Anti-IL-12/23 p40 antibody attenuates experimental chronic graft-versus-host disease via suppression of IFN-γ/IL-17-producing cells.
Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation. Recently, in addition to Th2 cells, Th1 and Th17 cells have been shown to contribute to chronic GVHD progression. IL-12 induces Th1 cells and IL-23 plays a role in stabilizing and/or amplifying Th17 cells, as well as in inducing IFN-γ/IL-17 double-producing cells. Because mAb targeting the p40 subunit common to both IL-12 and IL-23 can inhibit both IL-12R and IL-23R-mediated signaling, we investigated the effects of anti-p40 mAb on a well-defined chronic GVHD mice model. Treatment of anti-p40 mAb in allogeneic recipients significantly reduced the severity of clinical and pathological chronic GVHD. Intracellular staining revealed that IFN-γ single-positive (IL-17(-)) and IFN-γ/IL-17 double-positive cells were suppressed in anti-p40 mAb-treated allogeneic recipients compared with control recipients. The cytokine levels of IFN-γ and IL-17 were also decreased in serum from anti-p40 mAb-treated allogeneic recipients. T-bet expression of donor IL-17(+) CD4(+) T cells was reduced significantly in anti-p40 mAb-treated recipients, and this reduction in T-bet expression was associated with IL-22 production by donor T cells. These results suggested that anti-p40 mAb attenuated chronic GVHD via suppression of IFN-γ/IL-17-producing cells, and that targeting the IL-12/IL-23 pathway may represent a promising therapeutic strategy for preventing and treating chronic GVHD.


Enzymology and Ultrastructure of the in situ Pellicle in Caries-Active and Caries-Inactive Patients.
The present study aimed to evaluate the impact of caries activity on the key enzymes and the ultrastructure of the in situ pellicle. Pellicle formation was performed on bovine enamel slabs. Intraoral exposure (3, 30, and 120 min) was accomplished by 14 caries-active (DMFS: 22.7 ± 12.1) and 13 caries-inactive (DMFS: 1.5 ± 1.8) individuals. The enzyme activities (lysozyme, peroxidase, α-amylase, glycosyltransferase [GTF]) in the in situ pellicle and resting saliva of all participants were analyzed directly after oral exposure. In addition, a simultaneous visualization of these enzymes, extracellular glucans, and adherent bacteria was carried out. Fluorescent patterns were analyzed with fluorescence labeling and 4',6-diamidino-2-phenylindole/concanavalin A staining. In addition, the distribution of GTF B, C, and D and the ultrastructure of the pellicle were examined by gold immunolabeling and transmission electron microscopy with selected samples. Enzyme activities of amylase, peroxidase, lysozyme, and GTF were detected on all enamel slabs in an active conformation. Neither exposure time nor caries activity had an impact on the enzyme activities. Gold immunolabeling indicated that the pellicle of caries-active subjects tends to more GTF D molecules. The pellicles of caries-inactive and -active individuals revealed a similar ultrastructural pattern. The enzyme activities as well as the pellicle's ultrastructure are of high similarity in caries-active and -inactive subjects. Thereby, oral exposure time has no significant influence. This reflects a high uniformity during the initial phase of bioadhesion (3-120 min) concerning enzymatic functions. However, there is a tendency towards more GTF D in caries-active individuals.


Broadening understanding of accountability ecosystems in sexual and reproductive health and rights: A systematic review.
Accountability for ensuring sexual and reproductive health and rights is increasingly receiving global attention. Less attention has been paid to accountability mechanisms for sexual and reproductive health and rights at national and sub-national level, the focus of this systematic review. We searched for peer-reviewed literature using accountability, sexual and reproductive health, human rights and accountability instrument search terms across three electronic databases, covering public health, social sciences and legal studies. The search yielded 1906 articles, 40 of which met the inclusion and exclusion criteria (articles on low and middle-income countries in English, Spanish, French and Portuguese published from 1994 and October 2016) defined by a peer reviewed protocol. Studies were analyzed thematically and through frequencies where appropriate. They were drawn from 41 low- and middle-income countries, with just over half of the publications from the public health literature, 13 from legal studies and the remaining six from social science literature. Accountability was discussed in five health areas: maternal, neonatal and child health services, HIV services, gender-based violence, lesbian/gay/bisexual/transgender access and access to reproductive health care in general. We identified three main groupings of accountability strategies: performance, social and legal accountability. The review identified an increasing trend in the publication of accountability initiatives in Sexual and Reproductive Health and Rights (SRHR). The review points towards a complex 'accountability ecosystem' with multiple actors with a range of roles, responsibilities and interactions across levels from the transnational to the local. These accountability strategies are not mutually exclusive, but they do change the terms of engagement between the actors involved. The publications provide little insight on the connections between these accountability strategies and on the contextual conditions for the successful implementation of the accountability interventions. Obtaining a more nuanced understanding of various underpinnings of a successful approach to accountability at national and sub national levels is essential.


Biomarkers of Alzheimer Disease in Children with Obstructive Sleep Apnea: Effect of Adenotonsillectomy.
Obese children are at increased risk for developing obstructive sleep apnea (OSA), and both of these conditions are associated with an increased risk for end-organ morbidities. Both OSA and obesity (OB) have been associated with increased risk for Alzheimer disease (AD). This study aimed to assess whether OSA and OB lead to increased plasma levels of 2 AD markers amyloid β protein 42 (Aβ42) and pre-senilin 1 (PS1). Fasting morning plasma samples from otherwise healthy children with a diagnosis of OB, OSA, or both (OSA+OB), and controls, and in a subset of children with OSA after adenotonsillectomy (T&A) were assayed for Aβ42 and PS1 levels using commercial enzyme-linked immunosorbent assay kits. 286 children (mean age of 7.2 ± 2.7 y) were evaluated. Compared to control subjects, OB children had similar Aβ42 (108.3 ± 31.7 pg/mL versus 83.6 ± 14.6 pg/mL) and PS1 levels (0.89 ± 0.44 ng/mL versus 0.80 ± 0.29 pg/mL). However, OSA children (Aβ42: 186.2 ± 66.7 pg/mL; P < 0.001; PS1: 3.42 ± 1.46 ng/mL; P < 0.001), and particularly OSA+OB children had significant elevations in both Aβ42 (349.4 ± 112.9 pg/mL; P < 0.001) and PS1 (PS1: 4.54 ± 1.16 ng/mL; P < 0.001) circulating concentrations. In a subset of 24 children, T&A resulted in significant reductions of Aβ42 (352.0 ± 145.2 versus 151.9 ± 81.4 pg/mL; P < 0.0001) and PS1 (4.82 ± 1.09 versus 2.02 ± 1.18 ng/mL; P < 0.0001). Thus, OSA, and particularly OSA+OB, are associated with increased plasma levels of AD biomarkers, which decline upon treatment of OSA in a representative, yet not all- encompassing subset of patients, suggesting that OSA may accelerate AD-related processes even in early childhood. However, the cognitive and overall health-related implications of these findings remain to be defined.


The motivational salience of infant faces is similar for men and women.
Infant facial features are thought to be powerful elicitors of caregiving behaviour. It has been widely assumed that men and women respond in different ways to those features, such as a large forehead and eyes and round protruding cheeks, colloquially described as 'cute'. We investigated experimentally potential differences using measures of both conscious appraisal ('liking') and behavioural responsivity ('wanting') to real world infant and adult faces in 71 non-parents. Overall, women gave significantly higher 'liking' ratings for infant faces (but not adult faces) compared to men. However, this difference was not seen in the 'wanting' task, where we measured the willingness of men and women to key-press to increase or decrease viewing duration of an infant face. Further analysis of sensitivity to cuteness, categorising infants by degree of infantile features, revealed that both men and women showed a graded significant increase in both positive attractiveness ratings and viewing times to the 'cutest' infants. We suggest that infant faces may have similar motivational salience to men and women, despite gender idiosyncrasies in their conscious appraisal.


Primary Care Program in Prison: A Review of the Literature.
Nurses take on the role of primary caregiver in the prison setting, as they are usually the first to approach the prisoner, and they govern access to all aspects of the health care system. The aim of this review was to assess the effects of the use of the primary care model in a correctional setting. Major literature databases relevant to the specified areas were searched for studies published from 2004 to 2013. Three studies reported some implications for prisoners, nursing practice, and the correctional facility, as generated by using the primary care model in the prison setting. The primary care model can improve relevant outcomes for health management in the prison setting.


Complete sequence and genomic analysis of rhesus cytomegalovirus.
The complete DNA sequence of rhesus cytomegalovirus (RhCMV) strain 68-1 was determined with the whole-genome shotgun approach on virion DNA. The RhCMV genome is 221,459 bp in length and possesses a 49% G+C base composition. The genome contains 230 potential open reading frames (ORFs) of 100 or more codons that are arranged colinearly with counterparts of previously sequenced betaherpesviruses such as human cytomegalovirus (HCMV). Of the 230 RhCMV ORFs, 138 (60%) are homologous to known HCMV proteins. The conserved ORFs include the structural, replicative, and transcriptional regulatory proteins, immune evasion elements, G protein-coupled receptors, and immunoglobulin homologues. Interestingly, the RhCMV genome also contains sequences with homology to cyclooxygenase-2, an enzyme associated with inflammatory processes. Closer examination identified a series of candidate exons with the capacity to encode a full-length cyclooxygenase-2 protein. Counterparts of cyclooxygenase-2 have not been found in other sequenced herpesviruses. The availability of the complete RhCMV sequence along with the ability to grow RhCMV in vitro will facilitate the construction of recombinant viral strains for identifying viral determinants of CMV pathogenicity in the experimentally infected rhesus macaque and to the development of CMV as a vaccine vector.


Expression profile and prognostic role of sex hormone receptors in gastric cancer.
Increasing interest has been devoted to the expression and possible role of sex hormone receptors in gastric cancer, but most of these findings are controversial. In the present study, the expression profile of sex hormone receptors in gastric cancer and their clinicopathological and prognostic value were determined in a large Chinese cohort. The mRNA and protein expression of estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), progesterone receptor (PR), and androgen receptor (AR) in primary gastric tumors and corresponding adjacent normal tissues from 60 and 866 Chinese gastric cancer patients was detected by real-time quantitative PCR and immunohistochemistry method, respectively. The expression profile of the four receptors was compared and their associations with clinicopathological characteristics were assessed by using Chi-square test. The prognostic value of the four receptors in gastric cancer was evaluated by using univariate and multivariate Cox regression analysis. The presence of ERα, ERβ, PR, and AR in both gastric tumors and normal tissues was confirmed but their expression levels were extremely low except for the predominance of ERβ. The four receptors were expressed independently and showed a decreased expression pattern in gastric tumors compared to adjacent normal tissues. The positive expression of the four receptors all correlated with high tumor grade and intestinal type, and ERα and AR were also associated with early TNM stage and thereby a favorable outcome. However, ERα and AR were not independent prognostic factors for gastric cancer when multivariate survival analysis was performed. Our findings indicate that the sex hormone receptors may be partly involved in gastric carcinogenesis but their clinicopathological and prognostic significance in gastric cancer appears to be limited.


Serial MRI and CSF biomarkers in normal aging, MCI, and AD.
To compare the annual change in MRI and CSF biomarkers in cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer disease (AD). Comparisons were based on intergroup discrimination, correlation with concurrent cognitive/functional changes, relationships to APOE genotype, and sample sizes for clinical trials. We used data from the Alzheimer's Disease Neuroimaging Initiative study consisting of CN, aMCI, and AD cohorts with both baseline and 12-month follow-up CSF and MRI. The annual change in CSF (total-tau [t-tau], Abeta(1-42)) and MRI (change in ventricular volume) was obtained in 312 subjects (92 CN, 149 aMCI, 71 AD). There was no significant average annual change in either CSF biomarker in any clinical group except t-tau in CN; moreover, the annual change did not differ by clinical group in pairwise comparisons. In contrast, annual increase in ventricular volume increased in the following order, AD > aMCI > CN, and differences were significant between all clinical groups in pairwise comparisons. Ventricular volume increase correlated with concurrent worsening on cognitive/functional indices in aMCI and AD whereas evidence of a similar correlation with change in CSF measures was unclear. The annual changes in MRI differed by APOE epsilon4 status overall and among aMCI while annual changes in CSF biomarkers did not. Estimated sample sizes for clinical trials are notably less for MRI than the CSF or clinical measures. Unlike the CSF biomarkers evaluated, changes in serial structural MRI are correlated with concurrent change on general cognitive and functional indices in impaired subjects, track with clinical disease stage, and are influenced by APOE genotype.


Continuing medical education: AMEE Education Guide No 35.
This guide is designed to provide a foundation for developing effective continuing medical education (CME) for practicing physicians. For the purposes of this work, continuing medical education is defined as any activity which serves to maintain, develop, or increase the knowledge, skills and professional performance and relationships that a physician uses to provide services for patients, the public, or the profession (American Medical Association 2007; Accreditation Council for CME 2007). The term continuing professional development (CPD) is broader and has become more popular in many areas of the world. As defined by Stanton and Grant, CPD includes educational methods beyond the didactic, embodies concepts of self-directed learning and personal development and considers organizational and systemic factors (Stanton & Grant 1997). In fact, this guide describes many modalities that may be defined as CME or CPD. In the interest of simplicity, we will use the term continuing medical education (CME) throughout, with the understanding that the same strategies may be applied to non-clinical continuing professional education. For those who do not work exclusively in CME, many terms and processes may be unfamiliar. This guide is intended to provide a broad overview of the discipline of CME as well as a pragmatic approach to the practice of CME. The format provides an overview of CME including history and rationale for the discipline, followed by a practical approach to developing CME activities, the management of the overall CME programme and finally, future trends. At the end of the guide you will find resources including readings, websites and professional associations to assist in the development and management of CME programmes.


Dietary iron depletion at weaning imprints low microbiome diversity and this is not recovered with oral Nano Fe(III).
Alterations in the gut microbiota have been recently linked to oral iron. We conducted two feeding studies including an initial diet-induced iron-depletion period followed by supplementation with nanoparticulate tartrate-modified ferrihydrite (Nano Fe(III): considered bioavailable to host but not bacteria) or soluble ferrous sulfate (FeSO4: considered bioavailable to both host and bacteria). We applied denaturing gradient gel electrophoresis and fluorescence in situ hybridization for study-1 and 454-pyrosequencing of fecal 16S rRNA in study-2. In study-1, the within-community microbial diversity increased with FeSO4 (P = 0.0009) but not with Nano Fe(III) supplementation. This was confirmed in study-2, where we also showed that iron depletion at weaning imprinted significantly lower within- and between-community microbial diversity compared to mice weaned onto the iron-sufficient reference diet (P < 0.0001). Subsequent supplementation with FeSO4 partially restored the within-community diversity (P = 0.006 in relation to the continuously iron-depleted group) but not the between-community diversity, whereas Nano Fe(III) had no effect. We conclude that (1) dietary iron depletion at weaning imprints low diversity in the microbiota that is not, subsequently, easily recovered; (2) in the absence of gastrointestinal disease iron supplementation does not negatively impact the microbiota; and (3) Nano Fe(III) is less available to the gut microbiota.


Higher plain water intake is associated with lower type 2 diabetes risk: a cross-sectional study in humans.
The aim of this study was to investigate the relationship between plain water intake and type 2 diabetes (T2D) risk. It was hypothesized that higher plain water intake would be associated with a lower T2D risk score. One hundred thirty-eight adults from Southwest and Southeast England answered a cross-sectional online survey assessing T2D risk (using the Diabetes UK risk assessment); physical activity (using the short International Physical Activity Questionnaire); and consumption of fruits, vegetables, and beverages (using an adapted version of the Cambridge European Prospective Investigation into Cancer and Nutrition Food Frequency Questionnaire). There was a trend for differences in mean plain water intake between those stratified as having low, increased, moderate, or high risk of T2D; but these did not achieve significance (P = .084). However, plain water intake was significantly negatively correlated with T2D risk score (τ = -0°180, P = .005); and for every 240-mL cup of water consumed per day, T2D risk score was reduced by 0.72 point (range, 0-47) (B = -0.03, 95% confidence interval = -0.06 to -0.01, P = .014). The current study has provided preliminary results that are supported by theory; mechanisms need to be explored further to determine the true effect of plain water intake on disease risk. As increasing plain water intake is a simple and cost-effective dietary modification, its impact on T2D risk is important to investigate further in a randomized controlled trial. Overall, this study found that plain water intake had a significant negative correlation with T2D risk score; and regression analysis suggested that water may have a role in reducing T2D risk.


The phylogeographic history of the new world screwworm fly, inferred by approximate bayesian computation analysis.
Insect pest phylogeography might be shaped both by biogeographic events and by human influence. Here, we conducted an approximate Bayesian computation (ABC) analysis to investigate the phylogeography of the New World screwworm fly, Cochliomyia hominivorax, with the aim of understanding its population history and its order and time of divergence. Our ABC analysis supports that populations spread from North to South in the Americas, in at least two different moments. The first split occurred between the North/Central American and South American populations in the end of the Last Glacial Maximum (15,300-19,000 YBP). The second split occurred between the North and South Amazonian populations in the transition between the Pleistocene and the Holocene eras (9,100-11,000 YBP). The species also experienced population expansion. Phylogenetic analysis likewise suggests this north to south colonization and Maxent models suggest an increase in the number of suitable areas in South America from the past to present. We found that the phylogeographic patterns observed in C. hominivorax cannot be explained only by climatic oscillations and can be connected to host population histories. Interestingly we found these patterns are very coincident with general patterns of ancient human movements in the Americas, suggesting that humans might have played a crucial role in shaping the distribution and population structure of this insect pest. This work presents the first hypothesis test regarding the processes that shaped the current phylogeographic structure of C. hominivorax and represents an alternate perspective on investigating the problem of insect pests.


Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies.
Cornelia de Lange syndrome (CdLS), a disorder caused by mutations in cohesion proteins, is characterized by multisystem developmental abnormalities. PDS5, a cohesion protein, is important for proper chromosome segregation in lower organisms and has two homologues in vertebrates (PDS5A and PDS5B). Pds5B mutant mice have developmental abnormalities resembling CdLS; however the role of Pds5A in mammals and the association of PDS5 proteins with CdLS are unknown. To delineate genetic interactions between Pds5A and Pds5B and explore mechanisms underlying phenotypic variability, we generated Pds5A-deficient mice. Curiously, these mice exhibit multiple abnormalities that were previously observed in Pds5B-deficient mice, including cleft palate, skeletal patterning defects, growth retardation, congenital heart defects and delayed migration of enteric neuron precursors. They also frequently display renal agenesis, an abnormality not observed in Pds5B(-/-) mice. While Pds5A(-/-) and Pds5B(-/-) mice die at birth, embryos harboring 3 mutant Pds5 alleles die between E11.5 and E12.5 most likely of heart failure, indicating that total Pds5 gene dosage is critical for normal development. In addition, characterization of these compound homozygous-heterozygous mice revealed a severe abnormality in lens formation that does not occur in either Pds5A(-/-) or Pds5B(-/-) mice. We further identified a functional missense mutation (R1292Q) in the PDS5B DNA-binding domain in a familial case of CdLS, in which affected individuals also develop megacolon. This study shows that PDS5A and PDS5B functions other than those involving chromosomal dynamics are important for normal development, highlights the sensitivity of key developmental processes on PDS5 signaling, and provides mechanistic insights into how PDS5 mutations may lead to CdLS.


Do C-H...O hydrogen bonds contribute to the stability of nucleic acid base pairs?
The possible formation of inter-base C-H.O hydrogen bonds in A.T, A.U and certain non-Watson-Crick base pairs is examined. A geometrical analysis in conjunction with implications for the thermodynamic stability of the base pairs suggests that C-H.O hydrogen bonds could form in nucleic acid base pairs. They may alleviate destabilizing interactions that would arise if an unsatisfied hydrogen-bond acceptor were present and mediate secondary hydrogen-bonding effects in these base pairs.


Anti-inflammatory effect of astaxanthin in phthalic anhydride-induced atopic dermatitis animal model.
In this study, we investigated anti-dermatitic effects of astaxanthin (AST) in phthalic anhydride (PA)-induced atopic dermatitis (AD) animal model as well as in vitro model. AD-like lesion was induced by the topical application of 5% PA to the dorsal skin or ear of Hos:HR-1 mouse. After AD induction, 100 μL of 1 mg/mL and 2 mg/mL of AST (10 μg or 20 μg/cm2 ) was spread on the dorsum of ear or back skin three times a week for four weeks. We evaluated dermatitis severity, histopathological changes and changes in protein expression by Western blotting for inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and nuclear factor-κB (NF-κB) activity. We also measured tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and immunoglobulin E (IgE) concentration in the blood of AD mice by enzyme-linked immunosorbent assay (ELISA). AST treatment attenuated the development of PA-induced AD. Histological analysis showed that AST inhibited hyperkeratosis, mast cells and infiltration of inflammatory cells. AST treatment inhibited expression of iNOS and COX-2, and NF-κB activity as well as release of TNF-α, IL-1β, IL-6 and IgE. In addition, AST (5, 10 and 20 μM) potently inhibited lipopolysaccharide (LPS) (1 μg/mL)-induced nitric oxide (NO) production, expression of iNOS and COX-2 and NF-κB DNA binding activities in RAW 264.7 macrophage cells. Our data demonstrated that AST could be a promising agent for AD by inhibition of NF-κB signalling.


Association of Neonatologist Continuity of Care and Short-Term Patient Outcomes.
To describe neonatologist continuity of care and estimate the association between these transitions and selected patient outcomes. We linked Children's Hospitals Neonatal Database records with masked neonatologist daily schedules at 4 centers, which use 2- and 3-week and 1-month "on service" blocks to provide care. After describing the neonatologist transitions, we estimated associations between these transitions and selected short-term patient outcomes using multivariable Poisson, logistic, and linear regression analyses, independent of length of stay (LOS) and case-mix. We also completed analyses after stratifying the cohort by LOS, birthweight, age at admission categories, and selected diagnoses. Stratified by LOS, patient transitions varied between centers in both unadjusted (P < .001) and multivariable analyses (adjusted incidence rate ratio; 95% CI for center B = 3.98 (3.81-4.15), center C = 4.92 (4.71-5.13), center D = 4.2 (4.0-4.4), P < .001), independent of LOS, gestational age, birthweight, surgical intervention, ventilator duration, and mortality. Only central venous line duration (adjusted incidence rate ratio 1.015, 95% CI 1.01-1.02) was minimally and independently associated with the number of transitions. No differences were observed in ventilator duration, oxygen use at neonatal intensive care unit discharge, bloodstream infections, or urinary tract infections. Surviving infants with meconium aspiration, hypoxic ischemic encephalopathy, cerebral infarction, bronchopulmonary dysplasia, and diaphragmatic hernia demonstrated similar findings. Transitions in neonatologists are frequent in regional neonatal intensive care units but appear unrelated to short-term patient outcomes. Future work to define continuity of care and develop effective strategies that promote longitudinal inpatient management is needed.


The permeability of the endplate channel to organic cations in frog muscle.
The relative permeability of endplate channels to many organic cations was determined by reversal-potential criteria. Endplate currents induced by iontophoretic "puffs" of acetylcholine were studied by a Vaseline gap, voltage clamp method in cut muscle fibers. Reversal potential changes were measured as the NaCl of the bathing medium was replaced by salts of organic cations, and permeability ratios relative to Na+ ions were calculated from the Goldman-Hodgkin-Katz equation. 40 small monovalent organic cations had permeability ratios larger than 0.1. The most permeant including NH4+, hydroxylamine, hydrazine, methylamine, guanidine, and several relatives of guanidine had permeability ratios in the range 1.3--2.0. However, even cations such as imidazole, choline, tris(hydroxymethyl)aminomethane, triethylamine, and glycine methylester were appreciably permeant with permeability ratios of 0.13--0.95. Four compounds with two charged nitrogen groups were also permeant. Molecular models of the permeant ions suggest that the smallest cross-section of the open pore must be at least as large as a square, 6.5 A x 6.5 A. Specific chemical factors seem to be less important than access or friction in determining the ionic selectivity of the endplate channel.


Acute Effects of Parent Stimulant Medication Versus Behavioral Parent Training on Mothers' ADHD, Parenting Behavior, and At-Risk Children.
Attention-deficit/hyperactivity disorder (ADHD) is present in 25%-50% of parents of children with ADHD, compromising parenting and child behavioral treatment. Efforts to treat multiplex ADHD families have not compared behavioral parenting interventions to parent psychopharmacology without confounds of other treatments. This report describes a pilot early intervention study directly comparing parent lisdexamfetamine dimesylate (LDX) to behavioral parent training (BPT) in families in which the mother had currently untreated ADHD and the young child displayed ADHD symptoms. Mothers with ADHD (N = 35) of 4- to 8-year-old stimulant-naive children (N = 35) were randomly assigned to an 8-week trial of LDX (starting at 20 mg/d and titrated to a maximum of 70 mg/d) or BPT. Outcomes included multi-method, multi-informant measures of (1) maternal ADHD symptoms (Conners' Adult ADHD Rating Scales) and impairment (Clinical Global Impressions-Severity of Illness scale [CGI-S] and CGI-Improvement scale [CGI-I]), (2) parenting (Alabama Parenting Questionnaire [APQ] and Dyadic Parent-Child Interaction Coding System, Fourth Edition), and (3) child ADHD symptoms (Conners Parent Rating Scale Revised-Short Form and Conners Early Childhood Scale) and impairment (CGI-S, CGI-I, and Child Impairment Rating Scale). At 8 weeks, both treatments improved mothers' self-reported emotion regulation and mothers' functioning on the CGI, but only LDX improved mothers' self-reported core ADHD symptoms. LDX was associated with improvement in parents' perception of their own ADHD symptoms (Conners Inattention [P < .0001] and ADHD Index scores [P < .0001]) and their child's ADHD symptoms (P = .009). Fifty-six percent of the mothers treated with LDX (n = 10) were "much" or "very much" improved with regard to their adult ADHD based on the CGI-I scores versus 6% of mothers receiving BPT (n = 1; P = .003). BPT improved parenting on self-reported positive parenting (P = .007), inconsistent discipline (P > .0001), and corporal punishment (P = .001), while LDX improved reported inconsistent discipline (P = .001) and corporal punishment (P = .04) on the APQ, consistent with prior research. In contrast to parental LDX, which did not improve observed parenting, BPT was associated with increased positive parenting during child-directed play (P = .0002) and clean-up (P = .04) and less negative parenting (P = .04) during child-directed play. Six percent of children (n = 1) whose mothers were randomized to LDX (n = 18) were "much" or "very much" improved on the CGI-I compared to 35% (n = 16) of those treated with BPT (P = .04). LDX and BPT each had unique effects on maternal ADHD symptoms and parenting, but modest effects on at-risk children. In general, LDX was more effective at treating mothers' core ADHD symptoms, but both LDX and BPT improved mothers' emotion regulation, and BPT resulted in more consistent effects on parenting measures via both maternal report and direct observation. As most children remained significantly impaired after 8 weeks of unimodal treatment, combination treatment and/or longer treatment duration may be necessary to improve functioning of multiplex ADHD families. ClinicalTrials.gov identifier: NCT01816074.


Metabolic Profiling Analysis of Patients With Coronary Heart Disease Undergoing Xuefu Zhuyu Decoction Treatment.
Coronary heart disease (CHD) remains the leading cause of morbidity and mortality worldwide. Traditional Chinese medicine (TCM) is one of the effective complementary and alternative therapies used to improve the prognosis of CHD patients. Xuefu Zhuyu (XFZY) decoction, a classical traditional Chinese medication for regulating Qi and promoting blood circulation, has a clinical benefit in CHD; however, the underlying mechanism is not clear. Recently, it was found that the metabolites involved in amino acid metabolism and the tricarboxylic acid cycle were altered in CHD patients with Qi and Yin deficiency syndrome. To understand the material foundation of Qi, it is of great significance to study the differential metabolites involved in Qi during treatment of CHD with Qi-regulating and blood-promoting herbs. In this study, we investigated the metabolic profiles of serum in CHD patients by nontargeted metabolomics analysis to detect differential metabolites between the XFZY decoction group and placebo group. Ten CHD patients were enrolled and treated with placebo granules or XFZY decoction granules in a random and double-blind manner. Serum samples of all patients were evaluated by untargeted high-performance liquid chromatography with tandem mass spectrometry-based metabolomics. In total, 513 metabolites were detected in the serum of CHD patients, and six of these metabolites participating in seven metabolic pathways were significantly different between CHD patients treated with XFZY decoction and the placebo group. Among the six differential metabolites, FA (20:2)-H and tetracarboxylic acid (24:0), involved in fatty acid metabolism; cis-aconitic acid, which participates in the tricarboxylic acid cycle; 2-deoxy-D-glucose, involved in glucose metabolism; and N-acetylglycine, involved in amino acid metabolism, were decreased, whereas spermine, which participates in amino acid metabolism, was increased as compared with the placebo group. Our findings, combined with the perspective of biological functions, indicate that 2-deoxy-D-glucose and spermine might constitute the partial material foundation of Qi in CHD patients treated with XFZY decoction.


Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis.
Seasonal allergic rhinitis is common and troublesome. Sublingual immunotherapy (SLIT) has been proposed as an alternative to injection immunotherapy and might offer some advantages if it were effective and practical in a community setting. To assess the efficacy and side-effect profile of SLIT in patients with summer hay fever uncontrolled on current standard medication. To assess the feasibility of delivering SLIT in a United Kingdom general practice setting. Double-blind, placebo-controlled study in 186 patients with severe summer hay fever identified from 16 United Kingdom general practices. After a baseline year to ensure balanced groups, subjects were randomized, and SLIT was given for 1 or 2 years and compared with placebo. The principal outcome measure was symptoms as recorded on diary cards. Secondary criteria were skin and conjunctival reactivity, allergen-specific IgE and IgG 4 , and the frequency and severity of adverse effects. One hundred thirty-six subjects completed the study. After 1 year, no significant differences were found between actively treated subjects and the placebo group. After the second year of therapy, subjects who had received 2 years treatment were 6.8 times more likely to show a reduction in nose running (P <.001) and 2.4 times more likely to have reduced sneezing (P <.05) compared with subjects in the placebo group. Benefits for nasal blockage were found at the peak pollen season and were similar in both actively treated groups. Sublingual immunotherapy can be given successfully and safely in the community. High-dose SLIT has beneficial effects on nasal symptoms during the peak pollen season in patients with severe seasonal allergic rhinitis. At least 2 years of treatment with SLIT is required to show a benefit.


Evolution and functions of long noncoding RNAs.
RNA is not only a messenger operating between DNA and protein. Transcription of essentially the entire eukaryotic genome generates a myriad of non-protein-coding RNA species that show complex overlapping patterns of expression and regulation. Although long noncoding RNAs (lncRNAs) are among the least well-understood of these transcript species, they cannot all be dismissed as merely transcriptional "noise." Here, we review the evolution of lncRNAs and their roles in transcriptional regulation, epigenetic gene regulation, and disease.


Late diagnosis of primary hyperoxaluria after failed kidney transplantation.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive inborn error of the glyoxylate metabolism that is based on absence, deficiency or mislocalization of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase. Hyperoxaluria leads to recurrent formation of calculi and/or nephrocalcinosis and often early end-stage renal disease (ESRD) accompanied by systemic calcium oxalate crystal deposition. In this report, we describe an adult female patient with only one stone passage before development of ESRD. With unknown diagnosis of PH, the patient received an isolated kidney graft and developed an early onset of graft failure. Although initially presumed as an acute rejection, the biopsy revealed calcium oxalate crystals, which then raised a suspicion of primary hyperoxaluria. The diagnosis was later confirmed by hyperoxaluria, elevated plasma oxalate levels and mutation of the AGXT gene, showing the patient to be compound heterozygous for the c.33_34InsC and c.508G > A mutations. Plasma oxalate levels did not decrease after high-dose pyridoxine treatment. Based on this case report, we would recommend in all patients even with a minor history of nephrolithiasis but progression to chronic renal failure to exclude primary hyperoxaluria before isolated kidney transplantation is considered.


High-dose therapy in diffuse large cell lymphoma: results and prognostic factors in 452 patients from the GEL-TAMO Spanish Cooperative Group.
The purpose of this study was to analyse the results and prognostic factors influencing overall survival (OS) and disease-free survival (DFS) in 452 patients diagnosed with diffuse large cell lymphomas (DLCL) treated with high-dose therapy (HDT) included in the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL-TAMO) Spanish registry. At transplantation, median age was 42 years (range 15-73), 146 patients (32%) were transplanted in first complete remission (1st CR), 19% in second CR (2nd CR) and 47% had active disease: sensitive disease in 157 (35%) patients [95 were in first partial remission (1st PR) and 62 in second PR (2nd PR)] and refractory disease in 55 (12%) patients. Age-adjusted International Prognostic Index (IPI) was 2 or 3 in 51 patients (12%). Conditioning regimen consisted of BEAM (carmustine, etoposide, cytarabine and melphalan) in 39% of patients, BEAC (carmustine, etoposide, cytarabine and cyclophosphamide) in 33%, CBV (carmustine, etoposide and cyclophosphamide) in 10% and cyclophosphamide plus total body irradiation (TBI) in 12%. Estimated overall survival (OS) and disease-free survival (DFS) at 5 years were 53% and 43%, respectively. The transplant-related mortality was 11% (53 cases). By multivariate analysis three variables significantly influenced OS and DFS: number of protocols to reach 1st CR, disease status at transplant and TBI in the conditioning regimen. Age-adjusted IPI at transplantation also influenced OS. Prolonged OS and DFS can be achieved in patients with DLCL after HDT and our results suggest that the best line of chemotherapy should be used up-front in patients considered as candidates for HDT in order to obtain an early CR. Resistant patients are not good candidates for HDT and they should be offered newer strategies. Finally, polichemotherapy conditioning regimens offer better results compared with TBI.


The application of discriminant analysis and Machine Learning methods as tools to identify and classify compounds with potential as transdermal enhancers.
Discriminant analysis (DA) has previously been shown to allow the proposal of simple guidelines for the classification of 73 chemical enhancers of percutaneous absorption. Pugh et al. employed DA to classify such enhancers into simple categories, based on the physicochemical properties of the enhancer molecules (Pugh et al., 2005). While this approach provided a reasonable accuracy of classification it was unable to provide a consistently reliable estimate of enhancement ratio (ER, defined as the amount of hydrocortisone transferred after 24h, relative to control). Machine Learning methods, including Gaussian process (GP) regression, have recently been employed in the prediction of percutaneous absorption of exogenous chemicals (Moss et al., 2009; Lam et al., 2010; Sun et al., 2011). They have shown that they provide more accurate predictions of these phenomena. In this study several Machine Learning methods, including the K-nearest-neighbour (KNN) regression, single layer networks, radial basis function networks and the SVM classifier were applied to an enhancer dataset reported previously. The SMOTE sampling method was used to oversample chemical compounds with ER>10 in each training set in order to improve estimation of GP and KNN. Results show that models using five physicochemical descriptors exhibit better performance than those with three features. The best classification result was obtained by using the SVM method without dealing with imbalanced data. Following over-sampling, GP gives the best result. It correctly assigned 8 of the 12 "good" (ER>10) enhancers and 56 of the 59 "poor" enhancers (ER<10). Overall success rates were similar. However, the pharmaceutical advantages of the Machine Learning methods are that they can provide more accurate classification of enhancer type with fewer false-positive results and that, unlike discriminant analysis, they are able to make predictions of enhancer ability.


Prevention of hypertension and vascular changes by captopril treatment.
Treatment of female spontaneously hypertensive rats (SHR) and control Wistar-Kyoto (WKY) rats with captopril was carried out by the addition of the drug in the drinking water throughout pregnancy and lactation and after weaning. At 28 weeks of age, average systolic blood pressure of treated SHR was 113 +/- 3 mm Hg, which was below that of control SHR (188 +/- 3 mm Hg) and WKY rats (124 +/- 3 mm Hg). Body weight and heart rate of the SHR were not affected by the treatment. Tissue level of catecholamines was increased by captopril treatment in the superior cervical ganglia but remained unchanged in the plasma, heart, mesenteric arteries, and the adrenal glands of both SHR and WKY rats. Left ventricular weight, wall thickness, and internal diameter of the left ventricle in the SHR were reduced by the treatment. Morphometric measurements of the mesenteric arteries showed that vascular alterations present in the control SHR were prevented by the treatment. In the superior mesenteric artery and large mesenteric artery, smaller lumen size at maximal relaxation found in the control SHR was normalized to the level of the WKY rats. Hypertrophy of the medial wall in the superior mesenteric, large and small mesenteric arteries, and an increase in the number of smooth muscle cell layers in the large mesenteric artery of the SHR were prevented by the treatment. Perfusion study of the mesenteric vascular bed showed that reactivity of these vessels to norepinephrine was reduced, and sensitivity to norepinephrine (as determined by the effective dose that causes 50% of maximal response) was increased in the SHR by captopril treatment. Sensitivity of the tail artery in response to norepinephrine was not altered by the treatment. We conclude that long-term treatment with captopril of SHR before and after birth prevented the development of hypertension, structural and functional alterations of the mesenteric arteries, and cardiac hypertrophy.


Preoperative embolization of intracranial meningiomas.
The goal of preoperative embolization of intracranial meningiomas is to facilitate their surgical removal by reducing tumor vascularity and decreasing blood loss during surgery. This study is based on personal experience with about 100 embolized meningiomas and on the experience of others. Embolization is performed during the same session as diagnostic angiography. The appropriate embolic materials (absorbable or nonabsorbable) are chosen according to the location of the tumor, the size of the feeding arteries, the blood flow, and the presence of any potentially dangerous vessels (dangerous anastomoses between external carotid artery and internal carotid or vertebral arteries, arteries supplying the cranial nerves). Preoperative embolization appeared to be very useful in large tumors with pure or predominant external carotid artery supply (convexity meningiomas), in skull-base meningiomas, and in middle fossa and paracavernous meningiomas. It was also useful in falx and parasagittal meningiomas receiving blood supply from the opposite side and in posterior fossa meningiomas. CT low densities demonstrated after embolization did not always correlate with necrosis on microscopic examination, and large areas of infarction could be found despite normal CT. Embolic material was found on pathologic examination in 10%-30% of cases; fresh or recent ischemic and/or hemorrhagic necrosis consistent with technically successful embolization was demonstrated in 40%-60% of cases. With careful technique complications are rare.


A hybrid dielectrophoretic and hydrophoretic microchip for particle sorting using integrated prefocusing and sorting steps.
This work explores dielectrophoresis (DEP)-active hydrophoresis in sorting particles and cells. The device consists of prefocusing region and sorting region with great potential to be integrated into advanced lab-on-a-chip bioanalysis devices. Particles or cells can be focused in the prefocusing region and then sorted in the sorting region. The DEP-active hydrophoretic sorting is not only based on size but also on dielectric properties of the particles or cells of interest without any labelling. A mixture of 3 and 10 μm particles were sorted and collected from corresponding outlets with high separation efficiency. According to the different dielectric properties of viable and nonviable Chinese Hamster Ovary (CHO) cells at the medium conductivity of 0.03 S/m, the viable CHO cells were focused well and sorted from cell sample with a high purity.


Mail merge can be used to create personalized questionnaires in complex surveys.
Low response rates and inadequate question comprehension threaten the validity of survey results. We describe a simple procedure to implement personalized-as opposed to generically worded-questionnaires in the context of a complex web-based survey of corresponding authors of a random sample of 300 published cluster randomized trials. The purpose of the survey was to gather more detailed information about informed consent procedures used in the trial, over and above basic information provided in the trial report. We describe our approach-which allowed extensive personalization without the need for specialized computer technology-and discuss its potential application in similar settings. The mail merge feature of standard word processing software was used to generate unique, personalized questionnaires for each author by incorporating specific information from the article, including naming the randomization unit (e.g., family practice, school, worksite), and identifying specific individuals who may have been considered research participants at the cluster level (family doctors, teachers, employers) and individual level (patients, students, employees) in questions regarding informed consent procedures in the trial. The response rate was relatively high (64%, 182/285) and did not vary significantly by author, publication, or study characteristics. The refusal rate was low (7%). While controlled studies are required to examine the specific effects of our approach on comprehension, quality of responses, and response rates, we showed how mail merge can be used as a simple but useful tool to add personalized fields to complex survey questionnaires, or to request additional information required from study authors. One potential application is in eliciting specific information about published articles from study authors when conducting systematic reviews and meta-analyses.


Stereotactic laser ablation for nonlesional cingulate epilepsy: case report.
Stereotactic laser ablation (SLA) is being increasingly used to treat refractory focal epilepsy, especially mesial temporal lobe epilepsy. However, emerging evidence suggests it can be used for extratemporal lobe epilepsy as well.The authors report the case of a 17-year-old male who presented with refractory nocturnal seizures characterized by bilateral arms stiffening or rhythmic jerking lasting several seconds. Semiology suggested an epileptogenic zone close to one of the supplementary sensory motor areas. Electroencephalography showed seizures arising from the central region without consistent lateralization. Brain imaging showed no abnormality. An invasive evaluation using bilateral stereoelectroencephalography (SEEG) was utilized in 2 steps, first to establish the laterality of seizures, and second to further cover the mesial cingulate region of the right hemisphere. Seizures arose from the middle portion of the right cingulate gyrus. Extraoperative electrical mapping revealed that the seizure onset zone was adjacent to eloquent motor areas. SLA targeting the right midcingulate gyrus was performed. The patient has remained seizure free since immediately after the procedure with no postoperative deficits (follow-up of 17 months).This case highlights the utility of SEEG in evaluating difficult-to-localize, focal epilepsy. It also demonstrates that the use of SLA can be extended to nonlesional, extratemporal epilepsies.


In search of reflective behavior and shared understanding in ad hoc expert teams.
The work reported on here concentrates on virtual ad hoc expert teams for the integration of learning and working, as ad hoc teams seem to be one way to cope with complexity in a knowledge-intensive society. In order to let ad hoc teams learn and work together, group members require effective communication and shared understanding among each other. Two empirical studies were conducted to study collaborative learning and shared understanding, one exploratory study and one experiment. In the first study, it was explored how virtual design teams work and learn together. Based on conceptual ideas, collaborative learning and shared understanding were observed and assessed in a design team over a period of four months. It was concluded that shared understanding was suboptimal; mainly due to the effect that hardly any questions were raised and answered. The second study elaborates on the need to encourage question-answer patterns and reflective behavior in such teams. A tool was developed that supported questioning behavior. As it was hypothesized that this tool leads to better questioning behavior, which in turn results in more reflective behavior and in increased shared understanding, an experiment was conducted. In the exploratory study, as well as in the experimental study, the perceived shared understanding increased over time. However, in both studies suboptimal questioning behavior and little reflective activity were noticed. The main results of the two empirical studies are compared and discussed.


VENOM AND VENOM APPARATUS OF THE BULL ANT, MYRMECIA GULOSA (FABR.).
The venom of Myrmecia gulosa (Myrmeciinae, Formicidae) is of a proteinaceous type and is separated by electrophoresis into eight components. The venom contains histamine, a hyaluronidase, and a direct hemolytic factor. It also shows kinin-like activity. In structure the venom apparatus is found to be massively formed internally as well as externally. It is distinguished from the apparatus of representatives of other ant subfamilies by characteristics of the free gland filaments, the reservoir wall, the intra-reservoir glandular area, and the accessory gland.


What is Interaction for Data Visualization?
Interaction is fundamental to data visualization, but what "interaction" means in the context of visualization is ambiguous and confusing. We argue that this confusion is due to a lack of consensual definition. To tackle this problem, we start by synthesizing an inclusive view of interaction in the visualization community - including insights from information visualization, visual analytics and scientific visualization, as well as the input of both senior and junior visualization researchers. Once this view takes shape, we look at how interaction is defined in the field of human-computer interaction (HCI). By extracting commonalities and differences between the views of interaction in visualization and in HCI, we synthesize a definition of interaction for visualization. Our definition is meant to be a thinking tool and inspire novel and bolder interaction design practices. We hope that by better understanding what interaction in visualization is and what it can be, we will enrich the quality of interaction in visualization systems and empower those who use them.


[Senses and meanings of health socialized by cultural devices: readings of the warning images on cigarettes packs].
This article analyzes the images publicized on cigarettes packs that are part of the strategies from the Ministry of Health to combat the tabagism and available from the Cancer National Institute. These images bring the official speech of specialists and build narratives, understood such as truths, based on scientific knowledge. We have supported our thesis on theoretical referential of Cultural Studies, since its reflections help to understand that the subjectiveness is social and culturally built by different speeches and devices. We do not deny what is represented, but we establish dialogues with other possibilities of readings that can be present at these devices.We understand the propagated images as cultural pedagogies that behave as texts to be read, building up representations that can be assumed as true effect, and attributes to the citizen the necessity of constant control of its action. Reassuring the biomedicine and the health institutions, an onedimensional vision is propagated disregarding the complexity of this problem. We understand that the cultural pedagogies are part of competition territories, where the directions and meanings can be re-prepared producing hybrid identities that build up its own identity origins over this tangle of power relations.


Effect of Point-Spread Function Reconstruction for Indeterminate PSMA-RADS-3A Lesions on PSMA-Targeted PET Imaging of Men with Prostate Cancer.
Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is emerging as an important modality for imaging patients with prostate cancer (PCa). As with any imaging modality, indeterminate findings will arise. The PSMA reporting and data system (PSMA-RADS) version 1.0 codifies indeterminate soft tissue findings with the PSMA-RADS-3A moniker. We investigated the role of point-spread function (PSF) reconstructions on categorization of PSMA-RADS-3A lesions. This was a post hoc analysis of an institutional review board approved prospective trial. Around 60 min after the administration of 333 MBq (9 mCi) of PSMA-targeted 18F-DCFPyL, patients underwent PET/computed tomography (CT) acquisitions from the mid-thighs to the skull vertex. The PET data were reconstructed with and without PSF. Scans were categorized according to PSMA-RADS version 1.0, and all PSMA-RADS-3A lesions on non-PSF images were re-evaluated to determine if any could be re-categorized as PSMA-RADS-4. The maximum standardized uptake values (SUVs) of the lesions, mean SUVs of blood pool, and the ratios of those values were determined. A total of 171 PSMA-RADS-3A lesions were identified in 30 patients for whom both PSF reconstructions and cross-sectional imaging follow-up were available. A total of 13/171 (7.6%) were re-categorized as PSMA-RADS-4 lesions with PSF reconstructions. A total of 112/171 (65.5%) were found on follow-up to be true positive for PCa, with all 13 of the re-categorized lesions being true positive on follow-up. The lesions that were re-categorized trended towards having higher SUVmax-lesion and SUVmax-lesion/SUVmean-blood-pool metrics, although these relationships were not statistically significant. The use of PSF reconstructions for 18F-DCFPyL PET can allow the appropriate re-categorization of a small number of indeterminate PSMA-RADS-3A soft tissue lesions as more definitive PSMA-RADS-4 lesions. The routine use of PSF reconstructions for PSMA-targeted PET may be of value at those sites that utilize this technology.


Averting HIV infections in New York City: a modeling approach estimating the future impact of additional behavioral and biomedical HIV prevention strategies.
New York City (NYC) remains an epicenter of the HIV epidemic in the United States. Given the variety of evidence-based HIV prevention strategies available and the significant resources required to implement each of them, comparative studies are needed to identify how to maximize the number of HIV cases prevented most economically. A new model of HIV disease transmission was developed integrating information from a previously validated micro-simulation HIV disease progression model. Specification and parameterization of the model and its inputs, including the intervention portfolio, intervention effects and costs were conducted through a collaborative process between the academic modeling team and the NYC Department of Health and Mental Hygiene. The model projects the impact of different prevention strategies, or portfolios of prevention strategies, on the HIV epidemic in NYC. Ten unique interventions were able to provide a prevention benefit at an annual program cost of less than $360,000, the threshold for consideration as a cost-saving intervention (because of offsets by future HIV treatment costs averted). An optimized portfolio of these specific interventions could result in up to a 34% reduction in new HIV infections over the next 20 years. The cost-per-infection averted of the portfolio was estimated to be $106,378; the total cost was in excess of $2 billion (over the 20 year period, or approximately $100 million per year, on average). The cost-savings of prevented infections was estimated at more than $5 billion (or approximately $250 million per year, on average). Optimal implementation of a portfolio of evidence-based interventions can have a substantial, favorable impact on the ongoing HIV epidemic in NYC and provide future cost-saving despite significant initial costs.


Viewing the motion of human body parts activates different regions of premotor, temporal, and parietal cortex.
Activation of premotor and temporoparietal cortex occurs when we observe others movements, particularly relating to objects. Viewing the motion of different body parts without the context of an object has not been systematically evaluated. During a 3T fMRI study, 12 healthy subjects viewed human face, hand, and leg motion, which was not directed at or did not involve an object. Activation was identified relative to static images of the same human face, hand, and leg in both individual subject and group average data. Four clear activation foci emerged: (1) right MT/V5 activated to all forms of viewed motion; (2) right STS activated to face and leg motion; (3) ventral premotor cortex activated to face, hand, and leg motion in the right hemisphere and to leg motion in the left hemisphere; and (4) anterior intraparietal cortex (aIP) was active bilaterally to viewing hand motion and in the right hemisphere leg motion. In addition, in the group data, a somatotopic activation pattern for viewing face, hand, and leg motion occurred in right ventral premotor cortex. Activation patterns in STS and aIP were more complex--typically activation foci to viewing two types of human motion showed some overlap. Activation in individual subjects was similar; however, activation to hand motion also occurred in the STS with a variable location across subjects--explaining the lack of a clear activation focus in the group data. The data indicate that there are selective responses to viewing motion of different body parts in the human brain that are independent of object or tool use.


The HSC73 molecular chaperone: involvement in MHC class II antigen presentation.
Heat shock proteins (HSP) are conserved proteins, many of which share the ability for indiscriminate peptide binding and ATPase-coupled peptide release. In this paper, we show that heat shock cognate protein (HSC)73, a constitutively expressed member of the HSP70 family, could be a candidate for chaperone activity within the MHC class II presentation pathway. HSC73 expression in macrophages was shown to overlap with expression of MHC class II; overexpression of HSC73 in stable transfectants of a macrophage line markedly enhanced their presentation of exogenous Ag without affecting presentation of processing independent peptide. Ag from an exogenous source was demonstrated to associate with HSC73 in macrophages, and this association was sensitive to ATP treatment and inhibited by deoxyspergualin, an immunosuppressive agent that has previously been shown to bind specifically to HSC73. Furthermore, deoxyspergualin reduced Ag presentation by macrophages in relation to the amount of HSC73 expressed in these cells. The data are consistent with a potential role for HSC73 in binding and protecting peptides from extensive degradation and/or facilitating the kinetics of peptide transfer to MHC class II molecules.


Effects of sevoflurane postconditioning on cell death, inflammation and TLR expression in human endothelial cells exposed to LPS.
Sevoflurane is an anesthetic agent which also participates in protective mechanisms in sepsis, likely due to anti-inflammatory properties. A key tissue in sepsis is the endothelium, which expresses TLR2 and TLR4 receptors, known regulators of inflammatory mechanisms and potential therapeutic targets for this pathology. In this context, we explored the effect of sevoflurane postconditioning in an in vitro sepsis model. Primary cultures of human umbilical vein endothelial cells were used for two different experiments. In the first set, cultures were placed in an airtight incubation chamber and exposed to different concentrations of sevoflurane (0,1,3 or 7% vol,) for 1 hour. In the second set, lipopolysaccharide from Escherichia coli 0111:B4 (1 μg/mL) was added to culture medium for 3 hours and cells were subsequently exposed to sevoflurane (0,1,3 or 7% vol,) for 1 hour as explained before. In both cases, cell viability was measured by MTT and Trypan blue assays, TLR2 and TLR4 expression were analyzed by flow cytometry, and TNFα and IL-6 levels were quantified in cell culture media by an immunoassay immediately after exposure, at 6 and 24 hours. Exposure to 3% sevoflurane decreased TLR2 at 24 hours and TLR4 at 6 and 24 hours (both p<0.05), whereas exposure to 7% decreased TLR4 expression at 6 hours (p<0.05). Both 3 and 7% sevoflurane decreased TNF-α and IL-6 levels at 24 hours (both p<0.05). In LPS-stimulated cultures, exposure to 3% sevoflurane was cytoprotective at 6 and 24 hours (p<0.05) compared with control, and decreased TLR2 and TLR4 expression at 24 hours (p<0.05); whereas 7% decreased TLR4 expression at 24 hours (p<0.05). Both 3% and 7% sevoflurane decreased TNF-α and IL-6 levels at 24 hours (both p<0.05). Postconditioning with the halogenated anesthetic agent sevoflurane after LPS stimulation shows a cytoprotective effect in an in vitro model, decreasing cell death and reducing TLR2 and TLR4 expression as well as levels of the inflammatory mediators TNF-α and IL-6 in human endothelial cells.


Lessons from the 'Humanitarian Golden Rice' project: regulation prevents development of public good genetically engineered crop products.
Compared to a non-Genetically Engineered (GE) variety, the deployment of Golden Rice has suffered from a delay of at least ten years. The cause of this delay is exclusively GE-regulation. Considering the potential impact of Golden Rice on the reduction in vitamin A-malnutrition, this delay is responsible for an unjustifiable loss of millions of lives, mostly children and women. GE-regulation is also responsible for the fact that no public institution can deliver a public good GE-product and that thus we have a de facto monopoly in favour of a few potent industries. Considering the forgone benefits from prevented public good GE-products, GE-regulation is responsible for hundreds of millions of lives, all of them, of course, in developing countries. As there is no scientific justification for present GE-regulation, and as it has, so far, not prevented any harm, our society has the urgent responsibility to reconsider present regulation, which is based on an extreme interpretation of the precautionary principle, and change it to science-based regulation on the basis of traits instead of technology. GE-technology has an unprecedented safety record and is far more precise and predictable than any other 'traditional' and unregulated breeding technology. Not to change GE-regulation to a scientific basis is considered by the author 'a crime against humanity'.


To split or not to split: colostomy complications for anorectal malformations or hirschsprung disease: a single center experience and a systematic review of the literature.
The aim of this article is to identify the ideal type and location of colostomy in children with colorectal disease. A retrospective case study of children with an anorectal malformation who received a colostomy, born between January 1990 and July 2012. Furthermore, a systematic literature search on colostomies in neonates with an anorectal malformation or Hirschsprung disease. Colostomies were classified as loop or split colostomies in the transverse or sigmoid colon. Outcome measures were mortality and complications such as prolapse, technical difficulties with the reconstruction, urinary tract infections, and others. The mortality rate in the 180 children with anorectal malformation was 6%, and none of them were directly related to stoma formation or closure. The overall complication rate was 23% and the specific rates for the two types of procedures and the two locations of the colostomy did not differ (p = 0.389 and p = 0.667, respectively). All prolapses (n = 22) occurred in loop colostomies in the transverse colon. One colostomy required revision because of insufficient length for the reconstruction. Urinary tract infections were not documented. A total of eight studies were included in the systematic review (1982-2011; 2,954 patients). Mortality ranged between 0.1 and 11%. Loop colostomies had more complications than split colostomies (63 vs. 45%; p = 0.007), mainly prolapse (18 vs. 6%; p < 0.001). Overall complication rate differed between transverse en sigmoid colostomies (62 vs. 51%, p = 0.006), and prolapse occurred more often in the transverse colon (23 vs. 7%; p < 0.001). Revision because of insufficient length during the reconstruction was needed in 0 to 6%. Two studies reported on urinary tract infections which are as follows: One showed no difference between loop or split colostomies, whereas the other showed frequent episodes of urinary tract infections in 64% of the loop colostomies. The complication to be avoided in transverse colostomies is prolapse and the surgical technique should be modified accordingly. The procedure of split sigmoid colostomy is meticulous, and the risk of insufficient length for the reconstruction remains.


Transmission resonances of compound metallic gratings with two subwavelength slits in each period.
Based on the finite-difference time-domain method, we investigate the transmission resonances of compound metallic gratings with two subwavelength slits filled with different dielectrics inside each period in the visible and near infrared regions. The results show that the transmission spectrum is almost a compound of that of two corresponding simple gratings expect for the transmission feature at a certain resonant wavelength, where the Fabry-Pérot (FP)-like phenomena have been found both inside the two slits, but the orders of the FP-like modes are different. If the order of the FP-like mode inside one slit is one bigger than inside the other, the intensity of the transmission will be significantly weakened. We attribute this phenomenon to the phase resonance because the phases at the exits of the two slits are opposite to each other.


CD4+ T cell activation and associated susceptibility to HIV-1 infection in vitro increased following acute resistance exercise in human subjects.
Early studies in exercise immunology suggested acute bouts of exercise had an immunosuppressive effect in human subjects. However, recent data, show acute bouts of combined aerobic and resistance training increase both lymphocyte activation and proliferation. We quantified resistance exercise-induced changes in the activation state of CD4+ T lymphocytes via surface protein expression and using a medically relevant model of infection (HIV-1). Using a randomized cross-over design, 10 untrained subjects completed a control and exercise session. The control session consisted of 30-min seated rest while the exercise session entailed 3 sets × 10 repetitions of back squat, leg press, and leg extensions at 70% 1-RM with 2-min rest between each set. Venous blood samples were obtained pre/post each session. CD4+ T lymphocytes were isolated from whole blood by negative selection. Expression of activation markers (CD69 & CD25) in both nonstimulated and stimulated (costimulation through CD3+ CD28) cells were assessed by flow cytometry. Resistance exercised-induced effects on intracellular activation was further evaluated via in vitro infection with HIV-1. Nonstimulated CD4+ T lymphocytes obtained postexercise exhibited elevated CD25 expression following 24 h in culture. Enhanced HIV-1 replication was observed in cells obtained postexercise. Our results demonstrate that an acute bout of resistance exercise increases the activation state of CD4+ T lymphocytes and results in a greater susceptibility to HIV-1 infection in vitro. These findings offer further evidence that exercise induces activation of T lymphocytes and provides a foundation for the use of medically relevant pathogens as indirect measures of intracellular activation.


Shifting perspectives: adolescent-focused oncology nursing research.
To describe contextual features of the experience of adolescents with cancer in the United States; to relate these features to a different theoretical perspective, the Shifting Perspectives Model of Chronic Illness; and to derive implications from that model for conducting research with adolescents who have cancer. 64 qualitative and quantitative studies and clinical anecdotes. Unique features of adolescents with cancer related to person, disease, and treatment indicate that existing theories on adolescence do not adequately guide research efforts with this patient population, nor do they adequately assist in explaining study findings. The Shifting Perspectives Model of Chronic Illness is useful in generating potentially important hypotheses about adolescents and their experiences with cancer and has the promise of guiding research design and method selection for studies involving adolescents with cancer. The model also highlights a moral responsibility for researchers who conduct studies with this patient population. Nurse researchers who use this model to guide their research will create a purposeful balance in methods that allows adolescents with cancer to choose the amount of time and detail they will give to illness-related or to wellness-related responses in studies, particularly those that rely on self-report methods.


Joint attention initiation with and without positive affect: risk group differences and associations with ASD symptoms.
Infants at risk for autism spectrum disorders (ASD) may have difficulty integrating smiles into initiating joint attention (IJA) bids. A specific IJA pattern, anticipatory smiling, may communicate preexisting positive affect when an infant smiles at an object and then turns the smile toward the social partner. We compared the development of anticipatory smiling at 8, 10, and 12 months in infant siblings of children with ASD (high-risk siblings) and without ASD (low-risk siblings). High-risk siblings produced less anticipatory smiling than low-risk siblings, suggesting early differences in communicating preexisting positive affect. While early anticipatory smiling distinguished the risk groups, IJA not accompanied by smiling best predicted later severity of ASD-related behavioral characteristics among high-risk siblings. High-risk infants appear to show lower levels of motivation to share positive affect with others. However, facility with initiating joint attention in the absence of a clear index of positive affective motivation appears to be central to the prediction of ASD symptoms.


Cathelicidins Have Direct Antiviral Activity against Respiratory Syncytial Virus In Vitro and Protective Function In Vivo in Mice and Humans.
Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infection in infants, causing significant morbidity and mortality. No vaccine or specific, effective treatment is currently available. A more complete understanding of the key components of effective host response to RSV and novel preventative and therapeutic interventions are urgently required. Cathelicidins are host defense peptides, expressed in the inflamed lung, with key microbicidal and modulatory roles in innate host defense against infection. In this article, we demonstrate that the human cathelicidin LL-37 mediates an antiviral effect on RSV by inducing direct damage to the viral envelope, disrupting viral particles and decreasing virus binding to, and infection of, human epithelial cells in vitro. In addition, exogenously applied LL-37 is protective against RSV-mediated disease in vivo, in a murine model of pulmonary RSV infection, demonstrating maximal efficacy when applied concomitantly with virus. Furthermore, endogenous murine cathelicidin, induced by infection, has a fundamental role in protection against disease in vivo postinfection with RSV. Finally, higher nasal levels of LL-37 are associated with protection in a healthy human adult RSV infection model. These data lead us to propose that cathelicidins are a key, nonredundant component of host defense against pulmonary infection with RSV, functioning as a first point of contact antiviral shield and having additional later-phase roles in minimizing the severity of disease outcome. Consequently, cathelicidins represent an inducible target for preventative strategies against RSV infection and may inform the design of novel therapeutic analogs for use in established infection.


Combined Tensor Fitting and TV Regularization in Diffusion Tensor Imaging Based on a Riemannian Manifold Approach.
In this paper, we consider combined TV denoising and diffusion tensor fitting in DTI using the affine-invariant Riemannian metric on the space of diffusion tensors. Instead of first fitting the diffusion tensors, and then denoising them, we define a suitable TV type energy functional which incorporates the measured DWIs (using an inverse problem setup) and which measures the nearness of neighboring tensors in the manifold. To approach this functional, we propose generalized forward- backward splitting algorithms which combine an explicit and several implicit steps performed on a decomposition of the functional. We validate the performance of the derived algorithms on synthetic and real DTI data. In particular, we work on real 3D data. To our knowledge, the present paper describes the first approach to TV regularization in a combined manifold and inverse problem setup.


Human milk and host defence: immediate and long-term effects.
Convincing studies demonstrate significant protection during breastfeeding against diarrhoea, respiratory tract infections, otitis media, bacteraemia, bacterial meningitis, botulism, urinary tract infections and necrotizing enterocolitis. There is also good evidence for enhanced protection for years after the termination of breastfeeding against Haemophilus influenzae type b infections, otitis media, diarrhoea, respiratory tract infections and wheezing bronchitis. In some reports breastfeeding has also improved vaccine responses. Several studies show that milk may actively stimulate the immune system of the offspring via transfer of anti-idiotypic antibodies and lymphocytes. This may explain why breastfeeding diminishes the risk of developing coeliac disease. Some investigations suggest that there may also be a similar effect on allergic diseases and autoimmune diseases, as well as inflammatory bowel diseases and certain tumours. This needs to be confirmed.


How Do Masters of Public Health Programs Teach Monitoring and Evaluation?
The health systems in developing countries face challenges because of deficient monitoring and evaluation (M&E) capacity with respect to their knowledge, skills, and practices. Strengthening M&E training in public health education can help overcome the gaps in M&E capacity. There is a need to advance the teaching of M&E as a core element of public health education. To review M&E teaching across Masters of Public Health programs and to identify core competencies for M&E teaching in South Asian context. We undertook two activities to understand the M&E teaching across masters level programs: (1) desk review of M&E curriculum and teaching in masters programs globally and (2) review of M&E teaching across 10 institutions representing 4 South Asian countries. Subsequently, we used the findings of these two activities as inputs to identify core competencies for an M&E module through a consultative meeting with the 10 South Asian universities. Masters programs are being offered globally in 321 universities of which 88 offered a Masters in Public Health, and M&E was taught in 95 universities. M&E was taught as a part of another module in 49 institutions. The most common duration of M&E teaching was 4-5 weeks. From the 70 institutes where information on electives was available, M&E was a core module/part of a core module at 42 universities and an elective at 28 universities. The consultative meeting identified 10 core competencies and draft learning objectives for M&E teaching in masters programs in South Asia. The desk review showed similarities in M&E course content but variations in course structure and delivery. The core competencies identified during the consultation included basic M&E concepts. The results of the review and the core competencies identified at the consultation are useful resources for institutions interested in refining/updating M&E curricula in their postgraduate degree programs. Our approach for curriculum development as well as the consensus building experience could also be adapted for use in other situations.


Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma.
Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastro-oesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival. Thirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein-Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour-stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density. 12% of resections showed tumour cell membranous PD-L1 expression and 44% showed expression within the immune stroma. Two cases (6%) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (>500/mm2) were associated with worse progression-free survival (PFS) and overall survival (OS). PD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immune-based therapy.


Appropriateness of acute medical admissions and length of stay.
To use the Appropriateness Evaluation Protocol (AEP) to assess the extent of inappropriate utilisation of hospital beds by acute medical patients. To determine whether clinicians viewed the AEP decisions as valid. Retrospective review of the medical records of a 10% random sample of 8,210 patients admitted as medical emergencies. An objective independent review instrument (AEP) was used to assess the medical necessity for hospitalisation at admission and on each subsequent day. To test the validity of the screening instrument, a subsample of the reviewed records was further assessed by a panel of physicians. A district general hospital in the West Midlands region of England. Eight hundred and twenty-one adult patients admitted to general medicine during one calendar year. Proportions of admissions and days of care for which inpatient medical care was judged appropriate. Reasons for inappropriate utilisation and potential bed-days that could be saved by the development and use of alternative services were also considered. Validity of the AEP was tested by assessing agreement between the majority decision of an expert panel and the criterion-based AEP decision. AEP identified 51/821 (6%) admissions and 2,195/4,885 (45%) days of care as inappropriate. Over half the patients had a hospital stay in which at least half the days were judged inappropriate. The commonest reason for inappropriate days was remaining in hospital after the medical purpose for admission had been accomplished. This accounted for 38% of inappropriate days reviewed. In validity testing there was a high level of agreement between the physicians and the AEP, with kappa values greater than 0.80 for admissions and days of care. The AEP is a valid and useful instrument for assessing the utilisation of acute medical beds in a NHS hospital. In this study acute medical admissions were largely appropriate at the time of admission but a substantial proportion of subsequent days of care was considered inappropriate by AEP criteria. Most inappropriate utilisation was due to organisational issues within the hospital. As a result of this study, several service and policy developments were identified that should improve the efficiency of bed utilisation at the hospital.


Broadband boundary effects on Brownian motion.
Brownian motion of particles in confined fluids is important for many applications, yet the effects of the boundary over a wide range of time scales are still not well understood. We report high-bandwidth, comprehensive measurements of Brownian motion of an optically trapped micrometer-sized silica sphere in water near an approximately flat wall. At short distances we observe anisotropic Brownian motion with respect to the wall. We find that surface confinement not only occurs in the long time scale diffusive regime but also in the short time scale ballistic regime, and the velocity autocorrelation function of the Brownian particle decays faster than that of a particle in bulk fluid. Furthermore, at low frequencies the thermal force loses its color due to the reflected flow from the no-slip boundary. The power spectrum of the thermal force on the particle near a no-slip boundary becomes flat at low frequencies. This detailed understanding of boundary effects on Brownian motion opens a door to developing a 3D microscope using particles as remote sensors.


Increased circulating colony-stimulating factor-1 in patients with preleukemia, leukemia, and lymphoid malignancies.
Recently, several malignant cell types have been reported to express colony-stimulating factor-1 (CSF-1) transcripts; however, the clinical significance of CSF-1 in malignancy has not been investigated. Using a CSF-1 radioimmunoassay, we surveyed concentrations of biologically active CSF-1 in the peripheral blood of 316 patients with malignant and premalignant hematologic disorders; 75 had a myelodysplastic syndrome (MDS), 12 acute myelogenous leukemia (AML), 7 chronic myelogenous leukemia, 21 chronic lymphocytic leukemia (CLL), 106 non-Hodgkin's lymphoma (NHL; of low-, intermediate- and high-grade malignancy), 46 Hodgkin's disease (HD), 46 multiple myeloma (MM), and 3 monoclonal gammopathy of undetermined significance. Controls were 64 healthy subjects. The CSF-1 concentration was correlated with the type of disease, status of the disease, treatment status, and hematologic parameters. CSF-1 concentration was significantly elevated in 83.5% of the patients with active disease, and for each active disease group it was significantly greater (P less than .0001) than in the control. Thus, the high circulating CSF-1 concentration was not associated with a particular malignant phenotype or MDS subtype, but did correlate with the disease activity of both NHL and HD, and the tumor burden in MM, AML, and CLL. There was no correlation of the CSF-1 level with total counts of monocytes or neutrophils in patients with MDS or other malignancies. The cellular basis for the elevated circulating CSF-1 was not investigated. However, the results are consistent with the possibility that the premalignant or malignant cells themselves produce CSF-1 or regulate its production by normal cells.


Current Perception of Telemedicine in an EU Country.
To assess the perception and expectation of beneficiaries and providers of telemedicine services in Romania. Interview (on-line and face-to-face) of 109 representatives of medical community, from two categories: physicians, involved directly in the patient care, and medical and information technology directors of state and private owned clinics and hospitals. A third group, formed by executives from main technology service provider companies, was added in order to expand the results with their vision as potential suppliers of telemedicine projects. We evaluated 4 important aspects of telemedicine: actual status of the services, development efforts and allocated budget, expected future services, and stoppers and enablers. On the actual status we identified in 48% of the cases the existence of core services good enough to start advanced telemedicine services. We developed a metric (SOR = Supporter/Opponents Ratio) to evaluate the suitability of telemedicine services to evolve and to deliver on expectations. The analysis shows that physicians see potential for development for EHR and PACS (both with SOR >25), but the executives start looking forward to more advanced services like remote patient monitoring. Main impact is expected in collaboration and patient quality life areas and, by far, the main stoppers are reduced budgets and organizational problems to adapt to the new data models. We identified a strong support from the physicians related with the introduction of new type of healthcare services accompanied with high expectations. On the executive level, the expectations are different, ranging from low optimism on the technology side, to serious support on the medical side. However, there is a clear trend, able to create the first telemedicine services during the next years.


Coffee and tea consumption in the early adult lifespan and left ventricular function in middle age: the CARDIA study.
The long-term impact of coffee or tea consumption on subclinical left ventricular (LV) systolic or diastolic function has not been previously studied. We examined the association between coffee or tea consumption beginning in early adulthood and cardiac function in midlife. We investigated 2735 Coronary Artery Risk Development in Young Adults (CARDIA) study participants with long-term total caffeine intake, coffee, and tea consumption data from three visits over a 20 year interval and available echocardiography indices at the CARDIA Year-25 exam (2010-2011). Linear regression models were used to assess the association between caffeine intake, tea, and coffee consumption (independent variables) and echocardiography outcomes [LV mass, left atrial volume, and global longitudinal strain (GLS), LV ejection fraction (LVEF), and transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/e´)]. Models were adjusted for standard cardiovascular risk factors, socioeconomic status, physical activity, alcohol use, and dietary factors (calorie intake, whole and refined grain intake, and fruit and vegetable consumption). Mean (standard deviation) age was 25.2 (3.5) years at the CARDIA Year-0 exam (1985-1986), 57.4% were women, and 41.9% were African-American. In adjusted multivariable linear regression models assessing the relationship between coffee consumption and GLS, beta coefficients when comparing coffee drinkers of <1, 1-2, 3-4, and >4 cups/day with non-coffee drinkers were β = -0.30%, P < 0.05; β = -0.35%, P < 0.05; β = -0.32%, P < 0.05; β = -0.40%, P > 0.05; respectively (more negative values implies better systolic function). In adjusted multivariable linear regression models assessing the relationship between coffee consumption and E/e´, beta coefficients when comparing coffee drinkers of <1, 1-2, 3-4, and >4 cups/day with non-coffee drinkers were β = -0.29, P < 0.05; β = -0.38, P < 0.01; β = -0.20, P > .05; and β = -0.37, P > 0.05, respectively (more negative values implies better diastolic function). High daily coffee consumption (>4 cups/day) was associated with worse LVEF (β = -1.69, P < 0.05). There were no associations between either tea drinking or total caffeine intake and cardiac function (P > 0.05 for all). Low-to-moderate daily coffee consumption from early adulthood to middle age was associated with better LV systolic and diastolic function in midlife. High daily coffee consumption (>4cups/day) was associated with worse LV function. There was no association between caffeine or tea intake and cardiac function.


Internal medicine in the current health care environment: a need for reaffirmation.
Managed care has substantially changed the environment of health care delivery for general internists and internist-subspecialists. In the current system, one may wonder whether detailed and thoughtful workups still have a role when the direction of medical practice increasingly prizes a high volume of brief encounters. However, the very forces that drive managed care make the role of internist in the care of adults even more central. The internist's unique training and clinical approach should lead to both medically effective and cost-effective health care for adults. This type of health care will be increasingly important as the U.S. population ages and an increasing number of Americans have chronic, multisystem disease. Over the past century, internal medicine has evolved from a consultative model to a discipline that encompasses total adult care, from prevention to diagnosis and treatment of acute and chronic illness and from outpatient care in the office to inpatient care in the intensive care unit. However, the leadership role of internists in the medical care of adults is now being threatened by family medicine and by fragmentation within internal medicine itself. Managed care organizations and the general public must be shown why internists are better able than family physicians to meet the health care needs of adults. Furthermore, as the marketplace becomes more competitive, the issue of when care given by a subspecialist is superior to that given by an internist has become more prominent. The rapidly developing "hospitalist" movement also threatens the traditional role of the internist as the caregiver for adults in health and disease. Given the historic flexibility of internal medicine and the assumption that appropriate roles can be defined for family physicians, subspecialists, and hospitalists, internists will continue to play a central role in providing the best care for adults in the new world of health care delivery.


Collectin-11/MASP complex formation triggers activation of the lectin complement pathway--the fifth lectin pathway initiation complex.
Collectins and ficolins are important in the clearance of endogenous and exogenous danger materials. A new human collectin-11 was recently identified in low concentration in serum in complex with mannose-binding lectin (MBL)/ficolin-associated serine proteases. Collectin-11 binds to carbohydrate residues present on various microorganisms. Thus, we hypothesized that collectin-11 could be a novel initiation molecule in the lectin pathway of complement. We can show that collectin-11 associates with all the known MBL-associated serine proteases (MASP-1, MASP-2 and MASP-3) as well as the lectin complement pathway regulator MAP-1. Furthermore, we found that complex formation between recombinant collectin-11 and recombinant MASP-2 on Candida albicans leads to deposition of C4b. Native collectin-11 in serum mediated complement activation and deposition of C4b and C3b, and formation of the terminal complement complex on C. albicans. Moreover, spiking collectin-11-depleted serum, which did not mediate complement activation, with recombinant collectin-11 restored the complement activation capability. These results define collectin-11 as the fifth recognition molecule in the lectin complement pathway in addition to MBL, ficolin-1, ficolin-2 and ficolin-3.


Progress in Enzyme Replacement Therapy in Glycogen Storage Disease Type II.
Glycogen storage disease type II (GSDII) is an autosomal recessive lysosomal disorder caused by mutations in the gene encoding alpha-glucosidase (GAA). The disease can be clinically classified into three types: a severe infantile form, a juvenile and an adultonset form. Cases with juvenile or adult onset GSDII mimic limb-girdle muscular dystrophy or polymyositis and are often characterized by respiratory involvement. GSDII patients are diagnosed by biochemical assay and by molecular characterization of the GAA gene. Ascertaining a natural history of patients with heterogeneous late-onset GSDII is useful for evaluating their progressive functional disability. A significant decline is observed over the years in skeletal and respiratory muscle function. Enzyme replacement therapy (ERT) has provided encouraging results in the infantile form. It is not yet known if ERT is effective in late-onset GSDII. We examined a series of 11 patients before and after ERT evaluating muscle strength by MRC, timed and graded functional tests, 6-minute walk test (6MWT), respiratory function by spirometric parameters and quality of life. We observed a partial improvement during a prolonged follow-up from 3 to 18 months. The use of different clinical parameters in the proposed protocol seems crucial to determine the efficacy of ERT, since not all late-onset patients respond similarly to ERT.


Urban-rural differences in incidence rates of psychiatric disorders in Denmark.
People born in densely populated areas have a higher risk of developing schizophrenia, bipolar disorder and autism. The purpose of this study was to investigate whether urban-rural differences in place of birth influence a broad range of mental disorders. Population-based cohort study of everyone born in Denmark between 1955 and 2006 (n = 2 894 640). Main outcome measures were incidence rate ratios for five levels of urbanisation and summary estimates contrasting birth in the capital with birth in rural areas. For all psychiatric disorders, except intellectual disability (ICD-10 'mental retardation') and behavioural and emotional disorders with onset in childhood, people born in the capital had a higher incidence than people born in rural areas. Birth in an urban environment is associated with an increased risk for mental illness in general and for a broad range of specific psychiatric disorders. Given this new evidence that urban-rural differences in incidence are not confined to the well-studied psychotic disorders, further work is needed to identify the underlying aetiopathogenic mechanisms.