A homozygous MITF mutation leads to familial Waardenburg syndrome type 4

Waardenburg syndrome (WS) is a genetic disorder characterized by hearing loss and pigmentary abnormalities with variable penetrance. Though heterozygous mutations in MITF are a major cause for Waardenburg syndrome type 2 (WS2), homozygous mutations in this gene and the associated phenotype have been rarely characterized. In this study, we identified a novel p.R223H mutation in MITF in a Chinese Han family with variable WS features. Both parents carried a heterozygous p.R223H mutation. They had normal hearing, and premature greying of the hair is their only pigmentary abnormality. In contrast, their two children both carried a homozygous p.R223H mutation and had classic WS features including profound hearing loss, heterochromia irides and marked pigmentary abnormalities in hair and skin. Interestingly, the two affected children also have persistent chronic constipation since the neonatal period, symptoms suggestive of Waardenburg syndrome type 4 (WS4). Our study revealed a likely association between homozygous mutations in MITF and WS4, which implies a dosage effect for the underlying pathogenesis mechanism.     

Development of CD4+ T cell lines that suppress an antigen-specific immune response in vivo

It has been suggested for many years that the regulation of the immune system for the maintenance of peripheral tolerance may involve regulatory/suppressor T cells. In the past few years, several investigators have demonstrated that these cells can be generated in vitro. It has also been shown that they can inhibit the progression of various autoimmune disease models when infused into susceptible mice. We have generated two murine T cell lines in the presence of KLH-specific T cell clones from BALB/c or DBA2 mice. The lines are characterized by a low proliferative response to mitogens, the capacity to secrete high amounts of IL-10 and TGF-beta, and small amounts of IFN-gamma. Interestingly, these cells are unable to produce IL-2, IL-4 or IL-5. The study of the surface phenotype of both lines revealed CD4+, CD25high, CD44low and CTLA-4- cells. When injected intravenously in (CBy.D2) F1 mice, these cells were able to inhibit 50-100% of the TNP-specific antibody production, when the hapten was coupled to KLH. In the present study we offer another evidence for the existence of regulatory T cells in the T lymphocyte repertoire, suggesting that they can also regulate immune responses to foreign antigens. Furthermore, we demonstrate an alternative pathway to generate these cells different from approaches used thus far.     

Cord blood contains cells secreting antibodies to nervous system components.

Umbilical cord blood of newborns and peripheral blood of healthy adults were investigated by an immunospot assay for cells secreting IgG, IgA and IgM antibodies against myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG) which represent putative antigens for an autoimmune attack in multiple sclerosis (MS) and against acetylcholine receptor (AChR) which is considered an important autoantigen in myasthenia gravis. Cells secreting antibodies against one or more of these autoantigens were detected in 18 out of 24 newborns, and in eight out of 20 adults. Eight of the cord blood samples contained cells secreting antibodies of IgG, IgA and/or IgM isotypes to one antigen, five to two antigens, two to three antigens, two to four antigens, and one to five antigens. Most prominent were anti-MBP IgG antibody secreting cells which were detected in 13 newborns at a mean number of 1/20,000 cord blood cells, and in six adults at a mean number of 1/10(5) peripheral blood cells. Anti-AChR IgG antibody secreting cells were detected in four out of 12 newborns versus four out of 14 peripheral blood specimens, at mean values of 1/10(5) cells in both instances. Cells secreting autoantibodies of IgA and IgM isotypes were less frequent both in cord blood and peripheral blood. The occurrence of nervous tissue autoantibody secreting cells in newborns must be related to a possible primary role of such autoantibodies in MS and myasthenia gravis.     

Capsaicin induced release of multiple tachykinins (substance P, neurokinin A and eledoisin-like material) from guinea-pig spinal cord and ureter

The release of tachykinins from isolated slice preparations of the guinea-pig spinal cord and ureter was studied in vitro. Capsaicin (10 microM) caused release of substance P, neurokinin A and an eledoisin-like component from both the spinal cord and ureter. The release of tachykinins induced by capsaicin or potassium (60 mM) was calcium dependent. No detectable release of neurokinin B or neuropeptide K, an N-terminally extended form of neurokinin A, was induced by capsaicin. No detectable release of tachykinins could be demonstrated after exposure to agents which are known to activate C-fibre afferents, such as histamine, bradykinin, serotonin, prostaglandins E1, E2 or acetylcholine. Protein extravasation in the ureter, as determined by the Evans Blue extravasation technique was used as a functional correlate to the tachykinin release. Protein extravasation was induced in vivo by local intraluminal injections of capsaicin at several hundred-fold lower concentrations than those required to induce a detectable release of tachykinins in vitro. The difference may, however, partly depend on the experimental conditions and the detection limit of the tachykinin assay used. The protein extravasation response to capsaicin was absent after systemic capsaicin pretreatment, which causes a marked depletion of tachykinins in the ureter. In conclusion, capsaicin evokes release of several tachykinins from both central and peripheral endings of primary afferent neurons. The peptides released from sensory nerves in the periphery may induce effects such as protein extravasation and smooth muscle contraction.     

老年SH患者甲状腺激素水平与冠心病相关性探讨

目的:探讨老年亚临床甲状腺功能减退症血清甲状腺激素与冠心病病变程度的相关性.方法:70例冠心病患者根据冠脉造影结果分为造影正常组30例,单支病变组15例,多支病变组35例,采用放射免疫分析检测TT3,TT4,FT3,FT4,TSH水平.结果:多支病变组的亚临床甲减发生率明显高于造影正常对照组和单支病变组(P＜0.05),亚临床甲减与冠心病多支病变具有相关性(OR=2.20). 结论:亚临床甲状腺功能减退症是冠心病多支病变的危险因素之一.     

Comparison of deltaFVC between patients with allergic rhinitis with airway hypersensitivity and patients with mild asthma.

BACKGROUND: In asthmatic individuals, airway sensitivity and maximal airway response are increased. Airway sensitivity is usually evaluated by measuring the provocation concentration of inhaled methacholine or histamine that causes a decrease in forced expiratory volume in 1 second of 20% (PC20). The percentage decrease in forced vital capacity at the PC20 (deltaFVC) has been proposed as a surrogate marker for maximal airway response. Individuals with allergic rhinitis and no clinical evidence of asthma frequently exhibit airway hypersensitivity. OBJECTIVE: To compare the deltaFVC between patients with allergic rhinitis and mild asthmatic patients with a similar degree of airway hypersensitivity. METHODS: A retrospective analysis of methacholine challenge test data from 72 children with allergic rhinitis and airway hypersensitivity (methacholine PC20 < 16 mg/mL) (rhinitis group) and from 72 children with mild atopic asthma matched to the rhinitis group regarding the methacholine PC20 (asthma group). The deltaFVC was calculated on the concentration-response curve to methacholine. RESULTS: The mean +/- SD deltaFVC was significantly lower in the rhinitis group (15.0% +/- 3.6%) vs the asthma group (17.4% +/- 5.3%) (P = .002). There was no significant correlation between the deltaFVC and PC20 in the rhinitis (r = -0.101; P = .41) and asthma (r = -0.023; P = .85) groups when 2 patients with PC20 less than 1 mg/mL were excluded from each group. CONCLUSIONS: Patients with allergic rhinitis and airway hypersensitivity had a significantly lower deltaFVC than methacholine PC20-matched mild asthmatic patients, suggesting that the level of maximal airway response in patients with allergic rhinitis is lower than that in mild asthmatic patients with a similar degree of airway hypersensitivity.     

P物质和P物质受体在小鼠胚胎发育期脑内的表达

目的研究小鼠胚脑发育期间P物质（SP）和P物质受体（SPR）的表达。方法分别取孕11、13、15、17和19d的小鼠胚脑和新生鼠脑。采用SP和SPR酶标免疫组织化学染色观察SP和SPR表达的变化。结果SP自小鼠胚胎11d开始出现少量表达，并一直持续到出生后，主要出现在发育过程中的新纹状体等部位；SPR与SP同时出现并持续到出生后，主要出现在发育过程中的延髓中缝等部位。结论SP和SPR在小鼠发育期间的表达提示SP可能参与中枢神经系统神经元形成和成熟调控。     

Effect of anti-inflammatory medication on monocyte response to titanium particles

Cytokines produced by macrophages in the periprosthetic membranes surrounding joint replacements have been implicated as causal agents in osteolysis and prosthetic loosening. The present study characterizes the response of human peripheral blood monocytes to titanium particles. Monocytes were obtained from donated blood and were cultured in the presence of different-sized titanium particles. Exposure to titanium-aluminum-vanadium particles significantly changed the release of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 (IL-1), whereas there was no significant effect on the release of prostaglandin E(2) (PGE(2)). When monocytes were cultured with particles, the titanium alloy particles induced significantly more release of TNF-alpha and less IL-1 secretion. Ciprofloxacin inhibited production of TNF-alpha, IL-6, IL-1, and PGE(2) in human monocytes exposed to titanium particles. In contrast to ciprofloxacin, indomethacin was not a potent inhibitor of TNF-alpha production but potentiated IL-6 production in titanium-stimulated monocytes. Indomethacin had no effect on the production of IL-1 and was a potent inhibitor of PGE(2) production in titanium-stimulated monocytes. Pentoxifylline had an inhibitor effect on TNF-alpha production in titanium-stimulated monocytes. Pentoxifylline potentiated IL-6 and IL-1 production in monocytes exposed to titanium particles and had a biphasic effect on the PGE(2) production. The results of this study support our hypothesis that human monocytes release bone resorption mediators after in vitro exposure to TiAlV alloy particles. The results also demonstrate the differences of bone-resorbing mediators in response to different wear particle size. The pharmacologic agents (ciprofloxacin, pentoxifylline, and indomethacin) that can modulate the release of bone resorbing mediators such as PGE(2), TNF-alpha, IL-1, and IL-6 release from human monocytes. The results help to elucidate the differences in cellular response to wear particles but may not be directly transposed to the human situation.     

The role of intrahepatic lymphocytes in mediating protective immunity induced by attenuated Plasmodium berghei sporozoites

Summary: Exposure to irradiated Plasmodium sporozoites (g‐spz) results in protection against malaria. Like infectious spz, g‐spz colonize hepatocytes to undergo maturation. Disruption of liver stage development prevents the generation of protection, which appears, therefore, to depend on liver stage antigens. Although some mechanisms of protection have been identified, they do not include a role for intrahepatic mononuclear cells (IHMC). We demonstrated that P. berghei g‐spz‐immune murine IHMC adoptively transfer protection to naive recipients. Characterization of intrahepatic CD4+ T cells revealed an immediate, albeit transient, response to g‐spz, while the response of CD8+ T cells is delayed until acquisition of protection. It is presumed that activated CD8+ T cells home to the liver to die; g‐spz‐induced CD8+CD45RBloCD44hi T cells, however, persist in the liver, but not the spleen, during protracted protection. The association between CD8+CD45RBloCD44hi T cells and protection has been verified using MHC class I and CD1 knockout mice and mice with disrupted liver stage parasites. Based on kinetic studies, we propose that interferon‐g, presumably released by intrahepatic effector CD8+ T cells, mediates protection; the persistence of CD8+ T cells is, in turn, linked to Plasmodium antigen depots and cytokines released by CD4+ T cells and/or NK T cells.