The molecular basis of classic Ehlers-Danlos syndrome: a comprehensive study of biochemical and molecular findings in 48 unrelated patients

Classic Ehlers-Danlos syndrome (EDS) is characterized by fragile and hyperextensible skin, atrophic scarring, and joint hypermobility. Mutations in the COL5A1 and the COL5A2 gene encoding the alpha1(V) and the alpha2(V) chains, respectively, of type V collagen have been shown to cause the disorder, but it is unknown what proportion of classic EDS patients carries a mutation in these genes. We studied fibroblast cultures from 48 patients with classic EDS by SDS-PAGE for the presence of type V collagen defects. An abnormal collagen pattern was detected in only 2 out of 48 cell lines, making this a poor method for routine diagnostic evaluation. A total of 42 out of 48 (88%) patients were heterozygous for an expressed polymorphic variant in COL5A1. cDNA from 18 (43%) of them expressed only one COL5A1 allele. In 37 patients, the COL5A1/A2 genes were then analyzed by SSCP and conformation sensitive gel electrophoresis (CSGE). A total of 26 patients that were mutation-negative after SSCP/CSGE screening were reanalyzed by dHPLC. In addition, 11 other patients were analyzed by dHPLC only. In total, 17 mutations leading to a premature stop codon and five structural mutations were identified in the COL5A1 and the COL5A2 genes. In three patients with a positive COL5A1 null-allele test, no causal mutation was found. Overall, in 25 out of 48 patients (52%) with classic EDS, an abnormality in type V collagen was confirmed. Variability in severity of the phenotype was observed, but no significant genotype-phenotype correlations emerged. The relatively low mutation detection rate suggests that other genes are involved in classic EDS. We excluded the COL1A1, COL1A2, and DCN gene as major candidate genes for classic EDS, since no causal mutation in these genes was found in a number of patients who tested negative for COL5A1 and COL5A2.     

Treatment of idiopathic inflammatory myositis associated interstitial lung disease: A systematic review and meta-analysis

Objective

Interstitial lung disease (ILD) is the most severe complication of idiopathic inflammatory myositis (IIM), resulting in significant increase in morbidity and mortality and for which the best treatment remains controversial. We conducted a meta-analysis to evaluate the efficacy of therapies used for the management of IIM-related ILD.

Genotypic and phenotypic variability of 22q11.2 microduplications: An institutional experience

Duplications in the 22q11.2 region can cause 22q11.2 duplication syndrome and encompass a variety of phenotypes including developmental delays, facial abnormalities, cardiovascular defects, central nervous system delays, and other congenital abnormalities. However, the contribution of these contiguous duplicated regions to the clinical phenotypes has not been fully elucidated. In this study, we identified nine patients carrying different 22q11.2 microduplications detected by chromosomal microarray. Of these patients, seven pediatric patients presented with various clinical features including two neonate cases died shortly after birth, and two healthy adults. We examined region specific genotype–phenotype associations and found unpredictability associated with 22q11.2 duplications in these nine patients.     

Quantitative study of mesangial injury with proteinuria induced by monoclonal antibody 1-22-3.

Murine MoAb 1-22-3 has already been reported to bind to the mesangial cell surface and to cause transient proteinuria and mesangial morphological changes characterized by mesangiolysis, subsequent mesangial cell proliferation and mesangial matrix increase by a single i.v. injection. In this study, MoAb-induced glomerulopathy was quantitatively analysed. No correlation between the severity of mesangial morphological changes and the degree of proteinuria was detected (r = 0.190). The minimum dose injected to induce abnormal proteinuria was 25 micrograms. This dose corresponded to 1.79 micrograms/2 kidneys 30 min after MoAb injection. The highest average level of proteinuria was observed in rats injected with 500 micrograms of MoAb, and less proteinuria was observed in rats injected with 10.0, 5.0 and 2.0 mg. Although the amounts of kidney-fixing MoAb and the subsequent deposition of rat C3 in the high-dose-injected group were larger than in the 500 micrograms injected group, the numbers of infiltrating inflammatory cells were the same in both groups. No correlations between the degrees of such mediators and proteinuria were observed.     

Cellular immunity in experimental Echinococcus multilocularis infection. II. Sequential and comparative phenotypic study of the periparasitic mononuclear cells in resistant and sensitive mice.

Cellular immune responses have been shown to be associated with differential evolutions of E. multilocularis infection in intermediate hosts. A relationship between course of delayed-type hypersensitivity (DTH) against parasitic antigens and receptivity of murine strains has been demonstrated recently. The aim of this study was to correlate resistance and sensitivity to E. multilocularis infection with the phenotypic patterns of cells within the periparasitic granuloma. Evolution of the ratios, macrophages/T lymphocyte and Ly1/Ly2 T lymphocytes, was associated with the receptivity of the strains. Persistence of numerous L3T4 + T lymphocytes and low numbers of macrophages and Ly2 + T lymphocytes were observed in the 'resistant' C57BL.10 mice. Comparison of the results with course of the DTH against E. multilocularis antigens showed that the particular phenotypic pattern observed in resistant mice was associated with a particular profile of DTH after infection. These results and similar observations in human alveolar echinococcosis suggest that cell composition of the periparasitic granuloma might be of crucial importance in controlling the spontaneous development of E. multilocularis larvae in the intermediate host.     

重症SIRS患者的正常甲状腺病态综合征

目的：探索全身炎症反应综合征（SIRS）患者的正常甲状腺病态综合征（ESS）的发生规律。 方法： 测定50例SIRS病人的总三碘甲状腺原氨酸（TT3）、总四碘甲状腺原氨酸（TT4）、游离三碘甲状腺原氨酸（FT3）、游离四碘甲状腺原氨酸（FT4）、促甲状腺素（TSH），并根据是否多脏器功能障碍综合征（MODS）分组。计算急性生理和慢性健康评估Ⅱ（APACHEⅡ）评分，记录病人转归以及从发病到检测的时间（患病时间）。 结果： TT3或FT3降低的45例。TT3与APACHEⅡ评分呈对数负相关（r＝－0.330，P<0.05）,TT3/TT4与患病时间呈对数负相关（r=－0.316, P<0.05）。MODS组的TT3、TT4、FT3水平显著低于无MODS组（P<0.05）。 结论： SIRS和MODS病人发生低T3、低T4可能性大，反映炎症反应对甲状腺轴的影响，随着病情加重、患病时间延长，影响进一步深化。     

Expression of luminal and basal cytokeratins in human breast carcinoma

We have examined basal and luminal cell cytokeratin expression in 1944 cases of invasive breast carcinoma, using tissue microarray (TMA) technology, to determine the frequency of expression of each cytokeratin subtype, their relationships and prognostic relevance, if any. Expression was determined by immunocytochemistry staining using antibodies to the luminal cytokeratins (CKs) 7/8, 18 and 19 and the basal markers CK 5/6 and CK 14. Additionally, assessment of alpha-smooth muscle actin (SMA) and oestrogen receptor status (ER) was performed. The vast majority of the cases showed positivity for CK 7/8, 18 and 19 indicating a differentiated glandular phenotype, a finding associated with good prognosis, ER positivity and older patient age. In contrast, basal marker expression was significantly related to poor prognosis, ER negativity and younger patient age. Multivariate analysis showed that CK 5/6 was an independent indicator for relapse free interval. We were able to subgroup the cases into four distinct phenotype categories (pure luminal, mixed luminal/basal, pure basal and null), which had significant differences in relation to the biological features and the clinical course of the disease. Tumours classified as expressing a basal phenotype (the combined luminal plus basal and the pure basal) were in a poor prognostic subgroup, typically ER negative in most cases. These findings provide further evidence that breast cancer has distinct differentiation subclasses that have both biological and clinical relevance.     

Triple A syndrome: genotype-phenotype assessment

The triple A or Allgrove syndrome is an autosomal-recessive disease (MIM*231550) characterized by the triad of achalasia, alacrima and adrenocorticotropic hormone (ACTH)-resistant adrenal insufficiency. Associated features of the syndrome are neurological and dermatological abnormalities. Until the discovery of the AAAS gene as the responsible gene in triple A syndrome, the diagnosis was based on characteristic clinical features. Here we present the clinical and molecular genetic data which demonstrated the marked phenotypic variability in three unrelated patients with triple A syndrome. The final diagnosis of triple A syndrome was confirmed by molecular analysis. In one patient with isolated achalasia, the diagnosis of triple A syndrome could only be made on the basis of the molecular genetic analysis of the AAAS gene. We therefore suggest that the diagnosis of triple A syndrome should be considered in patients who exhibit only one or two of the main symptoms (i.e. alacrima, achalasia or adrenal insufficiency). These patients require careful neurological investigation, and mutation analysis of the AAAS gene should be performed.     

小胶质细胞极化介导炎症反应在脊髓损伤中的作用

背景:小胶质细胞极化参与脊髓损伤后的炎症反应,并在其中发挥关键作用。相关研究表明,有效诱导小胶质细胞从M1促炎表型向M2抗炎表型极化,可以减轻脊髓损伤后的炎症反应,促进组织的修复再生和神经功能的恢复。目的:文章对小胶质细胞的功能和极化、小胶质细胞极化对脊髓损伤的影响及其潜在调控策略以及脊髓损伤后炎症反应进行综述。方法:检索PubMed、Web of Science和中国知网数据库,英文检索词为“microglia,polarization,spinal cord injury,inflammation”,中文检索词为“小胶质细胞、极化、脊髓损伤、炎症”,按纳入和排除标准共纳入80篇文献进行总结。结果与结论:①由小胶质细胞介导的稳定而持续的炎症反应,对脊髓损伤的预后至关重要。②在生理条件下,小胶质细胞处于M0静止表型,但在脊髓损伤后,小胶质细胞活化,进而极化成M1促炎表型,导致神经组织修复能力降低和出现持续性神经炎症。③在脊髓损伤的炎症反应过程中,调控小胶质细胞向M2表型极化或至少向M2表型倾斜,有利于抑制氧化应激反应、调节突触重塑、促进轴突再生和血管生成,是一种有效的调控策略。④截止到目前的研究表明,间充质干细胞、外泌体、临床药物、天然产物、miRNAs和靶点分子可调控小胶质细胞在M1和M2表型之间的转换,这为脊髓损伤后神经组织的修复提供了一种新的思路,未来需进一步研究小胶质细胞在脊髓损伤过程中调控极化的详细机制。