Disruption of the coenzyme binding site and dimer interface revealed in the crystal structure of mitochondrial aldehyde dehydrogenase "Asian" variant.
Mitochondrial aldehyde dehydrogenase (ALDH2) is the major enzyme that oxidizes ethanol-derived acetaldehyde. A nearly inactive form of the enzyme, ALDH2*2, is found in about 40% of the East Asian population. This variant enzyme is defined by a glutamate to lysine substitution at residue 487 located within the oligomerization domain. ALDH2*2 has an increased Km for its coenzyme, NAD+, and a decreased kcat, which lead to low activity in vivo. Here we report the 2.1 A crystal structure of ALDH2*2. The structure shows a large disordered region located at the dimer interface that includes much of the coenzyme binding cleft and a loop of residues that form the base of the active site. As a consequence of these structural changes, the variant enzyme exhibits rigid body rotations of its catalytic and coenzyme-binding domains relative to the oligomerization domain. These structural perturbations are the direct result of the inability of lysine 487 to form important stabilizing hydrogen bonds with arginines 264 and 475. Thus, the elevated Km for coenzyme exhibited by this variant probably reflects the energetic penalty for reestablishing this site for productive coenzyme binding, whereas the structural alterations near the active site are consistent with the lowered Vmax.


Explaining educational differences in leisure-time physical activity in Europe: the contribution of work-related factors.
Although educational differences in leisure-time physical activity (LTPA) exist across Europe, the independent effect of educational level on leisure-time physical activity has rarely been explored. This study examines the relative contribution of occupational class, employment status, and educational level to LTPA across 12 European countries. The data were obtained from 12 European health surveys conducted at the turn of the century and identified in the EUROTHINE project. All information was self-reported. Logistic regression was applied and relative inequality index (RII) was calculated. Analyses were limited to those in the prime working-age (age 30-59; total N=137,646) men and women. In all 12 European countries, LTPA was more common in the high-educated than in the low-educated. The association between education and LTPA remained mostly unchanged after adjusting for marital status, urbanization, and self-rated health. After further adjusting for occupational class and employment status, the educational differences in LTPA were only slightly attenuated. An inverse association was found between educational level and LTPA across almost all 12 European countries. Occupational class and employment status had only a modest effect on educational differences in LTPA in most of the examined countries, suggesting that education remains an important predictor of LTPA.


The impact of different sources of heterogeneity on loss of accuracy from genomic prediction models.
Cross-study validation (CSV) of prediction models is an alternative to traditional cross-validation (CV) in domains where multiple comparable datasets are available. Although many studies have noted potential sources of heterogeneity in genomic studies, to our knowledge none have systematically investigated their intertwined impacts on prediction accuracy across studies. We employ a hybrid parametric/non-parametric bootstrap method to realistically simulate publicly available compendia of microarray, RNA-seq, and whole metagenome shotgun microbiome studies of health outcomes. Three types of heterogeneity between studies are manipulated and studied: (i) imbalances in the prevalence of clinical and pathological covariates, (ii) differences in gene covariance that could be caused by batch, platform, or tumor purity effects, and (iii) differences in the "true" model that associates gene expression and clinical factors to outcome. We assess model accuracy, while altering these factors. Lower accuracy is seen in CSV than in CV. Surprisingly, heterogeneity in known clinical covariates and differences in gene covariance structure have very limited contributions in the loss of accuracy when validating in new studies. However, forcing identical generative models greatly reduces the within/across study difference. These results, observed consistently for multiple disease outcomes and omics platforms, suggest that the most easily identifiable sources of study heterogeneity are not necessarily the primary ones that undermine the ability to accurately replicate the accuracy of omics prediction models in new studies. Unidentified heterogeneity, such as could arise from unmeasured confounding, may be more important.


Genome-wide allelotyping analysis reveals multiple sites of allelic loss in gallbladder carcinoma.
Although gallbladder carcinoma (GBC) is a highly malignant neoplasm, there is very limited information about the molecular changes involved in its pathogenesis. To identify the chromosomal locations of putative tumor suppressor gene loci involved in the pathogenesis of GBC, we conducted a genome-wide allelotyping or loss of heterozygosity (LOH) analysis of GBCS: Microdissected tissue from 24 archival GBCs and their matched control DNAs were analyzed for PCR-based LOH using 169 microsatellite markers spanning all nonacrocentric autosomal arms and the X chromosome. The chromosomal arms with the greatest frequencies of LOH (> or = 60%) were 3p, 6q, 7q, 8p, 9p, 9q, 11q, 12q, 17p, 18q, 19p, 22q, and XQ: The average fractional allele loss index in GBC cases was high (0.43) and frequent breakpoints were detected in gallbladder tumors. Of interest, 21 different regions of frequent LOH (hot spots) defined as > or = 50% for individual GBC samples were detected in this neoplasm, nearly half of them confined to one microsatellite marker. We conclude that in GBC at least 21 chromosomal regions with frequent allele losses are involved, suggesting that several putative tumor suppressor genes are inactivated in its pathogenesis. Overall, these data provide global estimates of the extent of genetic changes leading to GBC and will be useful for the identification of new tumor suppressor genes and for multiple new markers for translational research.


The moonlighting dilemma. Balancing education, service, and quality care while limiting risk exposure.
Moonlighting by medical residents is a highly controversial topic that has recently received new interest and concern as states are implementing legislative and regulatory efforts to limit residents' work hours and as teaching hospitals are increasingly concerned about liability exposure. Despite the potential problems, moonlighting, or outside employment, represents additional income to residents that enables repayment of massive student loans and/or improves their standard of living. It means additional clinical experience and responsibility, which many feel enhances their educational experience, and it permits essential night and weekend coverage for community hospital emergency departments and walk-in centers. Because of these important considerations for residents, community hospitals, and risk management, the University of Massachusetts Medical Center has developed a unique approach to the problems of moonlighting that addresses the concerns of all involved parties. The development of extended employment guidelines has also enabled the medical center to maintain a detailed database on the volume of such activity.


Predicting ionizing radiation exposure using biochemically-inspired genomic machine learning.
Background: Gene signatures derived from transcriptomic data using machine learning methods have shown promise for biodosimetry testing. These signatures may not be sufficiently robust for large scale testing, as their performance has not been adequately validated on external, independent datasets. The present study develops human and murine signatures with biochemically-inspired machine learning that are strictly validated using k-fold and traditional approaches. Methods: Gene Expression Omnibus (GEO) datasets of exposed human and murine lymphocytes were preprocessed via nearest neighbor imputation and expression of genes implicated in the literature to be responsive to radiation exposure (n=998) were then ranked by Minimum Redundancy Maximum Relevance (mRMR). Optimal signatures were derived by backward, complete, and forward sequential feature selection using Support Vector Machines (SVM), and validated using k-fold or traditional validation on independent datasets. Results: The best human signatures we derived exhibit k-fold validation accuracies of up to 98% ( DDB2, PRKDC, TPP2, PTPRE, and GADD45A) when validated over 209 samples and traditional validation accuracies of up to 92% ( DDB2, CD8A, TALDO1, PCNA, EIF4G2, LCN2, CDKN1A, PRKCH, ENO1, and PPM1D) when validated over 85 samples. Some human signatures are specific enough to differentiate between chemotherapy and radiotherapy. Certain multi-class murine signatures have sufficient granularity in dose estimation to inform eligibility for cytokine therapy (assuming these signatures could be translated to humans). We compiled a list of the most frequently appearing genes in the top 20 human and mouse signatures. More frequently appearing genes among an ensemble of signatures may indicate greater impact of these genes on the performance of individual signatures. Several genes in the signatures we derived are present in previously proposed signatures. Conclusions: Gene signatures for ionizing radiation exposure derived by machine learning have low error rates in externally validated, independent datasets, and exhibit high specificity and granularity for dose estimation.


Scaling up child and adolescent mental health services in South Africa: human resource requirements and costs.
Children and adolescents with mental health problems have poor service cover in low- and middle-income countries. Little is known about the resources that would be required to provide child and adolescent mental health services (CAMHS) in these countries. The purpose of this study was to calculate the human resources and associated costs required to scale up CAMHS in South Africa. A spreadsheet model was developed to calculate mental health service resources, based on an estimation of the need for services in a given population. The model can be adapted to specific settings by adjusting population size, age distribution, prevalence, comorbidity, levels of coverage, service utilisation rates, workloads, length of consultations and staff profile. Steps in the modelling include population identification; estimates of prevalence, service utilisation and staffing; and costing. Using a nominal total population of 100,000 (of which 43,170 would be children and adolescents under 20 years of age), the following full-time equivalent staff are required at minimum coverage level: 5.8 in PHC facilities, .6 in general hospital outpatient departments (OPDs), .1 in general hospital inpatient facilities, 1.1 in specialist CAMHS OPDs, .6 in specialist CAMHS inpatient facilities, .5 in specialist CAMHS day services, and .8 in regional CAMHS teams. This translates into roughly $21.50 and $5.99 per child or adolescent per annum nationally for the full coverage and minimum coverage scenarios respectively. When comparing the results of this model with current realities in South Africa, there remains a substantial shortfall in existing levels of CAMHS provision. The model can be used as an advocacy tool to engage with planners and policy makers on a rational basis. It can also be adapted for use in other countries, and is intended to support wider calls for a global scaling up of mental health services.


Innate immunity: cells, receptors, and signaling pathways.
Essential differences between the innate and acquired branches of immunity are described. These differences concern the detection system (receptors and pathogen structures) and the cells engaged in both systems as well as the effectory mechanisms. In contrast to those of the acquired system, receptors of the innate system, which developed during evolution, recognize unchanged structures on large groups of pathogens (e.g. lipopolysaccharide in Gram-negative bacteria). Two lineages, natural killer (NK) and dendritic cells (DCs), play important roles in the innate system. Phenotypic and functional differentiation is observed among NKs and DCs, so each of their sublineages plays a different role in the innate system. Every lineage of cells of the innate immune system express different stimulatory and sometimes also inhibitory receptors on their surfaces (e.g. NK cells). Among the stimulatory are Toll-like receptors (TLRs), mannose and scavenger receptors, and the stimulatory receptors of NK cells. All TLRs show similarity in structure and in the kind of molecules involved in intracellular signaling. The immune reactions of the innate system involve cytokine-dependent resistance of cells against infection with pathogen, production of cytokines (tumor necrosis factor, interferons, interleukins, chemokines) and MHC-independent killing. Although these reactions protect the host from invasion by microorganisms, they can also be responsible for significant tissue damage or may stimulate the development of autoimmunity. Therefore innate immunity must be under rigorous control. The possible regulatory mechanisms of innate immunity are discussed.


Development of a time-cycled volume-controlled pressure-limited respirator and lung mechanics system for total liquid ventilation.
Total liquid ventilation can support gas exchange in animal models of lung injury. Clinical application awaits further technical improvements and performance verification. Our aim was to develop a liquid ventilator, able to deliver accurate tidal volumes, and a computerized system for measuring lung mechanics. The computer-assisted, piston-driven respirator controlled ventilatory parameters that were displayed and modified on a real-time basis. Pressure and temperature transducers along with a lineal displacement controller provided the necessary signals to calculate lung mechanics. Ten newborn lambs (<6 days old) with respiratory failure induced by lung lavage, were monitored using the system. Electromechanical, hydraulic, and data acquisition/analysis components of the ventilator were developed and tested in animals with respiratory failure. All pulmonary signals were collected synchronized in time, displayed in real-time, and archived on digital media. The total mean error (due to transducers, analog-to-digital conversion, amplifiers, etc.) was less than 5% compared with calibrated signals. Components (tubing, pistons, etc.) in contact with exchange fluids were developed so that they could be readily switched, a feature that will be important in clinical settings. Improvements in gas exchange and lung mechanics were observed during liquid ventilation, without impairment of cardiovascular profiles. The total liquid ventilator maintained accurate control of tidal volumes and the sequencing of inspiration/expiration. The computerized system demonstrated its ability to monitor in vivo lung mechanics, providing valuable data for early decision making.


A zymogel enhances the self-cleaning abilities of the skin of the pilot whale (Globicephala melas).
Enzyme activity in the stratum corneum of the pilot whale Globicephala melas was investigated employing colorimetric enzyme screening assays combined with NATIVE PAGE, size exclusion chromatography (SEC) and histochemical staining procedures. Applying different substrates, several enzymes were detected. The histochemical demonstration of some selected hydrolytic enzymes enriched in the stratum corneum showed high extracellular accumulation. As demonstrated by size exclusion chromatography, high molar mass aggregates were built up from a glycoprotein-rich 20-30-kD fraction. Using NATIVE PAGE experiments under non-reducing conditions, a selection of five degrading enzymes was recovered within the above-reported aggregates. Activity of extracellular aggregate-attached enzymes in the superficial layer of the stratum corneum exhibited no remarkable decrease potentially resulting from self-degradation. We thus conclude that due to their enclosure within the microenvironment of aggregates, a zymogel is formed and autolysis of the stratum corneum is reduced. With respect to the skin surface, the zymogel with hydrolytic activities covering major parts of it enhances the self-cleaning abilities of the skin of the pilot whale based on physical pre-requisites by hydrolyzing adhesive glycoconjugates of settling biofouling organisms considered as primary steps in fouling.


AF-DX 384 binding in rabbit cingulate cortex: two site kinetics and section autoradiography.
Autoradiographic studies of muscarinic receptors are limited by the lack of selective ligands. Inasmuch as AF-DX 384 has a higher affinity for m2 than m4 receptors and pirenzepine (PZ) has a reverse affinity profile, competition between these ligands was used to label m2 receptors in homogenized and sectioned tissue. Rabbit cingulate cortex was used because m2 receptors are expressed by anterior thalamic axons in posterior cingulate cortex (PCC) and this region is easily deafferented with undercut lesions to demonstrate presynaptic binding. Saturation isotherms and Scatchard analysis of [3H]AF-DX 384 binding showed one binding site with a KD of 9 +/- 2.3 nM (mean +/- SEM) and a Bmax of 1405 +/- 146 fmol/mg protein. Competition studies with [3H]AF-DX 384 (2 nM) and 10(-10)-10(-4) M PZ were performed in anterior cingulate cortex (ACC) and PCC. In both regions, the best fit was a two site model for low (BL) and high (BH) affinity binding in which Bmax values were similar (ACC: BL = 535 +/- 62 fmol/mg, BH = 676 +/- 85; PCC: BL = 552 +/- 41; BH = 675 +/- 85). Although affinities for KH were similar in each region (ACC: KH = 4.69 +/- 1.36 nM; PCC: KH = 8.53 +/- 3.69 nM), those for KL were significantly different (ACC: 181 +/- 15.4 nM; PCC: 285 +/- 42; P = .018). Binding of [3H]AF-DX 384 with PZ (150 nM) was best fit with a single site model (KD = 6 +/- 0.01 nM; Bmax = 688 +/- 31 fmol/mg), suggesting that PZ blocks the lower affinity site. (ABSTRACT TRUNCATED AT 250 WORDS)


Influence of maternal and perinatal factors on subsequent hospitalisation for asthma in children: evidence from the Oxford record linkage study.
There is much interest in the possibility that perinatal factors may influence the risk of disease in later life. We investigated the influence of maternal and perinatal factors on subsequent hospital admission for asthma in children. Analysis of data from the Oxford record linkage study (ORLS) to generate a retrospective cohort of 248 612 records of births between 1970 and 1989, with follow-up to records of subsequent hospital admission for 4 017 children with asthma up to 1999. Univariate analysis showed significant associations between an increased risk of admission for asthma and later years of birth (reflecting the increase in asthma in the 1970s and 1980s), low social class, asthma in the mother, unmarried mothers, maternal smoking in pregnancy, subsequent births compared with first-born, male sex, low birth weight, short gestational age, caesarean delivery, forceps delivery and not being breastfed. Multivariate analysis, identifying each risk factor that had a significant effect independently of other risk factors, confirmed associations with maternal asthma (odds ratio (OR) 3.1, 95% confidence interval 2.7-3.6), male sex (versus female, 1.8, 1.7-2.0), low birth weight (1000-2999 g versus 3000-3999 g, 1.2, 1.1-1.3), maternal smoking (1.1, 1.0-1.3) and delivery by caesarean section (1.2; 1.0-1.3). In those first admitted with asthma under two years old, there were associations with having siblings (e.g. second child compared with first-born, OR 1.3, 1.0-1.7) and short gestational age (24-37 weeks versus 38-41 weeks, 1.6, 1.2-2.2). Multivariate analysis confined to those admitted with asthma aged six years or more, showed associations with maternal asthma (OR 3.8, 3.1-4.7), age of mother (under 25 versus 25-34 at birth, OR 1.16, 1.03-1.31; over 35 versus 25-34, OR 1.4, 1.1-1.7); high social class was protective (1 and 2, compared with 3, 0.72; 0.63-0.82). Hospital admission for asthma in people aged over six was more common in males than females (1.4; 1.2-1.5); but, by the teenage years, the sex ratio reversed and admission was more common in females than males. Several maternal characteristics and perinatal factors are associated with an elevated risk of hospital admission for asthma in the child in later life.


Cooperation of p27(Kip1) and p18(INK4c) in progestin-mediated cell cycle arrest in T-47D breast cancer cells.
The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. The long-term effect of progestins on T-47D breast cancer cells is inhibition of cellular proliferation. This is accompanied by decreased G(1) cyclin-dependent kinase (CDK) activities, redistribution of the CDK inhibitor p27(Kip1) among these CDK complexes, and alterations in the elution profile of cyclin E-Cdk2 upon gel filtration chromatography, such that high-molecular-weight complexes predominate. This study aimed to determine the relative contribution of CDK inhibitors to these events. Following progestin treatment, the majority of cyclin E- and D-CDK complexes were bound to p27(Kip1) and few were bound to p21(Cip1). In vitro, recombinant His(6)-p27 could quantitatively reproduce the effects on cyclin E-Cdk2 kinase activity and the shift in molecular weight observed following progestin treatment. In contrast, cyclin D-Cdk4 was not inhibited by His(6)-p27 in vitro or p27(Kip1) in vivo. However, an increase in the expression of the Cdk4/6 inhibitor p18(INK4c) and its extensive association with Cdk4 and Cdk6 were apparent following progestin treatment. Recombinant p18(INK4c) led to the reassortment of cyclin-CDK-CDK inhibitor complexes in vitro, with consequent decrease in cyclin E-Cdk2 activity. These results suggest a concerted model of progestin action whereby p27(Kip1) and p18(INK4c) cooperate to inhibit cyclin E-Cdk2 and Cdk4. Since similar models have been developed for growth inhibition by transforming growth factor beta and during adipogenesis, interaction between the Cip/Kip and INK4 families of inhibitors may be a common theme in physiological growth arrest and differentiation.


Ventriculoperitoneal Shunt Infection with Mycobacterium abscessus: A Rare Cause of Ventriculitis.
Mycobacterium abscessus is a rapidly growing atypical mycobacterium implicated in chronic lung disease, otitis media, surgical site infections, and disseminated cutaneous diseases. It is typically seen in patients with some degree of immunosuppression. Only 1 previous case has been reported in the setting of ventriculoperitoneal (VP) shunt infection. We report a case of M abscessus as the causative organism in a VP shunt infection in an immunocompetent adult. A 67-year-old woman required VP shunt placement after aneurysmal subarachnoid hemorrhage complicated by hydrocephalus. Her course was complicated by repeat hospitalization for 2 shunt infections, the second of which did not respond to standard antibiotic therapy. Cultures repeatedly grew M abscessus. The patient continued to decline and eventually died after transfer to the palliative care service. Nontuberculous mycobacteria are rare, atypical organisms in the setting of VP shunt infection. Patients with ventriculitis secondary to atypical mycobacteria may exhibit drug-resistant cerebrospinal fluid pleocytosis in the face of standard antibiotic regimens.


Hungry flies tune to vinegar.
Many molecular signals that represent hunger and satiety in the body have been identified, but relatively little is known about how these factors alter the nervous system to change behavior. Root et al. (2011) report that hunger modulates the sensitivity of specific olfactory sensory neurons in Drosophila and facilitates odor-search behavior.


Establishing, versus maintaining, brain function: a neuro-computational model of cortical reorganization after injury to the immature brain.
The effect of age at injury on outcome after acquired brain injury (ABI) has been the subject of much debate. Many argue that young brains are relatively tolerant of injury. A contrasting viewpoint due to Hebb argues that greater system integrity may be required for the initial establishment of a function than for preservation of an already-established function. A neuro-computational model of cortical map formation was adapted to examine effects of focal and distributed injury at various stages of development. This neural network model requires a period of training during which it self-organizes to establish cortical maps. Injuries were simulated by lesioning the model at various stages of this process and network function was monitored as "development" progressed to completion. Lesion effects are greater for larger, earlier, and distributed (multifocal) lesions. The mature system is relatively robust, particularly to focal injury. Activities in recovering systems injured at an early stage show changes that emerge after an asymptomatic interval. Early injuries cause qualitative changes in system behavior that emerge after a delay during which the effects of the injury are latent. Functions that are incompletely established at the time of injury may be vulnerable particularly to multifocal injury.


Measuring the psychological outcomes of falling: a systematic review.
The objectives were to identify fall-related psychological outcome measures and to undertake a systematic quality assessment of their key measurement properties. A Cochrane review of fall-prevention interventions in older adults was used to identify fall-related psychological measurements. PubMed, CINAHL, and PsycINFO were systematically searched to identify instruments not used in trials and papers reporting the methodological quality of relevant measures. Reference lists of articles were searched for additional literature, and researchers were contacted. Two reviewers undertook quality extraction relating to content, population, reliability, validity, responsiveness, practicality, and feasibility. Twenty-five relevant papers were identified. Twenty-three measures met the inclusion criteria: six single-item questions, Falls Efficacy Scale (FES), revised FES, modified FES, FES-UK, Activities-specific Balance and Confidence Scale (ABC), ABC-UK, Confidence in maintaining Balance Scale, Mobility Efficacy Scale, adapted FES, amended FES, Survey of Activities and Fear of Falling in the Elderly (SAFFE), University of Illinois at Chicago Fear of Falling Measure, Concern about Falling Scale, Falls Handicap Inventory, modified SAFFE, Consequences of Falling Scale, and Concern about the Consequences of Falling Scale. There is limited evidence about the measurement properties of single-item measures. Several multiitem measures obtained acceptable reliability and validity, but there is less evidence regarding responsiveness, practicality, and feasibility. Researchers should select measures based on the constructs they intend to study. Further research is needed to establish and compare the instruments' measurement properties.


Early Initiation of Antiretroviral Therapy Following In Utero HIV Infection Is Associated With Low Viral Reservoirs but Other Factors Determine Viral Rebound.
Early HIV diagnosis allows combination antiretroviral therapy (cART) initiation in the first days of life following in utero (IU) infection. The impact of early cART initiation on infant viral reservoir size in the setting of high-frequency cART nonadherence is unknown. Peripheral blood total HIV DNA from 164 early treated (day 0-21 of life) IU HIV-infected South African infants was measured using droplet digital PCR at birth and following suppressive cART. We evaluated the impact of cART initiation timing on HIV reservoir size and decay, and on the risk of subsequent plasma viremia in cART-suppressed infants. Baseline HIV DNA (median 2.8 log10 copies/million peripheral blood mononuclear cells, range 0.7-4.8) did not correlate with age at cART initiation (0-21 days) but instead with maternal antenatal cART use. In 98 infants with plasma viral suppression on cART, HIV DNA half-life was 28 days. However, the probability of maintenance of plasma aviremia was low (0.46 at 12 months) and not influenced by HIV DNA load. Unexpectedly, longer time to viral suppression was associated with protection against subsequent viral rebound. With effective prophylaxis against mother-to-child transmission, cART initiation timing in the first 3 weeks of life is not critical to reservoir size.


Characteristics and Circumstances of U.S. Women Who Obtain Very Early and Second-Trimester Abortions.
To determine which characteristics and circumstances were associated with very early and second-trimester abortion. Paper and pencil surveys were collected from a national sample of 8,380 non-hospital U.S. abortion patients in 2014 and 2015. We used self-reported LMP to calculate weeks gestation; when LMP was not provided we used self-reported weeks pregnant. We constructed two dependent variables: obtaining a very early abortion, defined as six weeks gestation or earlier, and obtaining second-trimester abortion, defined as occurring at 13 weeks gestation or later. We examined associations between the two measures of gestation and a range of characteristics and circumstances, including type of abortion waiting period in the patients' state of residence. Among first-trimester abortion patients, characteristics that decreased the likelihood of obtaining a very early abortion include being under the age of 20, relying on financial assistance to pay for the procedure, recent exposure to two or more disruptive events and living in a state that requires in-person counseling 24-72 hours prior to the procedure. Having a college degree and early recognition of pregnancy increased the likelihood of obtaining a very early abortion. Characteristics that increased the likelihood of obtaining a second-trimester abortion include being Black, having less than a high school degree, relying on financial assistance to pay for the procedure, living 25 or more miles from the facility and late recognition of pregnancy. While the availability of financial assistance may allow women to obtain abortions they would otherwise be unable to have, it may also result in delays in accessing care. If poor women had health insurance that covered abortion services, these delays could be alleviated. Since the study period, four additional states have started requiring that women obtain in-person counseling prior to obtaining an abortion, and the increase in these laws could slow down the trend in very early abortion.


First Report of Sclerotium rolfsii on Common Chickweed in North Carolina.
Common chickweed (Stellaria media (L.) Cyrillo) is a common weed species found in agricultural fields of northeastern North Carolina. Symptomatic plants of common chickweed were observed during a March 2001 survey of winter annual weed species in Perquimans County, NC. The plants were growing in a harvested peanut field with a known history of southern stem rot caused by Sclerotium rolfsii Sacc. Water-soaked, bleached stems and chlorotic leaves were collected from plants and brought to the laboratory for isolation. Small portions (1 to 2 cm) of symptomatic stems and entire leaves were rinsed with tap water and placed on potato dextrose agar (PDA). Developing colonies were transferred to obtain pure cultures. The rapidly growing cultures had coarse, white mycelium typical of S. rolfsii and produced abundant, small, round, brown sclerotia approximately 2.0 mm in diameter on the surface of the culture. Clamp connections were observed with microscopic examination of mycelia. Pathogenicity of isolates was tested by placing 4-mm-diameter agar plugs of 2-day-old fungal mycelium on stems of three mature, nonsymptomatic chickweed plants. Agar plugs without fungal mycelium were used for the control treatment. Plugs were held in place with self-sticking bandage gauze. Plants were misted with water, enclosed in plastic bags, and incubated on a laboratory counter top at ambient temperature (24°C). Abundant mycelia developed, and water-soaked lesions and necrotic stems were observed. Noninoculated plants remained healthy and free of signs and symptoms during the incubation period. The fungus was reisolated on PDA, and pure cultures of S. rolfsii were obtained. Koch's postulates confirmed common chickweed was a host of S. rolfsii. To our knowledge, this is the first report of common chickweed as a host of S. rolfsii. Crop species commonly used in peanut rotations (corn, small grains, sorghum, and cotton) do not support populations of S. rolfsii. Many dicotyledonous weed species have been reported as hosts of S. rolfsii, but our observation of active disease on a winter weed species was unexpected. Colonization of winter weed, if prevalent, may enhance survival of S. rolfsii between crops of susceptible hosts such as peanut.


Interface of signal transduction inhibition and immunotherapy in melanoma.
Food and Drug Administration-approved treatment for metastatic melanoma, including interferon alpha and interleukin-2, offer a modest benefit. Immunotherapy, although has not enjoyed high overall response rates, is capable of providing durable responses in a subset of patients. In recent years, new molecular-targeted therapies have become available and offer promise of clinical benefit, although low durability of response. It is not yet clear how best to integrate these 2 novel modalities that target the immune response to melanoma (immune therapy) or that target molecular signaling pathways in the melanoma cells (targeted therapy). Many signal transduction pathways are important in both tumor cell and T-cell proliferation and survival, which generate risk in combining targeted therapy and immunotherapy. This review focuses on the role of targeted therapy and immunotherapy in melanoma, and discusses how to combine the 2 modalities rationally for increased duration and response.


Neurexin in embryonic Drosophila neuromuscular junctions.
Neurexin is a synaptic cell adhesion protein critical for synapse formation and function. Mutations in neurexin and neurexin-interacting proteins have been implicated in several neurological diseases. Previous studies have described Drosophila neurexin mutant phenotypes in third instar larvae and adults. However, the expression and function of Drosophila neurexin early in synapse development, when neurexin function is thought to be most important, has not been described. We use a variety of techniques, including immunohistochemistry, electron microscopy, in situ hybridization, and electrophysiology, to characterize neurexin expression and phenotypes in embryonic Drosophila neuromuscular junctions (NMJs). Our results surprisingly suggest that neurexin in embryos is present both pre and postsynaptically. Presynaptic neurexin promotes presynaptic active zone formation and neurotransmitter release, but along with postsynaptic neurexin, also suppresses formation of ectopic glutamate receptor clusters. Interestingly, we find that loss of neurexin only affects receptors containing the subunit GluRIIA. Our study extends previous results and provides important detail regarding the role of neurexin in Drosophila glutamate receptor abundance. The possibility that neurexin is present postsynaptically raises new hypotheses regarding neurexin function in synapses, and our results provide new insights into the role of neurexin in synapse development.


Factors influencing the occurrence of airway hyperreactivity in the general population: the importance of atopy and airway calibre.
The factors that determine the occurrence of airway hyperreactivity in the general population are not clearly understood. This study was designed to assess the independent effects of age, atopy, smoking and airway calibre. In a random sample of 2,415 adults aged 18-70 yrs we measured reactivity to methacholine as the dose provoking a 20% fall (PD20) in one-second forced expiratory volume (FEV1), atopy as the mean skin wheal response to three common environmental allergens, and airway calibre as the baseline FEV1 in absolute terms, as percent predicted (FEV1 % predicted) and as percent forced vital capacity (FEV1 % FVC). Hyperreactivity, defined as a PD20 < or = 12.25 mumol, was present in 314 (13%) of the sample, and before adjustment for FEV1 was more common in females (independent odds ratio (OR) = 2.05 (95% confidence interval 1.6-2.7)), current smokers (OR = 1.89 (1.3-2.6)), atopics (OR = 1.39 (1.3-1.5) per mm skin wheal), and in older age groups (OR for age 60-70 yrs relative to 18-29 yrs = 2.70 (1.7-4.3)). However, the odds of hyperreactivity were also strongly and independently related to absolute FEV1 (OR = 0.46 (0.27-0.77) per litre), FEV1 % predicted (OR = 0.96 (0.94-0.98) per percent), and FEV1 % FVC (OR = 0.92 (0.90-0.94) per percent; combined chi-square on 3 df = 312, p << 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)


Deficits in hippocampal-dependent transfer generalization learning accompany synaptic dysfunction in a mouse model of amyloidosis.
Elevated β-amyloid and impaired synaptic function in hippocampus are among the earliest manifestations of Alzheimer's disease (AD). Most cognitive assessments employed in both humans and animal models, however, are insensitive to this early disease pathology. One critical aspect of hippocampal function is its role in episodic memory, which involves the binding of temporally coincident sensory information (e.g., sights, smells, and sounds) to create a representation of a specific learning epoch. Flexible associations can be formed among these distinct sensory stimuli that enable the "transfer" of new learning across a wide variety of contexts. The current studies employed a mouse analog of an associative "transfer learning" task that has previously been used to identify risk for prodromal AD in humans. The rodent version of the task assesses the transfer of learning about stimulus features relevant to a food reward across a series of compound discrimination problems. The relevant feature that predicts the food reward is unchanged across problems, but an irrelevant feature (i.e., the context) is altered. Experiment 1 demonstrated that C57BL6/J mice with bilateral ibotenic acid lesions of hippocampus were able to discriminate between two stimuli on par with control mice; however, lesioned mice were unable to transfer or apply this learning to new problem configurations. Experiment 2 used the APPswe PS1 mouse model of amyloidosis to show that robust impairments in transfer learning are evident in mice with subtle β-amyloid-induced synaptic deficits in the hippocampus. Finally, Experiment 3 confirmed that the same transfer learning impairments observed in APPswePS1 mice were also evident in the Tg-SwDI mouse, a second model of amyloidosis. Together, these data show that the ability to generalize learned associations to new contexts is disrupted even in the presence of subtle hippocampal dysfunction and suggest that, across species, this aspect of hippocampal-dependent learning may be useful for early identification of AD-like pathology.


Protecting residential care facilities from pandemic influenza.
It is widely believed that protecting health care facilities against outbreaks of pandemic influenza requires pharmaceutical resources such as antivirals and vaccines. However, early in a pandemic, vaccines will not likely be available and antivirals will probably be of limited supply. The containment of pandemic influenza within acute-care hospitals anywhere is problematic because of open connections with communities. However, other health care institutions, especially those providing care for the disabled, can potentially control community access. We modeled a residential care facility by using a stochastic compartmental model to address the question of whether conditions exist under which nonpharmaceutical interventions (NPIs) alone might prevent the introduction of a pandemic virus. The model projected that with currently recommended staff-visitor interactions and social distancing practices, virus introductions are inevitable in all pandemics, accompanied by rapid internal propagation. The model identified staff reentry as the critical pathway of contagion, and provided estimates of the reduction in risk required to minimize the probability of a virus introduction. By using information on latency for historical and candidate pandemic viruses, we developed NPIs that simulated notions of protective isolation for staff away from the facility that reduced the probability of bringing the pandemic infection back to the facility to levels providing protection over a large range of projected pandemic severities. The proposed form of protective isolation was evaluated for social plausibility by collaborators who operate residential facilities. It appears unavoidable that NPI combinations effective against pandemics more severe than mild imply social disruption that increases with severity.


A thin film optical cavity to induce absorption or thermal emission.
Several variations are given of a relatively simple thin film optical cavity construction which can be designed either to induce absorption in a weak absorber or to induce thermal emission from a weak emitter. In both cases the cavity is very selective with respect to polarization and wavelength.


The effect of APOE and other common genetic variants on the onset of Alzheimer's disease and dementia: a community-based cohort study.
Alzheimer's disease is one of the most heritable diseases in elderly people and the most common type of dementia. In addition to the major genetic determinant of Alzheimer's disease, the APOE gene, 23 genetic variants have been associated with the disease. We assessed the effects of these variants and APOE on cumulative risk and age at onset of Alzheimer's disease and all-cause dementia. We studied incident dementia in cognitively healthy participants (aged >45 years) from the community-based Rotterdam Study, an ongoing prospective cohort study based in Rotterdam, the Netherlands, focusing on neurological, cardiovascular, endocrine, and ophthalmological disorders, and other diseases in elderly people. The Rotterdam Study comprises participants in three baseline cohorts (initiated in 1990, 2000, and 2006), who are re-invited to the research centre every 3-4 years, and continuously monitored by records from general practitioners and medical specialists. Cumulative incidence curves up to age 100 years were calculated for Alzheimer's disease and dementia, taking into account mortality as a competing event. These risk curves were stratified by APOE genotypes, tertiles of a weighted genetic risk score (GRS) of 23 Alzheimer's disease-associated genetic variants, and parental history of dementia. 12 255 of 14 926 participants (58·5% women) from the Rotterdam Study were included in this study. During a median follow-up of 11·0 years (IQR 4·9-15·9; 133 123 person years), 1609 participants developed dementia, of whom 1262 (78%) were classified as having Alzheimer's disease; 3310 people died of causes other than dementia. Both APOE and the GRS significantly modified the risks of Alzheimer's disease and dementia. There was evidence for a significant interaction between APOE genotypes and the GRS for the association with Alzheimer's disease (p=0·03) and dementia (p=0·04); the risk for carriers homozygous for APOE ε4 was modified most by the GRS. In carriers homozygous for APOE ε4, the difference between the high-risk tertile and the low-risk tertile by age 85 years was 27·0% for Alzheimer's disease (p=8·5 × 10-3) and 37·2% for dementia (p=2·2 × 10-4), which translates to a 7-10 year difference in age at onset. Comparing the risk extremes, which were carriers homozygous for APOE ε2 or heterozygous with one copy each of the ε2 and ε3 alleles in the low-risk tertile of the GRS versus carriers homozygous for APOE ε4 in the high-risk tertile of the GRS, the difference in risk by age 85 years was 58·6% (4·1% vs 62·7%; p=6·2 × 10-13) for Alzheimer's disease, and 70·3% (7·2% vs 77·5%; p=3·0 × 10-23) for dementia. These risk differences translate into an 18-29 years difference in age at onset for Alzheimer's disease and an 18-23 year difference in age at onset dementia. This difference becomes more pronounced when parental history of dementia is considered (difference in risk 83·8%; p=1·1 × 10-20). Common variants with small individual effects jointly modify the risk and age at onset of Alzheimer's disease and dementia, particularly in APOE ε4 carriers. These findings highlight the potential of common variants in determining Alzheimer's disease risk. None.


Design and tolerance analysis of a router with an amplified resonator and Bragg gratings.
A novel ring resonator configuration with Bragg gratings is presented. The stability of this configuration is studied by a z-transform technique. A router design with a FWHM of 17 MHz, a -40-dB rejection ratio, and a 15-dB gain at the output port is reported. The influence of temperature and of fabrication tolerance on parameters of this router configuration implemented with fiber technology is reviewed. Deviations in design specification owing to parameter variations are studied and compensated for with a gain control of 2.4% in a specific design.


Palaeoproteomics gives new insight into early southern African pastoralism.
The advent of domestication is a major step that transformed the subsistence strategies of past human societies. In Africa, domestic caprines (sheep and goat) were introduced in the north-eastern part of the continent from the Near East more than 9000 years ago. However, their diffusion southwards was slow. They are thought to have made their first appearance in the southern part of the continent ca. 2000 years ago, at a few Later Stone Age sites, including Leopard Cave (Erongo region, Namibia), which provided the oldest directly dated remains assigned to sheep or goat on the basis of morphology of bones and teeth. However, similarities in morphology, not only between these two domesticated caprine species, but also between them and the small wild antelopes, raised questions about the morphological species attribution of these remains. Additionally, the high fragmentation of the site's osteological remains makes it difficult to achieve species-level taxonomic identification by comparative anatomy. In this paper, we report molecular species identification of the Leopard Cave remains using palaeoproteomics, a method that uses protein markers in bone and tooth collagen to achieve taxonomic identification of archaeological remains. We also report new direct radiocarbon dates. Wild antelope remains from museum collections were used to enrich the available protein record and propose de novo type I collagen sequences. Our results demonstrate that the remains morphologically described as domesticates actually belong to a wild antelope species and that domestic caprines first appeared at Leopard Cave 1500 years later than previously thought. This study illustrates that the use of palaeoproteomics coupled with direct radiocarbon dates is particularly suited to complement classic zooarchaeological studies, in this case concerning the arrival of the first herding practices in arid environments.


Phase function of a spherical particle when scattering an inhomogeneous electromagnetic plane wave.
In absorbing media, electromagnetic plane waves are most often inhomogeneous. Existing solutions for the scattering of an inhomogeneous plane wave by a spherical particle provide no explicit expressions for the scattering components. In addition, current analytical solutions require evaluation of the complex hypergeometric function F12 for every term of a series expansion. In this work, I develop a simpler solution based on associated Legendre functions with argument zero. It is similar to the solution for homogeneous plane waves but with new explicit expressions for the angular dependency of the far-field scattering components, that is, the phase function. I include recurrence formulas for practical evaluation and provide numerical examples to evaluate how well the new expressions match previous work in some limiting cases. The predicted difference in the scattering phase function due to inhomogeneity is not negligible for light entering an absorbing medium at an oblique angle. The presented theory could thus be useful for predicting scattering behavior in dye-based random lasing and in solar cell absorption enhancement.


[Influence of tenotomy on posttetanic responses of the rat fast and slow muscle].
The effect of two weeks of tenotomy on posttetanic isometric contractile responses of the rat fast: Extensor digitorum longus and slow: soleus muscles was studied in experiments on isolated muscle preparations. Direct tetanic stimulation (100 impulses, 50 Hz) increased the force of contractions by 20-25% (p < 0.05) of both, control and tenotomized fast muscles. Identical to above tetanic stimulation of control, slow muscle resulted in posttetanic depression, a decrease in the amplitude of contractile responses. Tenotomized slow muscles did not develop posttetanic depression. Caffeine (4 mM) increased and dandrolene (10 microM) decreased the force of unitary and tetanic contractions of control and tenotomized muscles. Neither drug, however, affected development of posttetanic phenomena in ether fast or slow muscles. The fact that in extensor digitorum longus, posttetanic potentiation is preserved for at least forty days of tenotomy but disappears after only 2 weeks of denervation suggests important role of neurotrophic influences in regulation of posttetanic responses of fast muscles.


ANTIBIOTIC RESISTANT BACTERIA IN WILDLIFE: PERSPECTIVES ON TRENDS, ACQUISITION AND DISSEMINATION, DATA GAPS, AND FUTURE DIRECTIONS.
The proliferation of antibiotic-resistant bacteria in the environment has potential negative economic and health consequences. Thus, previous investigations have targeted wild animals to understand the occurrence of antibiotic resistance in diverse environmental sources. In this critical review and synthesis, we summarized important concepts learned through the sampling of wildlife for antibiotic-resistant indicator bacteria. These concepts are helpful for understanding dissemination of resistance through environmental pathways and helping to guide future research efforts. Our review begins by briefly introducing antibiotic resistance as it pertains to bacteria harbored in environmental sources such as wild animals. Next, we differentiate wildlife from other animals in the context of how diverse taxa provide different information on antibiotic resistance in the environment. In the third section of our review, we identify representative research and seminal works that illustrate important associations between the occurrence of antibiotic-resistant bacteria in wildlife and anthropogenic inputs into the environment. For example, we highlight numerous investigations that support the premise that anthropogenic inputs into the environment drive the occurrence of antibiotic resistance in bacteria harbored by free-ranging wildlife. Additionally, we summarize previous research demonstrating foraging as a mechanism by which wildlife may be exposed to anthropogenic antibiotic resistance contamination in the environment. In the fourth section of our review, we summarize molecular evidence for the acquisition and dissemination of resistance among bacteria harbored by wildlife. In the fifth section, we identify what we believe to be important data gaps and potential future directions that other researchers may find useful toward the development of efficient, informative, and impactful investigations of antibiotic-resistant bacteria in wildlife. Finally, we conclude our review by highlighting the need to move from surveys that simply identify antibiotic-resistant bacteria in wildlife toward hypothesis-driven investigations that: 1) identify point sources of antibiotic resistance; 2) provide information on risk to human and animal health; 3) identify interventions that may interrupt environmentally mediated pathways of antibiotic resistance acquisition and transmission; and 4) evaluate whether management practices are leading to desirable outcomes.


Assessment of gene promoter G‑quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells.
Naphthalene diimide (NDI) derivatives have shown high affinity for telomeric guanine (G)‑quadruplexes and good antiproliferative activity in different human tumor experimental models. A trisubstituted compound (H‑NDI‑NMe2) has been reported to stabilize the telomeric G‑quadruplex and to cause telomere dysfunction and downregulation of telomerase expression. We further investigated its mechanism of action by analyzing the capability of the molecule to interfere with the expression levels of oncogenes, such as MYC, telome-rase reverse transcriptase (TERT), KIT and BCL2, known to bear G‑quadruplex‑forming sequences within their promoters, in human tumor cell lines of different histological origin. Exposure to H‑NDI‑NMe2 resulted in a cell type‑dependent perturbation of the expression levels of the four selected genes. Biophysical and molecular analyses revealed that H‑NDI‑NMe2 bound with high affinity and effectively stabilized mainly MYC and BCL2, which share long sequences and the possibility of multiple G‑quadruplex folding. The mRNA levels of both genes, but not protein amounts were affected by NDI treatment. Global gene expression analysis showed modulation of genes implicated in telomere function and mechanisms of cancer; however, G‑quadruplex‑mediated regulation of gene expression by H‑NDI‑NMe2 was largely dependent on the cell context. These data indicate that a deeper knowledge on the molecular mechanisms and biological effects of G‑quadruplex structures is still needed to help developing new effective anticancer agents.


A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part III. Clinical pathology and pathogenesis.
Crimean-Congo haemorrhagic fever (CCHF) was diagnosed in 8 patients; 7 were staff members at Tygerberg Hospital who had been infected by a patient in whom the disease had not initially been diagnosed. Two patients, the initial case and a staff member, died and 4 became seriously ill. The immunopathogenesis of CCHF appears to be multifactorial. Certain features were common to all patients--leucopenia, thrombocytopenia, elevated liver enzyme values and low serum total protein levels. Ultrastructural changes in and around skin capillaries, including intracytoplasmic endothelial tuboreticulated bodies, were found. Virus-like particles were found on electron microscopy. Important individual factors related to prognosis were identified. The patients who survived all mounted a good antibody response, and manifested no coagulation defect extensive enough to explain the haemorrhagic tendency. In the patients who died no evidence of antibody production was detected; both developed diffuse intravascular coagulation and in 1 evidence of immune complex formation and complement consumption was found. Hepatorenal failure and cardiovascular collapse characterized the terminal period. Early clinical recognition of CCHF with specific attention to factors amenable to treatment may vastly improve the prognosis.


Adult attachment as a predictor of posttraumatic stress and dissociation.
This study examined whether K. Bartholomew's (1990) self-report dimensions of adult attachment (secure, dismissing, preoccupied, and fearful) mediate or moderate links from victimization/abuse to posttraumatic stress and dissociation. Participants were 199 college women with and without a history of childhood physical abuse, childhood sexual victimization, and adolescent/adult sexual victimization. Path analysis revealed no significant mediation effects for attachment; however, hierarchical multiple linear regression indicated that dismissing attachment moderated the link between victimization/abuse and posttraumatic stress (i.e., the relationship was strongest for women with high dismissing scores). All 4 attachment dimensions uniquely predicted posttraumatic stress, whereas only fearful attachment uniquely predicted dissociation.


Complete genome anatomy of the emerging potato pathogen Dickeya solani type strain IPO 2222T.
Several species of the genus Dickeya provoke soft rot and blackleg diseases on a wide range of plants and crops. Dickeya solani has been identified as the causative agent of diseases outbreaks on potato culture in Europe for the last decade. Here, we report the complete genome of the D. solani IPO 2222T. Using PacBio and Illumina technologies, a unique circular chromosome of 4,919,833 bp was assembled. The G + C content reaches 56% and the genomic sequence contains 4,059 predicted proteins. The ANI values calculated for D. solani IPO 2222T vs. other available D. solani genomes was over 99.9% indicating a high genetic homogeneity within D. solani species.


Multidisciplinary approach for management of a patient with fibrous dysplasia of maxilla.
Fibrous dysplasia is a non-neoplastic hamartomatous developmental fibro-osseous lesion of bone. Monostotic fibrous dysplasia is more common than the polyostotic form and usually involves jaw bones, ribs and femur. Maxillary lesions may extend to involve the maxillary sinus, zygoma, sphenoid bone and floor of the orbit and require surgical intervention resulting in an acquired defect of the involved site. A multidisciplinary team approach involving an oral pathologist, oral surgeon, oral medicine expert and maxillofacial prosthodontist is required for successful treatment and rehabilitation of such patients. This article describes a case of a patient with fibrous dysplasia of the left maxilla, which was successfully managed by integrating surgical intervention and postoperative rehabilitation, with a surgical obturator and an interim partial denture prosthesis that successfully limited the detrimental effects of surgery, and helped the patient in resocialisation, thereby improving her quality of life.


Race: a Drosophila homologue of the angiotensin converting enzyme.
We report the isolation and characterization of a putative angiotensin converting enzyme (ACE) in Drosophila, called Race. General interest in mammalian ACE stems from its association with high blood pressure; ACE has also been implicated in a variety of other physiological processes including the processing of neuropeptides and gut peristalsis. Mammalian ACE is a membrane associated zinc binding protease that converts angiotensin I (A I) into angiotensin II (A II). A II functions as a potent vasoconstrictor by triggering a G-coupled receptor system in the smooth muscles that line blood vessels. Drosophila Race is composed of 615 amino acid residues, and shares extensive sequence identity with mammalian ACE over its entire length (over 42% overall identity and greater than 60% similarity). Evidence is presented that Race might correspond to a target of the homeobox regulatory gene, zerknullt (zen). Soon after zen expression is restricted to the dorsal-most regions of the embryonic ectoderm, Race is activated in a coincident pattern and becomes associated with the amnioserosa during germ band elongation, shortening and heart morphogenesis. After germ band elongation, Race is also expressed in both the anterior and posterior midgut, where it persists throughout embryogenesis. Race expression is lost from the dorsal ectoderm in either zen- or dpp- mutants, although gut expression is unaffected. P-transformation assays and genetic complementation tests suggest that Race corresponds to a previously characterized lethal complementation group, 1(2)34Eb. Mutants die during larval/pupal development, and transheterozygotes for two different lethal alleles exhibit male sterility. We propose that Race might play a role in the contractions of the heart, gut, or testes and also suggest that Hox genes might be important for coordinating both developmental and physiological processes.


Stemness or not stemness? Current status and perspectives of adult retinal stem cells.
Many retinal dystrophies are associated with photoreceptor loss, which causes irreversible blindness. The recent identification of various sources of stem cells in the mammalian retina has raised the possibility that cell-based therapies might be efficient strategies to treat a wide range of incurable eye diseases. A first step towards the successful therapeutic exploitation of these cells is to unravel intrinsic and extrinsic regulators that control their proliferation and cell lineage determination. In this review, we provide an overview of the different types and molecular fingerprints of retinal stem cells identified so far. We also detail the current knowledge on molecular cues that influence their self-renewal and proliferation capacity. In particular, we focus on recent data implicating developmental signaling pathways, such as Wnt, Notch and Hedeghog, both in the normal and regenerating retina in different animal models. Last, we discuss the potential of ES cells and various adult stem cells for retinal repair.


Monocyte function in cirrhosis.
Monocyte function has been studied in a total of 51 patients with biopsy-proven cirrhosis and 35 controls. There was significantly reduced monocyte spreading (p less than 0.05), chemotaxis (p less than 0.02), bacterial phagocytosis (p less than 0.05) and bacterial killing (p less than 0.02) in the cirrhotics compared to the controls. Monocytes from patients with cirrhosis produced significantly less of the lysosomal enzymes N-acetyl beta-glucosaminidase and beta-glucuronidase than those obtained from the controls (p less than 0.02). There was no significant difference in the number of monocytes obtained, the number of macrophage precursors, and the nitro-blue tetrazoline (NBT) reduction between the cirrhotic and the controls. The reduced function appeared to be mainly due to a circulating inhibitory factor and could be corrected by incubation of the cirrhotic cells in serum from control subjects. The response of monocytes from patients with cirrhosis did not differ from the controls in their response to added endotoxin or latex particles suggesting that they are capable of a normal response in the absence of the inhibitory factor. Paired specimens of portal and systemic serum were collected from patients with no evidence of liver disease undergoing vascular surgery. When added to normal human monocytes the portal serum caused a significant reduction in bacterial killing (p less than 0.02) and chemotaxis (p less than 0.05) compared to results obtained in the paired systemic serum. Mixing experiments suggests the presence of an active inhibitor in the portal serum. The results suggest that monocyte function is reduced in cirrhosis apparently due to a serum inhibitor which may have originated from the portal vein. The abnormalities may account in part for the increased susceptibility of these patients to infection.


[Agreement between Five Definitions of Metabolic Syndrome: Cartagena, Colombia].
During last decade the metabolic syndrome has been defined by five different guidelines. Discrepancies in such definitions could influence syndrome predictive ability over cardiovascular diseases. The aim of this study was to determine the degree of agreement between these five guidelines, in population from Cartagena (Colombia). A cross sectional study was conducted in adults from urban zone. Sample size was estimated based on 2005 DANE census, which included 670 individuals. The prevalence of metabolic syndrome was determined through the WHO (World Health Organization), AHA/NHLBI (American Heart Association/National Heart Lung and Blood Institute), ATP III (Adult Treatment Panel III), IDF (International Diabetes Federation) and JIS (Joint Interim Statement) guidelines. Frequencies obtained were compared through Cohen's kappa index. According to JIS, IDF, ATPIII, AHA/NHBLI and WHO guidelines, metabolic syndrome prevalence was 36.3% [32.6 - 39.9], 35.1%, 30.3%, 24.2% and 4.9%. Agreement between JIS and IDF was 0.893, while index for these two guidelines with AHA/NHLBI was 0.778 y 0.750, respectively. ATPIII had a lower agreement with JIS and IDF (0.711 and 0.645, respectively), however with AHA/NHLBI agreement was 0.863. WHO presented a agreement with the others guidelines between 0.14 and 0.16. Significant agreement was found between the four most recent guidelines. Abdominal obesity cut-off points might support differences agreement differences.


Drug silica nanocomposite: preparation, characterization and skin permeation studies.
The aim of this work was to evaluate silica nanocomposites as topical drug delivery systems for the model drug, caffeine. Preparation, characterization, and skin permeation properties of caffeine-silica nanocomposites are described. Caffeine was loaded into the nanocomposites by grinding the drug with mesoporous silica in a ball mill up to 10 h and the efficiency of the process was studied by XRPD. Formulations were characterized by several methods that include FTIR, XRPD, SEM and TEM. The successful loading of caffeine was demonstrated by XRPD and FTIR. Morphology was studied by SEM that showed particle size reduction while TEM demonstrated formation of both core-shell and multilayered caffeine-silica structures. Solid-state NMR spectra excluded chemical interactions between caffeine and silica matrix, thus confirming that no solid state reactions occurred during the grinding process. Influence of drug inclusion in silica nanocomposite on the in vitro caffeine diffusion into and through the skin was investigated in comparison with a caffeine gel formulation (reference), using newborn pig skin and vertical Franz diffusion cells. Results from the in vitro skin permeation experiments showed that inclusion into the nanocomposite reduced and delayed caffeine permeation from the silica nanocomposite in comparison with the reference, independently from the amount of the tested formulation.


Managing manifest diseases, but not health risks, saved PepsiCo money over seven years.
Workplace wellness programs are increasingly popular. Employers expect them to improve employee health and well-being, lower medical costs, increase productivity, and reduce absenteeism. To test whether such expectations are warranted, we evaluated the cost impact of the lifestyle and disease management components of PepsiCo's wellness program, Healthy Living. We found that seven years of continuous participation in one or both components was associated with an average reduction of $30 in health care cost per member per month. When we looked at each component individually, we found that the disease management component was associated with lower costs and that the lifestyle management component was not. We estimate disease management to reduce health care costs by $136 per member per month, driven by a 29 percent reduction in hospital admissions. Workplace wellness programs may reduce health risks, delay or avoid the onset of chronic diseases, and lower health care costs for employees with manifest chronic disease. But employers and policy makers should not take for granted that the lifestyle management component of such programs can reduce health care costs or even lead to net savings.


Sequence analysis of a rice BAC covering the syntenous barley Rpg1 region
In the course of map-based cloning of the barley stem rust resistance gene Rpg1, we identified a rice bacterial artificial chromosome (BAC) containing the Rpg1 flanking markers. Based on the excellent gene order colinearity between barley and rice in this region, we expected that this rice BAC would contain the barley Rpg1 homologue. In order to identify the putative rice homologue, we sequenced ca. 35 kb of the rice BAC at random and then an additional 33 kb of contiguous sequence between the two most closely spaced Rpg1 flanking markers. Sequence analysis revealed a total of 15 putative genes, 5 within the 33-kb contiguous region. A rice Rpg1 homologue was not identified, although a gene encoding a hypothetical polypeptide with similarity to a membrane protein could not be eliminated as a candidate. Surprisingly, four of the genes identified in the 33-kb contiguous rice sequence showed a high degree of similarity with genes on Arabidopsis chromosome 4. The genome regions harboring these genes showed some relatedness, but many rearrangements were also evident. These data suggest that some genes have remained linked even over the long evolutionary separation of Arabidopsis and rice, as has also been reported for mammals and invertebrates.


Comparative-effectiveness of vancomycin and linezolid as part of guideline-recommended empiric therapy for healthcare-associated pneumonia.
Linezolid has been directly compared to vancomycin in pneumonia; however, most clinical trials have not compared outcomes specifically in the healthcare-associated pneumonia (HCAP) population. The objective of this study was to compare the effectiveness of vancomycin and linezolid in a national cohort of hospitalized veterans with HCAP. This was a retrospective cohort study of Veterans Health Administration patients admitted to >150 hospitals across the United States between 2002 and 2007. Patients were included if they were at least 65 years old, had an ICD-9-CM code for pneumonia, had one or more HCAP risk factors, and received guideline-concordant antibiotic therapy with linezolid or vancomycin within 48 h of admission. Critically ill patients were excluded. Multivariable logistic regression models and propensity scores were used to examine the association between linezolid or vancomycin therapy and 30-day mortality. A total of 1211 patients met study criteria; 946 received vancomycin and 265 received linezolid. Thirty-day mortality was higher in patients treated with vancomycin (n = 243; 25.7 %) as compared to linezolid (n = 33; 12.5 %) (adjusted OR 2.56; 95 % CI 1.67-4.04). Vancomycin use (n = 945) was also predictive of 30-day mortality compared to linezolid use (n = 264) in the propensity score analysis (adjusted OR 2.55; 95 % CI 1.66-4.02). Linezolid was associated with decreased patient mortality compared to vancomycin in a national cohort of non-critically ill, hospitalized veterans with HCAP.


Task force of the EFMI journals: background, rationale and purpose.
The paper presents an analysis of how EFMI disseminates new knowledge and the active medical informatics journals in EFMI member countries was carried out as an outcome of the EFMI Council meeting in London in 2008. The analysis identifies eight active major informatics journals and a several other publications. Most are subscription-based and are published at least quarterly. There is a possibility for the editors to meet regularly and form a community of practice with the aim of further improving their effectiveness in disseminating new knowledge and best practice in medical informatics. It is feasible to share expertise and it may be possible to harmonise several aspects of preparation and submission of manuscripts so that some identified barriers in publishing are reduced.


YerA41, a Yersinia ruckeri Bacteriophage: Determination of a Non-Sequencable DNA Bacteriophage Genome via RNA-Sequencing.
YerA41 is a Myoviridae bacteriophage that was originally isolated due its ability to infect Yersinia ruckeri bacteria, the causative agent of enteric redmouth disease of salmonid fish. Several attempts to determine its genomic DNA sequence using traditional and next generation sequencing technologies failed, indicating that the phage genome is modified in such a way that it is an unsuitable template for PCR amplification and for conventional sequencing. To determine the YerA41 genome sequence, we performed RNA-sequencing from phage-infected Y. ruckeri cells at different time points post-infection. The host-genome specific reads were subtracted and de novo assembly was performed on the remaining unaligned reads. This resulted in nine phage-specific scaffolds with a total length of 143 kb that shared only low level and scattered identity to known sequences deposited in DNA databases. Annotation of the sequences revealed 201 predicted genes, most of which found no homologs in the databases. Proteome studies identified altogether 63 phage particle-associated proteins. The RNA-sequencing data were used to characterize the transcriptional control of YerA41 and to investigate its impact on the bacterial gene expression. Overall, our results indicate that RNA-sequencing can be successfully used to obtain the genomic sequence of non-sequencable phages, providing simultaneous information about the phage-host interactions during the process of infection.


Elevated HbA1c is an independent predictor of aggressive clinical behavior in patients with colorectal cancer: a case-control study.
The aim of this study was to seek an association between the control of type 2 diabetes mellitus (T2DM), as determined by hemoglobin A1c (HbA1c) levels, and the outcome of colorectal cancer (CRC). We performed a retrospective review of patients with T2DM who had CRC diagnosed between 1997 and 2001. We defined well-controlled T2DM as HbA1c < 7.5% and poorly controlled T2DM as HbA1c > or = 7.5%. A group of age- and gender-matched patients who had CRC without T2DM were used as controls. Forty clinical factors were reviewed, and those associated with poor clinical outcome in each group were examined by univariate analysis (UA) and by the maximum likelihood analysis of logistic regression to determine the independent predictors of cancer outcome. We identified 155 patients with T2DM and CRC, and 114 control patients who had CRC without T2DM. We found no significant differences in any clinical factor by UA between the patients with well-controlled T2DM and the patients who had CRC without T2DM. Compared to both of those patients groups, in contrast, the patients with poorly controlled T2DM had more right-sided CRCs (P = 0.04, OR = 2, 95% CI = 1-4.1), more advanced CRCs (P = 0.02, OR = 2.1, 95% CI = 1-4.4), a younger age of presentation (P = 0.05), greater use of exogenous insulin (P = 0.002), and a poorer 5-year survival (P = 0.001) by UA. Logistic regression showed that poorly controlled T2DM independently predicted the early onset of CRC, a more advanced stage at the time of presentation, poorer 5-year survival, and an increased incidence of right-sided CRCs. In patients with T2DM who have CRC, poor glycemic control is associated with a clinically aggressive course for the cancer.


A broadband planar terahertz metamaterial with nested structure.
We demonstrate the broadening of fundamental resonance in terahertz metamaterial by successive insertion of metal rings in the original unit cell of a split ring resonator (SRR) forming an inter connected nested structure. With the subsequent addition of each inner ring, the fundamental resonance mode shows gradual broadening and blue shift. For a total of four rings in the structure the resonance linewidth is enhanced by a factor of four and the blue shift is as large as 316 GHz. The dramatic increase in fundamental resonance broadening and its blue shifting is attributed to the decrease in the effective inductance of the entire SRR structure with addition of each smaller ring. We also observe that while the fundamental resonance is well preserved, the dipolar mode resonance undergoes multiple splittings with the addition of each ring in the nest. Such planar metamaterials, possessing broadband resonant response in the fundamental mode of operation, could have potential applications for extending the properties of metamaterials over a broader frequency range of operations.


Mycobacterium tuberculosis PPD-induced immune biomarkers measurable in vitro following BCG vaccination of UK adolescents by multiplex bead array and intracellular cytokine staining.
The vaccine efficacy reported following Mycobacterium bovis Bacillus Calmette Guerin (BCG) administration to UK adolescents is 77% and defining the cellular immune response in this group can inform us as to the nature of effective immunity against tuberculosis. The aim of this study was to identify which cytokines and lymphocyte populations characterise the peripheral blood cellular immune response following BCG vaccination. Diluted blood from before and after vaccination was stimulated with Mycobacterium tuberculosis purified protein derivative for 6 days, after which soluble biomarkers in supernatants were assayed by multiplex bead array. Ten out of twenty biomarkers measured were significantly increased (p < 0.0025) 1 month after BCG vaccination when compared to paired samples (n = 12) taken prior to vaccination (IFNgamma, TNFalpha, IL-1alpha, IL-2, IL-6, IL-10, IL-17, GM-CSF, MIP1alpha, IP-10). All of these remained detectable by multiplex bead array in samples taken 12 months after BCG vaccination of a partially overlapping adolescent group (n = 12). Intracellular cytokine staining after 24 hour Mycobacterium tuberculosis purified protein derivative stimulation of PBMC samples from the 12 month group revealed that IFNgamma expression was detectable in CD4 and CD8 T-cells and natural killer cells. Polyfunctional flow cytometry analysis demonstrated that cells expressing IFNgamma alone formed the majority in each subpopulation of cells. Only in CD4 T-cells and NK cells were there a notable proportion of responding cells of a different phenotype and these were single positive, TNFalpha producers. No significant expression of the cytokines IL-2, IL-17 or IL-10 was seen in any population of cells. The broad array of biomarker responses detected by multiplex bead array suggests that BCG vaccination is capable, in this setting, of inducing a complex immune phenotype. Although polyfunctional T-cells have been proposed to play a role in protective immunity, they were not present in vaccinated adolescents who, based on earlier epidemiological studies, should have developed protection against pulmonary tuberculosis. This may be due to the later sampling time point available for testing or on the kinetics of the assays used.


Extended-release naltrexone opioid treatment at jail reentry (XOR).
Extended-release naltrexone (XR-NTX) is an injectable monthly sustained-release mu opioid receptor antagonist, which blocks the typical effects of heroin and other opioid agonists. Use of XR-NTX among opioid dependent persons leaving jails and prisons is increasing despite scant high-quality evidence regarding XR-NTX's effectiveness at re-entry. This 24-week, open-label randomized controlled trial examines the effectiveness of XR-NTX as opioid relapse prevention at release from jail (N=85) compared to enhanced treatment as usual (ETAU, N=85). A third, non-randomized, quasi-experimental naturalistic arm of participants who have newly initiated a jail-to-community methadone treatment program (MTP, N=85) allows for comparisons to a methadone standard-of-care. We describe the rationale, design, and primary and secondary outcomes of the study. The primary outcome is an opioid relapse event; the primary contrast is a time-to-relapse comparison of XR-NTX and ETAU over a 24-week treatment phase. Secondary outcomes are rates of: (a) post-release opioid treatment participation, (b) opioid, alcohol, and cocaine use, (c) injection drug use and HIV sexual risk behaviors, (d) overdose (fatal and non-fatal) and all-cause mortality, and, (e) re-incarceration. XR-NTX is a potentially important, effective treatment and relapse prevention option for a large US population of persons with opioid use disorders leaving jails. This study will estimate XR-NTX's effectiveness relative to existing standards of care, including counseling-only treatment-as-usual and methadone maintenance.


Adult attention deficit hyperactivity symptoms and psychosis: Epidemiological evidence from a population survey in England.
Despite both having some shared features, evidence linking psychosis and adult attention deficit hyperactivity disorder (ADHD) is sparse and inconsistent. Hypotheses tested were (1) adult ADHD symptoms are associated with auditory hallucinations, paranoid ideation and psychosis (2) links between ADHD symptoms and psychosis are mediated by prescribed ADHD medications, use of illicit drugs, and dysphoric mood. The Adult Psychiatric Morbidity Survey 2007 (N=7403) provided data for regression and multiple mediation analyses. ADHD symptoms were coded from the ADHD Self-Report Scale (ASRS). Higher ASRS total score was significantly associated with psychosis, paranoid ideation and auditory hallucinations despite controlling for socio-demographic variables, verbal IQ, autism spectrum disorder traits, childhood conduct problems, hypomanic and dysphoric mood. An ASRS score indicating probable ADHD diagnosis was also significantly associated with psychosis. The link between higher ADHD symptoms and psychosis, paranoia and auditory hallucinations was significantly mediated by dysphoric mood, but not by use of amphetamine, cocaine or cannabis. In conclusion, higher levels of adult ADHD symptoms and psychosis are linked and dysphoric mood may form part of the mechanism. Our analyses contradict the traditional clinical view that the main explanation for people with ADHD symptoms developing psychosis is illicit drugs.


Disproportionate Participation of Males and Females in Academic Pediatric Orthopaedics: An Analysis of Abstract Authorship at POSNA 2009-2013.
Despite increasing numbers of female orthopaedic surgeons, we hypothesized that women were not actively participating at national and international meetings in numbers proportional to their membership. A retrospective review of the 2009-2013 POSNA Annual Meeting Final Programs was performed. The following information was recorded for all members: name, sex, membership level, years of membership, and if the individual was an author on at least 1 abstract. To compare proportion of abstract authorship between sexes across years, while controlling for years of membership, general estimating equations with a binomial model and logit link were used. The study population was limited to candidate and active POSNA members only, as this group represents the most active practicing pediatric orthopaedic surgeons. Over the 5-year period studied, females comprised 16.6% (204/1227) of the total POSNA membership and 20.9% (184/880) of members at candidate and active status. The percentage of females with candidate or active member status in POSNA who had at least 1 abstract presentation during the 5 years was 37% and this was significantly lower (P=0.003) than the percentage of men (49%) who presented at least 1 abstract. Analysis across the 5 years showed a consistent difference between the sexes with no trend of convergence in abstract rates (P=0.65). Controlling for years membership, female members still presented abstracts at lower rates than their male colleagues (P=0.002). Female members of POSNA, in the most active part of their careers, participated at significantly lower rates than their male peers as accepted abstract authors for the 2009-2013 POSNA meetings than would be expected for their proportional size of total membership.


Treatment of spinal deformity associated with myelomeningocele in young children with the use of the four-rib construct.
Surgery for myelomeningocele spinal deformity is accompanied by a high rate of complications. These include infection, pathological skin breakage, instrumentation failure, and neurological deterioration. The four-rib construct associated with the percutaneous technique in immature children with myelomeningocele and spinal deformity is introduced. The four-rib construct serves to correct for deformity and to allow for growth, with minimal complications. The study was small and retrospective, a level four case series. The results of four patients who underwent the four-rib construct surgery in 2008 and 2009 was revised. All four were nonambulatory, skeletally immature children, not previously corrected by bracing, with the progressive spinal deformity associated with myelomeningocele affecting their sitting position. Furthermore, the research protocol was approved by our institutional review board. Three patients were females and one was male. Two cases of kyphoscoliosis, one of kyphosis, and one of scoliosis. Age at the time of the initial procedure ranged between 64 and 82 months, with a mean age of 70 months. Follow-up time after surgery ranged from 24 to 39 months, with a mean of 31 months. Preoperatively, deformity angles were severe, averaging 55° for thoracic scoliosis, 67° for thoracolumbar scoliosis, and 85° for thoracolumbar kyphosis. Surgery mitigated the deformities markedly. Postoperative angles measured were 42° for thoracic scoliosis, 21° for thoracolumbar scoliosis, and 45° for thoracolumbar kyphosis. These observations indicate significant reductions in spinal deformity, by 24, 69, and 48%, respectively. In total, 14 procedures were performed: four initial implants and 10 lengthening and exchange procedures. There were no intraoperative complications. The postoperative complications that did arise consisted of two instances of skin breakage, one distal iliac screw dislodgement, and one shunt displacement. Significantly, no proximal fixation dislodgement, deep-seated infection, or damage in the pathological skin were detected. The four-rib construct technique can be considered as a potential surgical option in (powered by Editorial Manager and Preprint Manager; Aries Systems Corporation) treating spinal deformity associated with myelomeningocele, but still more patients with long term follow-up are needed to prove the efficacy of this procedure. The four-rib construct is simple, minimally invasive, and does not exclude alternative treatment. Moreover, the incidence of complications associated with the four-rib construct compares favorably with other growth techniques.


Molecular shape and medicinal chemistry: a perspective.
The eight contributions here provide ample evidence that shape as a volume or as a surface is a vibrant and useful concept when applied to drug discovery. It provides a reliable scaffold for "decoration" with chemical intuition (or bias) for virtual screening and lead optimization but also has its unadorned uses, as in library design, ligand fitting, pose prediction, or active site description. Computing power has facilitated this evolution by allowing shape to be handled precisely without the need to reduce down to point descriptors or approximate metrics, and the diversity of resultant applications argues for this being an important step forward. Certainly, it is encouraging that as computation has enabled our intuition, molecular shape has consistently surprised us in its usefulness and adaptability. The first Aurelius question, "What is the essence of a thing?", seems well answered, however, the third, "What do molecules do?", only partly so. Are the topics covered here exhaustive, or is there more to come? To date, there has been little published on the use of the volumetric definition of shape described here as a QSAR variable, for instance, in the prediction or classification of activity, although other shape definitions have been successful applied, for instance, as embodied in the Compass program described above in "Shape from Surfaces". Crystal packing is a phenomenon much desired to be understood. Although powerful models have been applied to the problem, to what degree is this dominated purely by the shape of a molecule? The shape comparison described here is typically of a global nature, and yet some importance must surely be placed on partial shape matching, just as the substructure matching of chemical graphs has proved useful. The approach of using surfaces, as described here, offers some flavor of this, as does the use of metrics that penalize volume mismatch less than the Tanimoto, e.g., Tversky measures. As yet, there is little to go on as to how useful a paradigm this will be because there is less software and fewer concrete results.Finally, the distance between molecular shapes, or between any shapes defined as volumes or surfaces, is a metric property in the mathematical sense of the word. As yet, there has been little, if any, application of this observation. We cannot know what new application to the design and discovery of pharmaceuticals may yet arise from the simple concept of molecular shape, but it is fair to say that the progress so far is impressive.


Reconstructing the phylogenetic history of long-term effective population size and life-history traits using patterns of amino acid replacement in mitochondrial genomes of mammals and birds.
The nearly neutral theory, which proposes that most mutations are deleterious or close to neutral, predicts that the ratio of nonsynonymous over synonymous substitution rates (dN/dS), and potentially also the ratio of radical over conservative amino acid replacement rates (Kr/Kc), are negatively correlated with effective population size. Previous empirical tests, using life-history traits (LHT) such as body-size or generation-time as proxies for population size, have been consistent with these predictions. This suggests that large-scale phylogenetic reconstructions of dN/dS or Kr/Kc might reveal interesting macroevolutionary patterns in the variation in effective population size among lineages. In this work, we further develop an integrative probabilistic framework for phylogenetic covariance analysis introduced previously, so as to estimate the correlation patterns between dN/dS, Kr/Kc, and three LHT, in mitochondrial genomes of birds and mammals. Kr/Kc displays stronger and more stable correlations with LHT than does dN/dS, which we interpret as a greater robustness of Kr/Kc, compared with dN/dS, the latter being confounded by the high saturation of the synonymous substitution rate in mitochondrial genomes. The correlation of Kr/Kc with LHT was robust when controlling for the potentially confounding effects of nucleotide compositional variation between taxa. The positive correlation of the mitochondrial Kr/Kc with LHT is compatible with previous reports, and with a nearly neutral interpretation, although alternative explanations are also possible. The Kr/Kc model was finally used for reconstructing life-history evolution in birds and mammals. This analysis suggests a fairly large-bodied ancestor in both groups. In birds, life-history evolution seems to have occurred mainly through size reduction in Neoavian birds, whereas in placental mammals, body mass evolution shows disparate trends across subclades. Altogether, our work represents a further step toward a more comprehensive phylogenetic reconstruction of the evolution of life-history and of the population-genetics environment.


Ecology of ontogenetic body-mass scaling of gill surface area in a freshwater crustacean.
Several studies have documented ecological effects on intraspecific and interspecific body-size scaling of metabolic rate. However, little is known about how various ecological factors may affect the scaling of respiratory structures supporting oxygen uptake for metabolism. To our knowledge, our study is the first to provide evidence for ecological effects on the scaling of a respiratory structure among conspecific populations of any animal. We compared the body-mass scaling of gill surface area (SA) among eight spring-dwelling populations of the amphipod crustacean Gammarus minus Although gill SA scaling was not related to water temperature, conductivity or G. minus population density, it was significantly related to predation regime (and secondarily to pH). Body-mass scaling slopes for gill SA were significantly lower in four populations inhabiting springs with fish predators than for four populations in springs without fish (based on comparing means of the population slopes, or slopes calculated from pooled raw data for each comparison group). As a result, gill SA was proportionately smaller in adult amphipods from springs with versus without fish. This scaling difference paralleled similar differences in the scaling exponents for the rates of growth and resting metabolic rate. We hypothesized that gill SA scaling is shallower in fish-containing versus fishless spring populations of G. minus because of effects of size-selective predation on size-specific growth and activity that in turn affect the scaling of oxygen demand and concomitantly the gill capacity (SA) for oxygen uptake. Although influential theory claims that metabolic scaling is constrained by internal body design, our study builds on previous work to show that the scaling of both metabolism and the respiratory structures supporting it may be ecologically sensitive and evolutionarily malleable.


The use of solid self-emulsifying systems in the delivery of diclofenac.
Goat fat and Tween 65 admixtures were used to formulate self-emulsifying tablets containing diclofenac. The tablets were formulated by pour moulding using a plastic mould. The tablets were evaluated using the following parameters: weight uniformity, absolute drug content, and liquefaction time. The dissolution profile of diclofenac from the self-emulsifying tablets was determined in simulated gastric fluid (SGF) without pepsin. Results obtained indicated that diclofenac could be comfortably administered in the form of self-emulsifying tablets using goat fat and Tween 65 admixtures.


Increased facial asymmetry in focal epilepsies associated with unilateral lesions.
The epilepsies are now conceptualized as network disruptions: focal epilepsies are considered to have network alterations in the hemisphere of seizure onset, whilst generalized epilepsies are considered to have bi-hemispheric network changes. Increasingly, many epilepsies are also considered to be neurodevelopmental disorders, with early changes in the brain underpinning seizure biology. The development of the structure of the face is influenced by complex molecular interactions between surface ectoderm and underlying developing forebrain and neural crest cells. This influence is likely to continue postnatally, given the evidence of facial growth changes over time in humans until at least 18 years of age. In this case-control study, we hypothesized that people with lateralized focal epilepsies (i.e. unilateral network changes) have an increased degree of facial asymmetry, compared with people with generalized epilepsies or controls without epilepsy. We applied three-dimensional stereophotogrammetry and dense surface models to evaluate facial asymmetry in people with epilepsy, aiming to generate new tools to explore pathophysiological mechanisms in epilepsy. We analysed neuroimaging data to explore the correlation between face and brain asymmetry. We consecutively recruited 859 people with epilepsy attending the epilepsy clinics at a tertiary referral centre. We used dense surface modelling of the full face and signature analyses of three-dimensional facial photographs to analyse facial differences between 378 cases and 205 healthy controls. Neuroimaging around the time of the facial photograph was available for 234 cases. We computed the brain asymmetry index between contralateral regions. Cases with focal symptomatic epilepsy associated with unilateral lesions showed greater facial asymmetry compared to controls (P = 0.0001, two-sample t-test). This finding was confirmed by linear regression analysis after controlling for age and gender. We also found a significant correlation between duration of illness and the brain asymmetry index of total average cortical thickness (r = -0.19, P = 0.0075) but not for total average surface area (r = 0.06, P = 0.3968). There was no significant correlation between facial asymmetry and asymmetry of regional cortical thickness or surface area. We propose that the greater facial asymmetry in cases with focal epilepsy caused by unilateral abnormality might be explained by early unilateral network disruption, and that this is independent of underlying brain asymmetry. Three-dimensional stereophotogrammetry and dense surface modelling are a novel powerful phenotyping tool in epilepsy that may permit greater understanding of pathophysiology in epilepsy, and generate further insights into the development of cerebral networks underlying epilepsy, and the genetics of facial and neural development.


Effects of olive leaf polyphenols against H₂O₂ toxicity in insulin secreting β-cells.
In pancreatic β-cells, although H₂O₂ is a metabolic signal for glucose stimulated insulin secretion, it may induce injury in the presence of increased oxidative stress (OS) as in the case of diabetic chronic hyperglycemia. Olea europea L. (olive) leaves contain polyphenolic compounds that may protect insulin-secreting cells against OS. The major polyphenolic compound in ethanolic olive leaf extract (OLE) is oleuropein (about 20%), thus we compared the effects of OLE with the effects of standard oleuropein on INS-1 cells. The cells were incubated with increasing concentrations of OLE or oleuropein for 24 h followed by exposure to H₂O₂ (0.035 mM) for 45 min. H₂O₂ alone resulted in a significantly decreased viability (MTT assay), depressed glucose-stimulated insulin secretion, increased apoptotic and necrotic cell death (AO/EB staining), inhibited glutathione peroxidase activity (GPx) and stimulated catalase activity that were associated with increased intracellular generation of reactive oxygen species (ROS) (fluorescence DCF). OLE and oleuropein partly improved the viability, attenuated necrotic and apoptotic death, inhibited the ROS generation and improved insulin secretion in H₂O₂-exposed cells. The effects of oleuropein on insulin secretion were more pronounced than those of OLE, while OLE exerted a stronger anti-cytotoxic effect than oleuropein. Unlike OLE, oleuropein had no significant preserving effect on GPx; however, both compounds stimulated the activity of catalase in H₂O₂-exposed cells. These findings indicate different modulatory roles of polyphenolic constituents of olive leaves on redox homeostasis that may have a role in the maintenance of β-cell physiology against OS.