Application of multiple imputation using the two-fold fully conditional specification algorithm in longitudinal clinical data.
Electronic health records of longitudinal clinical data are a valuable resource for health care research. One obstacle of using databases of health records in epidemiological analyses is that general practitioners mainly record data if they are clinically relevant. We can use existing methods to handle missing data, such as multiple imputation (mi), if we treat the unavailability of measurements as a missing-data problem. Most software implementations of MI do not take account of the longitudinal and dynamic structure of the data and are difficult to implement in large databases with millions of individuals and long follow-up. Nevalainen, Kenward, and Virtanen (2009, Statistics in Medicine 28: 3657-3669) proposed the two-fold fully conditional specification algorithm to impute missing data in longitudinal data. It imputes missing values at a given time point, conditional on information at the same time point and immediately adjacent time points. In this article, we describe a new command, twofold, that implements the two-fold fully conditional specification algorithm. It is extended to accommodate MI of longitudinal clinical records in large databases.


Highly efficient chemoenzymatic synthesis and facile purification of α-Gal pentasaccharyl ceramide Galα3nLc4βCer.
A highly efficient chemoenzymatic method for synthesizing glycosphingolipids using α-Gal pentasaccharyl ceramide as an example is reported here. Enzymatic extension of the chemically synthesized lactosyl sphingosine using efficient sequential one-pot multienzyme (OPME) reactions allowed glycosylation to be carried out in aqueous solutions. Facile C18 cartridge-based quick (<30 minutes) purification protocols were established using minimal amounts of green solvents (CH3CN and H2O). Simple acylation in the last step led to the formation of the target glycosyl ceramide in 4 steps with an overall yield of 57%.


Structural imaging reveals anatomical alterations in inferotemporal cortex in congenital prosopagnosia.
Congenital prosopagnosia (CP) refers to the lifelong impairment in face recognition in individuals who have intact low-level visual processing, normal cognitive abilities, and no known neurological disorder. Although the face recognition impairment is profound and debilitating, its neural basis remains elusive. To investigate this, we conducted detailed morphometric and volumetric analyses of the occipitotemporal (OT) cortex in a group of CP individuals and matched control subjects using high-spatial resolution magnetic resonance imaging. Although there were no significant group differences in the depth or deviation from the midline of the OT or collateral sulci, the CP individuals evince a larger anterior and posterior middle temporal gyrus and a significantly smaller anterior fusiform (aF) gyrus. Interestingly, this volumetric reduction in the aF gyrus is correlated with the behavioral decrement in face recognition. These findings implicate a specific cortical structure as the neural basis of CP and, in light of the familial history of CP, target the aF gyrus as a potential site for further, focused genetic investigation.


To what extent do people prefer health states with higher values? A note on evidence from the EQ-5D valuation set.
The EQ-5D general population valuation set (or 'tariff') is increasingly being used in the evaluation of health care interventions and has been recommended by the National Institute for Clinical Excellence (NICE) for use in cost-utility analyses of health technologies. To be of use to decision-makers, the health gain implied by changes in health state values must reflect individual preferences. At the simplest level, if State A has a higher mean value than State B, then the majority of people should consider a move from B to A to be a good thing. In this paper, we examine the extent to which this is true by re-analysing data from the general population study used to derive the EQ-5D tariff. We show that, on average, the difference in value between two states has to be as large as 0.20 (on a scale where one represents full and zero represents death) for 70% of respondents to agree with the sign of that difference (never mind its size). Results such as these have important implications for the use of the EQ-5D tariff that has been generated from these data.


Abnormal benzodiazepine and zinc modulation of GABAA receptors in an acquired absence epilepsy model.
Brain cholesterol synthesis inhibition (CSI) at a young age in rats has been shown to be a faithful model of acquired absence epilepsy, a devastating condition for which few therapies or models exist. We employed the CSI model to study cellular mechanisms of acquired absence epilepsy in Long-Evans Hooded rats. Patch-clamp, whole-cell recordings were compared from neurons acutely dissociated from the nucleus reticularis of thalamus (nRt) treated and untreated with a cholesterol synthesis inhibitor, U18666A. In U18666A-treated animals, 91% of rats developed EEG spike-waves (SWs). Patchclamp results revealed that although there was no remarkable change in GABAA receptor affinity, both a loss of ability of benzodiazepines to enhance GABAA-receptor responses and an increase of Zn2+ inhibition of GABAA-receptor responses of nRt neurons occurred in Long-Evans Hooded rats previously administered U18666A. This change was specific, since no significant changes were found in neurons exposed to the GABA allosteric modulator, pentobarbital. Taken collectively, these findings provide evidence for abnormalities in benzodiazepine and Zn2+ modulation of GABAA receptors in the CSI model, and suggest that decreased gamma2 subunit expression may underlie important aspects of generation of thalamocortical SWs in atypical absence seizures. The present results are also consistent with recent findings that mutation of the gamma2 subunit of the GABAA receptor changes benzodiazepine modulation in families with generalized epilepsy syndromes.


Overexpression of Bcl-2 or Bcl-XL transgenes and photoreceptor degeneration.
To test the hypothesis that overexpression of genes coding for the anti-apoptotic proteins Bcl-2 or Bcl-XL in photoreceptor cells may prevent or delay photoreceptor degenerations. Transgenic mice were generated in which the bcl-2 or bcl-XL transgenes were expressed in photoreceptor cells under the transcriptional control of a rhodopsin gene promoter. Bcl-2 or bcl-XL transgenic mice were crossed separately to a mouse strain carrying the rd/rd mutation and to another mouse line carrying a dominant rhodopsin gene mutation; both genetic defects result in photoreceptor degeneration. Photoreceptor cell death in mice expressing one of the bcl transgenes and carrying either the rd mutation homozygously or the rhodopsin mutation heterozygously was examined by histologic and electroretinographic measurements. Bcl-2 and bcl-XL transgenic mice also were tested for possible resistance to light-induced photoreceptor damage under two different experimental conditions. Bcl-2 or bcl-XL transgenes were expressed in photoreceptor cells of all lines of transgenic mice. In both the rd and the rhodopsin mutant mice, expression of either bcl-2 or bcl-XL transgenes did not prevent or measurably delay photoreceptor degeneration. Apoptosis-related nuclear DNA fragmentation, as assessed by in situ labeling with terminal deoxynucleotidyl transferase, was present in 13-day-old rd/rd mouse retinas with or without transgene expression. Twelve days after exposure to 2 hours of high-intensity light, bcl-2 transgenic mice retained approximately four rows of photoreceptor cells in the central retina as compared to none in littermate controls, whereas bcl-XL transgenic mice showed no increased resistance to light damage. Expression of the bcl-2 but not the bcl-XL transgene also was associated with a reduction in rhodopsin content. Overexpression of bcl-2 or bcl-XL transgenes does not rescue photoreceptor cells from apoptosis caused by the two genetic mutations tested. Resistance to light damage seen in the bcl-2 transgenic mice is likely from a reduction in rhodopsin content rather than an anti-cell death activity of Bcl-2. Cell death pathways not regulated by Bcl-2 may be operative in photoreceptor degeneration.


Silver(I) Oxide-/DBU-Promoted Synthesis of Dihydrofuran Units through Allenyl Silver Formation.
A formal [3+2] cyclization mediated by silver(I) oxide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is described herein. Through a broad variety of carbonyl compounds, this system can promote cyclization reactions with high yield (up to 85 %) and diastereoselectivity (up to 95:5) for a straightforward access to complex and congested dihydrofuran derivatives in one step under mild conditions. Based on DFT studies, the proposed mechanism would involve an allenyl silver intermediate.


R1R2R3-Myb proteins positively regulate cytokinesis through activation of KNOLLE transcription in Arabidopsis thaliana.
G2/M phase-specific gene transcription in tobacco cells is mediated by R1R2R3-Myb transcriptional activators, NtmybA1 and NtmybA2, which bind to mitosis-specific activator (MSA) elements. We show here that two structurally related genes, MYB3R1 and MYB3R4, which encode homologs of NtmybA1 and NtmybA2, play a partially redundant role in positively regulating cytokinesis in Arabidopsis thaliana. The myb3r1 myb3r4 double mutant often fails to complete cytokinesis, resulting in multinucleate cells with gapped walls and cell wall stubs in diverse tissues. These defects correlate with the selective reduction of transcript levels of several G2/M phase-specific genes, which include B2-type cyclin (CYCB2), CDC20.1 and KNOLLE (KN). These genes contain MSA-like motifs in their promoters and were activated by MYB3R4 in transient expression assays in tobacco cells. The KN gene encodes a cytokinesis-specific syntaxin that is essential for cell plate formation. The cytokinesis defects of myb3r1 myb3r4 double mutants were partially rescued by KN gene expression from heterologous promoters. In addition, a kn heterozygous mutation enhanced cytokinesis defects resulting from heterozygous or homozygous mutations in the MYB3R1 and MYB3R4 genes. Our results suggest that a pair of structurally related R1R2R3-Myb transcription factors may positively regulate cytokinesis mainly through transcriptional activation of the KN gene.


Childhood negative emotionality predicts biobehavioral dysregulation fifteen years later.
The temperamental trait of negative emotionality (NE) plays an important role in maladaptation among adults experiencing significant life stress. However, the prospective relation between childhood NE and subsequent interrelated behavioral, emotional, and biological dysregulation in later life has not yet been established among children who experience early adversity. Using a longitudinal sample of youth who experienced parental divorce during childhood (N = 160; 53% male; 83% White), we tested the hypothesis that childhood NE would predict physiological, emotional, and behavioral dysregulation 15 years later. NE was assessed by maternal report when youth were between 9 and 12 years old. Fifteen years later, young adults (mean age = 25.55 years) participated in a psychosocial stress task to assess cortisol reactivity and reported on internalizing symptoms and problematic alcohol use. Structural equation modeling revealed that higher childhood NE predicted significantly greater alcohol use, internalizing symptoms, and total cortisol output during a stress task 15 years later. Importantly, these findings held after adjusting for childhood internalizing symptoms. In addition, problematic alcohol use was associated with greater cortisol reactivity and internalizing symptoms. Findings suggest that childhood NE is a critical risk marker for interrelated forms of dysregulation in young adulthood among at-risk youth. (PsycINFO Database Record


Work as a nurse and a midwife and adverse pregnancy outcomes: a Finnish nationwide population-based study.
To assess whether work as a nurse and a midwife during pregnancy increases the risk of adverse pregnancy outcomes. We identified from the 1990-2006 Finnish Medical Birth Registry all singleton births to nurses (n=109,542), midwives (n=3,009), and teachers (n=23,454) (referents). The main outcomes were sexual differentiation, low and high birth weight, preterm and postterm delivery, small and large for gestational age, and perinatal death. The prevalence of low birth weight (2.9% vs. 2.5%), preterm delivery (4.4% vs. 4.1%), postterm delivery (4.7% vs. 4.1%), small for gestational age (1.8% vs. 1.4%), perinatal death (0.45% vs. 0.41%) and stillbirth (0.30% vs. 0.25%) was higher among the newborns of nurses than those of teachers. The adjusted odds ratio (OR) from generalized estimating equations was 1.17 (95% confidence interval [CI] 1.07-1.26) for low birth weight, 1.09 (95% CI 1.02-1.16) for preterm delivery, 1.11 (95% CI 1.03-1.18) for postterm delivery, 1.17 (95% CI 1.05-1.30) for small for gestational age, 1.12 (95% CI 0.90-1.35) for perinatal death, and 1.27 (95% CI 0.98-1.56) for stillbirth. For midwives, the risk of small for gestational age (OR=1.25, 95% CI 0.95-1.55) was elevated, but the 95% CI included unity. There was no substantial difference in the sex distribution. This study provides evidence that work as a nurse may reduce fetal growth and duration of pregnancy. The inference is based on the newborns of teachers as the reference group. However, the prevalence of most of the outcomes was higher among the newborns of all other working women combined than in the newborns of both nurses and teachers.


Use of Minimal Residual Disease Assessment to Redefine Induction Failure in Pediatric Acute Lymphoblastic Leukemia.
Purpose Our aim was to determine the role of end-of-induction (EOI) minimal residual disease (MRD) assessment in the identification and stratification of induction failure in patients with pediatric acute lymphoblastic leukemia (ALL) and to identify genetic abnormalities that drive disease in these patients. Patients and Methods Analysis included 3,113 patients who were treated in the Medical Research Council UKALL2003 multicenter randomized trial (NCT00222612) between 2003 and 2011. MRD was measured by using standardized real-time quantitative PCR. Median follow-up was 5 years 9 months. Results Fifty-nine patients (1.9%) had morphologic induction failure with 5-year event-free survival (EFS) of 50.7% (95% CI, 37.4 to 64.0) and 5-year overall survival of 57.7% (95% CI, 44.2 to 71.2). Of these, a small proportion of patients with M2 marrow (6 of 44) and a low EOI MRD level (< 0.01%) had 5-year EFS of 100%. Conversely, among patients with morphologic remission 2.3% (61 of 2,633) had high MRD (≥ 5%) and 5-year EFS of 47.0% (95% CI, 32.9 to 61.1), which was similar to those with morphologic induction failure. Redefining induction failure to include morphologic induction failure and/or MRD ≥ 5% identified 3.9% (120 of 3,133 patients) of the trial cohort with 5-year EFS of 48.0% (95% CI, 39.3 to 58.6). Induction failure (morphologic or MRD ≥ 5%) occurred most frequently in T-ALL (10.1%; 39 of 386 T-ALL cases) and B-other ALL, that is, lacking established chromosomal abnormalities (5.6%; 43 of 772 B-other cases). Genetic testing within the B-other group revealed the presence of PDGFRB gene fusions, particularly EBF1-PDGFRB, in almost one third of B-other ALL cases. Conclusion Integration of EOI MRD level with morphology identifies induction failure more precisely than morphology alone. Prevalence of EBF1-PDGFRB fusions in this group highlights the importance of genetic screening to identify abnormalities that may be targets for novel agents.


The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache.
The most important primary headaches (i.e. independent disorders that are not caused by another disease) are migraine, tension-type headache and cluster headache. All primary headaches are in need of better treatments. Migraine has a prevalence of 10% in the general population and its societal costs are high. Although the precise mechanisms underlying the pathophysiology of migraine are still elusive, the last decades have witnessed some progress (e.g. involvement of serotonin, calcitonin gene-related peptide, nitric oxide, etc). Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so called delayed headache that fulfils criteria for migraine without aura in migraine sufferers. Blockade of nitric oxide synthases (NOS) by L-NMMA effectively treats attacks of migraine without aura. Similar results have been obtained for chronic tension-type headache and cluster headache. Inhibition of the breakdown of cGMP also provokes migraine in sufferers, indicating that cGMP is the effector of NO-induced migraine. Several relationships exist between NO, calcitonin gene-related peptide and other molecules important in migraine. Also ion channels, particularly the K(ATP) channels, are important for the action of NO. In conclusion, inhibition of NO production or blockade of steps in the NO-cGMP pathway or scavenging of NO may be targets for new drugs for treating migraine and other headaches. Indeed, selective n-NOS and i-NOS inhibitors are already in early clinical development.


Differential regulation of the human IFN-gamma receptor expression in Raji and IM9 lymphoblastoid cells versus THP-1 monocytic cells by IFN-gamma and phorbol myristate acetate.
Expression of the human (hu) IFN-gamma-R has been studied in Raji and IM9 cells (two B lymphoblastoid cell lines) and in THP-1 cells (a monocytic cell line) with respect to IFN-gamma binding sites, receptor protein and mRNA levels. Although, in these three cell lines, the hu-IFN-gamma-R mRNA was expressed to the same extent, the high affinity receptor was expressed differently both in cell surface receptor binding and amount of receptor protein. Various ligands are able to modulate the expression of their own receptor. We investigated the modulation of the hu-IFN-gamma-R by its ligand. Hu-IFN-gamma induced a rapid and dose-dependent decrease of its cell surface receptor number without alteration of receptor affinity, amounts of receptor protein or hu-IFN-gamma-R mRNA accumulation and stability. Thus, in Raji, IM9, and THP-1 cells, the hu-IFN-gamma had no effect on its receptor gene expression and the cell surface decrease was simply due to ligand blocking and receptor internalization rather than true down-regulation. The second messenger in the hu-IFN-gamma signal transduction pathway is not well characterized, but activation of protein kinase C has been reported in some cases. Therefore, the modulation of the hu-IFN-gamma-R expression by PMA, a potent activator of protein kinase C and a modulator of other receptor expression, has been investigated. In Raji and IM9 cells, PMA had no or few effects on the cell surface receptor number and no detectable effect on the receptor protein or on mRNA levels. In contrast, in THP-1 cells, PMA treatment induced a time and dose-dependent five- to sixfold increase of the cell surface receptors due to a rapid and persistent increase of the hu-IFN-gamma-R gene expression in THP-1 cells was specifically inhibited or reversed by hu-IFN-gamma treatment. The modulation of the hu-IFN-gamma-R expression by PMA in THP-1 cells and by hu-IFN-gamma in PMA-treated THP-1 cells seems associated with their effect on monocyte-macrophage differentiation and/or macrophage activation.


Treating without Seeing: Pain Management Practice in a Thai Context.
Pain management is a core nursing function, and it plays a key role in postoperative care. It is important to understand the cultural context of nursing practices and how this affects effective pain management. The aim of this study was to describe the professional and cultural framework within which pain management is practiced on a Thai surgical ward. Spradley's ethnographic methodology was used. Data were collected through 98.5 hours of field observations and interviews at a surgical ward in Thailand. Three themes were constructed that describe the way Thai nurses practiced pain management: (i) complex communications system to address pain and to respond to it, (ii) the essence of Thai-ness, and (iii) a passive approach to pain management. The results indicate that, in the response to discomfort and pain, better pain management will result if there is a shift from functional to patient-centered care. The nursing culture needs to be further researched and discussed, in order to set priorities in line with the goals of national and international organizations for improving postoperative care and promoting patient comfort.


Comprehensive allelotyping of human hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common cancers in many parts of the world, however the molecular mechanisms underlying liver cell transformation remain obscure. A genome-wide scan of loss of heterozygosity (LOH) in tumors provides a powerful tool to search for genes involved in neoplastic processes. To identify recurrent genetic alterations in liver tumors, we examined DNAs isolated from 120 HCCs and their adjacent non tumorous parts for LOH using a collection of 195 microsatellite markers located roughly every 20 cM throughout 39 autosomal arms. The mean heterozygosity was 73%. Our findings provide additional support that LOH for loci on chromosomal arms 1p, 4q, 6q, 8p, 13q and 16p is significantly elevated in HCC. The highest percentage of LOH is found for a locus in 8p23 (42% of informative csaes). This corresponds to one of the most common genetic abnormalities reported to date in these tumors. In addition, high ratio of LOH (> or = 35%) is observed on chromosome arms which had not been implicated in previous studies, notably on 1q, 2q and 9q. No correlation was found between LOH of specific chromosomal regions and etiologic factors such as chronic infections with hepatitis B or C viruses. This first report of an extensive allelotypic analysis of HCC should help in identifying new genes whose loss of function contributes to the development of liver cancer.


A catalog of reference genomes from the human microbiome.
The human microbiome refers to the community of microorganisms, including prokaryotes, viruses, and microbial eukaryotes, that populate the human body. The National Institutes of Health launched an initiative that focuses on describing the diversity of microbial species that are associated with health and disease. The first phase of this initiative includes the sequencing of hundreds of microbial reference genomes, coupled to metagenomic sequencing from multiple body sites. Here we present results from an initial reference genome sequencing of 178 microbial genomes. From 547,968 predicted polypeptides that correspond to the gene complement of these strains, previously unidentified ("novel") polypeptides that had both unmasked sequence length greater than 100 amino acids and no BLASTP match to any nonreference entry in the nonredundant subset were defined. This analysis resulted in a set of 30,867 polypeptides, of which 29,987 (approximately 97%) were unique. In addition, this set of microbial genomes allows for approximately 40% of random sequences from the microbiome of the gastrointestinal tract to be associated with organisms based on the match criteria used. Insights into pan-genome analysis suggest that we are still far from saturating microbial species genetic data sets. In addition, the associated metrics and standards used by our group for quality assurance are presented.


A checklist to facilitate cultural awareness and sensitivity.
United States of America demographic profiles illustrate a nation rich in cultural and racial diversity. Approximately 29% of the population are minorities and demographic projections indicate an increase to 50% by the year 2050. This creates a highly mobile and constantly changing environment, revealing the need for new levels of cultural awareness and sensitivity. These issues are particularly critical in the medical community where medical professionals must understand the impact cultural differences and barriers can have on evaluation, treatment, and rehabilitation. During times of stress, such as when injury strikes, problems associated with lack of cultural sensitivity are intensified. Cultural diversity is of particular concern when standard measures for diagnosis and prognosis are derived from established norms for responding, because culture defines norms. This paper details a ten point checklist designed to facilitate cultural awareness and sensitivity in medical settings to ensure maximum successful recovery and outcomes for all patients.


Effects of a long-acting, trace mineral, reticulorumen bolus on range cow productivity and trace mineral profiles.
The objectives were to determine if strategic supplementation of range cows with a long-acting (6 mo), trace mineral, reticulorumen bolus containing Cu, Se, and Co would: (1) increase cow BCS and BW, and calf birth, weaning, and postweaning weights, or weight per day of age (WDA); (2) increase liver concentrations of Cu or Zn in cows, or blood Se, Cu, or Zn concentrations in cows and calves; and (3) vary by cow breed for any of these response variables. There were 192 control and 144 bolused Composite cows (C; 25% Hereford, Angus, Gelbevieh, and Senepol or Barzona); 236 control and 158 bolused Hereford (H) cows; and 208 control and 149 bolused Brahman cross (B) cows used in a 3-yr experiment. Cows were weighed and scored for body condition in January, May, and September, and all bolused cows received boluses in January. Each year, from among the 3 breed groups a subset of 15 control and 15 bolused cows (n = 90) had samples obtained in January and May for liver Cu and Zn, blood Se, and serum Cu and Zn. As for cows, blood and serum from the calves of these cows were sampled each year in May and September for Cu, Se, and Zn. There was a significant breed x year x treatment interaction (P = 0.001) for cow weight loss from January to May. Calf WDA, weaning, and postweaning weights did not differ (P > 0.40) between bolused and control cows, but there was a significant (P = 0.022) breed x year x treatment interaction for birth weight. Liver Cu was deficient (< 75 ppm; P < 0.001) in control cows and adequate (< 75 to 90 ppm) for bolused cows. Liver Cu differed by year (P < 0.001). Blood Se was adequate (< 0.1 ppm) for all cows except in January 2001 and 2002. There was no difference (P > 0.50) in blood Se between treatment groups in January, but bolused cows had greater (P < 0.01) blood Se in May. Breed differences for blood Se concentrations existed for bolused cows, with B having greater (P < 0.05) blood Se than either C or H cows. Breed differences also existed for control cows, with H having less blood Se (P < 0.04) than B or C cows. Calves from bolused cows had greater blood Se than calves from control cows (P = 0.01). Supplementation via a long-acting trace mineral bolus was successful in increasing liver Cu in cows and blood Se in cows and calves, but the responses varied by year. Bolus administration had variable effects on BW change in early lactation, depending on breed and year, which may indicate the need for breed- and year-specific supplementation programs.


Work-related injuries in Canadian occupational therapy practice.
No studies investigate work-related injuries experienced by Canadian occupational therapists. To identify the nature and prevalence of work-related injuries, impact of practice context, cultural and structural factors that influence response to these injuries, and strategies used to manage return-to-work after injury. Members of the Canadian Association of Occupational Therapists were sent an electronic survey in June 2009. Over half of the 600 respondents reported at least one injury episode. Patient-handling and equipment-related incidents accounted for the largest proportion of injuries. Almost one-third of respondents reported being threatened at work or experiencing workplace violence. Injured occupational therapists tended to minimize the extent and impact of their injuries by underreporting incidents and continuing to work after injury. These behaviours may contribute to a failure to recognize the reality of work-related injuries in occupational therapy practice and thereby limit the development of profession-specific, risk-minimization strategies.


Integrin β8 Deletion Enhances Vascular Dysplasia and Hemorrhage in the Brain of Adult Alk1 Heterozygous Mice.
Brain arteriovenous malformation (bAVM), characterized by tangled dysplastic vessels, is an important cause of intracranial hemorrhage in young adults, and its pathogenesis and progression are not fully understood. Patients with haploinsufficiency of transforming growth factor-β (TGF-β) receptors, activin receptor-like kinase 1 (ALK1) or endoglin (ENG) have a higher incidence of bAVM than the general population. However, bAVM does not develop effectively in mice with the same haploinsufficiency. The expression of integrin β8 subunit (ITGB8), another member in the TGF-β superfamily, is reduced in sporadic human bAVM. Brain angiogenic stimulation results at the capillary level of vascular malformation in adult Alk1 haploinsufficient (Alk1 +/- ) mice. We hypothesized that deletion of Itgb8 enhances bAVM development in adult Alk1 +/- mice. An adenoviral vector expressing Cre recombinase (Ad-Cre) was co-injected with an adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF) into the brain of Alk1 +/-;Itgb8-floxed mice to induce focal Itgb8 gene deletion and angiogenesis. We showed that compared with Alk +/- mice (4.75 ± 1.38/mm2), the Alk1 +/-;Itgb8-deficient mice had more dysplastic vessels in the angiogenic foci (7.14 ± 0.68/mm2, P = 0.003). More severe hemorrhage was associated with dysplastic vessels in the brain of Itgb8-deleted Alk1 +/- , as evidenced by larger Prussian blue-positive areas (1278 ± 373 pixels/mm2 vs. Alk1 +/- : 320 ± 104 pixels/mm2; P = 0.028). These data indicate that both Itgb8 and Alk1 are important in maintaining normal cerebral angiogenesis in response to VEGF. Itgb8 deficiency enhances the formation of dysplastic vessels and hemorrhage in Alk1 +/- mice.


Transient coherent nonlinear spectroscopy of single quantum dots.
We review our recent advances in four-wave mixing spectroscopy of single semiconductor quantum dots using heterodyne spectral interferometry, a novel implementation of transient nonlinear spectroscopy allowing the study of the transient nonlinear polarization emitted from individual electronic transitions in both amplitude and phase. We present experiments on individual excitonic transitions localized in monolayer islands of GaAs/AlAs quantum wells and in self-assembled CdTe/ZnTe quantum dots. We investigate the formation of the photon echo from individual transitions, both with increasing number of transitions in the ensemble, and in the presence of temporal jitter of the energy of a single transition. The detection of amplitude and phase of the signal allows the implementation of a two-dimensional femtosecond spectroscopy, in which mutual coherent coupling of single quantum dot states can observed and quantified.


Effects of Real-World Versus Virtual Environments on Joint Excursions in Full-Body Reaching Tasks.
Starting from an upright standing posture and reaching for a target that requires some forward bending of the trunk can involve many different configurations of the trunk and limb segments. We sought to determine if configurations of the limb and trunk segments during our standardized full-body reaching tasks were influenced by the visual environment. This paper examined movement patterns of healthy participants ([Formula: see text], eight female and nine male) performing full body reaching tasks to: 1) real-world targets; 2) virtual targets presented on a 3-D television; and 3) virtual targets presented using a head-mounted display. For reaches performed in the virtual world, the avatar was presented from a third-person perspective for the 3-D television and from a first-person perspective for the head-mounted display. Reaches to virtual targets resulted in significantly greater excursions of the ankle, knee, hip, spine, and shoulder compared with reaches made to real-world targets. This resulted in significant differences in the forward and downward displacements of the whole-body center of mass between the visual environments. Visual environment clearly influences how subjects perform full-body reaching tasks to static targets. Because a primary goal of virtual reality within rehabilitation is often to restore movement following orthopedic or neurologic injury, it is important to understand how visual environment will affect motor behavior. The present findings suggest that the existing game systems that track and present avatars from a third-person perspective elicit significantly different motor behavior when compared with the same tasks being presented from a first-person perspective.


ATP sensitivity of the ATP-sensitive K+ channel in intact and permeabilized pancreatic beta-cells.
ATP-sensitive K(+) channels (K(ATP) channels) couple cell metabolism to electrical activity and thereby to physiological processes such as hormone secretion, muscle contraction, and neuronal activity. However, the mechanism by which metabolism regulates K(ATP) channel activity, and the channel sensitivity to inhibition by ATP in its native environment, remain controversial. Here, we used alpha-toxin to permeabilize single pancreatic beta-cells and measure K(ATP) channel ATP sensitivity. We show that the channel ATP sensitivity is approximately sevenfold lower in the permeabilized cell than in the inside-out patch and that this is caused by interaction of Mg-nucleotides with the nucleotide-binding domains of the SUR1 subunit of the channel. The ATP sensitivity observed in permeabilized cells accounts quantitatively for K(ATP) channel activity in intact cells. Thus, our results show that the principal metabolic regulators of K(ATP) channel activity are MgATP and MgADP.


Environmental toxicology and health effects associated with hexachlorobenzene exposure.
The synthetic industrial chemical hexachlorobenzene (HCB) is a white crystalline solid compound. The substance is a bioaccumulative, persistent, and toxic pollutant. Historically HCB was commonly used as a pesticide and fungicide. Although HCB production and use has ceased in many countries, the compound is still generated inadvertently, as a byproduct and/or impurity in the manufacture of various chlorinated compounds, and released into the environment. Hexachlorobenzene is ubiquitous in air, water, soil, and biological matrices, as well as in major environmental compartments. Exposure to this substance is a public health concern because of its association with a wide range of adverse health effects. The International Agency for Research on Cancer and the United States Environmental Protection Agency classify HCB as a probable human carcinogen. Although globally the consumption of HCB-contaminated food is the principal source of environmental exposure, exposure can also occur through the inhalation of HCB-contaminated air, by dermal contact, or through in utero exposure and breast milk. In addition to cancer, the human health effects associated with HCB exposure involve systemic impairment (thyroid, liver, bone, skin), as well as damage to the kidneys and blood cells and the immune, endocrine, developmental, and nervous systems. In this review, we discuss the sources of HCB and the potential for human exposure, as well as systemic, carcinogenic, and teratogenic health effects.


Acute toxicity value extrapolation with fish and aquatic invertebrates.
Assessment of risk posed by an environmental contaminant to an aquatic community requires estimation of both its magnitude of occurrence (exposure) and its ability to cause harm (effects). Our ability to estimate effects is often hindered by limited toxicological information. As a result, resource managers and environmental regulators are often faced with the need to extrapolate across taxonomic groups in order to protect the more sensitive members of the aquatic community. The goals of this effort were to 1) compile and organize an extensive body of acute toxicity data, 2) characterize the distribution of toxicant sensitivity across taxa and species, and 3) evaluate the utility of toxicity extrapolation methods based upon sensitivity relations among species and chemicals. Although the analysis encompassed a wide range of toxicants and species, pesticides and freshwater fish and invertebrates were emphasized as a reflection of available data. Although it is obviously desirable to have high-quality acute toxicity values for as many species as possible, the results of this effort allow for better use of available information for predicting the sensitivity of untested species to environmental contaminants. A software program entitled "Ecological Risk Analysis" (ERA) was developed that predicts toxicity values for sensitive members of the aquatic community using species sensitivity distributions. Of several methods evaluated, the ERA program used with minimum data sets comprising acute toxicity values for rainbow trout, bluegill, daphnia, and mysids provided the most satisfactory predictions with the least amount of data. However, if predictions must be made using data for a single species, the most satisfactory results were obtained with extrapolation factors developed for rainbow trout (0.412), bluegill (0.331), or scud (0.041). Although many specific exceptions occur, our results also support the conventional wisdom that invertebrates are generally more sensitive to contaminants than fish are.


TopHat-Fusion: an algorithm for discovery of novel fusion transcripts.
TopHat-Fusion is an algorithm designed to discover transcripts representing fusion gene products, which result from the breakage and re-joining of two different chromosomes, or from rearrangements within a chromosome. TopHat-Fusion is an enhanced version of TopHat, an efficient program that aligns RNA-seq reads without relying on existing annotation. Because it is independent of gene annotation, TopHat-Fusion can discover fusion products deriving from known genes, unknown genes and unannotated splice variants of known genes. Using RNA-seq data from breast and prostate cancer cell lines, we detected both previously reported and novel fusions with solid supporting evidence. TopHat-Fusion is available at http://tophat-fusion.sourceforge.net/.


The effects of music therapy on the quality and length of life of people diagnosed with terminal cancer.
The purpose of this study was to evaluate the effects of music therapy on quality of life, length of life in care, physical status, and relationship of death occurrence to the final music therapy interventions of hospice patients diagnosed with terminal cancer. Subjects were adults who were living in their homes, receiving hospice care, and were diagnosed with terminal cancer. A total of 80 subjects participated in the study and were randomly assigned to one of two groups: experimental (routine hospice services and clinical music therapy) and control (routine hospice services only). Groups were matched on the basis of gender and age. Quality of life was measured by the Hospice Quality of Life Index-Revised (HQOLI-R), a self-report measure given every visit. Functional status of the subjects was assessed by the hospice nurse during every visit using the Palliative Performance Scale. All subjects received at least two visits and quality of life and physical status assessments. A repeated measures ANOVA revealed a significant difference between groups on self-report quality of life scores for visits one and two. Quality of life was higher for those subjects receiving music therapy, and their quality of life increased over time as they received more music therapy sessions. Subjects in the control group, however, experienced a lower quality of life than those in the experimental group, and without music, their quality of life decreased over time. There were no significant differences in results by age or gender of subjects in either condition. Furthermore, there were no significant differences between groups on physical functioning, length of life, or time of death in relation to the last scheduled visit by the music therapist or counselor. This study provides an overview of hospice/palliative care, explains the role of music therapy in providing care, and establishes clinical guidelines grounded in research for the use of music therapy in improving the quality of life among the terminally ill.


Churg-Strauss syndrome following cessation of allergic desensitization vaccination: a case report.
Churg-Strauss syndrome is a vasculitis of medium to small sized vessels. Diagnosis is mainly clinical with findings of asthma, eosinophilia, rhinosinusitis and signs of vasculitis in major organs. We present a case of a 19-year-old Persian male who developed signs and symptoms of this syndrome related to hyposensitization treatments for allergy control. No unifying etiology for the disease can be presented as it is found associated with environmental factors, medications, infections and is even considered a variant of asthma with predisposition to vasculitic involvement. Therefore, it is important to recognize this disease and be aware of underdiagnosis because of emphasis on pathologic evidence. Here, we present a case of allergic desensitization causing Churg-Strauss syndrome in the absence of other known factors.


Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression.
Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brain's emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes. Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode. Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region. The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection.


Terminal oxidase diversity and function in "Metallosphaera yellowstonensis": gene expression and protein modeling suggest mechanisms of Fe(II) oxidation in the sulfolobales.
"Metallosphaera yellowstonensis" is a thermoacidophilic archaeon isolated from Yellowstone National Park that is capable of autotrophic growth using Fe(II), elemental S, or pyrite as electron donors. Analysis of the draft genome sequence from M. yellowstonensis strain MK1 revealed seven different copies of heme copper oxidases (subunit I) in a total of five different terminal oxidase complexes, including doxBCEF, foxABCDEFGHIJ, soxABC, and the soxM supercomplex, as well as a novel hypothetical two-protein doxB-like polyferredoxin complex. Other genes found in M. yellowstonensis with possible roles in S and or Fe cycling include a thiosulfate oxidase (tqoAB), a sulfite oxidase (som), a cbsA cytochrome b(558/566), several small blue copper proteins, and a novel gene sequence coding for a putative multicopper oxidase (Mco). Results from gene expression studies, including reverse transcriptase (RT) quantitative PCR (qPCR) of cultures grown autotrophically on either Fe(II), pyrite, or elemental S showed that the fox gene cluster and mco are highly expressed under conditions where Fe(II) is an electron donor. Metagenome sequence and gene expression studies of Fe-oxide mats confirmed the importance of fox genes (e.g., foxA and foxC) and mco under Fe(II)-oxidizing conditions. Protein modeling of FoxC suggests a novel lysine-lysine or lysine-arginine heme B binding domain, indicating that it is likely the cytochrome component of a heterodimer complex with foxG as a ferredoxin subunit. Analysis of mco shows that it encodes a novel multicopper blue protein with two plastocyanin type I copper domains that may play a role in the transfer of electrons within the Fox protein complex. An understanding of metabolic pathways involved in aerobic iron and sulfur oxidation in Sulfolobales has broad implications for understanding the evolution and niche diversification of these thermophiles as well as practical applications in fields such as bioleaching of trace metals from pyritic ores.


The variable effect of low-dose volatile anaesthetics on the acute ventilatory response to hypoxia in humans: a quantitative review.
The purpose of this study was to review published studies (identified by a Medline-assisted search) on the effect of < or = 0.2 minimal alveolar concentration (MAC) halothane, isoflurane, enflurane and sevoflurane on the acute hypoxic ventilatory response in healthy subjects. Each article was examined for the anaesthetic agent, speed of hypoxic stimulus, background carbon dioxide and subject stimulation (audiovisual or painful). Analysis of variance was used to assess the significance of the influence of each of these factors on the standardised hypoxic response (the acute hypoxic ventilatory response in l.min(-1) in the presence of anaesthetic, expressed as a fraction of the response without anaesthetic). There were 37 separate studies within 21 published articles. The main factor influencing standardised hypoxic response was anaesthetic agent (p < 0.002). A second influential factor was subject stimulation (p < 0.014), but the interaction term of agent and stimulation was also significant (p < 0.039), suggesting that the influence of stimulation varied with the agent used. Speed of hypoxia and background carbon dioxide had no influence. In contrast to previous authors' assertions that study conditions have a major impact on the acute ventilatory response to hypoxia, this review suggests that the main determinant is simply the anaesthetic agent used. The review also highlights important gaps in the research literature, which may direct future research in this field. In particular, it would seem important to investigate the influence of arousal when different anaesthetic agents are used.


Estimating risk over time using data from targeted surveillance systems: application to bovine tuberculosis in Great Britain.
For infections that are typically asymptomatic, targeted surveillance systems (whereby individuals at increased risk are tested more frequently) will detect infections earlier on average than systems with random testing or in systems where all individuals are tested at the same intervals. However, estimating temporal trends in infection risk using data from such targeted surveillance systems can be challenging. This is similarly a problem for targeted surveillance to detect faults of individual industrial components. The incidence of bovine tuberculosis (TB) in British cattle has been generally increasing in the last thirty years. Cattle herds are routinely tested for evidence of exposure to the aetiological bacteria Mycobacterium bovis, in a targeted surveillance programme in which the testing interval is determined by past local TB incidence and local veterinary discretion. The UK Department for Environment, Food and Rural Affairs (Defra) report the monthly percentage of tests on officially TB-free (OTF) herds resulting in a confirmed positive test for M. bovis (i.e. the percentage of tested herds with OTF status withdrawn), which contains substantial fluctuations (three years apart) within the increasing trend. As the number of herds tested changes over time, this cyclic trend is difficult to interpret. Here we evaluate an alternative to the Defra method in which we distribute each incident event across the period at risk to infer the underlying trends in infection incidence using a stochastic model of cattle herd incidence and testing frequencies fitted to data on the monthly number of herds tested and number of these with OTF status withdrawn in 2003-2010. We show that for an increasing underlying incidence trend, the current Defra approach can produce artefactual fluctuations whereas the alternative method described provides more accurate descriptions of the underlying risks over time.


Slow non-dispersing wavepackets.
We show that in plasmonic or metamaterial slab waveguides, it is possible to generate slow non-dispersing wavepackets which undergo neither spatial diffraction nor temporal spreading with no nonlinear effects by forming a type of hybrid wavepacket between slow-light waveguide modes and diffraction-free Airy wavepackets. Three mechanisms are involved in their slowness: the slow-light feature of waveguide modes, the initial launching speed of hybrid wavepackets, and their acceleration along the time domain in a moving frame.


Malignant peripheral nerve sheath tumors: an update.
Malignant peripheral nerve sheath tumors (MPNSTs) are highly malignant cancers that account for approximately 5-10% of all soft tissue sarcomas. They occur either sporadically, in association with neurofibromatosis type 1 (NF1), or subsequent to radiation therapy. Histologically, MPNSTs resemble fibrosarcomas in their basic organization. Immunohistochemistry, particularly S100, plays an important role in the diagnosis. At the molecular level, loss of the NF1 gene and high levels of Ras-activity are hallmarks. Magnetic resonance imaging (MRI) is the most helpful imaging technique to clearly identify tumoral extent and to suggest neurogenic origin. The presence of heterogeneity with evidence of necrosis and hemorrhage on MRI and increased uptake on positron emission tomography scan may prove helpful in detecting malignant changes. MPNSTs need to be approached by a multidisciplinary team, assuring the complete surgical removal of the lesion. Disease-free and overall survival statistics reinforce the aggressive nature of this unique soft tissue tumor.


Histone deacetylase 1 deficiency impairs differentiation and electrophysiological properties of cardiomyocytes derived from induced pluripotent cells.
Epigenetic and chromatin modifications play particularly important roles in embryonic and induced pluripotent stem cells (ESCs and iPSCs) allowing for the cells to both differentiate and dedifferentiate back to a pluripotent state. We analyzed how the loss of a key chromatin-modifying enzyme, histone deacetylase 1 (HDAC1), affects early and cardiovascular differentiation of both ESCs and iPSCs. We also investigated potential differences between these two cell types when differentiation is induced. Our data indicate an essential role for HDAC1 in deacetylating regulatory regions of key pluripotency-associated genes during early differentiation. Although HDAC1 functions primarily as a HDAC, its loss also affects DNA methylation in ESCs and iPSCs both during pluripotency and differentiation. We show that HDAC1 plays a crucial, nonredundant role in cardiomyocyte differentiation and maturation. Our data also elucidate important differences between ESCs and iPSCs, when levels of this enzyme are reduced, that affect their ability to differentiate into functional cardiomyocytes. As varying levels of chromatin-modifying enzymes are likely to exist in patient-derived iPSCs, understanding the molecular circuitry of these enzymes in ESCs and iPSCs is critical for their potential use in cardiovascular therapeutic applications


Anopheline ecology and malaria infection during the irrigation development of an area of the Mahaweli Project, Sri Lanka.
A study on adult anopheline ecology and malaria vector incrimination was carried out from 1986 to 1989 during irrigation development in an area of the Mahaweli Project in eastern Sri Lanka. Eleven potential vector species were collected resting indoors or by using human or bovid bait, and from light trap catches. Overall, Anopheles vagus (Donitz), An. annularis (van der Wulp), and An. subpictus (Grassi) were the most prevalent, and An. culicifacies (Giles) and An. barbirostris (van der Wulp) were the least prevalent species. The abundance of An. aconitus (Donitz), An. jamesii (Theobald), An. pallidus (Theobald), and An. subpictus increased after irrigation development, while An. annularis, An. barbirostris, An. culicifacies and An. varuna (Iyengar) decreased. Populations of An. nigerrimus (Giles), An. tessellatus (Theobald), and An. vagus did not change substantially. Seven species were infected with malaria parasites, as determined by enzyme-linked immunosorbent assays (ELISA) done on mosquito head-thorax triturates. The main species involved were An. annularis, at peak abundance during the 1986-1987 period of development leading to the onset of irrigation, and An. subpictus, during times of seasonal abundance in the post-irrigation period of 1988 to 1989. Although occurring at low abundance, An. culicifacies was involved in malaria transmission irregularly throughout the study period. While there was strong ELISA-based evidence implicating An. subpictus as a major post-irrigation vector, confirmation of its vector status must await dissection and ELISA-based evidence of P. vivax and P. falciparum sporozoite infection rates in salivary glands.


Early decline in six-minute walk distance from the time of diagnosis predicts clinical worsening in pulmonary arterial hypertension.
The six-minute walk distance (6MWD) is commonly used to assess pulmonary arterial hypertension (PAH). However, the role of 6MWD in predicting outcomes in PAH is controversial. Clinical worsening is being increasingly considered as a clinically meaningful end point in PAH. We aimed to investigate whether early longitudinal changes in 6MWD (Δ6MWD) in meters and percent predicted (%pred) from the time of diagnosis predict clinical worsening of PAH. One hundred patients with group I PAH were retrospectively assessed. 6MWD was calculated using American (%pred US) or Canadian (%pred CAN) reference equations. Δ6MWD at 6 months were recorded. Clinical worsening was defined as either: development of right heart failure, hospital admission for PAH, referral for lung transplantation or initiation of prostanoids after oral therapy failed. Optimal 6-month differences in 6MWD to detect worsening were defined with receiver operating characteristics (ROC) analysis. Progressors, i.e. patients with clinical worsening, and nonprogressors showed significant differences in Δ6MWD. The most clinically significant declines in 6MWD at 6 months were ≥35 m, ≥8%pred US and ≥6%pred CAN. ROC and Cox proportional hazard analyses showed equivalent results for 6MWD %pred and meters. Six-month declines in 6MWD predicted worsening with a high specificity (94%) but a low sensitivity (33%). Early declines in 6MWD (within the first 6 months) predict future clinical worsening of PAH with high specificity. Δ6MWD may still be part of a comprehensive assessment of a patient's clinical status. However, given the poor sensitivity, a decline in 6MWD should be used with other clinical tools to make an appropriate assessment of the progression of PAH.


MSH2-MSH6 stimulates DNA polymerase eta, suggesting a role for A:T mutations in antibody genes.
Activation-induced cytidine deaminase deaminates cytosine to uracil (dU) in DNA, which leads to mutations at C:G basepairs in immunoglobulin genes during somatic hypermutation. The mechanism that generates mutations at A:T basepairs, however, remains unclear. It appears to require the MSH2-MSH6 mismatch repair heterodimer and DNA polymerase (pol) eta, as mutations of A:T are decreased in mice and humans lacking these proteins. Here, we demonstrate that these proteins interact physically and functionally. First, we show that MSH2-MSH6 binds to a U:G mismatch but not to other DNA intermediates produced during base excision repair of dUs, including an abasic site and a deoxyribose phosphate group. Second, MSH2 binds to pol eta in solution, and endogenous MSH2 associates with the pol in cell extracts. Third, MSH2-MSH6 stimulates the catalytic activity of pol eta in vitro. These observations suggest that the interaction between MSH2-MSH6 and DNA pol eta stimulates synthesis of mutations at bases located downstream of the initial dU lesion, including A:T pairs.


Asbestos in Asia.
Asbestos is a global killer. Despite lessons learned in the developed world on the use of asbestos and its hazardous pulmonary consequences, its use continues to increase in Asia. Although some countries such as Japan, Korea and Singapore have curtailed the use of this mineral, there are numerous countries in Asia that continue to mine, import and use this fibre, particularly China, which is one of the largest consumers in the world. Numerous factors ranging from political and economic to the lack of understanding of asbestos and the management of asbestos-related lung disease are keys to this observed trend. Awareness of these factors combined with early intervention may prevent the predicted Asian 'tsunami' of asbestos diseases.


Bee Venom Alleviates Atopic Dermatitis Symptoms through the Upregulation of Decay-Accelerating Factor (DAF/CD55).
Bee venom (BV)-a complex mixture of peptides and toxic proteins including phospholipase A2 and melittin-promotes blood clotting. In this study, we investigated the anti-atopic properties of BV and the mechanism associated with its regulation of the complement system. BV treatment upregulated the mRNA and protein levels of CD55 in THP-1 cells. Further experiments revealed that the phosphorylation of ERK was associated with upregulation of CD55. A complement-dependent cytotoxicity assay and a bacteria-killing assay showed that BV inactivated the complement system through the induction of CD55. The serum levels of C3 convertase (C3C) and Membrane attack complex (MAC) increased, while CD55 decreased in mice with AD-like lesions from DNCB treatment. However, the levels were inverted when the AD-like mice were treated with BV using subcutaneous injection, and we observed that the AD symptoms were alleviated. BV is often used to treat AD but its mechanism has not been elucidated. Here, we suggest that BV alleviates AD through the inactivation of the complement system, especially by the induction of CD55.


Just noticeable difference in olfaction: a discriminative tool between healthy elderly and patients with cognitive disorders associated with dementia.
Olfactory dysfunction appears to be one of the earliest signs of several age-related neurodegenerative disorders, including Alzheimer`s disease (AD) or Parkinson`s disease (PD). To rate performance and olfactory deficits in patients with cognitive disorders, various olfactory tasks have been used such as odor detection, discrimination, recognition memory, identification and naming but no study has been focused on just noticeable difference (JND), a sensitive tool of detection. The aim of this study was to investigate and compare variations in JNDs in healthy elderly and in patients with cognitive disorders associated with dementia. The results showed significantly higher olfactory JNDs in a population with cognitive disorders associated with dementia - i.e. a lower olfactory detection performance - compared to a control population paired in age, gender and education level. Additionally, the findings of the present study showed strong correlations between cognitive performances and JND scores in the control population contrary to the patient population. These findings are discussed in relation to the relevance of using olfactory JNDs in the diagnosis of dementias.


Diffusing a research-based physical activity promotion program for seniors into diverse communities: CHAMPS III.
Increasing the physical activity levels of older adults through diffusion of successful research-based programs into community settings is challenging because of differences between research and real-world settings. This project diffused the Community Healthy Activities Model Program for Seniors (CHAMPS) II, an individual-level research-based physical activity promotion program, through three community organizations to reach lower-income and minority (primarily Hispanic or Latino and African American) seniors. Through an academic-community partnership, university staff worked with each organization to adapt the program to be appealing and effective, enable their staff and volunteers to provide the program, increase participants' physical activity, and leave sustainable programs in place. Evaluation was based on methods recommended by the Centers for Disease Control and Prevention. The adapted programs, referred to as CHAMPS III, differed from the original program and among organizations. Group-based components and resource guides were included and new features were added; however, individualized components were not offered because of limited resources. A total of 321 people enrolled among three organizations; there was a trend toward increased physical activity at two organizations (an estimated increase of 481 kcal/week [P = .08] and 437 kcal/week [P = .06] expended in physical activity). Evaluation revealed challenges and unexpected community-level benefits. All organizations are continuing efforts to promote physical activity for older adults. This project enabled community organizations to implement physical activity promotion programs. The overarching challenge was to retain original program features within each organization's resources yet be sustainable. Although the programs differed from the original research program, they were a catalyst for numerous community-level changes. Our findings can guide similar projects to reach underserved older adults.


Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study.
To evaluate the use of prospective screening for the HLA-B*58:01 allele to identify Taiwanese individuals at risk of severe cutaneous adverse reactions (SCARs) induced by allopurinol treatment. National prospective cohort study. 15 medical centres in different regions of Taiwan, from July 2009 to August 2014. 2926 people who had an indication for allopurinol treatment but had not taken allopurinol previously. Participants were excluded if they had undergone a bone marrow transplant, were not of Han Chinese descent, and had a history of allopurinol induced hypersensitivity. DNA purified from 2910 participants' peripheral blood was used to assess the presence of HLA-B*58:01. Incidence of allopurinol induced SCARs with and without screening. Participants who tested positive for HLA-B*58:01 (19.6%, n=571) were advised to avoid allopurinol, and were referred to an alternate drug treatment or advised to continue with their prestudy treatment. Participants who tested negative (80.4%, n=2339) were given allopurinol. Participants were interviewed once a week for two months to monitor symptoms. The historical incidence of allopurinol induced SCARs, estimated by the National Health Insurance research database of Taiwan, was used for comparison. Mild, transient rash without blisters developed in 97 (3%) participants during follow-up. None of the participants was admitted to hospital owing to adverse drug reactions. SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B*58:01. By contrast, seven cases of SCARs were expected, based on the estimated historical incidence of allopurinol induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28% to 0.31%; P=0.0026; two side one sample binomial test). Prospective screening of the HLA-B*58:01 allele, coupled with an alternative drug treatment for carriers, significantly decreased the incidence of allopurinol induced SCARs in Taiwanese medical centres.


Heregulin-triggered Her-2/neu signaling enhances nuclear accumulation of p21WAF1/CIP1 and protects breast cancer cells from cisplatin-induced genotoxic damage.
Elevated levels of p21WAF1/CIP1, an important mediator of DNA repair, have been observed in various aggressive tumors as well as linked to chemoresistance. We examined whether heregulin (HRG), a member of the EGF-like growth factor family closely related to breast cancer tumorigenesis and metastasis, modulates p21WAF1/CIP1 expression and cellular localization. We used a model system that consisted of MCF-7 cells and MCF-7 cells engineered to overexpress the full-length cDNA of the human HRG gene (MCF-7/HRG). MCF-7/HRG cells demonstrate constitutive hyperactivation of Her-2/neu receptor as well as activation of down-stream PI-3'K/AKT and MAPK signaling cascades. Immunoblotting analyses showed that MCF-7/HRG cells significantly up-regulate p21WAF1/CIP1 expression relative to control MCF-7/pBABE cells, while a strong nuclear accumulation of p21WAF1/CIP1 in MCF-7/HRG cells was revealed by immunofluorescence microscopy studies. Protein degradation analyses demonstrated that the half-life of p21WAF1/CIP1 protein was increased from approximately 35 min in control MCF-7/pBABE cells to >/=3 h in MCF-7/HRG cells. Pharmacological inactivation of the PI-3'K/AKT and MAPK completely prevented HRG-induced accumulation of p21WAF1/CIP1. A structural deletion mutant of HRG (HRG-M4) lacking the N-terminus sequence and the cytoplasmic-transmembrane region of HRG was generated to investigate whether secretion of HRG and transactivation of Her-2/neu actively contributed to HRG-regulated p21WAF1/CIP1 expression and cellular localization. MCF-7 cells engineered to overexpress HRG-M4 did not demonstrate either activation of Her-2/neu, PI-3'K/AKT, or MAPK. Remarkably, HRG-M4 overexpression completely abolished the ability of HRG to promote nuclear accumulation of p21WAF1/CIP1 and concomitantly enhanced the apoptotic effects of cisplatin towards breast cancer cells. This novel interplay between HRG and p21WAF1/CIP1 strongly suggests that one mechanism of HRG-regulated breast cancer cell proliferation, survival, and/or sensitivity to genotoxic damage is to stabilize and promote a nuclear accumulation of p21WAF1/CIP1.


Vascular hypersensitivity to noradrenaline: a possible mechanism of hypertension in rats with chronic uraemia.
Studies were performed to evaluate the mechanism involved in the hypertension of moderate renal failure in partially (five-sixth) nephrectomized rats. Cardiac index (CI) was studied by means of the microsphere technique, and systemic vascular resistance (SVR) calculated from the mean arterial resistance MAP/CI, in four groups of experimental animals: (A) partially nephrectomized rats; (B) group A rats chronically treated with the calcium channel blocker verapamil; (C) sham-operated rats; (D) sham-operated rats treated with verapamil. The results demonstrate a significant increase in MAP in group A rats, which was due to a 72% increase in SVR as compared with groups C and D. In group B rats, MAP decreased significantly owing to a marked decrease in SVR (40%) as compared with group A. However, MAP remained higher in group B than in group C. The vascular responsiveness to noradrenaline was studied in group A, group C and group A rats after parathyroidectomy (group A1). An increased pressor responsiveness to noradrenaline was indicated by a shift of the noradrenaline dose-response curve to the left in group A rats as compared with group C rats. This change was corrected after partial nephrectomy. We conclude that hypertension in nephrectomized rats is due to an increase in SVR, and that an increased pressor responsiveness to catecholamines may play a role in this phenomenon. Furthermore, verapamil reduced the hypertension, and parathyroidectomy improved the abnormal sensitivity to noradrenaline in group A rats. These results raise the possibility that an abnormality in calcium metabolism, possibly due to secondary hyperparathyroidism, may be implicated in the hypertension of mildly uraemic rats.


Inferring B cell specificity for vaccines using a Bayesian mixture model.
Vaccines have greatly reduced the burden of infectious disease, ranking in their impact on global health second only after clean water. Most vaccines confer protection by the production of antibodies with binding affinity for the antigen, which is the main effector function of B cells. This results in short term changes in the B cell receptor (BCR) repertoire when an immune response is launched, and long term changes when immunity is conferred. Analysis of antibodies in serum is usually used to evaluate vaccine response, however this is limited and therefore the investigation of the BCR repertoire provides far more detail for the analysis of vaccine response. Here, we introduce a novel Bayesian model to describe the observed distribution of BCR sequences and the pattern of sharing across time and between individuals, with the goal to identify vaccine-specific BCRs. We use data from two studies to assess the model and estimate that we can identify vaccine-specific BCRs with 69% sensitivity. Our results demonstrate that statistical modelling can capture patterns associated with vaccine response and identify vaccine specific B cells in a range of different data sets. Additionally, the B cells we identify as vaccine specific show greater levels of sequence similarity than expected, suggesting that there are additional signals of vaccine response, not currently considered, which could improve the identification of vaccine specific B cells.


Identifying the most sensitive and specific sign and symptom combinations for cholera: results from an analysis of laboratory-based surveillance data from Haiti, 2012-2013.
Since October 2010, over 700,000 cholera cases have been reported in Haiti. We used data from laboratory-based surveillance for diarrhea in Haiti to evaluate the sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) of the cholera case definitions recommended by the World Health Organization (WHO). From April 2012 to May 2013, we tested 1,878 samples from hospitalized patients with acute watery diarrhea; 1,178 (62.7%) yielded Vibrio cholerae O1. The sensitivity and specificity of the WHO case definition for cholera in an epidemic setting were 91.3% and 43.1%, respectively, and the PPV and NPV were 72.8% and 74.8%, respectively. The WHO case definition for cholera in an area where cholera is not known to be present had lower sensitivity (63.1%) and NPV (55.1%) but higher specificity (74.2%) and PPV (80.0%). When laboratory diagnostic testing is not immediately available, clinicians can evaluate signs and symptoms to more accurately identify cholera patients.


Transcript-assisted transcriptional proofreading.
Fidelity of template-dependent nucleic acid synthesis is the main determinant of stable heredity and error-free gene expression. The mechanism (or mechanisms) ensuring fidelity of transcription by DNA-dependent RNA polymerases (RNAPs) is not fully understood. Here, we show that the 3' end-proximal nucleotide of the nascent transcript stimulates hydrolysis of the penultimate phosphodiester bond by providing active groups and coordination bonds to the RNAP active center. This stimulation is much higher in the case of misincorporated nucleotide. We show that during transcription elongation, the hydrolytic reaction stimulated by misincorporated nucleotides proofreads most of the misincorporation events and thus serves as an intrinsic mechanism of transcription fidelity.


The clinical and public health problem of relapse despite primaquine therapy: case review of repeated relapses of Plasmodium vivax acquired in Papua New Guinea.
Primaquine is the only drug available for preventing relapse following a primary attack by Plasmodium vivax malaria. This drug imposes several important problems: daily dosing over two weeks; toxicity in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency; partner blood schizontocides possibly impacting primaquine safety and efficacy; cytochrome P-450 abnormalities impairing metabolism and therapeutic activity; and some strains of parasite may be tolerant or resistant to primaquine. There are many possible causes of repeated relapses in a patient treated with primaquine. A 56-year-old Caucasian woman from New Zealand traveled to New Ireland, Papua New Guinea for two months in 2012. One month after returning home she stopped daily doxycycline prophylaxis against malaria, and one week later she became acutely ill and hospitalized with a diagnosis of Plasmodium vivax malaria. Over the ensuing year she suffered four more attacks of vivax malaria at approximately two-months intervals despite consuming primaquine daily for 14 days after each of those attacks, except the last. Genotype of the patient's cytochrome P-450 2D6 alleles (*5/*41) corresponded with an intermediate metabolizer phenotype of predicted low activity. Multiple relapses in patients taking primaquine as prescribed present a serious clinical problem, and understanding the basis of repeated therapeutic failure is a challenging technical problem. This case highlights these issues in a single traveler, but these problems will also arise as endemic nations approach elimination of malaria transmission.


Does health-related quality of life improve for advanced pancreatic cancer patients who respond to gemcitabine? Analysis of a randomized phase III trial of the cancer and leukemia group B (CALGB 80303).
Gemcitabine for advanced pancreatic cancer (APC) is palliative and the prognosis is poor, making health-related quality of life (HRQOL) particularly important. We evaluated HRQOL with the EuroQol (EQ-5D™) in patients with APC participating in Cancer and Leukemia Group B 80303, a multicenter, double-blind, randomized trial comparing overall survival (OS) between two treatment arms: gemcitabine with bevacizumab or gemcitabine with placebo. A consecutive subsample of patients was invited to complete the EQ-5D surveys. Because neither clinical nor HRQOL outcomes differed based on the study arm, analyses were pooled. Changes in mean scores from baseline to eight weeks and the prognostic value of the EQ-5D were evaluated. Mean index scores remained stable (0.78 at baseline [n=267], 0.79 at eight weeks [n=186], P=0.34, Wilcoxon signed rank test), attributable to a modest deterioration of physical function domain scores coincident with small improvements in pain and anxiety/depression scores. A small decline in visual analogue scale scores was observed (70.7 vs. 68.2, P=0.026). HRQOL changes within chemotherapy response strata revealed stable index scores but a trend of worsened physical function among patients with disease progression compared with those with stable or improved disease. Visual analogue scale scores trended downward over time irrespective of chemotherapy response status, with a statistically meaningful deterioration in patients who progressed (68.9 vs. 64.4, P=0.029). Baseline scores from both EQ-5D scales were significant predictors of OS in Cox proportional hazard models. Response to gemcitabine treatment in APC is not associated with appreciable improvement of global HRQOL. Small improvements in pain and mood are observed despite progressive functional decline. Those who respond to gemcitabine may experience a slight slowing of functional deterioration.


The use of digital technologies in dental practices in Switzerland: a cross-sectional survey
The aim of this cross-sectional survey was to identify the extent of digital technology infiltrating dental practices for the management and the treatment of patients. A survey (68 questions) was mailed to all members of the Swiss Dental Association (SSO). An online as well as postal answer was offered in order to maximise the response rate. The survey was mailed in June 2016 and answers were collected till the end of 2016. The total number of completed surveys was 1,238, which resulted in a response rate of 40%. Most dentists (97%) owned a private computer device and 74% used it for both, private and professional life. 69% of the dental offices had a homepage (69%), whereas a limited number (10%) used social media. The location of the practice influenced the extent of online presence. For patient administration a software application was used in 95% of the practices. The management of appointments was mainly organized by a digital agenda (73%). Patient's dental history was recorded digitally in half of the practices (53%), whereas in one third (38%) also dental/ endodontic/periodontal charts were recorded digitally. One quarter of the dentists (24%) used an additional dental software for patient treatment/ planning other than the administration software. In 23% of the dental practices a chairside CAD/CAM system was available. The survey demonstrated that i) the younger the dentist, ii) the more recent the opening of the practice, iii) the greater the patient catchment area, and iv) the more treatment rooms, the higher the grade of digitalisation of the dental practice.


Balance of risks and benefits in preparation for earthquakes.
Widespread proposals to benefit from lessons of the 17 October 1989 (Loma Prieta) earthquake dramatize the difficulties associated with reducing seismic risk. There are three main problems. First, the understanding of earthquake generation is far from complete. For example, the unanticipated source style of this earthquake raises vital questions; claims of predicting its occurrence are weak, and, for practical reasons, the detailed pattern of damaging strong ground shaking was not predicted. Second, although their interactions are not well understood, competing social forces continue to prevent the optimum growth and application of knowledge for earthquake hazard mitigation. Third, the recent use of the probabilities of seismic risk has had mixed results. Because of indecision between minimizing loss of life and maximizing broader benefits, general agreement on acceptable earthquake risk remains confused.


Application of dynamic light scattering to the study of small marine particles.
Small particles ranging from approximately 0.1 µm to several micrometers in size, which include detrital material, bacteria, and other planktonic microorganisms, make a significant contribution to light scattering in the upper ocean. The scattering properties of these particles are strongly dependent on their size, which is difficult to measure in the submicrometer range with commonly used electronic resistive counters and microscopic techniques. We examined the size of small marine particles by application of the dynamic light scattering (DLS) method. In this method the time-dependent autocorrelation function of scattered intensity by particles undergoing Brownian motion provides information about the size of particles. The samples were collected in clear oceanic waters off the coast of Southern California. The mean hydrodynamic diameter of particles, determined from the DLS measurements at a scattering angle of 45°, was 0.54µ m. This indicates that the major contribution to scattering at this angle comes rom submicrometer particles. We also described an inverse method for estimating the general slope of the size distribution of small marine particles from the mean hydrodynamic diameter. This method is based on calculations of the size distribution weighted by distribution from Mie theory and assumes that a power-law approximation represents the actual particle scattered intensity. These calculations suggested that particulate assemblage in our seawater samples was best characterized by a differential size distribution with a slope of -4.35. This estimation was supported by independent measurements of particle size distribution and the spectral beam attenuation coefficient taken from the same samples as those used for the DLS measurements. We also demonstrated that multiangle DLS measurements may be used to determine the representative value of the refractive index of particles.


Nutrition-related backgrounds and counseling practices of doctors of chiropractic.
A questionnaire was designed and mailed to the entire membership (no. = 438) of the San Francisco Bay Area Chiropractic Society to determine their nutrition education backgrounds and counseling practices and the relationship of backgrounds and counseling practices and the relationship of backgrounds and information resources to counseling practices. Results, based on the 23% response rate, indicated that the hours of formal nutrition education in chiropractic college varied widely in the five categories of responses from zero to more than 120, with the median respondent falling in the median category (81 to 100 hours). Sixty percent of the respondents indicated that they provided nutrition information to their patients on a routine basis, and 38% provided information on request only. The major forms of nutrition information dissemination were counseling (87%) and written materials (74%). The majority of respondents reported that they diagnose osteoporosis, arthritis, and allergies and use nutrition treatments for those disorders as a part of overall therapy. Chiropractic journals and texts were the most frequently used sources of nutrition information. Awareness of the educational backgrounds of registered dietitians correlated positively with the use of dietitians as a resource for nutrition information (p less than .005). The survey results suggest a need for dietitians to become involved in the nutrition-related practices of chiropractors as sources for information and referral.


Metabolic differences between normal and neoplastic cells: effects of aminonucleoside on cytoplasmic messenger RNA.
Treatment of cultured normal human fibroblasts with an adenosine analog (aminonucleoside of puromycin) rapidly inhibits the appearance of cytoplasmic messenger RNA, identified by its polyadenylate sequence. Similar treatment of SV40-transformed fibroblasts does not lead to such an inhibition. Cordycepin. another analog of adenosine. inlhibits polyadenylate-containing cytoplasmic RNA in both types of cell.


Optical higher-order symbolic recognition.
Several new higher-order spatial symbol recognition methods for optical symbolic substitution-based calculations are presented. In the case of logic processing, higher-order symbolic substitution (SS) rules can implement multivariable logic functions. For binary arithmetic calculations requiring carry propagation by simultaneously processing a number of bits, the computational speed increases. Finally, in image processing, the higher-order SS rules allow the use of larger local windows. For a higher-order spatial symbol recognition, both multiplicative and additive logic techniques are discussed. Four different higher-order SS recognition optical architectures are suggested: a multireflecting technique using an optical cavity, a lenslet array, an optical phase conjugation, and a content-addressable memory. Either dual-rail or triple-rail optical spatial intensity encoding is employed. Some preliminary experimental results are also presented.


Deficient use of visual information in estimating hand position in cerebellar patients.
We tested cerebellar degeneration in human patients in a task designed to isolate different aspects of motor planning and found a specific relationship between their ability to do inverse kinematic transformation and sparing of Crus I. Our approach was based on an experimental design introduced by Sober and Sabes (2003, 2005). Their paradigm allows behavioral deficits in planning of movement direction to be dissociated from deficits in generation of motor commands and also allows for the relative role played by visual and proprioceptive information to be quantified. Perturbation of visual information about hand position affected cerebellar degeneration patients (N = 12) and age-matched controls equally in determining movement direction, but had less of an effect in both groups in the transformation of movement direction to motor command. However, when provided with vision of the joints, control participants were more affected in generating the motor command in perturbed trials, and cerebellar degeneration participants were not. Thus, cerebellar patients were less able to use visual information about the joints in generating motor commands. Voxel-based morphometric analysis showed that this inability was primarily correlated with degeneration of Crus I. These results show that the cerebellum plays a role in motor planning, and specifically in the generation of inverse kinematic models for sensorimotor processing. The involvement of Crus I is consistent with an emerging picture in which increasingly posterior lobules of the anterior cerebellar cortex are associated with increasingly complex and abstract aspects of motor behavior.


Association of markers of chronic viral hepatitis and blood mercury levels in US reproductive-age women from NHANES 2001-2008: a cross-sectional study.
Methylmercury (MeHg) is a neurotoxin primarily found in seafood; exposures in reproductive-age women are of concern due to vulnerability of the developing fetus. MeHg is mainly eliminated via an enterohepatic cycle involving the liver and gallbladder. Dysfunction in these organs has been associated with slower MeHg elimination in laboratory animals. We hypothesized that women testing positive for chronic hepatitis B (HBV) or C (HCV), both associated with risk of longer-term liver and gallbladder impairment, would have higher total blood mercury (TBHg) concentrations than those negative for the viruses, reflecting slower MeHg elimination. Geometric mean (GM) TBHg levels from a representative sample of over 5,000 seafood-consuming, reproductive-age women from eight years (2001-2008) of the US NHANES survey were compared by viral hepatitis status (as determined by serological assay) using multiple linear regression. Adjustment was made for estimated MeHg intake from seafood consumption, social and demographic variables and other predictors. Women with chronic HBV had 1.52 (95% CI 1.13, 2.05, p < 0.01) times the GM TBHg of women who had not come into contact with the virus. The positive association was strongest in those with most severe disease. A modest negative association was found with HCV markers. While study design prevents inferences on causality, the finding that MeHg biomarkers differ by hepatitis status in this population suggests viral hepatitis may alter the pace of MeHg elimination. Offspring of HBV-infected seafood-consuming women may be at higher risk of MeHg-induced developmental delays than offspring of those uninfected. Possible reasons for the unanticipated negative association with HCV are explored.


Strain-Driven Stacking Faults in CdSe/CdS Core/Shell Nanorods.
Colloidal semiconductor nanocrystals are commonly grown with a shell of a second semiconductor material to obtain desired physical properties, such as increased photoluminescence quantum yield. However, the growth of a lattice-mismatched shell results in strain within the nanocrystal, and this strain has the potential to produce crystalline defects. Here, we study CdSe/CdS core/shell nanorods as a model system to investigate the influence of core size and shape on the formation of stacking faults in the nanocrystal. Using a combination of high-angle annular dark-field scanning transmission electron microscopy and pair-distribution-function analysis of synchrotron X-ray scattering, we show that growth of the CdS shell on smaller, spherical CdSe cores results in relatively small strain and few stacking faults. By contrast, growth of the shell on larger, prolate spheroidal cores leads to significant strain in the CdS lattice, resulting in a high density of stacking faults.


Evaporative Lithography in Open Microfluidic Channel Networks.
We demonstrate a direct capillary-driven method based on wetting and evaporation of various suspensions to fabricate regular two-dimensional wires in an open microfluidic channel through continuous deposition of micro- or nanoparticles under evaporative lithography, akin to the coffee-ring effect. The suspension is gently placed in a loading reservoir connected to the main open microchannel groove on a PDMS substrate. Hydrophilic conditions ensure rapid spreading of the suspension from the loading reservoir to fill the entire channel length. Evaporation during the spreading and after the channel is full increases the particle concentration toward the end of the channel. This evaporation-induced convective transport brings particles from the loading reservoir toward the channel end where this flow deposits a continuous multilayered particle structure. The particle deposition front propagates backward over the entire channel length. The final dry deposit of the particles is thereby much thicker than the initial volume fraction of the suspension. The deposition depth is characterized using a 3D imaging profiler, whereas the deposition topography is revealed using a scanning electron microscope. The patterning technology described here is robust and passive and hence operates without an external field. This work may well become a launching pad to construct low-cost and large-scale thin optoelectronic films with variable thicknesses and interspacing distances.


Detection of neolithic settlements in thessaly (Greece) through multispectral and hyperspectral satellite imagery.
Thessaly is a low relief region in Greece where hundreds of Neolithic settlements/tells called magoules were established from the Early Neolithic period until the Bronze Age (6,000 - 3,000 BC). Multi-sensor remote sensing was applied to the study area in order to evaluate its potential to detect Neolithic settlements. Hundreds of sites were geo-referenced through systematic GPS surveying throughout the region. Data from four primary sensors were used, namely Landsat ETM, ASTER, EO1 - HYPERION and IKONOS. A range of image processing techniques were originally applied to the hyperspectral imagery in order to detect the settlements and validate the results of GPS surveying. Although specific difficulties were encountered in the automatic classification of archaeological features composed by a similar parent material with the surrounding landscape, the results of the research suggested a different response of each sensor to the detection of the Neolithic settlements, according to their spectral and spatial resolution.


Food supplementation for improving the physical and psychosocial health of socio-economically disadvantaged children aged three months to five years.
Undernutrition contributes to five million deaths of children under five each year. Furthermore, throughout the life cycle, undernutrition contributes to increased risk of infection, poor cognitive functioning, chronic disease, and mortality. It is thus important for decision-makers to have evidence about the effectiveness of nutrition interventions for young children. Primary objective1. To assess the effectiveness of supplementary feeding interventions, alone or with co-intervention, for improving the physical and psychosocial health of disadvantaged children aged three months to five years.Secondary objectives1. To assess the potential of such programmes to reduce socio-economic inequalities in undernutrition.2. To evaluate implementation and to understand how this may impact on outcomes.3. To determine whether there are any adverse effects of supplementary feeding. We searched CENTRAL, Ovid MEDLINE, PsycINFO, and seven other databases for all available years up to January 2014. We also searched ClinicalTrials.gov and several sources of grey literature. In addition, we searched the reference lists of relevant articles and reviews, and asked experts in the area about ongoing and unpublished trials. Randomised controlled trials (RCTs), cluster-RCTs, controlled clinical trials (CCTs), controlled before-and-after studies (CBAs), and interrupted time series (ITS) that provided supplementary food (with or without co-intervention) to children aged three months to five years, from all countries. Adjunctive treatments, such as nutrition education, were allowed. Controls had to be untreated. Two or more review authors independently reviewed searches, selected studies for inclusion or exclusion, extracted data, and assessed risk of bias. We conducted meta-analyses for continuous data using the mean difference (MD) or the standardised mean difference (SMD) with a 95% confidence interval (CI), correcting for clustering if necessary. We analysed studies from low- and middle-income countries and from high-income countries separately, and RCTs separately from CBAs. We conducted a process evaluation to understand which factors impact on effectiveness. We included 32 studies (21 RCTs and 11 CBAs); 26 of these (16 RCTs and 10 CBAs) were in meta-analyses. More than 50% of the RCTs were judged to have low risk of bias for random selection and incomplete outcome assessment. We judged most RCTS to be unclear for allocation concealment, blinding of outcome assessment, and selective outcome reporting. Because children and parents knew that they were given food, we judged blinding of participants and personnel to be at high risk for all studies.Growth. Supplementary feeding had positive effects on growth in low- and middle-income countries. Meta-analysis of the RCTs showed that supplemented children gained an average of 0.12 kg more than controls over six months (95% confidence interval (CI) 0.05 to 0.18, 9 trials, 1057 participants, moderate quality evidence). In the CBAs, the effect was similar; 0.24 kg over a year (95% CI 0.09 to 0.39, 1784 participants, very low quality evidence). In high-income countries, one RCT found no difference in weight, but in a CBA with 116 Aboriginal children in Australia, the effect on weight was 0.95 kg (95% CI 0.58 to 1.33). For height, meta-analysis of nine RCTs revealed that supplemented children grew an average of 0.27 cm more over six months than those who were not supplemented (95% CI 0.07 to 0.48, 1463 participants, moderate quality evidence). Meta-analysis of seven CBAs showed no evidence of an effect (mean difference (MD) 0.52 cm, 95% CI -0.07 to 1.10, 7 trials, 1782 participants, very low quality evidence). Meta-analyses of the RCTs demonstrated benefits for weight-for-age z-scores (WAZ) (MD 0.15, 95% CI 0.05 to 0.24, 8 trials, 1565 participants, moderate quality evidence), and height-for-age z-scores (HAZ) (MD 0.15, 95% CI 0.06 to 0.24, 9 trials, 4638 participants, moderate quality evidence), but not for weight-for-height z-scores MD 0.10 (95% CI -0.02 to 0.22, 7 trials, 4176 participants, moderate quality evidence). Meta-analyses of the CBAs showed no effects on WAZ, HAZ, or WHZ (very low quality evidence). We found moderate positive effects for haemoglobin (SMD 0.49, 95% CI 0.07 to 0.91, 5 trials, 300 participants) in a meta-analysis of the RCTs.Psychosocial outcomes. Eight RCTs in low- and middle-income countries assessed psychosocial outcomes. Our meta-analysis of two studies showed moderate positive effects of feeding on psychomotor development (SMD 0.41, 95% CI 0.10 to 0.72, 178 participants). The evidence of effects on cognitive development was sparse and mixed.We found evidence of substantial leakage. When feeding was given at home, children benefited from only 36% of the energy in the supplement. However, when the supplementary food was given in day cares or feeding centres, there was less leakage; children took in 85% of the energy provided in the supplement. Supplementary food was generally more effective for younger children (less than two years of age) and for those who were poorer/ less well-nourished. Results for sex were equivocal. Our results also suggested that feeding programmes which were given in day-care/feeding centres and those which provided a moderate-to-high proportion of the recommended daily intake (% RDI) for energy were more effective. Feeding programmes for young children in low- and middle-income countries can work, but good implementation is key.


Internet use, social networking, and HIV/AIDS risk for homeless adolescents.
To examine the association between sexual health and internet use, including social networking websites such as MySpace and Facebook, among a sample of homeless adolescents at high risk of contracting HIV/AIDS. In 2009, a survey of internet use among 201 homeless adolescents was carried out. Multivariate logistic regression models assessed how patterns of use were associated with engaging in exchange sex (sex for money, drugs, or housing), recent HIV testing, and online partner-seeking behaviors. Among the surveyed adolescents, 96.5% reported internet use. Most youth accessed the internet at public libraries or youth service agencies. Increased time online and recent engagement in exchange sex were both positively associated with online partner-seeking. Youth connected to family members online were less likely to practice exchange sex and more likely to report a recent HIV test. Youth connected to street-based peers online were more likely to practice exchange sex, whereas youth connected to home-based peers online were more likely to report a recent HIV test. Although these data are preliminary, homeless youth need more access to the internet, as access facilitates connecting with family and home-based peers whose presence may reduce sexual risk-taking. Access, however, must be carefully monitored to prevent youth soliciting sex online.