Causation in evidence‐based medicine: in reply to Strand and Parkkinen

Strand and Parkkinen criticize our dispositional account of causation in evidence‐based medicine for failing to provide a proper epistemology of causal knowledge. In particular, they claim that we do not explain how causal inferences should be drawn. In response, we point out that dispositionalism does indeed have an account of the epistemology of causation, including counterfactual dependence, intervention, prediction and clinical decision. Furthermore, we argue that this is an epistemology that fits better with the known fallibility of even our best‐informed predictions. Predictions are made on the basis that causes dispose or tend towards their effects, rather than guarantee them. The ontology of causation remains a valuable study for, among other reasons, it tells us that powers do not always combine additively. This counts against the monocausality that is tested by randomized controlled trials.     

FS03.2Visual scoring of skin irritation reactions – what are the limits?

We have previously reported that, with suitable training and experience, skin irritation reactions can be graded visually with a high degree of sensitivity and precision. The objective of the work presented is to demonstrate the possibilities and limitations of the grading of skin irritation reactions by subjective visual assessment. In the present work, we have recorded a wide range of relatively minor skin irritation reactions using a high quality digital camera. The skin reactions recorded have then been graded by independent observers according to their appearance on a computer monitor. The results show that very subtle degrees of both erythema and skin dryness can be accurately described by trained skin graders in a reliable and reproducible manner. Examples of the grading scales and sensitivity of scoring will be shown. We conclude that visual scoring, when conducted well, represents a rapid and accurate method for the assessment of minor degrees of skin irritation. The present evidence, taken in combination with previously presented information on bioengineering techniques, leads us to the conclusion that visual assessment is both an adequate and a robust technique, delivering information of the quality necessary for safety assessment of consumer products.     

P06Axillary irritation: methods of assessment

A 37‐year‐old female cashier working in a drugstore developed a dyshidrotic hand eczema in summer 2001. Positive patch test results were obtained against nickel and cobalt. When the new euro coins were introduced in January 2002, the skin symptoms disappeared. Five months later the work‐related hand eczema flared up with massive aggravation. Money‐triggered hand eczema has occasionally been reported. Its low incidence is probably due to the absence of wet or irritant work. Coins are not mentioned in the EU nickel directive as "products intended to come into direct and prolonged contact with the skin". Nestle et al. (Nature, Vol 419, p 132, 2002) found that 1‐ and 2‐ euro coins released more nickel than pure nickel itself in vitro. A factor contributing to this high release of nickel is corrosion due to the bimetallic structure of these coins, which generates a galvanic potential of 30–40 mV in human sweat. A current can enhance galvanic corrosion and thereby cause more nickel release. In a thin irregular electrolyte layer such as a sweat deposit, galvanic corrosion occur primarily near the bimetallic junction owing to the high resistance to lateral current flow in the thin layer.     

Informativeness of a novel multiallelic marker‐set comprising an F8 intron 21 and three tightly linked loci for haemophilia A carriership analysis

Summary. The extraordinary heterogeneous nature of the deleterious mutations in the F8 gene that lead to functional deficiency of clotting factor VIII in haemophilia A makes routine direct mutation profiling difficult. When direct mutation analysis cannot be performed or a causative/candidate mutation is not found, a second‐line approach to track the defective F8 gene within at‐risk families is linkage genetic analysis with, tried‐and‐tested, F8‐intragenic and/or extragenic non‐recombining multiallelic short tandem repeats (STR). Although several typing STR loci within and around F8 have been described, there is need for improving assessment, because the combined informativeness of available assays rarely reaches 100%. Here, we characterized a newly identified 0.28 cM‐resolution marker‐set, consisting of a dinucleotide STR located on F8 intron 21 (F8Int21; [AC]_n) and three extragenic tetranucleotide STR located on GAB3 intron 1 (GAB3Int1; [TAAA]_n) and TMLHE intron 1 (TMLHEInt1.1; [GAAA]_n and TMLHEInt1.3; [ATTC]_n). Heterozygosity rates determined in 100 unrelated females ranged from 0.25 (GAB3Int1) to 0.63 (F8Int21). The set rendered a combined informativeness of 0.91 for at least one marker and 0.60 for a minimum of two loci, with at least one F8‐intragenic. Multiallelic interlocus non‐random association analysis revealed that GAB3Int1 is not in significant gametic disequilibrium (GD) with F8Int21, F8Int9.2, TMLHEInt1.3 or TMLHEInt1.1. Gametic disequilibrium breakdown attests historical recombination between GAB3Int1 and the F8 gene. Through computational analysis of reference assembly sequence data, we note in the GD breakdown region and in the F8 gene a higher than average density of the 13‐mer CCNCCNTNNCCNC consensus motif, commonly associated with recombination hotspots.     

受体相关蛋白不同区段对Heymann肾炎大鼠足细胞瞬时受体电位阳离子通道蛋白6、synaptopodin及podocalyxin表达和分布的影响

目的 观察受体相关蛋白(RAP)不同区段对被动型Heymann肾炎(PHN)大鼠足细胞瞬时受体电位阳离子通道蛋白6(TRPC6)、synaptopodin、podocalyxin表达和分布的影响.方法 给雄性SD大鼠分别注射兔抗RAP全长(RAP-FL组)、氨基端(RAP-N组)和羧基端(RAP-C组)抗血清,建立相应...     

Genome-wide copy number analysis in pediatric glioblastoma multiforme

Glioblastoma (GBM) is a very aggressive and lethal brain tumor with poor prognosis. Despite new treatment strategies, patients’ median survival is still less than 1 year in most cases. Few studies have focused exclusively on this disease in children and most of our understanding of the disease process and its clinical outcome has come from studies on malignant gliomas in childhood, combining children with the diagnosis of GBM with other pediatric patients harboring high grade malignant tumors other than GBM. In this study we investigated, using array-CGH platforms, children (median age of 9 years) affected by GBM (WHO-grade IV). We identified recurrent Copy Number Alterations demonstrating that different chromosome regions are involved, in various combinations. These observations suggest a condition of strong genomic instability. Since cancer is an acquired disease and inherited factors play a significant role, we compared for the first time the constitutional Copy Number Variations with the Copy Number Alterations found in tumor biopsy. We speculate that genes included in the recurrent 9p21.3 and 16p13.3 deletions and 1q32.1-q44 duplication play a crucial role for tumorigenesis and/or progression. In particular we suggest that the A2BP1 gene (16p13.3) is one possible culprit of the disease. Given the rarity of the disease, the poor quality and quantity of bioptic material and the scarcity of data in the literature, our findings may better elucidate the genomic background of these tumors. The recognition of candidate genes underlying this disease could then improve treatment strategies for this devastating tumor.     

Cardiac differentiation and electrophysiology characteristics of bone marrow mesenchymal stem cells

Objective  To review the progress of cardiac differentiation and electrophysiological characteristics of bone marrow mesenchymal stem cells.

Data sources  The databases of PubMed, Springer Link, Science Direct and CNKI were retrieved for papers published from January 2000 to January 2012 with the key words of “bone marrow mesenchymal stem cells, cardiac or heart, electrophysiology or electrophysiological characteristics”.

Study selection  The articles concerned cardiac differentiation and electrophysiological characteristics of bone marrow mesenchymal stem cells were collected. After excluding papers that study purposes are not coincident with this review or contents duplicated, 56 papers were internalized at last.

Results  For the treatment of myocardial infarction and myocardiac disease, the therapeutic effects of transplantation of bone marrow mesenchymal stem cells which have the ability to develop into functional myocardial cells by lots of methods have been proved by many researches. But the arrhythmogenic effect on ventricles after transplantation of bone marrow mesenchymal stem cells derived myocardial cells is still controversial in animal models. Certainly, the low differentiation efficiency and heterogeneous development of electricial function could be the most important risk for proarrhythmia.

Conclusion  Many studies of cardiac differentiation of bone marrow mesenchymal stem cells have paid attention to improve the cardiac differentiation rate, and the electrophysiology characteristics of the differentiated cells should be concerned for the risk for proarrhythmia as well.

     

PTPN22 and myasthenia gravis: replication in an Italian population and meta-analysis of literature data

Polymorphisms in PTPN22 are associated with many autoimmune diseases; while rs2476601 is supposed to play a major role, other experimental data suggest that rs2488457 may be even more important. Results in myasthenia gravis are controversial. In 356 Italian myasthenic patients and 439 controls genotyped for both polymorphisms, we found that rs2476601 was not associated with myasthenia, presence of autoantibodies, thymus pathology, sex or onset age unlike previous studies on other European populations (confirmed by the present meta-analysis). On the other hand, while rs2488457 was not associated with myasthenia or thymus pathology, we found a correlation of rs2488457 with low autoantibody titers and a trend of association with a less severe disease. Both polymorphisms were in tight linkage disequilibrium in controls, not in patients. Our results suggest that SNPs in this gene different from rs2476601, and/or epigenetic interactions, could play a greater role.     

骨形态蛋白2诱导大鼠骨髓间充质干细胞分化为心肌样细胞的实验研究

目的 观察骨形态蛋白2体外诱导骨髓间充质干细胞(BMMSCs)定向分化为心肌样细胞的作用.方法 采用密度梯度离心法分离大鼠BMMSCs,取第4代BMMSCs进行诱导:骨形态蛋白2组(BMP-2,终浓度为10 μg/L),空白对照组.诱导24h后更换常规培养液继续培养4周.倒置相差显微镜观察细胞的形态学变化,免疫荧光染色法鉴定诱导后BMMSCs中心肌特异性肌钙蛋白I(cTnI)的表达,Western Blot检测诱导2周和4周后Cx43以及cTnI的表达量,流式细胞计数法计算心肌样细胞诱导分化率.结果 原代培养的BMMSCs 2周形成集落,呈梭形或星形.传代细胞体积变大,诱导后细胞呈长梭形,呈一致性生长,并出现肌岛样结构.免疫荧光染色结果显示诱导后BMMSCs表达cTnI.Western Blot检测结果提示诱导后Cx43以及cTnI均明显增多,4周组明显高于2周组.流式细胞计数法显示:BMP-2组心肌样细胞诱导率为(17.9±0.8)％.结论 骨形态蛋白2可在体外诱导大鼠BMMSCs定向分化为心肌样细胞,其诱导分化率高.