Cephalic phase metabolic responses in normal weight adults.
The presence and physiologic importance of cephalic phase insulin release in humans remains controversial. The aim of these studies was to determine whether cephalic phase insulin release could be demonstrated in normal weight subjects and whether it would be associated with changes in blood glucose, free fatty acid, and pancreatic polypeptide levels. The studies were followed by a hyperglycemic clamp to determine whether cephalic responses would alter overall glucose disposal or glucose-stimulated insulin secretion. In all, 17 subjects were studied on two occasions with and without (control study) presentation of food stimuli. Tease-feeding alone (n = 6), or the administration of a sweet taste alone (aspartame, n = 5) failed to stimulate cephalic responses. However, the presentation of the combined stimuli (tease meals plus sweet taste, n = 7) resulted in a significant fall (P less than .005) in blood glucose levels and a variable rise in serum insulin (% insulin rise 38 +/- 15%, P less than .05) and C-peptide levels (7 +/- 6%, NS) within five minutes of the food presentation when compared with control studies, with no change seen in free fatty acid or pancreatic polypeptide levels. The blood glucose fall correlated strongly (r = .90, P less than .01) with a score of the subjective response to the food and taste.(ABSTRACT TRUNCATED AT 250 WORDS)


Facilitators, best practices and barriers to integrating family planning data in Uganda's health management information system.
Health management information systems (HMIS) are instrumental in addressing health delivery problems and strengthening health sectors by generating credible evidence about the health status of clients. There is paucity of studies which have explored possibilities for integrating family planning data from the public and private health sectors in Uganda's national HMIS. This study sought to investigate the facilitators, best practices and barriers of integrating family planning data into the district and national HMIS in Uganda. We conducted a qualitative study in Kampala, Jinja, and Hoima Districts of Uganda, based on 16 key informant interviews and a multi-stakeholder dialogue workshop with 11 participants. Deductive and inductive thematic methods were used to analyze the data. The technical facilitators of integrating family planning data from public and private facilities in the national and district HMIS were user-friendly software; web-based and integrated reporting; and availability of resources, including computers. Organizational facilitators included prioritizing family planning data; training staff; supportive supervision; and quarterly performance review meetings. Key behavioral facilitators were motivation and competence of staff. Collaborative networks with implementing partners were also found to be essential for improving performance and sustainability. Significant technical barriers included limited supply of computers in lower level health facilities, complex forms, double and therefore tedious entry of data, and web-reporting challenges. Organizational barriers included limited human resources; high levels of staff attrition in private facilities; inadequate training in data collection and use; poor culture of information use; and frequent stock outs of paper-based forms. Behavioral barriers were low use of family planning data for planning purposes by district and health facility staff. Family planning data collection and reporting are integrated in Uganda's district and national HMIS. Best practices included integrated reporting and performance review, among others. Limited priority and attention is given to family planning data collection at the facility and national levels. Data are not used by the health facilities that collect them. We recommend reviewing and tailoring data collection forms and ensuring their availability at health facilities. All staff involved in data reporting should be trained and regularly supervised.


Construction of a yeast artificial chromosome contig spanning the spinal muscular atrophy disease gene region.
The childhood spinal muscular atrophies (SMAs) are the most common, serious neuromuscular disorders of childhood second to Duchenne muscular dystrophy. A single locus for these disorders has been mapped by recombination events to a region of 0.7 centimorgan (range, 0.1-2.1 centimorgans) between loci D5S435 and MAP1B on chromosome 5q11.2-13.3. By using PCR amplification to screen yeast artificial chromosome (YAC) DNA pools and the PCR-vectorette method to amplify YAC ends, a YAC contig was constructed across the disease gene region. Nine walk steps identified 32 YACs, including a minimum of seven overlapping YAC clones (average size, 460 kb) that span the SMA region. The contig is characterized by a collection of 30 YAC-end sequence tag sites together with seven genetic markers. The entire YAC contig spans a minimum of 3.2 Mb; the SMA locus is confined to roughly half of this region. Microsatellite markers generated along the YAC contig segregate with the SMA locus in all families where the flanking markers (D5S435 and MAP1B) recombine. Construction of a YAC contig across the disease gene region is an essential step in isolation of the SMA-encoding gene.


Could Helicobacter pylori infection increase the risk of coronary heart disease by modifying serum lipid concentrations?
To investigate the relation between Helicobacter pylori infection and coronary heart disease (CHD). A case-control study. Northern Finland (about 650,000 inhabitants). 116 patients with angiographically documented CHD and 116 controls matched for age and gender randomly recruited from the register of the Finnish Social Insurance Institute. The odds ratio (OR) estimates for the association of H pylori infection with CHD. 64% of the CHD patients and 53% of the controls were seropositive for H pylori; the OR adjusted for age and gender was 1.5 (95% confidence interval (CI) 0.9 to 2.5). An additional adjustment for the common risk factors of CHD, including lipid concentrations, in a logistic regression analysis produced an OR estimate of 1.1 (95% CI 0.6 to 2.1). Among the controls, those who were H pylori positive had significantly (P = 0.03) higher concentrations of serum triglycerides than those who were H pylori negative: the trend among the cases was similar, but non-significant. The concentrations of HDL cholesterol tended to be lower in those who were H pylori positive than in those who were H pylori negative, among both the cases and the controls. The impact of H pylori infection as an independent risk factor for CHD seems to be minor. On the other hand the results are consistent with the hypothesis that H pylori infection might modify the serum lipid concentrations in a way that could increase the risk of CHD.


Detection of Leishmania infantum DNA mainly in Rhipicephalus sanguineus male ticks removed from dogs living in endemic areas of canine leishmaniosis.
Sand flies are the only biologically adapted vectors of Leishmania parasites, however, a possible role in the transmission of Leishmania has been proposed for other hematophagous ectoparasites such as ticks. In order to evaluate natural infection by Leishmania infantum in Rhipicephalus sanguineus ticks, taking into account its close association with dogs, 128 adult R. sanguineus ticks removed from 41 dogs living in endemic areas of canine leishmaniosis were studied. Individual DNA extraction was performed from each tick and whole blood taken from dogs. Dog sera were tested for IgG antibodies to L. infantum antigen by ELISA and L. infantum real-time PCR was performed from canine whole blood samples and ticks. Leishmania infantum PCR was positive in 13 ticks (10.1%) including one female, (2.0%) and 12 males (15.2%), and in only five dogs (12.2%). Male ticks had a significantly higher infection rate when compared to female R. sanguineus. The percentage of L. infantum seroreactive dogs was 19.5%. All but two PCR positive dogs were seroreactive. Leishmania infantum PCR positive ticks were removed from seropositive and seronegative dogs with a variety of PCR results. This study demonstrates high prevalence of L. infantum DNA in R. sanguineus ticks removed from L. infantum seropositive and seronegative dogs. The presence of L. infantum DNA was detected mainly in male ticks possibly due to their ability to move between canine hosts and feed on several canine hosts during the adult life stage. Additional studies are needed to further explore the role of R. sanguineus ticks and in particular, male adults, in both the epidemiology and immunology of L. infantum infection in dogs in endemic areas.


Spinal Cord Stimulator Implant Infection Rates and Risk Factors: A Multicenter Retrospective Study.
Spinal cord stimulation is an evidence-based treatment for a number of chronic pain conditions. While this therapy offers improvement in pain and function it is not without potential complications. These complications include device failure, migration, loss of therapeutic paresthesia, and infection. This article looked to establish a modern infection rate for spinal cord stimulators, assess the impact of known risk factors for surgical site infections and to determine the impact of certain preventative measures on the rate of infection. After institutional review board approval, a multisite, retrospective review was conducted on 2737 unique implants or revisions of SCS systems. Patient demographics, risk factors including diabetes, tobacco use, obesity, revision surgery, trial length, implant location, implant type, surgeon background, prophylactic antibiotic use, utilization of a occlusive dressing, and post-operative antibiotic use were recorded and analyzed. The overall infection rate was 2.45% (n = 67). Diabetes, tobacco use, and obesity did not independently increase the rate of infection. Revision surgeries had a trend toward higher infection rate; however, this did not meet statistical significance. There was no difference in the rate of infection between implants performed by physicians of different base specialties, cylinder leads vs. paddle leads, or between different prophylactic antibiotics. Implants performed at academic centers had a higher rate of infection when compared to implants performed in nonacademic settings. When patients received an occlusive dressing or post-operative antibiotics they had a lower rate of infection. The infection rate (2.45%) reported in this study is lower than the previously reported rates (3-6%) and are on par with other surgical specialties. This study did not show an increased rate of infection for patients that used tobacco, had diabetes or were obese. It's possible that given the low overall infection rate a larger study is needed to establish the true impact of these factors on infection. In addition, this study did not address the impact of poorly controlled diabetes mellitus (elevated hemoglobin A1c) vs. well-controlled diabetes. It can be concluded from this study that utilizing an occlusive dressing over the incision in the post-operative period decreases the rate of infection and should become the standard of care. This study also demonstrated the positive impact of post-operative antibiotics in decreasing the rate of infection. Studies in other surgical specialties have not shown this impact which would suggest that further research is needed.


A nomogram for P values.
P values are the most commonly used tool to measure evidence against a hypothesis. Several attempts have been made to transform P values to minimum Bayes factors and minimum posterior probabilities of the hypothesis under consideration. However, the acceptance of such calibrations in clinical fields is low due to inexperience in interpreting Bayes factors and the need to specify a prior probability to derive a lower bound on the posterior probability. I propose a graphical approach which easily translates any prior probability and P value to minimum posterior probabilities. The approach allows to visually inspect the dependence of the minimum posterior probability on the prior probability of the null hypothesis. Likewise, the tool can be used to read off, for fixed posterior probability, the maximum prior probability compatible with a given P value. The maximum P value compatible with a given prior and posterior probability is also available. Use of the nomogram is illustrated based on results from a randomized trial for lung cancer patients comparing a new radiotherapy technique with conventional radiotherapy. The graphical device proposed in this paper will enhance the understanding of P values as measures of evidence among non-specialists.


Fluoroquinolone-resistant and extended-spectrum β-lactamase-producing Escherichia coli from the milk of cows with clinical mastitis in Southern Taiwan.
Escherichia coli is a common pathogen to cause clinical and subclinical mastitis in cows. A total of 57 E. coli isolates from raw milk from cows were characterized genetically and biochemically. Extended-spectrum β-lactamase (ESBL) genes, the mechanism for fluoroquinolone resistance, and variations in virulence genes and genomes of these E. coli isolates were investigated by the antimicrobial susceptibility test, simplex and multiplex polymerase chain reaction (PCR), and pulsed-field gel electrophoresis (PFGE). All E. coli isolates were resistant to cloxacillin (100%) and to a lesser extent (50%) to tetracycline, neomycin, gentamycin, ampicillin, ceftriaxone, cefotaxime (CTX), and ceftazidime (CAZ). Nearly 70% of the isolates were resistant to at least two antimicrobials and 28.1% carried AmpA and AmpC genes simultaneously. The predominant bla gene was blaTEM, followed by blaCMY, blaCTX, blaSHV, and blaDHA. Among the six (10.5%) ESBL-producing E. coli carrying blaCTX-M15, blaCTX-M55, or blaCTX-M14, two isolates 31 of ST410 in the ST23 complex and 58 of ST167 in the ST10 complex were also resistant to ciprofloxacin, enrofloxacin, and levofloxacin, with mutations at codon 83 from serine to leucine and codon 87 from aspartic acid to asparagine in GyrA and at codon 80 from serine to isoleucine in ParC. These isolates were genetically diverse in pulsotype analysis, lacked toxin genes of human pathogenic E. coli and carried mostly the prevalent virulence genes fimH, papGII, and α-hemolysin. Lacking virulence genes examined, genetic diverse E. coli isolates are unrelated to human pathogenic E. coli. Enhancing sanitation in milk processing and transportation is needed to eliminate multidrug-resistant (MDR), fluoroquinolone-resistant, and ESBL-producing E. coli isolates.


Acoustic environments that support equally accessible oral higher education as a human right.
People have the right to freedom of opinion and expression, as defined in Article 19 of the Universal Declaration of Human Rights. Higher education plays a major role in helping students to develop and express their own opinions and, therefore, should be equally accessible to all. This article focuses on how students judge the accessibility to oral instruction in higher education listening contexts. We collected data from 191 students in higher education by means of a questionnaire, addressing understanding speech in different types of classrooms and various educational settings. In lecture halls, understanding speech was judged to be significantly worse than in smaller classrooms. Two important negative factors were identified: background noise in classrooms and lecture halls and the non-use of a microphone. In lecture halls students achieve good or excellent speech perception only when lecturers are using a microphone. Nevertheless, this is not a standard practice. To achieve genuine inclusion in tertiary education programs, it is essential to remove acoustic barriers to understanding speech as much as possible. This study is a first step to identify communication facilitators to oral higher education instruction, for students with hearing loss or communication impairment.


Comparative study of plasmonic antennas fabricated by electron beam and focused ion beam lithography.
We present a comparative study of plasmonic antennas fabricated by electron beam lithography and direct focused ion beam milling. We have investigated optical and structural properties and chemical composition of gold disc-shaped plasmonic antennas on a silicon nitride membrane fabricated by both methods to identify their advantages and disadvantages. Plasmonic antennas were characterized using transmission electron microscopy including electron energy loss spectroscopy and energy dispersive X-ray spectroscopy, and atomic force microscopy. We have found stronger plasmonic response with better field confinement in the antennas fabricated by electron beam lithography, which is attributed to their better structural quality, homogeneous thickness, and only moderate contamination mostly of organic nature. Plasmonic antennas fabricated by focused ion beam lithography feature weaker plasmonic response, lower structural quality with pronounced thickness fluctuations, and strong contamination, both organic and inorganic, including implanted ions from the focused beam. While both techniques are suitable for the fabrication of plasmonic antennas, electron beam lithography shall be prioritized over focused ion beam lithography due to better quality and performance of its products.


Comparative genomics of Eucalyptus and Corymbia reveals low rates of genome structural rearrangement.
Previous studies suggest genome structure is largely conserved between Eucalyptus species. However, it is unknown if this conservation extends to more divergent eucalypt taxa. We performed comparative genomics between the eucalypt genera Eucalyptus and Corymbia. Our results will facilitate transfer of genomic information between these important taxa and provide further insights into the rate of structural change in tree genomes. We constructed three high density linkage maps for two Corymbia species (Corymbia citriodora subsp. variegata and Corymbia torelliana) which were used to compare genome structure between both species and Eucalyptus grandis. Genome structure was highly conserved between the Corymbia species. However, the comparison of Corymbia and E. grandis suggests large (from 1-13 MB) intra-chromosomal rearrangements have occurred on seven of the 11 chromosomes. Most rearrangements were supported through comparisons of the three independent Corymbia maps to the E. grandis genome sequence, and to other independently constructed Eucalyptus linkage maps. These are the first large scale chromosomal rearrangements discovered between eucalypts. Nonetheless, in the general context of plants, the genomic structure of the two genera was remarkably conserved; adding to a growing body of evidence that conservation of genome structure is common amongst woody angiosperms.


Do exposures to aerosols pose a risk to dental professionals?
Dental care professionals are exposed to aerosols from the oral cavity of patients containing several pathogenic microorganisms. Bioaerosols generated during dental treatment are a potential hazard to dental staff, and there have been growing concerns about their role in transmission of various airborne infections and about reducing the risk of contamination. To investigate qualitatively and quantitatively the bacterial and fungal aerosols before and during clinical sessions in two dental offices compared with controls. An extra-oral evacuator system was used to measure bacterial and fungal aerosols. Macroscopic and microscopic analysis of bacterial species and fungal strains was performed and strains of bacteria and fungi were identified based on their metabolic properties using biochemical tests. Thirty-three bioaerosol samples were obtained. Quantitative and qualitative evaluation showed that during treatment, there is a significant increase in airborne concentration of bacteria and fungi. The microflora included mainly gram-positive organisms (Staphylococcus epidermidis and Micrococcus spp.), gram-positive rod-shaped bacteria and those creating endospores as well as non-porous bacteria and mould fungi (Cladosporium and Penicillium). Exposure to the microorganisms identified is not a significant occupational hazard for dental care professionals; however, evidence-based prevention measures are recommended.


A national perspective on prenatal testing for mitochondrial disease.
Mitochondrial diseases affect >1 in 7500 live births and may be due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Genetic counselling for families with mitochondrial diseases, especially those due to mtDNA mutations, provides unique and difficult challenges particularly in relation to disease transmission and prevention. We have experienced an increasing demand for prenatal diagnostic testing from families affected by mitochondrial disease since we first offered this service in 2007. We review the diagnostic records of the 62 prenatal samples (17 mtDNA and 45 nDNA) analysed since 2007, the reasons for testing, mutation investigated and the clinical outcome. Our findings indicate that prenatal testing for mitochondrial disease is reliable and informative for the nuclear and selected mtDNA mutations we have tested. Where available, the results of mtDNA heteroplasmy analyses from other family members are helpful in interpreting the prenatal mtDNA test result. This is particularly important when the mutation is rare or the mtDNA heteroplasmy is observed at intermediate levels. At least 11 cases of mitochondrial disease were prevented following prenatal testing, 3 of which were mtDNA disease. On the basis of our results, we believe that prenatal testing for mitochondrial disease is an important option for couples where appropriate genetic analyses and pre/post-test counselling can be provided.


Wide Variation and Overprescription of Opioids After Elective Surgery.
We aimed to identify opioid prescribing practices across surgical specialties and institutions. In an effort to minimize the contribution of prescription narcotics to the nationwide opioid epidemic, reductions in postoperative opioid prescribing have been proposed. It has been suggested that a maximum of 7 days, or 200 mg oral morphine equivalents (OME), should be prescribed at discharge in opioid-naïve patients. Adults undergoing 25 common elective procedures from 2013 to 2015 were identified from American College of Surgeons National Surgical Quality Improvement Program data from 3 academic centers in Minnesota, Arizona, and Florida. Opioids prescribed at discharge were abstracted from pharmacy data and converted into OME. Wilcoxon Rank-Sum and Kruskal-Wallis tests assessed variations. Of 7651 patients, 93.9% received opioid prescriptions at discharge. Of 7181 patients who received opioid prescriptions, a median of 375 OME (interquartile range 225-750) were prescribed. Median OME varied by sex (375 men vs 390 women, P = 0.002) and increased with age (375 age 18-39 to 425 age 80+, P < 0.001). Patients with obesity and patients with non-cancer diagnoses received more opioids (both P < 0.001). Subset analysis of the 5756 (75.2%) opioid-naïve patients showed the majority received >200 OME (80.9%). Significant variations in opioid prescribing practices were seen within each procedure and between the 3 medical centers. The majority of patients were overprescribed opioids. Significant prescribing variation exists that was not explained by patient factors. These data will guide practices to optimize opioid prescribing after surgery.


Dendritic cell based PSMA immunotherapy for prostate cancer using a CD40-targeted adenovirus vector.
Human prostate tumor vaccine and gene therapy trials using ex vivo methods to prime dendritic cells (DCs) with prostate specific membrane antigen (PSMA) have been somewhat successful, but to date the lengthy ex vivo manipulation of DCs has limited the widespread clinical utility of this approach. Our goal was to improve upon cancer vaccination with tumor antigens by delivering PSMA via a CD40-targeted adenovirus vector directly to DCs as an efficient means for activation and antigen presentation to T-cells. To test this approach, we developed a mouse model of prostate cancer by generating clonal derivatives of the mouse RM-1 prostate cancer cell line expressing human PSMA (RM-1-PSMA cells). To maximize antigen presentation in target cells, both MHC class I and TAP protein expression was induced in RM-1 cells by transduction with an Ad vector expressing interferon-gamma (Ad5-IFNγ). Administering DCs infected ex vivo with CD40-targeted Ad5-huPSMA, as well as direct intraperitoneal injection of the vector, resulted in high levels of tumor-specific CTL responses against RM-1-PSMA cells pretreated with Ad5-IFNγ as target cells. CD40 targeting significantly improved the therapeutic antitumor efficacy of Ad5-huPSMA encoding PSMA when combined with Ad5-IFNγ in the RM-1-PSMA model. These results suggest that a CD-targeted adenovirus delivering PSMA may be effective clinically for prostate cancer immunotherapy.


The Importance of Obligate Anaerobes and the Streptococcus anginosus Group in Pulmonary Abscess: A Clone Library Analysis Using Bronchoalveolar Lavage Fluid.
Appropriate antibiotic use reduces the mortality of patients with lung abscess; however, 40-60% of the bacterial etiologies in these patients have remained unknown with the culture methods. Obligate anaerobes and the Streptococcus anginosus group are common pathogens in lung abscess, but a precise evaluation of these bacteria by ordinary culture methods seems to be difficult due to upper respiratory tract contamination. The aim of this study was to assess the microbiota of lung abscess by bronchoalveolar lavage fluid (BALF) using the molecular method in comparison to culture methods. BALF samples obtained from the affected lesions and sputum samples of 59 patients with lung abscess were evaluated. The microbiota in BALF was analyzed according to the molecular method using the 16S ribosomal RNA gene. Fifty-six of the 59 BALF samples were positive in polymerase chain reaction analysis. Fusobacterium spp. (23.7%) were most frequently detected, followed by the S. anginosus group (15.3%), as the predominant phylotypes. Obligate anaerobes were detected in 42.4% of the BALF specimens as the predominant phylotypes, whereas the detection rate of obligate anaerobes was 13.6% by culture methods using BALF. In addition, the detection rate among those patients in whom the phylotype of obligate anaerobes was detected in >5% of the lung microbiota according to the molecular method was 86.5% in the 'mixed-bacterial' infection group. The findings by the molecular method suggest that obligate anaerobes play important roles in the pathogenesis of lung abscess and provide additional bacterial information regarding conventional culture methods.


The reduction in glutamate release is predictive of cognitive and emotional alterations that are corrected by the positive modulator of AMPA receptors S 47445 in perinatal stressed rats.
S 47445 is a positive modulator of glutamate AMPA-type receptors, possessing neurotrophic and enhancing synaptic plasticity effects as well as pro-cognitive and anti-stress properties. Here, the drug was assessed in the perinatal stress (PRS) rat model, known to have a high predictive validity with monoaminergic antidepressants. The effects of a chronic treatment (i.p.) with S 47445 were investigated on risk-taking, motivational and cognitive behavior. S 47445 (1 and 10 mg/kg) increased the exploration of the elevated-plus maze and light/dark box as well as the time spent grooming in the splash test, and improved social memory in PRS rats. Also, the effects of S 47445 were examined on the synaptic neurotransmission. The reduced depolarization-evoked glutamate release induced by PRS was corrected with S 47445 (10 mg/kg). Remarkably, the reduction in glutamate release induced by PRS and corrected by S 47445 chronic treatment was correlated with all the behavioral changes. S 47445 at 10 mg/kg also normalized the lower levels of synaptic vesicle-associated proteins in ventral hippocampus in PRS rats. Finally, S 47445 reversed the decrease of mGlu5 receptors, GR and OXTR induced by PRS. Collectively, in an animal model of stress-related disorders, S 47445 corrected the imbalance between excitatory and inhibitory neurotransmission by regulating glutamate-evoked release that is predictive of PRS behavioral alterations, and also normalized the reduction of trafficking of synaptic vesicles induced by PRS. These results support the interest of glutamatergic-based therapeutic strategies to alleviate stress-related disorders.


Challenges and successes in non-operative management of high-grade malignant bowel obstruction.
Malignant bowel obstruction (MBO) occurs in between 3% and 15% of patients with cancer, and portends a poor mean survival of four weeks for patients who are not able to undergo operative intervention. Surgical interventions may be fraught with complications since these patients typically have compromised nutritional status and progressive metastatic disease burden, with tumor type and degree of aggressiveness affecting outcomes. MBO is a dynamic and difficult process to treat, with adequate pain control being limited by unpredictable enteral absorption and need for prolonged parenteral analgesia (given limited enteral access) with its inherent risks. To explore these difficulties, we report the case of a 43-year-old patient who presented with multi-level MBO from metastatic rectal carcinoma, and explore the challenges and successes of symptom management in a non-operative MBO.


Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study.
Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10-9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10-5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10-44). This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.


An evaluation of transit procurement training.
We evaluated a training course called "Orientation to Transit Procurement", designed and conducted by the National Transit Institute. This course is designed to provide Federal Transit Administration (FTA) grantees an overview of regulations and best practices related to the procurement process. Our objective in conducting the evaluation was to understand how transit agency staff made changes in procurement practices in response to the course training. The evaluation was mixed mode: an Internet survey followed by in-depth interviews with a small group of respondents. Survey respondents were also provided with an open-ended question providing us with additional context for our evaluation. Results show that the training is substantially successful at meeting the goal of improving procurement practices at transit agencies; indeed, most respondents report making changes at their agencies as the proximate result of the training. This was at odds with our exploration of knowledge of procurement topics, as most respondents gave inaccurate answers on multiple-choice "knowledge questions". This may have been due to question structure or, more likely, the nature of online surveys. Suitable training on the procurement of information technology was also a main concern. The lack of training in this area is indicative of the broader challenge facing public transit agencies in how to incorporate new forms of technology into their existing practices and bureaucratic structures.


A practical approach to umbilical artery pH and blood gas determinations.
The use of the Apgar score as a means of identifying birth asphyxia has been challenged. Routine umbilical cord blood pH has been recommended as a more objective measure of the condition of the newborn. The purposes of this study were to evaluate a simplified and selective method of umbilical artery pH blood sampling and to determine the effect of delay in sampling upon umbilical artery pH, carbon dioxide pressure (PCO2), and oxygen pressure (PO2). Umbilical arterial blood of 25 patients was sampled from clamped umbilical cord segments every 15 minutes for 1 hour after delivery. The clamped umbilical cord segments were left at room temperature with no special care given. The blood samples were collected in non-heparinized and non-iced plastic syringes and processed promptly after sampling. During the 60 minutes after delivery, there were no statistically significant changes in pH, PCO2, or PO2 of umbilical arterial blood. Our results indicate that umbilical arterial blood may be obtained simply and reliably from clamped umbilical cord segments for pH and gas determinations for up to an hour after delivery.


Increased family reports of pain or distress in dying Oregonians: 1996 to 2002.
The aim of this study was to compare the prevalence of family-reported pain or distress during the last week of decedents' lives during two times: November 1996 to December 1997 and June 2000 to March 2002. We telephone-surveyed family caregivers of Oregonians who had died 2 to 5 months previously in private homes, nursing homes, and other community-based settings. Caregivers were asked to rate the level of pain or distress during the decedent's final week of life on a four-point scale. Data were collected from 340 respondents from 1996-1997 and 1384 respondents from 2000-2002. We found that the prevalence of family-reported moderate or severe pain or distress (compared to comfortable or mild pain or distress) in Oregon decedents increased from 30.8% in 1996-1997 to 48% in 2000-2002. Using a logistic regression model to control for differences between the two sampling times and other predictors of increased pain or distress, decedents in 2000-2002 remained approximately twice as likely to be reported to be in moderate or severe pain or distress during the last week of their lives (Time 2 vs. Time 1, odds ratio [OR] 2.09, 95% confidence interval [CI] 1.59-2.74). We discuss possible explanations for this finding, including media effect created by the publicity surrounding the second ballot measure and subsequent availability of physician-assisted suicide in November 1997. Alternatively, trends in under funding and under staffing of hospice and community nursing resources may have disproportionately affected care in the final week of life, which depends heavily on skilled nursing care for effective symptom control and psychosocial support of the patient and family.


Negative effects in psychotherapy: commentary and recommendations for future research and clinical practice.
Psychotherapy can alleviate mental distress and improve quality of life, but little is known about its potential negative effects and how to determine their frequency. To present a commentary on the current understanding and future research directions of negative effects in psychotherapy. An anonymous survey was distributed to a select group of researchers, using an analytical framework known as strengths, weaknesses, opportunities and threats. The researchers perceive an increased awareness of negative effects in psychotherapy in recent years, but also discuss some of the unresolved issues in relation to their definition, assessment and reporting. Qualitative methods and naturalistic designs are regarded as important to pursue, although a number of obstacles to using such methods are identified. Negative effects of psychotherapy are multifaceted, warranting careful considerations in order for them to be monitored and reported in research settings and routine care. None.


Fundamentals and innovations in regional anaesthesia for infants and children.
Regional anaesthesia in children has evolved rapidly in the last decade. Although it previously consisted of primarily neuraxial techniques, the practice now incorporates advanced peripheral nerve blocks, which were only recently described in adults. These novel blocks provide new avenues for providing opioid-sparing analgesia while minimising invasiveness, and perhaps risk, associated with older techniques. At the same time, established methods, such as infant spinal anaesthesia, under-utilised in the last 20 years, are experiencing a revival. The impetus has been the concern regarding the potential long-term neurocognitive effects of general anaesthesia in the young child. These techniques have expanded from single shot spinal anaesthesia to combined spinal/epidural techniques, which can now effectively provide surgical anaesthesia for procedures below the umbilicus for a prolonged period of time, thereby avoiding the need for general anaesthesia. Continuous 2-chloroprocaine infusions, previously only described for intra-operative regional anaesthesia, have gained popularity as a means of providing prolonged postoperative analgesia in epidural and continuous nerve block techniques. The rapid, liver-independent metabolism of 2-chloroprocaine makes it ideal for prolonged local anaesthetic infusions in neonates and small infants, obviating the increased risk of local anaesthetic systemic toxicity that occurs with amide local anaesthetics. Debate continues over certain practices in paediatric regional anaesthesia. While the rarity of complications makes comparative analyses difficult, data from large prospective registries indicate that providing regional anaesthesia to children while under general anaesthesia appears to be at least as safe as in the sedated or awake patient. In addition, the estimated frequency of serious adverse events demonstrates that regional blocks in children under general anaesthesia are no less safe than in awake adults. In infants, the techniques of direct thoracic epidural placement or caudal placement with cephalad threading each have distinct advantages and disadvantages. As the data cannot support the safety of one technique over the other, the site of epidural insertion remains largely a matter of anaesthetist discretion.


Interactions of alfalfa plant and sprout saponins with cholesterol in vitro and in cholesterol-fed rats.
The in vitro interactions of saponins from alfalfa plant and alfalfa sprouts with cholesterol and the effects of alfalfa plant and sprout and saponin-free alfalfa plant on diet-induced liver cholesterol accumulation, bile acid excretion, and jejunal and colonic morphology were examined. Cholesterol-saponin interactions have been suggested as mechanisms for the observed hypocholesterolemic effects of alfalfa as well as the changes in intestinal morphology. Alfalfa plant saponins bound significant quantities of cholesterol both from ethanol solution and from micellar suspension. Alfalfa sprout saponins interacted with cholesterol to a lesser but significant extent. Sprout saponins also inhibited growth of Trichoderma viride significantly, another measure of saponin-cholesterol interaction. Bile acid adsorption was greatest for alfalfa plant and was not reduced by removal of saponins from the plant material. The ability of alfalfa to reduce liver cholesterol accumulation in cholesterol-fed rats was enhanced by removal of saponins and alfalfa sprouts did not prevent accumulation. Removal of saponins from alfalfa reduced the changes in intestinal morphology previously reported, but interaction with membrane cholesterol did not appear to be the cause of this effect of saponins. Saponin-cholesterol interaction is an important part of the hypocholesterolemic action of alfalfa but interaction of bile acids with other components of alfalfa may be of equal importance.


Chronic treatment of cycling rhesus monkeys with low doses of the antiprogestin ZK 137 316: morphometric assessment of the uterus and oviduct.
The long-term effects of the antiprogestin ZK 137 316 on reproductive tract morphology in rhesus macaques were investigated. The monkeys were injected daily (i.m.) for five menstrual cycles with vehicle or 0.01, 0.03 or 0.1 mg ZK 137 316/kg body weight. Reproductive tracts (n = 3/ group) were collected during the mid-luteal phase (day 8) of the fifth cycle in the control, 0.01 and 0.03 mg/kg groups, or 6-7 days after the oestradiol peak in the 0.1 mg/kg group. ZK 137 316 treatment resulted in a dose-dependent atrophy of the endometrium, marked by reduced mitotic activity in the glands, compaction of the stroma, degradation of spiral arteries and dilation of veins. There was no effect of ZK 137 316 on myometrial or oviductal weight. Treatment with 0.1 and 0.03 mg/kg, but not 0.01 mg/kg resulted in fully ciliated and secretory oviducts, indicating a dose-dependent blockade of progesterone antagonism of oestrogen-dependent oviductal differentiation. In the endometrium, the suppressive action of progesterone on oestrogen and progestin receptors was also blocked by ZK 137 316 in a dose-dependent manner. However, endometrial atrophy appeared due to inhibition of progesterone action together with a blockade of oestrogen-dependent proliferation. The profoundly suppressed endometrium produced by chronic low-dose ZK 137 316 treatment is unlikely to support implantation. Such treatment may therefore provide a novel contraceptive modality.


A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain.
More than 4 million children are exposed annually to sedatives and general anaesthetics (GAs) in the USA alone. Recent data suggest that common GAs can be detrimental to brain development causing neurodegeneration and long-term cognitive impairments. Challenged by a recent US Food and Drug Administration (FDA) warning about potentially neurotoxic effects of GAs in children, there is an urgent need to develop safer GAs. Postnatal Day 7 (P7) rat pups of both sexes were exposed to six (repeated every 2 h) injections of equipotent hypnotic doses of ketamine or the neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) for 12 h. Loss of righting reflex was used to assess hypnotic properties and therapeutic index; quantitative caspase-3 immunohistochemistry was used to assess developmental neuroapoptosis; patch-clamp recordings in acute brain slices were used to assess the effects of 3β-OH on neuronal excitability and synaptic transmission. Cognitive abilities of rats exposed to ketamine, 3β-OH, or vehicle at P7 were assessed in young adulthood using the radial arm maze. The neuroactive steroid 3β-OH has a therapeutic index similar to ketamine, a commonly used clinical GA. We report that 3β-OH is safe and, unlike ketamine, does not cause neuroapoptosis or impair cognitive development when administered to P7 rat pups. Interestingly, 3β-OH blocks T-type calcium channels and presynaptically dampens synaptic transmission at hypnotically-relevant brain concentrations, but it lacks a direct effect on γ-aminobutyric acid A or glutamate-gated ion channels. The neurosteroid 3β-OH is a relatively safe hypnotic that warrants further consideration for paediatric anaesthesia.


Genomic organization of the selectin family of leukocyte adhesion molecules on human and mouse chromosome 1.
A structurally and functionally related group of genes, lymph node homing receptor (LHR), granule membrane protein 140 (GMP-140), and endothelial leukocyte adhesion molecule 1 (ELAM-1) are shown to constitute a gene cluster on mouse and human chromosome 1. In situ hybridization mapped GMP-140 to human chromosome 1 bands 21-24 consistent with chromosomal localization of LHR. Gene linkage analysis in the mouse indicated that these genes and serum coagulation factor V (FV) all map to a region of distal mouse chromosome 1 that is syntenic with human chromosome 1, with no crossovers identified between these four genes in 428 meiotic events. Moreover, long range restriction site mapping demonstrated that these genes map to within 300 kb in both the human and mouse genomes. These data suggest that LHR, ELAM-1, and GMP-140 comprise an adhesion protein family, the selectins, that arose by multiple gene duplication events before divergence of mouse and human. Furthermore, the location of these genes on mouse and human chromosome 1 is consistent with a close evolutionary relationship to the complement receptor-related genes, which also are positioned on the same chromosomes in both species and with which these genes share a region of sequence homology. These data characterize the organization of a genomic region that may be critical for intercellular communication within the immune system.


The prevalence of hypocobalaminaemia in cats with spontaneous hyperthyroidism.
To determine the prevalence of hypocobalaminaemia in cats with moderate to severe hyperthyroidism and to investigate the relationship between cobalamin status and selected haematologic parameters. Serum cobalamin concentrations were measured in 76 spontaneously hyperthyroid cats [serum thyroxine (T(4) ) concentration ≥100 nmol/L] and 100 geriatric euthyroid cats. Erythrocyte and neutrophil counts in hyperthyroid cats with hypocobalaminaemia were compared with those in hyperthyroid cats with adequate serum cobalamin concentrations (≥290 ng/L). The median cobalamin concentration in hyperthyroid cats was lower than the control group (409 versus 672 ng/L; P=0·0040). In addition, 40·8% of hyperthyroid cats had subnormal serum cobalamin concentrations compared with 25% of controls (P=0·0336). Weak negative correlation (coefficient: -0·3281) was demonstrated between serum cobalamin and T(4) concentrations in the hyperthyroid population, and the median cobalamin concentration was lower in cats with T(4) above the median of 153 nmol/L compared with cats with T(4) below this value (P=0·0281). Hypocobalaminaemia was not associated with neutropenia or anaemia in hyperthyroid cats. This study indicates that a substantial proportion of cats with T(4) ≥100 nmol/L are hypocobalaminaemic and suggests that hyperthyroidism directly or indirectly affects cobalamin uptake, excretion or utilisation in this species.


High Lysyl Oxidase (LOX) in the Non-Malignant Prostate Epithelium Predicts a Poor Outcome in Prostate Cancer Patient Managed by Watchful Waiting.
Lysyl oxidase (LOX) has been shown to both promote and suppress tumor progression, but its role in prostate cancer is largely unknown. LOX immunoreactivity was scored in prostate tumor epithelium, tumor stroma and in the tumor-adjacent non-malignant prostate epithelium and stroma. LOX scores in tumor and non-malignant prostate tissues were then examined for possible associations with clinical characteristics and survival in a historical cohort of men that were diagnosed with prostate cancer at transurethral resection and followed by watchful waiting. Men with a low LOX score in the non-malignant prostate epithelium had significantly longer cancer specific survival than men with a high score. Furthermore, LOX score in non-malignant prostate epithelium remained prognostic in a multivariable analysis including Gleason score. LOX score in prostate tumor epithelium positively correlated to Gleason score and metastases but was not associated with cancer survival. LOX score in tumor and non-malignant prostate stroma appeared unrelated to these tumor characteristics. In radical prostatectomy specimens, LOX immune-staining corresponded to LOX in-situ hybridization and LOX mRNA levels were found to be similar between tumor and adjacent non-malignant areas, but significantly increased in bone metastases samples. LOX levels both in tumors and in the surrounding tumor-bearing organ are apparently related to prostate cancer aggressiveness.


Torpedo nuclease Rat1 is insufficient to terminate RNA polymerase II in vitro.
Termination of RNA polymerase (pol) II transcription in vivo requires the 5'-RNA exonuclease Rat1. It was proposed that Rat1 degrades RNA from the 5'-end that is created by transcript cleavage, catches up with elongating pol II, and acts like a Torpedo that removes pol II from DNA. Here we test the Torpedo model in an in vitro system based on bead-coupled pol II elongation complexes (ECs). Recombinant Rat1 complexes with Rai1, and with Rai1 and Rtt103, degrade RNA extending from the EC until they reach the polymerase surface but fail to terminate pol II. Instead, the EC retains an approximately 18-nucleotide RNA that remains with its 3'-end at the active site and can be elongated. Thus, pol II termination apparently requires a factor or several factors in addition to Rat1, Rai1, and Rtt103, post-translational modifications of these factors, or unusual reaction conditions.


[DPP-4 inhibitors in nephropatics].
The use of glucose-lowering drugs in advanced stage diabetic nephropathic patients should be done very carefully. Some drugs are contraindicated or not recommended. The same insulin needs a dose reduction to avoid dangerous hypoglycemia. For some years the use of inhibitors of the DDP-4 has been approved in T2DM patients with CKD III and IV stage, proposing the use without limitations even in case of ESRD. We conducted a prospective observational study of a cohort of 60 patients with T2DM and CKD stage IV, selecting a sample of 15 patients taking an inhibitor of DPP-4 and comparing it with those who took therapy "old" drugs, despite having similar characteristics of CKD. In both groups, we found: 1) the effectiveness of therapy, through the assessment of glycated hemoglobin and glycemic profile; 2) the possible occurrence of "hypoglycemia", "side effects", accelerating the progression of CKD. No patients being treated with inhibitors of DPP-4 have experienced hypoglycemia, or adverse events, or adverse effects on the progression of CKD. The glycated hemoglobin, revealed more stability than the comparison group. Hypoglycaemic episodes were present only in the group receiving intensive insulin. Although kidneys and their dose, in case of high degree of CKD, primarily eliminate inhibitors of DPP-4, with some exceptions, should be reduced, in our experience they have proven beneficial drugs in diabetics with kidney disease, being effective and well tolerated in the case of ESRD, where the only treatment option was represented by insulin.


Effects of 17β-estradiol and bisphenol A on the formation of reproductive organs in planarians.
Planarians have a remarkable capacity for regeneration after ablation, and they reproduce asexually by fission. However, some planarians can also reproduce and maintain their sexual organs. During the regenerative process, their existing sexual organs degenerate and new ones develop. However, little is known about hormonal regulation during the development of reproductive organs in planarians. In this study, we investigated the effects of 17β-estradiol (a steroid) and bisphenol A (an endocrine disrupter) on the formation of sexual organs in the hermaphroditic planarian Dugesia ryukyuensis. Under control conditions, all worm tissues regenerated into sexual planarians with sexual organs within 4 weeks after ablation. However, in the presence of bisphenol A or 17β-estradiol, although they apparently regenerated into sexual planarians, the yolk glands, which are one of the female sexual organs, failed to regenerate even 7 weeks after ablation. These data suggest that planarians have a steroid hormone system, which plays a key role in the formation and maturation of sexual organs.


Does a Change from Whole to Powdered Food (Artemia franciscana eggs) Increase Oviposition in the Ladybird Coleomegilla maculata?
The limited availability of alternative foods to replace natural prey hinders cost-effective mass production of ladybird beetles for augmentative biological control. We compared the effects of powdered vs. whole Artemia franciscana (A. franciscana) (brine shrimp) eggs with or without a dietary supplement on development and reproduction of Coleomegilla maculata (C. maculata) (Coleoptera: Coccinellidae). We tested the hypotheses that (1) powdered A. franciscana eggs are more suitable than whole eggs; and (2) palmitic acid, a common fatty acid in natural prey, i.e., aphids, is an effective dietary supplement. Development time, pre-imaginal survival, sex ratio, and body weight of adults did not differ significantly amongst individuals fed powdered vs. whole eggs, with or without 5% palmitic acid. Significantly more oviposition occurred when females were fed powdered eggs than whole eggs and powdered eggs with 5% palmitic acid than whole eggs with or without 5% palmitic acid. A weak functional relationship was found between pre-oviposition time and total oviposition by females fed powdered eggs with 5% palmitic acid; pre-oviposition time decreased as oviposition increased. Food treatments had no significant differential effect on progeny (egg) hatch rate. In conclusion, a simple change in A. franciscana egg texture and particle size (i.e., blending whole eggs into a dust-like powder) increases oviposition in C. maculata. Supplementing powdered eggs with 5% palmitic acid might accelerate oogenesis (egg maturation) in some females.


Worthy of swift trust? How brief interpersonal contact affects trust accuracy.
Organizational scholars have long underscored the positive consequences of trust, yet trust can also have dysfunctional effects if it is not placed wisely. Though much research has examined conditions that increase individuals' tendencies to trust others, we know very little about the circumstances under which individuals are likely to make more accurate trust decisions (i.e., neither misplace their trust nor refrain from trusting when doing so would have been beneficial), especially when they must do so rapidly and in the absence of an exchange history. Put simply, we have little understanding of what drives the accuracy of swift trust judgments. Building on relevant literatures, we propose that short episodes of prior interpersonal contact with a partner can increase the accuracy of swift trust decisions. Across two experimental studies, we demonstrate that brief interpersonal contact leads trustors to both (a) become more accurate in their trust decisions; and (b) engage in other-focused perspective taking, which mediates the effect of interpersonal contact on trust accuracy. We then show that it is specifically because of verbal cues, rather than visual cues, that brief interpersonal contact enables other-focused perspective taking, and in turn, trust accuracy (Study 3). We contribute to the literature on trust by examining trust accuracy (rather than mere trust levels), identifying the significant role of brief interpersonal contact, and revealing other-focused perspective taking as a key mechanism in accurate swift trust decisions. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Genetic population structure accounts for contemporary ecogeographic patterns in tropic and subtropic-dwelling humans.
Contemporary human populations conform to ecogeographic predictions that animals will become more compact in cooler climates and less compact in warmer ones. However, it remains unclear to what extent this pattern reflects plastic responses to current environments or genetic differences among populations. Analyzing anthropometric surveys of 232,684 children and adults from across 80 ethnolinguistic groups in sub-Saharan Africa, Asia and the Americas, we confirm that body surface-to-volume correlates with contemporary temperature at magnitudes found in more latitudinally diverse samples (Adj. R2 = 0.14-0.28). However, far more variation in body surface-to-volume is attributable to genetic population structure (Adj. R2 = 0.50-0.74). Moreover, genetic population structure accounts for nearly all of the observed relationship between contemporary temperature and body surface-to-volume among children and adults. Indeed, after controlling for population structure, contemporary temperature accounts for no more than 4% of the variance in body form in these groups. This effect of genetic affinity on body form is also independent of other ecological variables, such as dominant mode of subsistence and household wealth per capita. These findings suggest that the observed fit of human body surface-to-volume with current climate in this sample reflects relatively large effects of existing genetic population structure of contemporary humans compared to plastic response to current environments.


miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice.
Activation of an osteogenic transcriptional program contributes to the initiation of aortic calcification in atherosclerosis. The role of microRNAs in regulating aortic calcification is understudied. We tested the hypothesis that miR-30e regulates an osteogenic program in bone marrow-derived mesenchymal stem cells (MSCs), aortic smooth muscle cells (SMCs), and ApoE(-/-) mice. In aortas of wild-type mice, we found that miR-30e is highly expressed in medial SMCs. In aortas of old ApoE(-/-) mice, we found that miR-30e transcripts are down-regulated in an inverse relation to the osteogenic markers Runx2, Opn, and Igf2. In vitro, miR-30e over-expression reduced the proliferation of MSCs and SMCs while increasing adipogenic differentiation of MSCs and smooth muscle differentiation of SMCs. In MSCs and SMCs over-expressing miR-30e, microarrays and qPCR showed repression of an osteogenic gene panel including Igf2. Inhibiting miR-30e in MSCs increased Igf2 transcripts. In SMCs, IGF2 recombinant protein rescued miR-30e-repressed osteogenic differentiation. Luciferase and mutagenesis assays showed binding of miR-30e to a novel and essential site at the 3'UTR of Igf2. In ApoE(-/-) mice, injections of antimiR-30e oligos increased Igf2 expression in the aortas and livers and significantly enhanced OPN protein expression and calcium deposition in aortic valves. miR-30e represses the osteogenic program in MSCs and SMCs by targeting IGF2 and drives their differentiation into adipogenic or smooth muscle lineage, respectively. Our data suggest that down-regulation of miR-30e in aortas with age and atherosclerosis triggers vascular calcification. The miR-30e pathway plays an important regulatory role in vascular diseases.


Design by dragging: an interface for creative forward and inverse design with simulation ensembles.
We present an interface for exploring large design spaces as encountered in simulation-based engineering, design of visual effects, and other tasks that require tuning parameters of computationally-intensive simulations and visually evaluating results. The goal is to enable a style of design with simulations that feels as-direct-as-possible so users can concentrate on creative design tasks. The approach integrates forward design via direct manipulation of simulation inputs (e.g., geometric properties, applied forces) in the same visual space with inverse design via 'tugging' and reshaping simulation outputs (e.g., scalar fields from finite element analysis (FEA) or computational fluid dynamics (CFD)). The interface includes algorithms for interpreting the intent of users' drag operations relative to parameterized models, morphing arbitrary scalar fields output from FEA and CFD simulations, and in-place interactive ensemble visualization. The inverse design strategy can be extended to use multi-touch input in combination with an as-rigid-as-possible shape manipulation to support rich visual queries. The potential of this new design approach is confirmed via two applications: medical device engineering of a vacuum-assisted biopsy device and visual effects design using a physically based flame simulation.


Cultural continuity and Inuit health in Arctic Canada.
Previous research association increased levels of cultural continuity and decreased rates of youth suicide in First Nations communities. We investigate the relationship between cultural continuity and self-rated health looking specifically at Inuit living in the Canadian Arctic. The Arctic Supplements of the Aboriginal Peoples Survey from years 2001 and 2006 were appended to explore the relationship between various measures of cultural continuity and self-rated health. These measures include access to government services in an Aboriginal language, Inuit cultural variables, community involvement and governance. Literature related to Inuit social determinants of health and health-related behaviours were used to build the models. All measures of cultural continuity were shown to have a positive association with self-rated health for Inuit participants. Background and other control variables influenced the strength of the association but not the direction of the association. Access to services in an Aboriginal language, harvesting activities and government satisfaction were all significantly related to the odds of better health outcomes. Finally, the study contributes a baseline from a known data horizon against which future studies can assess changes and understand future impacts of changes. The Canadian government and other agencies should address health inequalities between Inuit and non-Inuit people through programmes designed to foster cultural continuity at a community level. Providing access to services in an Aboriginal language is a superficial way of promoting cultural alignment of these services; however, more inclusion of Inuit traditional knowledge is needed to have a positive influence on health.


Dynamics of 4-oxo-TEMPO-d16-(15)N nitroxide-propylene glycol system studied by ESR and ESE in liquid and glassy state in temperature range 10-295K.
ESR spectra and electron spin relaxation of nitroxide radical in 4-oxo-TEMPO-d16-(15)N in propylene glycol were studied at X-band in the temperature range 10-295K. The spin-lattice relaxation in the liquid viscous state determined from the resonance line shape is governed by three mechanisms occurring during isotropic molecular reorientations. In the glassy state below 200K the spin-lattice relaxation, phase relaxation and electron spin echo envelope modulations (ESEEM) were studied by pulse spin echo technique using 2-pulse and 3-pulse induced signals. Electron spin-lattice relaxation is governed by a single non-phonon relaxation process produced by localized oscillators of energy 76cm(-1). Electron spin dephasing is dominated by a molecular motion producing a resonance-type peak in the temperature dependence of the dephasing rate around 120K. The origin of the peak is discussed and a simple method for the peak shape analysis is proposed, which gives the activation energy of a thermally activated motion Ea=7.8kJ/mol and correlation time τ0=10(-8)s. The spin echo amplitude is strongly modulated and FT spectrum contains a doublet of lines centered around the (2)D nuclei Zeeman frequency. The splitting into the doublet is discussed as due to a weak hyperfine coupling of nitroxide unpaired electron with deuterium of reorienting CD3 groups.


Microbe-independent entry of oomycete RxLR effectors and fungal RxLR-like effectors into plant and animal cells is specific and reproducible.
A wide diversity of pathogens and mutualists of plant and animal hosts, including oomycetes and fungi, produce effector proteins that enter the cytoplasm of host cells. A major question has been whether or not entry by these effectors can occur independently of the microbe or requires machinery provided by the microbe. Numerous publications have documented that oomycete RxLR effectors and fungal RxLR-like effectors can enter plant and animal cells independent of the microbe. A recent reexamination of whether the RxLR domain of oomycete RxLR effectors is sufficient for microbe-independent entry into host cells concluded that the RxLR domains of Phytophthora infestans Avr3a and of P. sojae Avr1b alone are NOT sufficient to enable microbe-independent entry of proteins into host and nonhost plant and animal cells. Here, we present new, more detailed data that unambiguously demonstrate that the RxLR domain of Avr1b does show efficient and specific entry into soybean root cells and also into wheat leaf cells, at levels well above background nonspecific entry. We also summarize host cell entry experiments with a wide diversity of oomycete and fungal effectors with RxLR or RxLR-like motifs that have been independently carried out by the seven different labs that coauthored this letter. Finally we discuss possible technical reasons why specific cell entry may have been not detected by Wawra et al. (2013).


Iteration method for predicting essential proteins based on orthology and protein-protein interaction networks.
Identification of essential proteins plays a significant role in understanding minimal requirements for the cellular survival and development. Many computational methods have been proposed for predicting essential proteins by using the topological features of protein-protein interaction (PPI) networks. However, most of these methods ignored intrinsic biological meaning of proteins. Moreover, PPI data contains many false positives and false negatives. To overcome these limitations, recently many research groups have started to focus on identification of essential proteins by integrating PPI networks with other biological information. However, none of their methods has widely been acknowledged. By considering the facts that essential proteins are more evolutionarily conserved than nonessential proteins and essential proteins frequently bind each other, we propose an iteration method for predicting essential proteins by integrating the orthology with PPI networks, named by ION. Differently from other methods, ION identifies essential proteins depending on not only the connections between proteins but also their orthologous properties and features of their neighbors. ION is implemented to predict essential proteins in S. cerevisiae. Experimental results show that ION can achieve higher identification accuracy than eight other existing centrality methods in terms of area under the curve (AUC). Moreover, ION identifies a large amount of essential proteins which have been ignored by eight other existing centrality methods because of their low-connectivity. Many proteins ranked in top 100 by ION are both essential and belong to the complexes with certain biological functions. Furthermore, no matter how many reference organisms were selected, ION outperforms all eight other existing centrality methods. While using as many as possible reference organisms can improve the performance of ION. Additionally, ION also shows good prediction performance in E. coli K-12. The accuracy of predicting essential proteins can be improved by integrating the orthology with PPI networks.


Facilitating community connections among people with mental illnesses: Perspectives from grassroots community leaders.
We conducted focus groups comprising 20 grassroots community leaders to identify social and structural elements that affect community engagement among people with serious mental illnesses. Community leaders not affiliated with mental health systems have been mostly left out of the discussions about inclusion and engagement, even though they possess unique information about the places where they live and can be essential partners in making community connections. The findings from the focus groups point to elements that both facilitate and inhibit connections, as well as roles community mental health practitioners may take on, to engage with community leaders and people with mental illness to minimize barriers and foster connections in community settings. Additionally, the focus groups elucidated the interplay between the right to be a member of one's community and a community's responsibility to create a welcoming environment. The current study garnered information regarding the broader needs and implications of community connections, as well as some specific suggestions to enhance community engagement among people with serious mental illness. Hesitation and stigma around engaging individuals with mental illnesses were identified as barriers to inclusion. Further study about how community leaders and groups may be involved in facilitating meaningful community connections is recommended.


Fabrication of an integrated holographic imaging element for a three-dimensional eye-gaze detection system.
We evaluate the imaging characteristics of an integrated optical imaging element that is used to obtain images from opposite directions in one imaging sensor for a three-dimensional eye-gaze detection system. The element consists of a transmission-type holographic imaging element, a reflection-type holographic imaging element, and a noise reduction filter. In the evaluation of the imaging characteristics, modulation transfer functions of both the reflection-type and the transmission-type holographic imaging elements are evaluated. Results indicate that both holographic imaging elements have enough resolution, even under white-light illumination conditions, for eye-gaze detection. We also demonstrate the simultaneous detection of images by an artificial eye and objects by using the integrated element under white light or sunlight.


Energy level diagram of HC(NH2)2PbI3 single crystal evaluated by electrical and optical analyses.
Recently, organic-inorganic halide perovskites have received attention for applications in solar cells. Measurements of high-quality single crystals reveal lower defect densities and longer carrier lifetimes than those of conventional thin films, which result in improved electrical and optical properties. However, single crystal surfaces are sensitive to exposure to ambient conditions, and degrade under long-term storage in air. The surface also shows differences from the bulk in terms of its optical and electronic characteristics. For a heterojunction device, the interface at the single crystal is important. Understanding the difference between the surface and bulk properties offers insights into device design. Here, we prepared non-sliced and sliced formamidinium lead iodide (FAPbI3; FA+ = HC(NH2)2+) single crystals with a bandgap of 1.4 eV, which matches well with the requirements for solar cell photoabsorption layers. We evaluate the energy level diagrams of the surface and bulk regions, respectively. Our data indicate that the valence band maximum of the surface region is at a higher energy level than that of the bulk region. We also discuss hypotheses for the well-known and unexplained phenomena (multiple bandgaps and bandgap narrowing) seen in the absorption and photoluminescence spectra of single crystals. We conclude that these effects are likely caused by a combination of the degraded surface, Rashba-splitting in bulk, and self-absorption by the single crystal itself.


Cell adhesion molecules in bladder cancer: soluble serum E-cadherin correlates with predictors of recurrence.
Sera from 40 patients with newly diagnosed bladder cancer (28 superficial tumours (pTa and pT1) and 12 muscle-invasive tumours) were assessed by enzyme-linked immunosorbent assay (ELISA) to determine the concentrations of soluble E-cadherin (sE-cadherin), soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1). Corresponding frozen sections of primary tumour were analysed for E-cadherin expression using the monoclonal antibody, HECD-1 and standard immunohistochemistry. Patients with bladder cancer had significantly higher concentrations of sE-cadherin compared with a control group (P = 0.017). No difference was found between the two groups with regard to sE-selection (P = 0.403), sVCAM-1 (P = 0.942) and sICAM-1 (P = 0.092). High levels of sE-cadherin were related to poor histological grade (P = 0.009), number of superficial tumours at presentation (P = 0.008) and a positive 3 month check cytoscopy in superficial disease (P = 0.036). Abnormal E-cadherin expression was associated with increasing tumour stage (P = 0.009) and grade (P = 0.03). There was no correlation between high levels of soluble E-cadherin in sera and abnormal E-cadherin expression by the tumour (P = 0.077). Elevated levels of sE-cadherin are found in sera of patients with bladder cancer and correlate with known prognostic factors.


Conditional rotation of two strongly coupled semiconductor charge qubits.
Universal multiple-qubit gates can be implemented by a set of universal single-qubit gates and any one kind of entangling two-qubit gate, such as a controlled-NOT gate. For semiconductor quantum dot qubits, two-qubit gate operations have so far only been demonstrated in individual electron spin-based quantum dot systems. Here we demonstrate the conditional rotation of two capacitively coupled charge qubits, each consisting of an electron confined in a GaAs/AlGaAs double quantum dot. Owing to the strong inter-qubit coupling strength, gate operations with a clock speed up to 6 GHz have been realized. A truth table measurement for controlled-NOT operation shows comparable fidelities to that of spin-based two-qubit gates, although phase coherence is not explicitly measured. Our results suggest that semiconductor charge qubits have a considerable potential for scalable quantum computing and may stimulate the use of long-range Coulomb interaction for coherent quantum control in other devices.


Stress echocardiogaphy: a useful test for assessing cardiac risk in diabetes.
Cardiovascular disease is the leading cause of death in patients with diabetes therefore prompt diagnosis and treatment of high risk groups is essential. Dobutamine stress echocardiography is a safe, cheap and reliable method for coronary artery disease diagnosis and provides important long term prognostic information. The diagnostic accuracy and prognostic power of this technique has been validated by a number of studies on patients with and without diabetes. This article discusses the application, interpretation, and accuracy of stress echocardiography both in the general population and in patients with diabetes. The role of advanced imaging modalites such as myocardial contrast agents and tissue Doppler imaging is also explored.


Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone.
The objective of this study was to investigate pharmacokinetic and pharmacodynamic interactions between midazolam and fluoxetine, fluvoxamine, nefazodone, and ketoconazole. Forty healthy subjects were randomized to receive one of the four study drugs for 12 days in a parallel study design: fluoxetine 60 mg per day for 5 days, followed by 20 mg per day for 7 days; fluvoxamine titrated to a daily dose of 200 mg; nefazodone titrated to a daily dose of 400 mg; or ketoconazole 200 mg per day. All 40 subjects received oral midazolam solution before and after the 12-day study drug regimen. Blood samples for determination of midazolam concentrations were drawn for 24 hours after each midazolam dose and used for the calculation of pharmacokinetic parameters. The effects of the study drugs on midazolam pharmacodynamics were assessed using the symbol digit modalities test (SDMT). The mean area under the curve (AUC) for midazolam was increased 771.9% by ketoconazole and 444.0% by nefazodone administration. However, there was no significant change in midazolam AUC as a result of fluoxetine (13.4% decrease) and a statistical trend for fluvoxamine (66.1% increase) administration. Pharmacodynamic data are consistent with pharmacokinetic data indicating that nefazodone and ketoconazole resulted in significant increases in midazolam-related cognition impairment. The significant impairment in subjects' cognitive function reflects the changes in midazolam clearance after treatment with ketoconazole and nefazodone. These results suggest that caution with the use of midazolam is warranted with potent CYP3A4 inhibitors.


Structural evidence for enhancement of sequential vitamin D3 hydroxylation activities by directed evolution of cytochrome P450 vitamin D3 hydroxylase.
Vitamin D(3) hydroxylase (Vdh) isolated from actinomycete Pseudonocardia autotrophica is a cytochrome P450 (CYP) responsible for the biocatalytic conversion of vitamin D(3) (VD(3)) to 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)VD(3)) by P. autotrophica. Although its biological function is unclear, Vdh is capable of catalyzing the two-step hydroxylation of VD(3), i.e. the conversion of VD(3) to 25-hydroxyvitamin D(3) (25(OH)VD(3)) and then of 25(OH)VD(3) to 1α,25(OH)(2)VD(3), a hormonal form of VD(3). Here we describe the crystal structures of wild-type Vdh (Vdh-WT) in the substrate-free form and of the highly active quadruple mutant (Vdh-K1) generated by directed evolution in the substrate-free, VD(3)-bound, and 25(OH)VD(3)-bound forms. Vdh-WT exhibits an open conformation with the distal heme pocket exposed to the solvent both in the presence and absence of a substrate, whereas Vdh-K1 exhibits a closed conformation in both the substrate-free and substrate-bound forms. The results suggest that the conformational equilibrium was largely shifted toward the closed conformation by four amino acid substitutions scattered throughout the molecule. The substrate-bound structure of Vdh-K1 accommodates both VD(3) and 25(OH)VD(3) but in an anti-parallel orientation. The occurrence of the two secosteroid binding modes accounts for the regioselective sequential VD(3) hydroxylation activities. Moreover, these structures determined before and after directed evolution, together with biochemical and spectroscopic data, provide insights into how directed evolution has worked for significant enhancement of both the VD(3) 25-hydroxylase and 25(OH)VD(3) 1α-hydroxylase activities.


Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartment.
DNA methylation has been implicated as an epigenetic component of mechanisms that stabilize cell-fate decisions. Here, we have characterized the methylomes of human female hematopoietic stem/progenitor cells (HSPCs) and mature cells from the myeloid and lymphoid lineages. Hypomethylated regions (HMRs) associated with lineage-specific genes were often methylated in the opposing lineage. In HSPCs, these sites tended to show intermediate, complex patterns that resolve to uniformity upon differentiation, by increased or decreased methylation. Promoter HMRs shared across diverse cell types typically display a constitutive core that expands and contracts in a lineage-specific manner to fine-tune the expression of associated genes. Many newly identified intergenic HMRs, both constitutive and lineage specific, were enriched for factor binding sites with an implied role in genome organization and regulation of gene expression, respectively. Overall, our studies represent an important reference data set and provide insights into directional changes in DNA methylation as cells adopt terminal fates.


Efficacy of a bacteriophage isolated from chickens as a therapeutic agent for colibacillosis in broiler chickens.
The efficacy of bacteriophage EC1, a lytic bacteriophage, against Escherichia coli O78:K80, which causes colibacillosis in poultry, was determined in the present study. A total of 480 one-day-old birds were randomly assigned to 4 treatments groups, each with 4 pens of 30 birds. Birds from the control groups (groups I and II) received PBS (pH 7.4) or 10(10) pfu of bacteriophage EC1, respectively. Group III consisted of birds challenged with 10(8) cfu of E. coli O78:K80 and treated with 10(10) pfu of bacteriophage EC1 at 2 h postinfection, whereas birds from group IV were challenged with 10(8) cfu of E. coli O78:K80 only. All the materials were introduced into the birds by intratracheal inoculation. Based on the results of the present study, the infection was found to be less severe in the treated E. coli-challenged group. Mean total viable cell counts of E. coli identified on eosin methylene blue agar (designated EMB + E. coli) in the lungs were significantly lower in treated, E. coli-challenged birds than in untreated, E. coli-challenged birds on d 1 and 2 postinfection. The EMB + E. coli isolation frequency was also lower in treated birds; no E. coli was detectable in blood samples on any sampling day, and E. coli were isolated only in the liver, heart, and spleen of treated chickens at a ratio of 2/6, 1/6, and 3/6, respectively, at d 1 postinfection. The BW of birds from the E. coli-challenged group treated with bacteriophage EC1 were not significantly different from those of birds from both control groups but were 15.4% higher than those of the untreated, E. coli-challenged group on d 21 postinfection. The total mortality rate of birds during the 3-wk experimental period decreased from 83.3% in the untreated, E. coli-challenged birds (group IV) to 13.3% in birds treated with bacteriophage EC1 (group III). These results suggest that bacteriophage EC1 is effective in vivo and could be used to treat colibacillosis in chickens.


Advances in the use of CO2 as a renewable feedstock for the synthesis of polymers.
Carbon dioxide offers an accessible, cheap and renewable carbon feedstock for synthesis. Current interest in the area of carbon dioxide valorisation aims at new, emerging technologies that are able to provide new opportunities to turn a waste into value. Polymers are among the most widely produced chemicals in the world greatly affecting the quality of life. However, there are growing concerns about the lack of reuse of the majority of the consumer plastics and their after-life disposal resulting in an increasing demand for sustainable alternatives. New monomers and polymers that can address these issues are therefore warranted, and merging polymer synthesis with the recycling of carbon dioxide offers a tangible route to transition towards a circular economy. Here, an overview of the most relevant and recent approaches to CO2-based monomers and polymers are highlighted with particular emphasis on the transformation routes used and their involved manifolds.


Emotion and decision making.
A revolution in the science of emotion has emerged in recent decades, with the potential to create a paradigm shift in decision theories. The research reveals that emotions constitute potent, pervasive, predictable, sometimes harmful and sometimes beneficial drivers of decision making. Across different domains, important regularities appear in the mechanisms through which emotions influence judgments and choices. We organize and analyze what has been learned from the past 35 years of work on emotion and decision making. In so doing, we propose the emotion-imbued choice model, which accounts for inputs from traditional rational choice theory and from newer emotion research, synthesizing scientific models.


Water-Soluble Fish Protein Intake Led to Lower Serum and Liver Cholesterol Concentrations in Obese Zucker fa/fa Rats.
Proteins from different fish species and different raw materials such as fish fillets and by-products have shown promising cardioprotective effects in rodents and humans, including effects on cholesterol metabolism. Blue whiting is used mainly to produce fish meal for the feed industry and during this production, a water-soluble protein fraction, containing small peptides that are easily absorbed and may hold bioactive properties, is isolated. The effects of water-soluble fish protein on cholesterol metabolism were investigated in twelve male obese Zucker fa/fa rats. Rats were fed diets with water-soluble protein from blue whiting (BWW) as 1/3 of the total protein and the remaining 2/3 as casein (BWW group) or with casein as the sole protein source (control group). After 5 weeks intervention, the BWW group had lower serum total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol concentrations and lower cholesteryl ester concentration compared to controls. Hepatic concentrations of cholesterol, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and LDL receptors were also lower in the BWW group. The groups had a similar concentration of serum total bile acids and similar fecal excretions of cholesterol and bile acids. To conclude, the BWW diet led to lower concentrations of serum and liver cholesterol in obese Zucker fa/fa rats, probably due to lower hepatic cholesterol synthesis.


An Ion-Permeable State of the Glycine Receptor Captured by Molecular Dynamics.
Glycine receptors (GlyR) mediate fast inhibitory neurotransmission by switching between discrete states in response to ligand-binding events. Recent high-resolution structures from cryoelectron microscopy (cryo-EM) and X-ray crystallography have provided atomistic models for the open and closed states. Notably, the cryo-EM structure in complex with glycine illuminated a previously unreported wide-open state, whose physiological significance is debated. Here, we present the structure of an ion-conducting state of GlyR α1 captured by molecular dynamics and validate its physiological relevance with computational electrophysiology and polyatomic anion permeation simulations. Our analysis suggests that none of the experimental structures is a true representation of the physiologically active state, although previously characterized open channels in GLIC at pH 4, or GluCl/GlyR with ivermectin bound, provide reasonable models. These results open the door to an original functional annotation and support the conclusion that pore closing by desensitization versus deactivation involves the reorientation of the pore-lining helices in opposite directions.


Multiple origins of cultivated grapevine (Vitis vinifera L. ssp. sativa) based on chloroplast DNA polymorphisms.
The domestication of the Eurasian grape (Vitis vinifera ssp. sativa) from its wild ancestor (Vitis vinifera ssp. sylvestris) has long been claimed to have occurred in Transcaucasia where its greatest genetic diversity is found and where very early archaeological evidence, including grape pips and artefacts of a 'wine culture', have been excavated. Whether from Transcaucasia or the nearby Taurus or Zagros Mountains, it is hypothesized that this wine culture spread southwards and eventually westwards around the Mediterranean basin, together with the transplantation of cultivated grape cuttings. However, the existence of morphological differentiation between cultivars from eastern and western ends of the modern distribution of the Eurasian grape suggests the existence of different genetic contribution from local sylvestris populations or multilocal selection and domestication of sylvestris genotypes. To tackle this issue, we analysed chlorotype variation and distribution in 1201 samples of sylvestris and sativa genotypes from the whole area of the species' distribution and studied their genetic relationships. The results suggest the existence of at least two important origins for the cultivated germplasm, one in the Near East and another in the western Mediterranean region, the latter of which gave rise to many of the current Western European cultivars. Indeed, over 70% of the Iberian Peninsula cultivars display chlorotypes that are only compatible with their having derived from western sylvestris populations.


On the Duality of Forward and Inverse Light Transport.
Inverse light transport seeks to undo global illumination effects, such as interreflections, that pervade images of most scenes. This paper presents the theoretical and computational foundations for inverse light transport as a dual of forward rendering. Mathematically, this duality is established through the existence of underlying Neumann series expansions. Physically, it can be shown that each term of our inverse series cancels an interreflection bounce, just as the forward series adds them. While the convergence properties of the forward series are well known, we show that the oscillatory convergence of the inverse series leads to more interesting conditions on material reflectance. Conceptually, the inverse problem requires the inversion of a large light transport matrix, which is impractical for realistic resolutions using standard techniques. A natural consequence of our theoretical framework is a suite of fast computational algorithms for light transport inversion--analogous to finite element radiosity, Monte Carlo and wavelet-based methods in forward rendering--that rely at most on matrix-vector multiplications. We demonstrate two practical applications, namely, separation of individual bounces of the light transport and fast projector radiometric compensation, to display images free of global illumination artifacts in real-world environments.


Survivorship: pain version 1.2014.
Many posttreatment cancer survivors experience chronic pain, often leading to psychological distress; decreased activity, motivation, and personal interactions; and an overall poor quality of life. This section of the NCCN Guidelines for Survivorship provides screening and management recommendations for pain in survivors. A multidisciplinary approach is recommended, with a combination of pharmacologic treatments, psychosocial and behavioral interventions, physical therapy and exercise, and interventional procedures.


Heat stress increases insulin sensitivity in pigs.
Proper insulin homeostasis appears critical for adapting to and surviving a heat load. Further, heat stress (HS) induces phenotypic changes in livestock that suggest an increase in insulin action. The current study objective was to evaluate the effects of HS on whole-body insulin sensitivity. Female pigs (57 ± 4 kg body weight) were subjected to two experimental periods. During period 1, all pigs remained in thermoneutral conditions (TN; 21°C) and were fed ad libitum. During period 2, pigs were exposed to: (i) constant HS conditions (32°C) and fed ad libitum (n = 6), or (ii) TN conditions and pair-fed (PFTN; n = 6) to eliminate the confounding effects of dissimilar feed intake. A hyperinsulinemic euglycemic clamp (HEC) was conducted on d3 of both periods; and skeletal muscle and adipose tissue biopsies were collected prior to and after an insulin tolerance test (ITT) on d5 of period 2. During the HEC, insulin infusion increased circulating insulin and decreased plasma C-peptide and nonesterified fatty acids, similarly between treatments. From period 1 to 2, the rate of glucose infusion in response to the HEC remained similar in HS pigs while it decreased (36%) in PFTN controls. Prior to the ITT, HS increased (41%) skeletal muscle insulin receptor substrate-1 protein abundance, but did not affect protein kinase B or their phosphorylated forms. In adipose tissue, HS did not alter any of the basal or stimulated measured insulin signaling markers. In summary, HS increases whole-body insulin-stimulated glucose uptake.


Effect of wear, acetabular cup inclination angle, load and serum degradation on the friction of a large diameter metal-on-metal hip prosthesis.
The large-scale clinical problem caused by unacceptable tribological behaviour of certain large diameter metal-on-metal prosthetic hips has directed attention to adverse condition testing. High metal-on-metal wear is connected with adverse reaction to metal debris. Friction is important because high friction may be associated with high wear, risk the fixation of the cup, and cause detrimental heating of periprosthetic tissues. A friction measurement system was added to a multidirectional, established hip joint wear simulator, and its functionality was evaluated. In preliminary tests, a 50 mm diameter metal-on-metal prosthesis was tested in an optimal acetabular cup inclination angle (48°) and in a steep angle (70°) using a normal peak load (2 kN) and an increased peak load (3 kN). The test length was 100 h. Long-term adverse condition tests of 3 million cycles were run for three 52 mm metal-on-metal prostheses. The lubricant was diluted calf serum at 37 °C. In the 100 h tests, metal-on-metal frictional torque was not highly sensitive to the angle, load and serum degradation, and it was close to that of a conventional 28 mm prosthesis with a polyethylene cup, mostly below 5 Nm. However, a manyfold higher frictional torque (10 to 20 Nm) was observed in long-term metal-on-metal tests with substantial wear. To obtain a realistic prediction of the frictional behaviour of a hip design, long-term, multidirectional wear tests are necessary. The friction should preferably be measured during the wear test. In addition to normal conditions, adverse condition testing is strongly recommended.


Natural attenuation process via microbial oxidation of arsenic in a high Andean watershed.
Rivers in northern Chile have arsenic (As) concentrations at levels that are toxic for humans and other organisms. Microorganism-mediated redox reactions have a crucial role in the As cycle; the microbial oxidation of As (As(III) to As(V)) is a critical transformation because it favors the immobilization of As in the solid phase. We studied the role of microbial As oxidation for controlling the mobility of As in the extreme environment found in the Chilean Altiplano (i.e., > 4000 meters above sea level (masl) and < 310 mm annual rainfall), which are conditions that have rarely been studied. Our model system was the upper Azufre River sub-basin, where the natural attenuation of As from hydrothermal discharge (pH 4-6) was observed. As(III) was actively oxidized by a microbial consortium, leading to a significant decrease in the dissolved As concentrations and a corresponding increase in the sediment's As concentration downstream of the hydrothermal source. In-situ oxidation experiments demonstrated that the As oxidation required biological activity, and microbiological molecular analysis confirmed the presence of As(III)-oxidizing groups (aroA-like genes) in the system. In addition, the pH measurements and solid phase analysis strongly suggested that the As removal mechanism involved adsorption or coprecipitation with Fe-oxyhydroxides. Taken together, these results indicate that the microorganism-mediated As oxidation contributed to the attenuation of As concentrations and the stabilization of As in the solid phase, therefore controlling the amount of As transported downstream. This study is the first to demonstrate the microbial oxidation of As in Altiplano basins and its relevance in the immobilization of As.


Trends in the outcomes for patients with limited stage small cell lung cancer: An analysis of the Surveillance, Epidemiology, and End Results database.
We used the Surveillance, Epidemiology, and End Results (SEER) database to examine the outcomes of patients with limited stage small cell lung cancer (LS-SCLC) over time and to determine if any trends were present with respect to the publication of significant clinical trials. We assembled a cohort of 6271 patients aged 21 years and older with LS-SCLC diagnosed from 1983 to 1998 and followed through 2005. Potential covariates included patient age at diagnosis, sex, race, year of diagnosis, laterality, tumor size, and location (upper lobe, middle lobe, lower lobe, or main bronchus). In multivariate analysis, older age, male sex, African American race, and main bronchus location were all associated with a statistically significant increase in the mortality hazard. When compared to patients diagnosed in 1983-1987 who did not receive radiotherapy, the hazard for mortality was significantly reduced for patients diagnosed in 1988-1992 regardless of whether they received radiotherapy (HR=0.59; CI 0.52-0.65; p<0.0001) or not (HR=0.67; CI 0.60-0.75; p<0.0001). Patients who were diagnosed in 1993-1998 and received radiotherapy had similarly improved survival (HR=0.53; CI 0.47-0.58; p<0.0001), which was better than patients from the same time era who did not receive radiotherapy (HR=0.77; CI 0.69-0.85; p<0.0001). In conclusion, the survival for patients with LS-SCLC has improved over time. Many factors are likely involved, however we believe that part of this improvement was the result of clinical trials which investigated and subsequently defined chemoradiotherapy as the standard of care. In order to continue to improve clinical outcomes, clinical trials investigating new treatment paradigms are needed.