Use of E mu-PIM-1 transgenic mice short-term in vivo carcinogenicity testing: lymphoma induction by benzo[a]pyrene, but not by TPA

E mu-pim-1 transgenic mice are predisposed to develop lymphomas. Due to their low spontaneous tumour incidence and their increased sensitivity towards the lymphomagen ethylnitrosourea these mice may present an interesting model for short-term carcinogenicity testing. Here, we report on the further exploration of this transgenic mouse model with two additional carcinogens known to have, among others, the lymphohaematopoietic system as target, i.e. benzo[a]pyrene (B[a]P) and 12-O-tetradecanoylphorbol-13-acetate (TPA). B[a]P, given three times a week (by gavage) for 13 weeks at 4.3, 13 or 39 mg/kg body weight, resulted in a dose-related increase in lymphomas up to a 90% incidence in E(mu)-pim-1 mice during the observation period of 40 weeks. B[a]P also induced tumours of the forestomach within this observation period, though at a lower incidence and apparently equally effective in wildtype and transgenic mice. TPA, on the other hand, was unable to induce lymphomas (or tumours in any other organ) in either transgenic or wildtype animals within the observation period of 44 weeks, when applied dermally at the maximum tolerated dose of 3 microg/mouse, twice a week for 35 weeks. Molecular analysis showed that B[a]P-induced lymphomas in transgenic mice were of T-cell origin, 80% of which had elevated levels of c-myc expression. None of the lymphomas had increased N-myc expression and mutation analysis of the ras-gene family revealed a K-ras mutation in only one out of eight tumours investigated. Also, none of the lymphomas showed aberrant expression of p53 as determined by immunohistochemistry. It is concluded that the E mu-pim-1 mouse model will not be very suitable for short-term carcinogenicity testing in general: only genotoxic chemicals that have the lymphohaematopoietic system as target for carcinogenesis in wild- type mice, appear to be efficiently identified.      

应用白芨建立门静脉高压动物模型

目的寻求制作门静脉高压动物模型的最佳方法，并以此为基础从事肝硬化后门静脉血液动力学基础研究。方法以3组共15只兔为动物模型，分别以0.2％、0．4％、0.8％浓度的白芨粉为栓塞材料，开腹注入兔门静脉内，手术前后行门静脉测压、血管造影及病理学检查，最长观察时间阎周.结果以0．4％浓度白芨粉制作门静脉高压模型最佳，4周后肝脏体积缩小20％，门静脉压平均升高40％，病理呈典型坏死后肝硬化表现。结论以白芨粉为栓塞材料制作肝硬化门静脉高压动物模型方法简单、效果可靠已重复性好.以不同浓度的白芨栓塞剂来控制坏死后肝纤维化的程度是本试验的一大特点,本动物模型的建立对深入研究肝硬化门静脉高压的成因及治疗措施有着重要意义。     

原发性颅内恶性淋巴瘤的CT诊断

原发性颅内恶性淋巴瘤的ＣＴ诊断郭凡樊长姝北京铁路总医院ＣＴ室１０００３８提要对６例经手术病理证实的原发性颅内恶性淋巴瘤的ＣＴ表现进行分析后，认为对发生在中线区表现为均匀高密度，边缘清楚具有分叶征象的病灶，可作为ＣＴ的表现的特点。在放、化疗过程中出现肿...     

NPY neurons express somatostatin receptor subtype 1 in the arcuate nucleus

The regulation of growth hormone (GH) secretion involves hypothalamic somatostatin and its specific receptors (sst1-sst5). sst1 is highly expressed in the arcuate nucleus (AN), and several data suggest that sst1 receptors are preferentially involved in the somatotropic hypothalamic network. Neuropeptide Y (NPY)-containing neurons function as direct transducers for GH feedback. Interestingly, there is an overlap in the distribution of NPY and sst1 containing cells in the AN. To determine whether these NPY cells are target for somatostatin we used a double label in situ hybridization histochemistry. Image analysis revealed that approximately 7% of NPY-hybridizing neurons coexpressed sst1 mRNA. These results further support the evidence for the direct interactions between the somatotropic axis and the neuroendocrine regulatory loops of energy homeostasis.     

A role for mannose-binding lectin dysfunction in generation of autoantibodies in systemic lupus erythematosus

OBJECTIVE: To investigate the possible association of the mannose binding lectin (MBL) pathway of complement activation with different disease parameters and disease activity in patients with systemic lupus erythematosus (SLE). METHODS: MBL genotype, MBL serum concentration, MBL complex activity and MBL pathway activity were assessed in 53 patients. The activity of the MBL-MASP complex was assessed on the basis of its ability to activate exogenous C4. For MBL pathway activity the formation of the terminal complex of complement activation (C5b-9) was measured. Results were analysed in relation to clinical variables and autoantibody profiles in these patients. RESULTS: MBL complex activity and MBL pathway activity were both reduced in patients carrying MBL variant alleles. Anticardiolipin and anti-C1q autoantibodies were observed significantly more frequently in patients with MBL variant alleles. Furthermore, the presence of these autoantibodies was associated with a decreased MBL concentration and function. In contrast, anti-MBL autoantibodies were not found in patients with MBL variant alleles, possibly related to impaired binding of variant MBL to apoptotic material. CONCLUSION: In patients with SLE, a reduced functional activity of the MBL pathway of complement, in relation to expression of MBL variant alleles, is associated with increased levels of autoantibodies against cardiolipin and C1q, but not against MBL. We hypothesize that an enhanced production of autoantibodies may be related to disturbed clearance of apoptotic material due to impaired MBL function.     

Multisequence magnetic resonance imaging study of neuropsychiatric systemic lupus erythematosus

OBJECTIVE: To investigate the relationship between magnetization transfer imaging (MTI), diffusion-weighted imaging (DWI), proton magnetic resonance spectroscopy (H-MRS), and T2 relaxometry findings in patients with primary neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: The study group consisted of 24 female patients (mean age 36 years [range 23-65]) who had had a variety of neuropsychiatric symptoms that were judged to be due to NPSLE according to the criteria of the American College of Rheumatology. Patients with current active disease were excluded from participation. Quantitative MTI, DWI, H-MRS, and T2 relaxometry data were acquired in all patients, and the correlation coefficients were calculated. RESULTS: MTI results reflecting a decrease in homogeneity of cerebral parenchyma correlated significantly with H-MRS results representing axonal damage. MTI results also correlated significantly with DWI results reflecting increased diffusivity in the cerebral parenchyma. Finally, MTI results reflecting decreased cerebral homogeneity correlated significantly with increased T2 relaxation time, associated with either edema or gliosis. Increased T2 relaxation time correlated significantly with DWI results reflecting increased diffusivity. With the exception of the correlation between H-MRS and MTI findings, there was no significant correlation between H-MRS results and any other parameter. CONCLUSION: The selected study parameters represent different biologic features in the human brain and can be informative with regard to different pathologic processes in NPSLE. The demonstrated associations between MTI, DWI, H-MRS, and T2 data in patients with a history of NPSLE suggest that there is one pathogenesis and/or common neuropathologic outcome in NPSLE despite differences in clinical presentation.     

Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis

OBJECTIVE: The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long-lived B cell responses and generation of high-affinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA-specific IgG antibodies against cyclic citrullinated peptides (anti-CCP antibodies). METHODS: High-resolution HLA-DR and DQ typing and anti-CCP-2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti-CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method. RESULTS: Carriership of the individual alleles HLA-DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was associated with the presence of anti-CCP antibodies. Carriers of DQ-DR genotypes containing proposed RA susceptibility alleles were significantly more often anti-CCP antibody positive. Carriership of one or two HLA-DRB1 shared epitope (SE) alleles was significantly associated with production of anti-CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8-6.0 and OR 13.3, 95% CI 4.6-40.4, respectively). An increased rate of joint destruction was observed in SE+, anti-CCP+ patients (mean Sharp score 7.6 points per year) compared with that in SE-, anti-CCP+ patients (2.4 points per year) (P = 0.04), SE+, anti-CCP- patients (1.6 points per year) (P < 0.001), and SE-, anti-CCP- patients (1.6 points per year) (P < 0.001). CONCLUSION: HLA class II RA susceptibility alleles are associated with production of anti-CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti-CCP antibodies and SE alleles.     

Impaired executive function in male MDMA (“ecstasy”) users

Rationale Long-term users of ecstasy have shown impaired performance on a multitude of cognitive abilities (most notably memory, attention, executive function). Research into the pattern of MDMA effects on executive functions remains fragmented, however.Objectives To determine more systematically what aspects of executive function are affected by a history of MDMA use, by using a model that divides executive functions into cognitive flexibility, information updating and monitoring, and inhibition of pre-potent responses.Methods MDMA users and controls who abstained from ecstasy and other substances for at least 2 weeks were tested with a computerized cognitive test battery to assess their abilities on tasks that measure the three submodalities of executive function, and their combined contribution on two more complex executive tasks. Because of sex-differential effects of MDMA reported in the literature, data from males and females were analyzed separately.Results Male MDMA users performed significantly worse on the tasks that tap on cognitive flexibility and on the combined executive function tasks; no differences were found on the other cognitive tasks. Female users showed no impairments on any of the tasks.Conclusions The present data suggest that a history of MDMA use selectively impairs executive function. In male users, cognitive flexibility was impaired and increased perseverative behavior was observed. The inability to adjust behavior rapidly and flexibly may have repercussions for daily life activities.