Virus Infections in Early Childhood, Cow’s Milk Formula Exposure and Genetic Predisposition in the Development of Diabetes-Associated Autoimmunity

Varhaislapsuuden virusinfektioiden, lehmänmaitopohjaisen äidinmaitovastikeen ja geneettisen alttiuden merkitys diabetekseen liittyvän autoimmuniteetin kehittymisessä Tyypin 1 diabetes on autoimmuunisairaus, joka syntyy haiman insuliinia tuottavien beta-solujen tuhouduttua elimistön oman immuunipuolustusjärjestelmän hyökkäyksen seurauksena. Sekä perimän että ympäristötekijöiden arvellaan vaikuttavan tautiprosessiin, mutta taudin tarkkaa syntymekanismia ei tunneta. Tutkimuksen tarkoituksena oli selvittää varhaislapsuuden ympäristötekijöiden vaikutusta beta-soluautoimmuniteetin syntyyn, erityispaino tutkimuksessa oli ympäristötekijöiden yhteisvaikutuksessa sekä geneettisten riskitekijöiden ja ympäristötekijöiden vuorovaikutuksessa. Varhaislapsuudessa sairastettu sytomegalovirus- tai enterovirusinfektio ei lisännyt beta-soluautoimmuniteetin riskiä lapsilla, joilla on geneettisesti kohonnut riski sairastua tyypin 1 diabetekseen. Ennen puolen vuoden ikää sairastettu rotavirusinfektio lisäsi hieman tyypin 1 diabetekseen liittyvän autoimmuniteetin riskiä. Tarkemmassa analyysissa varhaislapsuuden enterovirusinfektio osoittautui kuitenkin autovasta-aineiden muodostumisen riskitekijäksi niiden lasten joukossa, jotka olivat saaneet lehmänmaitopohjaista äidinmaidon vastiketta ensimmäisten elinkuukausien aikana. Tämä löydös viittaa enterovirusinfektion ja lehmänmaitopohjaisen vastikkeen yhteisvaikutukseen tyypin 1 diabetekseen liittyvän autoimmuniteetin synnyssä. Löydösten mukaan PTPN22 geenin C1858T polymorfismi vaikuttaa CD4+ T solujen aktivaatioon ja proliferaatiovasteeseen, 1858T alleeliin liittyy alentunut T-soluresepto-rivälitteinen aktivaatio. 1858T alleelin kantajuuteen liittyy lisäksi lisääntynyt autovasta-aineiden ja kliinisen diabeteksen ilmaantuvuus. Tämä yhteys rajoittui yksilöihin, jotka olivat altistuneet lehmänmaitopohjaiselle vastikkeelle ennen kuuden kuukauden ikää. Tulosten mukaan sekä ympäristötekijöiden väliset yhteisvaikutukset että perimä vaikuttavat yksittäisen ympäristötekijän merkitykseen tyypin 1 diabetekseen liittyvän autoimmuniteetin synnyssä. Nämä yhteisvaikutukset ympäristötekijöiden kesken ja perimän ja ympäristötekijöiden välillä selittävät aiemmin julkaistujen tulosten ristiriittaisuutta tutkimuksissa, joissa on analysoitu vain yhden ympäristötekijän vaikutusta diabeteksen ilmaantuvuuteen.

Analytical challenges in breath analysis and its application to exposure monitoring

There is an increasing interest in the use of breath analysis for monitoring human physiology and exposure to toxic substances or environmental pollutants. This review focuses on the current status of the sampling procedures, collection devices and sample-enrichment methodologies used for exhaled breath-vapor analysis. We discuss the different parameters affecting each of the above steps, taking into account the requirements for breath analysis in exposure assessments and the need to analyze target compounds at sub-ppbv levels. Finally, we summarize the practical applications of exposure analysis in the past two decades

Predictors of smoking craving during virtual reality exposure

Cue exposure treatment (CET) consists of controlled and repeated exposure to drugrelated stimuli in order to reduce cue-reactivity. Virtual reality (VR) has proved to be a promising tool for exposition. However, identifying the variables that can modulate the efficacy of this technique is essential for selecting the most appropriate exposure modality. The aim of this study was to determine the relation between several individual variables and self-reported craving in smokers exposed to VR environments. Fortysix smokers were exposed to seven complex virtual environments that reproduce typical situations in which people smoke. Self-reported craving was selected as the criterion variable and three types of variables were selected as the predictor variables: related to nicotine dependence, related to anxiety and impulsivity, and related to the sense of presence in the virtual environments. Sense of presence was the only predictor of self-reported craving in all the experimental virtual environments. Nicotine dependence variables added predictive power to the model only in the virtual breakfast at home. No relation was found between anxiety or impulsivity and self-reported craving. Virtual reality technology can be very helpful for improving CET for substance use disorders. However, the use of virtual environments would make sense only insofar as the sense of presence was high. Otherwise, the effectiveness of exposure might be affected. © 2012 by the Massachusetts Institute of Technology.

Association between Long-Term Exposure to Traffic-Related Air Pollution and Subclinical Atherosclerosis: The REGICOR Study

Background: Epidemiological evidence of the effects of long-term exposure to air pollu tion on the chronic processes of athero genesis is limited. Objective: We investigated the association of long-term exposure to traffic-related air pollu tion with subclinical atherosclerosis, measured by carotid intima media thickness (IMT) and ankle–brachial index (ABI). Methods: We performed a cross-sectional analysis using data collected during the reexamination (2007–2010) of 2,780 participants in the REGICOR (Registre Gironí del Cor: the Gerona Heart Register) study, a population-based prospective cohort in Girona, Spain. Long-term exposure across residences was calculated as the last 10 years’ time-weighted average of residential nitrogen dioxide (NO2) estimates (based on a local-scale land-use regression model), traffic intensity in the nearest street, and traffic intensity in a 100 m buffer. Associations with IMT and ABI were estimated using linear regression and multinomial logistic regression, respectively, controlling for sex, age, smoking status, education, marital status, and several other potential confounders or intermediates. Results: Exposure contrasts between the 5th and 95th percentiles for NO2 (25 μg/m), traffic intensity in the nearest street (15,000 vehicles/day), and traffic load within 100 m (7,200,000 vehicle-m/day) were associated with differences of 0.56% (95% CI: –1.5, 2.6%), 2.32% (95% CI: 0.48, 4.17%), and 1.91% (95% CI: –0.24, 4.06) percent difference in IMT, respectively. Exposures were positively associated with an ABI of > 1.3, but not an ABI of < 0.9. Stronger associations were observed among those with a high level of education and in men ≥ 60 years of age. Conclusions: Long-term traffic-related exposures were associated with subclinical markers of atherosclerosis. Prospective studies are needed to confirm associations and further examine differences among population subgroups.key words: ankle–brachial index, average daily traffic, cardiovascular disease, exposure assessment, exposure to tailpipe emissions, intima media thickness, land use regression model, Mediterranean diet, nitrogen dioxide

Exposure to Tobacco Smoke and Markers of Subclinical Atherosclerosis in Children and Adolescents. The STRIP Study.

Background: Measurement of serum cotinine, a major metabolite of nicotine, provides a valid marker for quantifying exposure to tobacco smoke. Exposure to tobacco smoke causes vascular damage by multiple mechanisms, and it has been acknowledged as a risk factor for atherosclerosis. Multifactorial atherosclerosis begins in childhood, but the relationship between exposure to tobacco smoke and arterial changes related to early atherosclerosis have not been studied in children. Aims: The aim of the present study was to evaluate exposure to tobacco smoke with a biomarker, serum cotinine concentration, and its associations with markers of subclinical atherosclerosis and lipid profile in school-aged children and adolescents. Subjects and Methods: Serum cotinine concentration was measured using a gas chromatographic method annually between the ages 8 and 13 years in 538-625 children participating since infancy in a randomized, prospective atherosclerosis prevention trial STRIP (Special Turku coronary Risk factor Intervention Project). Conventional atherosclerosis risk factors were measured repeatedly. Vascular ultrasound studies were performed among 402 healthy 11-year-old children and among 494 adolescents aged 13 years. Results: According to serum cotinine measurements, a notable number of the school aged children and adolescents were exposed to tobacco smoke, but the exposure levels were only moderate. Exposure to tobacco smoke was associated with decreased endothelial function as measured with flow-mediated dilation of the brachial artery, decreased elasticity of the aorta, and increased carotid and aortic intima-media thickness. Longitudinal exposure to tobacco smoke was also related with increased apolipoprotein B and triglyceride levels in 13-year-old adolescents, whose body mass index and nutrient intakes did not differ. Conclusions: These findings suggest that exposure to tobacco smoke in childhood may play a significant role in the development of early atherosclerosis. Key Words: arterial elasticity, atherosclerosis, children, cotinine, endothelial function, environmental tobacco smoke, intima-media thickness, risk factors, ultrasound

Percutaneous access versus standard femoral exposure for endovascular abdominal aortic aneurysm repair: a randomized, controlled trial

The treatment of abdominal aortic aneurysm (AAA) has shifted from the exposure of the aorta artery in an open repair technique to a small groin cut in an endovascular repair. Recently, a percutaneous access for endovascular repair has appeared. This new technique aims to minimize the complications of the common femoral artery exposure, the patient discomfort and the length of hospitalizationObjectives: To compare the proportion of discharged patients within the first 48 postoperative hours of two common femoral artery accesses for endovascular repair of AAA: the open exposure technique and the percutaneous technique. Secondary objectives include to evaluate the total procedure time, the femoral access complications, the need for extra analgesia and the patient satisfaction and groin discomfort of the two techniquesDesign: Randomized controlled trial conducted between 2014 and 2017Participants: Patients diagnosed with abdominal aortic aneurysm with elective endovascular repair indication

Nutrimetabolomics fingerprinting to identify biomarkers of bread exposure in a free-living population from the PREDIMED study cohort

Bread is one of the most widely consumed foods. Its impact on human health is currently of special interest for researchers. We aimed to identify biomarkers of bread consumption by applying a nutrimetabolomic approach to a free-living population. An untargeted HPLC q-TOF-MS and multivariate analysis was applied to human urine from 155 subjects stratified by habitual bread consumption in three groups: non-consumers of bread (n = 56), white-bread consumers (n = 48) and whole-grain bread consumers (n = 51). The most differential metabolites (variable importance for projection ≥1.5) included compounds originating from cereal plant phytochemicals such as benzoxazinoids and alkylresorcinol metabolites, and compounds produced by gut microbiota (such as enterolactones, hydroxybenzoic and dihydroferulic acid metabolites). Pyrraline, riboflavin, 3-indolecarboxylic acid glucuronide, 2,8-dihydroxyquinoline glucuronide and N-α-acetylcitrulline were also tentatively identified. In order to combine multiple metabolites in a model to predict bread consumption, a stepwise logistic regression analysis was used. Receiver operating curves were constructed to evaluate the global performance of individual metabolites and their combination. The area under the curve values [AUC (95 % CI)] of combined models ranged from 77.8 % (69.1 86.4 %) to 93.7 % (89.4 98.1 %), whereas the AUC for the metabolites included in the models had weak values when they were evaluated individually: from 58.1 % (46.6 69.7 %) to 78.4 % (69.8 87.1 %). Our study showed that a daily bread intake significantly impacted on the urinary metabolome, despite being examined under uncontrolled free-living conditions. We further concluded that a combination of several biomarkers of exposure is better than a single biomarker for the predictive ability of discriminative analysis.

Nutrimetabolomics fingerprinting to identify biomarkers of bread exposure in a free-living population from the PREDIMED study cohort

Bread is one of the most widely consumed foods. Its impact on human health is currently of special interest for researchers. We aimed to identify biomarkers of bread consumption by applying a nutrimetabolomic approach to a free-living population. An untargeted HPLC q-TOF-MS and multivariate analysis was applied to human urine from 155 subjects stratified by habitual bread consumption in three groups: non-consumers of bread (n = 56), white-bread consumers (n = 48) and whole-grain bread consumers (n = 51). The most differential metabolites (variable importance for projection ≥1.5) included compounds originating from cereal plant phytochemicals such as benzoxazinoids and alkylresorcinol metabolites, and compounds produced by gut microbiota (such as enterolactones, hydroxybenzoic and dihydroferulic acid metabolites). Pyrraline, riboflavin, 3-indolecarboxylic acid glucuronide, 2,8-dihydroxyquinoline glucuronide and N-α-acetylcitrulline were also tentatively identified. In order to combine multiple metabolites in a model to predict bread consumption, a stepwise logistic regression analysis was used. Receiver operating curves were constructed to evaluate the global performance of individual metabolites and their combination. The area under the curve values [AUC (95 % CI)] of combined models ranged from 77.8 % (69.1 86.4 %) to 93.7 % (89.4 98.1 %), whereas the AUC for the metabolites included in the models had weak values when they were evaluated individually: from 58.1 % (46.6 69.7 %) to 78.4 % (69.8 87.1 %). Our study showed that a daily bread intake significantly impacted on the urinary metabolome, despite being examined under uncontrolled free-living conditions. We further concluded that a combination of several biomarkers of exposure is better than a single biomarker for the predictive ability of discriminative analysis.

Mun sieluni sun ylläs väräjää

Soitinnus: lauluääni, orkesteri.

Sun rauhaas lemmin

Soitinnus: lauluääni, orkesteri.

Mun sieluni sun ylläs väräjää

Soitinnus: laulu, piano.

Targeted Therapy Possibilities for Metastatic Melanoma

The incidence of malignant melanoma of the skin has been steadily rising worldwide during the past decades. Most early detected primary tumors can be removed surgically and the prognosis is good. However, at the same time there still is no permanent cure for metastatic melanoma and its prognosis is poor, although lately new effective drugs have emerged. In this thesis, four different approaches of experimental therapy for metastatic melanoma were studied. Endogenous cis-Urocanic acid (UCA) is found in every individual’s skin, where exposure to UV light from the sun generates it from its inactive trans conformation. Cis- UCA was found to destroy malignant melanoma cells in culture under an acidified pH and sufficient concentration through caspase-3 mediated apoptosis. Furthermore, cis-UCA is able to considerably diminish the growth rate in human melanoma tumors on living SCID mice. Using replication-competent Semliki Forest viruses, human melanoma tumors grown in SCID mice were dramatically shrunken as the fulminant production of viruses in melanoma cells leads them to apoptosis within 72 hours. Small oligopeptides attaching to melanoma cells were identified using in vivo phage display. The melanoma-specific peptides found were further tested in vitro on adenoviruses. Ultimately, the adenoviral retargeting using the peptides was tested in vivo. One peptide homed to human transferring receptor upregulated on melanoma cells. In order to kill the malignant melanoma cells with the retargeted adenoviruses, the viruses should carry genetic material producing apoptotic proteins in the cancer tissue. TIMP-3 has been identified as a good candidate for such a protein, as it inhibits malignant cell adhesion as well as promotes apoptosis through a caspase-8 pathway. It is further shown here that adenovirally delivered TIMP-3 is even more potent, as it could kill non-adherent cancer cells, lacking the fully functional death receptor signalling pathway. Adenovirally delivered TIMP-2 also showed marked antitumor effects in human malignant melanoma xenografts on SCID mice both in ex vivo and systemic delivery.

[Sun on mun sydämein]

Soitinnus: lauluääni (tenori), orkesteri.

Sun haltuus, rakas Isäni

Anonyymi (1543), Ranska.