Undiscovered Pulsar in the Local Bubble as an Explanation of the Local High Energy Cosmic Ray All-Electron Spectrum.

Cosmic ray electrons and positrons are tracers of particle propagation in the interstellar medium (ISM). A recent measurement performed using the High Energy Stereoscopic System extends the all-electron (electron+positron) spectrum up to 20 TeV, probing very local sources and transport due to the ∼10 kyr cooling time of these particles. An additional key local measurement was the recent estimation of the ISM diffusion coefficient around Geminga performed using the High-Altitude Water Cherenkov Observatory. The inferred diffusion coefficient is much lower than typically assumed values. It has been argued that if this diffusion coefficient is representative of the local ISM, pulsars would not be able to account for the all-electron spectrum measured at Earth. Here we show that a low diffusion coefficient in the local ISM is compatible with a pulsar wind nebula origin of the highest energy electrons, if a so-far-undiscovered pulsar with spin-down power ∼10^{33-34} erg/s exists within 30-80 pc of Earth. The existence of such a pulsar is broadly consistent with the known population and may be detected in near future survey observations.

Prevention of postsurgical wound dehiscence after abdominal surgery with NPWT: a multicentre randomised controlled trial protocol.

OBJECTIVE: The effectiveness of negative pressure wound therapy (NPWT) in the prevention of postoperative surgical wound dehiscence (SWD) is the subject of much debate and remains to be determined. This study will identify individuals at risk of postoperative SWD and trial the use of NPWT as a prophylactic measure against the occurrence of SWD, compared with a non-NPWT standard surgical dressing (SSD). METHOD: A prospective multicentre randomised controlled trial comparing NPWT dressing against standard surgical dressings (SSD) will be conducted. An intention-to-treat (ITT) approach will be used for the trial. AIMS: The primary outcome is the prevention of postoperative SWD up to and including day 30 postoperative. Secondary outcomes are: prevention of surgical site infection (SSI) and economic analysis of treatment groups. CONCLUSION: This study will determine the effectiveness of NPWT in the prevention of postoperative abdominal SWD in a predefined level of risk population. This level 1 study will provide further data for abdominal SWD risk classification, which is anticipated to inform preventive postoperative management. The study design uses a prospective real-world scenario in order to identify clinically significant differences between the intervention and control groups. TRIAL REGISTRATION: This trial was prospectively registered on 10 December 2012 with Australian and New Zealand Clinical Trials Network (ANZCTR): 12612001275853.

A trial of a self-assessment tool of problems following treatment of colorectal cancer: a prospective study in Australia primary care.

Patients treated for colorectal cancer (CRC) experience considerable physical, social and psychological morbidity. In this study, 66 participants with stages I-III CRC were enrolled in this study. Participants completed the self-assessment tool for patients (SATp) over a 5-month period and visited a general practitioner with a copy of their SATp to assist in the management of any problems associated with CRC treatment. General practitioners' notes were reviewed for management actions. Of the 66 participants, 57 visited a general practitioner over the 5-month study period. A total of 547 problems were identified (median 7; IQR: 3-12.25). Participants with physical problems were more likely to consult their general practitioner (OR: 1.84, CI: 1.05-3.21, P = 0.03) compared to those with psychological problems. The number of problems experienced by participants did not have any influence on the decision to visit a general practitioner. Psychological problems (P < 0.01) significantly reduced over the 5-month study period. Regular use of the SATp facilitates the identification of long-term CRC treatment-related problems. Some of these problems could then be addressed in primary care.

The effects of firocoxib on cautery disbudding pain and stress responses in preweaned dairy calves.

Perioperative analgesic effects of oral firocoxib following cautery disbudding were investigated in preweaned calves. Twenty Holstein calves approximately 4 to 6wk old received a single oral dose of firocoxib, a nonsteroidal antiinflammatory, at 0.5mg/kg (n=10) or placebo (n=10) in a randomized controlled clinical trial. Responses, including ocular temperature determined by infrared thermography, pressure algometry measuring mechanical nociception threshold, and heart rate, were evaluated at 2, 4, 7, 8, and 24h after cornual nerve block and cautery disbudding. Blood samples were collected over 96h and analyzed for plasma cortisol and substance P concentrations by RIA. Additionally, ex vivo prostaglandin E2 concentrations were determined over a 72-h study period using an enzyme immunoassay. Data were analyzed using a linear mixed effects model with repeated measures. An inhibition of ex vivo prostaglandin E2 synthesis was observed from 12 to 48h following disbudding in calves treated with firocoxib. Cautery disbudding was associated with an increased nociception for the duration of sampling (24h). During the initial 24-h period following disbudding, no difference in response between treatment groups was noted. Following 24h, mean cortisol concentrations diverged between the 2 study groups with placebo-treated calves having increased cortisol concentrations at approximately 48h after disbudding. Furthermore, the overall integrated cortisol response as calculated as area under the effect curve tended to be reduced in firocoxib-treated calves. The prolonged effects of cautery dehorning require further investigation. Moreover, the effect of firocoxib on cortisol reduction observed in this study requires additional exploration.

The economic value of organic dairy farms in Vermont and Minnesota.

This study quantifies the overall economic values of organic dairy farms in Vermont and Minnesota and estimates the economic impacts of organic dairy farm sales relative to an equivalent level of sales from conventional dairy farms in those states. This question is of interest because the development of the organic dairy sector has allowed some farms that likely would not have remained in the conventional dairy business to continue being economically viable as organic dairy farms. Thus, these sales provide an economic impact in regions when this milk is exported to nonproducing regions. Organic and conventional dairy farm financial data in Vermont and Minnesota were collected and assembled to develop dairy farm production functions by region and dairy type. These production functions were then used in state-level input-output models to calculate economic impacts. The opportunity costs of organic dairy farm production were also estimated by comparing the relative statewide economic impacts of organic and conventional dairy farms if both experience a hypothetical 5-million-dollar increase in sales. Between 2008 and 2010, Vermont's 180 organic dairy farms annually contributed $76.3 million in output (the value of an industry's production within the state), 808 jobs, $34.1 million in gross state product, and $26.3 million in labor income to Vermont's economy. Between 2009 and 2011, Minnesota's 114 organic dairy farms annually contributed $77.7 million in output, 552 jobs, $32.1 million in gross state product, and $21 million in labor income to Minnesota's economy. In Vermont, organic dairy farm sales revenue would result in greater state-wide impacts of 3% in output, 39% in labor income, 33% in gross state product, and 46% in employment relative to the impacts from an equivalent level of sales revenue to conventional dairy farms. In Minnesota, these economic impacts are 4, 9, 11, and 12% greater, respectively, for organic dairy farms relative to conventional dairy farms. This study concludes that organic dairy farms may contribute more to the local economy than average and similar-size conventional dairy farms in the Northeast and Upper Midwest and that organic dairy farm milk production supports economic development in rural communities.

Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability.

Microsatellite instability has been observed in both sporadic and hereditary forms of colorectal cancer. In the hereditary form, this instability is generally due to germline mutations in mismatch repair (MMR) genes. However, only one in ten patients with sporadic tumours exhibiting microsatellite instability had a detectable germline mutation. Moreover, only three of seven sporadic tumour cell lines with microsatellite instability had mutations in a MMR gene, and these mutations could occur somatically. These results demonstrate that tumours can acquire somatic mutations that presumably do not directly affect cell growth but result only in genetic instability. They also suggest that many sporadic tumours with microsatellite instability have alterations in genes other than the four now known to participate in MMR.

Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.

Cowden disease (CD) is an autosomal dominant cancer predisposition syndrome associated with an elevated risk for tumours of the breast, thyroid and skin. Lhermitte-Duclos disease (LDD) cosegregates with a subset of CD families and is associated with macrocephaly, ataxia and dysplastic cerebellar gangliocytomatosis. The common feature of these diseases is a predisposition to hamartomas, benign tumours containing differentiated but disorganized cells indigenous to the tissue of origin. Linkage analysis has determined that a single locus within chromosome 10q23 is likely to be responsible for both of these diseases. A candidate tumour suppressor gene (PTEN) within this region is mutated in sporadic brain, breast and prostate cancer. Another group has independently isolated the same gene, termed MMAC1, and also found somatic mutations throughout the gene in advanced sporadic cancers. Mutational analysis of PTEN in CD kindreds has identified germline mutations in four of five families. We found nonsense and missense mutations that are predicted to disrupt the protein tyrosine/dual-specificity phosphatase domain of this gene. Thus, PTEN appears to behave as a tumour suppressor gene in the germline. Our data also imply that PTEN may play a role in organizing the relationship of different cell types within an organ during development.

The Stickland Reaction Precursor trans-4-Hydroxy-l-Proline Differentially Impacts the Metabolism of Clostridioides difficile and Commensal Clostridia.

An intact gut microbiota confers colonization resistance against Clostridioides difficile through a variety of mechanisms, likely including competition for nutrients. Recently, proline was identified as an important environmental amino acid that C. difficile uses to support growth and cause significant disease. A posttranslationally modified form, trans-4-hydroxyproline, is highly abundant in collagen, which is degraded by host proteases in response to C. difficile toxin activity. The ability to dehydrate trans-4-hydroxyproline via the HypD glycyl radical enzyme is widespread among gut microbiota, including C. difficile and members of the commensal Clostridia, suggesting that this amino acid is an important nutrient in the host environment. Therefore, we constructed a C. difficile ΔhypD mutant and found that it was modestly impaired in fitness in a mouse model of infection, and was associated with an altered microbiota when compared to mice challenged with the wild-type strain. Changes in the microbiota between the two groups were largely driven by members of the Lachnospiraceae family and the Clostridium genus. We found that C. difficile and type strains of three commensal Clostridia had significant alterations to their metabolic gene expression in the presence of trans-4-hydroxyproline in vitro. The proline reductase (prd) genes were elevated in C. difficile, consistent with the hypothesis that trans-4-hydroxyproline is used by C. difficile to supply proline for energy metabolism. Similar transcripts were also elevated in some commensal Clostridia tested, although each strain responded differently. This suggests that the uptake and utilization of other nutrients by the commensal Clostridia may be affected by trans-4-hydroxyproline metabolism, highlighting how a common nutrient may be a signal to each organism to adapt to a unique niche. Further elucidation of the differences between them in the presence of hydroxyproline and other key nutrients will be important in determining their role in nutrient competition against C. difficile. IMPORTANCE Proline is an essential environmental amino acid that C. difficile uses to support growth and cause significant disease. A posttranslationally modified form, hydroxyproline, is highly abundant in collagen, which is degraded by host proteases in response to C. difficile toxin activity. The ability to dehydrate hydroxyproline via the HypD glycyl radical enzyme is widespread among gut microbiota, including C. difficile and members of the commensal Clostridia, suggesting that this amino acid is an important nutrient in the host environment. We found that C. difficile and three commensal Clostridia strains had significant, but different, alterations to their metabolic gene expression in the presence of hydroxyproline in vitro. This suggests that the uptake and utilization of other nutrients by the commensal Clostridia may be affected by hydroxyproline metabolism, highlighting how a common nutrient may be a signal to each organism to adapt to a unique niche. Further elucidation of the differences between them in the presence of hydroxyproline and other key nutrients will be important to determining their role in nutrient competition against C. difficile.

Genetic instability occurs in the majority of young patients with colorectal cancer.

Replication errors (RER) associated with genetic instability have been found in cancers of several different types and particularly in the tumours of patients with hereditary non-polyposis colorectal cancer (HNPCC). We have here determined the prevalence of such instability in relation to age among patients without HNPCC. Colorectal cancers (CRCs) in the majority of patients 35 years of age or younger exhibited instability (58% of 31 patients), whereas CRCs from patients older than 35 uncommonly did (12% of 158, p < 0.0001). Twelve of the patients under 35 with instability were evaluated for alterations of mismatch repair genes, and five were found to harbour germline mutations. These data suggest that the mechanisms underlying tumour development in young CRC patients differ from those in most older patients, regardless of HNPCC status. The results have important implications for genetic testing and management of young CRC patients and their families.

Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by the early onset of colorectal cancer and linked to germline defects in at least four mismatch repair genes. Although much has been learned about the molecular pathogenesis of this disease, questions related to effective presymptomatic diagnosis are largely unanswered because of its genetic complexity. In this study, we evaluated tumors from 74 HNPCC kindreds for genomic instability characteristic of a mismatch repair deficiency and found such instability in 92% of the kindreds. The entire coding regions of the five known human mismatch repair genes were evaluated in 48 kindreds with instability, and mutations were identified in 70%. This study demonstrates that a combination of techniques can be used to genetically diagnose tumor susceptibility in the majority of HNPCC kindreds and lays the foundation for genetic testing of this relatively common disease.

Economic feasibility of converting cow manure to electricity: a case study of the CVPS Cow Power program in Vermont.

A case study of the Central Vermont Public Service Corporation (CVPS) Cow Power program examines the economic feasibility for dairy farms to convert cow manure into electricity via anaerobic methane digestion. The study reviews the mechanism for CVPS, dairy farms, electricity customers, and government agencies to develop and operate the program since 2004, examines the costs and returns for the participating dairy farms, and assesses their cash flow over a period of 7 yr under different scenarios. With 6 dairy farms generating about 12 million kilowatt-hours of electricity per year and more than 4,600 CVPS electricity customers voluntarily paying premiums of $0.04 per kilowatt-hour, or a total of about $470,000 per year, the CVPS Cow Power program represents a successful and locally sourced renewable energy project with many environmental and economic benefits. Factors for the successful development and operation of the program include significant grants from government agencies and other organizations, strong consumer support, timely adjustments to the basic electricity price paid to the farms, and close collaboration among the participating parties. This study confirms that it is technically feasible to convert cow manure to electricity on farms, but the economic returns depend highly on the base electricity price, premium rate, financial supports from government agencies and other organizations, and sales of the byproducts of methane generation.

Parkinson's Disease Master Regulators on Substantia Nigra and Frontal Cortex and Their Use for Drug Repositioning.

Parkinson's disease (PD) is among the most prevalent neurodegenerative diseases. Available evidences support the view of PD as a complex disease, being the outcome of interactions between genetic and environmental factors. In face of diagnosis and therapy challenges, and the elusive PD etiology, the use of alternative methodological approaches for the elucidation of the disease pathophysiological mechanisms and proposal of novel potential therapeutic interventions has become increasingly necessary. In the present study, we first reconstructed the transcriptional regulatory networks (TN), centered on transcription factors (TF), of two brain regions affected in PD, the substantia nigra pars compacta (SNc) and the frontal cortex (FCtx). Then, we used case-control studies data from these regions to identify TFs working as master regulators (MR) of the disease, based on region-specific TNs. Twenty-nine regulatory units enriched with differentially expressed genes were identified for the SNc, and twenty for the FCtx, all of which were considered MR candidates for PD. Three consensus MR candidates were found for SNc and FCtx, namely ATF2, SLC30A9, and ZFP69B. In order to search for novel potential therapeutic interventions, we used these consensus MR candidate signatures as input to the Connectivity Map (CMap), a computational drug repositioning webtool. This analysis resulted in the identification of four drugs that reverse the expression pattern of all three MR consensus simultaneously, benperidol, harmaline, tubocurarine chloride, and vorinostat, thus suggested as novel potential PD therapeutic interventions.

The effect of DNA recovery on the subsequent quality of latent fingermarks: A pseudo-operational trial.

The recovery of fingermarks and DNA from the same location at a crime scene can be problematic because of contamination issues associated with powdering or laboratory-based visualisation processes and/or the perceived destructive impact of commonly employed 'swabbing' approaches to DNA recovery. Previous research in a controlled environment demonstrated that it was possible to recover DNA and latent fingermarks from the same location on various substrates when an adhesive approach to DNA recovery was used. The aim of this research was to conduct a pseudo-operational trial into the dual recovery of DNA and fingermarks using gel lifters for DNA recovery. Participants were asked to voluntarily and anonymously donate a wide variety of porous and non-porous substrates post handling. No instruction as to fingermark deposition nor environmental storage was provided. BVDA gel lifters were applied to the substrates to replicate DNA recovery followed by the application of fingermark visualisation processes. The number and quality of the fingermarks was established using a grading approach. Application factors were also investigated to consider the effects of user variation. The results demonstrated that it was possible to recover DNA and fingermarks considered to be capable of supporting an identification. Fingermark quality post lifting was dependant on the substrates used. The weight applied to the gel during its application was a lesser contributing factor than the duration of its contact with the surface. There was a greater chance of leaving the fingermarks unaltered with the application of a low weight and instantaneous retraction.

Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN.

The tumor suppressor PTEN is a phosphatase with sequence similarity to the cytoskeletal protein tensin. Here the cellular roles of PTEN were investigated. Overexpression of PTEN inhibited cell migration, whereas antisense PTEN enhanced migration. Integrin-mediated cell spreading and the formation of focal adhesions were down-regulated by wild-type PTEN but not by PTEN with an inactive phosphatase domain. PTEN interacted with the focal adhesion kinase FAK and reduced its tyrosine phosphorylation. Overexpression of FAK partially antagonized the effects of PTEN. Thus, PTEN phosphatase may function as a tumor suppressor by negatively regulating cell interactions with the extracellular matrix.

Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability.

Transforming growth factor-beta (TGF-beta) is a potent inhibitor of epithelial cell growth. Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-beta receptor (RII) gene. Eight such examples, due to three different mutations, were identified. The mutations were clustered within small repeated sequences in the RII gene, were accompanied by the absence of cell surface RII receptors, and were usually associated with small amounts of RII transcript. RII mutation, by inducing the escape of cells from TGF-beta-mediated growth control, links DNA repair defects with a specific pathway of tumor progression.

Mutations of GTBP in genetically unstable cells.

The molecular defects responsible for tumor cell hypermutability in humans have not yet been fully identified. Here the gene encoding a G/T mismatch-binding protein (GTBP) was localized to within 1 megabase of the related hMSH2 gene on chromosome 2 and was found to be inactivated in three hypermutable cell lines. Unlike cells defective in other mismatch repair genes, which display widespread alterations in mononucleotide, dinucleotide, and other simple repeated sequences, the GTBP-deficient cells showed alterations primarily in mononucleotide tracts. These results suggest that GTBP is important for maintaining the integrity of the human genome and document molecular defects accounting for variation in mutator phenotype.

Mismatch repair deficiency in phenotypically normal human cells.

Tumor cells in patients with hereditary nonpolyposis colorectal cancer (HNPCC) are characterized by a genetic hypermutability caused by defects in DNA mismatch repair. A subset of HNPCC patients was found to have widespread mutations not only in their tumors, but also in their non-neoplastic cells. Although these patients had numerous mutations in all tissues examined, they had very few tumors. The hypermutability was associated with a profound defect in mismatch repair at the biochemical level. These results have implications for the relation between mutagenesis and carcinogenesis, and they suggest that mismatch repair deficiency is compatible with normal human development.

PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.

Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers. In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas. The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions. These homologies suggest that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions.

Induction dose of propofol in patients using cannabis.

BACKGROUND AND OBJECTIVE: An estimated 150 million people worldwide use cannabis. The effect of cannabis on anaesthetic requirements in humans does not appear to have been studied. METHODS: In this prospective, randomized, single-blinded study, 30 male patients using cannabis more than once per week (group C) and 30 nonusers (group NC), aged 18-50 years, were induced with propofol 1.5, 2, 2.5, 3 or 3.5 mg kg. Additional doses were given when required. The primary outcome was the 50% effective dose of propofol and successful induction was determined by loss of consciousness with a bispectral index value of less than 60 and satisfactory insertion of a laryngeal mask. Propofol requirements to achieve these outcomes were recorded. RESULTS: The dose required to achieve the target bispectral index value was not significantly higher in group C, but group C required a significantly higher propofol dose to achieve laryngeal mask insertion (314.0 +/- 109.3 vs. 263.2 +/- 69.5 mg, P < 0.04). The estimated effective propofol induction dose in 50-95% of patients did not significantly differ between groups. CONCLUSION: We conclude that cannabis use increases the propofol dose required for satisfactory clinical induction when inserting a laryngeal mask.

Love thy neighbor--but does that include a six hundred eighty-four cow dairy operation? A survey of community perceptions.

The juxtaposition of nonfarming residences to operating dairy farms often precipitates conflict over appropriate land use. This was the situation facing the residents of the town of Charlotte, Vermont, in 2002 when a local dairy farmer proposed expanding from 225 to 684 cows with the construction of a new dairy facility and manure storage lagoon. The proposal raised considerable concern within the community and presented a unique opportunity for extension researchers to examine and analyze the attitudes and concerns of local residents toward the planned expansion, including their reasons for supporting or opposing the expansion, and to develop recommendations for farm operators considering future expansions. A survey instrument was developed and inserted in a local newspaper that was delivered to all households of Charlotte to identify important concerns of the community and explanatory factors differing between supporters and nonsupporters. Of those responding to the survey, 44.3% opposed the proposed dairy facility, 30.6% supported it, 17.9% needed more information to make a decision, and 7.2% had no opinion or were unaware of the proposal. There were no significant demographic (age, gender, educational attainment) differences between supporters and nonsupporters. Yet, the closer the proximity of the respondent's residence to the farm, the more likely he or she was to oppose it (beta = 1.018). The concerns of greatest importance were water quality (4.42/5), effect on property values (3.07/5), and animal welfare (3.58/5). Responses to the open-ended questions on the survey revealed strong views toward the farmer personally as well as concentrated animal feeding operations in general. The results indicate that farmers and extension need to take proactive steps to provide education and information relevant to the facts and issues surrounding new dairy facilities for 500 to 700 dairy cows.