Rapid Divergence of Predator Functional Traits Affects Prey Composition in Aquatic Communities.
Identifying traits that underlie variation in individual performance of consumers (i.e., trait utility) can help reveal the ecological causes of population divergence and the subsequent consequences for species interactions and community structure. Here, we document a case of rapid divergence (over the past 100 generations, or ∼150 years) in foraging traits and feeding efficiency between a lake and stream population pair of threespine stickleback. Building on predictions from functional trait models of fish feeding, we analyzed foraging experiments with a Bayesian path analysis and elucidated the traits explaining variation in foraging performance and the species composition of ingested prey. Despite extensive previous research on the divergence of foraging traits among populations and ecotypes of stickleback, our results provide novel experimental evidence of trait utility for jaw protrusion, gill raker length, and gill raker spacing when foraging on a natural zooplankton assemblage. Furthermore, we discuss how these traits might contribute to the differential effects of lake and stream stickleback on their prey communities, observed in both laboratory and mesocosm conditions. More generally, our results illustrate how the rapid divergence of functional foraging traits of consumers can impact the biomass, species composition, and trophic structure of prey communities.


Effects of exercise and enrichment on behaviour in CD-1 mice.
A host of scholarly work has characterized the positive effects of exercise and environmental enrichment on behaviour and cognition in animal studies. The purpose of this study was to investigate the uptake and longitudinal impact of exercise and enrichment on the behavioural phenotype of male and female CD-1 mice. CD-1 mice housed in standard (STD) or exercise and enrichment (EE) conditions post-weaning were tested in the 3-chamber sociability test, open field, and elevated plus maze and exercise activity was monitored throughout the enrichment protocol. Male and female EE mice both showed reduced anxiety and activity in the open field and elevated plus maze relative to sex-matched STD mice. EE altered social behaviours in a sex-specific fashion, with only female EE mice showing increased social preference relative to female STD mice and a preference for social novelty only present in male EE mice. This sexual dimorphism was not observed to be a product of exercise uptake, as CD-1 mice of both sexes demonstrated a consistent trend of wheel rotation frequencies. These findings suggest the importance of considering variables such as sex and strain on experimental design variables in future work on environmental enrichment.


Synthesis and characterization of a lipidic alpha amino acid: solubility and interaction with serum albumin and lipid bilayers.
The lipidic α-amino acid with 11 carbons in the alkyl lateral chain (α-aminotridecanoic acid) was synthesized via multicomponent hydroformylation/Strecker reaction, which is a greener synthetic approach to promote this transformation relative to previously described methods. Its solubility and aggregation behavior in aqueous solutions was characterized, as well as the interaction with lipid bilayers. Lipidic amino acids are very promising molecules in the development of prodrugs with increased bioavailability due to the presence of the two polar functional groups and nonpolar alkyl chain. They are also biocompatible surfactants that may be used in the food and pharmaceutical industry. In this work we have conjugated the lipidic amino acid with a fluorescent polar group (7-nitrobenz-2-oxa-1,3-diazol-4-yl), to mimic drug conjugates, and its association with serum proteins and lipid bilayers was characterized. The results obtained indicate that conjugates of polar molecules with lipidic α-amino acid, via covalent attachment to the amine group, have a relatively high solubility in aqueous solutions due to their negative global charge. They bind to serum albumin with intermediate affinity and show a very high partition coefficient into lipid bilayers in the liquid-disordered state. The attachment of the polar group to the lipidic amino acid increased strongly the aqueous solubility of the amphiphile, although the partition coefficient into lipid membranes was not significantly reduced. Conjugation of polar drugs with lipidic amino acids is therefore an efficient approach to increase their affinity for biomembranes.


Closure of large oroantral communication using coronoid process pedicled on temporalis muscle flap: a new alternative approach.
Proximity of maxillary molar teeth roots to the maxillary sinus floor can potentiate oroantral communication (OAC) after extraction. Considering the defect size and situation, surgical treatment may become essential. Surgical treatment modalities are variable and would be indicated in special clinical circumstances.In this article, a chronic case of OAC with a size of 25 × 15 mm(2) in a 30-year old man with history of heavy smoking and drug abuse was treated with combination of buccal fat pad (for covering sinus floor), coronoid process pedicled on temporalis flap, and mucosal closure. There was no complication during and after operation. Short- and long-term follow-up revealed success of this novel technique despite the patient's poor compliance.


Evaluation of a feline-specific multiplex, bead-based assay for detection of cytokines, chemokines, growth factors, and other immunologically active proteins in serum and plasma samples from cats.
OBJECTIVE To evaluate a feline-specific multiplex, bead-based assay system for detection of recombinant and native proteins in serum samples and in EDTA-treated and heparinized plasma samples. SAMPLE Serum samples and EDTA-treated and heparinized plasma samples from 30 sick cats and 9 healthy client-owned cats and heparinized whole blood samples from 5 healthy purpose-bred cats. PROCEDURES Ability of the assay system to detect 19 recombinant and native immunologically active proteins in plasma and serum samples from healthy and purpose-bred cats was evaluated via spike-and-recovery tests, assessments of inter- and intra-assay variation, linearity results, and leukocyte stimulation. Effects of various concentrations of heparin and serum matrix solution on percentages of analytes recovered were also evaluated. Analyte concentrations in samples from healthy and sick cats were measured and compared between groups. RESULTS Percentages of analytes recovered were unsatisfactory for most assays. Serum and heparinized plasma samples yielded better recovery results than did EDTA-treated plasma samples. Use of serum matrix solution did not improve results. Use of heparin concentrations greater than the recommended range affected the results. Linearity of results was difficult to assess because of the poor recovery. For the analytes that were recovered sufficiently for assessment, linearity appeared to be reasonable despite the limited detection. CONCLUSIONS AND CLINICAL RELEVANCE Poor percentages of analytes recovered and adverse effects of sample protein matrix limited the usefulness of the multiplex, bead-based assay system for measurement of immunologically active proteins in solutions with high protein content; however, recovery results were fairly linear, potentially allowing evaluation of feline plasma or serum samples with high analyte concentrations.


Modification of radiation induced damage in mouse intestine by WR-2721.
Intestinal protection in mice against radiation injury by WR-2721 (300 mg/kg body wt, i.p., 30 min before irradiation) was studied after whole body gamma irradiation (0.5, 1.5, 3.0, 4.5, or 6.0 Gy). Crypt survival and induction of apoptosis, and abnormal mitoses in crypt cells in the jejunum were studied on day 1, 3 and 7 after irradiation. Irradiation produced a significant decrease in crypt survival, whereas apoptosis and abnormal mitoses showed a significant increase from sham-treated control animals. Maximum changes in all the parameters were observed on day 1 after irradiation and the effect increased linearly with radiation dose. There was recovery at later intervals, which was inversely related to radiation dose. WR-2721 pre-treatment resulted in a significant increase in the number of surviving crypts, whereas the number of apoptotic cells in the crypts showed a significant decrease from respective irradiated controls on day 1 after exposure. The recovery was also faster in WR-2721 pre- treated animals. It is concluded that WR-2721 protects against gastrointestinal death by reducing radiation induced cell death, thereby maintaining a higher number of stem cells in the proliferating compartment.


Infiltration of tumor-associated macrophages is involved in tumor programmed death-ligand 1 expression in early lung adenocarcinoma.
Programmed death-ligand 1 (PD-L1) is an immune modulator that promotes immunosuppression by binding to programmed death-1 of T-lymphocytes. Although tumor cell PD-L1 expression has been shown to be associated with the clinical response to anti-PD-L1 antibodies, its concise regulatory mechanisms remain elusive. In this study, we evaluated the associations of tumor PD-L1 expression and immune cell infiltrating patterns in 146 cases of early lung adenocarcinoma (AC) to investigate the possible extrinsic regulation of tumor PD-L1 by immune cells. Using immunohistochemistry, cell surface PD-L1 expression in tumor cells was observed in 18.5% of stage 0-IA lung AC patients. Tumor PD-L1 positivity was significantly associated with stromal invasion, which was accompanied by increased tumor-associated macrophages (TAM), CD8+ cytotoxic T cells and FoxP3+ regulatory T cells. Among these immune cells, TAM and CD8+ T cells significantly accumulated in PD-L1-positive carcinoma cell areas, which showed a tumor cell nest-infiltrating pattern. Although CD8+ T cells are known to induce tumor PD-L1 expression via interferon-ɣ production, the increased TAM within tumors were also associated with tumor cell PD-L1 positivity, independently of CD8+ T cell infiltration. Our in vitro experiments revealed that PD-L1 expression in lung cancer cell lines was significantly upregulated by co-culture with M2-differentiated macrophages; expression of PD-L1 was reduced to baseline levels following treatment with a transforming growth factor-β inhibitor. These results demonstrated that tumor-infiltrating TAM are extrinsic regulators of tumor PD-L1 expression, indicating that combination therapy targeting both tumor PD-L1 and stromal TAM might be a possible strategy for effective treatment of lung cancer.


Shattered Shangri-la: differences in depressive and anxiety symptoms in students born in Tibet compared to Tibetan students born in exile.
As a result of ongoing political tensions within Tibetan regions of the People's Republic of China, several thousand Tibetans escape across the Himalayas every year to seek refuge in India and Nepal. Prior studies have found a high prevalence of depressive and anxiety symptoms in these refugees, many of whom are young and have been exposed to significant trauma. However, it is not known whether depressive and anxiety symptoms are more prevalent in these refugees than in ethnic Tibetans born and raised in the relative political and social stability of exile communities in North India and Nepal. We conducted a cross-sectional survey of a convenience sample of 319 students attending school at the Tibetan Children's Villages in Northern India to test the a priori hypothesis that adolescents and young adults who escaped from Tibet to India would demonstrate increased depressive and anxiety symptoms when compared to ethnic Tibetans born and raised in exile. The Hopkins Symptom Checklist-25 (HSCL-25) was used to measure depressive and anxiety symptoms. In addition, demographic information on age, sex, country of birth and frequency of family contact was collected. Students born in Tibet had higher mean HSCL-25 depressive and anxiety symptom scores than did ethnic Tibetans born in exile. Female students demonstrated higher depressive and anxiety scores, as did those with limited contact with immediate family. After adjusting for sex, age and frequency of family contact, being born in Tibet was associated with increased HSCL-25 depressive and anxiety symptom scores (depression: F[2, 316] = 29.96, P < 0.0001; anxiety: F[4, 316] = 43.57, P < 0.0001). The experience of being raised in Tibet and escaping to India appears to be a risk factor for increased depressive and anxiety symptoms when compared to being born and raised within an exile community in India or Nepal.


Ultrastructure of the mature spermatozoa of caecilians (Amphibia: Gymnophiona).
The spermatozoa of Gymnophiona show the following autapomorphies: 1) penetration of the distal centriole by the axial fiber; 2) presence of an acrosomal baseplate; 3) presence of an acrosome seat (flattened apical end of nucleus); and 4) absence of juxta-axonemal fibers. The wide separation of the plasma membrane bounding the undulating membrane is here also considered to be apomorphic. Three plesiomorphic spermatozoal characters are recognized that are not seen in other Amphibia but occur in basal amniotes: 1) presence of mitochondria with a delicate array of concentric cristae (concentric cristae of salamander spermatozoa differ in lacking the delicate array); 2) presence of peripheral dense fibers associated with the triplets of the distal centriole; and 3) presence of a simple annulus (a highly modified, elongate annulus is present in salamander sperm). The presence of an endonuclear canal containing a perforatorium is a plesiomorphic feature of caecilian spermatozoa that is shared with urodeles, some basal anurans, sarcopterygian fish, and some amniotes. Spermatozoal synapomorphies are identified for 1) the Uraeotyphlidae and Ichthyophiidae, and 2) the Caeciliidae and Typhlonectidae, suggesting that the members of each pair of families are more closely related to each other than to other caecilians. Although caecilian spermatozoa exhibit the clear amphibian synapomorphy of the unilateral location of the undulating membrane and its axial fiber, they have no apomorphic characters that suggest a closer relationship to either the Urodela or Anura.


Micropollutants in European rivers: A mode of action survey to support the development of effect-based tools for water monitoring.
Environmental quality monitoring of water resources is challenged with providing the basis for safeguarding the environment against adverse biological effects from exposure to anthropogenic chemicals originating from diffuse and point sources. Although current regulatory efforts focus on monitoring and assessing a few legacy chemicals, many more anthropogenic chemicals are and will become detected in aquatic resources as a result of progress in analytical techniques. Assessing this type of exposure information based on available standard approaches from prospective risk assessment for single chemicals inevitably leads to indication of risk in most surface water bodies. As an alternative to generic assessment approaches, effect-based monitoring approaches are suggested. This offers the advantage of reducing uncertainties of effect extrapolation and additionally accounts for mixture effects. To become a credible complement to chemical monitoring information, however, a better understanding of the capabilities and gaps of available effect-based tools is needed. The authors therefore undertook to 1) compile organic contaminants detected in freshwater monitoring studies, 2) provide a synopsis of the mode of action knowledge available for the detected compounds, 3) perform a hazard ranking to identify priority mixtures, and 4) reflect on the challenges to make bioassays fit for effect-based monitoring. The present Focus article shows that chemical occurrence in European freshwaters seems to be highly variable in composition and relative abundancies. Further, although the present mode of action knowledge remains limited, the authors already see the need for batteries of effect-based tools if a more comprehensive coverage of prevailing effect qualities for mixtures is to be targeted. Finally, they suggest a list of organic compounds that could serve as a reference list for effect-based tool validation studies. Environ Toxicol Chem 2016;35:1887-1899. © 2016 SETAC.


Trade-offs in the effects of the apolipoprotein E polymorphism on risks of diseases of the heart, cancer, and neurodegenerative disorders: insights on mechanisms from the Long Life Family Study.
The lack of evolutionary established mechanisms linking genes to age-related traits makes the problem of genetic susceptibility to health span inherently complex. One complicating factor is genetic trade-off. Here we focused on long-living participants of the Long Life Family Study (LLFS), their offspring, and spouses to: (1) Elucidate whether trade-offs in the effect of the apolipoprotein E e4 allele documented in the Framingham Heart Study (FHS) are a more general phenomenon, and (2) explore potential mechanisms generating age- and gender-specific trade-offs in the effect of the e4 allele on cancer, diseases of the heart, and neurodegenerative disorders assessed retrospectively in the LLFS populations. The e4 allele can diminish risks of cancer and diseases of the heart and confer risks of diseases of the heart in a sex-, age-, and LLFS-population-specific manner. A protective effect against cancer is seen in older long-living men and, potentially, their sons (>75 years, relative risk [RR]>75=0.48, p=0.086), which resembles our findings in the FHS. The protective effect against diseases of the heart is limited to long-living older men (RR>76=0.50, p=0.016), as well. A detrimental effect against diseases of the heart is characteristic for a normal LLFS population of male spouses and is specific for myocardial infarction (RR=3.07, p=2.1×10(-3)). These trade-offs are likely associated with two inherently different mechanisms, including disease-specific (detrimental; characteristic for a normal male population) and systemic, aging-related (protective; characteristic for older long-living men) mechanisms. The e4 allele confers risks of neurological disorders in men and women (RR=1.98, p=0.046). The results highlight the complex role of the e4 allele in genetic susceptibility to health span.


Trichome structure and evolution in Neotropical lianas.
Trichomes are epidermal outgrowths generally associated with protection against herbivores and/or desiccation that are widely distributed from ferns to angiosperms. Patterns of topological variation and morphological evolution of trichomes are still scarce in the literature, preventing valid comparisons across taxa. This study integrates detailed morphoanatomical data and the evolutionary history of the tribe Bignonieae (Bignoniaceae) in order to gain a better understanding of current diversity and evolution of trichome types. Two sampling schemes were used to characterize trichome types: (1) macromorphological characterization of all 105 species currently included in Bignonieae; and (2) micromorphological characterization of 16 selected species. Individual trichome morphotypes were coded as binary in each vegetative plant part, and trichome density and size were coded as multistate. Ancestral character state reconstructions were conducted using maximum likelihood (ML) assumptions. Two main functional trichome categories were found: non-glandular and glandular. In glandular trichomes, three morphotypes were recognized: peltate (Pg), stipitate (Sg) and patelliform/cupular (P/Cg) trichomes. Non-glandular trichomes were uniseriate, uni- or multicellular and simple or branched. Pg and P/Cg trichomes were multicellular and non-vascularized with three clearly distinct cell layers. Sg trichomes were multicellular, uniseriate and long-stalked. ML ancestral character state reconstructions suggested that the most recent common ancestor (MRCA) of Bignonieae probably had non-glandular, Pg and P/Cg trichomes, with each trichome type presenting alternative histories of appearance on the different plant parts. For example, the MRCA of Bignonieae probably had non-glandular trichomes on the stems, prophylls, petiole, petiolule and leaflet veins while P/Cg trichomes were restricted to leaflet blades. Sg trichomes were not present in the MRCA of Bignonieae independently of the position of these trichomes. These trichomes had at least eight independent origins in tribe. The patterns of trichome evolution indicate that most morphotypes are probably homologous in Bignonieae and could be treated under the same name based on its morphological similarity and common evolutionary history, in spite of the plethora of names that have been previously designated in the literature. The trichome descriptions presented here will facilitate comparisons across taxa, allowing inferences on the relationsthips between trichome variants and future studies about their functional properties.


Provision of social norm feedback to high prescribers of antibiotics in general practice: a pragmatic national randomised controlled trial.
Unnecessary antibiotic prescribing contributes to antimicrobial resistance. In this trial, we aimed to reduce unnecessary prescriptions of antibiotics by general practitioners (GPs) in England. In this randomised, 2 × 2 factorial trial, publicly available databases were used to identify GP practices whose prescribing rate for antibiotics was in the top 20% for their National Health Service (NHS) Local Area Team. Eligible practices were randomly assigned (1:1) into two groups by computer-generated allocation sequence, stratified by NHS Local Area Team. Participants, but not investigators, were blinded to group assignment. On Sept 29, 2014, every GP in the feedback intervention group was sent a letter from England's Chief Medical Officer and a leaflet on antibiotics for use with patients. The letter stated that the practice was prescribing antibiotics at a higher rate than 80% of practices in its NHS Local Area Team. GPs in the control group received no communication. The sample was re-randomised into two groups, and in December, 2014, GP practices were either sent patient-focused information that promoted reduced use of antibiotics or received no communication. The primary outcome measure was the rate of antibiotic items dispensed per 1000 weighted population, controlling for past prescribing. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN32349954, and has been completed. Between Sept 8 and Sept 26, 2014, we recruited and assigned 1581 GP practices to feedback intervention (n=791) or control (n=790) groups. Letters were sent to 3227 GPs in the intervention group. Between October, 2014, and March, 2015, the rate of antibiotic items dispensed per 1000 population was 126.98 (95% CI 125.68-128.27) in the feedback intervention group and 131.25 (130.33-132.16) in the control group, a difference of 4.27 (3.3%; incidence rate ratio [IRR] 0.967 [95% CI 0.957-0.977]; p<0.0001), representing an estimated 73,406 fewer antibiotic items dispensed. In December, 2014, GP practices were re-assigned to patient-focused intervention (n=777) or control (n=804) groups. The patient-focused intervention did not significantly affect the primary outcome measure between December, 2014, and March, 2015 (antibiotic items dispensed per 1000 population: 135.00 [95% CI 133.77-136.22] in the patient-focused intervention group and 133.98 [133.06-134.90] in the control group; IRR for difference between groups 1.01, 95% CI 1.00-1.02; p=0.105). Social norm feedback from a high-profile messenger can substantially reduce antibiotic prescribing at low cost and at national scale; this outcome makes it a worthwhile addition to antimicrobial stewardship programmes. Public Health England.


[Infestation with the tapeworm Diphyllobothrium latum after eating raw fish].
A 31-year-old man with no relevant medical history encountered a white, ribbon-shaped object, 15 cm long and approximately 1 cm wide, in his faeces. It turned out to be Diphyllobothrium latum, a tapeworm that has fish as the intermediate host. The patient had eaten raw fish and shellfish during a holiday in Brazil 5 months before. He recovered after a single dose of praziquantel.


B-DNA to zip-DNA: simulating a DNA transition to a novel structure with enhanced charge-transport characteristics.
The forced extension of a DNA segment is studied in a series of steered molecular dynamics simulations, employing a broad range of pulling forces. Throughout the entire force range, the formation of a zipper-like (zip-) DNA structure is observed. In that structure, first predicted by Lohikoski et al., the bases of the DNA strands interdigitate with each other and form a single-base aromatic stack. Similar motifs, albeit only a few base pairs in extent, have been observed in experimental crystal structures. Analysis of the dynamics of structural changes in pulled DNA shows that S-form DNA, thought to be adopted by DNA under applied force, serves as an intermediate between B-DNA and zip-DNA. Therefore, the phase transition plateau observed in force-extension curves of DNA is suggested to reflect the B-DNA to zip-DNA structural transition. Electronic structure analysis of purine bases in zip-DNA indicates a several-fold to order of magnitude increase in the π-π electronic coupling among nearest-neighbor nucleobases, compared to B-DNA. We further observe that zip-DNA does not require base pair complementarity between DNA strands, and we predict that the increased electronic coupling in zip-DNA will result in a much higher rate of charge transfer through an all-purine zip-DNA compared to B-DNA of equal length.


Sleep Disturbances and Suicide Risk in an 8-Year Longitudinal Study of Schizophrenia-Spectrum Disorders.
Disrupted sleep is one of the prominent but often overlooked presenting symptoms in the clinical course of psychotic disorders. The aims of this study were to examine the prevalence of sleep disturbances, particularly insomnia and nightmares, and their prospective associations with the risk of suicide attempts in patients with schizophrenia-spectrum disorders. A naturalistic longitudinal study was conducted in outpatients diagnosed with schizophrenia-spectrum disorders recruited from the psychiatric outpatient clinic of a regional university-affiliated public hospital in Hong Kong. A detailed sleep questionnaire was completed by 388 patients at baseline in May-June 2006. Relevant clinical information was extracted from clinical case notes from June 2007-October 2014. Prevalence of frequent insomnia and frequent nightmares was 19% and 9%, respectively. Baseline frequent insomnia was significantly associated with an increased incidence of suicide attempts during the follow-up period (adjusted hazard ratio = 4.63, 95% confidence interval 1.40-15.36, P < 0.05). Nightmare complaint alone did not predict the occurrence of suicide attempts, but the comorbidity of nightmares and insomnia was associated with the risk of suicide attempt over follow-up (adjusted HR = 11.10, 95% confidence interval: 1.68-73.43, P < 0.05). Sleep disturbances are common in patients with schizophrenia-spectrum disorders. The association between sleep disturbances and suicidal risk underscores the need for enhanced clinical attention and intervention on sleep disturbances in patients with schizophrenia.


Using simplified peer review processes to fund research: a prospective study.
To prospectively test two simplified peer review processes, estimate the agreement between the simplified and official processes, and compare the costs of peer review. A prospective parallel study of Project Grant proposals submitted in 2013 to the National Health and Medical Research Council (NHMRC) of Australia. The official funding outcomes were compared with two simplified processes using proposals in Public Health and Basic Science. The two simplified processes were: panels of 7 reviewers who met face-to-face and reviewed only the nine-page research proposal and track record (simplified panel); and 2 reviewers who independently reviewed only the nine-page research proposal (journal panel). The official process used panels of 12 reviewers who met face-to-face and reviewed longer proposals of around 100 pages. We compared the funding outcomes of 72 proposals that were peer reviewed by the simplified and official processes. Agreement in funding outcomes; costs of peer review based on reviewers' time and travel costs. The agreement between the simplified and official panels (72%, 95% CI 61% to 82%), and the journal and official panels (74%, 62% to 83%), was just below the acceptable threshold of 75%. Using the simplified processes would save $A2.1-$A4.9 million per year in peer review costs. Using shorter applications and simpler peer review processes gave reasonable agreement with the more complex official process. Simplified processes save time and money that could be reallocated to actual research. Funding agencies should consider streamlining their application processes.


Anxiety Disorders are Associated with Reduced Heart Rate Variability: A Meta-Analysis.
Anxiety disorders increase risk of future cardiovascular disease (CVD) and mortality, even after controlling for confounds including smoking, lifestyle, and socioeconomic status, and irrespective of a history of medical disorders. While impaired vagal function, indicated by reductions in heart rate variability (HRV), may be one mechanism linking anxiety disorders to CVD, prior studies have reported inconsistent findings highlighting the need for meta-analysis. Studies comparing resting-state HRV recordings in patients with an anxiety disorder as a primary diagnosis and healthy controls were considered for meta-analysis. Meta-analyses were based on 36 articles, including 2086 patients with an anxiety disorder and 2294 controls. Overall, anxiety disorders were characterized by lower HRV [high frequency (HF): Hedges' g = -0.29. 95% CI: -0.41 to -0.17, p < 0.001; time domain: Hedges' g = -0.45, 95% CI: -0.57 to -0.33, p < 0.001] than controls. Panic disorder (n = 447), post-traumatic stress disorder (n = 192), generalized anxiety disorder (n = 68), and social anxiety disorder (n = 90), but not obsessive-compulsive disorder (n = 40), displayed reductions in HF HRV relative to controls (all ps < 0.001). Anxiety disorders are associated with reduced HRV, findings associated with a small-to-moderate effect size. Findings have important implications for future physical health and well-being of patients, highlighting a need for comprehensive cardiovascular risk reduction.


A Study on Postpartum Depression and its Association with Infant Feeding Practices and Infant Nutritional Status among Mothers Attending the Anganwadi Centers of Valsad District, Gujarat, India.
Systematic reviews on postpartum depression (PPD) suggest that PPD mothers are more likely to interrupt exclusive breastfeeding with inappropriate feeding practices resulting malnutrition in child. A community-based study was planned with the objective to find the risk factors associated with PPD and its possible association on infant feeding practices and infant nutritional status. This was a cross-sectional study conducted among 116 postpartum mothers attending Anganwadi centers under the Urban Health Training Centre and Rural Health Training Centre of Medical College. A purposive sampling technique was applied. Informed and written consent in local language was taken. Data were collected in predesigned, pretested, and semi-structured pro forma. The mothers were screened for possible PPD using the 10-item well-validated Edinburgh PPD Scale in Gujarati language. The cutoff point is score more than 10.5 based on previous studies. Infant's nutritional status and breastfeeding practices were assessed according to the WHO Growth Chart and Infant and Young Child Feeding guidelines. (1) 6.8% of the prevalence of PPD was reported in the study; (2) sociodemographic factors such as relationship of mothers with in-laws/husbands, help at home in childcare, literacy status, age at marriage and first child, and own desired/in-laws of sex of child are found to be significantly associated with PPD. (3) The Association of PPD and poor nutritional status of child was statistically significant. The study highlights the need of screening for PPD in the community. The potential risk factors for PPD can be taken into consideration during routine antenatal/postnatal care and for planning of preventive strategies.


Advancing the use of evidence-based decision-making in local health departments with systems science methodologies.
We assessed how systems science methodologies might be used to bridge resource gaps at local health departments (LHDs) so that they might better implement evidence-based decision-making (EBDM) to address population health challenges. We used the New York Academy of Medicine Cardiovascular Health Simulation Model to evaluate the results of a hypothetical program that would reduce the proportion of people smoking, eating fewer than 5 fruits and vegetables per day, being physically active less than 150 minutes per week, and who had a body mass index (BMI) of 25 kg/m(2) or greater. We used survey data from the Behavioral Risk Factor Surveillance System to evaluate health outcomes and validate simulation results. Smoking rates and the proportion of the population with a BMI of 25 kg/m(2) or greater would have decreased significantly with implementation of the hypothetical program (P < .001). Two areas would have experienced a statistically significant reduction in the local population with diabetes between 2007 and 2027 (P < .05). The use of systems science methodologies might be a novel and efficient way to systematically address a number of EBDM adoption barriers at LHDs.


The ubiquitous nature of epistasis in determining susceptibility to common human diseases.
There is increasing awareness that epistasis or gene-gene interaction plays a role in susceptibility to common human diseases. In this paper, we formulate a working hypothesis that epistasis is a ubiquitous component of the genetic architecture of common human diseases and that complex interactions are more important than the independent main effects of any one susceptibility gene. This working hypothesis is based on several bodies of evidence. First, the idea that epistasis is important is not new. In fact, the recognition that deviations from Mendelian ratios are due to interactions between genes has been around for nearly 100 years. Second, the ubiquity of biomolecular interactions in gene regulation and biochemical and metabolic systems suggest that relationship between DNA sequence variations and clinical endpoints is likely to involve gene-gene interactions. Third, positive results from studies of single polymorphisms typically do not replicate across independent samples. This is true for both linkage and association studies. Fourth, gene-gene interactions are commonly found when properly investigated. We review each of these points and then review an analytical strategy called multifactor dimensionality reduction for detecting epistasis. We end with ideas of how hypotheses about biological epistasis can be generated from statistical evidence using biochemical systems models. If this working hypothesis is true, it suggests that we need a research strategy for identifying common disease susceptibility genes that embraces, rather than ignores, the complexity of the genotype to phenotype relationship.


Public perception of drinking water safety in South Africa 2002-2009: a repeated cross-sectional study.
In low and middle income countries, public perceptions of drinking water safety are relevant to promotion of household water treatment and to household choices over drinking water sources. However, most studies of this topic have been cross-sectional and not considered temporal variation in drinking water safety perceptions. The objective of this study is to explore trends in perceived drinking water safety in South Africa and its association with disease outbreaks, water supply and household characteristics. This repeated cross-sectional study draws on General Household Surveys from 2002-2009, a series of annual nationally representative surveys of South African households, which include a question about perceived drinking water safety. Trends in responses to this question were examined from 2002-2009 in relation to reported cholera cases. The relationship between perceived drinking water safety and organoleptic qualities of drinking water, supply characteristics, and socio-economic and demographic household characteristics was explored in 2002 and 2008 using hierarchical stepwise logistic regression. The results suggest that perceived drinking water safety has remained relatively stable over time in South Africa, once the expansion of improved supplies is controlled for. A large cholera outbreak in 2000-02 had no apparent effect on public perception of drinking water safety in 2002. Perceived drinking water safety is primarily related to water taste, odour, and clarity rather than socio-economic or demographic characteristics. This suggests that household perceptions of drinking water safety in South Africa follow similar patterns to those observed in studies in developed countries. The stability over time in public perception of drinking water safety is particularly surprising, given the large cholera outbreak that took place at the start of this period.


Access, demand, and utilization of childhood immunization services: A cross-sectional household survey in Western Area Urban district, Sierra Leone, 2019.
Urban childhood immunization programs face unique challenges in access, utilization, and demand due to frequent population movement between and within localities, sprawling informal settlements, and population heterogeneity. We conducted a cross-sectional household survey in the Western Area Urban district, Sierra Leone, stratified by slums and non-slums as defined by the United Nations Development Program. Based on data from child vaccination cards, weighted vaccination coverage was estimated from 450 children aged 12-36 months (household response rate = 83%). Interviews with 444 caregivers identified factors related to accessing routine immunization services. Factors associated with coverage in bivariate analyses were examined in multivariate models using backward stepwise procedure. Coverage was similar in slums and non-slums for 3-doses of diphtheria-tetanus-pertussis-hepatitis B-Haemophilus influenzae type b (pentavalent) vaccine (86%, 92%) and second dose of measles vaccine (33%, 29%). In a multivariate logistic regression model, incomplete pentavalent vaccine coverage was associated with being second or later birth order (adjusted odds ratio (aOR) = 4.5 (95% confidence interval (CI) = 1.4-14.9), a household member not approving of childhood vaccinations (aOR = 7.55, 95% CI = 1.52-37.38), self-reported delay of child receiving recommended vaccinations (aOR = 4.8, 95% CI = 1.0-22.1), and living in a household made of natural or rudimentary materials (aOR = 3.5, 95% CI = 1.2-10.6). Overall, the majority (>70%) of caregivers reported occupation as petty trader and <50% reported receiving vaccination information via preferred communication sources. Although vaccination coverage in slums was similar to non-slums, study findings support the need for targeted interventions to improve coverage, especially for the second dose of measles vaccine to avoid large scale measles outbreaks. Strategies should focus on educating household members via preferred communication channels regarding the importance of receiving childhood vaccinations on time for all offspring, not just the first born. Vaccination coverage could be further improved by increasing accessibility through innovative strategies such as increasing the number of vaccination days and modifying hours.


Abstraction, Sensory-Motor Coordination, and the Reality Gap in Evolutionary Robotics.
One of the major challenges of evolutionary robotics is to transfer robot controllers evolved in simulation to robots in the real world. In this article, we investigate abstraction of the sensory inputs and motor actions as a tool to tackle this problem. Abstraction in robots is simply the use of preprocessed sensory inputs and low-level closed-loop control systems that execute higher-level motor commands. To demonstrate the impact abstraction could have, we evolved two controllers with different levels of abstraction to solve a task of forming an asymmetric triangle with a homogeneous swarm of micro air vehicles. The results show that although both controllers can effectively complete the task in simulation, the controller with the lower level of abstraction is not effective on the real vehicle, due to the reality gap. The controller with the higher level of abstraction is, however, effective both in simulation and in reality, suggesting that abstraction can be a useful tool in making evolved behavior robust to the reality gap. Additionally, abstraction aided in reducing the computational complexity of the simulation environment, speeding up the optimization process. Preeminently, we show that the optimized behavior exploits the environment (in this case the identical behavior of the other robots) and performs input shaping to allow the vehicles to fly into and maintain the required formation, demonstrating clear sensory-motor coordination. This shows that the power of the genetic optimization to find complex correlations is not necessarily lost through abstraction as some have suggested.


Humidity effects on response ofArgas persicus (Oken) to guanine, an assembly pheromone of ticks.
The assembly behavior of the tickArgas persicus Oken in response to guanine has been found to be humidity dependent. Nymphal and adult maleA. persicus assemble on guanine-treated paper disks only at low relative humidities (25 ± 5%). Exposure of the ticks to high relative humidities (85 ± 5%) results in a gradual induction of a negative response to the pheromone.


The calcium store sensor, STIM1, reciprocally controls Orai and CaV1.2 channels.
Calcium signals, pivotal in controlling cell function, can be generated by calcium entry channels activated by plasma membrane depolarization or depletion of internal calcium stores. We reveal a regulatory link between these two channel subtypes mediated by the ubiquitous calcium-sensing STIM proteins. STIM1 activation by store depletion or mutational modification strongly suppresses voltage-operated calcium (Ca(V)1.2) channels while activating store-operated Orai channels. Both actions are mediated by the short STIM-Orai activating region (SOAR) of STIM1. STIM1 interacts with Ca(V)1.2 channels and localizes within discrete endoplasmic reticulum/plasma membrane junctions containing both Ca(V)1.2 and Orai1 channels. Hence, STIM1 interacts with and reciprocally controls two major calcium channels hitherto thought to operate independently. Such coordinated control of the widely expressed Ca(V)1.2 and Orai channels has major implications for Ca(2+) signal generation in excitable and nonexcitable cells.


Use of Lactic Acid Bacteria to Reduce Methane Production in Ruminants, a Critical Review.
Enteric fermentation in ruminants is the single largest anthropogenic source of agricultural methane and has a significant role in global warming. Consequently, innovative solutions to reduce methane emissions from livestock farming are required to ensure future sustainable food production. One possible approach is the use of lactic acid bacteria (LAB), Gram positive bacteria that produce lactic acid as a major end product of carbohydrate fermentation. LAB are natural inhabitants of the intestinal tract of mammals and are among the most important groups of microorganisms used in food fermentations. LAB can be readily isolated from ruminant animals and are currently used on-farm as direct-fed microbials (DFMs) and as silage inoculants. While it has been proposed that LAB can be used to reduce methane production in ruminant livestock, so far research has been limited, and convincing animal data to support the concept are lacking. This review has critically evaluated the current literature and provided a comprehensive analysis and summary of the potential use and mechanisms of LAB as a methane mitigation strategy. It is clear that although there are some promising results, more research is needed to identify whether the use of LAB can be an effective methane mitigation option for ruminant livestock.


[Comparative study on effects of rutin and quercetin on metabolism in osteoblast cells].
To investigate the mechanism of rutin and its aglycone (quercetin) in preventing and treating osteoporosis and their effects on stimulating bone formation were studied comparatively in osteoblast cells. The effects of rutin and quercetin on the proliferation, differentiation and mineralization were studied respectively by using tetrazolium (MTT), alkaline phosphatase (ALP) and mineralized nodules assays in newborn rat calvarial osteoblast (ROB) cells. Quercetin showed significant stimulatory effects on proliferation and mineralization in ROB cells, so it could promote bone formation. However, rutin could not imporve stimulation of bone formation because it increased proliferation and inhibited differentation and had no remarkable influence on ROB cells in vitro. Rutin showed less activity than quercetin on bone formation in ROB cells in vitro. Therefore the mechanism that some foods and traditional Chinese medicine containing rutin can prevent and treat osteoporosis is that its metaboite in vivo can promote bone formation in ROB cells.


Choroidal neovascularization regression on fluorescein angiography after VEGF blockade.
Intravitreal vascular endothelial growth factor (VEGF) inhibitors stabilize vision in a majority of patients with neovascular age-related macular degeneration (AMD) and can improve vision in almost 40% of patients. However, some individuals who respond to anti-VEGF treatment still lose vision due to the formation of geographic atrophy (GA). While optical coherence tomography is often the primary imaging modality used, fluorescein angiography (FA) can provide useful information on GA development after choroidal neovascularization (CNV) regression. A retrospective chart review was conducted to evaluate the changes seen on FA over a 47-month period for 3 patients with neovascular AMD treated with anti-VEGF inhibitors. All 3 patients were initially noted to have subfoveal CNV due to AMD at baseline; they were followed up monthly and treated on an as needed basis for at least 47 months with intravitreal VEGF inhibitors. All subjects had regression of their CNV lesions after VEGF blockade. Two subjects developed foveal atrophy. This case series depicts the changes on FA seen over a 4-year period and shows that GA can occur with regression of CNV after treatment with VEGF inhibitors.


Reclassification of giant viruses composing a fourth domain of life in the new order Megavirales.
Interest in giant viruses has risen sharply since 2003, following the discovery of the Mimivirus and four other protist-infecting giant viruses that are linked to the nucleocytoplasmic large DNA viruses (NCLDVs). Despite considerable heterogeneity in hosts and genome sizes, the NCLDVs have been shown to be monophyletic based on analyses of their sequences and gene repertoires and recent studies have proposed that these viruses share a common ancient ancestor and compose a fourth domain of life. In addition, several characteristics of these giant viruses contradict or do not match the criteria used for the canonical definition of viruses, and the NCLDV denomination is not completely appropriate. We propose here to define a new viral order named Megavirales.


Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis.
Analog development of existing drugs and direct drug delivery to the lungs by inhalation as treatments for multiple and extensively drug resistant (MDR and XDR) tuberculosis (TB) represent new therapeutic strategies. Pyrazinamide (PZA) is critical to drug sensitive TB therapy and is included in regimens for MDR TB. However, PZA-resistant Mycobacterium tuberculosis (Mtb) strains threaten its use. Pyrazinoic acid esters (PAEs) are PZA analogs effective against Mtb in vitro, including against the most common PZA resistant strains. However, PAEs require testing for TB efficacy in animal models. PAEs were delivered daily as aqueous dispersions from a vibrating mesh nebulizer to Mtb infected guinea pigs for 4 weeks in a regimen including orally administered first-line TB drugs. PAEs tested as a supplement to oral therapy significantly reduced the organ bacterial burden in comparison to infected, untreated control animals. Thus, PAE aerosol therapy is a potentially significant addition to the regimen for PZA resistant MDR-TB and XDR-TB treatment. Interestingly, low dose oral PZA treatment combined with standard therapy also reduced bacterial burden. This observation may be important for PZA susceptible disease treatment. The present study justifies further evaluation of PZA analogs and their lung delivery to treat TB.


Acupuncture for alcohol dependence: a systematic review.
Acupuncture has been used in the treatment of substance-related disorders for the past 30 years. However, a systematic review to assess the effect of various types of acupuncture for alcohol dependence has not yet been performed. The present systematic review assessed the results of randomized controlled trials (RCTs). Nineteen electronic databases, including English, Korean, Japanese, and Chinese databases, were systematically searched for RCTs of acupuncture for alcohol dependence up to June 2008 with no language restrictions. The methodological qualities of eligible studies were assessed using the criteria described in the Cochrane Handbook. Eleven studies, which comprised a total of 1,110 individual cases, were systematically reviewed. Only 2 of 11 trials reported satisfactorily all quality criteria. Four trials comparing acupuncture treatment and sham treatments reported data for alcohol craving. Three studies reported that there were no significant differences. Among 4 trials comparing acupuncture and no acupuncture with conventional therapies, 3 reported significant reductions. No differences between acupuncture and sham treatments were found for completion rates (Risk Ratio = 1.07, 95% confidence interval, CI = 0.91 to 1.25) or acupuncture and no acupuncture (Risk Ratio = 1.15, 95% CI = 0.79 to 1.67). Only 3 RCTs reported acupuncture-related adverse events, which were mostly minimal. The results of the included studies were equivocal, and the poor methodological quality and the limited number of the trials do not allow any conclusion about the efficacy of acupuncture for treatment of alcohol dependence. More research and well-designed, rigorous, and large clinical trials are necessary to address these issues.


Modeling MIC copper release from drinking water pipes.
Copper is used for household drinking water distribution systems given its physical and chemical properties that make it resistant to corrosion. However, there is evidence that, under certain conditions, it can corrode and release unsafe concentrations of copper to the water. Research on drinking water copper pipes has developed conceptual models that include several physical-chemical mechanisms. Nevertheless, there is still a necessity for the development of mathematical models of this phenomenon, which consider the interaction among physical-chemical processes at different spatial scales. We developed a conceptual and a mathematical model that reproduces the main processes in copper release from copper pipes subject to stagnation and flow cycles, and corrosion is associated with biofilm growth on the surface of the pipes. We discuss the influence of the reactive surface and the copper release curves observed. The modeling and experimental observations indicated that after 10h stagnation, the main concentration of copper is located close to the surface of the pipe. This copper is associated with the reactive surface, which acts as a reservoir of labile copper. Thus, for pipes with the presence of biofilm the complexation of copper with the biomass and the hydrodynamics are the main mechanisms for copper release.


KCTD2, an adaptor of Cullin3 E3 ubiquitin ligase, suppresses gliomagenesis by destabilizing c-Myc.
Cullin3 E3 ubiquitin ligase ubiquitinates a wide range of substrates through substrate-specific adaptors Bric-a-brac, Tramtrack, and Broad complex (BTB) domain proteins. These E3 ubiquitin ligase complexes are involved in diverse cellular functions. Our recent study demonstrated that decreased Cullin3 expression induces glioma initiation and correlates with poor prognosis of patients with malignant glioma. However, the substrate recognition mechanism associated with tumorigenesis is not completely understood. Through yeast two-hybrid screening, we identified potassium channel tetramerization domain-containing 2 (KCTD2) as a BTB domain protein that binds to Cullin3. The interaction of Cullin3 and KCTD2 was verified using immunoprecipitation and immunofluorescence. Of interest, KCTD2 expression was markedly decreased in patient-derived glioma stem cells (GSCs) compared with non-stem glioma cells. Depletion of KCTD2 using a KCTD2-specific short-hairpin RNA in U87MG glioma cells and primary Ink4a/Arf-deficient murine astrocytes markedly increased self-renewal activity in addition with an increased expression of stem cell markers, and mouse in vivo intracranial tumor growth. As an underlying mechanism for these KCTD2-mediated phenotypic changes, we demonstrated that KCTD2 interacts with c-Myc, which is a key stem cell factor, and causes c-Myc protein degradation by ubiquitination. As a result, KCTD2 depletion acquires GSC features and affects aerobic glycolysis via expression changes in glycolysis-associated genes through c-Myc protein regulation. Of clinical significance was our finding that patients having a profile of KCTD2 mRNA-low and c-Myc gene signature-high, but not KCTD2 mRNA-low and c-Myc mRNA-high, are strongly associated with poor prognosis. This study describes a novel regulatory mode of c-Myc protein in malignant gliomas and provides a potential framework for glioma therapy by targeting c-Myc function.


Validation of the Social Appearance Anxiety Scale in Patients With Systemic Sclerosis: A Scleroderma Patient-Centered Intervention Network Cohort Study.
Systemic sclerosis (SSc) is an autoimmune disease that can cause disfiguring changes in appearance. This study examined the structural validity, internal consistency reliability, convergent validity, and measurement equivalence of the Social Appearance Anxiety Scale (SAAS) across SSc disease subtypes. Patients enrolled in the Scleroderma Patient-centered Intervention Network Cohort completed the SAAS and measures of appearance-related concerns and psychological distress. Confirmatory factor analysis (CFA) was used to examine the structural validity of the SAAS. Multiple-group CFA was used to determine whether SAAS scores can be compared across patients with limited and diffuse disease subtypes. Cronbach's alpha was used to examine internal consistency reliability. Correlations of SAAS scores with measures of body image dissatisfaction, fear of negative evaluation, social anxiety, and depression were used to examine convergent validity. SAAS scores were hypothesized to be positively associated with all convergent validity measures, with correlations significant and moderate to large in size. A total of 938 patients with SSc were included. CFA supported a 1-factor structure (Comparative Fit Index 0.92, Standardized Root Mean Residual 0.04, and Root Mean Square Error of Approximation 0.08), and multiple-group CFA indicated that the scalar invariance model best fit the data. Internal consistency reliability was good in the total sample (α = 0.96) and in disease subgroups. Overall, evidence of convergent validity was found with measures of body image dissatisfaction, fear of negative evaluation, social anxiety, and depression. The SAAS can be reliably and validly used to assess fear of appearance evaluation in patients with SSc, and SAAS scores can be meaningfully compared across disease subtypes.


Cloning of the gene encoding the major outer membrane protein of Haemophilus influenzae type b.
The major outer membrane protein (P2) of Haemophilus influenzae type b (Hib) with an apparent molecular weight of 37,000 to 40,000 has been previously shown to function as a porin and also as a target for antibodies protective against experimental Hib disease. The gene encoding the Hib P2 protein was cloned by using a shuttle vector capable of replication in both Escherichia coli and H. influenzae. The amino acid sequence of the amino terminus of the Hib P2 protein was determined and used to design an oligonucleotide probe corresponding to the first 20 amino acids of this protein. This oligonucleotide probe was used to identify Hib chromosomal DNA fragments containing the Hib P2 gene. These DNA fragments were ligated into the plasmid vector pGJB103 and then used to transform a rec-1 mutant of H. influenzae Rd. Recombinant clones expressing the Hib P2 protein were identified in a colony blot-radioimmunoassay by using a monoclonal antibody specific for a surface epitope of the Hib P2 protein. The gene encoding this Hib protein was present on a 10-kilobase Hib DNA insert in the recombinant plasmid. Transformation experiments involving the recombinant plasmid suggested that unregulated synthesis of Hib P2 is a lethal event in E. coli. The recombinant Hib P2 protein was exposed on the surface of the recombinant H. influenzae strain. This recombinant strain was used to develop a system for detecting polyclonal serum antibodies directed against surface determinants of the Hib P2 protein. The availability of the gene encoding the Hib P2 protein should facilitate investigation of both the immunogenicity and the structure-function relationship(s) of this major outer membrane protein.


[Relationship between post-traumatic stress disorder, child sexual abuse and sexual re-victimization].
There is a relationship between child sexual abuse and adult psychopathology. We report a 35 year-old woman derived to the Psychiatric Service of the Curicó Hospital due to anxiety and depressive symptoms lasting eight years, to illustrate the above mentioned relationship. At the psychiatric unit, a post traumatic stress disorder of belated onset, triggered by sexual abuse during childhood, re-edited after her daughter's birth, was diagnosed. This case illustrates different factors, which, in retrospective studies, have been associated with the morbid consequences of child sexual abuse, and allows an understanding of how different sexually traumatic events, during a person's lifetime, contribute to the development of a psychopathology. The problem was confronted by the mental health team at different levels and symptoms subsided in few interventions. An active search of the traumatic sexual background, allowed this achievement. The importance of studying and validating clinical situations as the present case, with methodologies based on evidence, is stressed.


Abnormalities of renal perfusion and the renal pressor system in dogs with chronic aortic coarctation.
To clarify the role of the renin-angiotensin system in coarctation hypertension, 2-year-old inbred dogs with chronic neonatally induced thoracic aortic coarctation were subjected to 6 days of rigorous salt restriction. The following parameters were then measured: glomerular filtration rate, renal plasma flow, plasma renin activity, plasma renin concentration, renin reactivity, and renin substrate concentration. Glomerular filtration rate and renal plasma flow were significantly lower in salt-restricted coarcted dogs: 3.0 +/- 0.2 and 9.0 +/- 1.5 ml/min kg-1, respectively, compared with values of 4.0 +/- 0.2 (P less than 0.005) and 13.2 +/- 0.6 (P less than 0.025) ml/min kg-1 in salt-restricted controls. Plasma renin activity was abnormally high in experimental dogs: 13.5 +/- 2.5 vs. 4.5 +/- 1.5 ng angiotensin I/ml hour-1 in controls (P less than 0.005). In addition, a significant elevation of renin reactivity (indicating a relative increase in circulating accelerators or a relative decrease in inhibitors of the renin reaction) was apparent in the plasma of coarcted dogs. Plasma renin concentration was elevated but to an insignificant degree in coarcted dogs, and renin substrate concentration was comparable with that of controls. The impaired renal perfusion and abnormal elevation of plasma renin activity during salt restriction is analogous to clinical and experimental observations in hypertensive states associated with total renal underperfusion and supports a major role for the renal pressor system in the pathogenesis of coarctation hypertension. The insignificant elevation of plasma renin concentration is not incompatible with this view. The demonstration of increased renin reactivity in coarctation hypertension provides additional evidence that acceleration of the renin reaction is common to all hypertensive states.


Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C.
Lymphatic vessels are mainly regarded as passive conduits for the dissemination of cancer cells. In this study, we investigate whether and how the tumor-associated lymphatic vessels may play an active role in tumor metastasis. In situ laser capture microdissection of lymphatic vessels followed by cDNA microarray analysis was used to determine the expression profiling of lymphatic endothelial cells (LEC). Gene expression levels and activity of signaling pathways were measured by real-time RT-PCR, ELISA, or immunoblotting. Lymphangiogenesis was assessed by IHC. Lymph node metastasis was measured using fluorescence imaging. The effects of SEMA4C on lymphangiogenesis in vitro were evaluated using migration assay and tube-formation assay of LECs. Tumor-associated LECs are molecularly and functionally different from their normal counterparts. In addition to expressing high levels of membrane-bound SEMA4C, tumor-associated LECs also produced soluble SEMA4C (sSEMA4C). Increased serum sSEMA4C was detected in patients with breast cancer and cervical cancer. Patients with metastasis had much higher levels of serum sSEMA4C. sSEMA4C promoted lymphangiogenesis by activating PlexinB2-ERBB2 signaling in LECs, and promoted the proliferation and migration of tumor cells by activating PlexinB2-MET signaling, thus promoting lymphatic metastasis. Although the SEMA4C signaling pathways differ between LECs and tumor cells, RHOA activation was necessary for the effects of SEMA4C in both types of cells. Tumor-associated LECs produce sSEMA4C to promote lymphatic metastasis of tumors. Our results suggest that SEMA4C and RHOA might be potential therapeutic targets, and that higher serum sSEMA4C could be a marker for breast cancer and cervical cancer. Clin Cancer Res; 23(1); 214-24. ©2016 AACR.


In vitro assessment of drug delivery through an endotracheal tube using a dry powder inhaler delivery system.
Jet nubulisers and metered dose inhalers are widely used to deliver aerosolised drugs to the lungs of intubated patients in adult intensive care units. Drug delivery using these systems has been shown to be inefficient and both forms of delivery have the potential to induce paradoxical bronchoconstriction in patients with reactive airways disease. Experiments were carried out to determine whether it was possible to deliver drug from a dry powder delivery system through an endotracheal tube. A 200 micrograms budesonide Turbohaler was enclosed in a chamber which allowed it to be inserted into a ventilator circuit. Experiments were performed with a multistage liquid impinger in which drug was drawn through the Turbohaler and endotracheal tube at 60 l/min providing an index of the maximum drug delivery achievable via this route. A second series of experiments was performed in which the Turbohaler was placed in a ventilator circuit using a Servo 900C volume cycled ventilator. Drug delivered from the Turbohaler during the inspiratory phase was collected on a filter placed between the end of a 9 mm endotracheal tube and a model lung. A tidal volume of 500 ml and inspiratory time of 0.5 seconds was used. Budesonide was assayed using an ultraviolet spectrophotometric assay. Thirty percent of the nominal dose passed through the endotracheal tube and was collected in the multistage liquid impinger. Mean drug delivery to the filter in the ventilator circuit was 20%. This in vitro study indicates that drugs from dry powder inhalers (in this case the Turbohaler) can be satisfactorily delivered through endotracheal tubes and that clinical evaluation of this technique is now indicated.


Evaluation of the Effect of Source Geometry on the Output of Miniature X-ray Tube for Electronic Brachytherapy through Simulation.
The use of miniature X-ray source in electronic brachytherapy is on the rise so there is an urgent need to acquire more knowledge on X-ray spectrum production and distribution by a dose. The aim of this research was to investigate the influence of target thickness and geometry at the source of miniature X-ray tube on tube output. Five sources were simulated based on problems each with a specific geometric structure and conditions using MCNPX code. Tallies proportional to the output were used to calculate the results for the influence of source geometry on output. The results of this work include the size of the optimal thickness of 5 miniature sources, energy spectrum of the sources per 50 kev and also the axial and transverse dose of simulated sources were calculated based on these thicknesses. The miniature source geometric was affected on the output x-ray tube. The result of this study demonstrates that hemispherical-conical, hemispherical and truncated-conical miniature sources were determined as the most suitable tools.


Conventional rotator cuff repair complemented by the aid of mononuclear autologous stem cells.
To investigate the behavior of rotator cuff tears treated with conventional repair technique with the aid of autologous bone marrow mononuclear cells (BMMC). Fourteen consecutive patients (9 women, 5 men, mean age of 59.2 years) with complete rotator cuff tears (mean preoperative UCLA score of 12 ± 3.0) were fixed by transosseous stitches through mini-open incision, with subsequent injection of BMMC into the tendon borders, obtained from the iliac crest just prior to surgery. Magnetic resonance images (MRI) were acquired before and after surgery and evaluated by two musculoskeletal radiologists regarding new postoperative findings of patients treated with BMMC. After a minimum 12-month follow-up period, the UCLA score increased from 12 ± 3.0 to 31 ± 3.2. Clinical findings remained unaltered in the following year in all but one patient (13/14). MRI analysis after a 12-month follow-up period demonstrated tendon integrity in all cases (14/14), presence of low-signal intensity areas along the supraspinatus tendon and distal muscle belly in 8 cases (8/14), and high-intensity blooming small round artifact at the bursal and tendon topography in 11 cases (11/14). Six patients (6/14) showed formation of a high-signal intensity zone at the critical zone. Clinical findings remained unaltered in the following year in all but one patient, who relapsed into loss of strength and pain, being considered a bad result. Implantation of BMMC in rotator cuff sutures appears to be a safe and promising alternative to other biological approaches currently used to enhance tissue quality in affected tendons.


[Primary prevention of coronary heart disease: possibilities and limitations].
Cardiovascular diseases are still the most important cause of death in industrialized countries. In spite of enormous progress regarding prevention, diagnostic and therapeutic procedures, coronary heart disease remains the most important cardiovascular cause for early invalidity, professional inactivity and premature death. The direct and indirect costs of cardiovascular diseases amount to 14.8% of total disease-related costs. The practicing physician has an important role to play in the prevention of cardiovascular diseases. In order for the physician to understand his critical role and to act accordingly, some fundamental epidemiological principles are introduced. Particularly, the notion of population attributable risk is important: As a consequence for the health of whole population groups, it is as important to advise the many at intermediate risk as the few at high risk of a cardiovascular accident. The future challenges are clear. This disease group is to a large extent preventable; efficient intervention models, both on an individual and on a community level, are available.


Do mutational dynamics in stem cells explain the origin of common cancers?
For more than 60 years, we have known that the incidence of certain common human cancers increases with age. Recently in Science, Tomasetti and Vogelstein (2015) refined this model by providing a potential explanation, arguing that early random mutational events within individual stem cells of regenerating organs may underlie this correlation.


Solution structure of the LDL receptor EGF-AB pair: a paradigm for the assembly of tandem calcium binding EGF domains.
From the observed structure and sequence of a pair of calcium binding (cb) epidermal growth factor-like (EGF) domains from human fibrillin-1, we proposed that many tandem cbEGF domains adopt a conserved relative conformation. The low-density lipoprotein receptor (LDLR), which is functionally unrelated to fibrillin-1, contains a single pair of EGF domains that was chosen for study in the validation of this hypothesis. The LDLR is the protein that is defective in familial hypercholesterolaemia, a common genetic disorder that predisposes individuals to cardiovascular complications and premature death. Here, we present the solution structure of the first two EGF domains from the LDL receptor, determined using conventional NMR restraints and residual dipolar couplings. The cbEGF domains have an elongated, rod-like arrangement, as predicted. The new structure allows a detailed assessment of the consequences of mutations associated with familial hypercholesterolaemia to be made. The validation of the conserved arrangement of EGF domains in functionally distinct proteins has important implications for structural genomics, since multiple tandem cbEGF pairs have been identified in many essential proteins that are implicated in human disease. Our results provide the means to use homology modeling to probe structure-function relationships in this diverse family of proteins and may hold the potential for the design of novel diagnostics and therapies in the future.


Tuning the properties of metal-organic framework nodes as supports of single-site iridium catalysts: node modification by atomic layer deposition of aluminium.
The metal-organic framework NU-1000, with Zr6-oxo, hydroxo, and aqua nodes, was modified by incorporation of hydroxylated Al(iii) ions by ALD-like chemistry with [Al(CH3)2(iso-propoxide)]2 followed by steam (ALD = atomic layer deposition). Al ions were installed to the extent of approximately 7 per node. Single-site iridium diethylene complexes were anchored to the nodes of the modified and unmodified MOFs by reaction with Ir(C2H4)2(acac) (acac = acetylacetonate) and converted to Ir(CO)2 complexes by treatment with CO. Infrared spectra of these supported complexes show that incorporation of Al weakened the electron donor tendency of the MOF. Correspondingly, the catalytic activity of the initial supported iridium complexes for ethylene hydrogenation increased, as did the selectivity for ethylene dimerization. The results of density functional theory calculations with a simplified model of the nodes incorporating Al(iii) ions are in qualitative agreement with some catalyst performance data.


Clonality in sarcoidosis, granuloma annulare, and granulomatous mycosis fungoides.
The histological discrimination of granulomatous cutaneous T-cell lymphomas (CTCLs) from reactive granulomatous disorders such as sarcoidosis and granuloma annulare (GA) may be difficult due to overlapping histological features. We analyzed the T-cell receptor gene rearrangement in sarcoidosis and GA to investigate the value of the detection of clonal T cells as an adjunctive diagnostic marker in the differentiation between sarcoidosis and GA versus granulomatous CTCLs. Rearrangement of T-cell receptor γ genes was examined by the use of automated high-resolution polymerase chain reaction fragment analysis in 35 cases of sarcoidosis and 15 cases of GA and compared with a series of 19 cases of granulomatous CTCLs. A monoclonal T-cell population was found in none of the cases of sarcoidosis and in 2 of 15 cases of GA (13%). In granulomatous CTCLs, a neoplastic T-cell clone was detected in 94%. Presence of clonal T cells argues in favour of a granulomatous CTCL, while a polyclonal T-cell population makes the presence of a sarcoidosis or a GA more likely. The analysis of T-cell clonality is a useful diagnostic adjunct in the differentiation between sarcoidosis and GA from granulomatous CTCLs.


Ageism in Health Care: A Systematic Review of Operational Definitions and Inductive Conceptualizations.
International and national bodies have identified tackling ageism in health care as an urgent goal. However, health professionals, researchers, and policy makers recognize that it is not easy to identity and fight ageism in practice, as the identification of multiple manifestations of ageism is dependent on the way it is defined and operationalized. This article reports on a systematic review of the operational definitions and inductive conceptualizations of ageism in the context of health care. We reviewed scientific articles published from January 1995 to June 2015 and indexed in the electronic databases Web of Science, PubMed, and Cochrane. Electronic searches were complemented with visual scanning of reference lists and hand searching of leading journals in the field of ageing and social gerontology. The review reveals that the predominant forms of operationalization and inductive conceptualization of ageism in the context of health care have neglected some components of ageism, namely the self-directed and implicit components. Furthermore, the instruments used to measure ageism in health care have as targets older people in general, not older patients in particular. The results have important implications for the advancement of research on this topic, as well as for the development of interventions to fight ageism in practice. There is a need to take into account underexplored forms of operationalization and inductive conceptualizations of ageism, such as self-directed ageism and implicit ageism. In addition, ageism in health care should be measured by using context-specific instruments.


Role of reactive oxygen species in myocardial remodeling.
Adverse cardiac remodeling is a fundamental process in the progression to chronic heart failure. Although the mechanisms underlying cardiac remodeling are multi-factorial, a significant body of evidence points to the crucial roles of increased reactive oxygen species. This article reviews recent advances in delineating the different sources of production for reactive oxygen species (namely mitochondria, xanthine oxidase, uncoupled nitric oxide synthases, and NADPH oxidases) that may be involved in cardiac remodeling and the aspects of the remodeling process that they affect. These data could suggest new ways of targeting redox pathways for the prevention and treatment of adverse cardiac remodeling.


Starch: A Flexible, Adaptable Carbon Store Coupled to Plant Growth.
Research in the past decade has uncovered new and surprising information about the pathways of starch synthesis and degradation. This includes the discovery of previously unsuspected protein families required both for processes and for the long-sought mechanism of initiation of starch granules. There is also growing recognition of the central role of leaf starch turnover in making carbon available for growth across the day-night cycle. Sophisticated systems-level control mechanisms involving the circadian clock set rates of nighttime starch mobilization that maintain a steady supply of carbon until dawn and modulate partitioning of photosynthate into starch in the light, optimizing the fraction of assimilated carbon that can be used for growth. These discoveries also uncover complexities: Results from experiments with Arabidopsis leaves in conventional controlled environments are not necessarily applicable to other organs or species or to growth in natural, fluctuating environments.


[Fontan-type procedure for an adult case of double-outlet right ventricle (S, D, L)].
The double-outlet right ventricle with L-malposition (DORV (S, D, L)) is one of the rare congenital heart diseases. Intracardiac rerouting with a internal conduit has been indicated in principle to it as the radical operation. DORV (S, D, L) is often combined with the pulmonic stenosis (PS), and Rastelli's operation is indicated to the case in which release of PS is difficult. We report a case of DORV (S, D, L) combined with PS and the hypoplastic right ventricle which is treated by the Fontan-type procedure. The patient was a 35-year-old female who had undergone Glenn's operation at 10 years of age under the diagnosis of transposition of the great arteries. Recently she complained of aggravation of the cyanosis and dyspnea on exertion. After thorough examinations, the disease was diagnosed as DORV (S, D, L) with doubly committed VSD which was combined with severe PS, hypoplastic right ventricle (29% of normal) and left-sided juxtaposition of atrial appendages. The development of her distal pulmonary arteries was estimated well enough (PA-index 448 mm2/m2). We judged that intracardiac rerouting with an internal conduit could not be applied due to her severe pulmonic stenosis, and that Rastelli's operation as the biventricular repair was also impossible because of her hypoplastic right ventricle. Thus we adopted the Fontan-type procedure with a new septation in the right atrium, namely oblique partition, and attained a good result. To our knowledge, this case is the fourth case report in Japan of DORV (S, D, L) treated with the Fontan-type procedure.(ABSTRACT TRUNCATED AT 250 WORDS)


Divided Zygomatic Bone in Primates With Implications of Skull Morphology and Biomechanics.
Typically the zygoma is a single bone in the facial skeleton whose shape uniquely copes with loads associated with mastication. Rarely but naturally, the zygoma is divided into two or more parts by supernumerary sutures. These extra intrazygomatic sutures are located at an area of critical morphological and biomechanical importance, yet their impacts have not been studied. In this study, the morphological and possible biomechanical consequences of the divided zygoma (DZ) were investigated in primates including rhesus macaques (Macaca mulatta), orangutans (Pongo abelii and P. pygmaeus), and modern humans (Homo sapiens). Results demonstrated that a unilateral supernumerary suture within the zygoma affected facial symmetry. The superior division of the divided zygoma was normally slender along with the adjacent frontal bone parts; while the inferior division of the divided zygoma was normally more robust, along with stronger temporal and maxillary bones. These were possible biomechanical consequences, in which the stresses incurred during normal masticatory activities were shunted from the upper face to the lower face, especially along the zygomatic arch. These findings revealed that the DZ condition would alter overall morphology of the midface of the affected side, and unfavorably affect the pattern of stress distribution in the loaded side of the face during mastication. The developmental mechanisms for the supernumerary sutures dividing the zygoma were unclear. Further insights into this rare condition may deepen our understanding of craniofacial form, adaptation, developmental plasticity, and evolution, and help to improve therapeutic philosophies in corrective and regenerative medicine. Anat Rec, 299:1801-1829, 2016. © 2016 Wiley Periodicals, Inc.


Survey of emergency medicine resident debt status and financial planning preparedness.
Most resident physicians accrue significant financial debt throughout their medical and graduate medical education. The objective of this study was to analyze emergency medicine resident debt status, financial planning actions, and educational experiences for financial planning and debt management. A 22-item questionnaire was sent to all 123 Accreditation Council on Graduate Medical Education-accredited emergency medicine residency programs in July 2001. Two follow-up mailings were made to increase the response rate. The survey addressed four areas of resident debt and financial planning: 1) accrued debt, 2) moonlighting activity, 3) financial planning/debt management education, and 4) financial planning actions. Descriptive statistics were used to analyze the data. Survey responses were obtained from 67.4% (1,707/2,532) of emergency medicine residents in 89 of 123 (72.4%) residency programs. Nearly one half (768/1,707) of respondents have accrued more than 100,000 dollars of debt. Fifty-eight percent (990/1,707) of all residents reported that moonlighting would be necessary to meet their financial needs, and more than 33% (640/1,707) presently moonlight to supplement their income. Nearly one half (832/1,707) of residents actively invested money, of which online trading was the most common method (23.3%). Most residents reported that they received no debt management education during residency (82.1%) or medical school (63.7%). Furthermore, 79.1% (1,351/1,707) of residents reported that they received no financial planning lectures during residency, although 84.2% (1,438/1,707) reported that debt management and financial planning education should be available during residency. Most emergency medicine residency programs do not provide their residents with financial planning education. Most residents have accrued significant debt and believe that more financial planning and debt management education is needed during residency.


Evaluation of a combination of sodium hypochlorite and polyhexamethylene biguanide as an egg wash for red-eared slider turtles (Trachemys scripta elegans) to suppress or eliminate Salmonella organisms on egg surfaces and in hatchlings.
To evaluate a combination of 2 nonantibiotic microbicide compounds, sodium hypochlorite (NaOCl) and polyhexamethylene biguanide (PHMB), as a treatment to suppress or eliminate Salmonella spp from red-eared slider (RES) turtle (Trachemys scripta elegans) eggs and hatchlings. 2,738 eggs from 8 turtle farms in Louisiana. Eggs were randomly sorted into 3 or, when sufficient eggs were available, 4 treatment groups as follows: control, pressure-differential egg treatment with NaOCl and gentamicin, NaOCl and PHMB bath treatment, and pressure-differential egg treatment with NaOCl and PHMB. Bacterial cultures were performed from specimens of eggs and hatchlings and evaluated for Salmonella spp. RES turtle eggs treated with NaOCl and PHMB as a bath (odds ratio [OR], 0.2 [95% confidence interval (CI), 0.1 to 0.3]) or as a pressure-differential dip (OR, 0.01 [95% CI, 0.001 to 0.07]) or with gentamicin as a pressure-differential dip (OR, 0.1 [95% CI, 0.06 to 0.2]) were significantly less likely to have Salmonella-positive culture results than control-group eggs. Concern over reptile-associated salmonellosis in children in the United States is so great that federal regulations prohibit the sale of turtles that are < 10.2 cm in length. Currently, turtle farms treat eggs with gentamicin solution. Although this has reduced Salmonella shedding, it has also resulted in antimicrobial resistance. Results of our study indicate that a combination of NaOCl and PHMB may be used to suppress or eliminate Salmonella spp on RES turtle eggs and in hatchlings.


Upregulation of urotensin II receptor in preeclampsia causes in vitro placental release of soluble vascular endothelial growth factor receptor 1 in hypoxia.
Preeclampsia is a hypertensive disorder of pregnancy caused by abnormal placental function, partly because of chronic hypoxia at the utero-placental junction. The increase in levels of soluble vascular endothelial growth factor receptor 1, an antiangiogenic agent known to inhibit placental vascularization, is an important cellular factor implicated in the onset of preeclampsia. We investigated the ligand urotensin II (U-II), a potent endogenous vasoconstrictor and proangiogenic agent, for which levels have been reported to increase in patients with preeclampsia. We hypothesized that an increased sensitivity to U-II in preeclampsia might be achieved by upregulation of placental U-II receptors. We further investigated the role of U-II receptor stimulation on soluble vascular endothelial growth factor receptor 1 release in placental explants from diseased and normal patients. Immunohistochemistry, real-time PCR, and Western blotting analysis revealed that U-II receptor expression was significantly upregulated in preeclampsia placentas compared with controls (P<0.01). Cellular models of syncytiotrophoblast and vascular endothelial cells subjected to hypoxic conditions revealed an increase in U-II receptor levels in the syncytiotrophoblast model. This induction is regulated by the transcriptional activator hypoxia-inducible factor 1alpha. U-II treatment is associated with increased secretion of soluble vascular endothelial growth factor receptor 1 only in preeclamptic placental explants under hypoxia but not in control conditions. Interestingly, normal placental explants did not respond to U-II stimulation.


Serum containing Buyang Huanwu decoction prevents age-associated migration and invasion of human vascular smooth muscle cells by up regulating SIRT1 expression.
The migration and invasion of vascular smooth muscle cells (VSMCs) caused by advanced aging play an important role in diffuse intimal thickening, facilitate adverse arterial remodeling and contribute to the initiation and progression of cardiovascular diseases. The inhibitory function of Buyang Huanwu decoction (BYHWD) has been found on aortic intimal hyperplasia and VSMC proliferation, but its effect on age-associated migration and invasion remains unknown. Here, we used an in vitro angiotensin II (Ang II)-induced senescence model to study the effects of serum containing BYHWD (BYHWS) on the migratory and invasive capacities, matrix metalloprotease type 2 (MMP-2) expression and modulation of sirtuin1 (SIRT1) signaling in human aorta VSMCs (HA-VAMCs). Our results showed that BYHWS was able to inhibit Ang II-induced migration and invasion, with down-regulation of MMP-2. In addition, manipulation of SIRT1 by either over-expression or siRNA knockdown ameliorated or promoted cellular migration and invasion, respectively. Moreover, BYHWS reversed senescence-mediated decrease of SIRT1 levels and SIRT1 was required for BYHWS regulation on migration and invasion of senescent HA-VAMCs. In summary, our data demonstrated that BYHWS suppressed the migration and invasion of age-associated VSMC via an increase of the SIRT1 level, which provides novel insights for the therapy of age-associated cardiovascular diseases.


DNA is a fractal antenna in electromagnetic fields.
To review the responses of deoxyribonucleic acid (DNA) to electromagnetic fields (EMF) in different frequency ranges, and characterise the properties of DNA as an antenna. We examined published reports of increased stress protein levels and DNA strand breaks due to EMF interactions, both of which are indicative of DNA damage. We also considered antenna properties such as electronic conduction within DNA and its compact structure in the nucleus. EMF interactions with DNA are similar over a range of non-ionising frequencies, i.e., extremely low frequency (ELF) and radio frequency (RF) ranges. There are similar effects in the ionising range, but the reactions are more complex. The wide frequency range of interaction with EMF is the functional characteristic of a fractal antenna, and DNA appears to possess the two structural characteristics of fractal antennas, electronic conduction and self symmetry. These properties contribute to greater reactivity of DNA with EMF in the environment, and the DNA damage could account for increases in cancer epidemiology, as well as variations in the rate of chemical evolution in early geologic history.


Dopamine autoreceptor regulation of release and uptake in mouse brain slices in the absence of D(3) receptors.
The effects of the dopamine D(3) receptor, a putative autoreceptor, have been investigated by comparing behavioral and neurochemical properties of wild-type mice and mice with a genetic deletion of the D(3) receptor. The D(3) knock-out mice were modestly hyper-responsive to a novel environment relative to wild-type mice, and, consistent with this, quantitative in vivo microdialysis revealed elevated striatal dopamine extracellular levels. The dynamic actions of autoreceptors on electrically evoked dopamine release were examined in striatal brain slices from these animals and monitored with fast scan cyclic voltammetry at carbon-fiber microelectrodes. Quinpirole, a dopamine receptor agonist with potency at both D(2) and D(3) receptors, inhibited evoked dopamine in a dose-dependent manner with a slightly higher dose required in the knock-out animals (EC(50) of 60+/-10 nM in wild-type animals and 130+/-40 in D(3) knock-out animals; both curves had a Hill slope near 2). Dopamine synthesis inhibition with alpha-methyl-p-tyrosine caused released dopamine levels to decrease in each genotype. However, regulation of secretion by autoreceptors was still operant. Dose-response curves to quinpirole were unchanged in D(3) knock-out tissue, but secretion-regulated release exhibited a Hill slope decreased to 1 in the wild-type animals. In both genotypes, similar quinpirole-evoked increases in uptake rate were evident following synthesis inhibition. These data are consistent with the D(3) receptor having a small but significant role as a dopamine autoreceptor that partially regulates secretion, but not synthesis, in the caudate-putamen.


Electrode interfaces switchable by physical and chemical signals for biosensing, biofuel, and biocomputing applications.
This review outlines advances in designing modified electrodes with switchable properties controlled by various physical and chemical signals. Irradiation of the modified electrode surfaces with various light signals, changing the temperature of the electrolyte solution, application of a magnetic field or electrical potentials, changing the pH of the solutions, and addition of chemical/biochemical substrates were used to change reversibly the electrode activity. The increasing complexity in the signal processing was achieved by integration of the switchable electrode interfaces with biomolecular information processing systems mimicking Boolean logic operations, thus allowing activation and inhibition of electrochemical processes on demand by complex combinations of biochemical signals. The systems reviewed range from simple chemical compositions to complex mixtures modeling biological fluids, where the signal substrates were added at normal physiological and elevated pathological concentrations. The switchable electrode interfaces are considered for future biomedical applications where the electrode properties will be modulated by the biomarker concentrations reflecting physiological conditions.


Scoliosis rates in symptomatic patients as demonstrated with weight-bearing or supine MR imaging.
In the United States an estimated 6 million persons are affected by scoliosis, which is characterized by a 3-dimensional deformity of the spine that involves a curvature in the sagittal, frontal, and transverse planes. To determine the rates of scoliosis in patients with spine-related pain unassociated with cancer, as demonstrated by magnetic resonance (MR) images obtained with patients in either a weight-bearing or a supine position. The authors conducted a retrospective review of MR images obtained during a 2-year period in patients referred because of symptoms of radiculopathy or other spine-related pain unassociated with cancer and unresolved after conservative treatment. Images were obtained either with the patient supine or with the patient in a weight-bearing, seated position, and all images were reviewed by a neuroimaging physician. Scoliosis was assessed according to the Cobb angle method. A total of 1982 MR images from 1486 patients were reviewed. Of those, 986 images in 761 patients were obtained with a low-field-strength (0.3-T) MR imager with the patient supine, and 996 images in 725 patients were obtained with a mid-field-strength (0.6-T) MR imager with the patient in a weight-bearing, seated position. Scoliosis (dextroscoliosis, levoscoliosis, or both) was identified in 958 MR images (48.3%), of which 779 (78.2%) were obtained with patients in a weight-bearing position and 179 (18.2%) were obtained with patients in a supine position. The scoliosis rate was lower in the supine MR imaging group than in the weight-bearing MR imaging group. Scoliosis rates may be affected by the position in which the patient is examined, with the possibility that the weight-bearing position differentially exposes scoliosis, compared with the supine position.


Eastern European transition and suicide mortality.
The current paper seeks to systematize the discussion on the causes of the changes in Eastern European countries' suicide mortality during the last 15 years by analyzing the changes in relation to some common causes: alcohol consumption, economic changes, "general pathogenic social stress", political changes, and social disorganization. It is found that the developments in suicide have been very different in different countries, and that the same causes cannot apply to all of them. However, the relation between suicide mortality and social processes is obvious. A model consisting of the hypothetical general stress (as indicated by mortality/life expectancy), democratization, alcohol consumption, and social disorganization (with a period-dependent effect) predicted the percentual changes in the suicide rates in 16 out of the 28 Eastern Bloc countries in 1984-89 and 1989-94 fairly accurately, while it failed to do this for Albania, Poland, Romania, Slovakia, and the Caucasian and Central Asian newly independent states. Most interesting were the strong roles played by changes in life expectancy, the causes of which are discussed, and the fact that economic change seemed to lack explanatory power in multiple analyses. The data are subject to many potential sources of error, the small number of units and the large multicollinearity between the independent variables may distort the results. Nevertheless, the results indicate that the changes in Eastern European suicide mortality, both decreases and increases, may be explained with the same set of variables. However, more than one factor is needed, and the multicollinearity will continue to pose problems.


Integrating computational methods to retrofit enzymes to synthetic pathways.
Microbial production of desired compounds provides an efficient framework for the development of renewable energy resources. To be competitive to traditional chemistry, one requirement is to utilize the full capacity of the microorganism to produce target compounds with high yields and turnover rates. We use integrated computational methods to generate and quantify the performance of novel biosynthetic routes that contain highly optimized catalysts. Engineering a novel reaction pathway entails addressing feasibility on multiple levels, which involves handling the complexity of large-scale biochemical networks while respecting the critical chemical phenomena at the atomistic scale. To pursue this multi-layer challenge, our strategy merges knowledge-based metabolic engineering methods with computational chemistry methods. By bridging multiple disciplines, we provide an integral computational framework that could accelerate the discovery and implementation of novel biosynthetic production routes. Using this approach, we have identified and optimized a novel biosynthetic route for the production of 3HP from pyruvate.


Minimization of monotonically levelable higher order MRF energies via graph cuts.
A feature of minimizing images of submodular binary Markov random field energies is introduced. Using this novel feature, the collection of minimizing images of levels of higher order, monotonically levelable multi label MRF energies is shown to constitute a monotone collection. This implies that these minimizing binary images can be combined to give minimizing images of the multi label MRF energies. Thanks to the graph cuts framework, the mentioned class of binary MRF energies is known to be minimized by maximum flow computations on appropriately constructed graphs. With the aid of these developments an exact and efficient algorithm to minimize monotonically levelable multi label MRF energies of any order, which is composed of a series of maximum flow computations, is proposed and an application of the proposed algorithm to image denoising is given.