A molecular profile of T-cell exhaustion in cancer.

The first gene profiling study of cancer-specific CD8+ T-cells demonstrates that lymphocyte dysfunction in cancer tissue is due to multiple molecular alterations,(1) similar as in "exhausted" T-cells in chronic infection.(2) The data suggest novel drug targets, and show that T-cell exhaustion is reversible and limited to anatomical sites of disease.

The profile of general practitioners (GPs) who publish in selected family practice journals

Background: Providing support for research is one of the key issues in the ongoing attempts to improve Primary Care. However, when patient care takes up a significant part of a GP's time, conducting research is difficult. In this study we examine the working conditions and profile of GPs who publish in three leading medical journals and propose possible remedial policy actions. Findings: The authors of all articles published in 2006 and 2007 in three international Family Medicine journals - Annals of Family Medicine, Family Practice, and Journal of Family Practice - were contacted by E-mail. They were asked to complete a questionnaire investigating the following variables: availability of specific time for research, time devoted to research, number of patients attended, and university affiliation. Only GPs were included in the study. Three hundred and ten relevant articles published between 2006 and 2007 were identified and the authors contacted using a survey tool. 124 researchers responded to our questionnaire; 45% of respondents who were not GPs were excluded. On average GPs spent 2.52 days per week and 6.9 hours per day on patient care, seeing 45 patients per week. Seventy-five per cent of GPs had specific time assigned to research, on average 13 hours per week; 79% were affiliated to a university and 69% held teaching positions. Conclusions: Most GPs who publish original articles in leading journals have time specifically assigned to research as part of their normal working schedule. They see a relatively small number of patients. Improving the working conditions of family physicians who intend to investigate is likely to lead to better research results.

Long-lasting stem cell-like memory CD8+ T cells with a naïve-like profile upon yellow fever vaccination.

Efficient and persisting immune memory is essential for long-term protection from infectious and malignant diseases. The yellow fever (YF) vaccine is a live attenuated virus that mediates lifelong protection, with recent studies showing that the CD8(+) T cell response is particularly robust. Yet, limited data exist regarding the long-term CD8(+) T cell response, with no studies beyond 5 years after vaccination. We investigated 41 vaccinees, spanning 0.27 to 35 years after vaccination. YF-specific CD8(+) T cells were readily detected in almost all donors (38 of 41), with frequencies decreasing with time. As previously described, effector cells dominated the response early after vaccination. We detected a population of naïve-like YF-specific CD8(+) T cells that was stably maintained for more than 25 years and was capable of self-renewal ex vivo. In-depth analyses of markers and genome-wide mRNA profiling showed that naïve-like YF-specific CD8(+) T cells in vaccinees (i) were distinct from genuine naïve cells in unvaccinated donors, (ii) resembled the recently described stem cell-like memory subset (Tscm), and (iii) among all differentiated subsets, had profiles closest to naïve cells. Our findings reveal that CD8(+) Tscm are efficiently induced by a vaccine in humans, persist for decades, and preserve a naïveness-like profile. These data support YF vaccination as an optimal mechanistic model for the study of long-lasting memory CD8(+) T cells in humans.

Forage preservation (grazing vs. hay) fed to ewes affects the fatty acid profile of milk and CPT1B gene expression in the sheep mammary gland

Background: Alterations in lipid metabolism occur when animals are exposed to different feeding systems. In the last few decades, the characterisation of genes involved in fat metabolism and technological advances have enabled the study of the effect of diet on the milk fatty acid (FA) profile in the mammary gland and aided in the elucidation of the mechanisms of the response to diet. The aim of this study was to evaluate the effect of different forage diets (grazing vs. hay) near the time of ewe parturition on the relationship between the fatty acid profile and gene expression in the mammary gland of the Churra Tensina sheep breed. Results: In this study, the forage type affected the C18:2 cis-9 trans-11 (CLA) and long-chain saturated fatty acid (LCFA) content, with higher percentages during grazing than during hay feeding. This may suggest that these FAs act as regulatory factors for the transcriptional control of the carnitine palmitoyltransferase 1B (CPT1B) gene, which was more highly expressed in the grazing group (GRE). The most highly expressed gene in the mammary gland at the fifth week of lactation is CAAT/ enhancer- binding protein beta (CEBPB), possibly due to its role in milk fat synthesis in the mammary gland. More stable housekeeping genes in the ovine mammary gland that would be appropriate for use in gene expression studies were ribosomal protein L19 (RPL19) and glyceraldehyde- 3- phosphate dehydrogenase (GAPDH). Conclusions: Small changes in diet, such as the forage preservation (grazing vs. hay), can affect the milk fatty acid profile and the expression of the CPT1B gene, which is associated with the oxidation of fatty acids. When compared to hay fed indoors, grazing fresh low mountain pastures stimulates the milk content of CLA and LCFA via mammary uptake. In this sense, LCFA in milk may be acting as a regulatory factor for transcriptional control of the CPT1B gene, which was more highly expressed in the grazing group.

Research resource: the dynamic transcriptional profile of sertoli cells during the progression of spermatogenesis.

Sertoli cells (SCs), the only somatic cells within seminiferous tubules, associate intimately with developing germ cells. They not only provide physical and nutritional support but also secrete factors essential to the complex developmental processes of germ cell proliferation and differentiation. The SC transcriptome must therefore adapt rapidly during the different stages of spermatogenesis. We report comprehensive genome-wide expression profiles of pure populations of SCs isolated at 5 distinct stages of the first wave of mouse spermatogenesis, using RNA sequencing technology. We were able to reconstruct about 13 901 high-confidence, nonredundant coding and noncoding transcripts, characterized by complex alternative splicing patterns with more than 45% comprising novel isoforms of known genes. Interestingly, roughly one-fifth (2939) of these genes exhibited a dynamic expression profile reflecting the evolving role of SCs during the progression of spermatogenesis, with stage-specific expression of genes involved in biological processes such as cell cycle regulation, metabolism and energy production, retinoic acid synthesis, and blood-testis barrier biogenesis. Finally, regulatory network analysis identified the transcription factors endothelial PAS domain-containing protein 1 (EPAS1/Hif2α), aryl hydrocarbon receptor nuclear translocator (ARNT/Hif1β), and signal transducer and activator of transcription 1 (STAT1) as potential master regulators driving the SC transcriptional program. Our results highlight the plastic transcriptional landscape of SCs during the progression of spermatogenesis and provide valuable resources to better understand SC function and spermatogenesis and its related disorders, such as male infertility.

Safety profile of prasugrel and clopidogrel in patients with acute coronary syndromes in Switzerland.

OBJECTIVE: To assess safety up to 1 year of follow-up associated with prasugrel and clopidogrel use in a prospective cohort of patients with acute coronary syndromes (ACS). METHODS: Between 2009 and 2012, 2286 patients invasively managed for ACS were enrolled in the multicentre Swiss ACS Bleeding Cohort, among whom 2148 patients received either prasugrel or clopidogrel according to current guidelines. Patients with ST-elevation myocardial infarction (STEMI) preferentially received prasugrel, while those with non-STEMI, a history of stroke or transient ischaemic attack, age ≥75 years, or weight <60 kg received clopidogrel or reduced dose of prasugrel to comply with the prasugrel label. RESULTS: After adjustment using propensity scores, the primary end point of clinically relevant bleeding events (defined as the composite of Bleeding Academic Research Consortium, BARC, type 3, 4 or 5 bleeding) at 1 year, occurred at a similar rate in both patient groups (prasugrel/clopidogrel: 3.8%/5.5%). Stratified analyses in subgroups including patients with STEMI yielded a similar safety profile. After adjusting for baseline variables, no relevant differences in major adverse cardiovascular and cerebrovascular events were observed at 1 year (prasugrel/clopidogrel: cardiac death 2.6%/4.2%, myocardial infarction 2.7%/3.8%, revascularisation 5.9%/6.7%, stroke 1.0%/1.6%). Of note, this study was not designed to compare efficacy between prasugrel and clopidogrel. CONCLUSIONS: In this large prospective ACS cohort, patients treated with prasugrel according to current guidelines (ie, in patients without cerebrovascular disease, old age or underweight) had a similar safety profile compared with patients treated with clopidogrel. CLINICAL TRIAL REGISTRATION NUMBER: SPUM-ACS: NCT01000701; COMFORTABLE AMI: NCT00962416.

Measurement of the air permeability profile on SC paper machine

Tämän diplomityön tarkoituksena oli asentaa ja kehittää UPM-Kymmene Rauman tehtaiden PK2:lle luotettava ja toimiva ilmanläpäisyprofiilin mittaus. Työn tarkoituksena oli myös kartoittaa tietoja ilmanläpäisyprofiiliin vaikuttavista seikoista sekä mahdollisuuksista säätää ilmanläpäisyprofiilia. Lisäksi työn tavoitteena oli löytää toimiva menetelmä verrata online mitattua ilmanläpäisyprofiilia laboratoriossa mitattuun ilmanläpäisyprofiiliin online mittauksen luotettavuuden näkökulmasta. Työn aikana selvitettiin myös ilmanläpäisyprofiilin mittauksen mahdollisuutta superkalanteroidusta SC paperista. Työn kirjallisessa osassa käsiteltiin paperin huokoisuutta ja ilmanläpäisyä, huokoisuustasoon ja huokoisuus profiiliin vaikuttavia tekijöitä, ilmanläpäisevyyden merkitystä SC paperin valmistukselle ja SC paperin painettavuudelle sekä ilmanläpäisevyyden laboratorio- sekä online mittausta. Kirjallisessa osassa käsiteltiin myös Honeywellin uutta Poros ilmanläpäisysensoria. Työn kokeellisessa osassa tutkittiin ilmanläpäisyprofiilimittauksen luotettavuutta CD ja MD suunnassa sekä laboratorio- ja online-mittausten välisiä eroavaisuuksia ennen PK2 uusintaa. PK2 uusinnan jälkeen kokeellisessa osassa keskityttiin luotettavuuden varmentamiseen CD ja MD suunnassa sekä kartoittamaan tekijöitä, jotka aiheuttivat pieniä tasoeroja mittausten välillä. Mittaukset todettiin luotettaviksi ja niiden pohjalta suoritettiin mitattujen online profiilien välisiä vertailuja. Ilmanläpäisyprofiililla todettiin olevan positiivinen korrelaatio neliömassaprofiilin ja kosteusprofiilin kanssa sekä negatiivinen korrelaatio tuhkaprofiilin kanssa. PK2 uusinnan yhteydessä tehtiin koeajoja, jotka liittyivät laadunoptimointiin viira- ja puristinosalla. Koeajoissa tutkittujen asioiden lisäksi tutkittiin muutettujen parametrien vaikutusta ilmanläpäisyprofiiliin. Höyrylaatikon vaikutusta ilmanläpäisyprofiiliin tutkittiin säätöjen virityksen yhteydessä.

Carotenoids profile and total polyphenols in fruits of Pereskia aculeata Miller

Pereskia aculeata Mill. (Ora-pro-nóbis) is a native cactaceae from tropical America, whose leaves have high protein content. In Brazil it is found in all territorial extension between the states of Bahia and Rio Grande do Sul. Most studies have focused on chemical characterization of the leaves of this specie. The objective was to assess the carotenoids profile and the total polyphenols present in the fruits of P. aculeate. Carotenoids were determined by HPLC-PAD (high performance liquid chromatography - photodiode array detector), total polyphenols were determined by Folin-Ciocalteu and vanillin methods. Trans-β-carotene was the main carotenoid, followed by α-carotene, lutein and other minor carotenoids. It was found 64.9 ± 1.1 mg.100g-1 of gallic acid equivalent, 14.8 ± 0.2 mg.100g-1 of catechin equivalent. Carotenoid identification of P. aculeate fruits are presented here by the first time and indicate that these fruits can be researched as source of bioactive substances, especially antioxidant and provitamin A carotenoids.

The effects of milk as a food matrix for polyphenols on the excretion profile of cocoa (-)-Epicatechin metabolites in healthy humans subjects

The effect of different food matrices on the metabolism and excretion of polyphenols is uncertain. The objective of the study was to evaluate the possible effect of milk on the excretion of (2)-epicatechin metabolites from cocoa powder after its ingestion with and without milk. Twenty-one volunteers received the following three test meals each in a randomised cross-over design with a 1-week interval between meals: (1) 250 ml whole milk as a control; (2) 40 g cocoa powder dissolved in 250 ml whole milk (CC-M); (3) 40 g cocoa powder dissolved in 250 ml water (CC-W). Urine was collected before consumption and during the 0-6, 6-12 and 12-24 h periods after consumption. (2)-Epicatechin metabolite excretion was measured using liquid chromatography-MS. One (2)-epicatechin glucuronide and three (2)-epicatechin sulfates were detected in urine excreted after the intake of the two cocoa beverages (CC-M and CC-W). The results show that milk does not significantly affect the total amount of metabolites excreted in urine. However, differences in metabolite excretion profiles were observed; there were changes in the glucuronide and sulfate excretion rates, and the sulfation position between the period of excretion and the matrix. The matrix in which polyphenols are consumed can affect their metabolism and excretion, and this may affect their biological activity. Thus, more studies are needed to evaluate the effect of these different metabolite profiles on the body.

Vitamin D time profile based on the contribution of non-genetic and genetic factors in HIV-infected individuals of European ancestry.

BACKGROUND: Vitamin D deficiency is prevalent in HIV-infected individuals and vitamin D supplementation is proposed according to standard care. This study aimed at characterizing the kinetics of 25(OH)D in a cohort of HIV-infected individuals of European ancestry to better define the influence of genetic and non-genetic factors on 25(OH)D levels. These data were used for the optimization of vitamin D supplementation in order to reach therapeutic targets. METHODS: 1,397 25(OH)D plasma levels and relevant clinical information were collected in 664 participants during medical routine follow-up visits. They were genotyped for 7 SNPs in 4 genes known to be associated with 25(OH)D levels. 25(OH)D concentrations were analysed using a population pharmacokinetic approach. The percentage of individuals with 25(OH)D concentrations within the recommended range of 20-40 ng/ml during 12 months of follow-up and several dosage regimens were evaluated by simulation. RESULTS: A one-compartment model with linear absorption and elimination was used to describe 25(OH)D pharmacokinetics, while integrating endogenous baseline plasma concentrations. Covariate analyses confirmed the effect of seasonality, body mass index, smoking habits, the analytical method, darunavir/ritonavir and the genetic variant in GC (rs2282679) on 25(OH)D concentrations. 11% of the inter-individual variability in 25(OH)D levels was explained by seasonality and other non-genetic covariates, and 1% by genetics. The optimal supplementation for severe vitamin D deficient patients was 300,000 IU two times per year. CONCLUSIONS: This analysis allowed identifying factors associated with 25(OH)D plasma levels in HIV-infected individuals. Improvement of dosage regimen and timing of vitamin D supplementation is proposed based on those results.

An Evaluation of the Paper Profile - a comparative assessment of the applicability of an emerging environmental communication tool in pulp and paper industry

Diplomityön tavoitteena oli arvioida uutta sellu-, paperi- ja kartonkiteollisuuden Paper Profile -ympäristötuoteselostetta. Paper Profilen tarkoituksena on tarjota paperiteollisuuden asiakkaille ja muille kiinnostuneilla sidosryhmille yhtenäistä ympäristöinformaatiota koskien paperituotteiden koostumusta ja tuotteiden tärkeimpiä ympäristöparametrejä. Työn tärkein tavoite oli arvioida kriittisesti Paper Profilea ja verrata konseptia ISO:n, Kansainvälisen stardardisoimisliiton tuoteselosteeseen sekä löytää konseptien yhtäläisyydet ja erot. Tärkein tehtävä oli tunnistaa ne avaintekijät, joiden avulla Paper Profile -tuoteselostetta voitaisiin pitää yhtenevänä ISO/TR 14025 teknisen raportin kanssa. Lisäksi Paper Profile -tuoteselosteen mahdolliset kehittämistarpeet arvioitiin ISO-tuoteselosteen näkökulmasta. Työn toinen tavoite oli kerätä ja analysoida uuteen tuoteselosteeseen liittyvä asiakaspalaute ja verrata sitä Stora Enson tehtaiden ympäristöpäälliköiden antamiin Paper Profilea koskeviin kommentteihin. Työn tuloksena huomattiin, että Paper Profile -konsepti sellaisenaan ei ole kovin informatiivinen vaan tuoteseloste jättää monia ympäristökysymyksiä avoimeksi. Siitä huolimatta Paper Profile tarjoaa riittävän taustan eri paperituotteiden ympäristökuormitusten keskinäiselle vertailuille. Konseptin viestinnällinen näkökulma paranisi huomattavasti, jos tuoteselosteeseen lisättäisiin kolmannen osapuolen verifiointi. Lisäksi referenssiarvot kertoisivat asiakkaille paremmin esitettyjen parametrien taustoista. Stora Enson tehtaiden ympäristöpäälliköiden, samoin kuin asiakkaidenkin mielestä Paper Profile on yleisesti ottaen potentiaalinen ympäristöviestinnän työkalu, mutta silti konseptiin ehdotettiin joitakin pieniä muutoksia. Avoinna olevat metsäsertifiointikysymykset ja niiden puutteellinen tiedottaminen tuoteselosteessa puhututtivat sekä tehtaiden henkilöstöä että yritysasiakkaita.

Executive functions profile in extreme eating/weight conditions: from anorexia nervosa to obesity

Extreme weight conditions (EWC) groups along a continuum may share some biological risk factors and intermediate neurocognitive phenotypes. A core cognitive trait in EWC appears to be executive dysfunction, with a focus on decision making, response inhibition and cognitive flexibility. Differences between individuals in these areas are likely to contribute to the differences in vulnerability to EWC. The aim of the study was to investigate whether there is a common pattern of executive dysfunction in EWC while comparing anorexia nervosa patients (AN), obese subjects (OB) and healthy eating/weight controls (HC).

Primary care in Switzerland: evolution of physicians' profile and activities in twenty years (1993-2012).

BACKGROUND: According to the Organization for Economic Cooperation and Development, the Swiss healthcare system is one of the most effective in the world. Yet, as other occidental countries, it has to face the increase of chronic diseases frequency and its resulting cost, particularly for primary care (PC). However very few consistent data are available to describe PC features and its evolution over time. The aim of this study is to describe the evolution of the Swiss PC physicians' (PCPs) profile and activities between 1993 and 2012. METHODS: The date come from two independent European surveys carried out in Switzerland respectively in 1993 and 2012. Both surveys were cross-sectional ones and based on representative samples of 200 PCPs, interviewed by questionnaire. RESULTS: In 20 years, PCPs became older (median age 46 vs 56, p < 0.001) and more feminized (7 % vs 22 %, p < 0.001). Nowadays, they more often work in group practices (28 % vs 52 % in 2012, p < 0.001) and are more involved in other paid activities (28 % vs 66 % in 2012, p < 0.001). All the PCPs have a computer in 2012 (78 % in 1993, p < 0.001) and it is mostly used for keeping records of consultations (47 %). The number of daily face-to-face contacts with patients decreased from 31 to 24 but the average length rose from 15 to 20 min (p < 0.001). PCPs provide fewer pediatric and gynecological services but their activity remains globally unchanged in other domains. The frequency of meetings with other disciplines decreased significantly (e.g. once/month face-to-face meets with ambulatory specialists: 78 % vs 23 % in 2012, p < 0.001). The involvement of PCPs in follow-up and treatment of chronic disease globally little differed. In 2012, 8.5 % of the PCPs never performed any chirurgical acts (vs 0 % in 1993, p < 0.001). CONCLUSION: This study showed a substantial evolution of Swiss PC over the last twenty years in terms of socio-demographic, organizational and service provided. The main changes include: feminization and ageing, lower diversity in services provided, fewer but longer consultations. These changes may have important implications for patients' management and will need to be considered for health planning purposes.

Striatal pre- and postsynaptic profile of adenosine A2A receptor antagonists

Striatal adenosine A2A receptors (A2ARs) are highly expressed in medium spiny neurons (MSNs) of the indirect efferent pathway, where they heteromerize with dopamine D2 receptors (D2Rs). A2ARs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A1 receptors (A1Rs). It has been hypothesized that postsynaptic A2AR antagonists should be useful in Parkinson's disease, while presynaptic A2AR antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A2AR antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261) showed no clear preference. Radioligand-binding experiments were performed in cells expressing A2AR-D2R and A1R-A2AR heteromers to determine possible differences in the affinity of these compounds for different A2AR heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A2AR when co-expressed with D2R than with A1R. KW-6002 showed the best relative affinity for A2AR co-expressed with D2R than co-expressed with A1R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile. On the basis of their preferential pre- versus postsynaptic actions, SCH-442416 and KW-6002 may be used as lead compounds to obtain more effective antidyskinetic and antiparkinsonian compounds, respectively.