c-myb对胚胎干细胞体外造血分化及定型的影响

目的　通过体外胚胎干细胞培养体系对ES细胞进行c- myb等位基因打靶,建立c -myb 及c -myb ES细 胞模型的基础上,探讨转录因子c- myb在造血定型和分化中的作用。方法　通过体外ES细胞去除LIF半固体介质EBs的 造血分化体系,采用甲基纤维素克隆形成分析和real timePCR观察c- myb 及c -myb ES细胞,比较分析其不同分化过 程及阶段中造血各系形成和相关基因表达变化。结果　c -myb 及c -myb ES胚胎体(EBs)大小及形态相似,c -myb ESEBs形成显著多于c -myb 。c -myb 组CFU- E出现在第6天,高峰为第8天;c- myb 组也有相似的改变,但其 CFU- E数目少于c -myb 。c -myb 组CFU- M高峰为第7天;c- myb 也有相似的改变,但其CFU- M数目高于c- myb 。c -myb CFU -GM出现在第7天,高峰为第12天,而c -myb 未见CFU -GM形成。real timePCR分析显示,c -myb 及 c- myb β globin,zeta globin,Lys,C- fms基因表达无显著变化。结论　低水平的c -myb不影响祖细胞的扩增,但影响其 终末分化。低水平的c -myb表达在造血定型中对红系的发育具有一定的影响,而对巨噬细胞的发育成熟无明显影响。 c -myb的表达水平对造血分化相关基因的表达没有明显的影响。     

Detrimental role of CC chemokine receptor 4 in murine polymicrobial sepsis

CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are critically involved in different immune processes. In models of lipopolysaccharide-induced shock, CCR4-deficient (CCR4^−/−) mice showed improved survival rates associated with attenuated proinflammatory cytokine release. Using CCR4^−/− mice with a C57BL/6 background, this study describes for the first time the role of CCR4 in a murine model of polymicrobial abdominal sepsis, the colon ascendens stent peritonitis (CASP). CASP-induced sepsis led to a massive downregulation of CCR4 in lymphoid and nonlymphoid tissues, whereas the expression of CCL17 and CCL22 was independent of the presence of CCR4. After CASP, CCR4^−/− animals showed a strongly enhanced bacterial clearance in several organs but not in the peritoneal lavage fluid and the blood. In addition, significantly reduced levels of proinflammatory cytokines/chemokines were measured in organ supernatants as well as in the sera of CCR4^−/− mice. CCR4 deficiency consequently resulted in an attenuated severity of systemic sepsis and a strongly improved survival rate after CASP or CASP with intervention. Thus, our data provide clear evidence that CCR4 plays a strictly detrimental role in the course of polymicrobial sepsis.     

Pathways involved in human conscious vision contribute to obstacle-avoidance behaviour

Human patients with visual field defects following damage to their primary visual cortex (V1) will often misperceive the midpoint of a horizontal line. They tend to shift the midpoint away from the real position towards their blind field. In patients with unilateral neglect, where midpoint shifts can also be observed, these perceptual errors do not lead to errors in an obstacle-avoidance task, which also requires the ability to find the midpoint between two obstacles. This dissociation in neglect patients was taken as evidence that obstacle-avoidance performance is guided by visual information from the dorsal visual stream. Recently it was shown that a patient with hemianopia could avoid an obstacle presented in his blind field. This suggests that obstacle-avoidance behaviour can be guided by subconscious vision alone involving a direct route from extrageniculate structures in the brain to dorsal stream areas. To investigate whether obstacle avoidance relies only on this subconscious route or also uses information from pathways involved in conscious vision, we examined the effect of the hemianopic shift on obstacle-avoidance behaviour. This shift is found in tasks where a conscious visual judgement is required and presumably arises in pathways underlying conscious vision (V1 and ventral stream areas). We compared the performance of six patients with left hemianopia with the performance of six patients with right hemianopia. We found a clear bias in both groups, which also affected obstacle-avoidance performance. It is thus concluded that obstacle avoidance does not bypass the system for conscious vision completely.     

Studies in humans and mice implicate neurocan in the etiology of mania

OBJECTIVE Genome-wide association has been reported between the NCAN gene and bipolar disorder. The aims of this study were to characterize the clinical symptomatology most strongly influenced by NCAN and to explore the behavioral phenotype of Ncan knockout (Ncan-/-) mice. METHOD Genotype/phenotype correlations were investigated in patients with bipolar disorder (N=641) and the genetically related disorders major depression (N=597) and schizophrenia (N=480). Principal components and genotype association analyses were used to derive main clinical factors from 69 lifetime symptoms and to determine which of these factors were associated with the NCAN risk allele. These analyses were then repeated using the associated factor(s) only in order to identify the more specific clinical subdimensions that drive the association. Ncan-/- mice were tested using diverse paradigms, assessing a range of behavioral traits, including paradigms corresponding to bipolar symptoms in humans. RESULTS In the combined patient sample, the NCAN risk allele was significantly associated with the "mania" factor, in particular the subdimension "overactivity." Ncan-/- mice were hyperactive and showed more frequent risk-taking and repetitive behaviors, less depression-like conduct, impaired prepulse inhibition, amphetamine hypersensitivity, and increased saccharin preference. These aberrant behavioral responses normalized after the administration of lithium. CONCLUSIONS NCAN preferentially affected mania symptoms in humans. Ncan-/- mice showed behavioral abnormalities that were strikingly similar to those of the human mania phenotype and may thus serve as a valid mouse model.     

Determinants of mortality in patients with type 2 diabetes: a review

We aimed to review and summarize the evidence from accomplished trials analyzing factors influencing mortality in patients with T2DM and to provide some recommendations for targets and treatment in the European region. The following databases were searched for relevant trials: PubMed and the Cochrane Library. Of 3.806 citations, 134 trials met our inclusion criteria. Results: The reduction in lifetime for 65 + ?years-old patients having less than 10 years T2DM amounts to 1.8 years. Having T2DM for more than 10 years lifetime will be reduced by 2.7 years. However, the lifetime shortening factor of T2DM will even be stronger for 40 + ?years-old patients at onset. Males will lose 11.6 years of life and 18.6 QUALYs. T2DM among females will reduce life by 14 QUALYs by 22 years. From a statistical point of view, the highest mortality rate will occur in an over 55-years-old European smoking and non-compliant diabetic woman with alcohol abuse living in a rural area with a low level of education and a low socio-economic status. Furthermore, other co-morbidities such as cardiovascular diseases, gout, and depression affect mortality. Additionally, mortality will increase with a BMI over 35 and also with a BMI under 20–25. This refers to the obesity paradox indicating a higher mortality rate among normal weight patients with T2DM compared to overweight patients with T2DM. HbA1c-levels between 6.5 % and 7 % are associated with the lowest impact on mortality.     

Rehabilitation bei Menschen mit Behinderungen

Zeitschrift für Epileptologie - Nach dem 9. Sozialgesetzbuch (SGB) soll eine medizinische Rehabilitation (Reha) die Teilhabeeinschränkungen einer Behinderung mindern und eine...     

The Occurrence of Mycotoxins in Raw Materials and Fish Feeds in Europe and the Potential Effects of Deoxynivalenol (DON) on the Health and Growth of Farmed Fish Species—A Review

The first part of this study evaluates the occurrence of mycotoxin patterns in feedstuffs and fish feeds. Results were extrapolated from a large data pool derived from wheat (n = 857), corn (n = 725), soybean meal (n = 139) and fish feed (n = 44) samples in European countries and based on sample analyses by liquid chromatography/tandem mass spectrometry (LC-MS/MS) in the period between 2012–2019. Deoxynivalenol (DON) was readily present in corn (in 47% of the samples) > wheat (41%) > soybean meal (11%), and in aquafeeds (48%). Co-occurrence of mycotoxins was frequently observed in feedstuffs and aquafeed samples. For example, in corn, multi-mycotoxin occurrence was investigated by Spearman’s correlations and odd ratios, and both showed co-occurrence of DON with its acetylated forms (3-AcDON, 15-AcDON) as well as with zearalenone (ZEN). The second part of this study summarizes the existing knowledge on the effects of DON on farmed fish species and evaluates the risk of DON exposure in fish, based on data from in vivo studies. A meta-analytical approach aimed to estimate to which extent DON affects feed intake and growth performance in fish. Corn was identified as the ingredient with the highest risk of contamination with DON and its acetylated forms, which often cannot be detected by commonly used rapid detection methods in feed mills. Periodical state-of-the-art mycotoxin analyses are essential to detect the full spectrum of mycotoxins in fish feeds aimed to prevent detrimental effects on farmed fish and subsequent economic losses for fish farmers. Because levels below the stated regulatory limits can reduce feed intake and growth performance, our results show that the risk of DON contamination is underestimated in the aquaculture industry.     

The mediating effect of work–life interference on the relationship between work-time control and depressive and musculoskeletal symptoms

Objectives:Evidence shows that work-time control (WTC) affects health but underlying mechanisms are still unclear. Work–life interference (WLI) might be a step on the causal pathway. The present study examined whether WLI mediates effects on mental and physical health and contrasted these to other causal pathways.Methods:Four biennial waves from the Swedish Longitudinal Occupational Survey of Health (SLOSH, N=26 804) were used. Cross-lagged analyses were conducted to estimate if WLI mediated effects from WTC (differentiating between control over daily hours and time off) to subsequent depressive and musculoskeletal symptoms. Other causal directions (reversed mediation, direct and reversed direct effects) and robustness of mediation (by including covariates) were examined.Results:WLI partially mediated the relationship of WTC (control over daily hours/time off) with both health outcomes. Indirect effect estimates were small for depressive symptoms (-0.053 for control over time off and -0.018 for control over daily hours) and very small for musculoskeletal symptoms (-0.007 and -0.003, respectively). While other causal directions were generally weaker than causal mediational pathways, they played a larger role for musculoskeletal compared to depressive symptoms. Estimates relating to control over time off were in general larger than for control over daily hours.Conclusions:Our results suggest that WLI mediates part of the effect from WTC to mental/musculoskeletal symptoms, but small estimates suggest that (i) WTC plays a small but consistent role in effects on health and (ii) particularly regarding musculoskeletal disorders, other causal directions and mediators need to be further examined.     

Modeling of drug-transporter interactions using structural information

Drug-transporter interactions have recently been demonstrated to play an important part in multidrug resistance, drug-drug interactions and drug disposition. Such interactions can occur as inhibition of transport, efflux out of cellular systems or enhanced transport into cellular systems. Modeling efforts are currently being undertaken using both ligand- and transporter-based methods, such as (3D) quantitative structure-activity relationship studies, pharmacophore modeling, homology modeling and molecular dynamics studies. The aim of these efforts is to explain how differences in chemical structures either enhance or weaken interactions with the transporter, or to elucidate how the transporter functions in general. This review summarizes recent modeling efforts in the light of difficulties such as the lack of X-ray crystal structures and the complexity and inconsistency of available experimental data on drug-transporter interactions.