Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs

The capacity of platelets to generate thromboxane A2, reflected by measurement of serum thromboxane B2 (TxB2), greatly exceeds the systemic production of thromboxane in vivo. Thus, it is possible that substantial but incomplete inhibition of thromboxane formation ex vivo would still allow marked augmentation of thromboxane production in vivo. To address this hypothesis, we administered aspirin 120 mg, a selective inhibitor of thromboxane synthase (TxSl), 3-(1H-imidazol-1-yl- methyl)-2-methyl-1H-indole-1-propanoic acid (UK-38, 485) 200 mg, and a combination of both drugs to 12 healthy volunteers and measured the effects on serum TxB2 and urinary 2,3-dinor-thromboxane B2 (Tx-M), an index of endogenous thromboxane biosynthesis. Although serum TxB2 was maximally inhibited by 94 +/- 1% after aspirin and 96 +/- 2% after the TxSl, maximal depression of Tx-M was only 28 +/- 8% and 37 +/- 9%, respectively. Combination of aspirin with the TxSl resulted in a small but significant increase in inhibition of thromboxane generation ex vivo (98 +/- 1% v 94 +/- 1%; P less than 0.05), but a disproportionately greater fall in thromboxane synthesis in vivo (58 +/- 7%; P less than 0.01). Consistent with further inhibition of platelet thromboxane synthesis, addition of the TxSl abolished the transient decline in prostacyclin formation after aspirin alone. Administration of a lower dose of aspirin (20 mg) to 6 healthy subjects caused a small reduction in Tx-M (12 +/- 4%; P less than 0.05) and inhibited serum TxB2 by 48 +/- 2%. The relationship between inhibition of platelet capacity to form thromboxane ex vivo (serum TxB2) and synthesis in vivo (Tx-M) departed markedly from the line of identity. When total blockade of the capacity of platelets to generate thromboxane is approached, minor decrements in capacity result in a disproportionate depression of actual thromboxane biosynthesis. These results imply that pharmacologic inhibition of serum TxB2 must be virtually complete before thromboxane- dependent platelet activation is influenced in vivo.     

Ectopic expression of rhombotin-2 causes selective expansion of CD4-CD8- lymphocytes in the thymus and T-cell tumors in transgenic mice

Although the proto-oncogene rhombotin-2 (RBTN-2) is widely expressed in most tissues, it is not expressed in T cells. We investigated the potential for overexpression of RBTN-2 to cause tumors in T cells and other tissues by constructing transgenic mice that expressed RBTN-2 under control of the metallothionein-1 promoter. Despite overexpression of RBTN-2 in all tissues, transgenic mice developed T-cell tumors only, thus indicating that tumorigenesis caused by RBTN-2 is T-cell-specific. Thymic tumors were found between 37 and 71 weeks and were invariably associated with metastasis to nonlymphoid organs. Thymuses from apparently healthy transgenic mice were also examined. In some mice there was an 10-fold increase in the CD4-CD8- thymocyte subset, yet the total number of thymocytes was the same as that in wild-type mice. Thymic homeostasis was maintained by a compensatory reduction in the CD4+CD8+ subset. The expansion of CD4-CD8- thymocytes was associated with increased expression of RBTN-2 and with increased cell proliferation. No differences were found in the proportion of thymocytes undergoing apoptosis in transgenic mice. Furthermore, RBTN-2- induced expansion of CD4-CD8- cells did not block differentiation of these cells. Thymuses with 30% CD4-CD8- cells were essentially monoclonal, indicating that all thymic immunophenotypes were derived from a single clone. Overall, our data are consistent with the following scenario: (1) RBTN-2 expression in T cells causes selective and polyclonal proliferation of CD4-CD8- thymocytes accompanied by a compensatory decrease in other thymocyte subsets; (2) a clone with growth advantage and differentiation potential is selected and populates the thymus; and (3) this clone eventually breaches homeostasis of the thymus, accompanied or followed by metastasis to other organs.     

江苏省太仓市胆囊结石危险因素病例对照研究

胆石症是江苏省太仓市的常见病,１９９７年江苏省太仓市人民医院外科手术病例的１／４是胆石症。本文概括胆囊结石的主要危险因素,为当地胆石症的预防和干预提供科学依据。材料与方法本研究采用了基本人群的成组病例对照研究设计。在太仓市选取５个自然村,作为研究现场。病例通过Ｂ超检查获取,共检查３５～７９岁居民２４５８例,以受检人群中胆囊结石病人为研究对象。对照为随机人群,共６１１例。直接面访被调查者,对研究对象实施同一问卷的询问调查。调查内容包括一般情况、饮食、行为、胆石症家族史、既往史、女性生理与生育因素等…     

Enhanced leukocyte binding by intestinal microvascular endothelial cells in inflammatory bowel disease

BACKGROUND & AIMS: Microvascular endothelial cells mediate leukocyte homing, angiogenesis, and inflammation and healing and show tissue- specific adhesion molecules and functions. The activation of human intestinal mucosal microvascular endothelial cells (HIMECs) was studied in vitro to uncover possible abnormalities associated with inflammatory bowel disease. METHODS: HIMECs were isolated from normal and inflammatory bowel disease mucosa and assessed for phenotypic and morphological features, proliferative response, leukocyte binding capacity, and adhesion molecule expression. RESULTS: Basal proliferation by HIMECs was less than that of human umbilical vein endothelial cells (HUVECs) but increased proportionally more in response to vascular endothelial growth factor. Proinflammatory stimuli induced an activated, spindle-shaped morphology in HIMEC monolayers. Compared with HUVECs, unstimulated HIMECs showed less adhesiveness for U937 and MOLT4 cells and neutrophils, but cytokines and lipopolysaccharide substantially increased the binding capacity of HIMECs. HIMECs derived from inflammatory bowel disease mucosa showed a markedly greater leukocyte-binding capacity than normal mucosal HIMECs. Patterns of intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and E-selectin messenger RNA expression were distinct in HIMECs, HUVECs, and mucosal mesenchymal cells. CONCLUSIONS: HIMECs represent differentiated endothelial cells with unique functional properties. Their dramatically enhanced capacity to bind leukocytes in inflammatory bowel disease suggests that HIMECs play an important role in initiating or maintaining inflammation. (Gastroenterology 1997 Jun;112(6):1895-907)     

EGFR、p53在db/db自发性糖尿病小鼠颌下腺的表达

目的 观察表皮生长因子受体（EGFR）、p53在糖尿病小鼠颌下腺中的表达。方法 选取3、4、6、8、10月龄db／db糖尿病小鼠及相应月龄的db／＋m正常小鼠颌下腺。应用HE染色及免疫组织化学方法染色后进行图像分析，统计EGFR、p53在颌下腺组织内表达的细胞阳性率。结果 随着糖尿病的发展，颌下腺组织出现腺叶萎缩及实质细胞排列不整齐，堆集呈簇。纤维及血管增多；EGFR、p53在对 照组及糖尿病组颌下腺中均有表达。其细胞阳性率随月龄增大均呈增高趋势。且糖尿病组显著高于对照组。结论 ①db／db糖尿病可导致颌下腺组织萎缩及实质细胞形态学改变。②EGFR、p53表达增多。说明糖尿病时EGFR作为多效应受体，可能被激活从而诱导了颌下腺的细胞凋亡；p53表达的上升。提示随着糖尿病发展，颌下腺实质细胞有凋亡趋势。     

The kinetic occipital (KO) region in man: an fMRI study

We used functional magnetic resonance imaging to explore, in individual subjects, the properties of the kinetic occipital (KO) region, which previous position emission tomography studies have shown to be involved in the processing of kinetic boundaries. The KO region was significantly activated in 23/25 subjects tested in the subtraction of uniform motion from kinetic gratings. The KO region is genuinely specialized for processing kinetic boundaries since it is significantly more activated by kinetic gratings than by luminance-defined gratings, uniform motion or transparent motion. This leaves only the kinetic boundaries, created by discontinuities in motion direction, as the specific stimulus aspect, activating the KO region. The KO region is anatomically and functionally distinct from areas MT/V5, V3 and V3A. It also has minimal overlap with the lateral occipital (LO) region. The selective activation of the KO region is robust and relatively immune to changes in stimulus size, spatial frequency and type of kinetic boundary. These results strongly argue for the view that the KO region is a new, separate, functional region in human occipital cortex.