Clustering of autoimmune disease in parents of siblings from the Type 1 diabetes Warren repository.

AIMS: Autoimmune disorders co-exist in the same individuals and in families, implying a shared aetiology. The aim of this study was to compare the prevalence of the common autoimmune diseases in the parents of siblings from the Type 1 diabetes Warren repository with the general population. METHODS: Between 1989 and 1996, 505 British families with at least two siblings affected by Type 1 diabetes were recruited. Clinical information was collected regarding the presence of autoimmune disease in the parents and the prevalence of disease in the parents was compared with that expected in the general population. RESULTS: The prevalence of autoimmune disease in the parents was significantly higher in the repository compared with that expected in the general population [P-value = 1.98 x 10(-5) (female), P-value = 1.1 x 10(-8) (male)]. Type 1 diabetes was recorded in 63/1010 (6.2%) parents with a marked paternal preponderance (9.5 vs. 3%P = 0.002). Other autoimmune diseases affected 27% of parents with diabetes and 13.2% of parents without diabetes (P < 0.01). CONCLUSION: These data confirm the importance of family history as a significant risk factor for the development of Type 1 diabetes and support the hypothesis that the common autoimmune diseases share at least some aetiological mechanisms.     

Gastro-duodenal digestion products of the major peanut allergen Ara h 1 retain an allergenic potential

BACKGROUND: The process of gastro-duodenal digestion may play a role in determining the allergenic properties of food proteins. The sensitizing and allergenic potential of digestion products of highly degraded allergens, such as the major peanut allergen Ara h 1, is currently under debate. We evaluated the effect of in vitro gastro-duodenal digestion of Ara h 1 on T cell reactivity and basophil histamine release. METHODS: An in vitro model of gastro-duodenal digestion was used to investigate changes in the allergenic properties of Ara h 1 using in vitro assays monitoring T cell reactivity (proliferation, cytokine production) and histamine release of basophils from peanut allergic individuals. The digestion process was monitored using an SDS-PAGE gel. RESULTS: In vitro gastric digestion led to rapid degradation of Ara h 1 into small fragments M(r) L5600. Gastric digestion did not affect the ability of Ara h 1 to stimulate cellular proliferation. Gastro-duodenal digestion significantly reduced its ability to stimulate clonal expansion (P<0,05; Wilxocon's signed rank test). The Th-2 type cytokine polarization of T cells from peanut allergic donors (IFN-gamma/IL-13 ratio and IFN-gamma/IL-4 ratio of CFSE(low) CD4(+) T cells) remained unchanged regardless of the level of digestion. Histamine release of basophils from peanut allergic individuals was induced to the same extent by native Ara h 1 and its digestion products. CONCLUSION: Gastro-duodenal digestion fragments of Ara h 1 retain T cell stimulatory and IgE-binding and cross-linking properties of the intact protein.     

原发性肝癌患者肝切除术前、后免疫细胞表型分析

目的研究原发性肝癌(PrimaryLiverCarcinoma,PLC)患者肝切除术前、后免疫细胞表型的变化。方法采用直接免疫荧光标记,流量血细胞计数法(FlowCytometry,FCM)检测方法,动态观察120例PLC患者肝切除术前后外周血T淋巴细胞亚群、NK细胞和HLA鄄DR含量变化。结果肝切除术前肝功能Child鄄PughB级、OGTTL型和术前施行肝动脉栓塞化疗患者外周血CD8+T细胞含量明显低于正常人组,CD4+/CD8+比值则较高(P<0郾05)。全部肝癌患者肝切除术前、后CD3+CD4+T细胞和NK细胞(CD3-CD16+CD56+)含量无明显差异。术后第1天、第3天、第7天和第2周外周血淋巴细胞CD3+CD8+含量明显低于肝切除术前和术后第3周(P<0.01);而CD4+/CD8+比值则显著高于肝切除术前和术后第3周(P<0郾01)。结论PLC合并肝硬变肝储备功能不足、术前肝动脉栓塞化疗和肝切除术可导致机体细胞免疫功能低下,PLC患者肝切除术前行肝动脉栓塞化疗的价值有待深入研究。     

Investigation of the negative chronotropic action of SK&F 86466 in the pithed normotensive rat

SK&F 86466, 6-chloro-3-methyl-2,3,4,5-tetrahydro-1-H-3-benzazepine, is a potent and selective antagonist of the α₂-adrenoceptor in vitro. This compound produced a small pressor response accompanied by a marked bradycardia when administered i.v. to the pithed normotensive rat. The pressor response was not affected by reserpine treatment, pretreatment with α- or β-adrenoceptor antagonists, atropine, or hexamethonium. The bradycardia was markedly reduced by bilateral vagotomy and pretreatment with atropine and attenuated by hexamethonium. The negative chronotropic action of SK&F 86466 was abolished by a combination of vagotomy and atropine. Mediation of the bradycardia by a baroreceptor reflex was ruled out by the observations that a lack of change in heart rate was associated with the vasopressor response to phenylephrine in the pithed rat pretreated with propranolol. It is concluded that the negative chronotropic action of SK&F 86466 in the pithed rat is mediated indirectly by activation of the cholinergic innervation of the heart.     

Inhaled allergen-driven CD1c up-regulation and enhanced antigen uptake by activated human respiratory-tract dendritic cells in atopic asthma

Background Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory‐tract DC (hRTDC) in atopic asthma remains poorly defined. Recent data suggest that CD1 antigen presentation by hRTDC may contribute to asthma pathogenesis. Objective To investigate the influence of hRTDC on the balance between atopy and allergic asthma in human subjects and to determine whether CD1 expression by hRTDC is modulated during asthmatic inflammation. Methods Sputum cells were induced from steroid‐naïve, allergen‐challenged and allergen‐naïve subjects (atopic asthmatics, atopic non‐asthmatics and non‐atopic controls). hRTDC were identified using monoclonal antibody labelling and analysis by flow cytometry. Results hRTDC stained HLA‐DR⁺ (negative for markers of other cell lineages) were predominantly myeloid and comprised ∼0.5% of viable sputum cells. Sputum cells were potent stimulators of allogeneic CD4⁺ naïve T cells and enrichment/depletion experiments correlated stimulatory potency with DC numbers. Sputum contained cells that exhibited typical dendritic morphology when analysed by electron microscopy. Myeloid hRTDC were endocytically active, but uptake of FITC‐dextran was enhanced in cells from asthmatics (P<0.001). Despite their increased endocytic capacity, asthmatic myeloid hRTDC appeared mature and expressed increased levels of maturation markers (P<0.05–P<0.001), CD1c, CD1d and langerin (P<0.05). CD1c expression by asthmatic myeloid hRTDC was enhanced upon in vivo allergen challenge (three to ninefold within 24 h; P<0.05). CD11c⁻CD123^high hRTDC were only detected in asthmatic sputum and were increased in number following allergen challenge. Conclusion Despite limited cell numbers, it proved possible to analyse human RTDC in induced sputum, providing evidence that increased antigen uptake and enhanced CD1 presentation by activated hRTDC may contribute to allergic airway disease. CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies.     

前列腺素E1对大鼠肝移植肾功能的保护作用

目的探讨术中应用前列腺素E1（prostaglandin E1，PGE1）对大鼠肝移植肾功能的保护作用。方法大鼠原位肝移植术中经颈内静脉灌注PGE1为治疗组，生理盐水和空白为对照组，观察术后1周存活率、1h的尿量，测定血浆肌酐、尿素氮和肾组织中丙二醛（malondjaldehyde，MDA）、谷胱甘肽（glutathione，GSH）含量，肾组织病理检查。结果PGE1治疗组术后1h尿量较对照组明显增加，肌酐和尿素氮水平均较对照组降低，PGE1治疗组肾组织中GSH含量显著高于两对照组，MDA含量低于两对照组。病理检查PGE1治疗组肾脏组织形态学损伤明显减轻。结论术中应用PGE1能显著改善大鼠肝移植后的肾功能，其机制可能与对抗氧自由基损伤作用有关。     

胰岛素样生长因子1对新生大鼠缺氧缺血性脑损伤保护机制的研究

目的　建立单侧缺氧缺血性脑损伤 (HIBD)动物模型 ,研究胰岛素样生长因子 1(IGF 1)对HIBD的影响和可能机制。　方法　选择健康 7日龄Wistar大鼠 12 0只 ,建立HIBD模型 ,随机分成假手术组、HIBD组、HIBD后 0 .2mg/kg人基因重组IGF 1干预组 (RH IGF 1组 )、0 .0 6 6mg/kg人基因重组IGF 1干预组 (SRH IGF 1组 )及盐水对照组 (对照组 )。各组按观察时段进一步分为 2 4、4 8、72h组 ,每组 8只。各组于规定时刻观测脑形态学改变、谷氨酸 (Glu)含量、凋亡细胞计数、Bcl 2蛋白表达。　结果　 (1)HIBD 4 8h组Glu(116 2 .2± 10 8.1)mg/kg ,较假手术组(75 0 .9± 5 3.4 )mg/kg明显升高 (P <0 .0 5 ) ;HIBD组凋亡细胞计数 [2 4h :(7.6± 1.9) % ,4 8h(12 .6±1.2 ) % ,72h :(13.8± 0 .9) % ],较假手术组 [2 4h(2 .0± 0 .2 ) % ,4 8h(2 .0± 0 .3) % ,72h(2 .0±0 .2 ) % ]明显增加 (P均 <0 .0 5 )。 (2 )与对照组相比 ,RH IGF 1组脑组织病变减轻 ;干预 4 8h组Glu[SRH IGF 1组 (781.4± 5 4 .2 )mg/kg ,RH IGF 1组 (74 0 .5± 4 6 .6 )mg/kg],较对照组 (112 6 .6± 4 8.0 )mg/kg明显降低 (P均 <0 .0 5 ) ;RH IGF 1组凋亡细胞计数 [2 4h :(3.6± 0 .9) % ,4 8h(8.2± 2 .2 ) % ,72h(9.4± 1.4 ) % ],较对     

Expression of the T-cell markers CD2 and CD28 in healthy and atopic children during the first 18 months of life

Atopy may be associated with a reduced T-cell function early in life, particularly regarding maturation of Th1 responses. The T-cell surface molecules CD2 and CD28 are involved in important T-cell activation pathways. Stimulation via the CD2 receptor increases the responsiveness to interleukin (IL)-12, which is a potent inducer of Th1 responses, whereas CD28 stimulation is critical for Th2 differentiation. Our aim was to prospectively study the expression of the cell-surface markers CD2 and CD28 on T-cells in relation to development of atopic disease. Children (n = 172) were followed from birth to 18 months and the cumulative history of atopic disease was recorded. Blood samples were obtained at birth and at 18 months, and in a subgroup of 78 infants also at 3, 6 and 12 months. Flow cytometry was used to analyze the T-cell markers CD2 and CD28, the latter also within the subsets of T-helper (CD4+) and T-cytotoxic (CD8+) cells. At 18 months, 31 children had and 118 did not have atopic symptoms. At this age, skin prick test (SPT) positive children with atopic symptoms with or without an atopic family history (AFH) showed a lower expression of CD2 mode fluorescence intensity (FI) as well as a lower proportion of CD2+ cells, as compared with non-sensitized children with neither atopic symptoms nor AFH. This was accompanied by a higher expression of CD28 FI on CD2+CD8+CD28+ cells. No significant differences were seen at time points before 18 months, although the proportion of CD2+ tended to be low also earlier in life. In conclusion, the observed reduced expression of CD2 in atopic infants may support previous findings that atopy is associated with a reduced CD2 function. The high CD28 FI in SPT positive children with atopic symptoms may possibly be a consequence of a TH2-skewed immune system.     

Sick day management using blood 3-hydroxybutyrate (3-OHB) compared with urine ketone monitoring reduces hospital visits in young people with T1DM: a randomized clinical trial.

AIMS: Diabetic ketoacidosis (DKA), a life-threatening acute complication of Type 1 diabetes, may be preventable with frequent monitoring of glycaemia and ketosis along with timely supplemental insulin. This prospective, two-centre study assessed sick day management using blood 3-hydroxybutyrate (3-OHB) monitoring compared with traditional urine ketone testing, aimed at averting emergency assessment and hospitalization. METHODS: One hundred and twenty-three children, adolescents and young adults, aged 3-22 years, and their families received sick day education. Participants were randomized to receive either a blood glucose monitor that also measures blood 3-OHB (blood ketone group, n = 62) or a monitor plus urine ketone strips (urine ketone group, n = 61). All were encouraged to check glucose levels > or = 3 times daily and to check ketones during acute illness or stress, when glucose levels were consistently elevated (> or = 13.9 mmol/l on two consecutive readings), or when symptoms of DKA were present. Frequency of sick days, hyperglycaemia, ketosis, and hospitalization/emergency assessment were ascertained prospectively for 6 months. RESULTS: There were 578 sick days during 21,548 days of follow-up. Participants in the blood ketone group checked ketones significantly more during sick days (276 of 304 episodes, 90.8%) than participants in the urine ketone group (168 of 274 episodes, 61.3%) (P < 0.001). The incidence of hospitalization/emergency assessment was significantly lower in the blood ketone group (38/100 patient-years) compared with the urine ketone group (75/100 patient-years) (P = 0.05). CONCLUSIONS: Blood ketone monitoring during sick days appears acceptable to and preferred by young people with Type 1 diabetes. Routine implementation of blood 3-OHB monitoring for the management of sick days and impending DKA can potentially reduce hospitalization/emergency assessment compared with urine ketone testing and offers potential cost savings.