutch Dairy Foundation on Nutrition and Health, Cargill BV, the Institute of Food Research Norwich Laboratory, the Nutrition Branch of the Ministry of Agriculture, Fisheries and Food, the International Fishmeal and Oil Manufacturers' Association, Kraft Foods, NV Vandemoortele Coordination Center, Danone Group, McDonalds Deutschland Inc, Danish Veterinary and Food Administration, Valio Ltd, Raisio Group. European Journal of Clinical Nutrition (2000) 54, 126-135


Bone marrow staging in patients with non-Hodgkin's lymphoma: is flow cytometry a useful test?
Flow cytometric analysis of bone marrow often is used as an adjunct to morphologic evaluation in the staging of patients with non-Hodgkin's lymphoma (NHL). The goal of this study was to define objectively the benefit of flow cytometry in this setting. The authors reviewed retrospectively all bone marrow specimens submitted between January 1992 and December 1994 to the Washington University Department of Pathology for flow cytometric immunophenotyping to rule out NHL. Results of morphologic examination and flow cytometry were reviewed independently and the ability to detect bone marrow involvement compared. Two hundred and seventy-three bone marrow specimens from 190 patients with an established diagnosis of NHL were submitted for flow cytometric analysis at initial presentation, restaging, and/or recurrence. Morphologic evaluation was negative in 69%, positive in 23%, and equivocal in 8%. Flow cytometry was negative in all but 1 morphologically negative bone marrow specimens and 40% of morphologically involved bone marrow specimens. Two of 23 morphologically equivocal bone marrow specimens were positive by flow cytometry. An additional 86 specimens were obtained to rule out NHL in patients without an established diagnosis of NHL. The majority of patients had a history of human immunodeficiency virus infection, cytopenia, or unexplained fevers. Morphologically, one specimen was involved with NHL, 5 were equivocal, and 80 were negative. All specimens were negative by flow cytometry. In this study, flow cytometric analysis improved the detection of NHL in bone marrow in only 3 of 273 samples, 2 of which were suspicious morphologically. Flow cytometry of bone marrow aspirates has a limited role in the routine staging and follow-up of patients with an established diagnosis of NHL.


Efficacy of bladder training in older women with urinary incontinence.
The efficacy of bladder training was evaluated in a randomized clinical trial involving 123 noninstitutionalized women 55 years and older with urinary incontinence. Subjects were urodynamically categorized as those with urethral sphincteric incompetence (N = 88) and those with detrusor instability with or without concomitant sphincteric incompetence (N = 35). Bladder training reduced the number of incontinent episodes by 57%; the effect was similar for both urodynamic diagnostic groups. The quantity of fluid loss was reduced by 54%. This was greater for patients with detrusor instability than for those without it. Diurnal and nocturnal voluntary micturitions were also reduced. The effect on nocturnal micturition, however, was not observed in subjects with unstable detrusor function. It is recommended that bladder training be considered as an initial step in treatment of women with urinary incontinence. Provided prior comprehensive clinical evaluation is done, it can be prescribed without the need for urodynamic characterization.


Stratosphere and Troposphere: Transport of Material between Them.
Data from two almost simultaneous balloon soundings show that ozone and dust in combination are transported from their stratospheric reservoirs into the troposphere by way of thin laminae measuring about 1 kilometer vertically by at least 480 kilometers horizontally. Transport in this layer occurs across the top of the jet stream in a region of very great vertical wind shear. Stratospheric aerosol may be an important instrument for the destruction of ozone within the stratosphere.


Gestational hypertension and preeclampsia in living kidney donors.
Young women wishing to become living kidney donors frequently ask whether nephrectomy will affect their future pregnancies. We conducted a retrospective cohort study of living kidney donors involving 85 women (131 pregnancies after cohort entry) who were matched in a 1:6 ratio with 510 healthy nondonors from the general population (788 pregnancies after cohort entry). Kidney donations occurred between 1992 and 2009 in Ontario, Canada, with follow-up through linked health care databases until March 2013. Donors and nondonors were matched with respect to age, year of cohort entry, residency (urban or rural), income, number of pregnancies before cohort entry, and the time to the first pregnancy after cohort entry. The primary outcome was a hospital diagnosis of gestational hypertension or preeclampsia. Secondary outcomes were each component of the primary outcome examined separately and other maternal and fetal outcomes. Gestational hypertension or preeclampsia was more common among living kidney donors than among nondonors (occurring in 15 of 131 pregnancies [11%] vs. 38 of 788 pregnancies [5%]; odds ratio for donors, 2.4; 95% confidence interval, 1.2 to 5.0; P=0.01). Each component of the primary outcome was also more common among donors (odds ratio, 2.5 for gestational hypertension and 2.4 for preeclampsia). There were no significant differences between donors and nondonors with respect to rates of preterm birth (8% and 7%, respectively) or low birth weight (6% and 4%, respectively). There were no reports of maternal death, stillbirth, or neonatal death among the donors. Most women had uncomplicated pregnancies after donation. Gestational hypertension or preeclampsia was more likely to be diagnosed in kidney donors than in matched nondonors with similar indicators of baseline health. (Funded by the Canadian Institutes of Health Research and others.).


Interpretation of electron micrographs of single and serial sections.
A method of securing serial sections for electron microscopy is described. Serial sections present certain anomalies of interpretation of a nature such that a complete and detailed three-dimensional reconstruction of the sectioned tissue cannot be made. These anomalies are discussed, as well as those which have been encountered in the interpretation of single sections. Observations of the following kinds have been made in an attempt to elucidate the interpretation of single and serial sections: differing methods of mounting adjacent sections, observation of the same section by high-angle stereoscopy, and examination of sections which have been shadowed prior to and subsequent to electron microscopy. It is found that the appearance of sections is independent of the choice of side to be placed against the formvar films. Stereoscopy shows that the appearance of fine structures is strongly dependent upon the direction of the penetrating electron beam with respect to the plane of the structures. Stereoscopy, combined with shadowing, shows quantitatively that extensive sublimation of polymer occurs upon normal exposure in the electron microscope. Observation of sections shadowed prior to electron microscopy indicates that varying amounts of material are removed between sections by the action of microtomy; i.e., it is probable that the sum of the thicknesses of several serial sections is considerably less than the total thickness of material removed from the block. It is believed that this effect, combined with the effect of sublimation, aids in explaining the failure of adjacent sections to exhibit continuity in their detailed structures.


The effects of hydrocortisone on cognitive and neural function: a behavioral and event-related potential investigation.
Research indicates that glucocorticoids affect hippocampal function and the form of cognition that the hippocampus is thought to subserve, explicit memory. However, some studies suggest that glucocorticoids affect the frontal lobe, attention and working memory. Thus, it is not clear whether glucocorticoids specifically target the hippocampus and explicit memory or if the effects are more ubiquitous. By simultaneously measuring event-related potentials and behavioral performance in tasks designed to tap particular cognitive and neural processes, the present study examined the effects of hydrocortisone on 24 healthy humans. In an intentional face recognition memory task where the stimuli were presented again after a brief delay (6-18 s) and a long delay (30 min), hydrocortisone altered the P600 component (an electrophysiological index of recognition memory and hippocampal activity) following the brief delay and impaired behavioral performance after the long delay. ERPs and behavioral performance were not affected in the attention and working memory tasks. These findings are consistent with reports indicating that glucocorticoids affect explicit memory and hippocampal function.


Metabolic engineering of soybean affords improved phytosterol seed traits.
Different combinations of three rate-limiting enzymes in phytosterol biosynthesis, the Arabidopsis thaliana hydroxyl methylglutaryl CoA1 (HMGR1) catalytic subunit linked to either constitutive or seed-specific β-conglycinin promoter, and the Glycine max sterol methyltransferase1 (SMT1) and sterol methyltransferase2-2 (SMT2-2) genes, under the control of seed-specific Glycinin-1 and Beta-phaseolin promoters, respectively, were engineered in soybean plants. Mature seeds of transgenic plants displayed modest increases in total sterol content, which points towards a tight control of phytosterol biosynthesis. However, in contrast to wild-type seeds that accumulated about 35% of the total sterol in the form of intermediates, in the engineered seeds driven by a seed-specific promoter, metabolic flux was directed to Δ(5) -24-alkyl sterol formation (99% of total sterol). The engineered effect of end-product sterol (sitosterol, campesterol, and stigmasterol) over-production in soybean seeds resulted in an approximately 30% increase in overall sitosterol synthesis, a desirable trait for oilseeds and human health. In contradistinction, increased accumulation of cycloartenol and 24(28)-methylencylartanol (55% of the total sterol) was detected in plants harbouring the constitutive t-HMGR1 gene, consistent with the previous studies. Our results support the possibility that metabolic flux of the phytosterol family pathway is differentially regulated in leaves and seeds.


[Bacteriological and clinical studies on meropenem in the pediatric field].
Bacteriological and clinical studies have been performed on meropenem (MEPM, SM-7338), a newly developed carbapenem antibiotic, in the pediatric field. 1. Antibacterial activities of MEPM against 24 clinical isolates were determined. MEPM showed excellent activity against Gram-positive bacteria including Staphylococcus aureus and Gram-negative bacteria, especially Escherichia coli and Branhamella catarrhalis. Against Haemophilus influenzae, MEPM had a higher activity than imipenem and flomoxef, but had a lower activity than piperacillin and cefoperazone. 2. Clinical efficacies of MEPM were evaluated in 32 cases with bacterial infections. A poor efficacy was observed in 1 patient with phlegmon but excellent or good efficacies were obtained in other 31 patients with tonsillitis (1), pneumonia (17), UTI (12), or SSSS (1). The overall efficacy rate was 96.9%. All strains except 1 of S. aureus were eradicated by the administration of MEPM, and a high eradication rate of 95.8% (23 out of 24 strains) was obtained. 3. No side effects were observed in 35 evaluated cases. As abnormal laboratory test results, elevated GOT, elevated GPT, eosinophilia and neutropenia were noted in 4, 4, 4 and 2 patients, respectively. 4. Influences on blood coagulation parameters were studied. PIVKA II was elevated upon administration of MEPM in some cases, but no changes in ATT, TT, HPT or Fbg were observed during the treatment. Based on the above results, it has been concluded that MEPM is a safe and effective drug to use in the treatment of pediatric infections. The usual recommended dosage and administration should be 10 to 20 mg/kg of MEPM at a time, using intravenous drip infusion, 3 times a day.


Decreased Nutrient Intake Is Associated With Premature Cervical Remodeling.
To examine the direct relationship between nutrient intake and cervical remodeling. Longitudinal descriptive design. Maternal-fetal medicine clinic in a Midwestern urban city. Forty-seven pregnant African American women. Participants completed the Block brief food frequency questionnaire at 19 to 24 weeks and 27 to 29 weeks gestation and had quantitative ultrasonic attenuation estimates at 19 to 21 weeks, 23 to 25 weeks, 27 to 29 weeks, 31 to 33 weeks, and 35 to 37 weeks gestation. Trajectory mixture models identified two subpopulations within our sample: those at risk (n = 36) and at less risk (n = 11) for premature cervical remodeling. More participants in the less-risk group consumed the dietary reference intake for calcium, vitamin A, folate, vitamin E, zinc, and vitamin D than in the at-risk group. The percentage of participants in the less-risk group who consumed the recommended dietary reference intake for vitamin E was twice the percentage of women in the at-risk group (82% and 44%, respectively; p = .004). Mean intake of calcium was almost 1.3 times more (p = .05) and for zinc was 1.5 times more (p = .04) in the less-risk group than in the at-risk group. Practitioners can inform women that certain nutrients, particularly zinc, calcium, and vitamin E, could be important to the health of the cervix and inhibit premature cervical remodeling, which in turn may help prevent preterm birth.


Bugs and the gut: an unstable marriage.
There is a symbiotic relationship between the gastrointestinal microflora and the human host. Commensal bacteria provide essential nutrients to the epithelium and promote healthy immune responses in the gut. Commensal bacteria such as Escherichia coli can, however, transform into pathogens when they acquire genetic material encoding virulence factors such as adhesins, enterotoxins, invasins and cytotoxins. Enterovirulent organisms 'communicate' with the host by a variety of diverse mechanisms; these underpin the pathogenic processes that are essential for the expression of diarrhoeal disease. Many of these mechanisms involve the activation of signal transduction pathways in epithelial cells. Classical pathways include activation of adenylate or guanylate cyclases to produce chloride secretion, and subversion of cytoskeletal functions to effect intimate attachment with or without invasion of epithelial cells. Other systems are also involved, including inflammatory cells and local neuroendocrine networks. Understanding the complex interactions between the human gastrointestinal tract and the commensals and pathogens which it encounters will hopefully help us to exploit further the beneficial effects of the 'marriage' and to find new ways of preventing and treating microbial disease of the intestine which occurs when the symbiotic arrangement breaks down.


Dietary and physical activity behaviors among adults successful at weight loss maintenance.
There is limited population-based data on behavioral factors found to be important for successful weight loss maintenance among adults. Data from the 2004 Styles surveys, mailed to U.S. adults aged > or = 18 years were used to examine the difference in selected weight loss strategies and attitudes among persons who reported successful weight loss attempts (lost weight and able to keep it off) and persons who were not successful (previous attempts to lose weight were unsuccessful or they could not keep the lost weight off). Behaviors examined included modification of diet, leisure-time and sports activities, and self-monitoring, and barriers to weight management. Among adults who reported losing weight or trying to lose weight, 31.0% had been successful at both losing weight and maintenance after weight loss. Successful weight loss status differed by sex, age, and current weight status. Assessment of reported weight loss strategies, found that exercising > or = 30 minutes/day and adding physical activity to daily life were significantly higher among successful versus unsuccessful weight losers. Individuals who were successful at weight loss and maintenance were less likely to use over-the-counter diet products than those who were unsuccessful at weight loss. Significantly more successful versus unsuccessful weight losers reported that on most days of the week they planned meals (35.9% vs. 24.9%), tracked calories (17.7% vs. 8.8%), tracked fat (16.4% vs. 6.6%), and measured food on plate (15.9% vs. 6.7%). Successful losers were also more likely to weigh themselves daily (20.3% vs. 11.0%). There were a significantly higher proportion of successful losers who reported lifting weights (19.0%) versus unsuccessful (10.9%). The odds of being a successful weight loser were 48%-76% lower for those reporting exercise weight control barriers were influencing factors (e.g., no time, too tired to exercise, no one to exercise with, too hard to maintain exercise routine) compared to those who reported little or no influence of exercise; similarly, the odds were 48-64% lower for those who found certain dietary barriers to be influential (e.g., eat away from home too often, diet/health food costs too much). Self-monitoring strategies such as weighing oneself, planning meals, tracking fat and calories, exercising 30 or more minutes daily, and/or adding physical activity to daily routine may be important in successful weight loss maintenance. Leisure-time activities such as lifting weights or cooking/baking for fun are common strategies reported by those who were successful weight losers.


Efficacy and Tolerability of Telmisartan/Amlodipine and Rosuvastatin Coadministration in Hypertensive Patients with Hyperlipidemia: A Phase III, Multicenter, Randomized, Double-blind Study.
Dyslipidemia and hypertension increase the risk for cardiovascular disease. Combination therapy improves patient compliance. This study was conducted to compare the efficacy and tolerability of the combination therapies telmisartan/amlodipine + rosuvastatin, telmisartan/amlodipine, and telmisartan + rosuvastatin in patients with hypercholesterolemia and hypertension. In this Phase III, multicenter, 8-week randomized, double-blind study, participants with hypertension and dyslipidemia (defined as a sitting systolic blood pressure [sitSBP] of ≥140 mm Hg, a low-density lipoprotein-cholesterol [LDL-C] level of ≤250 mg/dL, and a triglyceride level of ≤400 mg/dL) were screened. After a 4-week washout/run-in period involving therapeutic lifestyle changes and telmisartan 80 mg once a day, eligible patients had a sitSBP of ≥140 mm Hg and met the LDL-C level criteria according to the National Cholesterol Education Program Adult Treatment Panel III cardiovascular disease risk category. Patients were randomly assigned to 1 of 3 groups: (1) telmisartan/amlodipine 80/10 mg + rosuvastatin 20 mg (TAR group); (2) telmisartan/amlodipine 80/10 mg (TA group); or (3) telmisartan 80 mg + rosuvastatin 20 mg (TR group). The primary efficacy end points were the percentage changes from baseline in LDL-C in the TAR and TA groups and the mean changes in sitSBP in the TAR and TR groups at week 8 compared to baseline. Continuous variables were compared using the unpaired t test or the Wilcoxon rank sum model, and categorical variables were compared using the χ2 or Fisher exact test. Tolerability was assessed based on adverse events found on physical examination including vital sign measurements, laboratory evaluations, and 12-lead ECG. A total of 134 patients were enrolled. The least squares mean percentage changes in LDL-C at 8 weeks after administration of the drug compared to baseline were -51.9% (3.0%) in the TAR group and -3.2% (2.9%) in the TA group (P < 0.001). At 8 weeks after baseline, the least squares mean (SE) changes sitSBP were -28.3 (2.4) mm Hg in the TAR group and -10.7 (2.1) mm Hg in the TR group (P < 0.001). The prevalence rates of treatment-emergent adverse events were 15.0%, 25.0%, and 12.2% in the TAR, TA, and TR groups, respectively; those of adverse drug reactions were 15.0%, 22.7%, and 10.2%. None of the differences in rates were significant among 3 groups. Triple therapy with TAR can be an effective treatment in patients with dyslipidemia and hypertension. The TAR combination has value for hypertensive patients with hyperlipidemia in terms of convenience, tolerability, and efficacy. ClinicalTrials.gov identifier: NCT03566316.


A description of medical conditions in adults with autism spectrum disorder: A follow-up of the 1980s Utah/UCLA Autism Epidemiologic Study.
This study describes medical conditions experienced by a population-based cohort of adults with autism spectrum disorder whose significant developmental concerns were apparent during childhood. As part of a 25-year outcome study of autism spectrum disorder in adulthood, medical histories were collected on 92 participants (N = 69 males) who were first ascertained as children in the mid-1980s, 11 of whom were deceased at the time of follow-up. Questionnaires queried medical symptoms, disorders, hospitalizations, surgeries, and medication use. Median age at follow-up was 36 years (range: 23.5-50.5 years), and intellectual disability co-occurred in 62%. The most common medical conditions were seizures, obesity, insomnia, and constipation. The median number of medical conditions per person was 11. Increased medical comorbidity was associated with female gender (p = 0.01) and obesity (p = 0.03), but not intellectual disability (p = 0.79). Adults in this cohort of autism spectrum disorder first ascertained in the 1980s experience a high number of chronic medical conditions, regardless of intellectual ability. Understanding of these conditions commonly experienced should direct community-based and medical primary care for this population.


Prevalence and factors associated with the occurrence of preterm birth in Irbid governorate of Jordan: A retrospective study.
Prevention is important to reduce the prevalence of preterm births. Although prematurity has been well studied in developed countries, data from developing countries, such as Jordan, are still limited. This retrospective study analysed medical records to determine possible risk factors leading to preterm birth in the Irbid governorate of Jordan. All preterm births during the year 2011 were reviewed. Abstracted data included mother's age and gravidity. Newborn information included gender, birthweight and gestational age at birth. A total of 647 singleton births were included. There were more females than males (54.9% vs. 45.1%), with 75.6% being the second child or more. Half the mothers (50.2%) were 25-35 years of age. Factors associated with preterm birth were male gender (P = 0.008), maternal age > 35 years (P = 0.005) and first birth (P = 0.003). Nurses need to provide support and education to mothers with potential risk about reproductive health and family planning.


Environmental Risk Factors for Congenital Heart Disease.
Congenital heart disease (CHD) has many forms and a wide range of causes. Clinically, it is important to understand the causes. This allows estimation of recurrence rate, guides treatment options, and may also be used to formulate public health advice to reduce the population prevalence of CHD. The recent advent of sophisticated genetic and genomic methods has led to the identification of more than 100 genes associated with CHD. However, despite these great strides, to date only one-third of CHD cases have been shown to have a simple genetic cause. This is because CHD can also be caused by oligogenic factors, environmental factors, and/or gene-environment interaction. Although solid evidence for environmental causes of CHD have been available for almost 80 years, it is only very recently that the molecular mechanisms for these risk factors have begun to be investigated. In this review, we describe the most important environmental CHD risk factors, and what is known about how they cause CHD.


Cochlear-Internal Canal and Cochlear-Facial Dehiscence: A Novel Entity.
Different types of otic capsule dehiscence restricted to the cochlea have been described. Here we describe the case of a patient with a cochlear-internal auditory canal dehiscence associated with a cochlear-facial dehiscence not reported before. A 53-year-old patient with severe to profound sensorineural hearing loss due to bilateral Meniere's disease underwent a cochlear implant surgery on the right ear. Preoperative brain magnetic resonance imaging findings were reported to be normal; during surgery, a cerebrospinal fluid gusher occurred at the time of round window opening. Postoperative computed tomography imaging showed a bony dehiscence at two levels of the otic capsule.


Thermodynamics of nanoalloys.
This article reviews recent advances in our understanding of how temperature affects the structure and the phase of multimetallic nanoparticles. Focusing on bimetallic systems, we discuss the interplay of size, shape and chemical order on the stable configurations at thermal equilibrium. Besides some considerations about experimental evidence for thermally-induced transformations, most insight is generally gained from theory and computation. The perspectives offered by mesoscopic approaches (i.e. corrected from the bulk) and atomistic simulations complement each other and often provide detailed information about the respective roles of coordination, composition and more generally surface effects to be evaluated. Order-disorder transitions and the melting phase change are strongly altered in nanoscale systems, and we describe how they possibly impact entire phase diagrams.


DISTILLER: a data integration framework to reveal condition dependency of complex regulons in Escherichia coli.
We present DISTILLER, a data integration framework for the inference of transcriptional module networks. Experimental validation of predicted targets for the well-studied fumarate nitrate reductase regulator showed the effectiveness of our approach in Escherichia coli. In addition, the condition dependency and modularity of the inferred transcriptional network was studied. Surprisingly, the level of regulatory complexity seemed lower than that which would be expected from RegulonDB, indicating that complex regulatory programs tend to decrease the degree of modularity.


Adolescents developing life skills for managing type 1 diabetes: a qualitative, realistic evaluation of a guided self-determination-youth intervention.
To explore and illustrate how the Guided Self-Determination-Youth method influences the development of life skills in adolescents with type 1 diabetes supported by their parents and healthcare providers. Evidence-based methods that accomplish constructive cooperation between adolescents with poorly controlled type 1 diabetes, their parents and healthcare providers are needed. We adjusted an adult life skills intervention comprising reflection sheets and advanced communication for use by adolescent-parent-professional triads in outpatient visits. A qualitative realistic evaluation design comprising eight context-mechanism-outcome configurations directed the analysis of the Guided Self-Determination-Youth's influence on adolescent-parent-professional triads to evaluate what worked for whom, how and in what circumstances. Thirteen adolescents aged 13-18 years diagnosed with type 1 diabetes for ≥1 year and having poor glycaemic control participated together with 17 parents and eight healthcare providers. Data were collected from December 2009-March 2012 and consisted of digitally recorded outpatient Guide Self-Determination-Youth visits collected during the intervention period (11·5-24·5 months) and semi-structured interviews at 6-month follow-up. Emerging life skills in adolescents were identified as: (1) developing new relatedness with healthcare providers and parents; (2) becoming decision makers in their own lives with diabetes; and (3) growing personally. Reflection sheets combined with healthcare providers' advanced communication were central to promoting mutual problem-solving. A life skills approach turned outpatient visits into person-specific visits with improved cooperation patterns in the triads. Combining reflection sheets and advanced communication skills supported adolescents in beginning a process of developing life skills.


Reprogramming by lineage specifiers: blurring the lines between pluripotency and differentiation.
The generation of human induced pluripotent stem cells (iPS) has raised enormous expectations within the biomedical community due to their potential vast implications in regenerative and personalized medicine. However, reprogramming to iPS is still not fully comprehended. Difficulties found in ascribing specific molecular patterns to pluripotent cells (PSCs), and inherent inter-line and intra-line variability between different PSCs need to be resolved. Additionally, and despite multiple assumptions, it remains unclear whether the current in vitro culturing conditions for the maintenance and differentiation of PSCs do indeed recapitulate the developmental processes observed in vivo. As a consequence, basic questions such as what is the actual nature of PSCs remain unanswered and different theories have emerged in regards to the identity of these valuable cell population. Here we discuss on the published theories for defining PSC identity, the implications that the different postulated models have for the reprogramming field as well as speculate on potential future directions that might be opened once a precise knowledge on the nature of PSCs is accomplished.


An inside-out approach to storing electrostatic energy.
The ability to achieve high-energy densities is the central challenge in energy storage and recovery. A promising strategy for increasing energy storage is to use high-performance dielectric materials, such as highly polarizable nanoparticles or polymers, or nanocomposites of the two. In this issue, Kim et al. use a molecular coating and clever chemistry to combine oxide nanoparticles with a polymer matrix, thereby producing an improved nanocomposite dielectric. Some advantages and challenges of using nanocomposites as improved dielectric materials are presented in this Perspective.


Comparative Genomics and Characterization of Hybrid Shigatoxigenic and Enterotoxigenic Escherichia coli (STEC/ETEC) Strains.
Shigatoxigenic Escherichia coli (STEC) and enterotoxigenic E. coli (ETEC) cause serious foodborne infections in humans. These two pathogroups are defined based on the pathogroup-associated virulence genes: stx encoding Shiga toxin (Stx) for STEC and elt encoding heat-labile and/or est encoding heat-stable enterotoxin (ST) for ETEC. The study investigated the genomics of STEC/ETEC hybrid strains to determine their phylogenetic position among E. coli and to define the virulence genes they harbor. The whole genomes of three STEC/ETEC strains possessing both stx and est genes were sequenced using PacBio RS sequencer. Two of the strains were isolated from the patients, one with hemolytic uremic syndrome, and one with diarrhea. The third strain was of bovine origin. Core genome analysis of the shared chromosomal genes and comparison with E. coli and Shigella spp. reference genomes was performed to determine the phylogenetic position of the STEC/ETEC strains. In addition, a set of virulence genes and ETEC colonization factors were extracted from the genomes. The production of Stx and ST were studied. The human STEC/ETEC strains clustered with strains representing ETEC, STEC, enteroaggregative E. coli, and commensal and laboratory-adapted E. coli. However, the bovine STEC/ETEC strain formed a remote cluster with two STECs of bovine origin. All three STEC/ETEC strains harbored several other virulence genes, apart from stx and est, and lacked ETEC colonization factors. Two STEC/ETEC strains produced both toxins and one strain Stx only. This study shows that pathogroup-associated virulence genes of different E. coli can co-exist in strains originating from different phylogenetic lineages. The possibility of virulence genes to be associated with several E. coli pathogroups should be taken into account in strain typing and in epidemiological surveillance. Development of novel hybrid E. coli strains may cause a new public health risk, which challenges the traditional diagnostics of E. coli infections.


Studies on antibody-producing cells. II. Appearance of 3 H-thymidine-labeled rosette-forming cells.
A study of the kinetics of antibody-producing cells has been carried out by the use of rosette formation for detection of individual antibody-producing cells, and labeling with tritiated thymidine, in cells obtained from mouse spleens at intervals after injection of SRBC. Following a primary injection of the antigen, the number of RFC per million cells was found to increase to a peak at 5 days, then, after a decrease, to a second peak at about the 10th day. The curve of tritium labeling of RFC was also biphasic, with peaks on the 3rd and 7th day. The second increase in rosette-forming cells could be shown to involve, especially between the 7th and 9th day, a second increase in lymphoid cell RFC and, among these, 7S antibody-producing cells. When the population examined was restricted to large lymphocytes, two peaks of RFC per million cells and two peaks of labeling were again found. In this case, however, the peaks of RFC and of labeling were reached on the same day in each instance, rather than with the 2 day difference found in the entire spleen cell suspension or the entire lymphoid cell population. Electron microscopic examination of labeled rosette-forming cells showed these to be largely lymphocytes, but to include rather well differentiated plasmablasts as well. No macrophages were found among labeled RFC in the primary response. A substantial number of labeled lymphocytes were found in close contiguity with rosette-forming macrophages. The percentage of labeling in such lymphocytes was as high, on the respective days, as the percentage of labeled cells among the RFC of the entire suspension.


Measurements of tissue viability in transplantation.
Near-infrared spectroscopy has primarily been used in monitoring changes in cerebral haemoglobin oxygenation and haemodynamics. However its use as a method for the assessment of tissue viability following transplantation has recently been explored experimentally in our laboratory. The ability to measure changes in oxygenation and perfusion during harvesting and following transplantation of organs or transfer of free and pedicled flaps potentially important in reconstructive surgery. We have found that near-infrared spectroscopy is extremely useful in detecting vaso-occlusive events and can accurately and reliably distinguish between arterial, venous or total occlusions. Venous congestion indicated by raised levels of deoxygenated haemoglobin with a concomitant increase in blood volume and the presence and magnitude of reactive hyperaemia are both easily recognizable features by near-infrared spectroscopy. We have shown that near-infrared spectroscopy measurements of venous congestion in kidneys (and other tissues) following prolonged storage correlate with medullary vascular congestion confirmed by angiographical and histological analysis of intrarenal perfusion. Clinically we have shown that flap perfusion can be improved by altering fluid replacement regimes and the addition of ionotropes. Cerebral near-infrared spectroscopy measurements in a liver transplant model showed statistically significant differences within minutes after the anhepatic phase in cerebral perfusion and oxygenation, between animals transplanted with ischaemically damaged livers compared to those isografted with minimally stored livers. Similarly we have found that near-infrared spectroscopy can be used as a monitor to assess the adequacy of fluid or blood replacement in haemorrhagic and hypovolaemic models. We believe that near-infrared spectroscopy provides a sensitive and reliable postoperative method for the assessment of tissue viability following the transfer of free and pedicled flaps and organs.


Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons.
Neurite outgrowth is key to the formation of functional circuits during neuronal development. Neurotrophins, including nerve growth factor (NGF), increase neurite outgrowth in part by altering the function and expression of Ca(2+)-permeable cation channels. Here we report that transient receptor potential vanilloid 2 (TRPV2) is an intracellular Ca(2+)-permeable TRPV channel upregulated by NGF via the mitogen-activated protein kinase (MAPK) signaling pathway to augment neurite outgrowth. TRPV2 colocalized with Rab7, a late endosome protein, in addition to TrkA and activated extracellular signal-regulated kinase (ERK) in neurites, indicating that the channel is closely associated with signaling endosomes. In line with these results, we showed that TRPV2 acts as an ERK substrate and identified the motifs necessary for phosphorylation of TRPV2 by ERK. Furthermore, neurite length, TRPV2 expression, and TRPV2-mediated Ca(2+) signals were reduced by mutagenesis of these key ERK phosphorylation sites. Based on these findings, we identified a previously uncharacterized mechanism by which ERK controls TRPV2-mediated Ca(2+) signals in developing neurons and further establish TRPV2 as a critical intracellular ion channel in neuronal function.


High dose haemodialysis and haemodiafiltration parameters and the relationship with advanced vascular calcification.
Vascular calcification (VC) is a risk factor for cardiovascular disease in end-stage renal disease (ESRD) patients undergoing maintenance haemodialysis (MHD). However, evidence is still insufficient about the association between dialysis parameters and VC. Thus, this study was to evaluate association of dialysis parameters with VC. We enrolled 297 ESRD patients undergoing MHD at six distinct centers in Korea. Study participants were categorized into 3 groups by the scoring system of abdominal aortic calcification based on lateral lumbar radiography (no VC group: 0, mild VC group: 1-7 and advanced VC group: 8-24). We compared the features of dialysis parameters according to the severity of VC. Multivariate logistic regression analysis was used to calculate adjusted odd ratios (ORs) and 95% confidence interval (CI) for mild and advanced VC in each haemodialysis parameter (adjusted OR [95% CI]). Pooled Kt/V (spKt/V), equilibrated Kt/V (eKt/V), standard Kt/V (stdKt/V) and the proportion of haemodiafiltration were increased along with the severity of VC. Multivariate regression analysis indicated that advanced VC was positively associated with spKt/V (5.27 [1.51-18.41]), eKt/V (6.16 [1.45-26.10]), stdKt/V (10.67 [1.74-65.52]) and haemodiafiltration (3.27 [1.74 to 6.16]). High dose dialysis and haemodiafiltration were significantly associated with advanced VC.


Origin and evolution of sulfadoxine resistant Plasmodium falciparum.
The Thailand-Cambodia border is the epicenter for drug-resistant falciparum malaria. Previous studies have shown that chloroquine (CQ) and pyrimethamine resistance originated in this region and eventually spread to other Asian countries and Africa. However, there is a dearth in understanding the origin and evolution of dhps alleles associated with sulfadoxine resistance. The present study was designed to reveal the origin(s) of sulfadoxine resistance in Cambodia and its evolutionary relationship to African and South American dhps alleles. We sequenced 234 Cambodian Plasmodium falciparum isolates for the dhps codons S436A/F, A437G, K540E, A581G and A613S/T implicated in sulfadoxine resistance. We also genotyped 10 microsatellite loci around dhps to determine the genetic backgrounds of various alleles and compared them with the backgrounds of alleles prevalent in Africa and South America. In addition to previously known highly-resistant triple mutant dhps alleles SGEGA and AGEAA (codons 436, 437, 540, 581, 613 are sequentially indicated), a large proportion of the isolates (19.3%) contained a 540N mutation in association with 437G/581G yielding a previously unreported triple mutant allele, SGNGA. Microsatellite data strongly suggest the strength of selection was greater on triple mutant dhps alleles followed by the double and single mutants. We provide evidence for at least three independent origins for the double mutants, one each for the SGKGA, AGKAA and SGEAA alleles. Our data suggest that the triple mutant allele SGEGA and the novel allele SGNGA have common origin on the SGKGA background, whereas the AGEAA triple mutant was derived from AGKAA on multiple, albeit limited, genetic backgrounds. The SGEAA did not share haplotypes with any of the triple mutants. Comparative analysis of the microsatellite haplotypes flanking dhps alleles from Cambodia, Kenya, Cameroon and Venezuela revealed an independent origin of sulfadoxine resistant alleles in each of these regions.


Familial clustering of major depression and anxiety disorders in Australian and Dutch twins and siblings.
The aim of this study was to investigate familial influences and their dependence on sex for panic disorder and/or agoraphobia, social phobia, generalized anxiety disorder and major depression. Data from Australian (N = 2287) and Dutch (N = 1185) twins and siblings who were selected for a linkage study and participated in clinical interviews to obtain lifetime Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) diagnoses were used. In a liability model, tetrachoric correlations were estimated in sibling pairs and sex differences between sibling correlations were tested. For each diagnosis, the sibling correlations could be constrained to be equal across the Australian and Dutch samples. With the exception of panic disorder and/or agoraphobia, all sibling correlations were the same for brother, sister and opposite-sex sibling pairs and were around .20. For panic disorder and/or agoraphobia, the correlation was .23 in brother and sister pairs, but absent in opposite-sex sibling pairs. From these results it can be concluded that upper heritability estimates, based on twice the correlations in the sibling pairs, vary between 36% (major depression) and 50% (social phobia). Furthermore, different genetic risk factors appear to contribute to the vulnerability for panic disorder and/or agoraphobia in men and women. No other sex differences were found.


Effects of measurement method, wavelength, and source-detector distance on the fast optical signal.
Fast optical signals can be used to study the time course of neuronal activity in localized cortical areas. The first report of such signals [Gratton, G., Corballis, P. M., Cho, E., Fabiani, M., Hood, D., 1995a. Shades of gray matter: Noninvasive optical images of human brain responses during visual stimulation. Psychophysiol, 32, 505-509.] was based on photon delay measures. Subsequently, other laboratories have also measured fast optical signals, but a debate still exists about how these signals are generated and optimally recorded. Here we report data from a visual stimulation paradigm in which different parameters (continuous: DC intensity; modulated: AC intensity and photon delay), wavelengths (shorter and longer than the hemoglobin isosbestic point), and source-detector distances (shorter and longer than 22.5 mm) were used to record fast signals. Results indicate that a localized fast signal (peak latency=80 ms) can be detected with both delay and AC intensity measures in visual cortex, but not with unmodulated DC measures. This is likely due to the fact that differential measures (delay and AC intensity) are less sensitive to superficial noise sources, which heavily influence DC intensity. The fast effect had similar sign at wavelengths shorter and longer than the hemoglobin isosbestic point, consistent with light scattering but not rapid deoxygenation accounts of this phenomenon. Finally, the fast signal was only measured at source-detector distances greater than 22.5 mm, consistent with the intracranial origin of the signal, and providing indications about the minimum distance for recording. These data address some of the open questions in the field and provide indications about the optimal recording methods for fast optical signals.


Synthetic Activators of Cell Migration Designed by Constructive Machine Learning.
Constructive machine learning aims to create examples from its learned domain which are likely to exhibit similar properties. Here, a recurrent neural network was trained with the chemical structures of known cell-migration modulators. This machine learning model was used to generate new molecules that mimic the training compounds. Two top-scoring designs were synthesized, and tested for functional activity in a phenotypic spheroid cell migration assay. These computationally generated small molecules significantly increased the migration of medulloblastoma cells. The results further corroborate the applicability of constructive machine learning to the de novo design of druglike molecules with desired properties.


Nutrients associated with diseases related to aging: a new healthy aging diet index for elderly population.
several indexes are used to measure the quality of nutrition in advanced ages. None of them were designed to evaluate nutrition to avoid disabilities in elderly population. to retrieve from literature "nutrients and intakes" showing to be involved in aging, and propose a new index, considering this information, to evaluate the quality of nutrition for preventing diseases related to aging. a bibliographic review was performed, retrieving information on nutrients associated with aging. All these nutrients were incorporated into a new Healthy Aging Diet Index (HADI). Next, a cross-sectional study was carried out with two convenience samples of elderly, collecting the nutritional and dietary data, calculating different validated indexes and comparing them with HADI to validate the results. forty-eight manuscripts were retrieved for full-text analysis. Associations were found between cardiovascular diseases and macronutrients,dietary fibre, sodium and vitamin D; cancer and fatty acids; diabetes and fatty acids, fibre and simple sugars; osteopenia/osteoporosis and calcium and vitamin D; sarcopenia and proteins, calcium, and vitamin D; and between cognitive impairment and fatty acids and folates. Sample 2, associated with rural areas, obtained lower indexes' scores. The behavior of HADI is similar to the other indexes (6.24/14 and 6.10/14 in samples 1 and 2, respectively). the presented collection of nutrients adds useful evidence for the design of diets that allow healthy aging. The new index proposed is a tool of specific nutritional measurement in studies aimed to prevent diseases related to aging.


Differential risks of cancer types in people with Parkinson's disease: a national record-linkage study.
There is evidence that people with Parkinson's disease (PD) have a decreased risk of developing cancer. PD has also variably been shown to be associated with an increased risk of cancers like melanoma and breast. We investigated this relationship in a very large cohort of PD patients. We constructed two cohorts of people from an all-England record-linked hospital and mortality dataset spanning 1999-2011. One cohort comprised people with a record of PD; the other comprised people without a record of PD. We 'followed up' these two cohorts to determine observed and expected numbers of people with subsequent primary cancers in each, based on person-years at risk, and calculated standardised rate ratios (RRs). In 219,194 people with PD, the RR for all subsequent primary malignant cancers combined was 0.92 (95% confidence interval (CI) 0.91-0.93). Increased RRs (p<0.05) were found for six out of the 31 cancer types investigated, including breast, melanoma, uterus, kidney, and neurological malignancies. Decreased RRs were found for 11 cancer sites, including lung and colon cancer. We corroborate the findings of a reduced risk for the development of cancers in PD patients shown in smaller studies, including cancers associated and not known to be associated with smoking; and of an increased risk of melanoma and breast cancer. To the best of our knowledge, this is the first study to report an association between PD and elevated rates of uterine and renal cancer. Further work is warranted to understand the mechanisms behind these findings.


Complement regulator factor H as a serum biomarker of multiple sclerosis disease state.
Multiple sclerosis has a variable phenotypic presentation and subsequent disease course that, although unpredictable at disease onset, is of crucial importance in guiding interventions. Effective and accessible biomarkers are required in order to stratify patients and inform treatment. We examined whether the complement regulator factor H and its Tyr402His polymorphism, recently implicated as biomarkers in other chronic inflammatory central nervous system conditions, might identify or predict specific pathological processes and outcomes in multiple sclerosis. Employing novel assays, we measured factor H and its His402 variant in serum from 350 patients with multiple sclerosis classified according to disease course and relapse status. Serum factor H levels were significantly higher in progressive disease (P < 0.001) compared to controls and relapsing patients, after controlling for variables including disease duration, age, gender, disability and treatment. Serum factor H levels were capable of distinguishing secondary progressive from relapsing remitting disease (excluding patients in clinical relapse) with a sensitivity of 89.41%, specificity of 69.47% and a positive predictive value of 72.38%. Acute relapse was also associated with transiently increased factor H levels (P = 0.009) compared to stable relapsing disease. In clinically stable patients, factor H levels remained constant over 1 year (coefficient of variation percentage = 6.8), however, in patients in transition from relapsing to progressive disease, factor H levels significantly increased over a period of 2 years (P = 0.007). Concentration of the His402 variant in heterozytgotes was significantly higher in secondary progressive (P < 0.01) and primary progressive (P < 0.05) disease, suggesting altered expression or consumption of variants when factor H is upregulated. Serum factor H may be an effective indicator of progression and a practical and accessible biomarker and stratifying tool in determining disease course, providing objective evidence to help guide therapeutic decisions.


Play fighting social networks do not predict injuries from later aggression.
Early play fighting mimics later aggression in many species, and may, therefore, be expected to reduce costs from later aggressive interactions. Using social network analysis (SNA) the effect of a central play fighting network position on later skin lesions from aggression was assessed in domestic pigs. Piglets (n = 263) were kept in litter groups or socialised pre-weaning with another litter to enhance play fighting experience. Play fighting was recorded for 1.5 h per day over 6 days pre-weaning. Play fighting network centrality was quantified using measures of individual network position and entire network structure (degree, eigenvector, betweenness, clustering coefficient). Skin lesions from aggression were counted after a dyadic contest and at 24 h and 3 weeks following group mixing. Pigs with play fighting interactions with many partners experienced fewer lesions from the dyadic contest (in-degree, p = 0.01) and tended to received fewer lesions 3 weeks after group mixing (degree, p = 0.088) but no other play fighting centrality measures affected the number of lesions at any point. The benefits of play fighting were therefore limited to specific aggressive social contexts. The tendency of socialised piglets to play fight with non-littermates did not affect subsequent lesions. We advocate the use of SNA over approaches that only consider dyadic interactions to further our understanding of the influence of early social group interactions on later life experience.


Boronic acid-DMAPO cooperative catalysis for dehydrative condensation between carboxylic acids and amines.
Arylboronic acid and 4-(N,N-dimethylamino)pyridine N-oxide (DMAPO) cooperatively catalyse the dehydrative condensation reaction between carboxylic acids and amines to give the corresponding amides under azeotropic reflux conditions. This cooperative use is much more effective than their individual use as catalysts, and chemoselectively promotes the amide condensation of (poly)conjugated carboxylic acids. The present method is practical and scalable, and has been applied to the synthesis of sitagliptin and a drug candidate.


Understanding and Design of Bidirectional and Reversible Catalysts of Multielectron, Multistep Reactions.
Some enzymes, including those that are involved in the activation of small molecules such as H2 or CO2, can be wired to electrodes and function in either direction of the reaction depending on the electrochemical driving force and display a significant rate at very small deviations from the equilibrium potential. We call the former property "bidirectionality" and the latter "reversibility". This performance sets very high standards for chemists who aim at designing synthetic electrocatalysts. Only recently, in the particular case of the hydrogen production/evolution reaction, has it been possible to produce inorganic catalysts that function bidirectionally, with an even smaller number that also function reversibly. This raises the question of how to engineer such desirable properties in other synthetic catalysts. Here we introduce the kinetic modeling of bidirectional two-electron-redox reactions in the case of molecular catalysts and enzymes that are either attached to an electrode or diffusing in solution in the vicinity of an electrode. We emphasize that trying to discuss bidirectionality and reversibility in relation to a single redox potential leads to an impasse: the catalyst undergoes two redox transitions, and therefore two catalytic potentials must be defined, which may depart from the two potentials measured in the absence of catalysis. The difference between the two catalytic potentials defines the reversibility; the difference between their average value and the equilibrium potential defines the directionality (also called "preference", or "bias"). We describe how the sequence of events in the bidirectional catalytic cycle can be elucidated on the basis of the voltammetric responses. Further, we discuss the design principles of bidirectionality and reversibility in terms of thermodynamics and kinetics and conclude that neither bidirectionality nor reversibility requires that the catalytic energy landscape be flat. These theoretical findings are illustrated by previous results obtained with nickel diphosphine molecular catalysts and hydrogenases. In particular, analysis of the nickel catalysts highlights the fact that reversible catalysis can be achieved by catalysts that follow complex mechanisms with branched reaction pathways.