Mutations in the gene encoding KIAA1199 protein,an inner-ear protein expressed in Deiters’ cells and the fibrocytes,as the cause of nonsyndromic hearing loss

We report three possibly disease-causing point mutations in one of the inner-ear-specific genes, KIAA1199. We identified an R187C mutation in one family, an R187H mutation in two unrelated families, and an H783Y mutation in one sporadic case of nonsyndromic hearing loss. In situ hybridization indicated that the murine homolog of KIAA1199 mRNA is expressed specifically in Deiters cells in the organ of Corti at postnatal day zero (Pn) P0 before the onset of hearing, but expression in those cells disappears by day P7. The signal of KIAA1199 was also observed in fibrocytes of the spiral ligament and the spiral limbus through to P21, when the murine cochlea matures. Thus, the gene product may be involved in uptake of potassium ions or trophic factors with a particular role in auditory development. Although the R187C and R187H mutations did not appear to affect subcellular localization of the gene product in vitro, the H783Y mutation did present an unusual cytoplasmic distribution pattern that could underlie the molecular mechanism of hearing impairment. Our data bring attention to a novel candidate for hearing loss and indicate that screening of mutations in inner-ear-specific genes is likely to be an efficient approach to finding genetic elements responsible for deafness.Nucleotide sequence data reported herein are available in the DDBJ/EMBL/GenBank databases; for details, see the electronic eatabase section of this article.     

Postnatal development of somatostatin-containing neurons in the visual cortex of normal and dark-reared rats

Summary The distribution of somatostatin (SRIF)-immunoreactive neurons in the visual cortical areas 17, 18 and 18a of Wistar rats from birth to adulthood was followed in both normal and dark-reared animals. The SRIF neurons show difference in distribution amongst the three cortical areas studied as early as the first postnatal week. Area 17 was distinguished by fewer SRIF cells in the upper layers (I–III), which results in a lower overall density. The SRIF neurons in all areas appeared to increase in numbers up to about 3 weeks and then decline dramatically to adult levels, which were 14–19% of the peak levels. Although this decline was still obvious, it moderated to 25–31% in dark-reared animals. The greatest effect was seen in area 18 where, at 60 days of age, there were twice as many SRIF cells in darkreared as in normal controls. It is suggested that, under conditions of dark rearing, the overall pattern of development of SRIF neurons, being uninfluenced by extrinsic factors, reveals the cells' genetic potential.     

白细胞介素3基因疗法和白细胞介素6基因疗法的联合造血调控作用

研究了成纤维细胞介导的ＩＬ－３基因疗法，ＩＬ－６基因疗法以两者联合后对造血系统的影响。结果发现，单用ＩＬ－基因疗法的小鼠白细胞总数，中性粒细胞，骨髓ＣＦＵ－ＧＭ，ＣＦＵ－ＭＫ等显著上升，但血小板上升程度经，单用ＩＬ－６基因疗法的小鼠血小板，中性粒细胞，骨髓ＣＦＵ－ＧＭ，ＣＦＵ－ＭＫ上晚为显著。     

严重烧伤患者血清IL-18、sFas和sFasL水平的变化规律及其相关性研究

目的 :探讨严重烧伤患者血清IL 18、sFas和sFasL水平间的变化及其与病情的关系。方法 :选择烧伤总面积(TBSA)≥ 30 %的严重烧伤患者 30例 ,其中死亡 3例 ;正常对照组 4 5例。采用ELISA法对不同时相点 (伤后 1、3、5、7、14、2 1、2 8和 35天 )患者血中IL 18、sFas和sFasL水平进行检测。结果 :与正常对照组比较 ,患者血清IL 18、sFas和sFasL水平均呈显著性上升 (P <0 0 1～ 0 0 5 ) ,并分别持续至伤后 2 8,2 1和 2 1天 ;感染组患者血清IL 18、sFas和sFasL水平均显著地高于非感染组 (P <0 0 1～ 0 0 5 ) ;死亡组患者血清IL 18水平下降 ,而sFasL水平则升高。患者血清IL 18和sFasL水平与烧伤面积相关 ;患者血清IL 18、sFas和sFasL之间也呈显著正相关 (P <0 0 1)。结论 :患者血清IL 18、sFas和sFasL水平与烧伤严重程度及伤后感染密切相关 ,在烧伤后免疫功能及凋亡调控中可能起一定作用。     

调控中性白细胞凋亡有关因素的体外实验

目的:用体外实验观察多种因素(包括亚砷酸钠、TNF-α、IL-6及烧伤血清、创伤血清)对中性白细胞(PMN)凋亡的影响,为探索一种新的保护组织免遭继发性损害的方法提供依据。方法:分离纯化人外周血PMN,与亚砷酸钠(Ars)、TNF-α、IL-6及烧伤血清、创伤血清作用后,测定凋亡比例、CD 11 b表达、呼吸爆发、胞质Ca²⁺浓度的改变。结果:Ars浓度与PMN凋亡呈剂量依赖关系,激活的PMN却对Ars失敏;IL-6使PMN凋亡延迟(与24 h对照相比,P＜0.05),抑制CD 11 b表达(与24 h对照相比,P＜0.01);烧伤血清和创伤血清的作用较IL-6更为明显。结论:发现PMN激活后对Ars失敏,其机理不清;CD 11 b表达升高与PMN凋亡增多呈正相关;IL-6、烧伤血清、创伤血清能延迟PMN凋亡,部分恢复PMN的功能。     

Role of CD40 antigen and interleukin-2 in T cell-dependent human B lymphocyte growth

In the present study, we examined the participation of CD40 ligand (L)-CD40 interaction in T cell-dependent B cell responses. To this end, purified B lymphocytes were cultured over irradiated CD4⁺ cloned T cells activated with immobilized anti-CD3 antibody. The anti-CD40 mAb 89 strongly blocked, in a specific fashion, both proliferation and Ig secretion of tonsil B cells. Interestingly, proliferation of surface (s)IgD⁺ B cell was significantly less inhibited by anti-CD40 than that of sIgD^? cells. Preactivated T cells induced B cells to grow and secrete immunoglobulins preferentially in response to IL-2. This contrasts with the CD40 system where B cells are essentially responsive to IL-4 and IL-10 but not to IL-2 alone. Collectively, these data indicate that CD40L-CD40 interaction plays an important role in IL-2-mediated T cell-dependent B cell responses. However, the activation of a subset of sIgD⁺ cells may be independent of this interaction.     

Interleukin-1 dysregulation is an intrinsic defect in macrophages from MRL autoimmune-prone mice

Macrophages (M?) from pre-diseased autoimmune-prone MRL mice (both MRL/+ and MRL/1pr) dramatically underproduce the cytokine interleukin-1 (IL-1) in comparison to M? from a number of normal strains. In this study we show that IL-1 dysregulation by MRL M? is fully expressed at birth, and that this defect does not change with time or the development of disease. We also constructed adult irradiation chimeras (consisting of A/J → MRL and MRL → A/J mice), and show that M? isolated from these chimeras display a pattern of IL-1 production indistinguishable from that of the donor strain controls. Moreover, when we constructed a mixed chimera (A/J + MRL → A/J), the A/J and MRL M? coexisting within the same animal retained their individual patterns of IL-1 production when isolated by negative selection. Taken together, these results provide the first substantive evidence for an intrinsic defect (IL-1 dysregulation) in M? from MRL autoimmune-prone mice.     

Cells with dendritic morphology and bright interleukin-1 alpha staining circulate in the blood of patients with rheumatoid arthritis.

Freshly isolated peripheral blood mononuclear cells (PBMC) from 10 healthy volunteers, 28 patients with rheumatoid arthritis (RA), eight patients with osteoarthritis, and five patients with ankylosing spondylitis were examined for interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) production using monoclonal antibodies and an indirect immunofluorescent method. In freshly isolated PBMC from healthy controls very few cells were stained for either IL-1 type. All 20 RA patients who were not receiving parenteral gold therapy had PBMC staining for IL-1 alpha. In these patients, up to 7.5% of PBMC showed bright IL-1 alpha staining (range 1.2-7.5%). No IL-1 beta staining was seen. These IL-1 alpha-staining cells had a dendritic morphology and the percentage of cells staining correlated well with levels of C-reactive protein, an index of disease activity in these RA patients. Significantly fewer IL-1 alpha-staining cells were present in the peripheral blood of RA patients receiving gold therapy and in the blood of patients with osteoarthritis and ankylosing spondylitis. These IL-1 alpha-containing cells, circulating in the blood of RA patients and correlating with disease activity have not been previously described. These results support the idea that IL-1 alpha plays an important role in the pathogenesis of rheumatoid inflammation.     

Treg-Cell Control of a CXCL5-IL-17 Inflammatory Axis Promotes Hair-Follicle-Stem-Cell Differentiation During Skin-Barrier Repair

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