Critical role of CD28/B7 costimulation in the development of human Th2 cytokine-producing cells

CD28 is a major costimulatory signal receptor for T cells. We have used human naive CD4+ cells from cord blood to analyze the effect of the CD28/B7 costimulatory pathway on development of T helper (Th) subsets. We show that CD28 costimulation is critical for development of the Th2 cytokine-producing cells and that in the absence of CD28 costimulation, cells are not primed to produce Th2 cytokines and consequently "default" to the Th1 subset, independent of the presence of exogenous cytokines. After CD28 costimulation, cells differentiate into a subset that produces Th2 cytokines. However, further CD28 costimulation is not required to maintain Th2 cytokine production. We conclude that D28 costimulation is critical for the development of Th0 and Th2 subsets, but not for the maintenance of cytokine production.     

维A类化合物4-APR抑制肿瘤侵袭、转移的作用

用体内外实验模型,研究了新维A类化合物4-乙酰胺苯基维A酸酯(4-APR)对肿瘤侵袭、转移的抑制作用。4-APR 43.3mg·kg^-1po即能减少小鼠Lewis肺癌的自发性肺转移瘤数。半体内实验证明4-APR10^-5mol·L^-1和10^-6mol·L^-1对B16-F10癌细胞的人工肺转移瘤数分别抑制67.9%和36.6%。体外实验显示,4-APR对B16-F10细胞侵袭重组基底膜的抑制率分别为54.2%和41.9%。     

炎宁冲剂的抗炎与解热作用研究

目的：研究炎宁冲剂的抗炎与解热作用。方法：采用角叉菜胶致大鼠足跖炎性肿胀。二甲苯致小鼠耳毛细血管通透性增高,以及大鼠皮下羧甲基纤维素囊中白细胞出游等急性炎症模型研究炎宁冲剂的抗炎作用。采用啤酒酵母液引起家兔发热的方法研究炎宁冲剂的解热作用。结果：炎宁冲剂对以上实验动物均具有明显的抗炎和解热作用。结论：炎宁冲剂对急性炎症具有明显的抗炎作用。对啤酒酵母液引起家兔发热具有明显解热作用。     

A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis

Background

In humans, in utero exposure to ionising radiation results in an increased prevalence of neurological aberrations, such as small head size, mental retardation and decreased IQ levels. Yet, the association between early damaging events and long-term neuronal anomalies remains largely elusive.

Methods

Mice were exposed to different X-ray doses, ranging between 0.0 and 1.0 Gy, at embryonic days (E) 10, 11 or 12 and subjected to behavioural tests at 12 weeks of age. Underlying mechanisms of irradiation at E11 were further unravelled using magnetic resonance imaging (MRI) and spectroscopy, diffusion tensor imaging, gene expression profiling, histology and immunohistochemistry.

Results

Irradiation at the onset of neurogenesis elicited behavioural changes in young adult mice, dependent on the timing of exposure. As locomotor behaviour and hippocampal-dependent spatial learning and memory were most particularly affected after irradiation at E11 with 1.0 Gy, this condition was used for further mechanistic analyses, focusing on the cerebral cortex and hippocampus. A classical p53-mediated apoptotic response was found shortly after exposure. Strikingly, in the neocortex, the majority of apoptotic and microglial cells were residing in the outer layer at 24 h after irradiation, suggesting cell death occurrence in differentiating neurons rather than proliferating cells. Furthermore, total brain volume, cortical thickness and ventricle size were decreased in the irradiated embryos. At 40 weeks of age, MRI showed that the ventricles were enlarged whereas N-acetyl aspartate concentrations and functional anisotropy were reduced in the cortex of the irradiated animals, indicating a decrease in neuronal cell number and persistent neuroinflammation. Finally, in the hippocampus, we revealed a reduction in general neurogenic proliferation and in the amount of Sox2-positive precursors after radiation exposure, although only at a juvenile age.

Conclusions

Our findings provide evidence for a radiation-induced disruption of mouse brain development, resulting in behavioural differences. We propose that alterations in cortical morphology and juvenile hippocampal neurogenesis might both contribute to the observed aberrant behaviour. Furthermore, our results challenge the generally assumed view of a higher radiosensitivity in dividing cells. Overall, this study offers new insights into irradiation-dependent effects in the embryonic brain, of relevance for the neurodevelopmental and radiobiological field.

Electronic supplementary material

The online version of this article (doi:10.1186/1866-1955-7-3) contains supplementary material, which is available to authorized users.     

Sleeping position and sudden infant death syndrome (SIDS): effect of an intervention programme to avoid prone sleeping

The proportion of prone sleeping among sudden infant death syndrome (SIDS) victims and infants in general, and the rate of SIDS were prospectively studied in the county of Hordaland, Norway, three years before (1987–89) and three years after (1990–92) a campaign to discourage prone sleeping. Before the campaign, 64% of random reference infants were put prone versus 8% after (p < 0.0001). Concurrently, the rate of SIDS decreased from 3.5 to 1.6 per 1000 live births (63 infants before and 30 after the campaign, p = 0.0002). Prone sleeping was not considered a statistically significant risk factor for SIDS before (OR 2.0,95% CI 0.8–4.5), but was highly significant (OR 11.3,95% CI 3.6–36.5) after the campaign. Prone sleeping is an important risk factor for SIDS, but the association may be missed in epidemiological studies if prone is the predominant sleeping position. Behaviour with regard to sleeping position may be changed rapidly by means of a simple campaign.     

Identification of the key amino acids of gliai cell line-derived neurotrophic factor family receptor alpha 1 involved in its biological function

Glial cell line-derived neurotrophic factor （GDNF） plays a critical role in neurodevelopment and survival of midbrain dopaminergic and spinal motor neurons in vitro and in vivo. The biological actions of GDNF are mediated by a two-receptor complex consisting of a glycosylphosphatidylinositol-linked cell surface molecule, the GDNF family receptor alpha 1 （GFR alpha 1）, and receptor protein tyrosine kinase Ret. Although structural analysis of GDNF has been extensively examined, less is known about the structural basis of GFR alpha 1 function. In this study, based on evolutionary trace method and relative solvent accessibility prediction of residues, a set of trace residues that are solvent-accessible was selected for site-directed mutagenesis. A series of GFR alpha 1 mutations was made, and PC12 cell lines stably expressing different GFR alpha 1 mutants were generated. According to the survival and differentiation responses of these stable PC12 cells upon GDNF stimulation and the GDNF- GFR alpha 1-Ret interaction assay, residues 152NN153, Arg259, and 316SNS318 in the GFR alpha 1 central region were found to be critical for GFR alpha 1 binding to GDNF and eliciting downstream signal transduction. The single mutation R259A in the GFR alpha 1 molecule simultaneously lost its binding ability to GDNF and Ret. However N152A/N153A or S316A/N317A/ S318A mutation in the GFR alpha 1 molecule still retained the ability to bind with Ret. These findings suggest that distinct structural elements in GFR alpha 1 may be involved in binding to GDNF and Ret.     

Practice MRI: Reducing the need for sedation and general anaesthesia in children undergoing MRI

The aim of this study was to evaluate the effectiveness of a practice magnetic resonance unit, in preparing children to undergo magnetic resonance procedures without general anaesthesia (GA) or sedation. The records of children who attended the practice MRI between February 2002 and April 2004 were retrospectively reviewed. Each record was assessed as to whether the child had passed or failed the practice MRI intervention. Those children who were considered to have passed and were proceeded to a clinical non‐GA MRI had the report of the clinical scan reviewed. If the scan had been reported as non‐diagnostic because of movement artefact it was classified as a failed scan, otherwise it was considered a pass. One hundred and thirty‐four children undertook a practice MRI (age range 4.1–16.1 years, median age 7.7 years, 47% boys) and 120/134 (90%) passed the practice session. In all, 117/120 (98%) subsequently had a clinical non‐GA MRI and 110/117 (94%) passed (median age 7.8 years, 47% boys). Preparation is a safe and effective method to reduce the need for sedation and GA in children undergoing a clinical MRI scan. It provides a positive medical experience for children, parents and staff, and results in cost savings for the hospital.     

Long-term propofol infusion and cardiac failure in adult head-injured patients

Five adult patients with head injuries inexplicably had fatal cardiac arrests In our neurosurgical intensive-care unit after the introduction of a sedation formulation containing an increased concentration of propofol. To examine the possible relation further, we did a retrospective cohort analysis of head-injured adults admitted to our unit between 1996 and 1999 who were sedated and mechanically ventilated. 67 patients met the inclusion criteria, of whom seven were judged to have died from propofol-infusion syndrome. The odds ratio for the occurrence of the syndrome was 1.93 (95% CI 1.12-3.32, p=0.018) for every mg/kg per h increase in mean propofol dose above 5 mg/kg per h. We suggest that propofol infusion at rates higher than 5 mg/kg per h should be discouraged for long-term sedation in the intensive-care unit.