The chloroplast genome of a Symbiodinium sp. clade C3 isolate.
Dinoflagellate algae of the genus Symbiodinium form important symbioses within corals and other benthic marine animals. Dinoflagellates possess an extremely reduced plastid genome relative to those examined in plants and other algae. In dinoflagellates the plastid genes are located on small plasmids, commonly referred to as 'minicircles'. However, the chloroplast genomes of dinoflagellates have only been extensively characterised from a handful of species. There is also evidence of considerable variation in the chloroplast genome organisation across those species that have been examined. We therefore characterised the chloroplast genome from an environmental coral isolate, in this case containing a symbiont belonging to the Symbiodinium sp. clade C3. The gene content of the genome is well conserved with respect to previously characterised genomes. However, unlike previously characterised dinoflagellate chloroplast genomes we did not identify any 'empty' minicircles. The sequences of this chloroplast genome show a high rate of evolution relative to other algal species. Particularly notable was a surprisingly high level of sequence divergence within the core polypeptides of photosystem I, the reasons for which are currently unknown. This chloroplast genome also possesses distinctive codon usage and GC content. These features suggest that chloroplast genomes in Symbiodinium are highly plastic.


Comparison of the effectiveness of the pulsed dye laser 585 nm versus 595 nm in the treatment of new surgical scars.
The aim of this study was to compare the effects of the pulsed-dye laser (PDL) at a wavelength of 585 nm with those at 595 nm in the treatment of post-surgical scars, starting on the day of suture removal. The study was a prospective, non-randomized, double-blind, controlled, clinical trial, set in an outpatient clinic. Fifteen outpatients with 21 post-operative scars at least 3 cm long were recruited, and 14 patients with 19 scars completed the study. Scars were divided into three equal portions. Each outer portion was randomly allocated to PDL at 585 nm or at 595 nm (3.5 J/cm(2), 450 micros, 10 mm spot size), and the center was an untreated control; treatment was composed of three laser sessions at 4-week intervals. A blinded examiner evaluated the three scar sections using the Vancouver scar scale for pigmentation, vascularity, pliability, and height. Cosmetic appearance was evaluated with a visual analog scale. Punch biopsies of three randomly selected scars were evaluated. Pigmentation: more scars after laser treatments were of normal color than in the control, but the difference was not statistically significant. Vascularity: after treatment, more scars had normal vascularity in all three groups than at baseline (P < 0.05); the largest increase was with a wavelength of 585 nm (10.5-94.7%), then 595 nm (15.8-78.9%), then control (5.2-36.6%). Pliability: there was more normal pliability in all three groups than at baseline (P < 0.05), with greater improvements in the laser-treated groups. Height: significantly more flat scars after 585 nm PDL (63.2%) than at baseline (21.1%) (P < 0.05). We observed a slight but non-significant decrease in the scar heights with 595 nm PDL in comparison with the control. after laser irradiation, the treated sections were more similar to a non-scarring process than the control. Cosmetic outcome: visual analog scales increased in all groups (P < 0.05), but the greatest increases were observed in the 585 nm and 595 nm laser-treated groups (50% and 60%, respectively) compared with controls (30%). There were significantly higher scores with the lasers than for the control (P < 0.001) at each visit after baseline. Both the 585 nm and 595 nm PDL treatments were effective in improving the appearance and normalizing the vascularity and pliability of post-operative scars. Both wavelengths improved the scars' visual appearance more than controls. We found that 585 nm appears to be the preferred wavelength, as it substantially normalized the height in addition to the vascularity and pliability in a significant number of scars.


Obstructive sleep apnea and psychiatric disorders: a systematic review.
Obstructive sleep apnea (OSA) has been associated with psychiatric pathology. Psychiatric comorbidity in OSA may affect patient quality of life and adherence to CPAP. A focused evaluation of OSA in highly selected groups of primarily psychiatric patients may provide further insights into the factors contributing to comorbidity of OSA and psychopathology. The goal of this study is to examine the prevalence and treatment of OSA in psychiatric populations. A systematic review following the PRISMA guidelines was conducted to determine the prevalence of OSA in schizophrenia and other psychotic disorders, mood disorders, and anxiety disorders, and to examine potential interventions. The PubMed, EMBASE, and PsycINFO databases were searched (last search April 26, 2014) using keywords based on the ICD-9-CM coding for OSA and the DSM-IV-TR diagnostic groups. The search retrieved 47 records concerning studies of OSA in the selected disorders. The prevalence studies indicate that there may be an increased prevalence of OSA in individuals with major depressive disorder (MDD) and posttraumatic stress disorder (PTSD), despite considerable heterogeneity and a high risk of bias. There was insufficient evidence to support increased OSA in schizophrenia and psychotic disorders, bipolar and related disorders, and anxiety disorders other than PTSD. Studies of treatment of OSA indicate an improvement in both OSA and psychiatric symptoms. CPAP adherence was reduced in veterans with PTSD. OSA prevalence may be increased in MDD and PTSD. In individuals with OSA and psychiatric illness, treatment of both disorders should be considered for optimal treatment outcomes.


Protocol for verifying expertise in locating fibromyalgia tender points.
To develop a protocol for determining when an individual is adequately trained to locate the tender points relative to fibromyalgia in an exam. The error distance for each tender point was established by polling individuals with experience in conducting tender point exams. Bayesian statistical methods were employed to form a protocol for determining an individual's proficiency in locating the tender points. A predictive distribution was utilized to find the probability of remaining trained at locating tender points. Also, the probability of classifying at least 11 tender points as tender (mild) under different "locating" criteria and different number of points that are truly tender was computed. Critical values indicating the number of tender points needed in the qualification process for various standards of reliability--80%, 85%, and 90%--are presented. To be certified after 3 subjects have been examined in the 80%, 85%, and 90% criteria, one has to correctly identify 48, 50, and 52, respectively, out of the 54 possible tender points. We believe that at least 3 subjects should be examined before certification is granted using any of the 3 criteria--80%, 85%, and 90%. In our example, when using the 85% criterion, the qualification process required 7 subjects to certify an individual.


Parasitoids, Nematodes, and Protists in Populations of Striped Cucumber Beetle (Coleoptera: Chrysomelidae).
The striped cucumber beetle, Acalymma vittatum (Fabricius), is an important pest of cucurbit production in the eastern United States, where most commercial producers rely on insecticides to control this pest species. Biological control provides an alternative to insecticide use, but for A. vittatum, top-down control has not been well developed. In the northeastern United States, two parasitoid species, Celatoria setosa (Coquillett) (Diptera: Tachinidae) and Centistes diabroticae (Gahan) (Hymenoptera: Braconidae) have been reported from A. vittatum, but their distribution is poorly known. To determine whether these parasitoid species are attacking A. vittatum in Pennsylvania and the amount of mortality they provide, we characterized the parasitoid dynamics in two distinct efforts. First, we reared parasitoids from beetles captured at two research farms. Second, we focused on one of these farms and dissected beetles to quantify both parasitoid and parasite species attacking A. vittatum. Both efforts confirmed Cl. setosa and Cn. diabroticae, and parasitism rates varied widely between locations and among years (4-60%). Unexpectedly, our dissections revealed that a potentially undescribed nematode species (Howardula sp.) as the most common parasite in the community. We also discovered gregarine protists. Despite being smaller than females, males were more commonly attacked by parasitic species, but we detected no relationship between the size of beetles and abundance of parasitic species in A. vittatum. This work provides a baseline understanding of the parasitoid and parasite community attacking A. vittatum and advances opportunities for conservation biological control using these natural-enemy species.


Ineffectiveness of reverse wording of questionnaire items: let's learn from cows in the rain.
We examined the effectiveness of reverse worded items as a means of reducing or preventing response bias. We first distinguished between several types of response bias that are often confused in literature. We next developed arguments why reversing items is probably never a good way to address response bias. We proposed testing whether reverse wording affects response bias with item-level data from the Multidimensional Fatigue Inventory (MFI-20), an instrument that contains reversed worded items. With data from 700 respondents, we compared scores on items that were similar with respect either to content or to direction of wording. Psychometric properties of sets of these items worded in the same direction were compared with sets consisting of both straightforward and reversed worded items. We did not find evidence that ten reverse-worded items prevented response bias. Instead, the data suggest scores were contaminated by respondent inattention and confusion. Using twenty items, balanced for scoring direction, to assess fatigue did not prevent respondents from inattentive or acquiescent answering. Rather, fewer mistakes are made with a 10-item instrument with items posed in the same direction. Such a format is preferable for both epidemiological and clinical studies.


Crystal structure of Venezuelan hemorrhagic fever virus fusion glycoprotein reveals a class 1 postfusion architecture with extensive glycosylation.
Guanarito virus (GTOV) is an emergent and deadly pathogen. We present the crystal structure of the glycosylated GTOV fusion glycoprotein to 4.1-Å resolution in the postfusion conformation. Our structure reveals a classical six-helix bundle and presents direct verification that New World arenaviruses exhibit class I viral membrane fusion machinery. The structure provides visualization of an N-linked glycocalyx coat, and consideration of glycan dynamics reveals extensive coverage of the underlying protein surface, following virus-host membrane fusion.


Lectin-binding patterns of small lymphocytes in bone marrow, thymus and spleen: demonstration of lymphocyte subsets by quantitative radioautography.
Cells from mouse bone marrow, thymus and spleen were exposed to 125I-labeled concanavalin A (Con A). Lens culinaris lectin (LCL), soybean agglutinin (SBA), Helix pomatia agglutinin (HPA), phytohemagglutinin-P (PHA-P), peanut agglutinin (PNA), or wheat germ agglutinin (WGA) in a range of concentrations and examined radioautographically. Small lymphocytes in the three organs differed in the minimal concentration of each lectin which gave detectable surface labeling, while at optimal lectin concentrations, their labeling intensity profiles differed markedly. Inhibition by sugars demonstrated the labeling specificity. Major populations of bone marrow small lymphocytes bound WGA strongly, while Con A, SBA, HPA, PHA-P and LCL were bound only weakly, and PNA binding was lacking. Most thymus cells bound Con A, SBA, HPA, PHA-P and PNA strongly, WGA and LCL weakly. Subsets of bone marrow and thymus small lymphocytes differed from the major populations in their lectin-binding intensities. Spleen small lymphocytes were heterogeneous in the binding of each lectin. However, a major population bound LCL exceptionally strongly, while few cells bound PNA. Using a panel of lectins under standardized conditions, these studies show distinctive lectin-binding patterns for small lymphocytes in the bone marrow, thymus and spleen, respectively. Major and minor cell populations are distinguishable in each organ, providing an approach to discriminating lymphocyte lineages, subtypes and differentiation stages.


Mid-infrared optical parametric oscillators and frequency combs for molecular spectroscopy.
Nonlinear optical frequency conversion is one of the most versatile methods to generate wavelength-tunable laser light in the mid-infrared region. This spectral region is particularly important for trace gas detection and other applications of molecular spectroscopy, because it accommodates the fundamental vibrational bands of several interesting molecules. In this article, we review the progress of the most significant nonlinear optics instruments for widely tunable, high-resolution mid-infrared spectroscopy: continuous-wave optical parametric oscillators and difference frequency generators. We extend our discussion to mid-infrared optical frequency combs, which are becoming increasingly important spectroscopic tools, owing to their capability of highly sensitive and selective parallel detection of several molecular species. To illustrate the potential and limitations of mid-infrared sources based on nonlinear optics, we also review typical uses of these instruments in both applied and fundamental spectroscopy.


Climate Change and Bivalve Mass Mortality in Temperate Regions.
One of the fastest-growing global food sectors is the bivalve aquaculture industry. Bivalves particularly oysters, mussels and clams are important sources of animal protein (Tan and Ransangan 2016a, b). Bivalve aquaculture represents 14-16% of the average per capita animal protein for 1.5 billion people and supports over 200,000 livelihoods, mostly in developing countries (FAO 2018). Most of the bivalves produced around the world (89%) are from aquaculture (FAO 2016). To date, mollusc aquaculture have accounted for 21.42% (17.14 million tonnes) of the total aquaculture production, with Asia being the largest contributor (92.27%) (FAO 2018).


Varicella in infants after implementation of the US varicella vaccination program.
To describe varicella disease in infants since implementation of the varicella vaccination program in the United States. From 1995 to 2008, demographic, clinical, and epidemiologic data on cases of varicella in infants were collected prospectively through a community-based active surveillance project. We examined disease patterns for infants in 2 age groups: 0 to 5 and 6 to 11 months. Infant varicella disease incidence declined 89.7% from 1995 to 2008. Infants aged 0 to 5 months had milder clinical disease than those aged 6 to 11 months: ≥50 lesions, 49% vs 58% (P = .038); fever (body temperature > 38°C), 12% vs 21% (P = .014); and varicella-related complications, 6% vs 14% (P = .009), respectively. Age was an independent predictor of the occurrence of complications. The varicella vaccination program has resulted in substantial indirect benefits for infants, who are not eligible for vaccination. Presence of maternal varicella-zoster virus antibodies might explain attenuated disease in very young infants likely born to mothers with history of varicella. Although varicella disease incidence has declined, exposure to varicella-zoster virus continues to occur. Improving varicella vaccination coverage in all age groups will further reduce the risk of varicella exposure and protect those not eligible for varicella vaccination.


Cardiovascular risk factors in relation to dietary patterns in 50-year-old men and women: a feasibility study of a short FFQ.
We aimed to assess the feasibility of a simple new fifteen-item FFQ as a tool for screening risk of poor dietary patterns in a healthy middle-aged population and to investigate how the results of the FFQ correlated with cardiovascular risk factors and socio-economic factors. A randomized population-based cross-sectional study. Metabolic measurements for cardiovascular risk factors and information about lifestyle were collected. A fifteen-item FFQ was created to obtain information about dietary patterns. From the FFQ, a healthy eating index was created with three dietary groups: good, average and poor. Multivariate logistic regression was used to assess relationships between dietary patterns and cardiovascular risk factors. Sweden. Men and women aged 50 years and living in Gothenburg, Sweden. In total, 521 middle-aged adults (257 men, 264 women) were examined. With good dietary pattern as the reference, there was a gradient association of having obesity, hypertension and high serum TAG in those with average and poor dietary patterns. After adjustment for education and lifestyle factors, individuals with a poor dietary pattern still had significantly higher risk (OR; 95 % CI) of obesity (2·33; 1·10, 4·94), hypertension (2·73; 1·44, 5·20) and high serum TAG (2·62; 1·33, 5·14) compared with those with a good dietary pattern. Baseline data collected by a short FFQ can predict cardiovascular risk factors in middle-aged Swedish men and women. The FFQ could be a useful tool in health-care settings, when screening for risk of poor dietary patterns.


Quantitative analysis of molecular transport across liposomal bilayer by J-mediated 13C Overhauser dynamic nuclear polarization.
We introduce a new NMR technique to dramatically enhance the solution-state (13)C NMR sensitivity and contrast at 0.35 T and at room temperature by actively transferring the spin polarization from Overhauser dynamic nuclear polarization (ODNP)-enhanced (1)H to (13)C nuclei through scalar (J) coupling, a method that we term J-mediated (13)C ODNP. We demonstrate the capability of this technique by quantifying the permeability of glycine across negatively charged liposomal bilayers composed of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG). The permeability coefficient of glycine across this DPPC/DPPG bilayer is measured to be (1.8 ± 0.1) × 10(-11)m/s, in agreement with the literature value. We further observed that the presence of 20 mol % cholesterol within the DPPC/DPPG lipid membrane significantly retards the permeability of glycine by a factor of 4. These findings demonstrate that the high sensitivity and contrast of J-mediated (13)C ODNP affords the measurement of the permeation kinetics of small hydrophilic molecules across lipid bilayers, a quantity that is difficult to accurately measure with existing techniques.


Fabrication and characterization of silicon woodpile photonic crystals with a complete bandgap at telecom wavelengths.
By using direct laser writing into a novel commercially available photoresist and a silicon-double-inversion procedure followed by tempering of the silicon structures, we realize high-quality centered-tetragonal woodpile photonic crystals with complete photonic bandgaps near 1.55 microm wavelength. The 6.9% gap-to-midgap ratio bandgap is evidenced by the comparison of measured transmittance and reflectance spectra with band-structure and scattering-matrix calculations.


Endobronchial Valves Therapy for Advanced Emphysema: A Meta-Analysis of Randomized Trials.
Trials suggest that bronchoscopic lung volume reduction (BLVR) with endobronchial valve (EBV) implantation may produce similar effects as lung volume reduction surgery, by inducing atelectasis and reducing hyperinflation through a minimally invasive procedure. This study sought to investigate the efficacy and safety of BLVR with EBV for advanced emphysema. We searched PubMed, EMBASE, Web of Science, CINAHL, ClinicalTrials.gov, and Cochrane Library databases for randomized controlled trials comparing EBV implantation versus standard medical treatment or sham bronchoscopy. The main outcome of interest was the percentage change of forced expiratory volume in 1 second. Data analyzed from 5 randomized controlled trials with 703 patients revealed improvement in percentage change of forced expiratory volume in 1 second in EBV group compared with control group [weighted mean difference (WMD)=11.43; 95% confidence interval (CI), 6.05-16.80; P<0.0001] and improvement in the St. George's Respiratory Questionnaire score (WMD=-5.69; 95% CI, -8.67 to -2.70; P=0.0002). There is no difference shown in the 6-minute walking test (WMD=14.12; 95% CI, -4.71 to 32.95; P=0.14). The overall complication rate of EBV was not significantly different except for an increased rate of pneumothorax [relative risk (RR)=8.16; 95% CI, 2.21-30.11; P=0.002), any hemoptysis (RR=5.01; 95% CI, 1.12-22.49; P=0.04)] and valve migration (RR=8.64; 95% CI, 2.01-37.13; P=0.004). BLVR using EBV shows short-term improvement in lung function and quality of life, but with increased risk of minor hemoptysis, pneumothorax, and valve migration. Follow-up data on the studies are needed to determine its long-term efficacy.


Controllable hierarchical self-assembly of gemini supra-amphiphiles: the effect of spacer length.
Gemini supra-amphiphiles with different spacer lengths, [M-n-M]2+@2[DBS]- (n = 2, 6, 10), were easily constructed. The conformational flexibility and hydrophobicity of the spacer group can be effectively tailored through regulating the spacer length, leading to the fine control of the topologies and subsequent hierarchical self-assemblies of [M-n-M]2+@2[DBS]-. Vesicles are primarily fabricated by [M-n-M]2+@2[DBS]-, and then successively fused into vesicle clusters, nanotubes, and planar bilayers, whose bilayer curvatures are gradually decreased, with increasing spacer length. Coating [M-10-M]2+ with β-CD can reduce the flexibility and hydrophobicity of the decyl spacer, resulting in the reversion from planar bilayers to vesicles. Furthermore, stable aqueous two-phase systems (ATPSs) that spontaneously formed via vesicle fusion in the solutions of [M-n-M]2+@2[DBS]- (n = 6, 10) can act as functional supramolecular systems in the isolation and purification of oil-soluble biomaterials.


The Political Face of Public Health.
Public health is politically paradoxical because its core conceptual components - the exercise of public authority and the promotion of population health - stand in practical tension that belies their theoretical promise. Across Western nations, public policymakers stand accused of failing properly to honor and support the crucial contributions that public health makes to the improvement of health outcomes and of overinvesting in acute medical care services, the need for which timely interventions in prevention and health promotion might have averted. The dramatic budgetary discrepancies in Western nations between the massive funds devoted to medical care and the minuscule sums allotted to public health are often taken as evidence that in such matters, political leaders are irrational (or perhaps uninformed, or captured by big-moneyed medical interests) and that good public policy would have epidemiologists and other public health experts running, or at least orchestrating, the show. This paper explores the sources of this tension between population health and political power within the concept of public health and seeks to show why these strains prove to be so durable, indeed irresolvable. The argument and evidence draw largely on the United States, but the supposition - yway, the hope - is that the analysis will also throw light on the politics of public health in other nations.


Trends in smokeless tobacco use among adults and adolescents in the United States.
Smokeless tobacco has many adverse health effects. We analyzed long-term national trends in smokeless tobacco use. We used 1987 to 2000 National Health Interview Survey data for adults aged 18 years and older, 1986 to 2003 data from Monitoring the Future surveys of adolescents, and 1991 to 2003 data from the Youth Risk Behavior Survey for 9th- to 12th-grade students to examine overall and demographic-specific trends. Smokeless tobacco use among adult and adolescent females was low and showed little change. Smokeless tobacco use among men declined slowly (relative decline=26%), with the largest declines among those aged 18 to 24 years or 65 years and older, Blacks, residents of the South, and persons in more rural areas. Overall and demographic-specific data for adolescent boys indicate that smokeless tobacco use increased for 12th-grade students from 1986 until the early 1990s, but has subsequently declined rapidly in all grades since then (range of relative overall declines=43% to 48%). Smokeless tobacco use has declined sharply, especially among adolescent boys. Ongoing prevention and cessation efforts are needed to continue this trend.


Myocardial expression and redistribution of GRKs in hypertensive hypertrophy and failure.
G-protein-coupled receptor kinases (GRKs) are involved in cardiac hypertrophy and failure. But their temporal expression and cellular localization during the development of hypertrophy and its transition to failure remains to be investigated. In this study, we determined the expression and subcellular distribution of GRK2, GRK3, GRK5, and GRK6 in cardiac myocytes of 2- to 24-month-old spontaneously hypertensive heart failure (SHHF) rats. GRK2 increased in the intercalated disks in 6-, 12-, and 24-month-old SHHF rats, although total expression remained relatively constant from 2 to 24 months in both SHHF and normotensive rats. GRK3 expression progressively increased in 6-, 12-, and 24-month-old SHHF rats and was significantly higher than in age-matched controls. Immunolabeling of GRK3 showed a typical pattern of cross-striations that colocalized with alpha-actinin and G(alphas) at Z-lines in both SHHF and control rats. GRK5 expression showed no change from 2 to 24 months in both SHHF and normotensive rats. Confocal analysis revealed nuclear translocation of GRK5 in myocytes of SHHF rats. GRK6 had a striated pattern colocalized with alpha-actinin at Z-lines in the cytoplasm and was also present in the intercalated disks of cardiac myocytes from both SHHF and control rats. GRK6 expression increased in 12- and 24-month-old SHHF rats and was significantly higher than in age-matched controls. GRK6 labeling was reduced at the intercalated disks, but increased in the cytoplasm of cardiac myocytes from SHHF rats compared to age-matched controls. The increased expression of GRK3 and GRK6 and subcellular redistribution of GRK2, GRK5, and GRK6 in SHHF rats may be involved in abnormal remodeling of cardiac myocytes in hypertensive hypertrophy and failure.


Body mass index, diabetes, hypertension, and short-term mortality: a population-based observational study, 2000-2006.
Published studies about the association of obesity with mortality have used body mass index (BMI) data collected more than 10 years ago, potentially limiting their current applicability, particularly given evidence of a secular decline in obesity-related mortality. The objective of this study was to examine the association between BMI and mortality in a representative, contemporary United States sample. This was a population-based observational study of data from 50,994 adults aged 18 to 90 years who responded to the 2000 to 2005 Medical Expenditures Panel Surveys. Cox regression analyses were employed to model survival during up to 6 years of follow-up (ascertained via National Death Index linkage) by self-reported BMI category (underweight, <20 kg/m(2); normal weight, 20-<25 [reference]; overweight, 25-<30; obese, 30-<35; severely obese, ≥35), without and with adjustment for diabetes and hypertension. Survival by BMI category also was modeled for diabetic and hypertensive individuals. All models were adjusted for sociodemographics, smoking, and Medical Expenditures Panel Surveys response year. In analyses not adjusted for diabetes or hypertension, only severe obesity was associated with mortality (adjusted hazard ratio, 1.26; 95% confidence interval, 1.00-1.59). After adjusting for diabetes and hypertension, severe obesity was no longer associated with mortality, and milder obesity (BMI 30-<35) was associated with decreased mortality (adjusted hazard ratio, 0.81; 95% confidence interval, 0.68-0.97). There was a significant interaction between diabetes (but not hypertension) and BMI (F [4, 235] = 2.71; P = .03), such that the mortality risk of diabetes was lower among mildly and severely obese persons than among those in lower BMI categories. Obesity-associated mortality risk was lower than estimated in studies employing older BMI data. Only severe obesity (but not milder obesity or overweight) was associated with increased mortality, an association accounted for by coexisting diabetes and hypertension. Mortality in diabetes was lower among obese versus normal weight individuals.


User perceptions of and willingness to pay for household container-based sanitation services: experience from Cap Haitien, Haiti.
Household-level container-based sanitation (CBS) services may help address the persistent challenge of providing effective, affordable sanitation services for which low-income urban households are willing to pay. Little is known, however, about user perceptions of and demand for household CBS services. This study presents the results of a pilot CBS service programme in Cap Haitien, Haiti. One hundred and eighteen households were randomly selected to receive toilets and a twice-weekly collection service. After three months, changes in these households' satisfaction with their sanitation situation, along with feelings of pride, modernity and personal safety, were compared to 248 households in two comparison cohorts. Following the service pilot, 71 per cent of participating households opted to continue with the container-based sanitation service as paying subscribers. The results from this study suggest that, in the context of urban Haiti, household CBS systems have the potential to satisfy many residents' desire for safe, convenient and modern sanitation services.


Developmental axon pruning mediated by BDNF-p75NTR-dependent axon degeneration.
The mechanisms that regulate the pruning of mammalian axons are just now being elucidated. Here, we describe a mechanism by which, during developmental sympathetic axon competition, winning axons secrete brain-derived neurotrophic factor (BDNF) in an activity-dependent fashion, which binds to the p75 neurotrophin receptor (p75NTR) on losing axons to cause their degeneration and, ultimately, axon pruning. Specifically, we found that pruning of rat and mouse sympathetic axons that project to the eye requires both activity-dependent BDNF and p75NTR. p75NTR and BDNF are also essential for activity-dependent axon pruning in culture, where they mediate pruning by directly causing axon degeneration. p75NTR, which is enriched in losing axons, causes axonal degeneration by suppressing TrkA-mediated signaling that is essential for axonal maintenance. These data provide a mechanism that explains how active axons can eliminate less-active, competing axons during developmental pruning by directly promoting p75NTR-mediated axonal degeneration.


Action-specific influences on perception and postperceptual processes: Present controversies and future directions.
The action-specific perception account holds that people perceive the environment in terms of their ability to act in it. In this view, for example, decreased ability to climb a hill because of fatigue makes the hill visually appear to be steeper. Though influential, this account has not been universally accepted, and in fact a heated controversy has emerged. The opposing view holds that action capability has little or no influence on perception. Heretofore, the debate has been quite polarized, with efforts largely being focused on supporting one view and dismantling the other. We argue here that polarized debate can impede scientific progress and that the search for similarities between 2 sides of a debate can sharpen the theoretical focus of both sides and illuminate important avenues for future research. In this article, we present a synthetic review of this debate, drawing from the literatures of both approaches, to clarify both the surprising similarities and the core differences between them. We critically evaluate existing evidence, discuss possible mechanisms of action-specific effects, and make recommendations for future research. A primary focus of future work will involve not only the development of methods that guard against action-specific postperceptual effects but also development of concrete, well-constrained underlying mechanisms. The criteria for what constitutes acceptable control of postperceptual effects and what constitutes an appropriately specific mechanism vary between approaches, and bridging this gap is a central challenge for future research.


Aberrant Expression of NCAPG is Associated with Prognosis and Progression of Gastric Cancer.
Gastric cancer (GC), one of the most prevalent malignancies, is the third-leading cause of cancer-related deaths globally. The aim of this study is to investigate the involvement of non-structural maintenance of chromosomes condensin I complex subunit G (NCAPG) in the prognosis of GC. Western blotting and immunostaining were employed to measure the NCAPG level in gastric tissues and cells. Kaplan-Meier analysis was applied to analyze the prognostic value of NCAPG in GC. RNA interference was applied to investigate the influence of the NCAPG silencing on GC cell growth and spread. NCAPG overexpression was associated with several clinicopathologic characteristics, including nodal status (P = 0.0378), distant metastasis (P = 0.0088), staging (P = 0.0230), vascular invasion (P = 0.0012), and disease-free survival (P = 0.004). Kaplan-Meier analysis revealed that NCAPG overexpression was positively correlated to poor GC patients disease-free and overall survival (P = 0.004 and P < 0.001, respectively). Univariate Cox regression analysis showed that the overexpression of NCAPG was a prognostic biomarker of GC (P = 0.005). In cultured GC cells, the knockdown of NCAPG suppressed cell proliferation, migration and invasion. Meanwhile, further studies revealed that the NCAPG silencing induces the G0/G1 cell cycle arrest and accordingly represses cell division. Finally, Western blotting showed that NCPAG knockdown dysregulated cell cycle- and epithelial-mesenchymal transition-related molecules. Overall, the results reveal that NCAPG overexpression is a candidate prognostic biomarker and potential therapeutic target in GC.


Pretransplant prediction of posttransplant survival for liver recipients with benign end-stage liver diseases: a nonlinear model.
The scarcity of grafts available necessitates a system that considers expected posttransplant survival, in addition to pretransplant mortality as estimated by the MELD. So far, however, conventional linear techniques have failed to achieve sufficient accuracy in posttransplant outcome prediction. In this study, we aim to develop a pretransplant predictive model for liver recipients' survival with benign end-stage liver diseases (BESLD) by a nonlinear method based on pretransplant characteristics, and compare its performance with a BESLD-specific prognostic model (MELD) and a general-illness severity model (the sequential organ failure assessment score, or SOFA score). With retrospectively collected data on 360 recipients receiving deceased-donor transplantation for BESLD between February 1999 and August 2009 in the west China hospital of Sichuan university, we developed a multi-layer perceptron (MLP) network to predict one-year and two-year survival probability after transplantation. The performances of the MLP, SOFA, and MELD were assessed by measuring both calibration ability and discriminative power, with Hosmer-Lemeshow test and receiver operating characteristic analysis, respectively. By the forward stepwise selection, donor age and BMI; serum concentration of HB, Crea, ALB, TB, ALT, INR, Na(+); presence of pretransplant diabetes; dialysis prior to transplantation, and microbiologically proven sepsis were identified to be the optimal input features. The MLP, employing 18 input neurons and 12 hidden neurons, yielded high predictive accuracy, with c-statistic of 0.91 (P<0.001) in one-year and 0.88 (P<0.001) in two-year prediction. The performances of SOFA and MELD were fairly poor in prognostic assessment, with c-statistics of 0.70 and 0.66, respectively, in one-year prediction, and 0.67 and 0.65 in two-year prediction. The posttransplant prognosis is a multidimensional nonlinear problem, and the MLP can achieve significantly high accuracy than SOFA and MELD scores in posttransplant survival prediction. The pattern recognition methodologies like MLP hold promise for solving posttransplant outcome prediction.


Effects of a 3-week High-Fat-Low-Carbohydrate Diet on Lipid and Glucose Profiles in Experienced, Middle-age Male Runners.
This study examined glucose and lipid marker responses following a 3-week, ad libitum low-carbohydrate-high-fat diet (LCHF; ~70% kcals from fat, <50 g/day of net carbohydrates) versus the habitual mixed macronutrient diet (HMD) of eight middle-age, trained male runners (40 ± 10 years; V̇O2peak = 49 ± 4 mL·kg-1·min-1). Blood was drawn at 0600 from an antecubital vein after an overnight fast under conditions of no exercise/heat stress (NEXH; 48 h of restriction from intense exercise) or 24-h after exercise/heat stress (EXH; 60 min run in hot conditions plus 5-km time trial) for both dietary conditions. Glucose improvement during LCHF approached but did not reach statistical significance (p = 0.07). Pre-exercise triacylglycerol did not differ between treatments but decreased > 20 mg/dL (p < 0.05) for both treatments from NEXH to EXH (HMD = 42 ± 16; LCHF = 35 ± 21 mg/dL). Main effects for diet were exhibited for HDL-C during NEXH and EXH (HMD = 48 ± 10 and 50 ± 11; LCHF = 57 ± 13 and 60 ± 13 mg/dL), and LDL-C also increased (p = 0.02) by ~20 mg/dL for LCHF at both collection points resulting in ~30 mg/dL greater total cholesterol for LCHF before and 24-h after exercise (p < 0.05). A 3-week, ad libitum LCHF did not elicit significant negative cardiovascular disease risk in male runners 30-50 years of age with healthy pre-intervention lipid and glucose marker status.


Fabrication of two- and three-dimensional quasi-periodic structures with 12-fold symmetry by interference technique.
We demonstrate theoretically and experimentally a useful technique for fabrication of two- and three-dimensional (2D or 3D) quasi-periodic structures by a double-exposure of a periodic interference pattern. With three-beam and three-beam-plus-one interference techniques, one can fabricate a periodic 2D and 3D structure having six-fold symmetry, respectively. When this structure is duplicated in another orientation, its combination results in a quasi-periodic twelve-fold symmetry structure. Experimental results obtained by using two-exposure of three-beam and/or three-beam-plus-one interference pattern at 442 nm into a positive photoresist (AZ-4620) proved the theoretical predictions. This study is potentially useful for photonic researches and applications.


Graph Theory Approach to High-Throughput Surface Adsorption Structure Generation.
We present a methodology for graph based enumeration of surfaces and unique chemical adsorption structures bonded to those surfaces. Utilizing the graph produced from a bulk structure, we create a unique graph representation for any general slab cleave and further extend that representation to include a large variety of catalytically relevant adsorbed molecules. We also demonstrate simple geometric procedures to generate 3D initial guesses of these enumerated structures. While generally useful for generating a wide variety of structures used in computational surface science and heterogeneous catalysis, these techniques are also key to facilitating an informatics approach to the high-throughput search for more effective catalysts.


Young men's experience with condom breakage.
In a nationally representative sample of men aged 17-22, 23% of those using condoms reported experiencing at least one condom break during the previous 12 months. Of all condoms used, 2.5% had broken. In multivariate analyses, increased experience with condoms reduced the likelihood of experiencing condom breakage. Recent sex education was associated with an almost 80% decrease in the risk of breakage among young men who used condoms infrequently. Young males who had ever had a sexually transmitted disease (STD), or whose sexual partner had had an STD, were almost three times as likely as other respondents to have experienced condom breakage. In addition, young men with a household income of less than $60,000 were 2-3 times as likely to have broken a condom as were those with a higher household income.


Clinical and molecular findings in 37 Turkish patients with isolated methylmalonic acidemia
Isolated methylmalonic acidemia (MMA) is caused by complete or partial deficiency of the enzyme methylmalonyl- CoA mutase (mut0 or mut– enzymatic subtype), a defect of its cofactor adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. While onset of the disease ranges from the neonatal period to adulthood, most cases present with lethargy, vomiting and ketoacidosis in the early infancy. Major secondary complications are; growth failure, developmental delay, interstitial nephritis with progressive renal failure, basal ganglia injury and cardiomyopathy. We aimed to demonstrate clinical and molecular findings based on long-term follow up in our patient cohort. The study includes 37 Turkish patients with isolated MMA who were followed up for long term complications 1 to 14 years. All patients were followed up regularly with clinical, biochemical and dietary monitoring to determine long term complications. Next Generation Sequencing technique was used for mutation screening in five disease-causing genes including; MUT, MMAA, MMAB, MMADHC, MCEE genes. Mutation screening identified 30 different types of mutations. While 28 of these mutations were previously reported, one novel MMAA mutation p.H382Pfs*24 (c.1145delA) and one novel MUT mutation IVS3+1G>T(c.752+1G>T) has been reported. The most common clinical complications were growth retardation, renal involvement, mental motor retardation and developmental delay. Furthermore, one of our patients developed cardiomyopathy, another one died because of hepatic failure and one presented with lactic acidosis after linezolid exposure. We have detected two novel mutations, including one splice-site mutation in the MUT gene and one frame shift mutation in the MMAA gene in 37 Turkish patients. We confirm the genotype-phenotype correlation in the study population according to the long-term complications.


Degree and time sequence of hypothermic protection against experimental ischemic acute renal failure.
The purpose of this study was to assess the degree, time sequence, and biochemical correlates of hypothermic protection against ischemic acute renal failure. Rats subjected to 40 minutes of bilateral renal artery occlusion (RAO) were made mildly hypothermic (32 degrees-33 degrees C, by cold saline peritoneal lavage) during the following time periods: 1) RAO only, 2) reperfusion only (beginning at 0, 15, 30, or 60 minutes after RAO and maintained for 45 minutes), or 3) during and after (0-45 minutes) RAO. Continuously normothermic (37 degrees C) RAO rats served as controls. The control rats developed severe acute renal failure (blood urea nitrogen [BUN], 95 +/- 4 mg/dl; creatinine, 2.2 +/- 0.1 mg/dl; and extensive tubular necrosis at 24 hours). Hypothermia confined to RAO was highly protective (BUN, 33 +/- 5 mg/dl; creatinine, 0.62 +/- 0.07 mg/dl; and minimal necrosis). Hypothermia partially preserved ischemic renal adenylate high-energy phosphate (ATP and ADP), increased AMP and inosine monophosphate concentrations, and lessened hypoxanthine/xanthine buildup (assessed at end of RAO). Hypothermia confined to the reflow period (beginning at 0, 15, and 30 minutes) was only mildly protective (e.g., BUN, 58-63 mg/dl); the degree of protection did not differ according to the time of hypothermic onset. Lowering reflow temperature to 26 degrees C had no added benefit. Hypothermia that started at 60 minutes after RAO conferred no protection. Combining ischemic and postischemic hypothermia abolished all renal failure (assessed at 24 hours). This study offers the following conclusions: Mild hypothermia can totally prevent experimental ischemic acute renal failure. Hypothermia is highly effective during ischemia, and it is mildly protective during early reflow; these benefits are additive. During early reflow, hypothermic protection is not critically time dependent. By 60 minutes of reflow, no effect is elicited; this absence of effect possibly signals completion of the reperfusion injury process. Hypothermia's protective effects may be mediated, in part, by improvements in renal adenine nucleotide content and, possibly, by decreasing postischemic oxidant stress.


The Consortium of Metabolomics Studies (COMETS): Metabolomics in 47 Prospective Cohort Studies.
The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).


Attention deficits following ADEM ameliorated by guanfacine.
The authors report here the case of a patient with severe deficits in arousal and sustained attention, associated with hemispatial neglect. These impairments were secondary to acute disseminated encephalomyelitis, with bilateral involvement of the medial nuclei and pulvinar of the thalamus. Treatment with the noradrenergic agonist guanfacine, previously used for attention deficits in attention deficit/hyperactivity disorder and stroke, was associated with a significant amelioration of both the spatial and sustained attention impairments in neglect. Guanfacine may prove to be a useful tool in the treatment of disorders of attention associated with neurological conditions.


Placental mesenchymal and cord blood stem cell therapy for dilated cardiomyopathy.
Regenerative treatment of dilated, non-ischaemic cardiomyopathy represents a significant unmet clinical need. Intracoronary administration of autologous bone marrow stem cells has demonstrated positive results in treatment of post-infarct and chronic ischaemic patients. Limitations of this procedure include: invasiveness of bone marrow extraction and cardiac catheterization, and dependence on stem cell populations that are aged and possibly senescent. Here, the use of intravenously administered allogeneic placental matrix derived mesenchymal stem cells for treatment of dilated cardiomyopathy is discussed. Safety of this cell population has already been established in completed Phase I and II trials; however, to date, clinical implementation for dilated cardiomyopathy has not been reported. Preclinical studies have demonstrated that mesenchymal stem cells: (i) inhibit myocardial inflammation; (ii) inhibit cardiomyocyte apoptosis; (iii) stimulate angiogenesis; and (iv) display therapeutic activity in models of dilated cardiomyopathy. Clinical studies have demonstrated the ability of mesenchymal stem cells to inhibit post-infarct remodelling, as well as potently block inflammatory processes in graft versus host and Crohn disease. Presented here is case report of a patient with dilated cardiomyopathy treated with intravenous allogeneic mesenchymal stem cells and expanded umbilical cord blood CD34 cells who underwent a profound clinical improvement.


Rationale, Methodology, and Implementation of a Dispatcher-assisted Cardiopulmonary Resuscitation Trial in the Asia-Pacific (Pan-Asian Resuscitation Outcomes Study Phase 2).
Abstract Background. Survival outcomes from out-of-hospital cardiac arrest (OHCA) in Asia are poor (2-11%). Bystander cardiopulmonary resuscitation (CPR) rates are relatively low in Asia. Dispatcher-assisted CPR (DA-CPR) has recently emerged as a potentially cost-effective intervention to increase bystander CPR and survival from OHCA. The Pan-Asian Resuscitation Outcomes Study (PAROS), an Asia-Pacific cardiac arrest registry, was set up in 2009, with the aim of understanding OHCA as a disease in Asia and improving OHCA survival. The network has adopted DA-CPR as part of its strategy to improve OHCA survival. Objective. This article aims to describe the conceptualization, study design, potential benefits, and difficulties for implementation of DA-CPR trial in the Asia-Pacific. Methods. Two levels of intervention, basic and comprehensive, will be offered to PAROS participating sites. The basic level consists of implementation of a DA-CPR protocol and training program, while the comprehensive level consists of implementation of the basic level, with the addition of a dispatch quality measurement tool, quality improvement program, and community education program. Sites that are not able to implement the package will contribute control data. The primary outcome of the study is survival to hospital discharge or survival to 30 days post cardiac arrest. DA-CPR and bystander CPR are secondary outcomes. Conclusion. Implementation of DA-CPR requires concerted efforts by EMS leaders and supervisors, dispatchers, hospital stakeholders, policy makers, and the general public. The DA-CPR trial implemented by the PAROS sites, if successful, can serve as a model for other countries considering such an intervention in their EMS systems.


ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis).
Lynch syndrome, familial adenomatous polyposis, and Mut Y homolog (MYH)-associated polyposis are three major known types of inherited colorectal cancer, which accounts for up to 5% of all colon cancer cases. Lynch syndrome is most frequently caused by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 and is inherited in an autosomal dominant manner. Familial adenomatous polyposis is manifested as colonic polyposis caused by mutations in the APC gene and is also inherited in an autosomal dominant manner. Finally, MYH-associated polyposis is caused by mutations in the MUTYH gene and is inherited in an autosomal recessive manner but may or may not be associated with polyps. There are variants of both familial adenomatous polyposis (Gardner syndrome--with extracolonic features--and Turcot syndrome, which features medulloblastoma) and Lynch syndrome (Muir-Torre syndrome features sebaceous skin carcinomas, and Turcot syndrome features glioblastomas). Although a clinical diagnosis of familial adenomatous polyposis can be made using colonoscopy, genetic testing is needed to inform at-risk relatives. Because of the overlapping phenotypes between attenuated familial adenomatous polyposis, MYH-associated polyposis, and Lynch syndrome, genetic testing is needed to distinguish among these conditions. This distinction is important, especially for women with Lynch syndrome, who are at increased risk for gynecological cancers. Clinical testing for these genes has progressed rapidly in the past few years with advances in technologies and the lower cost of reagents, especially for sequencing. To assist clinical laboratories in developing and validating testing for this group of inherited colorectal cancers, the American College of Medical Genetics and Genomics has developed the following technical standards and guidelines. An algorithm for testing is also proposed.


Twist expression promotes migration and invasion in hepatocellular carcinoma.
Twist, a transcription factor of the basic helix-loop-helix class, is reported to regulate cancer metastasis. It is known to induce epithelial-mesenchymal transition (EMT). In this study, we evaluated the expression of twist and its effect on cell migration in hepatocellular carcinoma (HCC). We examined twist expression using immunohistochemistry in 20 tissue samples of hepatocellular carcinoma, and assessed twist expression in HCC cell lines by RT-PCR and Western blot analysis. Ectopic twist expression was created by introducing a twist construct in the twist-negative HCC cell lines. Endogenous twist expression was blocked by twist siRNA in the twist-positive HCC cell lines. We studied EMT related markers, E-cadherin, Vimentin, and N-cadherin by Western blot analysis. Cell proliferation was measured by MTT assay, and cell migration was measured by in vitro wound healing assay. We used immunofluorescent vinculin staining to visualize focal adhesion. We detected strong and intermediate twist expression in 7 of 20 tumor samples, and no significant twist expression was found in the tumor-free resection margins. In addition, we detected twist expression in HLE, HLF, and SK-Hep1 cells, but not in PLC/RPF/5, HepG2, and Huh7 cells. Ectopic twist-expressing cells demonstrated enhanced cell motility, but twist expression did not affect cell proliferation. Twist expression induced epithelial-mesenchymal transition together with related morphologic changes. Focal adhesion contact was reduced significantly in ectopic twist-expressing cells. Twist-siRNA-treated HLE, HLF, and SK-Hep1 cells demonstrated a reduction in cell migration by 50, 40 and 18%, respectively. Twist induces migratory effect on hepatocellular carcinoma by causing epithelial-mesenchymal transition.


PLP-dependent enzymes as entry and exit gates of sphingolipid metabolism.
Sphingolipids are membrane constituents as well as signaling molecules involved in many essential cellular processes. Serine palmitoyltransferase (SPT) and sphingosine-1-phosphate lyase (SPL), both PLP (pyridoxal 5'-phosphate)-dependent enzymes, function as entry and exit gates of the sphingolipid metabolism. SPT catalyzes the condensation of serine and a fatty acid into 3-keto-dihydrosphingosine, whereas SPL degrades sphingosine-1-phosphate (S1P) into phosphoethanolamine and a long-chain aldehyde. The recently solved X-ray structures of prokaryotic homologs of SPT and SPL combined with functional studies provide insight into the structure-function relationship of the two enzymes. Despite carrying out different reactions, the two enzymes reveal striking similarities in the overall fold, topology, and residues crucial for activity. Unlike their eukaryotic counterparts, bacterial SPT and SPL lack a transmembrane helix, making them targets of choice for biochemical characterization because the use of detergents can be avoided. Both human enzymes are linked to severe diseases or disorders and might therefore serve as targets for the development of therapeutics aiming at the modulation of their activity. This review gives an overview of the sphingolipid metabolism and of the available biochemical studies of prokaryotic SPT and SPL, and discusses the major similarities and differences to the corresponding eukaryotic enzymes.


Specific Sensory Techniques and Sensory Environmental Modifications for Children and Youth With Sensory Integration Difficulties: A Systematic Review.
This systematic review examined the effectiveness of specific sensory techniques and sensory environmental modifications to improve participation of children with sensory integration (SI) difficulties. Abstracts of 11,436 articles published between January 2007 and May 2015 were examined. Studies were included if designs reflected high levels of evidence, participants demonstrated SI difficulties, and outcome measures addressed function or participation. Eight studies met inclusion criteria. Seven studies evaluated effects of specific sensory techniques for children with autism spectrum disorder (ASD) or attention deficit hyperactivity disorder: Qigong massage, weighted vests, slow swinging, and incorporation of multisensory activities into preschool routines. One study of sensory environmental modifications examined adaptations to a dental clinic for children with ASD. Strong evidence supported Qigong massage, moderate evidence supported sensory modifications to the dental care environment, and limited evidence supported weighted vests. The evidence is insufficient to draw conclusions regarding slow linear swinging and incorporation of multisensory activities into preschool settings.


Evaluating an integrated primary care approach to improve well-being among frail community-living older people: A theory-guided study protocol.
A major challenge in primary healthcare is the substantial increase in the proportion of frail community-dwelling older persons with long-term conditions and multiple complex needs. Consequently, a fundamental transformation of current models of primary care by means of implementing proactive integrated care is necessary. Therefore, an understanding of the effects of integrated primary care approaches and underlying mechanisms is essential. This article presents the design of a theory-based evaluation of an integrated primary care approach to improve well-being among frail community-living older adults, which is called "Finding and Follow-up of Frail older persons" (FFF). First, we present a theoretical model to facilitate a sound theory-guided evaluation of integrated primary care approaches for frail community-dwelling older people. The model incorporates interrelated elements of integrated primary care approaches (e.g. proactive case finding and self-management support). Efforts to improve primary care should integrate these promising components to assure productive patient-professional interactions and to improve well-being. Moreover, cognitive and behavioral components of healthcare professionals and patients are assumed to be important. Second, we present the design of the study to evaluate the FFF approach which consists of the following key components: (1) proactive case finding, (2) case management, (3) medication review, (4) self-management support, and (5) working in multidisciplinary care teams. The longitudinal evaluation study has a matched quasi-experimental design with one pretest and one posttest (12 month follow-up) and is conducted in the Netherlands between 2014 and 2017. Both quantitative and qualitative methods are used to evaluate effectiveness, processes, and cost-effectiveness. In total, 250 frail older persons (75 years and older) of 11 GP (general practitioner) practices that implemented the FFF approach are compared with 250 frail older patients of 4 GP practices providing care as usual. In addition, data are collected from healthcare professionals. Outcome measures are based on our theoretical model. The proposed evaluation study will reveal insight into the (cost)effectiveness and underlying mechanisms of the proactive integrated primary care approach FFF. A major strength of the study is the comprehensive evaluation based on a theoretical framework. The quasi-experimental design presents some challenges.


Wound microenvironment sequesters adipose-derived stem cells in a murine model of reconstructive surgery in the setting of concurrent distant malignancy.
It is unclear whether mesenchymal stem cells that are applied to regenerate wound tissues can migrate to existing tumors and enhance their growth. The authors investigated whether adipose-derived stem cells had any effect on the growth and progression of distant tumors when applied to a skin wound. The authors subcutaneously injected murine 4T1 breast cancer cells into all BALB/c-nu/nu mice. After tumor injection, mice were randomized to five groups (five mice per group) based on the means of co-introduction of green fluorescent protein-labeled adipose-derived stem cells, if any. In group 1, adipose-derived stem cells were combined and co-injected subcutaneously. In group 2, they were injected subcutaneously at a distant anatomical site. In group 3, they were injected intravenously. In group 4, they were delivered via a human acellular dermal matrix to a distant skin wound. In group 5, no adipose-derived stem cells were introduced. After 2 weeks, tumor volume increased in group 1 (356.5 ± 44.4 mm(3)), followed by group 3 (256.6 ± 47.1 mm(3)) and then group 2 (201.6 ± 28.6 mm(3)). In group 4, in which adipose-derived stem cells carried on acellular dermal matrix were applied to a wound distant to the primary tumor, the tumor volume was 143.8 ± 50.9 mm(3), which was similar to that observed in the control group (group 5; 167.8 ± 29.9 mm(3)). The authors' findings suggest that the wound microenvironment can retain adipose-derived stem cells, preventing their homing and stromal contribution to a distant neoplastic focus. These findings are an important first step in establishing the feasibility and safety of utilizing adipose-derived stem cell therapy for reconstructive surgery in the setting of malignancy.


Passing membranes to autophagy: Unconventional membrane tethering by Atg17.
Macroautophagy delivers cytoplasmic material to lysosomal/vacuolar compartments for degradation. Conserved multisubunit complexes, composed of autophagy-related (Atg) proteins, initiate the formation of membrane precursors, termed phagophores. Under physiological conditions these cup-shaped structures can capture cytoplasmic material highly selectively. Starvation or cytotoxic stresses, however, initiate the formation of much larger phagophores to enclose cytoplasm nonselectively. The biogenesis of nonselective autophagosomes is initiated by the hierarchical assembly of the Atg1 kinase complex and the recruitment of Atg9 vesicles at the phagophore assembly site (PAS). In this punctum we summarize our recent findings regarding tethering of Atg9 vesicles by the Atg1 kinase complex. We discuss membrane tethering by and activation of its central subunit Atg17 in the context of other canonical membrane tethering factors. Our results show that Atg17 suffices to bind and tether Atg9 vesicles. The Atg31-Atg29 subcomplex inhibits Atg17 activity, and activation of Atg17 depends on the formation of the Atg1 kinase complex that involves recruiting Atg1-Atg13. Our studies lead to a model of unconventional membrane tethering in autophagy.


The unusual nature of recent snowpack declines in the North American cordillera.
In western North America, snowpack has declined in recent decades, and further losses are projected through the 21st century. Here, we evaluate the uniqueness of recent declines using snowpack reconstructions from 66 tree-ring chronologies in key runoff-generating areas of the Colorado, Columbia, and Missouri River drainages. Over the past millennium, late 20th century snowpack reductions are almost unprecedented in magnitude across the northern Rocky Mountains and in their north-south synchrony across the cordillera. Both the snowpack declines and their synchrony result from unparalleled springtime warming that is due to positive reinforcement of the anthropogenic warming by decadal variability. The increasing role of warming on large-scale snowpack variability and trends foreshadows fundamental impacts on streamflow and water supplies across the western United States.


[Left atrial thrombus in an 80-year-old woman scheduled to have an operation for uterus cancer; report of a case].
An 80-year-old woman was scheduled to have an operation for uterus cancer. Echocardiography revealed a giant mobile mass in the left atrium with a stalk at posterior wall of the left atrium. There was no significant mitral disease. Due to the risks of sudden circulatory collapse and systemic emboli, an emergency operation was indicated. Right side of the left atrium was opened under cardiopulmonary bypass following median sternotomy. The mass was attached to the posterior wall, 1.5 cm medial to the right upper pulmonary vein, with a thin stalk as diagnosed preoperatively. The mass (4.2 x 3.4 x 3.4 cm) was removed very easily. Pathological analysis revealed that the mass was a thrombus mixed with fibrin. A possible cause would be paroxysmal atrial fibrillation and/or hypercoagulative status due to malignancy. Anti-coagulation therapy was initiated postoperatively to prevent recurrence of thrombus. The patient recovered and discharged uneventfully.


Accommodating missingness when assessing surrogacy via principal stratification.
When an outcome of interest in a clinical trial is late-occurring or difficult to obtain, surrogate markers can extract information about the effect of the treatment on the outcome of interest. Understanding associations between the causal effect (CE) of treatment on the outcome and the causal effect of treatment on the surrogate is critical to understanding the value of a surrogate from a clinical perspective. Traditional regression approaches to determine the proportion of the treatment effect explained by surrogate markers suffer from several shortcomings: they can be unstable and can lie outside the 0-1 range. Furthermore, they do not account for the fact that surrogate measures are obtained post randomization, and thus, the surrogate-outcome relationship may be subject to unmeasured confounding. to avoid these problems are of key importance. Methods Frangakis and Rubin suggested assessing the CE within prerandomization 'principal strata' defined by the counterfactual joint distribution of the surrogate marker under the different treatment arms, with the proportion of the overall outcome CE attributable to subjects for whom the treatment affects the proposed surrogate as the key measure of interest. Li et al. developed this 'principal surrogacy' approach for dichotomous markers and outcomes, utilizing Bayesian methods that accommodated nonidentifiability in the model parameters. Because the surrogate marker is typically observed early, outcome data are often missing. Here, we extend Li et al. to accommodate missing data in the observable final outcome under ignorable and nonignorable settings. We also allow for the possibility that missingness has a counterfactual component, a feature that previous literature has not addressed. We apply the proposed methods to a trial of glaucoma control comparing surgery versus medication, where intraocular pressure (IOP) control at 12 months is a surrogate for IOP control at 96 months. We also conduct a series of simulations to consider the impacts of nonignorability, as well as sensitivity to priors and the ability of the decision information criterion (DIC) to choose the correct model when parameters are not fully identified. Because model parameters cannot be fully identified from data, informative priors can introduce nontrivial bias in moderate sample size settings, while more noninformative priors can yield wide credible intervals. Assessing the linkage between CEs of treatment on a surrogate marker and CEs of a treatment on an outcome is important to understanding the value of a marker. These CEs are not fully identifiable; hence, we explore the sensitivity and identifiability aspects of these models and show that relatively weak assumptions can still yield meaningful results.


[Myocarditis and cardiomyopathy: underestimated complications resulting from clozapine therapy].
Treatment with clozapine can affect the heart, leading to serious complications such as myocarditis and cardiomyopathy. When in their early stages both illnesses are difficult to diagnose; this can have serious consequences. Recent analyses of clozapine data suggest that particularly myocarditis is possibly more common than has been assumed hitherto. To determine the frequency of these complications and to find out what diagnostic tests are available and whether it is necessary or possible to adjust current guidelines on these complications. The relevant literature was consulted via PubMed, Embase Psychiatry and Psycinfo on the basis of the keywords 'clozapine' and 'myocarditis', 'cardiomyopathy' and 'heart failure'. Studies showed that the incidence of myocarditis varied from 0.015 to 1.3%. Cardiomyopathy was the subject of fewer studies, one study reported an incidence of 0.022%. More than 50% of the cases of myocarditis developed during the first few weeks of treatment, the average time being about 15 days. For an early diagnosis it is important to monitor the patient's symptoms carefully, especially during the first four weeks following the start of medication. Monitoring should include laboratory tests and electrocardiography. Echocardiography and MRI can be useful additions to the diagnostic process. Early diagnosis of myocarditis is important because it is a serious condition. Timely recognition of subclinical myocarditis could possibly prevent later complications such as cardiomyopathy. Clinical guidelines are proposed on the basis of the literature.


CSL protein regulates transcription of genes required to prevent catastrophic mitosis in fission yeast.
For every eukaryotic cell to grow and divide, intricately coordinated action of numerous proteins is required to ensure proper cell-cycle progression. The fission yeast Schizosaccharomyces pombe has been instrumental in elucidating the fundamental principles of cell-cycle control. Mutations in S. pombe 'cut' (cell untimely torn) genes cause failed coordination between cell and nuclear division, resulting in catastrophic mitosis. Deletion of cbf11, a fission yeast CSL transcription factor gene, triggers a 'cut' phenotype, but the precise role of Cbf11 in promoting mitotic fidelity is not known. We report that Cbf11 directly activates the transcription of the acetyl-coenzyme A carboxylase gene cut6, and the biotin uptake/biosynthesis genes vht1 and bio2, with the former 2 implicated in mitotic fidelity. Cbf11 binds to a canonical, metazoan-like CSL response element (GTGGGAA) in the cut6 promoter. Expression of Cbf11 target genes shows apparent oscillations during the cell cycle using temperature-sensitive cdc25-22 and cdc10-M17 block-release experiments, but not with other synchronization methods. The penetrance of catastrophic mitosis in cbf11 and cut6 mutants is nutrient-dependent. We also show that drastic decrease in biotin availability arrests cell proliferation but does not cause mitotic defects. Taken together, our results raise the possibility that CSL proteins play conserved roles in regulating cell-cycle progression, and they could guide experiments into mitotic CSL functions in mammals.


Texercise Effectiveness: Impacts on Physical Functioning and Quality of Life.
This study examines the effectiveness of Texercise Select, a 12-week lifestyle program to improve physical functioning (as measured by gait speed) and quality of life. Baseline and 12-week follow-up assessments were collected from 220 enrollees who were older (mean = 75 years), predominantly female (85%), White (82%), and experiencing multiple comorbidities (mean = 2.4). Linear mixed-models were fitted for continuous outcome variables and GEE models with logit link function for binary outcome variables. At baseline, over 52% of participants had Timed Up-and-Go (TUG) test times of 12 s or more, which indicates below-normal performance. On average, participants showed significant reductions in TUG test scores at the postintervention (11% reduction, p < .001). Participants also showed significant improvements in general health status (p = .002), unhealthy physical days (p = .032), combined unhealthy physical and mental days (p = .006), and days limited from usual activity (p = .045). Findings suggest that performance indicators can be objectively collected and integrated into evaluation designs of community-based, activity-rich lifestyle programs.


Associations between prediagnostic blood glucose levels, diabetes, and glioma.
Previous literature indicates that pre-diagnostic diabetes and blood glucose levels are inversely related to glioma risk. To replicate these findings and determine whether they could be attributed to excess glucose consumption by the preclinical tumour, we used data from the Apolipoprotein MOrtality RISk (AMORIS) (n = 528,580) and the Metabolic syndrome and Cancer project (Me-Can) cohorts (n = 269,365). We identified individuals who were followed for a maximum of 15 years after their first blood glucose test until glioma diagnosis, death, emigration or the end of follow-up. Hazard ratios (HRs), 95% confidence intervals (CIs) and their interactions with time were estimated using Cox time-dependent regression. As expected, pre-diagnostic blood glucose levels were inversely related to glioma risk (AMORIS, P trend = 0.002; Me-Can, P trend = 0.04) and pre-diagnostic diabetes (AMORIS, HR = 0.30, 95% CI 0.17 to 0.53). During the year before diagnosis, blood glucose was inversely associated with glioma in the AMORIS (HR = 0.78, 95% CI 0.66 to 0.93) but not the Me-Can cohort (HR = 0.99, 95% CI 0.63 to 1.56). This AMORIS result is consistent with our hypothesis that excess glucose consumption by the preclinical tumour accounts for the inverse association between blood glucose and glioma. We discuss additional hypothetical mechanisms that may explain our paradoxical findings.


Exploring the views of second-year Foundation Programme doctors and their educational supervisors during a deanery-wide pilot Foundation Programme.
To explore the views of second-year Foundation Programme doctors (F2s) and their educational supervisors taking part in a deanery-wide pilot Foundation Programme, in order to gain an understanding of their perceptions of the available learning experiences, support and supervision. 20 semi-structured interviews were undertaken with randomly selected F2 doctors and educational supervisors participating in the deanery-wide pilot Foundation Programme. F2 trainees received appropriate and sufficient support and supervision from a variety of sources during their placements; however, it was believed that additional training of educational supervisors was required. Trainees reported some problems with the perception of the role of an F2; further understanding of the purpose and role of the F2 programme is required at trust level. The portfolio was viewed positively as a record and a learning tool, but was thought to be too bureaucratic. Trainees believed that it was more beneficial to their careers to take part in a foundation programme as opposed to a traditional senior house officer post, but both trainees and educational supervisors expressed some concerns about the generic nature of some skills F2s were expected to acquire. This evaluation has highlighted successful aspects of the Foundation Programme, particularly with regard to the level of support and range of experiences provided for trainees. Issues of concern to both trainees and educational supervisors have been identified, which require additional understanding.


Implementation of a continuous scanning procedure and a line scan camera for thin-sheet laser imaging microscopy.
We report development of a continuous scanning procedure and the use of a time delay integration (TDI) line scan camera for a light-sheet based microscope called a thin-sheet laser imaging microscope (TSLIM). TSLIM is an optimized version of a light-sheet fluorescent microscope that previously used a start/stop scanning procedure to move the specimen through the thinnest portion of a light-sheet and stitched the image columns together to produce a well-focused composite image. In this paper, hardware and software enhancements to TSLIM are described that allow for dual sided, dual illumination lasers, and continuous scanning of the specimen using either a full-frame CCD camera and a TDI line scan camera. These enhancements provided a ~70% reduction in the time required for composite image generation and a ~63% reduction in photobleaching of the specimen compared to the start/stop procedure.


Late stage trifluoromethylthiolation strategies for organic compounds.
Substitution by the CF3S group allows for an increase in lipophilicity and electron-withdrawing properties along with an improvement in the bioavailability of medicinal targets; consequently, the late stage introduction of CF3S moieties into medicinal scaffolds is a sought-after strategy in synthetic organic chemistry. Different newly-developed electrophilic and nucleophilic reagents are used to effect the trifluoromethylthiolation of (hetero)aromatic compounds, aliphatic compounds (alkyl, alkenyl, alkynyl substrates), the trifluoromethylthiolation at the α- and β-carbonyl positions, and heteroatoms (N- and S-). Such reactions can involve homolytic substitutions, or functional-group substitutions (ipso). Addition reactions of electrophilic reagents to double and triple bonds followed by ring-cyclizations will be shown to yield relevant CF3S-substituted heteroaromatic compounds with relevant pharmacological action.


Social Relationships and Salivary Telomere Length Among Middle-Aged and Older African American and White Adults.
A common mechanism underlying premature morbidity may be accelerated biological aging as reflected by salivary telomere length (STL). This study examined the extent to which social relationships, both positive and negative, can be protective or confer risk relative to biological aging. Data from the Health and Retirement Study and multiple regression were used to examine cross-sectional associations between STL, self-reported social support, and negative interaction (e.g., conflict, criticism) with family in a nationally representative sample of African American and non-Hispanic White middle-aged and older adults (N = 4,080). Social support from family was associated with shorter STL. Negative interaction with family had no main effect on STL but interactions characterized by high social support and more frequent negative interactions were associated with longer STL. Negative interaction with family was negatively associated with STL for African Americans and Whites but the magnitude of the effect was greater for African Americans. Study findings highlight the role of social relationships in physiological deterioration among middle-aged and older adults and identify a potential mechanism whereby race is linked to accelerated biological aging. Findings highlight the importance of considering positive and negative aspects of social relationships to understand the consequences of social connections for cellular aging in diverse populations.


Does aging affect the allocation of visual attention in global and local information processing?
The earliest studies of Navon (1977) showed that in certain conditions the visual perception of hierarchical stimuli generates a global precedence effect. This hypothesis is based on the joint occurrence of two effects: a response time (RT) advantage for identifying global targets and interference by global distractors when responding to a local target. The aim of the present study was to determine the involvement of attentional mechanisms and whether certain aspects are specifically altered by normal aging. In a selective-attention task, a complete global precedence effect was found for young and old subjects. However, for the old subjects, global interference on local identification was more pronounced than for the young subjects. In a divided-attention task, the RT advantage was affected by attention shifts between global and local forms for both young and old subjects, but the global interference effect did not change.


Self-rated health and mortality in the UK: results from the first comparative analysis of the England and Wales, Scotland, and Northern Ireland Longitudinal Studies.
Previous studies have shown that self-reported health indicators are predictive of subsequent mortality, but that this association varies between populations and population sub-groups. For example, self-reported health is less predictive of mortality at older ages, has a stronger association with mortality for men than for women and is more predictive of mortality for those of lower than those of higher socio-economic status, particularly among middle aged working adults. This article explores this association using individual level, rather than ecological, data to see whether there are differences between the constituent countries of the UK in the relationship between self-reported health and subsequent mortality, and to investigate socio-economic inequalities in mortality more generally. Data are used from the three Census based longitudinal studies now available for England and Wales, Scotland and Northern Ireland.List of tables, 13.


Longitudinal changes of outcome measures in spinal and bulbar muscular atrophy.
Spinal and bulbar muscular atrophy is an adult-onset, hereditary motor neuron disease caused by the expansion of a trinucleotide CAG repeat within the gene encoding the androgen receptor. To date, several agents have been shown to prevent or slow disease progression in animal models of this disease. For the translational research of these agents, it is necessary to perform the detailed analysis of natural history with quantitative outcome measures and to establish sensitive and validated disease-specific endpoints in the clinical trials. To this end, we performed a prospective observation of disease progression over 3 years in 34 genetically confirmed Japanese patients with spinal and bulbar muscular atrophy by using quantitative outcome measures, including functional and blood parameters. The baseline evaluation revealed that CAG repeat length in the androgen receptor gene correlated not only with the age of onset but also with the timing of substantial changes in activity of daily living. Multiple regression analyses indicated that the serum level of creatinine is the most useful blood parameter that reflects the severity of motor dysfunction in spinal and bulbar muscular atrophy. In 3-year prospective analyses, a slow but steady progression was affirmed in most of the outcome measures we examined. In the analyses using random coefficient models that summarize the individual data into a representative line, disease progression was not affected by CAG repeat length or onset age. These models showed large interindividual variation, which was also independent of the differences of CAG repeat size. Analyses using these models also demonstrated that the subtle neurological deficits at an early or preclinical stage were more likely to be detected by objective motor functional tests such as the 6-min walk test and grip power or serum creatinine levels than by functional rating scales, such as the revised amyotrophic lateral sclerosis functional rating scale or modified Norris scale. Categorization of the clinical phenotypes using factor analysis showed that upper limb function is closely related to bulbar function, but not to lower limb function at baseline, whereas the site of onset had no substantial effects on disease progression. These results suggest that patients with spinal and bulbar muscular atrophy show a slow but steady progression of motor dysfunction over time that is independent of CAG repeat length or clinical phenotype, and that objective outcome measures may be used to evaluate disease severity at an early stage of this disease.


Inhibition of expression of delayed hypersensitivity by neutralizing monoclonal anti-T-cell fibronectin antibody.
T-cell fibronectin (FN) is a unique cellular FN that is rapidly synthesized by memory T cells in response to antigen. Monoclonal anti-T-cell FN antibodies have been used to clarify the role of T-cell FN in the in vivo expression of delayed hypersensitivity. IgGl(kappa) mouse anti-human T-cell FN monoclonal antibodies 231 and 248 recognized epitopes on the FN cell-binding domain, were cross-reactive with plasma FN, and neutralized human and guinea-pig T-cell FN monocyte agglutinating activity. When injected intradermally together with tuberculin or 30 min before topical application of reactive sensitizer, antibody 231 significantly decreased macroscopic expression of guinea-pig delayed hypersensitivity at 24 hr in a dose-dependent manner. Similar doses of antibody 248 caused a slight statistically non-significant enhancement of delayed-type hypersensitivity (DTH) expression. Inhibition of visible skin responses was not associated with qualitative or quantitative changes in cellular infiltrates at the reaction site. Antibody 231 modulated expression of delayed hypersensitivity in a qualitatively and quantitatively similar manner to the FN-binding mycobacterial antigen 85 proteins. This is consistent with anti-T-cell FN and antigen 85 acting on the same molecule in vivo.


Epidemio-allergological study in 155 cases of footwear dermatitis.
Footwear dermatitis represents a distinct and common group among all types of contact dermatitis cases seen in India. This ailment, however, often remains undiagnosed, misdiagnosed or empirically diagnosed without pinpointing the contributory allergens. This study was undertaken to detect the epidemio-allergological pattern of footwear dermatitis in India. A total number of 155 cases with footwear dermatitis were evaluated from July 2005 to June 2006, by detailed history and clinical examination. They were patch tested using Indian Standard Battery (ISB) approved by the Contact and Occupational Dermatoses Forum of India (CODFI) with pre- and post patch-test counseling. The proportion of footwear dermatitis was 24.22% (n=155) among a total of 640 patients patch tested during that period. Females [61.93% (n=96)] were commonly affected than males [38.06% (n=59)]. The ages ranged from 8 to 75 years. The age group that predominantly involved was the fifth decade [24.52% (n=38)]. Occupationwise housewives were most commonly involved [47.48 (n=66)]. Contributory allergens in order of frequency were: potassium dichromate, 45.8% (n=71); cobalt chloride, 38.06% (n=59); paraphenylenediamine, 32.25% (n=50); epoxy resin, 20% (n=31); black rubber mix, 20% (n=31); nickel sulfate, 14.83% (n=23); mercaptobenzothiazole, 12.9% (n=20); colophony, 11.6% (n=18); thiuram mix, 10.32 % (n=16); p-tert-butyl-formaldehyde resin, 9.67% (n=15); and formaldehyde, 4.5% (n=7). Among the different categories of footwear allergens, the highest positivity was shown by leather and leather-related chemicals in 61.9% cases (n=96). Footwear dermatitis, a common dermatosis, is mostly caused by leather processing chemicals, metal buckles, black dyes of shoes and socks, adhesives, plastic, rubber shoes and polishing agents in order of frequency.


Reconstruction of Par-dependent polarity in apolar cells reveals a dynamic process of cortical polarization.
Cellular polarization is fundamental for various biological processes. The Par network system is conserved for cellular polarization. Its core complex consists of Par3, Par6, and aPKC. However, the general dynamic processes that occur during polarization are not well understood. Here, we reconstructed Par-dependent polarity using non-polarized Drosophila S2 cells expressing all three components endogenously in the cytoplasm. The results indicated that elevated Par3 expression induces cortical localization of the Par-complex at the interphase. Its asymmetric distribution goes through three steps: emergence of cortical dots, development of island-like structures with dynamic amorphous shapes, repeating fusion and fission, and polarized clustering of the islands. Our findings also showed that these islands contain a meshwork of unit-like segments. Furthermore, Par-complex patches resembling Par-islands exist in Drosophila mitotic neuroblasts. Thus, this reconstruction system provides an experimental paradigm to study features of the assembly process and structure of Par-dependent cell-autonomous polarity.


Deep brain stimulation results in local glutamate and adenosine release: investigation into the role of astrocytes.
Several neurological disorders are treated with deep brain stimulation; however, the mechanism underlying its ability to abolish oscillatory phenomena associated with diseases as diverse as Parkinson's disease and epilepsy remain largely unknown. To investigate the role of specific neurotransmitters in deep brain stimulation and determine the role of non-neuronal cells in its mechanism of action. We used the ferret thalamic slice preparation in vitro, which exhibits spontaneous spindle oscillations, to determine the effect of high-frequency stimulation on neurotransmitter release. We then performed experiments using an in vitro astrocyte culture to investigate the role of glial transmitter release in high-frequency stimulation-mediated abolishment of spindle oscillations. In this series of experiments, we demonstrated that glutamate and adenosine release in ferret slices was able to abolish spontaneous spindle oscillations. The glutamate release was still evoked in the presence of the Na channel blocker tetrodotoxin, but was eliminated with the vesicular H-ATPase inhibitor bafilomycin and the calcium chelator 2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis acetoxymethyl ester. Furthermore, electrical stimulation of purified primary astrocytic cultures was able to evoke intracellular calcium transients and glutamate release, and bath application of 2-bis (2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis acetoxymethyl ester inhibited glutamate release in this setting. Vesicular astrocytic neurotransmitter release may be an important mechanism by which deep brain stimulation is able to achieve clinical benefits.


Rapid Increases in forest understory diversity and productivity following a mountain pine beetle (Dendroctonus ponderosae) outbreak in pine forests.
The current unprecedented outbreak of mountain pine beetle (Dendroctonus ponderosae) in lodgepole pine (Pinus contorta) forests of western Canada has resulted in a landscape consisting of a mosaic of forest stands at different stages of mortality. Within forest stands, understory communities are the reservoir of the majority of plant species diversity and influence the composition of future forests in response to disturbance. Although changes to stand composition following beetle outbreaks are well documented, information on immediate responses of forest understory plant communities is limited. The objective of this study was to examine the effects of D. ponderosae-induced tree mortality on initial changes in diversity and productivity of understory plant communities. We established a total of 110 1-m2 plots across eleven mature lodgepole pine forests to measure changes in understory diversity and productivity as a function of tree mortality and below ground resource availability across multiple years. Overall, understory community diversity and productivity increased across the gradient of increased tree mortality. Richness of herbaceous perennials increased with tree mortality as well as soil moisture and nutrient levels. In contrast, the diversity of woody perennials did not change across the gradient of tree mortality. Understory vegetation, namely herbaceous perennials, showed an immediate response to improved growing conditions caused by increases in tree mortality. How this increased pulse in understory richness and productivity affects future forest trajectories in a novel system is unknown.


Olanzapine withdrawal/discontinuation-induced hyperthermia in rats.
In female rats olanzapine (4 mg/kg b.i.d., i.p.) induced acute hypothermia, followed by very rapid full tolerance. With more prolonged treatment (over > 10 days) the hypothermic effect of olanzapine was reinstated. Subsequent withdrawal after 18 days of treatment induced very rapid onset (within 1 day) hyperthermia, which was time limited, dissipating completely over 3-4 days. These findings are similar to previous findings with clozapine [Goudie A Smith J Robertson A Cavanagh C (1999). Clozapine as a drug of dependence. Psychopharmacology; 142: 369-374.]. Although the mechanism(s) involved in the secondary hypothermic effect of olanzapine are, at present, unclear; the withdrawal hyperthermia observed represents the first report of a clear discontinuation effect of olanzapine. Such discontinuation effects are probably observed with many antipsychotic drugs. Since they have been suggested to facilitate relapse to psychosis and to interfere with subsequent clinical responses to antipsychotics, they merit further detailed analysis in both clinical and preclinical studies.


Folate receptor-β imaging using 99mTc-folate to explore distribution of polarized macrophage populations in human atherosclerotic plaque.
In atherosclerotic plaques, the risk of rupture is increased at sites of macrophage accumulation. Activated macrophages express folate receptor-β (FR-β), which can be targeted by folate coupled to radioactive ligands to visualize vulnerability. The aim of this study was to explore the presence of activated macrophages in human atherosclerotic plaques by (99m)Tc-folate imaging and to evaluate whether this technique can discriminate between an M1-like and M2-like macrophage phenotype. Carotid endarterectomy specimens of 20 patients were incubated with (99m)Tc-folate, imaged using micro-SPECT, and divided into 3-mm slices. The mean accumulation was calculated per slice, and the distribution of M1-like and M2-like macrophages per slice was quantified by immunohistochemical staining for CD86 as well as inducible nitric oxide synthase (iNOS) for M1 and CD163 and FR-β for M2 macrophages. Monocytes from healthy donors were differentiated toward M1-like or M2-like phenotype by in vitro culturing. Messenger RNA levels of specific M1 and M2 markers were measured by reverse-transcription polymerase chain reaction and expression of FR-β, CD86, and CD163 by flow cytometry. There was a heterogeneous accumulation of (99m)Tc-folate in plaques (median, 2.45 [0.77-6.40] MBq/g). Slices with the highest (99m)Tc-folate accumulation of each plaque showed significantly more expression of FR-β and CD163, compared with slices with the lowest (99m)Tc-folate accumulation, which showed significantly more expression of iNOS. In in vitro polarized macrophages, messenger RNA expression of FR-β, mannose receptor, IL-10, and matrix metalloproteinase-9 was significantly increased in M2-like macrophages, compared with M1-like macrophages. On a receptor level, CD86 was shown to be overexpressed on M1-like macrophages whereas FR-β and CD163 were overexpressed on M2-like macrophages measured by flow cytometry. Higher numbers of M2-like macrophages were present in areas of high (99m)Tc-folate accumulation than areas with low accumulation. It is anticipated that (99m)Tc-folate imaging using SPECT as a marker for M2-like macrophages in atherosclerosis might be a good indicator for plaque vulnerability.


Analysis of a microchannel interconnect based on the clustering of smart-pixel-device windows.
A design analysis of a telecentric microchannel relay system developed for use with a smart-pixel-based photonic backplane is presented. The interconnect uses a clustered-window geometry in which optoelectronic device windows are grouped together about the axis of each microchannel. A Gaussian-beam propagation model is used to analyze the trade-off between window size, window density, transistor count per smart pixel, and lenslet ƒ-number for three cases of window clustering. The results of this analysis show that, with this approach, a window density of 4000 windows/cm(2) is obtained for a window size of 30 µm and a device plane separation of 25 mm. In addition, an optical power model is developed to determine the nominal power requirements of a 32 × 32 smart-pixel array as a function of window size. The power requirements are obtained assuming a complementary metal-oxide semiconductor inverter-amplifier and dual-rail multiple-quantum-well self-electro-optic-effect devices as the receiver stage of the smart pixel.


European reservoir hosts of Borrelia burgdorferi sensu lato.
Existing knowledge on reservoir hosts of Borrelia burgdorferi sensu lato was collated and reviewed and several species, particularly birds, were identified as reservoir competent. At the present time, 9 small mammals, 7 medium-sized mammals and 16 bird species, including passerines, sea birds and pheasants, appear to be capable of transmitting spirochaetes to ticks and thus of participating in the natural circulation of B. burgdorferi s.l. in Europe. The house mouse, Mus musculus is strongly suspected of reservoir competence and many other small rodent species, particularly in eastern Europe and Russia, have been implicated. Ungulates are not thought to play a major role as reservoir hosts, though co-feeding transmission may permit some tick infection. The criteria for establishment of reservoir status are outlined and a method for identification of host blood meals of previous instars of unfed ticks, developed in a participant laboratory, is briefly described.