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Luis Puig1, Tao Fan,2 Qian Ding,2 Nancy E Smith2 1Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; 2Global Health Outcomes, Merck and Co., Inc., USA Background: Biologic therapies represent a significant advance in the treatment of psoriasis. However, no studies have examined the patient characteristics predictive of biologic treatment of psoriasis. The purpose of this study was to ascertain the frequency and predictors of treatment of psoriasis with biologics in three European countries, ie, France, Spain, and the UK. Methods: This was a cross-sectional analysis of physician-recorded demographic and clinical data on patients receiving either conventional or biologic treatments for psoriasis. Data were drawn from the Adelphi 2007 Psoriasis Disease Specific Program (DSP®), a multinational, real-world survey of patients with psoriasis consulting practicing dermatologists. The numbers of patients treated with biologic and nonbiologic agents were recorded. Data were subjected to bivariate analysis according to treatment regimen (biologic versus nonbiologic). Predictors of treatment with biologics were identified by logistic regression analysis. Results: A total of 2,509 psoriasis patients were included in this study (1,374 from France, 561 from Spain, and 574 from the UK). Biologic use was most prevalent in Spain (19.4% of patients), followed by the UK (9.1%), and France (8.4%). In the logistic regression analysis, psoriatic arthritis was a statistically significant predictor of increased biologic use in France (odds ratio [OR] 5.38, 95% confidence interval [CI] 3.32–8.77), Spain (OR 2.71, 95% CI 1.16–6.33), and the UK (OR 8.70, 95% CI 3.65–20.83). Physician-assessed moderate-to-severe disease was also a statistically significant predictor of increased biologic use in France (OR 5.08, 95% CI 2.01–12.82), Spain (OR 11.11, 95% CI 4.33–28.57), and the UK (OR 8.55, 95% CI 1.11–66.67). Conclusion: In this study, an average of about one tenth of psoriasis patients enrolled in Spain, France, and the UK were treated with biologics in 2007. Physician-assessed moderate-to-severe disease and presence of psoriatic arthritis were significantly associated with biologic use in all three countries. Keywords: psoriasis, drug therapy, tumor necrosis factor-alpha, antagonists, inhibitors, dermatologic agents, therapeutic use

A kritikai geográfusok 1997-es alakuló vancouveri konferenciája világossá tette, hogy szükség van nemzetközi kritikai geográfia létrehozására, kiteljesítésére – de, hogy mi számít kritikainak, az nagyon bizonytalanul definiált. E cikk igyekszik megragadni e kibontakozó politikai és szellemi csoport fő jellemzőit, illetve „jelszavait”. Ma a baloldal hagyományos tanítása a befogadásra és az önreflexivitásra buzdít. Olyan vélemény is létezik, hogy minden politikai harc egyenlő, a politikát pedig gyakran összekeverik az etikával. A cikk vitatja ezeknek az álláspontoknak a hasznosságát a 21. századi nemzetközi kritikai geográfia kontextusában, s a marxista kritika erejének újragondolására szólít fel.

Abstract Background To date there has been relatively little published about how research priorities are set, and even less about methods by which decision-makers can be engaged in defining a relevant and appropriate research agenda. We report on a recent effort in British Columbia to have researchers and decision-makers jointly establish an agenda for future research into questions of resource allocation. Methods The researchers enlisted decision-maker partners from each of British Columbia's six health authorities. Three forums were held, at which researchers and decision-makers from various levels in the health authorities considered possible research areas related to three key focus areas: (1) generation and use of decision criteria and measurement of 'benefit' against such criteria; (2) identification of so-called 'disinvestment' opportunities; and (3) evaluation of the effectiveness of priority setting procedures. Detailed notes were taken from each forum and synthesized into a set of qualitative themes. Results Forum participants suggested that future research into healthcare priority setting would benefit from studies that were longitudinal, comparative, and/or interdisciplinary. As well, participants identified two broad theme areas in which specific research projects were deemed desirable. First, future research might usefully consider how formal priority setting and resource allocation projects are situated within a larger organizational and political context. Second, additional research efforts should be devoted to better understanding and improving the actual implementation of priority setting frameworks, particularly with respect to issues of change management and the resolution of impediments to action on recommendations for resource allocation. Conclusion We were able to validate the importance of initial areas posed to the group and observed emergence of additional concerns and directions of critical importance to these decision-makers at this time. It is likely that the results are broadly applicable to other healthcare contexts. The implementation of this research agenda in British Columbia will depend upon the ability of the researchers and decision-makers to develop particular projects that fit within the constraints of existing funding opportunities. The process of engagement itself had benefits in terms of connecting decision-makers with their peers and sparking increased interest in the use and refinement of priority setting frameworks.

Abstract Background Depressive disorders are highly prevalent and of significant societal burden. In fall 2004, the 'Alberta Depression Initiative' (ADI) research program was formed with a mission to enhance the mental health of the Alberta population. A key expectation of the ADI is that research findings will be effectively translated to appropriate research users. To help ensure this, one of the initiatives funded through the ADI focused specifically on knowledge transfer and exchange (KTE). The objectives of this project were first to examine the state of the KTE literature, and then based on this review and a set of key informant interviews, design a KTE strategy for the ADI. Methods Face to face interviews were conducted with 15 key informants familiar with KTE and/or mental health policy and programs in Alberta. Interviews were transcribed and analyzed using the constant comparison method. Results This paper reports on findings from the qualitative interviews. Respondents were familiar with the barriers to and facilitators of KTE as identified in the existing literature. Four key themes related to the nature of effective KTE were identified in the data analysis: personal relationships, cultivating champions, supporting communities of practice, and building receptor capacity. These recommendations informed the design of a contextually appropriate KTE strategy for the ADI. The three-phased strategy involves preliminary research, public workshops, on-going networking and linkage activities and rigorous evaluation against pre-defined and mutually agreed outcome measures. Conclusion Interest in KTE on the part of ADI has led to the development of a strategy for engaging decision makers, researchers, and other mental health stakeholders in an on-going network related to depression programs and policy. A similarly engaged process might benefit other policy areas.

Abstract Background Decisions regarding the allocation of available resources are a source of growing dissatisfaction for healthcare decision-makers. This dissatisfaction has led to increased interest in research on evidence-based resource allocation processes. An emerging area of interest has been the empirical analysis of the characteristics of existing and desired priority setting processes from the perspective of decision-makers. Methods We conducted in-depth, face-to-face interviews with 18 senior managers and medical directors with the Vancouver Island Health Authority, an integrated health care provider in British Columbia responsible for a population of approximately 730,000. Interviews were transcribed and content-analyzed, and major themes and sub-themes were identified and reported. Results Respondents identified nine key features of a desirable priority setting process: inclusion of baseline assessment, use of best evidence, clarity, consistency, clear and measurable criteria, dissemination of information, fair representation, alignment with the strategic direction and evaluation of results. Existing priority setting processes were found to be lacking on most of these desired features. In addition, respondents identified and explicated several factors that influence resource allocation, including political considerations and organizational culture and capacity. Conclusion This study makes a contribution to a growing body of knowledge which provides the type of contextual evidence that is required if priority setting processes are to be used successfully by health care decision-makers.

Abstract Background Despite the high prevalence of co-morbid substance use among mental health service users (dual diagnosis), very few mental health workers in the UK have had training and/or clinical experience to equip them to deliver targeted interventions to this client group. Method In a randomised controlled trial of training for dual diagnosis interventions, 79 case managers from 12 community mental health teams in South London were randomly allocated to either receive training and follow-up supervision (experimental group) or no training and supervision (control group). Baseline measures of attitude, self-efficacy and knowledge were collected prior to randomisation, and were repeated at 18 months post-training. An intention to treat analysis of follow-up data (adjusted for baseline score for that outcome and team) was performed. Results At 18 months post-training, the AAPPQ (The Alcohol and Alcohol Problems Perception Questionnaire) total score was did not differ significantly between the two groups (adjusted difference 7.43 [95% CI -0.86 to 15.71], p = 0.08). There were significant differences in favour of the experimental group on 2 of the 6 subscales of the AAPPQ: 'adequacy of knowledge and skills in working with alcohol" (adjusted difference 3.598 [95% CI 1.03 to 6.16], p = 0.007) and "self-esteem in working with alcohol" (adjusted difference 3.00 [95% CI 0.46 to 5.54], p = 0.021). In addition there were significant improvements for the experimental group on "Knowledge About Dual Diagnosis" (adjusted difference 2.00 [95% CI 0.80 to 3.22], p = 0.002) and "Self-Efficacy Scale" (adjusted difference 13.55 [95% CI 8.00 to 26.86], p = 0.001). The effect of membership of teams was added to the analysis of covariance and this changed the results for only one variable: "self-esteem working with drinkers" was no longer significant. Conclusion A brief training course in dual diagnosis interventions had a significant effect on secondary measures of knowledge and self-efficacy that was detectable at 18 months post-training. Improvements in attitudes towards working with drinkers and drug users in mental health settings failed to reach statistical significance. Future research should explore the effects of dose of dual diagnosis training, and the successful integration of skills gained into routine care. Trial Registration: ISRCTN98891022 14th March 2007

The long noncoding RNA NEAT1 is known to be heavily dysregulated in many cancers. A single exon gene produces two isoforms, NEAT1_1 and NEAT1_2, through alternative 3'-end processing. As the longer isoform, NEAT1_2 is an essential scaffold for nuclear paraspeckle formation. It was previously thought that the short NEAT1_1 isoform only exists to keep the NEAT1 locus active for rapid paraspeckle formation. However, a recent glycolysis-enhancing function for NEAT1_1 , contributing to cancer cell proliferation and the Warburg effect, has been demonstrated. Previous studies have mainly focused on quantifying total NEAT1 and NEAT1_2 expression levels. However, in light of the NEAT1_1 role in cancer cell metabolism, the contribution from specific NEAT1 isoforms is no longer clear. Here, the roles of NEAT1_1 and NEAT1_2 in metabolism and cancer progression are discussed.

Context.—: Acquiring objective, timely, and comprehensive feedback on resident diagnostic performance is notoriously difficult., Objective.—: To implement a custom software application (Resident Case Tracker) to improve evaluative diagnostic analysis for residency programs., Design.—: Residents and faculty use a graphical user interface with restricted access to their own cases and evaluations. For each sign-out, residents enter their diagnoses and comments for each case. Faculty are provided a sign-out queue to review the resident diagnosis and select their level of agreement alongside optional comments. After sign-out, residents can review the agreement level and comments for each case, overall sign-out statistics, and organ-specific performance, and they have the option of opening and reviewing groups of cases by agreement status. A sign-out evaluation is automatically generated and stored alongside additional reports. Administrative access allows privileged users to readily review data analytics at both an individual and residency-wide global level., Results.—: A marked increase in completed evaluations and feedback was noted in the initial 36 months of implementation. During a 3-year academic period, faculty completed individual feedback on 33 685 cases and 1073 overall sign-out evaluations., Conclusions.—: Resident Case Tracker is an invaluable tool for our residency program and has provided unparalleled feedback and data analytics. Throughout residency, trainees have access to each completed sign-out, with the ability to learn from discrepant cases while also monitoring improvements in diagnostic acumen over time. Faculty are able to assess resident milestones much more effectively while more readily identifying residents who would benefit from targeted study., Competing Interests: The views expressed herein are those of the author and do not reflect the official policy or position of Brooke Army Medical Center, the US Army Medical Department, the US Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force and Department of Defense, or the US government.

Epigenetics are known to be involved in various disorders, including neurobiological disorders like autism. Dietary factors such as folic acid can affect epigenetic marks using methylenetetrahydrofolate reductase (MTHFR) to metabolize folic acid to a one-carbon methyl group. As MTHFR mutations are frequent, it is curious as to whether excess folic acid, with or without functioning MTHFR, could affect gene expression, epigenetics, and neuromorphology. Here, we investigated gene expression and activity of epigenetic modifying enzymes, genome-wide DNA methylation, histone 3 modifications, and dendritic spine densities in SH-SY5Y cells with or without a knockdown of MTHFR and with or without an excess of folic acid. We found alterations to gene expression of epigenetic modifying enzymes, including those associated with disorders like autism. Grouping the epigenetic modifying enzymes by function indicated that gene expression was widely affected for genes that code for enzymes affecting DNA methylation, histone acetylation, histone methylation, histone phosphorylation, and histone ubiquitination when excess folic acid treatment occurred with or without the knockdown of MTHFR. MTHFR was significantly reduced upon excess folic acid treatment whether MTHFR was knocked-down or not. Further, methyl-CpG binding protein 2 expression was significantly decreased with excess folic acid treatment with and without proper MTHFR expression. Global DNA methylation decreased due to the knockdown alone while global hydroxymethylated DNA increased due to the knockdown alone. TET2 expression significantly increased with the MTHFR knockdown alone. Excess folic acid alone induced a decrease in TET3 expression. Excess folic acid induced an increase in dendritic spines without the MTHFR knockdown, but folic acid induced a decrease in dendritic spines when MTHFR was knocked-down. The knockdown alone also increased the dendritic spines significantly. Histone 3 acetylation at lysine 18 was significantly increased when excess folic acid was applied to cells with the MTHFR knockdown, as was histone 3 phosphorylation at serine 10. Broadly, our results indicate that excess folic acid, even with functioning MTHFR, could have detrimental effects on cells., Competing Interests: No authors have competing interests.

We analysed gross primary productivity (GPP), total ecosystem respiration (TER) and the resulting net ecosystem exchange (NEE) of carbon dioxide (CO 2 ) by the terrestrial biosphere during the summer of 2018 through observed changes across the Integrated Carbon Observation System (ICOS) network, through biosphere and inverse modelling, and through remote sensing. Highly correlated yet independently-derived reductions in productivity from sun-induced fluorescence, vegetative near-infrared reflectance, and GPP simulated by the Simple Biosphere model version 4 (SiB4) suggest a 130-340 TgC GPP reduction in July-August-September (JAS) of 2018. This occurs over an area of 1.6 × 10 6 km 2 with anomalously low precipitation in northwestern and central Europe. In this drought-affected area, reduced GPP, TER, NEE and soil moisture at ICOS ecosystem sites are reproduced satisfactorily by the SiB4 model. We found that, in contrast to the preceding 5 years, low soil moisture is the main stress factor across the affected area. SiB4's NEE reduction by 57 TgC for JAS coincides with anomalously high atmospheric CO 2 observations in 2018, and this is closely matched by the NEE anomaly derived by CarbonTracker Europe (52 to 83 TgC). Increased NEE during the spring (May-June) of 2018 (SiB4 -52 TgC; CTE -46 to -55 TgC) largely offset this loss, as ecosystems took advantage of favourable growth conditions. This article is part of the theme issue 'Impacts of the 2018 severe drought and heatwave in Europe: from site to continental scale'.

Background: Accurate staging of lung cancer is paramount for directing treatment. After an internal audit suggested a higher than expected rate of synchronous multiple primary lung cancers (SMPLC), we have sought to evaluate the prevalence of SMPLC at our single, large academic center., Methods: From January 2019 to September 2019, patients with non-small cell lung cancer who underwent surgical resection were retrospectively reviewed. Clinical characteristics, pre- and post-op imaging, 30-day morbidity and mortality, as well as pathological findings were reviewed. SMPLCs were defined using modified Martini criteria., Results: Among 83 patients who underwent surgical resection for primary lung cancer with the intention of cure, 17 (20.5%) had pathologically confirmed SMPLC's, 53 (64%) were single primary lung cancers, and 13 (16%) had metastatic lesions from primary lung cancer or extra-thoracic cancers. Mean length of stay was 2 days with no mortalities. Of the SMPLC group, 9 (53%) had previous extra-thoracic neoplasms, compared with 8 (15%) in the single primary group. Four (24%) had a history of resected lung cancers more than 2 years previously, and were participating in lung cancer surveillance programs., Conclusions: The rate of SMPLC at our institution appears to be considerably higher than traditionally reported. Failure to recognize the high incidence of synchronous primary lung cancers exposes patients to the risks of under treatment and poor outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-19-3990). The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Context.—: A common concern in pathology residency training is the variability with which incoming trainees have attained basic pathology competencies during undergraduate medical education. While multifactorial deficiencies are likely due to recent de-emphasis of dedicated pathology courses during preclinical training, accelerating the transition from medical student to pathology resident is critical-particularly in military practice where a greater degree of autonomy is required of recent graduates., Objective.—: To describe the implementation and results of a 4-week surgical pathology "boot camp" in the largest military pathology residency program in the United States., Design.—: Interns were administered an assessment on basic pathology knowledge, slide practicals, and a skills self-assessment. All specimens were grossed by interns with constant direct supervision. A daily microscopic didactic session was given by an upper level resident and a daily gross conference was led by the interns. Subsequent academic performance was evaluated via monthly slide practicals and diagnostic agreement with faculty., Results.—: Following boot camp, average scores on the knowledge assessment increased from 36.0% ± 16.2% (standard deviation [SD]) to 80.0% ± 12.6% (SD) ( P < .001). Slide practical scores showed an increase from 32% ± 12.0% (SD) to 74.0% ± 16.2% (SD) ( P < .001). Skills self-assessment showed a global increase across all measures. Throughout the following academic year, postgraduate year 1 (PGY1) residents performed at the same level of current PGY2 residents, based on surgical pathology faculty diagnostic agreement and slide practical performance., Conclusions.—: An intense 4-week surgical pathology rotation specifically tailored to incoming interns was successful in transitioning medical students to pathology residents within a relatively short time.

The tropical carbon balance dominates year-to-year variations in the CO 2 exchange with the atmosphere through photosynthesis, respiration and fires. Because of its high correlation with gross primary productivity (GPP), observations of sun-induced fluorescence (SIF) are of great interest. We developed a new remotely sensed SIF product with improved signal-to-noise in the tropics, and use it here to quantify the impact of the 2015/2016 El Niño Amazon drought. We find that SIF was strongly suppressed over areas with anomalously high temperatures and decreased levels of water in the soil. SIF went below its climatological range starting from the end of the 2015 dry season (October) and returned to normal levels by February 2016 when atmospheric conditions returned to normal, but well before the end of anomalously low precipitation that persisted through June 2016. Impacts were not uniform across the Amazon basin, with the eastern part experiencing much larger (10-15%) SIF reductions than the western part of the basin (2-5%). We estimate the integrated loss of GPP relative to eight previous years to be 0.34-0.48 PgC in the three-month period October-November-December 2015.This article is part of a discussion meeting issue 'The impact of the 2015/2016 El Niño on the terrestrial tropical carbon cycle: patterns, mechanisms and implications'., (© 2018 The Authors.)

The 2015/2016 El Niño event caused severe changes in precipitation across the tropics. This impacted surface hydrology, such as river run-off and soil moisture availability, thereby triggering reductions in gross primary production (GPP). Many biosphere models lack the detailed hydrological component required to accurately quantify anomalies in surface hydrology and GPP during droughts in tropical regions. Here, we take the novel approach of coupling the biosphere model SiBCASA with the advanced hydrological model PCR-GLOBWB to attempt such a quantification across the Amazon basin during the drought in 2015/2016. We calculate 30-40% reduced river discharge in the Amazon starting in October 2015, lagging behind the precipitation anomaly by approximately one month and in good agreement with river gauge observations. Soil moisture shows distinctly asymmetrical spatial anomalies with large reductions across the north-eastern part of the basin, which persisted into the following dry season. This added to drought stress in vegetation, already present owing to vapour pressure deficits at the leaf, resulting in a loss of GPP of 0.95 (0.69 to 1.20) PgC between October 2015 and March 2016 compared with the 2007-2014 average. Only 11% (10-12%) of the reduction in GPP was found in the (wetter) north-western part of the basin, whereas the north-eastern and southern regions were affected more strongly, with 56% (54-56%) and 33% (31-33%) of the total, respectively. Uncertainty on this anomaly mostly reflects the unknown rooting depths of vegetation.This article is part of a discussion meeting issue 'The impact of the 2015/2016 El Niño on the terrestrial tropical carbon cycle: patterns, mechanisms and implications'., (© 2018 The Authors.)

Voltage gated sodium channels are the target of a range of local anesthetic, anti-epileptic and anti-arrhythmic compounds. But, gaining a molecular level understanding of their mode of action is difficult as we only have atomic resolution structures of bacterial sodium channels not their eukaryotic counterparts. In this study we used molecular dynamics simulations to demonstrate that the binding sites of both the local anesthetic benzocaine and the anti-epileptic phenytoin to the bacterial sodium channel NavAb can be altered significantly by the introduction of point mutations. Free energy techniques were applied to show that increased aromaticity in the pore of the channel, used to emulate the aromatic residues observed in eukaryotic Nav1.2, led to changes in the location of binding and dissociation constants of each drug relative to wild type NavAb. Further, binding locations and dissociation constants obtained for both benzocaine (660 μM) and phenytoin (1 μM) in the mutant channels were within the range expected from experimental values obtained from drug binding to eukaryotic sodium channels, indicating that these mutant NavAb may be a better model for drug binding to eukaryotic channels than the wild type.

DmpFG is a bifunctional enzyme comprised of an aldolase subunit, DmpG, and a dehydrogenase subunit, DmpF. The aldehyde intermediate produced by the aldolase is channeled directly through a buried molecular channel in the protein structure from the aldolase to the dehydrogenase active site. In this study, we have investigated the binding of a series of progressively larger substrates to the aldolase, DmpG, using molecular dynamics. All substrates investigated are easily accommodated within the active site, binding with free energy values comparable to the physiological substrate 4-hydroxy-2-ketovalerate. Subsequently, umbrella sampling was utilized to obtain free energy surfaces for the aldehyde intermediates (which would be generated from the aldolase reaction on each of these substrates) to move through the channel to the dehydrogenase DmpF. Small substrates were channeled with limited barriers in an energetically feasible process. We show that the barriers preventing bulky intermediates such as benzaldehyde from moving through the wild-type protein can be removed by selective mutation of channel-lining residues, demonstrating the potential for tailoring this enzyme to allow its use for the synthesis of specific chemical products. Furthermore, positions of transient escape routes in this flexible channel were determined., (Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

It has been hypothesized that the bifunctional enzyme DmpFG channels its intermediate, acetaldehyde, from one active site to the next using a buried intermolecular channel identified in the crystal structure. This channel appears to switch between an open and a closed conformation depending on whether the coenzyme NAD(+) is present or absent. Here, we applied molecular dynamics and metadynamics to investigate channeling within DmpFG in both the presence and absence of NAD(+). We found that substrate channeling within this enzyme is energetically feasible in the presence of NAD(+) but was less likely in its absence. Tyr-291, a proposed control point at the channel's entry, does not appear to function as a molecular gate. Instead, it is thought to orientate the substrate 4-hydroxy-2-ketovalerate in DmpG before reaction occurs, and may function as a proton shuttle for the DmpG reaction. Three hydrophobic residues at the channel's exit appear to have an important role in controlling the entry of acetaldehyde into the DmpF active site., (Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Primary melanoma of the bile duct is extremely rare with only nine cases of primary melanoma of the bile duct reported in the literature., Presentation of Case: A 55-year-old previously healthy gentleman developed increasing jaundice over several months and subsequently underwent an ERCP with stone extraction. Cytology brushings in an area of a distal stricture in the bile duct were concerning for cholangiocarcinoma. The patient was referred to our institution and underwent a pancreaticoduodenectomy. The surgical specimen showed a single 4.5cm polypoid lesion located in the bile duct. A diagnosis of melanoma was rendered after immunohistochemical studies on the tumor demonstrated positivity for melanoma markers. Follow-up of the patient with skin, ocular, and lymph node exams showed no evidence of melanoma. A PET scan 4 and 10 months post-surgery failed to reveal either a primary skin lesion or other sites of metastases., Discussion: The vast majority of melanomas of the bile duct represent metastases from a cutaneous source and tend to present as multiple flat pigmented lesions. Conversely, cases of primary bile duct melanoma are characterized by a distinct gross morphology consisting of a solitary intraluminal polypoid lesion attached by a pedicle with no other identifiable primary lesion. Other supporting criteria include absence of other involved sites and presence of an in situ junctional component., Conclusion: Given the clinical history, gross findings, and lack of a primary cutaneous site or other demonstrable metastases, this patient likely represents the tenth reported case of primary biliary tract melanoma., (Copyright © 2012 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

The regulation of expression of gluconeogenic genes including glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver plays an important role in glucose homeostasis, because aberrant expression of these genes contributes to the development of type 2 diabetes. Previous reports demonstrate that signal transducer and activator of transcription 3 (STAT3) plays a key role in regulating gluconeogenic gene expression, but the mechanism remains unclear. Herein we demonstrate that phosphorylated STAT3 is required for repression of G6Pase expression by IL-6 in both HepG2 cells and mouse liver. Interestingly, PEPCK expression is regulated by STAT3 independent of IL-6 activation. Using in vivo chromatin immunoprecipitation, we demonstrate that STAT3 binds to the promoters of the G6Pase, PEPCK, and suppressor of cytokine signaling (SOCS)3 genes, and its recruitment increases at the G6Pase and SOCS3 promoters with IL-6 treatment. Whereas persistent recruitment of RNA polymerase II is seen on the SOCS3 promoter, consistent with its induction by IL-6, a decrease in polymerase II recruitment and histone H4 acetylation is seen at the G6Pase promoter with IL-6 treatment. Thus STAT3 mediates negative regulation of hepatic gluconeogenic gene expression in vivo by interacting with regulatory regions of these genes.

Background: In early clinical studies, the live tuberculosis vaccine Mycobacterium bovis BCG exhibited 80% protective efficacy against pulmonary tuberculosis (TB). Although BCG still exhibits reliable protection against TB meningitis and miliary TB in early childhood it has become less reliable in protecting against pulmonary TB. During decades of in vitro cultivation BCG not only lost some genes due to deletions of regions of the chromosome but also underwent gene duplication and other mutations resulting in increased antioxidant production., Methodology/principal Findings: To determine whether microbial antioxidants influence vaccine immunogenicity, we eliminated duplicated alleles encoding the oxidative stress sigma factor SigH in BCG Tice and reduced the activity and secretion of iron co-factored superoxide dismutase. We then used assays of gene expression and flow cytometry with intracellular cytokine staining to compare BCG-specific immune responses in mice after vaccination with BCG Tice or the modified BCG vaccine. Compared to BCG, the modified vaccine induced greater IL-12p40, RANTES, and IL-21 mRNA in the spleens of mice at three days post-immunization, more cytokine-producing CD8+ lymphocytes at the peak of the primary immune response, and more IL-2-producing CD4+ lymphocytes during the memory phase. The modified vaccine also induced stronger secondary CD4+ lymphocyte responses and greater clearance of challenge bacilli., Conclusions/significance: We conclude that antioxidants produced by BCG suppress host immune responses. These findings challenge the hypothesis that the failure of extensively cultivated BCG vaccines to prevent pulmonary tuberculosis is due to over-attenuation and suggest instead a new model in which BCG evolved to produce more immunity-suppressing antioxidants. By targeting these antioxidants it may be possible to restore BCG's ability to protect against pulmonary TB.

This review aimed to combine the literature on major personality traits and physical activity alongside providing some meta-analytic summaries of the findings. Overall, 33 studies containing 35 independent samples, ranging from 1969 to 2006, met the inclusion criteria. Extraversion (r = 0.23), neuroticism (r = -0.11) and conscientiousness (r = 0.20) were identified as correlates of physical activity using random effects meta-analytic procedures correcting for sampling bias and attenuation of measurement error. The five-factor model traits of openness to experience/intellect and agreeableness, as well as Eysenck's psychoticism trait, were not associated with physical activity. Potential moderators of personality and physical activity relationships such as sex, age, culture/country, design and instrumentation were inconclusive given the small number of studies. Still, the existing evidence was suggestive that personality and physical activity relationships are relatively invariant to these factors. Studies examining personality and different physical activity modes suggested differences by traits such as extraversion, but more research is needed to make any conclusions. Future research using multivariate analyses, personality-channelled physical activity interventions, longitudinal designs and objective physical activity measurement is recommended.

Alternative models for analyses of liver and mammary transorgan data were formulated and fitted to liver and mammary data sets respectively. The models considered metabolite inputs to and effluxes from an extracellular pool. In general, fits were greatly improved over previous efforts using other models (Miller et al. 1991a; Hanigan et al. 1992; Wray-Cahen et al. 1997). Errors of prediction were generally less than 15% for liver and less than 20% for mammary glands. With the possible exception of glutamine for the udder, all metabolites exhibited linear responses to extracellular concentrations within the observed ranges of inputs. However, prediction biases were evident for beta-hydroxybutyrate, acetate, and propionate by liver and for arginine, histidine, citrulline and glycerol by mammary tissue. These biases were hypothesized to be caused by the existence of additional regulatory complexity. With the exception of histidine, parameter estimates for essential amino acid removal by liver were 2-3-fold lower than for mammary gland. Infusion of an amino acid mixture into the mesenteric vein did not alter parameter estimates for removal of amino acids by the liver. Treatment of cows with bovine somatotropin resulted in changes in mammary parameter estimates for aspartate, glutamate, leucine, phenylalanine, glucose, and glycerol.

Objectives: Is discharge destination a determinant of readmission? Studies to date have been inconclusive. The primary purpose of this study was to identify the role of discharge destination in the occurrence of repeat hospitalizations for a national sample of patients discharged from Veterans Health Administration (VHA) hospitals., Methods: The authors studied a 20% random sample of individual patients, 65 years of age or older, with either chronic obstructive pulmonary disease, stroke, or dementia who were discharged from a Veterans Health Administration hospital in 1988. All data for the study were obtained from secondary administrative sources. Multiple sources were used to determine discharge destination. The authors focused on personal home versus nursing home discharge destination. Both VHA and Medicare discharge data were used to track hospital readmissions. Proportional hazards regression models were used to examine the independent association of discharge destination with time to readmission within 30 days, 6 months, 1 year, and 2 years of discharge, adjusting for severity, other clinical and demographic characteristics, and censoring deaths., Results: After adjustment and including out-of-system (Medicare) use, we found that patients with chronic obstructive pulmonary disease and patients with dementia who were discharged to nursing homes (community and Veterans Health Administration, respectively) were less likely to be readmitted within 30 days after discharge than patients discharged to personal homes., Conclusions: These findings have important implications for adjusting hospital performance profiles based on discharge destination and for focussing efforts to reduce the frequency and associated costs of hospital readmissions.

The Australian Nutrition Foundation (ANF) conducted a survey of members which investigated their nutrition information needs together with their preferred communication formats, considering the technological advances in informatics. The survey was completed by 103 respondents with a large proportion of health professionals represented. It was found that members were quite satisfied with the performance of the ANF in critical areas like nutrition updates, but less satisfied with the ANF's response to topical nutrition issues in the media. Health professionals used the ANF as a source of nutrition information significantly less often than other occupation categories like teachers and the general public. Strategies were presented which could help the ANF management provide an improved service to the health professionals, a sector which is considered to be very important by the ANF. Print and electronic communication formats were those most preferred by the respondents for their nutrition information needs. Implications for the future directions of the ANF are discussed.

Patulin exhibits both cytotoxic and cytopathic effects on cultured Chang liver cells. The LD50 found was 1.85 mug per ml of patulin. Effects on growth were observed with as little as 0.1 mug per ml of patulin; a 50% reduction in growth was observed at 0.38 mug per ml of patulin. Using a challenge dose of 2.5 mug per ml of patulin, the cytotoxic effect was reversible after an exposure of 10 min, but was not reversible after 20 min. Protein synthesis was depressed after 60 min and RNA synthesis after 20 min of contact with patulin. Neither protein nor RNA synthesis was completely inhibited after 260 min.

Three trials were to evaluate effects of sodium bicarbonate in alfalfa hay-based diets. In Experiment 1, four Jersey cows were fed diets of 40:60 chopped alfalfa hay:grain with either 0, .25, .5, and .75% sodium bicarbonate in a 4 X 4 Latin square digestion trial. Dry matter and fiber digestion were unaffected. Volatile fatty acids of ruminal fluid and milk fatty acids were not different. In Experiment 2, two rumen fistulated cattle were fed diets of Experiment 1 for changes of ruminal fluid characteristics at -1, 2, 4, and 8 h postfeeding. Volatile fatty acids of ruminal fluid and hydrogen ion concentration were not different across time with sodium bicarbonate. In Experiment 3, four Holstein cows with rumen cannulae were fed diets of 30:70 chopped alfalfa hay:grain with 0, .4, .8, and 1.2% sodium bicarbonate in a 4 X 4 Latin square. Dry matter and fiber digestion were unaffected. Ruminal fluid samples were collected at -1, 3, 6, and 9 h postfeeding. Volatile fatty acids were different only at 6 h with 0 and 1.2% sodium bicarbonate diets displaying lower concentrations. Rate of increase of hydrogen ion concentration was greater for diets containing 0 and .4% compared with .8 and 1.2% sodium bicarbonate between -1 and 6 h. Milk fatty acid composition, ruminal liquid dilution rate, and dry matter disappearance from nylon bags suspended in the rumen were not affected by sodium bicarbonate.

Four lactating Holstein cows producing about 21 kg milk/day were fed complete rations containing 0, 5, 15, and 25% whole cottonseed in a 4 X 4 Latin square design. Diets were fed ad libitum. Periods were 21 days in length with total collections of feces and urine during the last 7 days of each period. Digestibilities o nitrogen, lipid, and energy increased with increasing cottonseed in the diet. There were no significant effects of cottonseed on digestibility or availability of fiber components, calcium, phosphorous, and magnesium. Cottonseed feeding did not affect dry matter intake or milk yield but did increase yields of milk fat and fat-corrected milk and decrease milk protein and solids-not-fat percentages. Synthesis of fatty acid in the mammary gland was depressed by about 50% on the 25% cottonseed diet, but transfer of dietary fat resulted in twofold increases in yields of stearic and oleic acids. Hydrogenation of cottonseed fatty acid in the rumen resulted in a fourfold increase in yield of trans oleic acid in milk fat. Samples from bulk milk tank and data collected from 55 commercial dairies showed similar changes in fatty acid composition of milk from cows fed whole cottonseed. There was no apparent effect of feeding up to 2.9 kg cottonseed dry matter per cow per day on calving interval or on incidence of displaced abomasum, ketosis, milk, fever, or retained placenta.

Mammary gland tissues from three lactating Holstein cows were sampled and slices incubated with various concentrations of glucose and in combinations with other substrates in Krebs-Ringer bicarbonate-based media. Conversions of 1-and 2-carbon-14 glucose to carbon dioxide, lactose, glyceride-glycerol, citrate, and fatty acids were determined. Glucose utilization increased asymptotically with glucose availability. Carbon dioxide, lactose, and glyceride glycerol production accounted for nearly 90% of glucose recovered. Only trace quantities of glucose were recovered as fatty acids. Estimates of apparent affinities for glucose use were in a physiological concentration range of glucose. Oxidation of glucose was positively correlated with availability of acetate. Acetate availability increased the ratio of 1-carbon-14 glucose to 2-carbon-14 glucose oxidation and decreased glucose conversion to fatty acids. Glucose conversion to glyceride-glycerol was not affected by acetate availability. Primary uses of glucose are in lactose and glyceride glycerol synthesis and formation of reduced nicotinamide adenine dinucleotide phosphate for lipogenesis. Extensive use of glucose for these purposes may limit amounts available for fatty acid synthesis.

Official methods were used to analyze composite samples of milk collected during the first 15 wk of lactation from 21 Holstein cows fed a milled ration containing 0 (basal), 15% (medium, or 30% (high) protected-tallow supplement (seven cows per treatment). Protein fractions and amino acid composition of the total proteins were determined from samples of individual milking. Melting characteristics of pooled samples were determined by nuclear magnetic resonance. Milk yield was similar for the three treatments, but percent fat and fat yield were higher for cows fed protected tallow. Percentages and yields of protein and solids-not-fat were decreased on the protected tallow treatments, especially for high tallow. The decrease in protein was in the casein fraction. Amino acid composition of the total proteins was similar for the three treatments. Feeding protected tallow caused decreases in all fatty acids except 4:0, 16:1, 18:0, and 18:1 which increased. Nuclear magnetic resonance indicated that butter from the basal group would be harder than that from cows fed protected tallow.

Mammary gland tissue slices from three lactating Holstein cows were incubated in Krebs-Ringer bicarbonate-based media with varying concentrations of lactate and other substrates. Conversions of 1- and 2-carbon-14 of lactate to carbon dioxide, fatty acids, citrate, glyceride glycerol, and lactose were determined. Effects of acetate, glucose, beta-hydroxybutyrate, stearate, and pyruvate on lactate metabolism were evaluated. Oxidation of lactate increased asymptotically with lactate concentration. Low acetate concentration stimulated oxidation of carbon 2 of lactate slightly while higher acetate availability inhibited lactate oxidation. Conversion of lactate to fatty acids increased linearly with lactate concentration. This conversion of lactate was inhibited strongly by acetate. Significant conversion of carbon 2 of lactate to glyceride-glycerol but not lactose was detected. Bovine mammary glands have the capacity of utilize sizeable quantities of lactate for oxidation and lipogenesis. Both phenomena are highly dependent on availability of acetate. Pyruvate dehydrogenase and citrate lyase could represent important regulatory sites in vivo for determination of tissue preference for acetate over lactate. Results indicate factors other than an inactive malate transhydrogenation cycle likely limit glucose conversion to fatty acids.

The influence of age, carbohydrate-fat ratios of milk replacers, and development of ruminal function on growth, health, and blood glucose concentrations were evaluated in calves. Colostrum-fed, 3-day-old Holstein bull calves were fed to 12 wk on one of three dietary treatments: 1) a high carbohydrate, low fat (60.5% glucose, 9.5% lactose, and 3% lard) milk replacer; 2) a low carbohydrate, high fat (23% glucose, 12.5% lactose, and 30% lard) milk replacer; and 3) weaning at 6 wk of age from high-fat replacer to a standard calf starter. The high fat milk replacer was superior to low fat milk replacer for total weight gains and efficiency of feed conversion. Rates of weight gain of starter calves were similar to those of calves fed low fat. Calves fed the diet with low fat had a high incidence of diarrhea, an occasional outbreak of a yeast-related ethanol intoxication syndrome, and high concentrations of glucose in urine. Irrespective of milk replacer composition or development of ruminal function, plasma and whole blood glucose concentrations declined rapidly in the first 6 wk. Corpuscular glucose declined steadily with age in all calves. This age-related decrease of blood glucose concentration of calves seems to be a constitutive phenomenon.

Rates of utilization of glucose, acetate, and lactate and activities of selected enzymes were determined in vitro to evaluate the effects of age and diet on lipogenesis in perirenal adipose tissue of calves. Three-day-old Holstein bull calves were fed up to 12 wk of age on one of three dietary treatments: a high carbohydrate milk replacer; a high fat milk replacer; and weaning at 6 wk of age from high fat replacer to calf starter. Adipose tissue biopsies were obtained from calves at 2, 5, 8, and 12 wk of age. Rates of fatty acid synthesis and activities of enzymes of the pentose phosphate and citrate cleavage pathways were increased in calves fed high carbohydrate milk replacer. These parameters were decreased in calves fed high fat replacer and were further depressed after weaning. Substrate preference for fatty acid synthesis in all calves was acetate, then lactate, then glucose. With increase in age from 2 to 12 wk, adipose tissue of calves fed milk replacer partitioned more acetate and lactate toward fatty acid synthesis and less toward oxidation. The pentose phosphate cycle was characterized by high rate of recycling and contributed at least 50% of reducing equivalents required for fatty acid synthesis. It appeared that several features of lipogenesis characteristic of functional ruminants are also shared by preruminant calves.

Thirty-eight older (second and greater lactation) and 15 Holstein cows in first lactation were in a full lactation (44 wk) study to evaluate the effect of either twice or three times daily milking on yield of milk and milk components, milk composition, feed intake, and body weight change. All cows were managed alike and were fed diets of high, medium, and low energy concentration as lactation progressed from calving to 44 wk. First lactation cows were switched from diets of high energy to lower energy at the same milk production as lactation advanced. Dietary changes for older cows milked twice and three times (A) were at similar production, whereas three times (B) cows were switched to lower energy at higher milk production. Older cows milked three times daily (A and B) produced 17 and 13% more milk over the entire lactation than cows milked twice daily. Dry matter and energy intakes were not affected by three times milking, but gain of body weight was reduced. Cows milked three times daily during their first lactation produced 6% more milk than their twice counterparts, although this increase was not significant. Dry matter and energy intakes were not affected by three times daily milking, but three times milking of first lactation cows reduced weight gain over the lactation. Reproductive performance of cows milked three times daily was not significantly different from cows milked twice daily. Herds milking three times will require high management of nutrition and reproduction.

In a calf nutrition-metabolism study in which a high glucose (60% glucose and 3% lard) versus a high fat (23% glucose and 30% lard) milk replacer were compared, a syndrome characterized by anorexia, an unstable gait, depression, a distended abdomen and an odor of alcohol on the breath was observed in some calves. These signs were associated with intoxicating levels of plasma ethanol and the predominance of the yeast species Torulopsis glabrata in gastrointestinal contents of afflicted calves. Nystatin, a yeast inhibitor, was extremely useful in preventing the problem.

Slices from mammary glands from six lactating Holstein cows were incubated in Krebs-Ringer bicarbonate-based media in the presence of varying concentrations of acetate, glucose, and lactate. Conversions of acetate to carbon dioxide, fatty acids, citrate, glyceride-glycerol, and lactose were determined. Specific effects of beta-hydroxybutyrate and stearate availability also were evaluated. Utilization of acetate for all functions usually followed Michaelis-Menten kinetics with apparent affinities in the physiological concentration range of acetate. Availability of glucose had a large "permissive" effect on acetate to conversion to fatty acids. However, acetate metabolism was independent of the availability of lactate. Conversion of acetate to glyceride-glycerol was significant. This indicates the possibility of bidirectional glycolytic flux, which could limit glucose conversion to fatty acids. Addition of stearate caused general increases of acetate metabolism. Conversion of acetate to fatty acids, carbon dioxide, and citrate was elevated in the absence of beta-hydroxybutyrate. The latter observation indicates beta-hydroxybutyrate may not be a required initiator of fatty acid synthesis in mammary tissue.