A role for Snf2-related nucleosome-spacing enzymes in genome-wide nucleosome organization.
The positioning of nucleosomes within the coding regions of eukaryotic genes is aligned with respect to transcriptional start sites. This organization is likely to influence many genetic processes, requiring access to the underlying DNA. Here, we show that the combined action of Isw1 and Chd1 nucleosome-spacing enzymes is required to maintain this organization. In the absence of these enzymes, regular positioning of the majority of nucleosomes is lost. Exceptions include the region upstream of the promoter, the +1 nucleosome, and a subset of locations distributed throughout coding regions where other factors are likely to be involved. These observations indicate that adenosine triphosphate-dependent remodeling enzymes are responsible for directing the positioning of the majority of nucleosomes within the Saccharomyces cerevisiae genome.


Three dimensional anatomy of complete duct systems in human breast: pathological and developmental implications.
To reconstruct the arrangement in space of all major ducts and their branches from nipple to periphery of a human breast obtained at necropsy. Duct tracing through cleared haematoxylin stained 2 mm sub-gross coronal slices of a complete necropsy breast and computer modelling of duct territories. All branches were traced for 10 complete duct systems of a single breast from a 19 year old girl. Their complexity prevented comprehensive modelling of individual ducts and rami using available computer software, but the territories (catchments) drained by individual duct systems did not overlap and could be reconstructed. Catchment volume and length of the central unbranched duct draining each catchment varied greatly. Duct spacing showed non-random uniformity which is also seen in rodent mammary glands. These spatial relations are consistent with mutual growth inhibition between duct systems during mammary development. Although there is no clear morphological distinction between mammary duct end buds and lateral buds in women, the present study does suggest that processes of branching morphogenesis occurring during development of the breasts in women do show some analogies with the growth of end buds/lateral branches/alveoli during rodent mammary gland development. Rodent models of mammary development may usefully suggest hypotheses about human breast biology. Less laborious methods of three dimensional reconstruction of mammary ducts and their branches from sub-gross slices, allowing more specimens to be studied, would be valuable for the study of normal human breast development and mammary intraepithelial neoplasia. Increasing power and decreasing costs of high definition image processing hardware and software may make such endeavours practicable.


In vitro Detection of Occlusal Caries on Permanent Teeth by a Visual, Light-Induced Fluorescence and Photothermal Radiometry and Modulated Luminescence Methods.
The paradigm shift towards the nonsurgical management of dental caries relies on the early detection of the disease. Detection of caries at an early stage is of unequivocal importance for early preventive intervention. The aim of this in vitro study is to evaluate the performance of a visual examination using the International Caries Detection and Assessment System (ICDAS) criteria, two quantitative light-induced fluorescence (QLF) systems--Inspektor™ Pro and QLF-D Biluminator™ 2 (Inspektor Research Systems B.V., Amsterdam, The Netherlands)--and a photothermal radiometry and modulated luminescence, The Canary System® (Quantum Dental Technologies, Toronto, Ont., Canada) on the detection of primary occlusal caries on permanent teeth. A total of 60 teeth with occlusal surface sites ranging from sound to noncavitated lesions (ICDAS 0-4) were assessed with each detection method twice in a random order. Histological validation was used to compare methods for sensitivity, specificity, percent correct, and the area under the receiver operating characteristic curve (AUC), at standard and optimum sound thresholds. Interexaminer agreement and intraexaminer repeatability were measured using intraclass correlation coefficients. Interexaminer agreement ranged between 0.48 (The Canary System®) and 0.96 (QLF-D Biluminator™ 2). Intraexaminer repeatability ranges were 0.33-0.63 (The Canary System®) and 0.96-0.99 (QLF-D Biluminator™ 2). The sensitivity range was 0.75-0.96 while that of specificity was 0.43-0.89. The AUC were 0.79 (The Canary System®), 0.87 (ICDAS), 0.90 (Inspektor™ Pro), and 0.94 (QLF-D Biluminator™ 2). ICDAS had the best combination of sensitivity and specificity followed by QLF-D Biluminator™ 2 at optimum threshold.


Cues for movement in monkeys (Macaca mulatta) with lesions in premotor cortex.
It has been shown previously that after removal of premotor cortex, monkeys are poor at selecting movements on the basis of a visual contextual cue. In those experiments, the monkeys had to pull or turn a handle depending on the color of a cue presented in the foreground or background. In the present experiments, it is shown that animals with lesions that include premotor cortex can select movements correctly if the cue is given by information about the handle itself. In the first experiment, the cue was provided by the direction in which the monkey had last moved the handle; the monkeys had been required to squeeze a handle if they had been forced to squeeze it 5 s earlier, and they were required to turn it if they had been forced to turn it. In the second experiment, the cue was provided by the identity of the handle itself: When presented with a blue handle, they had to pull the handle; when presented with a yellow handle, they had to turn it. It is argued that the animals are impaired only when the task is a true conditional task.


Breast cancer screening legislation in the United States.
We discuss some of the issues emerging from a powerful legislative movement for preventive services over the past three years. During this time an increasing number of states passed, considered, or are currently developing breast cancer screening legislation. Most of these laws require some form of third party payment for mammography or establish breast cancer screening programs. The legislation varies markedly with regard to periodicity of examinations, ages covered, type and extent of third party coverage, dosage regulation, and radiographic equipment standards. This shows a need for common standards. Legislation provides an essential incentive for a public health response to a serious problem, but more than laws are needed. Health care providers and the general public need to be aware and take advantage of the coverage provided as a result of legislation. Moreover, public health officials need to be aware that such legislation may lead to a demand for services that exceeds present capacity to deliver them.


Effect of NOD2/CARD15 variants in T-cell depleted allogeneic stem cell transplantation.
Three single nucleotide polymorphisms (SNP) in the NOD2/CARD15 gene have been associated with the incidence and the severity of acute graft-versus-host disease (GVHD) following allogeneic stem cell transplantation (SCT). We hypothesized that the clinical effect of SNP in NOD2/CARD15 might be different in patients submitted to T-cell-depleted allogeneic SCT, in which donor T cells, the main effectors of GVHD, are eliminated. SNP 8, 12 and 13 in NOD2/CARD15 were studied using a Taqman protocol in 85 patients undergoing HLA-identical, T-cell-depleted SCT and in 71 of their sibling donors. NOD2/CARD15 variants were present in nine (11%) patients and six (8%) donors. The incidences of acute GVHD and chronic GVHD were not associated with either the donors' or recipients' NOD2/CARD15 variants. In contrast, these genetic variants were associated with a lower disease-free survival (17% vs. 48%, p=0.03). Death due to pulmonary infection was more frequent in the group of patients with NOD2/CARD15 variants. In the multivariate analysis, only NOD2/CARD15 variants (RR 2.3, p=0.04) and older age (RR 2.2; p=0.04) were independent prognostic factors for disease-free survival. NOD2/CARD15 variants have a deleterious effect on clinical outcome in T-cell-depleted allogeneic SCT, which is independent of GVHD. These results supports the hypothesis that the detrimental effect of NOD2/CARD15 variants in such a transplant setting might be produced by an alteration of the innate immune system more than by activation of the adaptive immune system.


Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation.
The proteome contains hundreds of proteins that in theory could be excellent therapeutic targets for the treatment of human diseases. However, many of these proteins are from functional classes that have never been validated as viable candidates for the development of small molecule inhibitors. Thus, to exploit fully the potential of the Human Genome Project to advance human medicine, there is a need to develop generic methods of inhibiting protein activity that do not rely on the target protein's function. We previously demonstrated that a normally stable protein, methionine aminopeptidase-2 or MetAP-2, could be artificially targeted to an Skp1-Cullin-F-box (SCF) ubiquitin ligase complex for ubiquitination and degradation through a chimeric bridging molecule or Protac (proteolysis targeting chimeric molecule). This Protac consisted of an SCF(beta-TRCP)-binding phosphopeptide derived from IkappaBalpha linked to ovalicin, which covalently binds MetAP-2. In this study, we employed this approach to target two different proteins, the estrogen (ER) and androgen (AR) receptors, which have been implicated in the progression of breast and prostate cancer, respectively. We show here that an estradiol-based Protac can enforce the ubiquitination and degradation of the alpha isoform of ER in vitro, and a dihydroxytestosterone-based Protac introduced into cells promotes the rapid disappearance of AR in a proteasome-dependent manner. Future improvements to this technology may yield a general approach to treat a number of human diseases, including cancer.


Ultrafast all-optical logic operations in a nonlinear Sagnac interferometer with two control beams.
Ultrafast highly stable all-optical logic operations, including inversion, AND, XOR, and XOR, in a two-wavelength nonlinear Sagnac interferometer with two control beams have been reported. The interferometer consists of a dichroic polarization-maintaining fiber coupler and a 200-m-long dispersion-shifted polarization-maintaining fiber Sagnac loop. The logic operations were successfully demonstrated at multigigabit operation per second, and the required signal power was 1.8 W for a 200-m fiber.


An observational study of emergency department utilization among enrollees of Minnesota Health Care Programs: financial and non-financial barriers have different associations.
Emergency department (ED) use is costly, and especially frequent among publicly insured populations in the US, who also disproportionately encounter financial (cost/coverage-related) and non-financial/practical barriers to care. The present study examines the distinct associations financial and non-financial barriers to care have with patterns of ED use among a publicly insured population. This observational study uses linked administrative-survey data for enrollees of Minnesota Health Care Programs to examine patterns in ED use-specifically, enrollee self-report of the ED as usual source of care, and past-year count of 0, 1, or 2+ ED visits from administrative data. Main independent variables included a count of seven enrollee-reported financial concerns about healthcare costs and coverage, and a count of seven enrollee-reported non-financial, practical barriers to access (e.g., limited office hours, problems with childcare). Covariates included health, health care, and demographic measures. In multivariate regression models, only financial concerns were positively associated with reporting ED as usual source of care, but only non-financial barriers were significantly associated with greater ED visits. Regression-adjusted values indicated notable differences in ED visits by number of non-financial barriers: zero non-financial barriers meant an adjusted 78% chance of having zero ED visits (95% C.I.: 70.5%-85.5%), 15.9% chance of 1(95% C.I.: 10.4%-21.3%), and 6.2% chance (95% C.I.: 3.5%-8.8%) of 2+ visits, whereas having all seven non-financial barriers meant a 48.2% adjusted chance of zero visits (95% C.I.: 30.9%-65.6%), 31.8% chance of 1 visit (95% C.I.: 24.2%-39.5%), and 20% chance (95% C.I.: 8.4%-31.6%) of 2+ visits. Financial barriers were associated with identifying the ED as one's usual source of care but non-financial barriers were associated with actual ED visits. Outreach/literacy efforts may help reduce reliance on/perception of ED as usual source of care, whereas improved targeting/availability of covered services may help curb frequent actual visits, among publicly insured individuals.


The relationship between quality, spending and outcomes among women with breast cancer.
Substantial shortcomings in the quality of breast cancer (BC) care have been identified. While breast cancer is responsible for the largest share of cancer care spending, little is known about the value of care provided to US women with BC. For women aged 65 to 70 years diagnosed July 1997 through December 2005 with stage 0-III BC who were continuously enrolled in fee-for-service Medicare, we evaluated performance relative to 20 measures recommending for proven therapies and seven measures recommending against unnecessary therapies. Using health care service area as the unit of analysis, we characterized quality for recommended and unnecessary therapies, median per-patient cost in the year after diagnosis for Medicare parts A and B, and five-year overall survival. We analyzed the relationships between quality, cost, and survival. All statistical tests were two-sided. We assessed the care provided to 15357 women and compiled quality, cost, and outcomes data for 99 regions. The median number of patients/region was 85 (interquartile range = 47-158); the five-year overall survival was 87.5%. Part B expenditure correlated positively with measures of recommended therapy (P = .027) and negatively with measures of unnecessary therapy (P = .004). Survival did not correlate with quality or cost. Regions demonstrating lower quality for both recommended and unnecessary therapy measures exhibited higher part A expenditure. BC patients experience wide variation in quality, cost, and survival. Process measures that assess recommended and unnecessary therapies did not correlate with survival, but did shed light on spending for related and unrelated services. Additional efforts to identify factors that impact the relationships between quality, cost, and outcomes are needed.


Efficient recovery of centric heterochromatin P-element insertions in Drosophila melanogaster.
Approximately one-third of the human and Drosophila melanogaster genomes are heterochromatic, yet we know very little about the structure and function of this enigmatic component of eukaryotic genomes. To facilitate molecular and cytological analysis of heterochromatin we introduced a yellow(+) (y(+))-marked P element into centric heterochromatin by screening for variegated phenotypes, that is, mosaic gene inactivation. We recovered >110 P insertions with variegated yellow expression from approximately 3500 total mobilization events. FISH analysis of 71 of these insertions showed that 69 (97%) were in the centric heterochromatin, rather than telomeres or euchromatin. High-resolution banding analysis showed a wide but nonuniform distribution of insertions within centric heterochromatin; variegated insertions were predominantly recovered near regions of satellite DNA. We successfully used inverse PCR to clone and sequence the flanking DNA for approximately 63% of the insertions. BLAST analysis of the flanks demonstrated that either most of the variegated insertions could not be placed on the genomic scaffold, and thus may be inserted within novel DNA sequence, or that the flanking DNA hit multiple sites on the scaffold, due to insertions within different transposons. Taken together these data suggest that screening for yellow variegation is a very efficient method for recovering centric insertions and that a large-scale screen for variegated yellow P insertions will provide important tools for detailed analysis of centric heterochromatin structure and function.


Use of medications by people with chronic fatigue syndrome and healthy persons: a population-based study of fatiguing illness in Georgia.
Chronic fatigue syndrome (CFS) is a debilitating condition of unknown etiology and no definitive pharmacotherapy. Patients are usually prescribed symptomatic treatment or self-medicate. We evaluated prescription and non-prescription drug use among persons with CFS in Georgia and compared it to that in non-fatigued Well controls and also to chronically Unwell individuals not fully meeting criteria for CFS. A population-based, case-control study. To identify persons with possible CFS-like illness and controls, we conducted a random-digit dialing telephone screening of 19,807 Georgia residents, followed by a detailed telephone interview of 5,630 to identify subjects with CFS-like illness, other chronically Unwell, and Well subjects. All those with CFS-like illness (n = 469), a random sample of chronically Unwell subjects (n = 505), and Well individuals (n = 641) who were age-, sex-, race-, and geographically matched to those with CFS-like illness were invited for a clinical evaluation and 783 participated (48% overall response rate). Clinical evaluation identified 113 persons with CFS, 264 Unwell subjects with insufficient symptoms for CFS (named ISF), and 124 Well controls; the remaining 280 subjects had exclusionary medical or psychiatric conditions, and 2 subjects could not be classified. Subjects were asked to bring all medications taken in the past 2 weeks to the clinic where a research nurse viewed and recorded the name and the dose of each medication. More than 90% of persons with CFS used at least one drug or supplement within the preceding two weeks. Among users, people with CFS used an average of 5.8 drugs or supplements, compared to 4.1 by ISF and 3.7 by Well controls. Persons with CFS were significantly more likely to use antidepressants, sedatives, muscle relaxants, and anti-acids than either Well controls or the ISF group. In addition, persons with CFS were significantly more likely to use pain-relievers, anti-histamines and cold/sinus medications than were Well controls. Medical care providers of patients with chronic fatigue syndrome should be aware of polypharmacy as a problem in such patients, and the related potential iatrogenic effects and drug interactions.


Ecological Intensification: Bridging the Gap between Science and Practice.
There is worldwide concern about the environmental costs of conventional intensification of agriculture. Growing evidence suggests that ecological intensification of mainstream farming can safeguard food production, with accompanying environmental benefits; however, the approach is rarely adopted by farmers. Our review of the evidence for replacing external inputs with ecosystem services shows that scientists tend to focus on processes (e.g., pollination) rather than outcomes (e.g., profits), and express benefits at spatio-temporal scales that are not always relevant to farmers. This results in mismatches in perceived benefits of ecological intensification between scientists and farmers, which hinders its uptake. We provide recommendations for overcoming these mismatches and highlight important additional factors driving uptake of nature-based management practices, such as social acceptability of farming.


Pre-transition effects mediate forces of assembly between transmembrane proteins.
We present a mechanism for a generic, powerful force of assembly and mobility for transmembrane proteins in lipid bilayers. This force is a pre-transition (or pre-melting) effect for the first-order transition between ordered and disordered phases in the membrane. Using large-scale molecular simulation, we show that a protein with hydrophobic thickness equal to that of the disordered phase embedded in an ordered bilayer stabilizes a microscopic order-disorder interface. The stiffness of that interface is finite. When two such proteins approach each other, they assemble because assembly reduces the net interfacial energy. Analogous to the hydrophobic effect, we refer to this phenomenon as the 'orderphobic effect'. The effect is mediated by proximity to the order-disorder phase transition and the size and hydrophobic mismatch of the protein. The strength and range of forces arising from this effect are significantly larger than those that could arise from membrane elasticity for the membranes considered.


X-ray laser diffraction for structure determination of the rhodopsin-arrestin complex.
Serial femtosecond X-ray crystallography (SFX) using an X-ray free electron laser (XFEL) is a recent advancement in structural biology for solving crystal structures of challenging membrane proteins, including G-protein coupled receptors (GPCRs), which often only produce microcrystals. An XFEL delivers highly intense X-ray pulses of femtosecond duration short enough to enable the collection of single diffraction images before significant radiation damage to crystals sets in. Here we report the deposition of the XFEL data and provide further details on crystallization, XFEL data collection and analysis, structure determination, and the validation of the structural model. The rhodopsin-arrestin crystal structure solved with SFX represents the first near-atomic resolution structure of a GPCR-arrestin complex, provides structural insights into understanding of arrestin-mediated GPCR signaling, and demonstrates the great potential of this SFX-XFEL technology for accelerating crystal structure determination of challenging proteins and protein complexes.


The influence of cognitive processes on rural landholder responses to climate change.
Global climate change modelling has identified south-east Australia as a 'hot spot' for more frequent climatic extremes. Rural landholders may be vulnerable to the risks climate change presents. Australia's rural landholders are considered highly adaptable, with a history of responding to climatic uncertainty and variability. Yet it is possible that some of their adaptations will not be effective in reducing vulnerability, and may have downstream impacts. Rural landholder decision making is complex, and this is one of a limited number of papers examining rural landholder responses to climate change and the factors influencing their decisions. Data were gathered using semi-structured interviews and a mail survey of rural landholders in two districts. Established socio-psychological scales were employed to measure beliefs, values and attitudes that are expected to shape landholder behaviour. Most of the rural landholders surveyed were not climate change 'deniers' with 70% agreeing that the climate is changing and that human activity is a major influence. Climate change was nominated as an influence on six adaptive behaviours by 50% or more of survey respondents. However, there were no significant relationships between belief in climate change and adaptive actions. Personal values and worldviews were found to be the most frequent factors linked to adaptive behaviour. These findings illustrate the complex nature of rural landholder decision making: suggesting that many rural landholders do not need convincing of the existence of climate change; and that efforts to motivate rural landholders to respond to climate change risks should be based on sound knowledge of their values and worldviews.


Understanding the fate and transport of petroleum hydrocarbons from coal tar within gasholders.
Coal tars have been identified as posing a threat to human health due to their toxic, mutagenic and carcinogenic characteristics. Workers involved in former gasholders decommissioning are potentially exposed to relevant concentrations of volatile and semi-volatile hydrocarbons upon opening up derelict tanks and during tar excavation/removal. While information on contaminated sites air-quality and its implications on medium-long term exposure is available, acute exposure issues associated with the execution of critical tasks are less understood. Calculations indicated that the concentration of a given contaminant in the gasholder vapour phase only depends on the coal tar composition, being only barely affected by the presence of water in the gasholder and the tar volume/void space ratio. Fugacity modelling suggested that risk-critical compounds such as benzene, naphthalene and other monocyclic and polycyclic aromatic hydrocarbons may gather in the gasholder air phase at significant concentrations. Gasholder emissions were measured on-site and compared with the workplace exposure limits (WELs) currently in use in UK. While levels for most of the toxic compounds were far lower than WELs, benzene air-concentrations where found to be above the accepted threshold. In addition due to the long exposure periods involved in gasholder decommissioning and the significant contribution given by naphthalene to the total coal tar vapour concentration, the adoption of a WEL for naphthalene may need to be considered to support operators in preventing human health risk at the workplace. The Level I fugacity approach used in this study demonstrated its suitability for applications to sealed environments such as gasholders and its further refining could provide a useful tool for land remediation risk assessors.


Hepcidin and iron homeostasis during pregnancy.
Hepcidin is the master regulator of systemic iron bioavailability in humans. This review examines primary research articles that assessed hepcidin during pregnancy and postpartum and report its relationship to maternal and infant iron status and birth outcomes; areas for future research are also discussed. A systematic search of the databases Medline and Cumulative Index to Nursing and Allied Health returned 16 primary research articles including 10 human and six animal studies. Collectively, the results indicate that hepcidin is lower during pregnancy than in a non-pregnant state, presumably to ensure greater iron bioavailability to the mother and fetus. Pregnant women with undetectable serum hepcidin transferred a greater quantity of maternally ingested iron to their fetus compared to women with detectable hepcidin, indicating that maternal hepcidin in part determines the iron bioavailability to the fetus. However, inflammatory states, including preeclampsia, malaria infection, and obesity were associated with higher hepcidin during pregnancy compared to healthy controls, suggesting that maternal and fetal iron bioavailability could be compromised in such conditions. Future studies should examine the relative contribution of maternal versus fetal hepcidin to the control of placental iron transfer as well as optimizing maternal and fetal iron bioavailability in pregnancies complicated by inflammation.


Urban city transportation mode and respiratory health effect of air pollution: a cross-sectional study among transit and non-transit workers in Nigeria.
To assess the respiratory health effect of city ambient air pollutants on transit and non-transit workers and compare such effects by transportation mode, occupational exposure and sociodemographic characteristics of participants. Cross-sectional, randomised survey. A two primary healthcare centre survey in 2009/2010 in Uyo metropolis, South-South Nigeria. Of the 245 male participants recruited, 168 (50 taxi drivers, 60 motorcyclists and 58 civil servants) met the inclusion criteria. These include age 18-35 years, a male transit worker or civil servant who had worked within Uyo metropolis for at least a year prior to the study, and had no history of respiratory disorders/impairment or any other debilitating illness. The adjusted ORs for respiratory function impairment (force vital capacity (FVC) and/or FEV(1)<80% predicted or FEV(1)/FVC<70% predicted) using Global Initiative for Chronic Obstructive Lung Diseases (GOLD) and National Institute for Health and Clinical Excellence (NICE) criteria were calculated. In order to investigate specific occupation-dependent respiratory function impairment, a comparison was made between the ORs for respiratory impairment in the three occupations. Adjustments were made for some demographic variables such as age, BMI, area of residence, etc. Exposure to ambient air pollution by occupation and transportation mode was independently associated with respiratory functions impairment and incident respiratory symptoms among participants. Motorcyclists had the highest effect, with adjusted OR 3.10, 95% CI 0.402 to 16.207 for FVC<80% predicted and OR 1.71, 95% CI 0.61 to 4.76 for FEV(1)/FVC<70% predicted using GOLD and NICE criteria. In addition, uneducated, currently smoking transit workers who had worked for more than 1 year, with three trips per day and more than 1 h transit time per trip were significantly associated with higher odds for respiratory function impairment at p<0.001, respectively. Findings of this study lend weights to the existing literature on the adverse respiratory health effect of ambient air pollution on city transit workers globally. The role of other confounders acting synergistically to cause a more deleterious effect is obvious. In all, the effect depends on the mode and duration of exposure.


Metabolic correlates of hominid brain evolution.
Large brain sizes in humans have important metabolic consequences as humans expend a relatively larger proportion of their resting energy budget on brain metabolism than other primates or non-primate mammals. The high costs of large human brains are supported, in part, by diets that are relatively rich in energy and other nutrients. Among living primates, the relative proportion of metabolic energy allocated to the brain is positively correlated with dietary quality. Humans fall at the positive end of this relationship, having both a very high quality diet and a large brain size. Greater encephalization also appears to have consequences for aspects of body composition. Comparative primate data indicate that humans are 'under-muscled', having relatively lower levels of skeletal muscle than other primate species of similar size. Conversely, levels of body fatness are relatively high in humans, particularly in infancy. These greater levels of body fatness and reduced levels of muscle mass allow human infants to accommodate the growth of their large brains in two important ways: (1) by having a ready supply of stored energy to 'feed the brain', when intake is limited and (2) by reducing the total energy costs of the rest of the body. Paleontological evidence indicates that the rapid brain evolution observed with the emergence of Homo erectus at approximately 1.8 million years ago was likely associated with important changes in diet and body composition.


Survey of Mymarommatidae and their occurrence in agricultural systems in Brazil.
Mymarommatidae surveys were carried out through the use of yellow pan traps in crops of green dwarf coconut, Cocos nucifera L. (Arecales: Arecaceae), papaya, Carica papaya L. (Brassicales: Caricaceae), citrus, Citrus spp. L. (Sapindales: Rutaceae), and guava, Psidium guajava L. (Myrtales: Myrtaceae), in the northern Espirito Santo State, Brazil. 146 specimens of mymarommatids were collected, of which 71, 55, 16, and 4 exemplars were obtained in the area cultivated with guava, papaya, citrus, and coconut, respectively. The mean numbers of mymarommatids collected in the period from April to June 2011 were significantly higher than those obtained in the other nine months. Two genera, Mymaromma and Mymaromella, were identified The most abundant genus was Mymaromma, comprising 93.8% of the total collection; however, the genus Mymaromella was encountered in all crops. This is the first record of the presence of mymarommatids in these agricultural systems.


Water resources and nitrate discharges in relation to agricultural land uses in an intensively irrigated watershed.
Application of integrated hydrological models to manage water resources and non-point agricultural pollutants are increasingly used in decision-making processes. In this study SWAT (Soil and Water Assessment Tool) was used to simulate the water balance and nitrate pollution in an intensively irrigated agricultural catchment (Flumen River in Monegros, Aragon, NE Spain). Rainfall comprised only 45% of the inputs of water in the Flumen watershed and the rest is contributed through irrigation canals from two other rivers outside the Flumen watershed. Green water storage and green water flow are the dominant components of the water balance in the watershed, which is related to the important contribution of water for irrigation. In general, green water storage and green water flow are quite similar in the subwatersheds dominated by irrigation agriculture that are located in the central part of the watershed. A similar pattern was observed for blue water, with high amounts in the central irrigated subwatersheds compared to the non-irrigated subwatersheds. Consequently, nitrate infiltration in the aquifer was higher in the inner irrigated subwatersheds (100-250 kg N ha-1 year-1) but much lower than the lateral flow rates estimated in the non-irrigated subwatersheds (1400-2000 kg N ha-1 year-1). Two scenarios simulating the effects of expected climate change factors in this zone were performed. A reduction in the availability of water for irrigation will transform the area from irrigated crops to cereal. In this case the water flow of River Flumen at the outlet of the watershed is reduced by 15%. If a reduction of 40% nitrate fertilization is applied, the nitrate exported to Flumen River would decreased by 28%. These results suggest that dosing irrigation water and fertilizers in accordance with crop requirements would contribute to buffer peaks of water and nitrate discharges and to a more efficient agricultural use of the resources.


Centrally administered resistin enhances sympathetic nerve activity to the hindlimb but attenuates the activity to brown adipose tissue.
Resistin, an adipokine, is believed to act in the brain to influence energy homeostasis. Plasma resistin levels are elevated in obesity and are associated with metabolic and cardiovascular disease. Increased muscle sympathetic nerve activity (SNA) is a characteristic of obesity, a risk factor for diabetes and cardiovascular disease. We hypothesized that resistin affects SNA, which contributes to metabolic and cardiovascular dysfunction. Here we investigated the effects of centrally administered resistin on SNA to muscle (lumbar) and brown adipose tissue (BAT), outputs that influence cardiovascular and energy homeostasis. Overnight-fasted rats were anesthetized, and resistin (7 μg) was administered into the lateral cerebral ventricle (intracerebroventricular). The lumbar sympathetic nerve trunk or sympathetic nerves supplying BAT were dissected free, and nerve activity was recorded. Arterial blood pressure, heart rate, body core temperature, and BAT temperature were also recorded. Responses to resistin or vehicle were monitored for 4 h after intracerebroventricular administration. Acutely administered resistin increased lumbar SNA but decreased BAT SNA. Mean arterial pressure and heart rate, however, were not significantly affected by resistin. BAT temperature was significantly reduced by resistin, and there was a concomitant fall in body temperature. The findings indicate that resistin has differential effects on SNA to tissues involved in metabolic and cardiovascular regulation. The decreased BAT SNA and the increased lumbar SNA elicited by resistin suggest that it may contribute to the increased muscle SNA and reduced energy expenditure observed in obesity and diabetes.


Risk of Incident Diabetes Mellitus Associated With the Dosage and Duration of Oral Glucocorticoid Therapy in Patients With Rheumatoid Arthritis.
To quantify the risk of incident diabetes mellitus (DM) associated with the dosage, duration, and timing of glucocorticoid (GC) use in patients with rheumatoid arthritis (RA). We undertook a cohort study using 2 databases: a UK primary care database (the Clinical Practice Research Datalink [CPRD]) including 21,962 RA patients (1992-2009) and the US National Data Bank for Rheumatic Diseases (NDB) including 12,657 RA patients (1998-2013). Information on the dosage and timing of GC use was extracted. DM in the CPRD was defined using Read codes, at least 2 prescriptions for oral antidiabetic medication, or abnormal blood test results. DM in the NDB was defined through patient self-reports. Data were analyzed using time-dependent Cox models and a novel weighted cumulative dose (WCD) model that accounts for dosage, duration, and timing of treatment. The hazard ratio (HR) was 1.30 (95% confidence interval [95% CI] 1.17-1.45) and 1.61 (95% CI 1.37-1.89) in current GC users compared to nonusers in the CPRD and the NDB, respectively. A range of conventional statistical models consistently confirmed increases in risk with the GC dosage and duration. The WCD model showed that recent GC use contributed the most to the current risk of DM, while doses taken >6 months previously did not influence current risk. In the CPRD, 5 mg of prednisolone equivalent dose for the last 1, 3, and 6 months was significantly associated with HRs of 1.20, 1.43, and 1.48, respectively, compared to nonusers. GC use is a clinically important and quantifiable risk factor for DM. Risk is influenced by the dosage and treatment duration, although only for GC use within the last 6 months.


Transmission potential of two chimeric western equine encephalitis vaccine candidates in Culex tarsalis.
Western equine encephalitis virus (WEEV) is a zoonotic alphavirus that circulates in western North America between passerine birds and mosquitoes, primarily Culex tarsalis. Since it was isolated in 1930, WEEV has caused tens of thousands of equine deaths in addition to thousands of human cases. In addition because WEEV is a virus of agricultural importance in addition to a public health threat, we developed two live-attenuated chimeric vaccine candidates that have been shown to be immunogenic and efficacious in mouse models. Vaccine candidate strains were developed by inserting the structural protein genes of WEEV strain McMillan (McM) or CO92-1356 into a Sindbis virus (SINV) strain AR339 backbone. The SIN/McM chimera also derived the N-terminal half of its capsid gene from a North American eastern equine encephalitis virus (EEEV) strain FL39-939 (henceforth referred to as SIN/EEE/McM). Although these vaccines do not generate viremia in mice, we further assessed their safety by exposing Cx. tarsalis to artificial blood meals containing high viral titers of each vaccine candidate. Both viruses exhibited a decreased rate of infection, dissemination, and transmission potential compared with the parental alphaviruses. Specifically, SIN/CO92 infected 37% of mosquitoes and disseminated in 8%, but failed to reach the saliva of the mosquitoes. In contrast, the SIN/EEE/McM virus was unable to infect, disseminate, or be transmitted in the saliva of any mosquitoes. These findings suggest that both vaccine candidates are less competent than the parental strains to be transmitted by the primary mosquito vector, Cx. tarsalis, and are unlikely to be reintroduced into a natural WEEV transmission cycle.


Sex- and age-based differences in single tooth loss in adults.
The aim of this study was to investigate sex- and age-based differences in single tooth loss in adults. The data were obtained from the results of a periodontal disease examination carried out under a health promotion law in a city in Japan in 2005. Baseline data from a total of 3,872 participants aged 40 or 60 years comprising 1,302 men and 2,570 women were available. Only participants with 27 present teeth were eligible for inclusion in the analysis, giving a total of 218 men and 428 women. Third molars were excluded from the study. The bilateral total of each type of tooth was obtained. The mandibular first molar was missing in 26.7% of the men and 36.2% of the women among 40-year-olds and 35.3% of the men and 29.8% of the women among 60-year-olds. The mandibular second molar was missing in 14.7% of the men and 12.5% of the women among 40-year-olds, and 17.6% of the men and 18.4% of the women among 60-year-olds. Significant differences were observed between men and women in the mandibular second premolars and first molars among 40-year-olds. These results suggest that we need to pay more attention to individual teeth which are at particularly high risk for tooth loss, namely the mandibular first and second molars, and especially the mandibular first molars in middle-aged women.


The role of the viral glycoprotein in HIV-1 persistence.
The study of the immunological defects which arise from HIV infection has led to a deeper understanding both of the normal immune system and of the mechanisms by which it is damaged in disease. The interactions between viral and host factors during the early stages of HIV infection leads to a post-seroconversion steady state or 'set point' of viral RNA load, which has been shown to be a prognostic marker for subsequent progression rates, further underlining the important role of early immunological responses in the disease process. The changing immune response during the course of infection, together with the changing patterns of antigenicity and tropism leads to a complex series of evolutionary interactions which can be monitored as a series of changes in the properties of the virus over time. Furthermore, significant differences may be seen between the antigenicity of viruses adapted to grow in tissue culture and viruses cultured only briefly in primary cells, and also between the antigenicity of monomeric and oligomeric subunit immunogens. The immunodominant, highly polymorphic and rapidly changing envelope glycoproteins of HIV remains the single biggest target for the design of successful candidate vaccines. The recent crystallisation of one HIV envelope, the proven existence of functionally conserved neutralisation targets and our increasing knowledge of the behaviour of the envelope glycoprotein in vivo offers the possibility that the next generation of vaccine candidates will have a far higher chance of success than has currently been achieved.


Association of Very Low-Volume Practice With Vascular Surgery Outcomes in New York.
Little research has focused on very low-volume surgery, especially in the context of decreasing vascular surgery volume with the adoption of endovascular procedures. To investigate the existence and outcomes of open abdominal aortic aneurysm repair (OAR) and carotid endarterectomy (CEA) performed by very low-volume surgeons in New York. This cohort study examined inpatient data of patients undergoing elective OAR or CEA from 2000 to 2014 from all New York hospitals. Surgeons who performed 1 or less designated procedure per year on average were considered very low volume, as opposed to higher-volume surgeons. Temporal trends of the existence of very low-volume practice were evaluated. Hierarchical logistic regression was used to compare in-hospital outcomes and health care resource use between patients treated by very low-volume surgeons and higher-volume surgeons for both OAR and CEA, adjusting for patient, surgeon, and hospital characteristics. There were 8781 OAR procedures and 68 896 CEA procedures included in the study. The mean (SD) patient age was 71.7 (8.4) years for OAR and 71.5 (9.1) years for CEA. A total of 614 surgeons performed OAR and 1071 performed CEA in New York during the study period. Of these, 318 (51.8%) and 512 (47.8%), respectively, were very low-volume surgeons. Very low-volume surgeons were less likely to be vascular surgeons. The number and proportion of very low-volume surgeons decreased over years. Compared with patients treated by higher-volume surgeons, those treated by very low-volume surgeons were more likely to have higher in-hospital mortality (odds ratio [OR], 2.09; 95% CI, 1.41-3.08) following OAR and higher risks of postoperative myocardial infarction (OR, 1.83; 95% CI, 1.03-3.26) and stroke (OR, 1.78; 95% CI, 1.21-2.62) following CEA. Patients treated by very low-volume surgeons also had greater health care resource use following both surgeries, including prolonged length of stay (OR, 1.37; 95% CI, 1.11-1.70) following OAR as well as higher charges (OR, 1.28; 95% CI, 1.01-1.62) and increased 30-day readmission (OR, 1.30; 95% CI 1.04-1.62) following CEA. The OAR and CEA procedures performed by very low-volume surgeons resulted in worse postoperative outcomes and greater lengths of stay. Although the percentage of very low-volume surgeons declined from 2000 to 2014, it remains concerning, given ready access to higher-volume surgeons. Future research is needed to understand the existence of this practice pattern in other surgical fields. Efforts to eliminate this practice pattern are warranted to ensure high-quality care for all patients.


The effect of the remplissage procedure on shoulder range of motion: a cadaveric study.
The purpose of this in vitro biomechanical study was to assess the effects of the remplissage procedure for small- and large-sized Hill-Sachs lesions (HSLs) on shoulder range of motion (ROM) with a special interest in the apprehension position. HSLs of 50% and 100% of the glenoid width were simulated in 7 cadaveric shoulders as small and large lesions, respectively, and the postoperative condition was reproduced by placing suture anchors on the articular surface and tying down the infraspinatus at the medial edge of the would-be lesion site. ROMs were measured in abduction, internal rotation, and external rotation with the humerus in the adducted and abducted position. In addition, the ROM was measured in the anterior apprehension position, in which 2 torques of external rotation and extension were applied simultaneously, and external rotation and horizontal extension ROMs were measured with the humerus in different abduction angles (20°, 40°, and 60°). For standard ROMs, the procedure for the 50% HSL maintained complete ROMs, whereas the procedure for the 100% HSL significantly decreased external rotation ROM with the humerus in both the adducted and abducted positions, as well as abduction ROM. In the apprehension position, remplissage for the 50% HSL decreased extension ROM with the humerus abducted to 40° and 60°. Remplissage for the 100% HSL significantly decreased both external and extension ROMs regardless of the humeral abduction angle. In the cadaveric model with an intact humeral head and the simulated postoperative condition, the remplissage procedure for a large HSL caused significant restrictions in ROM of abduction in the scapular plane and external rotation with the humerus in both adduction and abduction. It also caused significant restrictions in both external rotation and extension ROMs in the apprehension position. The indication for the remplissage procedure for the larger HSL should be considered carefully, especially for the competitive throwing athlete who needs exceptional external rotation ROM for optimal overhead throwing performance.


Regulatory constraints in the generation and differentiation of IgE-expressing B cells.
B cells expressing antibodies of the immunoglobulin E (IgE) isotype are rare, yet are heavily implicated in the pathogenesis of allergies and asthma. This review discusses recent methodological advances that permit sensitive probing of IgE-expressing (IgE(+)) B cells in vivo and have accordingly clarified the basic behavior and fate of IgE(+) B cells during immune responses in mouse models. IgE antibody secreting plasma cells can arise from extrafollicular foci, germinal centers, and memory B cells. However, compared to B cells expressing other isotypes, IgE(+) B cells are susceptible to multiple additional regulatory constraints that restrict the size of the IgE(+) B cell pool at each stage, coordinately limiting the overall magnitude, affinity, and duration of the IgE antibody response.


Association between HLA-DQB1 alleles and HAM/TSP patients in Khorasan Province.
HTLVI-1 is the first human retrovirus with limited endemic regions in the world. The epidemiological studies have shown that the genetic background and immune response to the virus have a significant role in HTLV-I-associated diseases. Among the genes are involved in HTLV-I infection, the role of human leukocytes antigen (HLA) have been studied in different population. In the present study we examined the association between HLA-DQB1 alleles and HTLV-I infection in HAM/TSP patients, HTLV-I carriers and healthy controls in north east of Iran, Mashhad. The blood samples of 16 patients with HAM/TSP, 20 HTLV-1 carriers, and 30 healthy individuals were taken and DNA was extracted by salting out method. HLA-DQB1 typing was performed using PCR-SSP method and the frequency of HLA-DQB1 alleles were compared by Fischer Exact Test. There was a significant difference between HAM/TSP patients and healthy controls in the frequency of HLA-DQB1*07 (P=0.004, RR=7). Furthermore, we found that possession of HLA- DQB1*02 or HLA-DQB1*05 increased the risk of disease 1.5 times. The data presented here suggest that both HLA-DQB1*07 and HLA-DQB1*06 are associated with disease development.


ERK signaling pathway regulates sleep duration through activity-induced gene expression during wakefulness.
Wakefulness is accompanied by experience-dependent synaptic plasticity and an increase in activity-regulated gene transcription. Wake-induced genes are certainly markers of neuronal activity and may also directly regulate the duration of and need for sleep. We stimulated murine cortical cultures with the neuromodulatory signals that are known to control wakefulness in the brain and found that norepinephrine alone or a mixture of these neuromodulators induced activity-regulated gene transcription. Pharmacological inhibition of the various signaling pathways involved in the regulation of gene expression indicated that the extracellular signal-regulated kinase (ERK) pathway is the principal one mediating the effects of waking neuromodulators on gene expression. In mice, ERK phosphorylation in the cortex increased and decreased with wakefulness and sleep. Whole-body or cortical neuron-specific deletion of Erk1 or Erk2 significantly increased the duration of wakefulness in mice, and pharmacological inhibition of ERK phosphorylation decreased sleep duration and increased the duration of wakefulness bouts. Thus, this signaling pathway, which is highly conserved from Drosophila to mammals, is a key pathway that links waking experience-induced neuronal gene expression to sleep duration and quality.


Noninterferometric wide-field optical profilometry with nanometer depth resolution.
Applying the principle of differential confocal microscopy to wide-field optically sectioning microscopy, we develop a noninterferometric optical profilometer without scanning mechanisms. Depth resolution of 2 nm is achieved with a power-regulated tungsten-halogen lamp as the light source and a 14-bit CCD camera as the detector. The effects of inhomogeneous surface reflectivity are removed from topographic measurements by arithmetic division. The whole system can be constructed on a single silicon chip for use as a miniaturized optical profiler.


Straining Psychic and Social Sinew: Trauma among Adolescent Psychiatric Patients in New Mexico.
Drawing on data from a longitudinal study of 47 adolescents of diverse ethnic backgrounds hospitalized for psychiatric disorder in New Mexico, the article critically examines the relevance of post-traumatic stress disorder (PTSD) to address anthropological questions of how to define the problem. Factors include the utility/limitation of psychiatric diagnostic categories, the lived experience of severe distress, the socioeconomic and political conditions of suffering, and reciprocal relations between immediate and remote social institutions. I discuss the mental health care system for adolescents and present two case studies of young inpatients, emphasizing the need for dual specification of the conditions of trauma and the structure of experience. I argue for understanding patterns of abandonment that shape the raw existence of young people at both the personal and collective levels to apprehend their depth and durability.


Rescue of HIV-1 broad neutralizing antibody-expressing B cells in 2F5 VH x VL knockin mice reveals multiple tolerance controls.
The HIV-1 broadly neutralizing Ab (bnAb) 2F5 has been shown to be poly-/self-reactive in vitro, and we previously demonstrated that targeted expression of its VDJ rearrangement alone was sufficient to trigger a profound B cell developmental blockade in 2F5 V(H) knockin (KI) mice, consistent with central deletion of 2F5 H chain-expressing B cells. In this study, we generate a strain expressing the entire 2F5 bnAb specificity, 2F5 V(H) × V(L) KI mice, and find an even higher degree of tolerance control than observed in the 2F5 V(H) KI strain. Although B cell development was severely impaired in 2F5 V(H) × V(L) KI animals, we demonstrate rescue of their B cells when cultured in IL-7/BAFF. Intriguingly, even under these conditions, most rescued B cell hybridomas produced mAbs that lacked HIV-1 Envelope (Env) reactivity due to editing of the 2F5 L chain, and the majority of rescued B cells retained an anergic phenotype. Thus, when clonal deletion is circumvented, κ editing and anergy are additional safeguards preventing 2F5 V(H)/V(L) expression by immature/transitional B cells. Importantly, 7% of rescued B cells retained 2F5 V(H)/V(L) expression and secreted Env-specific mAbs with HIV-1-neutralizing activity. This partial rescue was further corroborated in vivo, as reflected by the anergic phenotype of most rescued B cells in 2F5 V(H) × V(L) KI × Eμ-Bcl-2 transgenic mice and significant (yet modest) enrichment of Env-specific B cells and serum Igs. The rescued 2F5 mAb-producing B cell clones in this study are the first examples, to our knowledge, of in vivo-derived bone marrow precursors specifying HIV-1 bnAbs and provide a starting point for design of strategies aimed at rescuing such B cells.


Brain tumor specifies intermediate progenitor cell identity by attenuating β-catenin/Armadillo activity.
During asymmetric stem cell division, both the daughter stem cell and the presumptive intermediate progenitor cell inherit cytoplasm from their parental stem cell. Thus, proper specification of intermediate progenitor cell identity requires an efficient mechanism to rapidly extinguish the activity of self-renewal factors, but the mechanisms remain unknown in most stem cell lineages. During asymmetric division of a type II neural stem cell (neuroblast) in the Drosophila larval brain, the Brain tumor (Brat) protein segregates unequally into the immature intermediate neural progenitor (INP), where it specifies INP identity by attenuating the function of the self-renewal factor Klumpfuss (Klu), but the mechanisms are not understood. Here, we report that Brat specifies INP identity through its N-terminal B-boxes via a novel mechanism that is independent of asymmetric protein segregation. Brat-mediated specification of INP identity is critically dependent on the function of the Wnt destruction complex, which attenuates the activity of β-catenin/Armadillo (Arm) in immature INPs. Aberrantly increasing Arm activity in immature INPs further exacerbates the defects in the specification of INP identity and enhances the supernumerary neuroblast mutant phenotype in brat mutant brains. By contrast, reducing Arm activity in immature INPs suppresses supernumerary neuroblast formation in brat mutant brains. Finally, reducing Arm activity also strongly suppresses supernumerary neuroblasts induced by overexpression of klu. Thus, the Brat-dependent mechanism extinguishes the function of the self-renewal factor Klu in the presumptive intermediate progenitor cell by attenuating Arm activity, balancing stem cell maintenance and progenitor cell specification.


Evidence of inadequate ventilation in portable classrooms: results of a pilot study in Los Angeles County.
The prevalence of prefabricated, portable classrooms (portables) for United States public schools has increased; in California, approximately one of three students learn inside portables. Limited research has been conducted on indoor air and environmental quality in American schools, and almost none in portables. Available reports and conference proceedings suggest problems from insufficient ventilation due to poor design, operation, and/or maintenance of heating, ventilation and air conditioning (HVAC) systems; most portables have one mechanical, wall-mounted HVAC system. A pilot assessment was conducted in Los Angeles County, including measurements of integrated ventilation rates based on a perfluorocarbon tracer gas technique and continuous monitoring of temperature (T) and relative humidity (RH). Measured ventilation rates were low [mean school day integrated average 0.8 per hour (range: 0.1-2.9 per hour)]. Compared with relevant standards, results suggested adequate ventilation and associated conditioning of indoor air for occupant comfort were not always provided to these classrooms. Future school studies should include integrated and continuous measurements of T, RH, and ventilation with appropriate tracer gas methods, and other airflow measures. Adequate ventilation has the potential to mitigate concentrations of chemical pollutants, particles, carbon dioxide, and odors in portable and traditional classrooms, which should lead to a reduction in reported health outcomes, e.g., symptoms of 'sick building syndrome', allergies, asthma. Investigations of school indoor air and environmental quality should include continuous temperature and relative humidity data with inexpensive instrumentation as indicators of thermal comfort, and techniques to measure ventilation rates.


Impaired response inhibition in veterans with post-traumatic stress disorder and mild traumatic brain injury.
Combat veterans with post-traumatic stress disorder (PTSD) can show impairments in executive control and increases in impulsivity. The current study examined the effects of PTSD on motor response inhibition, a key cognitive control function. A Go/NoGo task was administered to veterans with a diagnosis of PTSD based on semi-structured clinical interview using DSM-IV criteria (n = 40) and age-matched control veterans (n = 33). Participants also completed questionnaires to assess self-reported levels of PTSD and depressive symptoms. Performance measures from the patients (error rates and reaction times) were compared to those from controls. PTSD patients showed a significant deficit in response inhibition, committing more errors on NoGo trials than controls. Higher levels of PTSD and depressive symptoms were associated with higher error rates. Of the three symptom clusters, re-experiencing was the strongest predictor of performance. Because the co-morbidity of mild traumatic brain injury (mTBI) and PTSD was high in this population, secondary analyses compared veterans with PTSD+mTBI (n = 30) to veterans with PTSD only (n = 10). Although preliminary, results indicated the two patient groups did not differ on any measure (p > .88). Since cognitive impairments could hinder the effectiveness of standard PTSD therapies, incorporating treatments that strengthen executive functions might be considered in the future. (JINS, 2012, 18, 1-10).


Construct validation of the ProMIS simulator using a novel laparoscopic suturing task.
The use of simulation for minimally invasive surgery (MIS) skills training has many advantages over current traditional methods. One advantage of simulation is that it enables an objective assessment of technical performance. The purpose of this study was to determine whether the ProMIS augmented reality simulator could objectively distinguish between levels of performance skills on a complex laparoscopic suturing task. Ten subjects--five laparoscopic experts and five laparoscopic novices--were assessed for baseline perceptual, visio-spatial, and psychomotor abilities using validated tests. After three trials of a novel laparoscopic suturing task were performed on the simulator, measures for time, smoothness of movement, and path distance were analyzed for each trial. Accuracy and errors were evaluated separately by two blinded reviewers to an interrater reliability of >0.8. Comparisons of mean performance measures were made between the two groups using a Mann-Whitney U test. Internal consistency of ProMIS measures was assessed with coefficient alpha. The psychomotor performance of the experts was superior at baseline assessment (p < 0.001). On the laparoscopic suturing task, the experts performed significantly better than the novices across all three trials (p < 0.001). They performed the tasks between three and four times faster (p < 0.0001), had three times shorter instrument path length (p < 0.0001), and had four times greater smoothness of instrument movement (p < 0.009). Experts also showed greater consistency in their performance, as demonstrated by SDs across all measures, which were four times smaller than the novice group. Observed internal consistency of ProMIS measures was high (alpha = 0.95, p < 0.00001). Preliminary results of construct validation efforts of the ProMIS simulator show that it can distinguish between experts and novices and has promising psychometric properties. The attractive feature of ProMIS is that a wide variety of MIS tasks can be used to train and assess technical skills.


Matching by linear programming and successive convexification.
We present a novel convex programming scheme to solve matching problems, focusing on the challenging problem of matching in a large search range and with cluttered background. Matching is formulated as metric labeling with L1 regularization terms, for which we propose a novel linear programming relaxation method and an efficient successive convexification implementation. The unique feature of the proposed relaxation scheme is that a much smaller set of basis labels is used to represent the original label space. This greatly reduces the size of the searching space. A successive convexification scheme solves the labeling problem in a coarse to fine manner. Importantly, the original cost function is reconvexified at each stage, in the new focus region only, and the focus region is updated so as to refine the searching result. This makes the method well-suited for large label set matching. Experiments demonstrate successful applications of the proposed matching scheme in object detection, motion estimation, and tracking.


The application of methods of non-linear dynamics for the improved and predictive recognition of patients threatened by sudden cardiac death.
This study introduces new methods of non-linear dynamics (NLD) and compares these with traditional methods of heart rate variability (HRV) and high resolution ECG (HRECG) analysis in order to improve the reliability of high risk stratification. Simultaneous 30 min high resolution ECG's and long-term ECG's were recorded from 26 cardiac patients after myocardial infarction (MI). They were divided into two groups depending upon the electrical risk, a low risk group (group 2, n = 10) and a high risk group (group 3, n = 16). The control group consisted of 35 healthy persons (group 1). From these electrocardiograms we extracted standard measures in time and frequency domain as well as measures from the new non-linear methods of symbolic dynamics and renormalized entropy. Applying discriminant function techniques on HRV analysis the parameters of non-linear dynamics led to an acceptable differentiation between healthy persons and high risk patients of 96%. The time domain and frequency domain parameters were successful in less than 90%. The combination of parameters from all domains and a stepwise discriminant function separated these groups completely (100%). Use of this discriminant function classified three patients with apparently low (no) risk into the same cluster as high risk patients. The combination of the HRECG and HRV analysis showed the same individual clustering but increased the positive value of separation. The methods of NLD describe complex rhythm fluctuations and separate structures of non-linear behavior in the heart rate time series more successfully than classical methods of time and frequency domains. This leads to an improved discrimination between a normal (healthy persons) and an abnormal (high risk patients) type of heart beat generation. Some patients with an unknown risk exhibit similar patterns to high risk patients and this suggests a hidden high risk. The methods of symbolic dynamics and renormalized entropy were particularly useful measures for classifying the dynamics of HRV.


Bax/Bak-dependent, Drp1-independent Targeting of X-linked Inhibitor of Apoptosis Protein (XIAP) into Inner Mitochondrial Compartments Counteracts Smac/DIABLO-dependent Effector Caspase Activation.
Efficient apoptosis requires Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), which releases death-promoting proteins cytochrome c and Smac to the cytosol, which activate apoptosis and inhibit X-linked inhibitor of apoptosis protein (XIAP) suppression of executioner caspases, respectively. We recently identified that in response to Bcl-2 homology domain 3 (BH3)-only proteins and mitochondrial depolarization, XIAP can permeabilize and enter mitochondria. Consequently, XIAP E3 ligase activity recruits endolysosomes into mitochondria, resulting in Smac degradation. Here, we explored mitochondrial XIAP action within the intrinsic apoptosis signaling pathway. Mechanistically, we demonstrate that mitochondrial XIAP entry requires Bax or Bak and is antagonized by pro-survival Bcl-2 proteins. Moreover, intramitochondrial Smac degradation by XIAP occurs independently of Drp1-regulated cytochrome c release. Importantly, mitochondrial XIAP actions are activated cell-intrinsically by typical apoptosis inducers TNF and staurosporine, and XIAP overexpression reduces the lag time between the administration of an apoptotic stimuli and the onset of mitochondrial permeabilization. To elucidate the role of mitochondrial XIAP action during apoptosis, we integrated our findings within a mathematical model of intrinsic apoptosis signaling. Simulations suggest that moderate increases of XIAP, combined with mitochondrial XIAP preconditioning, would reduce MOMP signaling. To test this scenario, we pre-activated XIAP at mitochondria via mitochondrial depolarization or by artificially targeting XIAP to the intermembrane space. Both approaches resulted in suppression of TNF-mediated caspase activation. Taken together, we propose that XIAP enters mitochondria through a novel mode of mitochondrial permeabilization and through Smac degradation can compete with canonical MOMP to act as an anti-apoptotic tuning mechanism, reducing the mitochondrial contribution to the cellular apoptosis capacity.


Leaching behavior of total organic carbon, nitrogen, and phosphorus from banana peel.
The leaching behavior of organic carbon and nutrient compounds from banana peel (BP) was investigated in batch assays with respect to particle size, contact time, pH value, and temperature. The granularity, contact time, pH, and temperature caused no significant effects on the leaching of total phosphorus (TP) from the BP. The maximum leached total nitrogen (TN) content was found at pH 5.0 and 90 minutes, while no significant effects were caused by the granularity and temperature. The maximum leached total organic carbon (TOC) content was found by using a powder of 40 mesh, 150 minutes and at pH 6.0, while the temperature had no effect on the TOC leaching. The proportions of the TN, TP, and TOC contents leached from the dried BP ranged from 33.6% to 40.9%, 60.4% to 72.7%, and 8.2% to 9.9%, respectively, indicating that BP could be a potential pollution source for surface and ground water if discharged as domestic waste or reutilized without pretreatment.


Once-daily long-acting beta-agonists for chronic obstructive pulmonary disease: an indirect comparison of olodaterol and indacaterol.
In the absence of head-to-head clinical trials comparing the once-daily, long-acting beta2-agonists olodaterol and indacaterol for the treatment of chronic obstructive pulmonary disease (COPD), an indirect treatment comparison by systematic review and synthesis of the available clinical evidence was conducted. A systematic literature review of randomized, controlled clinical trials in patients with COPD was performed to evaluate the efficacy and safety of olodaterol and indacaterol. Network meta-analysis and adjusted indirect comparison methods were employed to evaluate treatment efficacy, using outcomes based on trough forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index, St George's Respiratory Questionnaire total score and response, rescue medication use, and proportion of patients with exacerbations. Eighteen trials were identified for meta-analysis (eight, olodaterol; ten, indacaterol). Olodaterol trials included patients of all severities, whilst indacaterol trials excluded patients with very severe COPD. Concomitant maintenance bronchodilator use was allowed in most olodaterol trials, but not in indacaterol trials. When similarly designed trials/data were analyzed for change from baseline in trough FEV1 (liters), the following mean differences (95% confidence interval) were observed: trials excluding concomitant bronchodilator: indacaterol 75 mcg versus olodaterol 5 mcg, -0.005 (-0.077 to 0.067), and indacaterol 150 mcg versus olodaterol 5 mcg, 0.020 (-0.036 to 0.077); trials with concomitant tiotropium: indacaterol 150 mcg versus olodaterol 5 mcg, 0.000 (-0.043 to 0.042). In sensitivity analyses of the full network, results for change from baseline in trough FEV1 favored indacaterol, but this dataset suffered from trial design heterogeneity. For the other endpoints investigated, no statistically significant differences were found when analyzed in the full network. When compared under similar trial conditions, olodaterol and indacaterol have similar efficacy in patients with COPD. This research highlights the importance of considering the concomitant COPD medication when evaluating treatment effects in COPD.


Overregularization in language acquisition.
Children extend regular grammatical patterns to irregular words, resulting in overregularizations like comed, often after a period of correct performance ("U-shaped development"). The errors seem paradigmatic of rule use, hence bear on central issues in the psychology of rules: how creative rule application interacts with memorized exceptions in development, how overgeneral rules are unlearned in the absence of parental feedback, and whether cognitive processes involve explicit rules or parallel distributed processing (connectionist) networks. We remedy the lack of quantitative data on overregularization by analyzing 11,521 irregular past tense utterances in the spontaneous speech of 83 children. Our findings are as follows. (1) Overregularization errors are relatively rare (median 2.5% of irregular past tense forms), suggesting that there is no qualitative defect in children's grammars that must be unlearned. (2) Overregularization occurs at a roughly constant low rate from the 2s into the school-age years, affecting most irregular verbs. (3) Although overregularization errors never predominate, one aspect of their purported U-shaped development was confirmed quantitatively: an extended period of correct performance precedes the first error. (4) Overregularization does not correlate with increases in the number or proportion of regular verbs in parental speech, children's speech, or children's vocabularies. Thus, the traditional account in which memory operates before rules cannot be replaced by a connectionist alternative in which a single network displays rotelike or rulelike behavior in response to changes in input statistics. (5) Overregularizations first appear when children begin to mark regular verbs for tense reliably (i.e., when they stop saying Yesterday I walk). (6) The more often a parent uses an irregular form, the less often the child overregularizes it. (7) Verbs are protected from overregularization by similar-sounding irregulars, but they are not attracted to overregularization by similar-sounding regulars, suggesting that irregular patterns are stored in an associative memory with connectionist properties, but that regulars are not. We propose a simple explanation. Children, like adults, mark tense using memory (for irregulars) and an affixation rule that can generate a regular past tense form for any verb. Retrieval of an irregular blocks the rule, but children's memory traces are not strong enough to guarantee perfect retrieval. When retrieval fails, the rule is applied, and overregularization results.


Increased diagnostic yield of small bowel tumors with PillCam: the role of capsule endoscopy in the diagnosis and treatment of gastrointestinal stromal tumors (GISTs). Italian single-center experience.
Gastrointestinal stromal tumors (GISTs) are rare tumors, accounting for 1-3% of all gastrointestinal malignancies; they are, however, the most common gastric and small bowel mesenchymal tumors. The length and relative inaccessibility of the small bowel have long constrained the diagnosis of GISTs mainly presenting with chronic or intermittent bleeding as the sole clinical manifestation. To report on the prevalence of small bowel GISTs in a prospectively recorded series of patients undergoing capsule endoscopy (CE). Between 2001 and 2007 five hundred patients were referred to our endoscopy unit for small bowel evaluation with capsule endoscopy. We retrospectively evaluated all charts. The main indications for CE were obscure-occult or obscure-overt bleeding. Two hundred eighty-nine patients underwent CE for either obscure-occult or obscure-overt bleeding and 211 for other indications. Patient outcome and care processes were measured by follow-up telephone interviews and chart review. Statistical computations were performed using Fisher's exact test and Student's t-test. CE identified a small bowel tumor in 20 patients (4.0%) and 9 tumors turned out to be GISTs (45.0%). Traditional endoscopic and radiological imaging failed to detect the GIST in all these cases. In one case a small bowel GIST was diagnosed by angiography and CE proved false negative. Overall, CE was able to diagnose a small bowel GIST in 9 out of 10 cases. All patients underwent surgical treatment and showed normalized hemoglobin levels at follow-up. The main limitation of this study is the small number of cases. CE is an effective and sensitive diagnostic device compared with conventional radiology and plays an important role in the algorithm for the diagnostic work-up of suspected small bowel tumors.


Multifunctional albumin nanoparticles as combination drug carriers for intra-tumoral chemotherapy.
Current cancer therapies are challenged by weakly soluble drugs and by drug combinations that exhibit non-uniform biodistribution and poor bioavailability. In this study, we have presented a new platform of advanced healthcare materials based on albumin nanoparticles (ANPs) engineered as tumor penetrating, delivery vehicles of combinatorially applied factors to solid tumors. These materials were designed to overcome three sequential key barriers: tissue level transport across solid tumor matrix; uptake kinetics into individual cancer cells; therapeutic resistance to single chemotherapeutic drugs. The ANPs were designed to penetrate deeper into solid tumor matrices using collagenase decoration and evaluated using a three-dimensional multicellular melanoma tumor spheroid model. Collagenase modified ANPs exhibited 1-2 orders of magnitude greater tumor penetration than unmodified ANPs into the spheroid mass after 96 hours, and showed preferential uptake into individual cancer cells for smaller sized ANPs (<100 nm). For enhanced efficacy, collagenase coated ANPs were modified with two therapeutic agents, curcumin and riluzole, with complementary mechanisms of action for combined cell cycle arrest and apoptosis in melanoma. The collagenase coated, drug loaded nanoparticles induced significantly more cell death within 3-D tumor models than the unmodified, dual drug loaded ANP particles and the kinetics of cytotoxicity was further influenced by the ANP size. Thus, multifunctional nanoparticles can be imbued with complementary size and protease activity features that allow them to penetrate solid tumors and deliver combinatorial therapeutic payload with enhanced cancer cytotoxicity but minimal collateral damage to healthy primary cells.


Postoperative Pneumonia is Associated with Long-Term Oncologic Outcomes of Definitive Chemoradiotherapy Followed by Salvage Esophagectomy for Esophageal Cancer.
As we previously indicated, postoperative pneumonia has a negative impact on the overall survival after planned esophagectomy. However, the impact of postoperative pneumonia after salvage esophagectomy on long-term oncologic outcomes still remains unclear. This study aimed to indicate the association between postoperative pneumonia and long-term outcomes of definitive chemoradiotherapy followed by salvage esophagectomy. Furthermore, we determined a prediction model for overall survival (OS) and disease-free survival (DFS) using a survival classification and regression tree (CART). Ninety-three patients who underwent CRT followed by esophagectomy for thoracic esophageal cancer were identified for this study. Forty-nine patients and 44 patients were included in the salvage and neoadjuvant groups, respectively. We investigated the association between postoperative pneumonia and long-term oncologic outcomes following salvage esophagectomy. Patients from the salvage group tended to have a lower OS compared to neoadjuvant group (median survival: salvage, 24 months vs neoadjuvant, 43 months, p = 0.117). Multivariate analyses revealed that postoperative pneumonia adversely affected both OS (p < 0.001) and DFS (p = 0.044) after salvage esophagectomy. We generated the prediction model for OS and DFS in the salvage group using survival CART. Postoperative pneumonia was the most important parameter for predicting the OS. The present study demonstrates the long-term outcomes and risk factors for mortality of salvage esophagectomy. To improve OS after salvage surgery, the development of a means of decreasing pulmonary complications is needed.


Racial and ethnic variation in health resource use and cost for prostate cancer.
To analyse the racial and ethnic variation in health resource use (HRU) and direct medical care (DMC) cost in elderly men with prostate cancer. This was a retrospective case-control study using the linked Surveillance, Epidemiology, and End Results Medicare database. Patients with prostate cancer diagnosed between 1995 and 1998 (50 147 men) were identified and followed retrospectively for 1 year before and 5 years after the diagnosis. Phase-specific HRU and DMC costs were compared between racial and ethnic groups using parametric and nonparametric analysis. To compute the incremental cost of prostate cancer, a matched non-cancer control group was extracted from Medicare database. Poisson and general linear models (log-link) were used to identify the association of race and ethnicity with HRU and DMC cost, after controlling for potentially influential clinical and demographic covariates. The African-American group was more likely to have emergency-room visits (odds ratio 1.19, 95% confidence interval 1.12-1.28) and less likely to have outpatient visits (0.96, 0.96-0.97) than whites. However, the Hispanic group was more likely to have inpatient and outpatient visits (odds ratio 0.88, 0.83-0.91; and 0.93, 0.91-0.95) than whites. Adjusted DMC cost showed racial and ethnic variation in all phases except the treatment and terminal phases. Factors associated with DMC cost varied among racial and ethnic groups. The incremental burden of prostate cancer remains significant in the long term. Overall, the cost of prostate cancer care was higher among African-American men than white and Hispanic men. This indicates the need for further research on care-level factors to comprehend the racial and ethnic disparity in HRU and cost.


The influence of asthma on face shape: a three-dimensional study.
Respiratory activity may have an influence on craniofacial development and interact with genetic and environmental factors. It has been suggested that certain medical conditions such as asthma have an influence on face shape. The aim of the study is to investigate whether facial shape is different in individuals diagnosed as having asthma compared with controls. Study design included observational longitudinal cohort study. Asthma was defined as reported wheezing diagnosed at age 7 years and 6 months. The cohort was followed to 15 years of age as part of the Avon Longitudinal Study of Parents and Children. A total of 418 asthmatics and 3010 controls were identified. Three-dimensional laser surface facial scans were obtained. Twenty-one reproducible facial landmarks (x, y, z co-ordinates) were identified. Average facial shells were created for asthmatic and non-asthmatic males and females to explore surface differences. The inter-ala distance was 0.4mm wider (95% CI) and mid-face height was 0.4mm (95% CI) shorter in asthmatic females when compared with non-asthmatic females. No facial differences were detected in male subjects. Small but statistically significant differences were detected in mid-face height and inter-ala width between asthmatic and non-asthmatic females. No differences were detected in males. The lack of detection of any facial differences in males may be explained by significant facial variation as a result of achieving different stages of facial growth due to pubertal changes, which may mask any underlying condition effect.


Comparison of clinical and electromyographic rest vertical dimensions in dolichofacial and brachyfacial young adults: A cross-sectional study.
Therapeutic procedures that increase occlusal vertical dimension (OVD) may have different responses in patients with different craniofacial vertical patterns. The effect on these patients of increasing their OVD is not well understood. The purpose of this clinical study was to compare measurements of vertical jaw separation (VJS) in patients with brachyfacial and dolichofacial craniofacial patterns in 2 vertical dimensions: the clinical rest/postural vertical dimension (CR/PVD) and electromyographic rest vertical dimension (EMGRVD). Sixty healthy dental students were selected at random after a lateral skull radiograph was made. The Ricketts (VERT index) analysis was used to determine 30 brachyfacial (G1) and 30 dolichofacial (G2) types. The VJS was measured for G1 and G2 types in the 2 rest vertical dimensions specified. CR/PVD was recorded using 2 methods: swallowing (CR/PVD-P1) and the phonetic breathing method (CR/PVD-P2). The Shapiro-Wilk test was used for data distribution, and the Mann-Whitney U test was used to accept or reject the null hypothesis (α=.05). Mean VJS in CR/PVD-P1 was 1.92 ±1.14 mm for the brachyfacial and 1.36 ±0.58 mm for the dolichofacial facial group (P=.05). The mean VJS in CR/PVD-P2 was 1.89 ±1.17 mm for the brachyfacial and 1.31 ±0.58 mm for the dolichofacial group (P=.03). The mean VJS in EMGRVD was 8.23 ±2.21 mm for the brachyfacial and 16.55 ±4.29 mm the dolichofacial group (P<.001). CR/PVD measurements in dolichofacial individuals were lower than those in brachyfacial individuals. EMGRVD measurements were higher in dolichofacial individuals than those in brachyfacial individuals. Biomechanical, physiological, and behavioral reasons might explain such diversity.


The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities.
The newly discovered endocannabinoid system (ECS; comprising the endogenous lipid mediators endocannabinoids present in virtually all tissues, their G-protein-coupled cannabinoid receptors, biosynthetic pathways and metabolizing enzymes) has been implicated in multiple regulatory functions both in health and disease. Recent studies have intriguingly suggested the existence of a functional ECS in the skin and implicated it in various biological processes (e.g. proliferation, growth, differentiation, apoptosis and cytokine, mediator or hormone production of various cell types of the skin and appendages, such as the hair follicle and sebaceous gland). It seems that the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. The disruption of this delicate balance might facilitate the development of multiple pathological conditions and diseases of the skin (e.g. acne, seborrhea, allergic dermatitis, itch and pain, psoriasis, hair growth disorders, systemic sclerosis and cancer).


Height and bone mineral density are associated with naevus count supporting the importance of growth in melanoma susceptibility.
Naevus count is the strongest risk factor for melanoma. Body Mass Index (BMI) has been linked to melanoma risk. In this study, we investigate the link between naevus count and height, weight and bone mineral density (BMD) in the TwinsUK cohort (N = 2119). In addition we adjusted for leucocyte telomere length (LTL) as LTL is linked to both BMD and naevus count. Naevus count was positively associated with height (p = 0.001) but not with weight (p = 0.187) despite adjusting for age and twin relatedness. This suggests that the previously reported melanoma association with BMI may be explained by height alone. Further adjustment for LTL did not affect the significance of the association between height and naevus count so LTL does not fully explain these results. BMD was associated with naevus count at the spine (coeff 18.9, p = 0.01), hip (coeff = 18.9, p = 0.03) and forearm (coeff = 32.7, p = 0.06) despite adjusting for age, twin relatedness, weight, height and LTL. This large study in healthy individuals shows that growth via height, probably in early life, and bone mass are risk factors for melanoma via increased naevus count. The link between these two phenotypes may possibly be explained by telomere biology, differentiation genes from the neural crests but also other yet unknown factors which may influence both bones and melanocytes biology.


DeFine: deep convolutional neural networks accurately quantify intensities of transcription factor-DNA binding and facilitate evaluation of functional non-coding variants.
The complex system of gene expression is regulated by the cell type-specific binding of transcription factors (TFs) to regulatory elements. Identifying variants that disrupt TF binding and lead to human diseases remains a great challenge. To address this, we implement sequence-based deep learning models that accurately predict the TF binding intensities to given DNA sequences. In addition to accurately classifying TF-DNA binding or unbinding, our models are capable of accurately predicting real-valued TF binding intensities by leveraging large-scale TF ChIP-seq data. The changes in the TF binding intensities between the altered sequence and the reference sequence reflect the degree of functional impact for the variant. This enables us to develop the tool DeFine (Deep learning based Functional impact of non-coding variants evaluator, http://define.cbi.pku.edu.cn) with improved performance for assessing the functional impact of non-coding variants including SNPs and indels. DeFine accurately identifies the causal functional non-coding variants from disease-associated variants in GWAS. DeFine is an effective and easy-to-use tool that facilities systematic prioritization of functional non-coding variants.


How Type of Treatment and Presence of PTSD affect Employment, Self-regulation, and Abstinence.
The present study examined self-regulation, unemployment, and substance use outcomes for individuals with and without posttraumatic stress disorder (PTSD) who had transitioned from substance use treatment centers to the community. Participants, recruited from substance abuse treatment centers, were randomly assigned to an Oxford House self-help communal living environment (n = 75) or received usual aftercare (n = 75). Among these 150 individuals, 32 participants (27 women, 5 men) were diagnosed with lifetime PTSD. At a two year follow-up, individuals with PTSD in the usual aftercare condition showed significantly lower levels of self-regulation than those in the Oxford House condition with or without PTSD. These findings highlight the importance of abstinence supportive settings following substance use treatment, especially for individuals with PTSD.


Hyperpolarized magnetic resonance shows that the anti-ischemic drug meldonium leads to increased flux through pyruvate dehydrogenase in vivo resulting in improved post-ischemic function in the diabetic heart.
The diabetic heart has a decreased ability to metabolize glucose. The anti-ischemic drug meldonium may provide a route to counteract this by reducing l-carnitine levels, resulting in improved cardiac glucose utilization. Therefore, the aim of this study was to use the novel technique of hyperpolarized magnetic resonance to investigate the in vivo effects of treatment with meldonium on cardiac metabolism and function in control and diabetic rats. Thirty-six male Wistar rats were injected either with vehicle, or with streptozotocin (55 mg/kg) to induce a model of type 1 diabetes. Daily treatment with either saline or meldonium (100 mg/kg/day) was undertaken for three weeks. in vivo cardiac function and metabolism were assessed with CINE MRI and hyperpolarized magnetic resonance respectively. Isolated perfused hearts were challenged with low-flow ischemia/reperfusion to assess the impact of meldonium on post-ischemic recovery. Meldonium had no significant effect on blood glucose concentrations or on baseline cardiac function. However, hyperpolarized magnetic resonance revealed that meldonium treatment elevated pyruvate dehydrogenase flux by 3.1-fold and 1.2-fold in diabetic and control animals, respectively, suggesting an increase in cardiac glucose oxidation. Hyperpolarized magnetic resonance further demonstrated that meldonium reduced the normalized acetylcarnitine signal by 2.1-fold in both diabetic and control animals. The increase in pyruvate dehydrogenase flux in vivo was accompanied by an improvement in post-ischemic function ex vivo, as meldonium elevated the rate pressure product by 1.3-fold and 1.5-fold in the control and diabetic animals, respectively. In conclusion, meldonium improves in vivo pyruvate dehydrogenase flux in the diabetic heart, contributing to improved cardiac recovery after ischemia.


Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study.
To evaluate the effectiveness of systemic hyperbaric oxygen therapy (s HBOT) in addition to a comprehensive protocol in decreasing major amputation rate in diabetic patients hospitalized for severe foot ulcer. From August 1993 to August 1995, 70 diabetic subjects were consecutively admitted into our diabetologic unit for foot ulcers. All the subjects underwent our diagnostic-therapeutic protocol and were randomized to undergo s-HBOT. Two subjects, one in the arm of the treated group and one in the arm of nontreated group, did not complete the protocol and were therefore excluded from the analysis of the results. Finally, 35 subjects received s-HBOT and another 33 did not. Of the treated group (mean session = 38.8 +/- 8), three subjects (8.6%) underwent major amputation: two below the knee and one above the knee. In the nontreated group, 11 subjects (33.3%) underwent major amputation: 7 below the knee and 4 above the knee. The difference is statistically significant (P = 0.016). The relative risk for the treated group was 0.26 (95% CI 0.08-0.84). The transcutaneous oxygen tension measured on the dorsum of the foot significantly increased in subjects treated with hyperbaric oxygen therapy: 14.0 +/- 11.8 mmHg in treated group, 5.0 +/- 5.4 mmHg in nontreated group (P = 0.0002). Multivariate analysis of major amputation on all the considered variables confirmed the protective role of s-HBOT (odds ratio 0.084, P = 0.033, 95% CI 0.008-0.821) and indicated as negative prognostic determinants low ankle-brachial index values (odds ratio 1.715, P = 0.013, 95% CI 1.121-2.626) and high Wagner grade (odds ratio 11.199, P = 0.022, 95% CI 1.406-89.146). s-HBOT, in conjunction with an aggressive multidisciplinary therapeutic protocol, is effective in decreasing major amputations in diabetic patients with severe prevalently ischemic foot ulcers.


Mind-Body Therapies in Children and Youth.
Mind-body therapies are popular and are ranked among the top 10 complementary and integrative medicine practices reportedly used by adults and children in the 2007-2012 National Health Interview Survey. A growing body of evidence supports the effectiveness and safety of mind-body therapies in pediatrics. This clinical report outlines popular mind-body therapies for children and youth and examines the best-available evidence for a variety of mind-body therapies and practices, including biofeedback, clinical hypnosis, guided imagery, meditation, and yoga. The report is intended to help health care professionals guide their patients to nonpharmacologic approaches to improve concentration, help decrease pain, control discomfort, or ease anxiety.


Estrogen and androgen receptor activities of hydraulic fracturing chemicals and surface and ground water in a drilling-dense region.
The rapid rise in natural gas extraction using hydraulic fracturing increases the potential for contamination of surface and ground water from chemicals used throughout the process. Hundreds of products containing more than 750 chemicals and components are potentially used throughout the extraction process, including more than 100 known or suspected endocrine-disrupting chemicals. We hypothesized that a selected subset of chemicals used in natural gas drilling operations and also surface and ground water samples collected in a drilling-dense region of Garfield County, Colorado, would exhibit estrogen and androgen receptor activities. Water samples were collected, solid-phase extracted, and measured for estrogen and androgen receptor activities using reporter gene assays in human cell lines. Of the 39 unique water samples, 89%, 41%, 12%, and 46% exhibited estrogenic, antiestrogenic, androgenic, and antiandrogenic activities, respectively. Testing of a subset of natural gas drilling chemicals revealed novel antiestrogenic, novel antiandrogenic, and limited estrogenic activities. The Colorado River, the drainage basin for this region, exhibited moderate levels of estrogenic, antiestrogenic, and antiandrogenic activities, suggesting that higher localized activity at sites with known natural gas-related spills surrounding the river might be contributing to the multiple receptor activities observed in this water source. The majority of water samples collected from sites in a drilling-dense region of Colorado exhibited more estrogenic, antiestrogenic, or antiandrogenic activities than reference sites with limited nearby drilling operations. Our data suggest that natural gas drilling operations may result in elevated endocrine-disrupting chemical activity in surface and ground water.


Effects of particle size on chemical speciation and bioavailability of copper to earthworms (Eisenia fetida) exposed to copper nanoparticles.
To investigate the role of particle size on the oxidation, bioavailability, and adverse effects of manufactured Cu nanoparticles (NPs) in soils, we exposed the earthworm Eisenia ferida to a series of concentrations of commercially produced NPs labeled as 20- to 40-nm or < 100-nm Cu in artificial soil media. Effects on growth, mortality, reproduction, and expression of a variety of genes associated with metal homeostasis, general stress, and oxidative stress were measured. We also used X-ray absorption spectroscopy and scanning X-ray fluorescence microscopy to characterize changes in chemical speciation and spatial distribution of the NPs in soil media and earthworm tissues. Exposure concentrations of Cu NPs up to 65 mg kg(-1) caused no adverse effects on ecologically relevant endpoints. Increases in metallothionein expression occurred at concentrations exceeding 20 mg kg(-1) of Cu NPs and concentrations exceeding 10 mg kg(-1) of CuSO4. Based on the relationship of Cu tissue concentration to metallothionein expression level and the spatial distribution and chemical speciation of Cu in the tissues, we conclude that Cu ions and oxidized Cu NPs were taken up by the earthworms. This study suggests that oxidized Cu NPs may enter food chains from soil but that adverse effects in earthworms are likely to occur only at relatively high concentrations (> 65 mg Cu kg(-1) soil).