We present genome-wide data from 40 individuals dating to c.16,900 to 550 years ago in northeast Asia. We describe hitherto unknown gene flow and admixture events in the region, revealing a complex ...population history. While populations east of Lake Baikal remained relatively stable from the Mesolithic to the Bronze Age, those from Yakutia and west of Lake Baikal witnessed major population transformations, from the Late Upper Paleolithic to the Neolithic, and during the Bronze Age, respectively. We further locate the Asian ancestors of Paleo-Inuits, using direct genetic evidence. Last, we report the most northeastern ancient occurrence of the plague-related bacterium,
Our findings indicate the highly connected and dynamic nature of northeast Asia populations throughout the Holocene.
For efficient pain reduction in severe skin wounds, topical opioids may be a new option – given that wound healing is not impaired and the vehicle allows for slow opioid release, since long intervals ...of painful wound dressing changes are intended. We investigated the influence of opioids on the wound healing process via in vitro models, migration assay and scratch test. In fact, morphine, hydromorphone, fentanyl and buprenorphine increased the number of migrated HaCaT cells (spontaneously transformed keratinocytes) twofold. In the scratch test, morphine accelerated the closure of a monolayer wound (scratch). As possible slow release application forms are nanoparticulate systems like solid lipid nanoparticles (SLN) and dendritic core-multishell (CMS) nanotransporters, we evaluated the effect of unloaded nanoparticles on HaCaT cell migration, too. CMS nanotransporters did not inhibit migration, SLN even enhanced it (twofold). Applying morphine plus unloaded nanoparticles reduced morphine effects possibly due to uptake into CMS nanotransporters and adsorption to the surface of SLN. In contrast to SLN, TGF-β1 was taken up by CMS nanotransporters, too. Both nanoparticles are tolerable by skin and eye as derived from Episkin-SM
TM skin irritation test and HET-CAM assay. No acute toxic effects were observed either. In conclusion, opioids as well as the investigated nanoparticulate carriers conform the essential conditions for topical pain reduction.
Objective: Demographic changes and aggressive platelet inhibition have resulted in a marked increase in blood- and coagulation product expenditure and costs in cardiac surgery. We analyzed ‘bedside’ ...coagulation test (ROTEM) in order to verify clot forming quality for the purpose of finding a cost-effective treatment path. Methods: Annual treatment costs of all cardiosurgical patients were analyzed before (729 patients) and after (693 patients) implementation of ‘bedside’ ROTEM. Cumulative numbers and costs of platelet concentrates (PltC), fresh frozen plasma (FFP), red blood cell units (RBC), and coagulation factors: pooled coagulation concentrates (PCC), recombinant factor VIIa (rFVIIa), factor XIII (FXIII), and fibrinogen were assessed. Average monthly numbers and costs were compared. Number of resternotomies and early mortality was assessed and compared in both periods. Results: After ROMTEM implementation cumulative RBC expenditure showed 25% decrease while PltC exhibited 50% decrease. FFP expenditure remained unchanged. PCC, FXIII were markedly reduced (−80%) while rFVIIa were entirely omitted. Fibrinogen, however, increased two-fold. Cumulative average monthly costs of all blood products decreased from 66,000€ to 45,000€ (−32%). Coagulation factor average monthly costs decreased from 60,000€ to 30,000€ (−50%) yielding combined savings of 44%. In contrast, average monthly costs for ROTEM were 1.580€. Total number of resternotomies decreased from 6.6% to 5.5% while early mortality (5.9%; 6.0%) remained stable. Conclusion: Cumulative costs for treatment of perioperative coagulation disorders can be reduced by ‘bedside’ ROTEM analysis to achieve a selective substitution management. Saved costs for blood- and coagulation products clearly outweighed the expenses of ROTEM. Adequate differential coagulation management can therefore be cost-effective.
T regulatory (Treg) cells are characterized by expression of suppressive cytokines and the transcription factor FOXP3. They play a key role in balancing immune responses and maintain peripheral ...tolerance against antigens and allergens. The loss of peripheral tolerance against allergens causes diseases that can be therapeutically controlled with glucocorticoids.
The present study investigates whether glucocorticoids affect the activity of Treg cells on the basis of FOXP3 and cytokine expression.
CD4+ T cells from healthy donors and glucocorticoid-treated asthmatic patients were isolated, and expression of FOXP3, along with IL-10 and TGF-β1, was determined. The effect of glucocorticoids on Treg cells was measured in vivo before and after GC treatment and in in vitro cultures.
FOXP3 mRNA expression was significantly increased in asthmatic patients receiving inhaled glucocorticoid treatment, systemic glucocorticoid treatment, or both. FOXP3 tightly correlated with IL10 mRNA expression. No correlation of FOXP3 mRNA expression was observed in relation to a (GT)n microsatellite promoter polymorphism on chromosome Xp11.23 or total IgE level. The frequency of CD25+ memory CD4+ T cells and transient FOXP3 mRNA expression by CD4+ T cells significantly increased after systemic glucocorticoid treatment, whereas TGFB1 expression did not change. Furthermore, glucocorticoids induced IL10 and FOXP3 expression in short-term and long-term cultures in vitro.
These findings demonstrate that glucocorticoid treatment is not only immunosuppressive and anti-inflammatory but also promotes or initiates differentiation toward TR1 cells by a FOXP3-dependent mechanism. Strategies that convert transient glucocorticoid-induced Treg activity into a stable phenotype might improve allergy and asthma therapy.
Typ-I-Interferonopathien Günther, C.; Schmidt, F.; König, N. ...
Zeitschrift für Rheumatologie,
03/2016, Letnik:
75, Številka:
2
Journal Article
Recenzirano
Zusammenfassung
Typ-I-Interferone dienen dem Organismus v. a. zur Abwehr von Viren. Die Induktion von Typ-I-Interferon wirkt stimulierend und modulierend sowohl auf das angeborene als auch das ...adaptive Immunsystem, was mit einer verminderten Toleranz gegenüber körpereigenen Strukturen einhergeht. Eine genetisch bedingte inadäquate Aktivierung des Typ-I-Interferon-Systems kann zu entzündlichen Systemerkrankungen führen, die unter dem Oberbegriff der Typ-I-Interferonopathien subsumiert werden. Das klinische Spektrum der Typ-I-Interferonopathien ist sehr breit und heterogen, wobei neurologische und kutane Manifestationen im Vordergrund stehen. Die klinischen Symptome entsprechen dabei oft Teilsymptomen multifaktorieller Autoimmunerkrankungen wie dem systemischen Lupus erythematodes oder systemischen Vaskulitiden. Einblicke in die molekulare Pathogenese der Typ-I-Interferonopathien bieten erste kausal orientierte Ansätze für therapeutische Interventionen.
Current diagnostic tools for prostate cancer lack specificity and sensitivity for detecting very early lesions. DNA methylation is a stable genomic modification that is detectable in peripheral ...patient fluids such as urine and blood plasma that could serve as a non-invasive diagnostic biomarker for prostate cancer.
We measured genome-wide DNA methylation patterns in 73 clinically annotated fresh-frozen prostate cancers and 63 benign-adjacent prostate tissues using the Illumina Infinium HumanMethylation450 BeadChip array. We overlaid the most significantly differentially methylated sites in the genome with transcription factor binding sites measured by the Encyclopedia of DNA Elements consortium. We used logistic regression and receiver operating characteristic curves to assess the performance of candidate diagnostic models.
We identified methylation patterns that have a high predictive power for distinguishing malignant prostate tissue from benign-adjacent prostate tissue, and these methylation signatures were validated using data from The Cancer Genome Atlas Project. Furthermore, by overlaying ENCODE transcription factor binding data, we observed an enrichment of enhancer of zeste homolog 2 binding in gene regulatory regions with higher DNA methylation in malignant prostate tissues.
DNA methylation patterns are greatly altered in prostate cancer tissue in comparison to benign-adjacent tissue. We have discovered patterns of DNA methylation marks that can distinguish prostate cancers with high specificity and sensitivity in multiple patient tissue cohorts, and we have identified transcription factors binding in these differentially methylated regions that may play important roles in prostate cancer development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Participants at the recent Translate! 2014 meeting in Berlin, Germany, reached a consensus on the rate-limiting factor for advancing translational medicine.
Obesity is a worldwide health problem. We conducted detailed analyses of anthropometric measures in a comprehensive, population-based, current cohort in Germany.
In the German National Cohort (NAKO), ...we analyzed cross-sectional data on body-mass index (BMI), waist and hip circumference, subcutaneous (SAT) and visceral adipose tissue (VAT) as measured by ultrasound, and body fat percentage. The data were stratified by sex, age, and self-reported physicians' diagnoses of cardiovascular diseases (CVD), metabolic diseases (MetD), cardiometabolic diseases (CMD), and cancer.
Data were available from 204 751 participants (age, 49.9 ± 12.8 years; 50.5% women). Body size measures generally increased with age. Men had a higher BMI, larger waist circumference, and more VAT than women, while women had a larger hip circumference, more SAT, and a higher body fat percentage than men. For example, the mean BMI of participants over age 60 was 28.3 kg/m2 in men and 27.6 kg/m2 in women. CVD, MetD, and CMD were associated with higher anthropometric values, while cancer was not. For example, the mean BMI was 25.3 kg/m2 in healthy women, 29.4 kg/m2 in women with CMD, and 25.4 kg/m2 in women with cancer.
Obesity is widespread in Germany, with notable differences between the sexes in anthropometric values. Obesity was more common in older participants and those with chronic diseases other than cancer. Elevated values were especially common in multimorbid individuals.
Obesity is a worldwide health problem. We conducted detailed analyses of anthropometric measures in a comprehensive, population-based, current cohort in Germany.BACKGROUNDObesity is a worldwide ...health problem. We conducted detailed analyses of anthropometric measures in a comprehensive, population-based, current cohort in Germany.In the German National Cohort (NAKO), we analyzed cross-sectional data on body mass index (BMI), waist and hip circumference, subcutaneous (SAT) and visceral adipose tissue (VAT) as measured by ultrasound, and body fat percentage. The data were stratified by sex, age, and self-reported physicians' diagnoses of cardiovascular diseases (CVD), metabolic diseases (MetD), cardiometabolic diseases (CMD), and cancer.METHODSIn the German National Cohort (NAKO), we analyzed cross-sectional data on body mass index (BMI), waist and hip circumference, subcutaneous (SAT) and visceral adipose tissue (VAT) as measured by ultrasound, and body fat percentage. The data were stratified by sex, age, and self-reported physicians' diagnoses of cardiovascular diseases (CVD), metabolic diseases (MetD), cardiometabolic diseases (CMD), and cancer.Data were available from 204 751 participants (age, 49.9 ± 12.8 years; 50.5% women). Body size measures generally increased with age. Men had a higher BMI, larger waist circumference, and more VAT than women, while women had a larger hip circumference, more SAT, and a higher body fat percentage than men. For example, the mean BMI of participants over age 60 was 28.3 kg/m2 in men and 27.6 kg/m2 in women. CVD, MetD, and CMD were associated with higher anthropometric values, while cancer was not. For example, the mean BMI was 25.3 kg/m2 in healthy women, 29.4 kg/m2 in women with CMD, and 25.4 kg/m2 in women with cancer.RESULTSData were available from 204 751 participants (age, 49.9 ± 12.8 years; 50.5% women). Body size measures generally increased with age. Men had a higher BMI, larger waist circumference, and more VAT than women, while women had a larger hip circumference, more SAT, and a higher body fat percentage than men. For example, the mean BMI of participants over age 60 was 28.3 kg/m2 in men and 27.6 kg/m2 in women. CVD, MetD, and CMD were associated with higher anthropometric values, while cancer was not. For example, the mean BMI was 25.3 kg/m2 in healthy women, 29.4 kg/m2 in women with CMD, and 25.4 kg/m2 in women with cancer.Obesity is widespread in Germany, with notable differences between the sexes in anthro - pometric values. Obesity was more common in older participants and those with chronic diseases other than cancer. Elevated values were especially common in multimorbid individuals.CONCLUSIONObesity is widespread in Germany, with notable differences between the sexes in anthro - pometric values. Obesity was more common in older participants and those with chronic diseases other than cancer. Elevated values were especially common in multimorbid individuals.
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