Model selection based on logistic regression in a highly correlated candidate gene region.
Our aim is to develop methods for identifying a (causal) variant or variants from a dense panel of single-nucleotide polymorphisms (SNPs) that are genotyped on the evidence of previous studies. Because a large number of SNPs are in close proximity to each other, the magnitude of linkage disequilibrium (LD) plays an important role. Namely, highly correlated SNPs may hamper standard methods such as multivariate logistic regression due to multicolinearity between the covariates. Sequences of models with high dimension naturally raise questions about model selection strategies. We investigate three variable selection methods based on logistic regression. The penalties on stepwise selection were imposed using the Akaike's Information Criterion (AIC), and using the lasso penalty. Finally, a Bayesian variable-selection logistic regression model was implemented. The methods are illustrated using the simulated dense SNPs including the causal DR/C locus on chromosome 6. We also evaluate model selection in terms of average prediction error across nine replicates. We conclude that for the Genetic Analysis Workshop 15 (GAW15) data, the newly developed Bayesian selection method performs well.


Quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health.
Cost-utility analysis in which health benefits are quantified in terms of quality-adjusted life-years (QALYs) has now become the standard type of cost-effectiveness analysis. These studies are potentially influential in determining the extent of funding for particular pediatric interventions, and so their methodologic quality is extremely important. The objective of this study was twofold: first, to critically appraise published cost-utility analyses of interventions in child and adolescent health care in terms of the methods used to derive QALYs and, second, to discuss unresolved methodologic issues that are pertinent to the measurement of QALYs in pediatric populations. A comprehensive search using computerized databases (including Medline, Embase, Econlit, and databases specific to economic evaluation), Web searches, and citation tracking was undertaken to identify cost-utility studies of interventions that were aimed at those who were younger than 16 years and published before April 2004. The methods of individual studies were compared with the recognized published guidelines of the US Panel on Cost-Effectiveness in Health and Medicine and the National Institute for Clinical Excellence in England and Wales, which recommend the use of a generic health state classification system (eg, Health Utility Index, EuroQol-5D), a choice-based valuation method (eg, standard gamble or time trade-off) and preferences of the general public in estimating QALYs. Studies therefore were categorized and evaluated according to the methods used to describe the health state, the valuation technique, and source of preferences. Fifty-four studies were reviewed, 34 (63%) of which were published in the past 5 years. A generic health status classification instrument was used in 22 (35%) cases; the remainder developed study-specific health state descriptions or elicited preferences directly from patients or proxies. In 3 (5%) cases, sources were unclear. Preference weights were elicited using choice-based techniques in 28 (42%) cases, either as tariffs for health status classification instruments (17 cases) or by directly valuing health state descriptions or patient health (11 cases). Preferences of the general public were used in only 23 (37%) cases. Four studies aggregated QALYs for mother/child or parents/child pairs without giving any theoretical justification. Although there was an increasing tendency for studies to use generic health status classification instruments, choice-based methods, and preferences of the general public, the majority of studies still did not adhere to these standard recommendations even in the period between January 2000 and March 2004. Despite increasing standardization in the methods advocated for economic evaluation over the past 10 years, there remains extensive variation in the actual methods used by researchers to calculate QALYs for children and adolescents. It is unclear whether these results suggest poor practice or a set of positive (or reactive) choices made by analysts in a methodologically uncertain area in which specific guidance is lacking regarding how to address the complexities of pediatric outcomes within the QALY framework. Many aspects of QALY measurement in children are not yet fully developed. In particular, there is (1) a lack of appropriate health state classification instruments that take account of the dynamics of child development, (2) a lack of health state classification instruments for use in children and infants who are younger than 5 years, and (3) the need to understand fully the role of proxies for measuring and valuing child health. Additional research efforts are also required to develop methods that account for the health benefits of parents or caregivers of the child and to consider the implications of combining different forms of utility measurement in childhood and adulthood. Although variations from standard recommendations may be attributable to poor practice among researchers who are either unaware of these recommendations or choose not to follow them, they could equally be the result of attempts to make research more rigorous and more defensible than it might be if the standard recommendations were followed. There are 4 potential approaches to conducting cost-utility analysis in pediatric populations: (1) the explicit development of a generic instrument designed to be applicable across both child and adult populations (likely to be difficult in practice), (2) insistence on use of a generic instrument developed for adults, (3) the use of generic instruments specifically developed for children without being concerned about comparability with interventions aimed at adults, and (4) abandoning attempts to use single outcome measures that combine mortality with quality weights. In the absence of a clear way forward, it is suggested that an expert panel be convened to debate and further consider these potential solutions and recommendations for best practice and future research. In the interim, comparisons of the relative cost-effectiveness reported as cost per QALY gained across interventions for different diseases and populations should be treated with extreme caution.


Force trace hysteresis and temperature dependence of bridging nanobubble induced forces between hydrophobic surfaces.
An atomic force microscope and the colloidal probe technique are used to probe the interaction between a hydrophobic particle and a hydrophobic surface in water. The characteristics of the observed force curves strongly suggest that a gas bubble is formed when the particle is moved toward the surface and that the bubble ruptures when the particle subsequently is retracted from the surface. We demonstrate that this type of interaction is not unique for hydrophobic surfaces in water since the interaction between hydrophilic surfaces in air provides very similar force curves. However, the interaction between hydrophobic surfaces vanish if water is replaced by an organic solvent with low polarity. The bridging bubble model is employed to explain the hysteresis observed between approach and retraction force traces and experimental conditions where the hysteresis can be almost eliminated are identified. Finally, it is demonstrated that the hydrophobic interaction is strongly temperature dependent and this dependence can be attributed mainly to the decreasing solubility of air in water with increasing temperature.


Neuroinvasive Flavivirus Pathogenesis Is Restricted by Host Genetic Factors in Collaborative Cross Mice, Independently of Oas1b.
Powassan virus (POWV) is an emerging tick-borne flavivirus that causes neuroinvasive diseases, including encephalitis, meningitis, and paralysis. Similar to other neuroinvasive flaviviruses, such as West Nile virus (WNV) and Japanese encephalitis virus (JEV), POWV disease presentation is heterogeneous, and the factors influencing disease outcome are not fully understood. We used Collaborative Cross (CC) mice to assess the impact of host genetic factors on POWV pathogenesis. We infected a panel of Oas1b-null CC lines with POWV and observed a range of susceptibility, indicating that host factors other than the well-characterized flavivirus restriction factor Oas1b modulate POWV pathogenesis in CC mice. Among the Oas1b-null CC lines, we identified multiple highly susceptible lines (0% survival), including CC071 and CC015, and two resistant lines, CC045 and CC057 (>75% survival). The susceptibility phenotypes generally were concordant among neuroinvasive flaviviruses, although we did identify one line, CC006, that was specifically resistant to JEV, suggesting that both pan-flavivirus and virus-specific mechanisms contribute to susceptibility phenotypes in CC mice. We found that POWV replication was restricted in bone marrow-derived macrophages from CC045 and CC057 mice, suggesting that resistance could result from cell-intrinsic restriction of viral replication. Although serum viral loads at 2 days postinfection were equivalent between resistant and susceptible CC lines, clearance of POWV from the serum was significantly enhanced in CC045 mice. Furthermore, CC045 mice had significantly lower viral loads in the brain at 7 days postinfection than did CC071 mice, suggesting that reduced central nervous system (CNS) infection contributes to the resistant phenotype of CC045 mice. IMPORTANCE Neuroinvasive flaviviruses, such as WNV, JEV, and POWV, are transmitted to humans by mosquitoes or ticks and can cause neurologic diseases, such as encephalitis, meningitis, and paralysis, and they can result in death or long-term sequelae. Although potentially severe, neuroinvasive disease is a rare outcome of flavivirus infection. The factors that determine whether someone develops severe disease after a flavivirus infection are not fully understood, but host genetic differences in polymorphic antiviral response genes likely contribute to the outcome of infection. We evaluated a panel of genetically diverse mice and identified lines with distinct outcomes following infection with POWV. We found that resistance to POWV pathogenesis corresponded to reduced viral replication in macrophages, more rapid clearance of virus in peripheral tissues, and reduced viral infection in the brain. These susceptible and resistant mouse lines will provide a system for investigating the pathogenic mechanisms of POWV and identifying polymorphic host genes that contribute to resistance.


Pregnancy hormones, pre-eclampsia, and implications for breast cancer risk in the offspring.
The aim of this study is to prospectively assess pregnancy hormone levels as correlates of subsequent development of pre-eclampsia, a condition that has been shown to be inversely associated with breast cancer risk in the offspring. A cohort of 260 Caucasian women in Boston, Massachusetts, was followed through pregnancy. Maternal blood was collected at the 16th and 27th weeks of gestation, and 18 women were diagnosed with pre-eclampsia after blood collection. Information on sociodemographic variables and risk factors of pre-eclampsia was collected through an interviewer-administered questionnaire and review of medical records. At the 16th week, there was a nonsignificant positive association between progesterone levels and pre-eclampsia [relative risk (RR) = 1.63, 95% confidence interval (CI), 0.97-2.74, per 1 SD increase]. By the 27th week, the association between progesterone and pre-eclampsia was strengthened (RR = 2.65, 95% CI, 1.46-4.81, per SD), and sex hormone-binding globulin levels were somewhat inversely related to pre-eclampsia (RR = 0.61, 95% CI, 0.31-1.20, per SD). No difference was found with respect to prolactin, estradiol, and estriol levels. Our findings indicate that progesterone may have a role in the late manifestation of pre-eclampsia pathology but are also compatible with the hypothesis that increases in progesterone represent an early compensatory mechanism.


Critical evaluation of buffering solutions for pKa determination by capillary electrophoresis.
The performance of the most common and also some other less common CE buffers has been tested for the pKa determination of several types of compounds (pyridine, amines, and phenols). The selected buffers cover a pH ranging from 3.7 to 11.8. Whereas some buffers, like acetic acid/acetate, BisTrisH+/BisTris, TrisH+/Tris, CHES/CHES-, and CAPS/CAPS- can be used with all type of analytes, others like ammonium/ammonia, butylammonium/butylammonia, ethylammonium/ethylammonia, diethylammonium/diethylammonia, and hydrogenphosphate/phosphate are not recommended because they interact with a wide range of compounds. The rest of the tested buffers (dihydrogenphosphate/hydrogenphosphate, MES/MES-, HEPES/HEPES-, and boric acid/borate) can show specific interactions depending on the nature of the analytes, and their use in some applications should be restricted.


Global transcriptome analysis reveals circadian regulation of key pathways in plant growth and development.
As nonmotile organisms, plants must rapidly adapt to ever-changing environmental conditions, including those caused by daily light/dark cycles. One important mechanism for anticipating and preparing for such predictable changes is the circadian clock. Nearly all organisms have circadian oscillators that, when they are in phase with the Earth's rotation, provide a competitive advantage. In order to understand how circadian clocks benefit plants, it is necessary to identify the pathways and processes that are clock controlled. We have integrated information from multiple circadian microarray experiments performed on Arabidopsis thaliana in order to better estimate the fraction of the plant transcriptome that is circadian regulated. Analyzing the promoters of clock-controlled genes, we identified circadian clock regulatory elements correlated with phase-specific transcript accumulation. We have also identified several physiological pathways enriched for clock-regulated changes in transcript abundance, suggesting they may be modulated by the circadian clock. Our analysis suggests that transcript abundance of roughly one-third of expressed A. thaliana genes is circadian regulated. We found four promoter elements, enriched in the promoters of genes with four discrete phases, which may contribute to the time-of-day specific changes in the transcript abundance of these genes. Clock-regulated genes are over-represented among all of the classical plant hormone and multiple stress response pathways, suggesting that all of these pathways are influenced by the circadian clock. Further exploration of the links between the clock and these pathways will lead to a better understanding of how the circadian clock affects plant growth and leads to improved fitness.


Screening for chlamydial infections and the risk of ectopic pregnancy in a county in Sweden: ecological analysis.
To analyse trends in rates of genital chlamydial infection and ectopic pregnancy between 1985 and 1995 in a county in Sweden. Uppsala county where screening for chlamydial infection, treatment, and contact tracing has been widespread and where ectopic pregnancies are recorded. Rates of chlamydial infections and ectopic pregnancy between 1985 and 1995 were calculated for women aged 20-39 years. Poisson and linear regression were used to examine the association between the risk of ectopic pregnancy and the current rates of chlamydial infection and rates of chlamydial infection from up to 5 years earlier. Rates of chlamydial infection per 100 examinations, rates of ectopic pregnancy per 1000 pregnancies, rate ratios and 95% confidence intervals for an increase in chlamydial infections of 5 new cases per 100 examinations. 103 870 cervical samples from women aged 15-39 years were analysed; 5648 (5.4%) were positive for chlamydia. 51 630 pregnancies were analysed; 930 (1.8%) were ectopic. Both rates declined over time. For women aged 20-24 years there was a strong correlation between the rate of ectopic pregnancy and the rate of chlamydial infection in the same year (r=0.93, P<0. 001); among older women correlations were stronger with rates of chlamydial infection occurring 1 or 2 years earlier. In Poisson regression ectopic pregnancy was most strongly associated with the current rate of chlamydial infection among women aged 20-24 (rate ratio 1.85, 95% confidence interval 1.44 to 2.38), with the rate of infection 1 year earlier among 25-29 year olds (rate ratio 1.72, 1. 33 to 2.22) and 30-34 year olds (rate ratio 2.27, 1.53 to 3.37); and with the rate 2 years earlier among 35 to 39 year olds (rate ratio 2. 58, 1.45 to 4.60). Declining rates of genital chlamydial infections have probably led to a fall in the rate of ectopic pregnancies. The timing of the decline in the rate of ectopic pregnancies varies with age. Among young women falling rates of chlamydial infection have been accompanied by an immediate reduction in the rate of ectopic pregnancy.


Cutaneous amebiasis of the face: a case report.
This paper describes a case of cutaneous amebiasis of the face in a 17-month-old girl. About four weeks prior to admission she had diarrhea with high suspicion of intestinal amebiasis. Fifteen days later she presented with edema of the right lower eyelid and epiphora. There was a vesicle in the inner angle of the eye which spontaneously drained, causing loss of the underlying tissue. The ulcer developed rapidly, destroying periorbital tissue. Both cytology and biopsy of the ulceration border showed abundant trophozoites of Entamoeba histolytica. Treatment was specific therapy and surgery.


Pest categorisation of Arboridia kakogawana.
The EFSA Panel on Plant Health performed a pest categorisation of the Japanese grape leafhopper, Arboridia kakogawana (Matsumura, 1932) (Hemiptera: Cicadellidae), for the EU territory. This species is not included in the EU Commission Implementing Regulation 2019/2072. Adults of A. kakogawana overwinter in broad-leaved and mixed forests and move to vineyards in the spring where there may be up to four generations, before adults move back to forests during late summer-early autumn to overwinter, possibly under diapause. A. kakogawana has a restricted host range (Vitis spp. and Parthenocissus quinquefolia). It is native to Eastern Asia, from where it moved westwards reaching southern Russia in 1999, and subsequently Ukraine, Romania, Bulgaria and Serbia in 2020. A. kakogawana develops on the abaxial side of the leaves causing chlorotic spots that reduce grape quality. Plants for planting of Vitis L. are banned from entering the EU except from Switzerland, where A. kakogawana is not known to occur. Therefore, this can be considered as a closed entry pathway. However, other plants for planting including the host P. quinquefolia and many broad-leaved trees where overwintering takes place, as well as isolated bark and wood with bark provide potential pathways which are partly regulated but remain open. There are no EU records of interception. Additional introductions and further spread of A. kakogawana into/within the EU, coupled with the ample availability of grapevines and the climatic conditions would most probably allow successful establishment in most EU member states. Should this happen, economic impact in table and wine grapes is anticipated. A. kakogawana satisfies all the criteria that are within the remit of EFSA to assess for it to be regarded as a potential Union quarantine pest (UQP).


The Quality Improvement Environment: Results of the 2016 AAHPM/HPNA Membership Needs Assessment Survey.
The American Academy of Hospice and Palliative Medicine (AAHPM) and Hospice and Palliative Nurses Association (HPNA) convened the Measuring What Matters (MWM) initiative in 2013, which recommended 10 quality performance measures; yet, little is known about the quality improvement (QI) environment and implementation of the MWM among hospices and palliative care services. The objective of this study was to describe the findings of the 2016 AAHPM/HPNA Needs Assessment survey exploring the QI environment among hospice and palliative care services. An online survey was distributed to approximately 16,500 AAHPM and HPNA members, and other hospice and palliative care organizations were invited to respond. Summary data and individual write-in responses were collated and analyzed. Data analysis included generating descriptive statistics and analyzing individual write-in responses for additional information and themes. More than 1000 responses were received. Most organizations had a designated QI leader and used an electronic medical record. Less than 50% of systems had fields for palliative care information. The top three MWM measures collected through an electronic medical record were pain treatment (66%), screening for physical symptoms (55%), and comprehensive assessment (54%). The most common barrier to implementing QI was time constraint. Most respondents had received no training and education in how to implement QI. The 2016 AAHPM/HPNA Needs Assessment Survey provided important information about the QI systems and measurement environment within hospice and palliative care services. Survey insights can aid AAHPM/HPNA in developing resources to empower hospice and palliative care clinicians to make QIs that matter for their patients and families.


Collaborative Cross Mice Yield Genetic Modifiers for Pseudomonas aeruginosa Infection in Human Lung Disease.
Human genetics influence a range of pathological and clinical phenotypes in respiratory infections; however, the contributions of disease modifiers remain underappreciated. We exploited the Collaborative Cross (CC) mouse genetic-reference population to map genetic modifiers that affect the severity of Pseudomonas aeruginosa lung infection. Screening for P. aeruginosa respiratory infection in a cohort of 39 CC lines exhibits distinct disease phenotypes ranging from complete resistance to lethal disease. Based on major changes in the survival times, a quantitative-trait locus (QTL) was mapped on murine chromosome 3 to the genomic interval of Mb 110.4 to 120.5. Within this locus, composed of 31 protein-coding genes, two candidate genes, namely, dihydropyrimidine dehydrogenase (Dpyd) and sphingosine-1-phosphate receptor 1 (S1pr1), were identified according to the level of genome-wide significance and disease gene prioritization. Functional validation of the S1pr1 gene by pharmacological targeting in C57BL/6NCrl mice confirmed its relevance in P. aeruginosa pathophysiology. However, in a cohort of Canadian patients with cystic fibrosis (CF) disease, regional genetic-association analysis of the syntenic human locus on chromosome 1 (Mb 97.0 to 105.0) identified two single-nucleotide polymorphisms (rs10875080 and rs11582736) annotated to the Dpyd gene that were significantly associated with age at first P. aeruginosa infection. Thus, there is evidence that both genes might be implicated in this disease. Our results demonstrate that the discovery of murine modifier loci may generate information that is relevant to human disease progression.IMPORTANCE Respiratory infection caused by P. aeruginosa is one of the most critical health burdens worldwide. People affected by P. aeruginosa infection include patients with a weakened immune system, such as those with cystic fibrosis (CF) genetic disease or non-CF bronchiectasis. Disease outcomes range from fatal pneumonia to chronic life-threatening infection and inflammation leading to the progressive deterioration of pulmonary function. The development of these respiratory infections is mediated by multiple causes. However, the genetic factors underlying infection susceptibility are poorly known and difficult to predict. Our study employed novel approaches and improved mouse disease models to identify genetic modifiers that affect the severity of P. aeruginosa lung infection. We identified candidate genes to enhance our understanding of P. aeruginosa infection in humans and provide a proof of concept that could be exploited for other human pathologies mediated by bacterial infection.


Preventive effects of chlorophyllin fixed on chitosan towards DNA adduct formation of 3-amino-1-methyl-5H-pyrido [4,3-b]indole in CDF1 mice.
Chlorophyllin, a water-soluble derivative of chlorophyll, is known to suppress the mutagenic and carcinogenic action of compounds having polycyclic structures, e.g., heterocyclic amines and aflatoxin B1. Recently, we reported that chlorophyllin fixed on chitosan (chl-chitosan), which is insoluble in water, can efficiently and tightly trap these heterocyclic amines. We have studied whether this adsorption to chl-chitosan can result in an interference with DNA-adduct formation caused by 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), a heterocyclic amine, in CDF1 mice, in which Trp-P-2 had been shown to induce hepatocellular carcinomas. Mice were fed a diet containing Trp-P-2 with or without chl-chitosan. After 3 d of feeding, DNA-adduct formation in liver and lung was examined by 32P-postlabeling analysis. Adducts formed from Trp-P-2 were significantly decreased by the chl-chitosan addition (p<0.05, t-test). These results suggest that the uptake of Trp-P-2 into the mouse was lowered by its adsorption to chl-chitosan, either within the digestive tract or within the food itself. This trapping agent, chl-chitosan, is thus worthy of study for cancer chemoprevention.


New mouse model of Alzheimer's.
Amyloid β-peptide (Aβ) accumulation is a key characteristic of Alzheimer's disease (AD); therefore, mouse models of AD exhibiting Aβ pathology are valuable tools for unraveling disease mechanisms. However, the overexpression of Aβ precursor protein (APP) used in previous mouse models may cause Aβ-independent artifacts that influence data interpretation. To circumvent these problems, we used an APP knock-in (KI) strategy to introduce mutations to the mouse APP gene to develop a new generation of AD mouse models. These new models, termed APP(NL-F) and APP(NL-G-F), have endogenous APP levels and develop robust Aβ amyloidosis, which induce synaptic degeneration and memory impairments. Thus, we suggest that these novel APP KI mice will serve as important tools to elucidate molecular mechanisms of AD.


A kinetic and equilibrium study of ligand binding to a Root-effect haemoglobin.
The blood of the striped marlin (Tetrapturus audax) contains one major Root-effect haemoglobin. Titrations of this haemoglobin with CO show that at high pH the molecule is highly co-operative (Hill coefficient 2.8) whereas at low pH the titration data can best be described as the sum of contributions from non-co-operating subunits of different affinity. In terms of the two-state model the R-state affinity constant is much more sensitive to pH than is that of the T state. Flash-photolysis studies were used to characterize the kinetics of ligand binding to this haemoglobin. Both T and R states show kinetic heterogeneity in their recombination time courses, associated with the alpha- and beta-chains of the molecule. The rate constants for ligand binding to each chain, in each quaternary state, were determined, and in conjunction with the allosteric equilibrium parameters determined at pH8.0 were used in the two-state analysis of reaction curves, over a range of ligand concentration. The two-state model, extended to take account of chain difference, adequately fits the homotrophic effects observed for this haemoglobin. The two-state model is, however, inadequate in its description of the heterotropic effects produced by protons.


CD8+ T cell subsets TC1 and TC2 cause different histopathologic forms of murine cardiac allograft rejection.
CD4+ T cell effector function is sufficient to mediate allograft rejection, and it is suggested that CD8+ T cell-mediated effects are dependent on CD4+ T cell help. CD8+ T cells can be classified into at least two functional subsets: Tc1, producing high amounts of interferon (IFN)-gamma and Tc2, producing interleukin (IL)-4, -5, -10, and -13 and low levels of IFN-gamma. Because these subsets express different chemokine receptors, they may have different capabilities of migrating into grafts. Once in the graft, each subset may perform different effector functions dependent on the cytokines it produces. We asked whether allospecific CD8+ T cells, in the absence of CD4+ T cells, are capable of mediating rejection of a primarily vascularized allograft, and if Tcl and Tc2 cells differ in their ability to mediate rejection. Hearts from H-2d mice were transplanted into H-2b RAG 1-/- recipients. Without manipulation, these fully mismatched allografts would survive indefinitely due to the absence of mature T and B cells. We adoptively transferred allo-(H-2d)-reactive Tcl or Tc2 cells from H-2b mice into each recipient. Grafts were harvested and analyzed on predefined timepoints, rejection was graded on a modified ISHLT scale. On day 7, grafts from Tc1- or Tc2-injected animals showed grade 1-2 parenchymal rejection with stable phenotype and comparable distribution of graft infiltrating CD8+ T cells. Adoptive transfer of IFN-gammahigh Tc1, but not of IFN-gammalow Tc2 cells was followed by the development of graft vasculitis, as well as graft arteriopathy. Adoptive transfer of IL-4high IL-5high Tc2, but not of IL-4low IL-5low Tc1 cells lead to extensive infiltration of eosinophils and formation of giant cells. Both Tc1 and Tc2 cells can mediate murine cardiac allograft rejection in the absence of CD4+ T cell help, although each subset elicits a different type of inflammatory response. In this model, cytokine secretion of either functional CD8+ T effector cell subset is an important effector mechanism in the process of allograft rejection: IFN-gammahigh Tc1 cells are important in early graft vasculitis, although IL-4high IL-5high Tc2 cells promote recruitment of secondary effectors like eosinophils.


Inwardly rectifying K(+) current and differentiation of human placental cytotrophoblast cells in culture.
Ion transport is important for driving nutrient transport across the syncytiotrophoblast and yet is poorly understood. We have examined K(+)currents under basal conditions in cultured cytotrophoblast cells, at various stages of differentiation, using the whole cell patch clamp technique. Cytotrophoblast cells were isolated from human term placenta and maintained in culture for up to 3 days. Cells were studied at four stages of progressive morphological differentiation: (i) mononuclear cells, (ii) mononuclear cells in aggregates, (iii) small multinucleate cells and (iv) large multinucleate syncytiotrophoblast-like cells. In the conditions of whole cell recording the only K(+) selective current identified in all cell types was a strong inwardly rectifying current which was sensitive to Ba(2+) and Cs(+). This current was unaffected by intracellular ATP whereas intracellular GTPgammas caused either run down of the current or activated a linear current. The characteristics of the current described are consistent with those of the inwardly rectifying K(+) channel Kir2.1. The inwardly rectifying K(+) current was observed in three out of 19 (16 per cent ) mononuclear cells, seven out of 21 (33 per cent ) mononuclear aggregates, eight out of 21 (38 per cent ) small multinucleate cells and 16 out of 19 (84 per cent ) large multinucleate cells. This inwardly rectifying K(+) current is likely to have an important role in determining net K(+) diffusion across the syncytiotrophoblast cell membrane, perhaps increasing in importance as the cells terminally differentiate.


[Daily consumption of soft drinks, sweets and fried foods among adolescents in the northeast of Brazil].
A school-based cross-sectional study in 2007 evaluated the prevalence and associated factors of daily consumption of soft drinks, sweets and fried foods among adolescents (15 to 20 years of age) in public schools in Caruaru in the state of Pernambuco. To evaluate the factors associated with the daily consumption of the above foods, a multivariate and hierarchical analysis was conducted using Poisson regression, with social and demographic variables at the first hierarchical level, behavioral variables at the second level and dietary standards at the third level. Consumption of soft drinks, sweets and fried foods at least once a week was declared by 90.9%, 95.4% and 89.6% of the adolescents, respectively. The corresponding prevalence of the daily consumption of these items was 30.2%, 42% and 28.3%. The daily consumption of sweets was 21% higher among girls and 25% higher among adolescents who ate rice and beans daily. With respect to fried foods, girls mentioned 37% greater consumption than boys. Adolescents who consumed meat every day admitted a 43% higher daily consumption of fried foods. The consumption of soft drinks, sweets and fried foods among the adolescents from Caruaru was high and showed a homogeneous consumption standard for most variables analyzed.


Zika virus and temperature modulate Elizabethkingia anophelis in Aedes albopictus.
Vector-borne pathogens must survive and replicate in the hostile environment of an insect's midgut before successful dissemination. Midgut microbiota interfere with pathogen infection by activating the basal immunity of the mosquito and by synthesizing pathogen-inhibitory metabolites. The goal of this study was to assess the influence of Zika virus (ZIKV) infection and increased temperature on Aedes albopictus midgut microbiota. Aedes albopictus were reared at diurnal temperatures of day 28 °C/night 24 °C (L) or day 30 °C/night 26 °C (M). The mosquitoes were given infectious blood meals with 2.0 × 108 PFU/ml ZIKV, and 16S rRNA sequencing was performed on midguts at 7 days post-infectious blood meal exposure. Our findings demonstrate that Elizabethkingia anophelis albopictus was associated with Ae. albopictus midguts exposed to ZIKV infectious blood meal. We observed a negative correlation between ZIKV and E. anophelis albopictus in the midguts of Ae. albopictus. Supplemental feeding of Ae. albopictus with E. anophelis aegypti and ZIKV resulted in reduced ZIKV infection rates. Reduced viral loads were detected in Vero cells that were sequentially infected with E. anophelis aegypti and ZIKV, dengue virus (DENV), or chikungunya virus (CHIKV). Our findings demonstrate the influence of ZIKV infection and temperature on the Ae. albopictus microbiome along with a negative correlation between ZIKV and E. anophelis albopictus. Our results have important implications for controlling vector-borne pathogens.


Efficacy of a topical formulation of henna (Lawsonia inermis L.) in contact dermatitis in patients using prosthesis: A double-blind randomized placebo-controlled clinical trial.
Contact dermatitis is a common complication in prosthetic limb users. There are no effective, available and cheap treatments for skin problems of these patients. In traditional Iranian medicine, henna (Lawsonia inermis L.) is a plant that has anti-inflammatory, antimicrobial and skin-enhancing properties, all of which are beneficial for people with artificial limbs. The aim of this study was to assess the efficacy of a topical henna preparation in management of contact dermatitis in patients using lower limb prosthetics. The current randomized, double-blind, placebo-controlled clinical trial was conducted on ninety-five participants with lower extremity amputation using limb prosthetics, aged 12-70 years who complained of contact dermatitis. They were randomly assigned to receive either two weeks of topical henna preparation every night as the intervention group, or topical placebo as the control group. Participants were instructed to spread henna preparation on the surfaces of the amputated limb that were in contact with the prosthesis. Severity of contact dermatitis symptoms was set as the primary outcome measure. Edema, papules and erythema were evaluated by a physician using standard color atlas. Secondary outcomes included symptoms such as burning, itching, pain, thickness and skin sweating evaluated by a self-administered questionnaire. A significant improvement was observed in the symptoms of contact dermatitis including skin edema, itching, sweating, skin thinning and pain (p-value<0.05) in the henna group compared to the placebo group. Skin burning decreased more in the henna group compared to the placebo group, but this was not statistically significant (p-value = 0.052). Moreover, skin redness significantly increased in the henna group (p-value = 0.001). Topical formulation of henna might be a complementary choice for improving contact dermatitis in patients using lower limb prosthetics.


The Totton-Ken Seibu earthquake and exacerbation of asthma in adults.
The aim of the study was to characterize patients at risk for exacerbations of their asthma as a result of the Tottori-Ken Seibu earthquake and to identify factors that predict exacerbation of asthma after an earthquake. A retrospective cohort study-analysis was conducted of 156 asthmatic patients, aged 18 to 89 years, who were out-patients of Tottori University Hospital and who had completely recorded their asthmatic symptoms and measured their peak expiratory flow (PEF) rates for more than one year prior to the earthquake. Seventeen (11%) patients who experienced the earthquake were identified as having an exacerbation within one month after the earthquake. Diurnal variability of PEF during the month after the earthquake was compared to values during a matched month one year previously. When factors associated with exacerbation were identified by a review of the medical case notes and the contribution of these factors to the exacerbation was determined using multivariate analysis, airflow limitation was shown to be independently associated with exacerbation after the earthquake. Acute asthma attacks are more likely to occur within the first week after the earthquake event without diurnal PEF variability. Asthma is likely to worsen after an earthquake.


Benign versus secondary-progressive multiple sclerosis: the potential role of proton MR spectroscopy in defining the nature of disability.
We determined the clinical utility of proton MR spectroscopy in defining the extent of disability in benign versus secondary-progressive multiple sclerosis (MS). Thirty patients with clinically definite MS, including 16 patients with benign MS and 14 with secondary-progressive MS, and a group of 13 healthy volunteers were studied with combined stimulated-echo acquisition mode proton MR spectroscopy and MR imaging (all patients received contrast material). Acute enhancing lesions of benign and secondary-progressive MS were characterized by a reduction in N-acetylaspartate (NAA)/choline and NAA/creatine and an increase in inositol compounds/creatine as compared with normal white matter. Such variations were also detected in chronic unenhancing lesions in patients with secondary-progressive MS, although they were not found in chronic unenhancing lesions in patients with benign MS. Chronic lesions of the two forms of the disease have significative differences in NAA and inositol signals. Proton MR spectroscopy is able to show metabolic changes occurring in the white matter of patients with MS. Such changes differ according to the phase (acute versus chronic) and the clinical form (benign versus secondary-progressive) of the disease.


Massively parallel transposon mutagenesis identifies temporally essential genes for biofilm formation in Escherichia coli.
Biofilms complete a life cycle where cells aggregate, grow and produce a structured community before dispersing to colonize new environments. Progression through this life cycle requires temporally controlled gene expression to maximize fitness at each stage. Previous studies have largely focused on identifying genes essential for the formation of a mature biofilm; here, we present an insight into the genes involved at different stages of biofilm formation. We used TraDIS-Xpress, a massively parallel transposon mutagenesis approach using transposon-located promoters to assay the impact of disruption or altered expression of all genes in the genome on biofilm formation. We identified 48 genes that affected the fitness of cells growing in a biofilm, including genes with known roles and those not previously implicated in biofilm formation. Regulation of type 1 fimbriae and motility were important at all time points, adhesion and motility were important for the early biofilm, whereas matrix production and purine biosynthesis were only important as the biofilm matured. We found strong temporal contributions to biofilm fitness for some genes, including some where expression changed between being beneficial or detrimental depending on the stage at which they are expressed, including dksA and dsbA. Novel genes implicated in biofilm formation included zapE and truA involved in cell division, maoP in chromosome organization, and yigZ and ykgJ of unknown function. This work provides new insights into the requirements for successful biofilm formation through the biofilm life cycle and demonstrates the importance of understanding expression and fitness through time.


Principles of evidence-based medicine.
Evidence-based medicine integrates clinical expertise, patients' values and preferences, and the best available evidence from the medical literature. Evidence-based orthopedics is a model to assist surgeons to improve the process of asking questions, obtaining relevant information efficiently, and making informed decisions with patients. With an increasing appreciation for higher levels of evidence, orthopedic surgeons should move away from lower forms of evidence. The adoption of randomized trials and high-quality prospective studies to guide patient care requires 2 prerequisites: (1) greater appreciation for the conduct of randomized trials in orthopedics and (2) improved education and training in evidence-based methodologies in surgery.


A Logic NAND Gate for Controlling Gene Expression in a Circadian Rhythm in Cyanobacteria.
To enable circadian control of gene expression in cyanobacteria, we constructed a genetic logic gate (NAND) using orthogonal promoters via modular CRISPR interference. The NAND gates were tested in Synechococcus elongatus PCC 7942 using a fluorescent reporter. The NAND gate dynamics were characterized based on the affinity of the dCas9 complex to the output element. Upon connecting tight gene repressions with the circadian promoter (the purF gene; peak expression at dawn), inversed peak expressions were obtained as an output of the NAND gate although the retroactivities were shown in the ON and OFF states. A dark-responsive genetic element of the NAND gate was also expanded to an AND gate in S. elongatus PCC 7942. These cyanobacterial NAND and AND gates could facilitate the control of gene expressions in dynamic metabolic engineering technologies, thereby enabling the cyanobacteria to serve as biosolar cell factories.


Mortality in psoriatic arthritis - a single-center study from the UK.
To determine whether the mortality in a cohort of patients with psoriatic arthritis (PsA) from a single center in the UK is significantly different from the general UK population. Patients who were entered onto the PsA database at the Royal National Hospital for Rheumatic Diseases, Bath, between 1985 and 2007 were included in this study. Information on patient deaths was collected retrospectively. The National Health Service (NHS) Strategic Tracing Service was used to establish which patients were alive and which had died. Date and cause of death were confirmed by death certificates from the Registry of Births, Marriages and Deaths. A standardized mortality ratio (SMR) was calculated by matching the patient data to single-year, 5-year age-banded England and Wales data from the Office of National Statistics. In this cohort of 453 patients with PsA (232 men, 221 women), there were 37 deaths. Sixteen men and 21 women died. The SMR for the men was 67.87% (95% CI 38.79, 110.22), and for the women, 97.01% (95% CI 60.05, 148.92) and the overall SMR for the PsA cohort was 81.82% (95% CI 57.61, 112.78). The leading causes of death in this cohort were cardiovascular disease (38%), diseases of the respiratory system (27%), and malignancy (14%). These results suggest that mortality in our single-center PsA cohort is not significantly different from the general UK population. No increased risk of death was observed in this cohort.


Pro-inflammatory Aorta-Associated Macrophages Are Involved in Embryonic Development of Hematopoietic Stem Cells.
Hematopoietic stem cells (HSCs) are generated from specialized endothelial cells of the embryonic aorta. Inflammatory factors are implicated in regulating mouse HSC development, but which cells in the aorta-gonad-mesonephros (AGM) microenvironment produce these factors is unknown. In the adult, macrophages play both pro- and anti-inflammatory roles. We sought to examine whether macrophages or other hematopoietic cells found in the embryo prior to HSC generation were involved in the AGM HSC-generative microenvironment. CyTOF analysis of CD45+ AGM cells revealed predominance of two hematopoietic cell types, mannose-receptor positive macrophages and mannose-receptor negative myeloid cells. We show here that macrophage appearance in the AGM was dependent on the chemokine receptor Cx3cr1. These macrophages expressed a pro-inflammatory signature, localized to the aorta, and dynamically interacted with nascent and emerging intra-aortic hematopoietic cells (IAHCs). Importantly, upon macrophage depletion, no adult-repopulating HSCs were detected, thus implicating a role for pro-inflammatory AGM-associated macrophages in regulating the development of HSCs.


Quantifiable effects of regular exercise on zinc status in a healthy population-A systematic review.
Zinc is an essential mineral of which its functions have potential implications on exercise performance and beneficial adaptations of physical activity. While the effects of aerobic exercise on zinc metabolism acutely have been well described, the effect of long-term exercise training on zinc status remains unclear. The present review aims to determine the effects of exercise training on markers of zinc status in an apparently healthy adult population. We conducted a systematic literature search on PubMed, Scopus, SPORTDiscus and Cochrane Library from inception to 28 January 2016 to identify interventional or cohort studies that investigated the effects of exercise training on indices of zinc status. Pairwise comparisons of mean differences in within-group change were calculated and summarised visually in forest plots. Six studies satisfied the inclusion criteria for the systematic review, of which 5 studies included data on changes in serum zinc concentrations and 3 studies provided changes in dietary zinc intake. Two comparisons showed significantly higher increase of serum zinc concentrations in the exercise group compared to control, while one comparison reported significantly lower change in serum zinc for the exercising group. The exercise groups consumed significantly higher dietary zinc compared to controls in two comparisons. The present review revealed an incomplete evidence base in evaluating the effect of long-term exercise training on markers of zinc status. Further well-designed investigations are required to elucidate the relationship for establishment of dietary recommendation in populations who are continuing exercise interventions.


Characteristic corrosion resistance of nanocrystalline TiN films prepared by high density plasma reactive magnetron sputtering.
Nanocytalline TiN films were deposited on non-alkali glass and Al substrates by reactive DC magnetron sputtering (DCMS) with an electromagnetic field system (EMF). The microstructure and corrosion resistance of the TiN-coated Al substrates were estimated by X-ray diffraction (XRD), scanning electron microscopy (SEM) and electrochemical methods. All the TiN films shows that they have a (111) preferred orientation at room temperature. TiN films deposited on Al substrate using only DCMS 400 W showed a sheet resistance of 3.22 x 10-1 omega/symbol see texts (resistivity, 3.22 x 10-5 omegacm). On the other hand, a relatively low sheet resistance of 1.91 x 10-1 omega/symbol see text (1.91 x 10-5 omegacm) was obtained for the dense nanocrystalline TiN film deposited on Al substrate using DCMS 375 W+ EMF 25 W, indicating that the introduction of an EMF system enhanced the electrical properties of the TiN film. TiN films deposited on Al substrate at 400 degreesC had a (200) preferred orientation with the lowest sheet resistance of 1.28x10-1 omega/symbol see texts (1.28 x 10-5 omegacm) which was attributed to reduced nano size defects and an improvement of the crystallinity. Potentiostatic and Potentiodynamic tests with a TiN-coated Al showed good corrosion resistance (l/corr, = 2.03 microA/cm2, Ecorr = -348 mV) compared to the uncoated Al substrate (/corr = 4.45 microA/cm2, Ecorr = -650 mV). Furthermore, EMF system showed that corrosion resistance of the TiN film also was enhanced compared to DCMS only. For the TiN film deposited on Al substrate at 400 degreesC, corrosion current and potential was 0.63 micro/cm2 and -1.5 mV, respectively. This improved corrosion resistance of the TiN film could be attributed to the densification of the film caused by enhancement of nitrification with increasing high reactive nitrogen radicals.


Gut microbiota regulate Alzheimer's disease pathologies and cognitive disorders via PUFA-associated neuroinflammation.
This study is to investigate the role of gut dysbiosis in triggering inflammation in the brain and its contribution to Alzheimer's disease (AD) pathogenesis. We analysed the gut microbiota composition of 3×Tg mice in an age-dependent manner. We generated germ-free 3×Tg mice and recolonisation of germ-free 3×Tg mice with fecal samples from both patients with AD and age-matched healthy donors. Microbial 16S rRNA sequencing revealed Bacteroides enrichment. We found a prominent reduction of cerebral amyloid-β plaques and neurofibrillary tangles pathology in germ-free 3×Tg mice as compared with specific-pathogen-free mice. And hippocampal RNAseq showed that inflammatory pathway and insulin/IGF-1 signalling in 3×Tg mice brain are aberrantly altered in the absence of gut microbiota. Poly-unsaturated fatty acid metabolites identified by metabolomic analysis, and their oxidative enzymes were selectively elevated, corresponding with microglia activation and inflammation. AD patients' gut microbiome exacerbated AD pathologies in 3×Tg mice, associated with C/EBPβ/asparagine endopeptidase pathway activation and cognitive dysfunctions compared with healthy donors' microbiota transplants. These findings support that a complex gut microbiome is required for behavioural defects, microglia activation and AD pathologies, the gut microbiome contributes to pathologies in an AD mouse model and that dysbiosis of the human microbiome might be a risk factor for AD.


Education techniques for lifelong learning: writing multiple-choice questions for continuing medical education activities and self-assessment modules.
The multiple-choice question (MCQ) is the most commonly used type of test item in radiologic graduate medical and continuing medical education examinations. Now that radiologists are participating in the maintenance of certification process, there is an increased need for self-assessment modules that include MCQs and persons with test item-writing skills to develop such modules. Although principles of effective test item writing have been documented, violations of these principles are common in medical education. Guidelines for test construction are related to development of educational objectives, defining levels of learning for each objective, and writing effective MCQs that test that learning. Educational objectives should be written in observable, behavioral terms that allow for an accurate assessment of whether the learner has achieved the objectives. Learning occurs at many levels, from simple recall to problem solving. The educational objectives and the MCQs that accompany them should target all levels of learning appropriate for the given content. Characteristics of effective MCQs can be described in terms of the overall item, the stem, and the options. Flawed MCQs interfere with accurate and meaningful interpretation of test scores and negatively affect student pass rates. Therefore, to develop reliable and valid tests, items must be constructed that are free of such flaws. The article provides an overview of established guidelines for writing effective MCQs, a discussion of writing appropriate educational objectives and MCQs that match those objectives, and a brief review of item analysis.


The association of pain interference and opioid use with healthcare utilization and costs, and wage loss among adults with osteoarthritis in the United States.
Aim: To examine associations of opioid use and pain interference with activities (PIA), healthcare resource utilization (HRU) and costs, and wage loss in noninstitutionalized adults with osteoarthritis in the United States (US). Methods: Adults with osteoarthritis identified from the Medical Expenditure Panel Survey for 2011/2013/2015 were stratified by no-opioid use with no/mild PIA, no-opioid use with moderate/severe PIA, opioid use with no/mild PIA, and opioid use with moderate/severe PIA. Outcomes included annualized total HRU, direct healthcare costs, and wage loss. Multivariable regression analyses were used for comparisons versus no-opioid use with no/mild PIA (referent). The counterfactual recycled prediction method estimated incremental costs. Results reflect weighted nationally representative data. Results: Of 4,921 participants (weighted n = 20,785,007), 46.5% had no-opioid use with no/mild PIA; 23.2% had no-opioid use with moderate/severe PIA; 9.6% had opioid use with no/mild PIA; and 20.7% had opioid use with moderate/severe PIA. Moderate/severe PIA and/or opioid use were associated with significantly higher HRU and associated costs, and wage loss. Relative to adults with no/mild PIA, opioid users with moderate/severe PIA were more likely to have hospitalizations, specialist visits, and emergency room visits (all p < .001). Relative to the referent, opioid use with no/mild PIA had higher per-patient incremental annual total healthcare costs ($11,672, 95% confidence interval [CI] = $11,435-$11,909) and wage loss ($1,395, 95% CI = $1,376-$1,414) as did opioid use with moderate/severe PIA ($13,595, 95% CI = $13,319-$13,871; and $2,331, 95% CI = $2,298-$2,363) (all p < .001). Compared with the referent, estimated excess national total healthcare costs/lost wages were $23.3 billion/$1.3 billion for opioid use with no/mild PIA, and $58.5 billion/$2.2 billion for opioid use with moderate/severe PIA. Limitations: Unobservable/unmeasured factors that could not be accounted for. Conclusions: Opioid use with moderate/severe PIA had significantly higher HRU, costs, and wage loss; opioid use was more relevant than PIA to the economic burden. These results suggest unmet needs for alternative pain management strategies.


A preliminary study of gender differences in autobiographical memory in children with an autism spectrum disorder.
Autobiographical memory was assessed in 24 children (12 male, 12 female, aged between 8 and 16 years) with autism spectrum disorder (ASD) and a comparison group of 24 typically developing (TD) children matched for age, IQ, gender and receptive language. Results suggested that a deficit in specific memory retrieval in the ASD group was more characteristic of male participants. Females in both the TD and ASD groups generated more detailed and emotional memories than males. They also demonstrated superior verbal fluency scores; verbal fluency and autobiographical memory cueing task performance were significantly positively correlated in females. Results are discussed in light of recent research suggesting gender differences in the phenotype of ASD.


Heightened Hippocampal β-Adrenergic Receptor Function Drives Synaptic Potentiation and Supports Learning and Memory in the TgF344-AD Rat Model during Prodromal Alzheimer's Disease.
The central noradrenergic (NA) system is critical for the maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer's disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathologic tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus is heavily innervated by LC-NA axons, where released NE acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex to facilitate long-term synaptic plasticity and memory formation. These synapses experience dysfunction in early AD before cognitive impairment. In the TgF344-AD rat model of AD, degeneration of LC-NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6- to 9-month-old wild-type and TgF344-AD rats, we discovered that the loss of LC-NA axons coincides with the heightened β-AR function at medial perforant path-dentate granule cell synapses that is responsible for the increase in LTP magnitude at these synapses. Furthermore, novel object recognition is facilitated in TgF344-AD rats that requires β-ARs, and pharmacological blockade of β-ARs unmasks a deficit in extinction learning only in TgF344-AD rats, indicating a greater reliance on β-ARs in both behaviors. Thus, a compensatory increase in β-AR function during prodromal AD in TgF344-AD rats heightens synaptic plasticity and preserves some forms of learning and memory.SIGNIFICANCE STATEMENT The locus coeruleus (LC), a brain region located in the brainstem which is responsible for attention and arousal, is damaged first by Alzheimer's disease (AD) pathology. The LC sends axons to hippocampus where released norepinephrine (NE) modulates synaptic function required for learning and memory. How degeneration of LC axons and loss of NE in hippocampus in early AD impacts synaptic function and learning and memory is not well understood despite the importance of LC in cognitive function. We used a transgenic AD rat model with LC axon degeneration mimicking human AD and found that heightened function of β-adrenergic receptors in the dentate gyrus increased synaptic plasticity and preserved learning and memory in early stages of the disease.


Optimal self-cleavage activity of the hepatitis delta virus RNA is dependent on a homopurine base pair in the ribozyme core.
A non-Watson-Crick G.G interaction within the core region of the hepatitis delta virus (HDV) antigenomic ribozyme is required for optimal rates of self-cleavage activity. Base substitutions for either one or both G's revealed that full activity was obtained only when both G's were replaced with A's. At those positions, substitutions that generate potential Watson-Crick, G.U, heteropurine, or homopyrimidine combinations resulted in dramatically lower cleavage activity. A homopurine symmetric base pair, of the same type identified in the high-affinity binding site of the HIV RRE, is most consistent with this data. Additional features shared between the antigenomic ribozyme and the Rev binding site in the vicinity of the homopurine pairs suggest some structural similarity for this region of the two RNAs and a possible motif associated with this homopurine interaction. Evidence for a homopurine pair at the equivalent position in a modified form of the HDV genomic ribozyme was also found. With the postulated symmetric pairing scheme, large distortions in the nucleotide conformation, the sugar-phosphate backbone, or both would be necessary to accommodate this interaction at the end of a helix; we hypothesize that this distortion is critical to the structure of the active site of the ribozyme and it is stabilized by the homopurine base pair.


How accurate and safe is the diagnosis of hazelnut allergy by means of commercial skin prick test reagents?
Allergy to tree nuts, like hazelnuts, ranks among the most frequently observed food allergies. These allergies can start at early childhood and are, in contrast to other food allergies, not always outgrown by the patient. Tree nut allergy is frequently associated with severe reactions. Diagnosis partially relies on in vivo testing by means of a skin prick test (SPT) using commercially available SPT reagents. Protein and allergen composition of nine commercial SPT solutions was evaluated using standard protein detection methods and specific immunoassays for measurement of five individual allergens. Diagnostic performance was assessed by SPT in 30 hazelnut-allergic subjects, of which 15 were provocation proven. Protein concentrations ranged from 0.2-14 mg/ml. SDS-PAGE/silver staining revealed clear differences in protein composition. The major allergen Cor a 1 was present in all extracts but concentrations differed up to a factor 50. An allergen associated with severe symptoms, Cor a 8 (lipid transfer protein), was not detected on immunoblot in three products, and concentrations varied by more than a factor 100 as was shown by RAST inhibition. Similar observations were made for profilin, thaumatin-like protein and a not fully characterized 38-kD allergen. Ratios of individual allergens were variable among the nine extracts. SPT showed significant difference, and 6/30 patients displayed false-negative results using 3/9 products. Variability in the composition of products for the diagnosis of hazelnut allergy is extreme. Sometimes, allergens implicated in severe anaphylaxis are not detected by immunoblotting. These shortcomings in standardisation and quality control can potentially cause a false-negative diagnosis in subjects at risk of severe reactions to hazelnuts.


Clinical reasons for returning hearing aids.
Increases in older aged populations and exposure to complicated noise environments have increased the number of hearing-impaired patients, creating greater demands for hearing aids. We have assessed the reasons that individuals rejected wearing and returned properly prescribed hearing aids, as well as differences in individual factors between younger and elderly adults. Of 1138 patients for whom hearing aids were prescribed at Kyung Hee University Medical Center Hearing Aid Clinic, 81 (6.14%) returned their hearing aids, including 36 patients aged <65 years and 45 aged ≥65 years. Patient-related, hearing-related, and hearing aid-related factors were assessed by retrospective chart analysis and phone survey and compared in the two groups. The primary symptoms reported by the 81 patients who returned their hearing aids were hearing disturbance, ringing, and fullness in the ear, in that order and in both groups. The rate of hearing aid return was similar in elderly females and males (p=0.288). The spondee recognition threshold was significantly higher in younger than in elderly adults (63.3±14.0 dB vs. 55.6±14.74 dB, p=0.019), but the hearing aid return rate was highest in patients with moderate hearing loss in both groups. In evaluating the reasons for return of hearing aids, we found that ineffectiveness of the device was the most frequent reason, accounting for 32.0% of returns, the highest percentage in both groups, with the most frequent patient problem caused by management difficulty in elderly and financial difficulty in younger adults. The reasons for hearing aid return were different in two groups. Financial considerations were cited more by younger adults, while difficulties in managing hearing aids were cited more frequently by elderly adults. Patients in both groups, however, reported that the most frequent reasons for return were inadequate hearing improvement and inconvenience wearing the hearing aid due to noise amplification.


The effect of honey gel on abdominal wound healing in cesarean section: a triple blind randomized clinical trial.
To assess whether honey can accelerate the wound healing in women undergoing cesarean section. This was a triple blinded randomized prospective clinical trial. Women with cesarean section were randomly designated as drug (37 cases) and placebo (38 cases) groups. The drug group received local honey gel 25% while the placebo group received similar free-honey gel on abdominal cesarean incision twice a day for 14 days. REEDA scale (Redness, Edema, Ecchymosis, Discharge and Approximation of wound edges) was used to assess wound healing. The mean REEDA was 2.27 ± 2.46 and 3.91 ± 2.74 (p=0.008) on the 7(th) day and 0.47 ± 0.84 and 1.59± 1.95 (p=0.002) on the 14(th) day for the drug and placebo groups, respectively. Redness, edema and hematoma in the drug group were significantly lower on the 7(th) and 14(th) days. Honey was effective in healing the cesarean section incision. Using topical honey is suggested as a natural product with rare side effects in order to reduce the complications of cesarean wounds.


Geographical and socioeconomic differences in uptake of Pap test and mammography in Italy: results from the National Health Interview Survey.
The Italian National Health Service instituted cervical and breast cancer screening programmes in 1999; the local health authorities have a mandate to implement these screening programmes by inviting all women aged 25-64 years for a Pap test every 3 years (or for an Human Papilloma Virus (HPV) test every 5 years) and women aged 50-69 years for a mammography every 2 years. However, the implementation of screening programmes throughout the country is still incomplete. This study aims to: (1) describe cervical and breast cancer screening uptake and (2) evaluate geographical and individual socioeconomic difference in screening uptake. Data both from the Italian National Health Interview Survey (NHIS) conducted by the National Institute of Statistics in 2012-2013 and from the Italian National Centre for Screening Monitoring (INCSM) were used. The NHIS interviewed a national representative random sample of 32 831 women aged 25-64 years and of 16 459 women aged 50-69 years. Logistic multilevel models were used to estimate the effect of socioeconomic variables and behavioural factors (level 1) on screening uptake. Data on screening invitation coverage at the regional level, taken from INCSM, were used as ecological (level 2) covariates. Total 3-year Pap test and 2-year mammography uptake were 62.1% and 56.4%, respectively; screening programmes accounted for 1/3 and 1/2 of total test uptake, respectively. Strong geographical differences were observed. Uptake was associated with high educational levels, healthy behaviours, being a former smoker and being Italian versus foreign national. Differences in uptake between Italian regions were mostly explained by the invitation coverage to screening programmes. The uptake of both screening programmes in Italy is still under acceptable levels. Screening programme implementation has the potential to reduce the health inequalities gap between regions but only if uptake increases.


Trends in the lifetime risk of developing cancer in Great Britain: comparison of risk for those born from 1930 to 1960.
Typically, lifetime risk is calculated by the period method using current risks at different ages. Here, we estimate the probability of being diagnosed with cancer for individuals born in a given year, by estimating future risks as the cohort ages. We estimated the lifetime risk of cancer in Britain separately for men and women born in each year from 1930 to 1960. We projected rates of all cancers (excluding non-melanoma skin cancer) and of all cancer deaths forwards using a flexible age-period-cohort model and backwards using age-specific extrapolation. The sensitivity of the estimated lifetime risk to the method of projection was explored. The lifetime risk of cancer increased from 38.5% for men born in 1930 to 53.5% for men born in 1960. For women it increased from 36.7 to 47.5%. Results are robust to different models for projections of cancer rates. The lifetime risk of cancer for people born since 1960 is >50%. Over half of people who are currently adults under the age of 65 years will be diagnosed with cancer at some point in their lifetime.


Microsatellite Genotyping of Plasmodium vivax Isolates from Pregnant Women in Four Malaria Endemic Countries.
Plasmodium vivax is the most widely distributed human parasite and the main cause of human malaria outside the African continent. However, the knowledge about the genetic variability of P. vivax is limited when compared to the information available for P. falciparum. We present the results of a study aimed at characterizing the genetic structure of P. vivax populations obtained from pregnant women from different malaria endemic settings. Between June 2008 and October 2011 nearly 2000 pregnant women were recruited during routine antenatal care at each site and followed up until delivery. A capillary blood sample from the study participants was collected for genotyping at different time points. Seven P. vivax microsatellite markers were used for genotypic characterization on a total of 229 P. vivax isolates obtained from Brazil, Colombia, India and Papua New Guinea. In each population, the number of alleles per locus, the expected heterozygosity and the levels of multilocus linkage disequilibrium were assessed. The extent of genetic differentiation among populations was also estimated. Six microsatellite loci on 137 P. falciparum isolates from three countries were screened for comparison. The mean value of expected heterozygosity per country ranged from 0.839 to 0.874 for P. vivax and from 0.578 to 0.758 for P. falciparum. P. vivax populations were more diverse than those of P. falciparum. In some of the studied countries, the diversity of P. vivax population was very high compared to the respective level of endemicity. The level of inter-population differentiation was moderate to high in all P. vivax and P. falciparum populations studied.


Smoking Cessation and Pancreatic Cancer Risk in Individuals With Prediabetes and Diabetes: A Nationwide Cohort Study.
Individuals with diabetes and prediabetes are at increased risk of pancreatic cancer. However, little is known about the effects of smoking or smoking cessation on pancreatic cancer risk in individuals with diabetes and prediabetes. We investigated the association between smoking status (particularly smoking cessation) and pancreatic cancer risk according to glycemic status. This nationwide cohort study included 9,520,629 adults without cancer who underwent the Korean National Health Screening in 2009 and were followed until 2018. Hazard ratios and 95% confidence intervals for pancreatic cancer were estimated after adjusting for potential confounders. During the 78.4 million person-years of follow-up, 15,245 patients were newly diagnosed with pancreatic cancer. Among individuals with diabetes and prediabetes, current smoking synergistically increased pancreatic cancer risk (all P<.01). However, quitters with diabetes and prediabetes had a pancreatic cancer risk comparable to that of never-smokers (all P>.05). For pancreatic cancer in current smokers, quitters, and never-smokers, respectively, the hazard ratios were 1.48 (95% CI, 1.40-1.58), 1.11 (95% CI, 1.03-1.19), and 1.00 (reference) among individuals with normoglycemia; 1.83 (95% CI, 1.70-1.97), 1.28 (95% CI, 1.18-1.39), and 1.20 (95% CI, 1.14-1.26) among individuals with prediabetes; and 2.72 (95% CI, 2.52-2.94), 1.78 (95% CI, 1.63-1.95), and 1.63 (95% CI, 1.54-1.72) among individuals with diabetes. There were no differences in risk between quitters with a <20 pack-year smoking history and never-smokers in all glycemic status groups. Pancreatic cancer risk synergistically increased in current smokers with diabetes and prediabetes. However, smoking cessation reduced the synergistically increased risk of pancreatic cancer to the level of never-smokers, especially when smoking history was <20 pack-years. More individualized and intensive cancer prevention education should be underscored for individuals at an increased risk of pancreatic cancer beyond the one-size-fits-all approach.


[Accreditation process of pediatric healthcare professionals in Chile].
In Chile since 1984, the Autonomous Corporation for Certification of Medical Specialties (CONACEM) has certified 12,294 medical specialists. The Pediatrics discipline began its certification processes in 1984; it had certified 1,329 specialists by December, 2012. There are three possible ways to get certified: a) to have passed the Training Graduate Degree Program, taken by 57% of the applicants; b) to meet the requirements for Training in Practice for 5 years, achieved by 39% of applicants; c) to have been trained oversees according to validated programs. There are 11 accredited 3-year long university programs, which take place in Santiago and Provinces with a total annual capacity of 96 students. With the exception of doctors approved by accredited medical university programs, the rest of the applicants must pass a practical examination. A written examination has been added since 2002, whose approval is required to take the practical examination, which has proven to have good discrimination (22% average rejection in 11 years). The certifications granted today are good for 10 years and recertification is good for 7 years. The expiration of the certification process is related to recertification. This review discusses the reasons behind it and discusses the requirements and a table of credits to complete. Current legislation requires the action of at least one certification body, a condition that has been legally and uniquely granted by the Ministry of Health to CONACEM since 2/11/2014.


Contribution of sexually transmitted infections to the sexual transmission of HIV.
We review recent evidence about the link between sexually transmitted infections (STI) and HIV transmission and consider implications for control programmes. New studies and meta-analyses confirm the association of HIV acquisition and transmission with recent STIs, although there is considerable heterogeneity between organisms and populations. Much of the recent evidence relates to herpes simplex virus type 2 (HSV-2), for which the population-attributable risk percentage (PAR%) for HSV-2 is between 25 and 35 in Africa. Mathematical models show how transmission attributable to STI varies with HIV epidemic phase, and HSV-2 becomes increasingly important as the epidemic matures. HSV-2 suppressive therapy reduces HIV concentrations in plasma and the genital tract in people coinfected with HSV-2, in part due to direct inhibition of HIV reverse transcriptase. Recent trials of HSV-2 suppressive therapy have not shown an impact on the risk of HIV acquisition, nor in controlling transmission from dually infected people to their serodiscordant heterosexual partners. Although there is a plausible link between STI and HIV risk, intervention studies continue to be disappointing. This fact does not disprove a causal link, but mechanisms of action and the design and implementation of interventions need to be better understood.


Evolutionary tuning of a fuzzy dispatching system for automated guided vehicles.
This paper develops a novel genetic algorithm (GA) based methodology for optimal tuning of a reported fuzzy dispatching system for a fleet of automated guided vehicles in a flexible manufacturing environment. The reported dispatching rules are transformed into a continuously adaptive procedure to capitalize the on-line information available from a shop floor at all times. Simulation results obtained show that the GA is very powerful and effective to achieve optimal fuzzy dispatching rules for higher shop floor productivity and operational efficiency.


Tick-borne bacteria in free-living jaguars (Panthera onca) in Pantanal, Brazil.
Tick-borne bacteria were investigated in 10 free-living jaguars and their ticks in the Pantanal biome, Brazil. Jaguar sera were tested by indirect fluorescent antibody assays using Rickettsia rickettsii, Rickettsia parkeri, Rickettsia amblyommii, Rickettsia rhipicephali, Rickettsia felis, Rickettsia bellii, Ehrlichia canis, and Coxiella burnetii as crude antigens. All 10 jaguar sera reacted (titer ≥ 64) to at least one Rickettsia species; 4 and 3 sera reacted with E. canis and C. burnetii, respectively. One jaguar presented antibody titer to R. parkeri at least fourfold higher than those to any of the other five Rickettsia antigens, suggesting that this animal was infected by R. parkeri. Ticks collected from jaguars included the species Amblyomma cajennense, Amblyomma triste, and Rhipicephalus (Boophilus) microplus. No Rickettsia DNA was detected in jaguar blood samples, but an A. triste specimen collected on a jaguar was shown by PCR to be infected by R. parkeri. The blood of two jaguars and samples of A. triste, A. cajennense, and Amblyomma sp. yielded Ehrlichia DNA by PCR targeting the ehrlichial genes 16S rRNA and dsb. Partial DNA sequences obtained from PCR products resulted in a new ehrlichial strain, here designated as Ehrlichia sp. strain Jaguar. A partial DNA sequence of the 16S rRNA gene of this novel strain showed to be closest (99.0%) to uncultured strains of Ehrlichia sp. from Japan and Russia and 98.7% identical to different strains of Ehrlichia ruminantium. The ehrlichial dsb partial sequence of strain jaguar showed to be at most 80.7% identical to any Ehrlichia species or genotype available in GenBank. Through phylogenetic analysis, Ehrlichia sp. strain jaguar grouped in a cluster, albeit distantly, with different genotypes of E. ruminantium. Results highlight risks for human and animal health, considering that cattle ranching and ecotourism are major economic activities in the Pantanal region of Brazil.


[Multiple sclerosis associated with myasthenia].
Two patients with a rare combination of generalized myasthenia (M) and multiple sclerosis (MS) have been studied. The development of both diseases in the same patient, despite the rarity of such reports in the world literature, does not appear accidental and may be due to the common nature of pathogenetic mechanisms. The authors believe that the fundamental homogeneity of the diseases lies in impairment of immunological homeostasis characteristic of both autoimmune diseases. Myasthenic manifestations in MS may widely vary from mild subclinical forms of impairment of neuromuscular conductivity to severe generalized forms of M. The authors discuss possible mechanisms of blockage of the neuromuscular conductivity in cases of association of the above nosological entities.


Left atrial myxoma and unrelated mitral valve disease.
Two cases of left atrial myxoma and concomitant, but unrelated mitral valve disease are reported. The first patient had severe mitral stenosis and mitral regurgitation due to rheumatic heart disease in addition to a large immobile left atrial myxoma. At surgery, the tumor was considered unresectable because of its size and widespread attachment to the left atrium. A mitral commissurotomy was performed with temporary improvement. The second patient had mitral regurgitation due to mitral valve prolapse (myxomatous degeneration) and an unrelated tumor. The patient's condition improved after mitral valve reconstruction and resection of the tumor. In both cases, the relatively immobile tumor was not physically in contact with the mitral valve and probably was not responsible for the valve disease. Both patients presented with dyspnea, to which the tumors may have contributed by causing partial obstruction of the pulmonary veins. Diagnostic and therapeutic problems resulting from the association of atrial myxoma and unrelated mitral valve disease are discussed.


Bacterial colonization and granulocyte activation in chronic maxillary sinusitis in asthmatics and non-asthmatics.
The impact of bacterial colonization on the severity and pattern of chronic inflammation in rhinosinusitis is not clear. In this study, it was hypothesized that bacterial colonization of the sinus mucosa would have a greater impact on inflammatory response modulation in asthmatic patients than in non-asthmatic patients with chronic rhinosinusitis. In order to test this hypothesis, granulocyte activation was measured and related to bacteria identified in the sinus lavage. Lavages from the maxillary sinuses of 21 asthmatic and 19 non-asthmatic patients with chronic rhinosinusitis (CRS) were microbiologically examined for aerobic and anaerobic growth. Eosinophil cationic protein (ECP), an eosinophil activation marker, and myeloperoxidase (MPO), a neutrophil activation marker, were measured in the sinus lavages. Bacteria were recovered in 20/32 samples from the asthmatics and in 21/33 samples from the non-asthmatics. Gram-positive aerobes and anaerobes were slightly more common than Gram-negative bacteria. A different bacterial profile was found when comparing Gram-negatives between the groups. Concentrations of MPO were significantly higher in samples with bacterial recovery from asthmatic patients, compared to sterile samples of both groups. Concentrations of ECP in the samples from asthmatic patients were significantly higher than in the controls, with no significant difference related to bacterial colonization. Bacterial colonization in chronically inflamed sinuses may have an impact on neutrophil granulocyte activation in patients with bronchial asthma, which was not confirmed for patients with CRS without asthma.


Stromal-cell derived factor is expressed by dendritic cells and endothelium in human skin.
Stromal-cell derived factor or SDF-1 is a CXC chemokine constitutively expressed by stromal bone marrow cell cultures that binds to the G-protein-coupled receptor CXCR4. SDF-1/CXCR4 represents a unique, nonpromiscuous ligand/receptor pair that plays an essential role in prenatal myelo- and lymphopoiesis as well as in cardiovascular and neural development. SDF-1 prevents entry of CXCR4-dependent (X4) HIV viruses in T lymphocytes, by binding and internalizing CXCR4. The expression pattern of SDF-1 protein in normal tissues is not known. Here we describe an analysis of SDF-1 mRNA and protein in normal and inflamed skin by in situ hybridization and immunohistochemistry, using a novel anti-SDF-1 monoclonal antibody. We also describe the expression pattern of CXCR4 receptor by immunohistochemistry. Our results show that SDF-1 protein and mRNA are normally expressed by endothelial cells, pericytes, and either resident or explanted CD1a+ dendritic cells. Epithelial cells of sweat glands but not keratinocytes also express SDF-1. In various inflammatory skin diseases, a large number of mononuclear cells and fibroblasts in close contact with CXCR4-positive lymphocytic infiltrates also express SDF-1. CXCR4 was also detected in many different normal cell types, including endothelial and epithelial cells, which points to a role for SDF-1/CXCR4 cell signaling in vascular and epithelial homeostasis. The demonstration of SDF-1 expression in dendritic and endothelial cells provides new insights into the mechanisms of normal and pathological lymphocyte circulation and makes it possible to envisage a role for locally secreted SDF-1 in the selective incapacity of mucosal dendritic cells to support and propagate infection by X4 HIV isolates.


Transfer Entropy Analysis of Interactions between Bats Using Position and Echolocation Data.
Many animal species, including many species of bats, exhibit collective behavior where groups of individuals coordinate their motion. Bats are unique among these animals in that they use the active sensing mechanism of echolocation as their primary means of navigation. Due to their use of echolocation in large groups, bats run the risk of signal interference from sonar jamming. However, several species of bats have developed strategies to prevent interference, which may lead to different behavior when flying with conspecifics than when flying alone. This study seeks to explore the role of this acoustic sensing on the behavior of bat pairs flying together. Field data from a maternity colony of gray bats (Myotis grisescens) were collected using an array of cameras and microphones. These data were analyzed using the information theoretic measure of transfer entropy in order to quantify the interaction between pairs of bats and to determine the effect echolocation calls have on this interaction. This study expands on previous work that only computed information theoretic measures on the 3D position of bats without echolocation calls or that looked at the echolocation calls without using information theoretic analyses. Results show that there is evidence of information transfer between bats flying in pairs when time series for the speed of the bats and their turning behavior are used in the analysis. Unidirectional information transfer was found in some subsets of the data which could be evidence of a leader-follower interaction.


A Study of the Mean Field Approach to Knapsack Problems.
The mean field theory approach to knapsack problems is extended to multiple knapsacks and generalized assignment problems with Potts mean field equations governing the dynamics. Numerical tests against "state of the art" conventional algorithms shows good performance for the mean field approach. The inherently parallelism of the mean field equations makes them suitable for direct implementations in microchips. It is demonstrated numerically that the performance is essentially not affected when only a limited number of bits is used in the mean field equations. Also, a hybrid algorithm with linear programming and mean field components is showed to further improve the performance for the difficult homogeneous N x M knapsack problem. Copyright 1997 Elsevier Science Ltd. All Rights Reserved.


Effect of duty cycle in different frequency domains on SSVEP based BCI: a preliminary study.
Compared with the well learned amplitude-frequency characteristic of Steady State Visual Evoked Potential (SSVEP), the effect of duty cycle is still unclear. In this work, the influence of duty cycle on SSVEP response is investigated in differnt frequency domains. The amplitude surface with the change of both frequencies and duty cycles is plotted. To get a stable response, the experiment arranged in 3 days, and each result is an average of 12 repetitions. It is interesting that the results from power spectral density (PSD) and canonical correlation analysis (CCA) method are not consistent. In addition, the relation between the fundamental component and its second harmonic component with the change of duty cycle is quite different at frequency of 7 Hz, 10 Hz and 13 Hz. Based on the amplitude surface, we try to configure the subject-specific SSVEP based BCI. The frequencies and duty cycles of the stimulus are selected corresponding to the higher SSVEP response in the amplitude surface. Cross validation results show a significant improvement in the performance for the adjustment of duty cycle.


Symposium on computerized behavioral testing of humans in neurotoxicology research: overview of the proceedings.
The Symposium on Computerized Behavioral Testing of Humans in Neurotoxicology Research, held in Portland, OR (USA), on June 21-23, 1995, is the subject of the 23 articles in this issue of Neurotoxicology and Teratology. It is the first open forum to focus exclusively on computer-implemented behavioral test methods for neurotoxicology. Both the Symposium and this proceedings have been organized around the topics: new technologies and new batteries, confounders and methodologic factors, special populations (children), sensory and motor testing, clinical applications, and neurotoxicology research. The Symposium emphasized common approaches to computerized testing, highlighted fundamental differences in strategies for the selection of tests, and produced tangible evidence that the NES2 test battery has become a pervasively used instrument for presenting valid tests in human neurotoxicology research. However, the dominant impression drawn from the Symposium is that there is a methodologic vigor in the field of computerized behavioral testing. This is revealed by the appearance of new test batteries, criticism of existing procedures, challenges to the existing order of test selection, and the identification of analytic covariates for commonly used tests.


Alzheimer's disease and alpha-synuclein pathology in the olfactory bulbs of infants, children, teens and adults ≤ 40 years in Metropolitan Mexico City. APOE4 carriers at higher risk of suicide accelerate their olfactory bulb pathology.
There is growing evidence that air pollution is a risk factor for a number of neurodegenerative diseases, most notably Alzheimer's (AD) and Parkinson's (PD). It is generally assumed that the pathology of these diseases arises only later in life and commonly begins within olfactory eloquent pathways prior to the onset of the classical clinical symptoms. The present study demonstrates that chronic exposure to high levels of air pollution results in AD- and PD-related pathology within the olfactory bulbs of children and relatively young adults ages 11 months to 40 years. The olfactory bulbs (OBs) of 179 residents of highly polluted Metropolitan Mexico City (MMC) were evaluated for AD- and alpha-synuclein-related pathology. Even in toddlers, hyperphosphorylated tau (hTau) and Lewy neurites (LN) were identified in the OBs. By the second decade, 84% of the bulbs exhibited hTau (48/57), 68% LNs and vascular amyloid (39/57) and 36% (21/57) diffuse amyloid plaques. OB active endothelial phagocytosis of red blood cell fragments containing combustion-derived nanoparticles (CDNPs) and the neurovascular unit damage were associated with myelinated and unmyelinated axonal damage. OB hTau neurites were associated mostly with pretangle stages 1a and 1b in subjects ≤ 20 years of age, strongly suggesting olfactory deficits could potentially be an early guide of AD pretangle subcortical and cortical hTau. APOE4 versus APOE3 carriers were 6-13 times more likely to exhibit OB vascular amyloid, neuronal amyloid accumulation, alpha-synuclein aggregates, hTau neurofibrillary tangles, and neurites. Remarkably, APOE4 carriers were 4.57 times more likely than non-carriers to die by suicide. The present findings, along with previous data that over a third of clinically healthy MMC teens and young adults exhibit low scores on an odor identification test, support the concept that olfactory testing may aid in identifying young people at high risk for neurodegenerative diseases. Moreover, results strongly support early neuroprotective interventions in fine particulate matter (PM2.5) and CDNP's exposed individuals ≤ 20 years of age, and the critical need for air pollution control.


A standardized aortic aneurysm model for the assessment of endovascular stent-graft technology.
Reliable models of aortic aneurysms are required to test endovascular stent-graft technology prior to human use. We describe the creation of a standardized prosthetic aneurysm in an ovine model to assess endovascular technology. In an adult ovine model under general anesthesia, a polyester sphere measuring 6 cm across was sutured onto the infrarenal aorta following aortotomy. Two weeks later an endovascular stent-graft was deployed in the aorta. Exclusion was confirmed on monthly ultrasound duplex and during angiography at three months and under terminal anesthesia at six months. Autopsy along with histology of the specimen were then performed. A total of 10 sheep underwent aneurysm implantation. Nine received a straight tube endovascular stent-graft (Lombard Medical, Abingdon, Oxon, UK) and seven completed the study. Five prosthetic aneurysms shrank during serial imaging with duplex ultrasound and angiography. However, two remained the same size. One of these had a type I endoleak whereas the other had endotension (type I endoleak confirmed at autopsy). This animal model provides a reliable and reproducible method of creating prosthetic aneurysms for assessing endovascular stent-grafts. It was possible to assess aneurysm exclusion non-invasively using duplex ultrasound. Aneurysms effectively excluded from the circulation shrank whereas those with an endoleak did not.


Oxygen consumption of tissues in the human lung.
A method for estimating the metabolic rate of the human pulmonary tissues is described. Six patients with far advanced pulmonary tuberculosis showed an average rate of 12 percent of the total oxygen consumption. A method for measuring the right ventricular output with an inert gas is also outlined, and the use of this approach to minimize errors in the estimation of the tissue metabolic rate is described.


Transoesophageal echocardiography-guided hybrid balloon valvuloplasty for severe pulmonic stenosis in small dogs.
Pulmonic stenosis (PS) is the most common congenital heart disease in dogs and is commonly seen in small breeds, such as Chihuahuas. Conventional treatments have limitations specific to small dogs, including the invasive nature of open-heart surgery and size limitations in percutaneous balloon valvuloplasty. Here, transoesophageal echocardiography (TEE)-guided balloon valvuloplasty via thoracotomy was performed for three small dogs with PS. The procedure was feasible in all cases, including those for which percutaneous treatment was not an option. Although the procedure is invasive, because of the need for thoracotomy, it is one of the treatment options that may be effective for PS, especially in small dogs, as it allows visualisation of the pulmonary artery lesion without relying on the experience of the surgeon.


Incidence and cost of CAP in a large working-age population.
To estimate incidence rates and quantify excess medical and productivity cost of community-acquired pneumonia (CAP) in a commercially insured, working-age population. Using the Thomson Reuters MarketScan Commercial Claims and Encounters Database, we estimated the annual incidence of CAP from 2003 through 2007 and evaluated its excess direct medical and productivity costs due to short-term disability and workplace absenteeism for adult patients aged 18 to 64 years. A cohort of CAP patients was 1:3 propensity score matched to a control cohort without pneumonia. Both excess direct medical costs and excess productivity costs were estimated in multivariate ordinary least squares (OLS) and generalized linear model (GLM) adjusting for demographic and clinical characteristics. A total of 402,831 patients with CAP and 1,208,231 matched controls were included. Overall annual CAP incidence was 4.89 cases per 1000 person-years. Excess annual medical cost of CAP ranged from $7220 by OLS to $11,443 by GLM. Inpatient costs, outpatient costs, and pharmacy costs explained 34%, 51%, and 15% of this excess cost of the GLM models, respectively. CAP patients had an additional productivity cost of $2391. Among adults younger than 65 years, these estimates imply an incidence of CAP of 950,000 annual cases at a cost of $10.6 billion (range: $9.04-$13.1), of which 80% are direct medical costs and 20% are productivity costs. CAP is a frequent and costly event in a working-age population with a national cost of $10.6 billion. Interventions that could successfully prevent CAP could have a significant impact on healthcare costs and productivity.


Gender differences in non-small-cell lung cancer survival: an analysis of 4,618 patients diagnosed between 1997 and 2002.
Gender has been reported as a predictor for nonsmall cell lung cancer (NSCLC) survival. Most of the reports are limited to selected groups of patients. The magnitude of gender effect on NSCLC survival across disease stage, tumor histology, and therapies needs to be further characterized. A cohort of 4,618 patients diagnosed with NSCLC was prospectively enrolled and actively followed. Vital status of each patient was verified through multiple complementary sources. Cox proportional hazards models were developed to compare postdiagnosis survival between genders adjusting for age at diagnosis, tumor histology and grade, stage, pack-years smoked, and treatment received (resection, radiation, or chemotherapy). There were 2,724 men (59%) and 1,894 women (41%), with a median age at diagnosis of 68 years in men and 66 in women (p < 0.01). More men smoked and were heavier smokers than women. Adenocarcinoma was the most frequent histology in both genders. No difference was found in stage and treatment between genders. The estimated survival in men was 51% (95% CI: 49%, 53%) and 15% (95% CI: 12%, 17%) at one and five years, respectively, and in women was 60% (95% CI: 58%, 62%) and 19% (95% CI: 16%, 22%). Men were at a significantly increased risk of mortality compared to women following a diagnosis of NSCLC (adjusted relative risk: 1.20, 95% CI: 1.11, 1.30), particularly for patients with stage III/IV disease or adenocarcinoma. Male gender is confirmed to be an independent unfavorable prognostic indicator for NSCLC survival.