Assessment of fetal behavior and general movements by four-dimensional sonography

The aim of this paper was to review the clinical applications of four-dimensional ultrasonography in the assessment of fetal behavior. With the use of a computerized database, articles on three-dimensional ultrasonography were reviewed. Several applications of dynamic three-dimensional ultrasonography have been reported, including imaging of fetal movements, facial expression and fetal hand movements. The importance of the assessment of fetal behavior by four-dimensional sonography is stressed. Four-dimensional sonography seems to be a useful imaging tool for clinical problem solving in perinatology, especially in observing the development of the central nervous system in utero.     

Vitiligo in children and adolescents: association with thyroid dysfunction

Background The clinical characteristics of vitiligo in children and adolescents with an emphasis on thyroid dysfunction have only been reported in a few studies. Objective The purpose of this study was to examine the characteristics of children and adolescents with vitiligo and compare the incidence of thyroid dysfunction between them and controls without vitiligo at the same age. Methods A retrospective analysis of 324 Korean children and adolescents with vitiligo was performed. The results of thyroid function screening tests in them (n = 254) were compared with controls (n = 122). Results Of the total 324 children and adolescents with vitiligo, vitiligo vulgaris was the most common type (42.3%) and the most commonly involved site was the face (54.6%). A total of 15 of 254 (5.9%) patients screened for thyroid function were diagnosed with thyroid disease (four had Hashimoto’s thyroiditis; two, Graves’ disease; seven, subclinical hypothyroidism; and two, subclinical hyperthyroidism). None of the 50 patients with segmental vitiligo showed any thyroid dysfunction (P = 0.047). There was no significant difference in the incidence of thyroid disease between children and adolescents with vitiligo and the control group, in which seven of 122 (5.7%) showed thyroid dysfunction. Conclusion In this study, we demonstrated the characteristics of children and adolescents with vitiligo and also observed no significant difference in the incidence of thyroid disease between children and adolescents with vitiligo and the control group.     

国人缺血性心血管病发病危险的评估方法及简易评估工具的开发研究

目的 研究开发适合我国人群疾病特点且方便临床使用的心血管病发病危险度评估方法和评估工具。方法 依据中美心肺血管疾病流行病学合作研究队列随访资料，采用Cox比例风险模型拟合最优预测模型，并校正人群危险因素长期变化趋势的影响，采用独立人群回代检验和计算ROC曲线下面积来检验模型的预测能力。进一步建立简易预测模型，并据此制定适合我国人群的心血管病综合危险度简易评估工具。结果 中美心肺血管疾病流行病学合作研究1983～1984年基线调查年龄35～59岁，剔除基线患有冠心病、脑卒中及主要危险因素资料不全者后男女共计9903人，截止到2000年平均随访15．1年，共发生冠心病事件105例、缺血性脑卒中266例、缺血性心血管病360例。基线年龄、性别、血压、血清总胆固醇、体重指数、吸烟和糖尿病与冠心病、缺血性脑卒中和缺血性心血管病(ischemic cardiovascular diseases，ICVD)事件发病有互相独立的显著关联，且联系的方向和规律一致。据此建立的分性别ICVD事件10年发病危险预测模型，经过校正人群危险因素的长期变化趋势，证明能够很好地用于1992～1994年新建立队列的ICVD发病预测，其ROC曲线下面积(AUC)男性最优模型为0．799，女性最优模型为0．844。简易模型的AUC与最优模型几乎相同。结论 初步开发的ICVD事件10年发病危险预测模型和简易评估工具具有令人满意的预测能力，也能够较好地反映国人发生心血管病的综合危险。     

Granulocyte colony-stimulating factor administration to healthy volunteers: analysis of the immediate activating effects on circulating neutrophils

In four healthy volunteers, we analyzed in detail the immediate in vivo effects on circulating neutrophils of subcutaneous administration of 300 micrograms of granulocyte colony-stimulating factor (G-CSF). Neutrophil activation was assessed by measurement of degranulation. Mobilization of secretory vesicles was shown by a decrease in leukocyte alkaline phosphatase content of the circulating neutrophils. Furthermore, shortly postinjection, Fc gamma RIII was found to be upregulated from an intracellular pool that we identified by immunoelectron microscopy as secretory vesicles. Intravascular release of specific granules was shown by increased plasma levels of lactoferrin and by upregulation of the expression of CD66b and CD11b on circulating neutrophils. Moreover, measurement of fourfold elevated plasma levels of elastase, bound to its physiologic inhibitor alpha 1- antitrypsin, indicated mobilization of azurophil granules. However, no expression of CD63, a marker of azurophil granules, was observed on circulating neutrophils. G-CSF--induced mobilization of secretory vesicles and specific granules could be mimicked in whole blood cultures in vitro, in contrast to release of azurophil granules. Therefore, we postulate that the most activated neutrophils leave the circulation, as observed shortly postinjection, and undergo subsequent stimulation in the endothelial microenvironment, resulting in mobilization of azurophil granules. Our data demonstrate that G-CSF should be regarded as a potent immediate activator of neutrophils in vivo.     

Expanding the mutational spectrum of LZTR1 in schwannomatosis

Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. Constitutional inactivating variants in two genes, SMARCB1 and, very recently, LZTR1, have been reported. We performed exome sequencing of 13 schwannomatosis patients from 11 families without SMARCB1 deleterious variants. We identified four individuals with heterozygous loss-of-function variants in LZTR1. Sequencing of the germline of 60 additional patients identified 18 additional heterozygous variants in LZTR1. We identified LZTR1 variants in 43% and 30% of familial (three of the seven families) and sporadic patients, respectively. In addition, we tested LZTR1 protein immunostaining in 22 tumors from nine unrelated patients with and without LZTR1 deleterious variants. Tumors from individuals with LZTR1 variants lost the protein expression in at least a subset of tumor cells, consistent with a tumor suppressor mechanism. In conclusion, our study demonstrates that molecular analysis of LZTR1 may contribute to the molecular characterization of schwannomatosis patients, in addition to NF2 mutational analysis and the detection of chromosome 22 losses in tumor tissue. It will be especially useful in differentiating schwannomatosis from mosaic Neurofibromatosis type 2 (NF2). However, the role of LZTR1 in the pathogenesis of schwannomatosis needs further elucidation.     

Anti-factor VIII antibodies of hemophiliac patients are frequently directed towards nonfunctional determinants and do not exhibit isotypic restriction

A significant proportion of hemophilia A patients receiving transfusions of factor VIII (FVIII) develop a specific antibody response towards FVIII. These antibodies are usually detected by assays in which they inhibit the function of the molecule, such as the Bethesda clotting test. We have prepared anti-FVIII antibodies by specific immunoadsorption from the plasma of four hemophiliacs with stable inhibitor levels. The isotypic distribution of such antibodies was determined and their capacity to bind to insolubilized FVIII was compared with their inhibitory activity in two functional assays, namely, the Bethesda assay and a chromogenic assay. In addition, the FVIII epitope specificity was determined by competition with monoclonal antibodies for the binding to insolubilized FVIII. We show here that (1) anti-FVIII antibodies are not isotypically restricted; thus, a significant proportion of specific IgG2 was found; (2) antibodies are frequently directed towards epitopes of FVIII that are not directly involved in the function of the molecule and therefore escape detection in the Bethesda method or chromogenic assay; and (3) each patient shows a unique pattern of FVIII epitope recognition. We conclude that evaluation of anti-FVIII antibodies by a functional method does not provide an accurate evaluation of the specific antibody response. These findings have important implications for the comparison of the immunogenicity of FVIII molecules produced by different technologies and for the development of methods to control anti-FVIII antibody production.