Shear‐induced unfolding activates von Willebrand factor A2 domain for proteolysis

Summary. Background: To avoid pathological platelet aggregation by von Willebrand factor (VWF), VWF multimers are regulated in size and reactivity for adhesion by ADAMTS13‐mediated proteolysis in a shear flow dependent manner. Objective and methods: We examined whether tensile stress in VWF under shear flow activates the VWF A2 domain for cleavage by ADAMTS13 using molecular dynamics simulations. We generated a full length mutant VWF featuring a homologous disulfide bond in A2 (N1493C and C1670S), in an attempt to lock A2 against unfolding. Results: We indeed observed stepwise unfolding of A2 and exposure of its deeply buried ADAMTS13 cleavage site. Interestingly, disulfide bonds in the adjacent and highly homologous VWF A1 and A3 domains obstruct their mechanical unfolding. We find this mutant A2 (N1493C and C1670S) to feature ADAMTS13‐resistant behavior in vitro. Conclusions: Our results yield molecular‐detail evidence for the force‐sensing function of VWF A2, by revealing how tension in VWF due to shear flow selectively exposes the A2 proteolysis site to ADAMTS13 for cleavage while keeping the folded remainder of A2 intact and functional. We find the unconventional ‘knotted’ Rossmann fold of A2 to be the key to this mechanical response, tailored for regulating VWF size and activity. Based on our model we discuss the pathomechanism of some natural mutations in the VWF A2 domain that significantly increase the cleavage by ADAMTS13 without shearing or chemical denaturation, and provide with the cleavage‐activated A2 conformation a structural basis for the design of inhibitors for VWF type 2 diseases.     

祛白酊质量标准的实验研究

目的：建立祛白酊的质量标准。方法：采用薄层色谱法鉴别其中的补骨脂素,异补骨脂素,栀子苷;导数分光光度法测定其中醋酸氢化可的松的含量。结果;薄层色谱鉴别方法有良好的重现性,专属性;醋酸氢化可的松在11－19ug.ml^-1呈良好的线性关系（r=0.9996)其含量测定平均回收率100．9％,RSD＝0．9％（n=5)。结论：制定的质量标准可以保证祛白酊的质量。     

Complex orofacial movements and the disappearance of cerebellar mutism: report of five cases

A syndrome of mutism and subsequent dysarthria occurs frequently in children after resection of a cerebellar tumour. The role of orofacial and speech motor control in this syndrome has not been studied systematically. We examined simple and complex orofacial movements during the mute phase and shortly after the resumption of speech in five children with mutism and subsequent dysarthria. The recovery of complex orofacial movements coincided with the disappearance of the mutism     

Interleukin-5 is at 5q31 and is deleted in the 5q- syndrome

Human interleukin-5 (IL-5) is a selective eosinophilopoietic and eosinophil-activating growth hormone. By in situ hybridization this gene is mapped to chromosome 5q23.3 to 5q32. It is shown to be deleted in two patients with the 5q-syndrome and in one patient previously diagnosed with myelodysplasia whose condition had progressed to acute myeloblastic leukemia. The clustering of other genes involved in hematopoiesis (IL-3, granulocyte-macrophage colony-stimulating factor, feline sarcoma viral oncogene homolog, colony-stimulating factor 1) to the same region as IL-5 suggests a nonrandom localization and raises interesting questions concerning the evolution and regulation of these genes.     

CQI-2 — a new measure of holistic interpersonal care in primary care consultations

BACKGROUND: The Consultation Quality Index (CQI) is a holistic quality marker for GPs based on patient enablement, continuity of the care and consultation length. AIM: To evaluate the CQI-2, a new version of the CQI incorporating a process measure of GP empathy (the Consultation and Relational Empathy Measure). DESIGN OF STUDY: Cross-sectional questionnaire study. SETTING: General practice in the west of Scotland. METHOD: Empathy, enablement, continuity, and consultation length were measured in 3044 consultations involving 26 GPs in 26 different practices in the west of Scotland. CQI-2 scores were calculated and correlated with additional data on GPs' and patients' attitudes. Comparisons were also made with the UK-wide data from which the original CQI had been calculated. RESULTS: CQI-2 scores were independent of deprivation, access, demographics, and case-mix. GPs with lower CQI-2 scores valued empathy and longer consultations less than these GPs with higher CQI-2 scores. 'Below average CQI-2' GPs (those in the bottom 25%) also felt less valued by patients and colleagues. Patients' showed less confidence in and gained less satisfaction from these doctors. Data ranges from the study were comparable with the UK data ranges used to construct the original CQI. CONCLUSIONS: The CQI-2 is a new measure of holistic interpersonal care. In a small but representative sample of GPs it appears to differentiate between below and above average doctors. CQI-2 scores may reflect important aspects of morale, core values and patient-centred care. There may be potential for its use as part of professional development and as a component of the general medical services contract.     

Large umbilical cord: a normal finding in some fetuses

We report two cases in which the umbilical cords of fetuses were large on prenatal ultrasound scans. The pregnancies terminated uneventfully, however, and the babies were healthy at birth and on follow-up visits. We discuss the various etiologies of a large umbilical cord and conclude that, although a large cord may suggest the presence of an underlying abnormality, in some instances it may represent a normal finding.     

An analysis of fetal hemoglobin variation in sickle cell disease: the relative contributions of the X-linked factor, beta-globin haplotypes, alpha-globin gene number, gender, and age

Five factors have been shown to influence the 20-fold variation of fetal hemoglobin (Hb F) levels in sickle cell anemia (SS): age, sex, the alpha-globin gene number, beta-globin haplotypes, and an X-linked locus that regulates the production of Hb F-containing erythrocytes (F cells), ie, the F-cell production (FCP) locus. To determine the relative importance of these factors, we studied 257 Jamaican SS subjects from a Cohort group identified by newborn screening and from a Sib Pair study. Linear regression analyses showed that each variable, when analyzed alone, had a significant association with Hb F levels (P < .05). Multiple regression analysis, including all variables, showed that the FCP locus is the strongest predictor, accounting for 40% of Hb F variation. beta-Globin haplotypes, alpha-globin genes, and age accounted for less than 10% of the variation. The association between the beta-globin haplotypes and Hb F levels becomes apparent if the influence of the FCP locus is removed by analyzing only individuals with the same FCP phenotype. Thus, the FCP locus is the most important factor identified to date in determining Hb F levels. The variation within each FCP phenotype is modulated by factors associated with the three common beta-globin haplotypes and other as yet unidentified factor(s).