西洛他唑对磷脂多糖诱导的粘附及粘附分子释放的影响

目的　研究磷酸二酯酶 3型抑制剂西洛他唑对磷脂多糖 (LPS)诱导的粘附及血管内皮细胞 (ECs)释放可溶性细胞粘附分子 (sCAMs)的影响。方法　体外培养第 4～ 6代人脐静脉血管内皮细胞 (HUVECs) ,以LPS(5mg·L- 1)刺激 ,并与西洛他唑 (1～ 10 μmol·L- 1)共培养 2 4h ,观察西洛他唑对由LPS诱导的HUVECs与中性粒细胞之间的粘附的影响 ;另取培养上清 ,以ELISA法测定HUVECs释放可溶性血管细胞粘附分子 1(sVCAM 1)、细胞间粘附分子 1(sICAM 1)以及E 选择素 (sE selectin ,sELAM 1)。结果　西洛他唑抑制由LPS诱导的HUVECs与中性粒细胞之间的粘附以及HUVECs释放sVCAM 1,而对sICAM 1和sE 选择素无影响。并且 ,该药对于sVCAM 1的抑制作用被蛋白激酶A(PKA)抑制剂H 89所阻断。结论　西洛他唑对由细胞因子LPS诱导的粘附反应以及ECs释放sVCAM 1有抑制作用 ,后者可能与PKA依赖性通路相关     

An angiogenesis inhibitor E7820 shows broad-spectrum tumor growth inhibition in a xenograft model: possible value of integrin alpha2 on platelets as a biological marker.

We reported previously that an angiogenesis inhibitor, E7820, inhibits in vitro tube formation of human umbilical vein endothelial cell through the suppression of integrin alpha2 expression. Here we describe the antiangiogenic and antitumor effects of E7820 in mice and discuss the feasibility of using platelet integrin alpha2 expression on platelets as a biological marker of the efficacy of E7820. Oral administration of E7820 significantly inhibited basic fibroblast growth factor-induced angiogenesis in Matrigel implants and human colon WiDr tumor-induced angiogenesis in a dorsal air sac model. Twice-daily treatment with E7820 clearly inhibited the s.c. tumor growth of seven tumor cell lines derived from human colon, breast, pancreas, and kidney, and completely suppressed the growth of human pancreatic KP-1 and human colon LoVo cell lines. Moreover, E7820 significantly inhibited the growth of KP-1 and human colon tumor Colo320DM cells orthotopically implanted in the pancreas and cecum, respectively. The efficacy of E7820 was comparable in the s.c. and orthotopic transplantation models. Immunohistochemical analyses using anti-CD31 antibody showed that E7820 significantly reduced microvessel density in orthotopically implanted KP-1 tumor. E7820 reduced integrin alpha2 expression on a megakaryocytic cell line, Dami cells, induced by phorbol 12-myristate 13-acetate treatment. It also decreased the expression level of integrin alpha2 on platelets withdrawn from mice bearing s.c. KP-1 tumor at a dosage close to that affording antitumor activity. These data demonstrate that E7820 showed a broad-spectrum antitumor effect in mice through inhibition of angiogenesis and indicate that the decrease of integrin alpha2 on platelets might serve as a biological marker for the antitumor efficacy of E7820.     

Altered expression of amyloid precursors proteins after traumatic brain injury in rats: in situ hybridization and immunohistochemical study

The expression of alternatively spliced mRNAs for amyloid precursor protein (APP) isoforms and their translation products were examined in the rat cerebral cortex 1, 3, 6, and 12 h and 1, 3, and 7 days (n = 4-5 in each group) after fluid-percussion brain injury. In situ hybridization studies demonstrated that the expression of APP695 mRNA decreased in and around the damaged area of the cerebral cortex exposed to fluid-percussion injury 1 h after the insult. On the other hand, APP751/770 mRNAs were increased in the regions surrounding the damaged cortical areas 1 day after the injury. An increase of immunoreactive APP was detected in the regions around the damaged cortical areas 3 h after traumatic injury and maintained for the following 3 days. The APP immunoreactivity in the damaged cortices declined to the level of sham-operated animals by post-experimental day 7. Using an anti-amyloid beta (Abeta) protein (17-24) antibody, no deposits of immunoreactive Abeta (17-24) were observed in any of the samples examined in these experiments. These results suggest that the induction of Kunitz-type protease inhibitor (KPI) domain-containing APP mRNAs and the increased accumulation of APP are involved in the physiological and neuropathological responses of brains under various neurodegenerative conditions, including head trauma.     

新型PDE3抑制剂西洛他唑对fMLP诱导的HL-60细胞超氧自由基生成和钙离子浓度升高的影响

目的　研究新型磷酸二酯酶 (PDE) 3抑制剂西洛他唑(cilostazol)对中性粒细胞超氧自由基 (O·2 )和钙离子浓度([Ca2 + ]i)的影响。方法　体外培养急性早幼粒细胞白血病HL 6 0细胞 ,以 1 3%DMSO分化诱导为中性粒细胞样细胞后 ,采用特制新型仪器 ,同时实现化学发光法测定O·2 和荧光法测定 [Ca2 + ]i,观察西洛他唑对趋化肽N 甲酰 甲硫氨酰 亮氨酰苯丙氨酸 (fMLP)刺激引起的中性粒细胞样HL 6 0细胞O·2 生成和 [Ca2 + ]i 升高的影响以及二者变化的时相关系。结果　西洛他唑 (1～ 30 μmol·L-1)明显抑制由fMLP诱导的中性粒细胞O·2 生成和 [Ca2 + ]i 升高 ,其中 10和 30 μmol·L-1浓度的西洛他唑组与对照组相比差异有统计学意义 (P<0 0 1)。在时相关系上 ,fMLP诱导O·2 生成的达峰时间较之 [Ca2 + ]i 的变化略显滞后 ,而 10 μmol·L-1西洛他唑对fMLP诱导O·2 生成和 [Ca2 + ]i 升高的影响表现出一致性 ,几乎同步。结论　西洛他唑对fMLP 诱导的中性粒细胞样细胞内O·2 生成和 [Ca2 + ]i 具有同步的抑制作用 ,提示该药的药理学作用部分是通过影响中性粒细胞功能而实现的     

Feasibility of transperineal prostate biopsy under interventional magnetic resonance guidance

A patient, who was not suited for ultrasound-guided biopsy, was biopsied in an interventional magnetic resonance unit at Brigham and Women's Hospital. Real-time magnetic resonance imaging provided verification of placement before tissue samples were taken. This technique successfully sampled tissue from the prostate and led to a diagnosis of cancer.     

Penetrating lung and diaphragmatic injuries with no abnormal finding of chest X-ray: a case report

A case of penetrating lung and diaphragmatic injuries with no abnormal findings of chest X-ray is reported. A 76-year-old man was admitted to our hospital due to penetrating chest trauma. A simple X-ray film of the chest on admission revealed no abnormal finding. An emergency operation was performed. On exploring the back open wound, we found a laceration of 7 cm in diameter in the right diaphragm and lung laceration. Then we repaired primarily with absorbable material. The postoperative course was uneventful, and the patient was discharged 12 days later. Penetrating truncal traumas can result in diaphragmatic injury. Sometimes the clinical and roentgenographic findings are unreliable. If the diagnosis is missed, a diaphragmatic injury may occur delayed diaphragmatic hernias within hours to years. Accordingly, initial wound exploration are important for the diagnosis of diaphragmatic injury in avoiding serious complications.     

Adenovirus-mediated genetic manipulation of the myocardial beta-adrenergic signaling system in transplanted hearts

OBJECTIVES: Ex vivo perfusion of the cardiac allograft during organ procurement is an ideal environment for adenoviral vectors with transgenes that target improving graft contractility. One such target is the beta-adrenergic receptor-signaling system, in which alterations in transgenic mice have elucidated novel means to improve the function of the heart in vivo. The purpose of the current study was to determine the functional consequences of beta-adrenergic receptor manipulation in a rabbit model of cardiac allograft transplantation. METHODS: New Zealand White rabbits weighing 3 kg served as recipients to 1-kg outbred donors. Donor hearts were arrested and harvested, and 1 of 3 adenoviral constructs was administered into the aortic root perfusing the graft. Transgenes delivered encoded either the human beta(2)-adrenergic receptor, a peptide inhibitor of beta-adrenergic receptor densensitization, or the marker transgene beta-galactosidase. RESULTS: Five days after cervical heterotopic transplantation, left ventricular performance was measured on a Langendorff apparatus. A moderate pattern of rejection was seen in all grafts. Biventricular myocyte expression of beta-galactosidase was observed, and beta(2)-adrenergic receptor density was elevated 10-fold in grafts that received adeno-beta(2)-adrenergic receptor. Left ventricular systolic and diastolic performance was significantly increased in grafts transfected with either adeno-beta(2)-adrenergic receptor or adeno-beta-adrenergic receptor densensitization compared with control grafts that received adeno-beta-galactosidase. CONCLUSIONS: Ex vivo adenovirus-mediated gene transfer is feasible in a rabbit allograft model and, more important, genetic manipulation of beta-adrenergic receptor signaling either by increasing beta(2)-adrenergic receptor density or blocking endogenous receptor desensitization improves graft function acutely in this allograft model.     

Psychophysiological correlates of social skills deficits in persons with schizophrenia

Social skill deficits in schizophrenia profoundly affect patients' life-long outcome, although the profile of the underlying cognitive dysfunction still remains a matter of debate. In the present study, we investigated the relationship between social skills and event-related potentials (ERPs) in an auditory selective attention task, in addition to the neurocognitive indices obtained from the degraded-stimulus continuous performance test (CPT) and clinical indices, such as Brief Psychiatric Rating Scale (BRPS) and global assessment of function (GAF) scores. Social skills were assessed using a Japanese version of the structured role play test. Fourteen persons with schizophrenia participated in the study. Non-verbal skills showed a positive correlation with GAF, the performance level, N1 and N2b amplitude in the ERP task, and hit rate in the CPT, and a negative correlation with reaction time in the CPT. Verbal communication skills showed a positive correlation with GAF, the performance level and N2b amplitude in the ERP task, and hit rate in the CPT, and a negative correlation with reaction time in the CPT. Processing skills showed a positive correlation with the performance level and N1 amplitude in the ERP task and a negative correlation with reaction time in the CPT. These findings suggested that the social skill deficits of persons with schizophrenia were related to the vigilance level and controlled stimulus detection processing.     

Caspase-3 activation and inflammatory responses in rat hippocampus inoculated with a recombinant adenovirus expressing the Alzheimer amyloid precursor protein

To elucidate the mechanism of neuronal death in Alzheimer's disease, we investigated the effects of overexpression of wild-type Alzheimer amyloid precursor protein (APP) on neuronal cells and glial cells in vivo. When an APP695-expressing adenovirus was injected into the dorsal hippocampal region, a number of neurons in remote areas were positively stained with anti-APP monoclonal antibody, and underwent severe degeneration from 3 to 7 days after viral inoculation. Most degenerating neurons were immunopositive with both APP and activated caspase-3, but some neurons that expressed activated caspase-3 were not expressing APP from 7 to 14 days after virus injection. In the neighborhood of the degenerating neurons, activated microglia/macrophages, which were identified by the phenotypic marker C3bi receptor (CD11b/c; OX-42), were observed, and some of them appeared to phagocytose the caspase-3-immunopositive degenerating neurons. In addition to microglia/macrophages, infiltrating leukocytes expressing CD45 or CD4 were also detected. These results suggest that the increased accumulation of APP induced not only caspase-3-mediated death machinery, but also inflammatory responses including microglial activation. These inflammatory responses might cause further neurodegeneration through the alternative pathway that might activate the caspase-3-mediated death machinery without APP expression.     

Four-dimensional sonographic assessment of fetal facial expression early in the third trimester.

OBJECTIVE: To evaluate the characteristic patterns of facial expression in fetuses aged from 28 to 34 weeks using 4-dimensional (4-D) ultrasonography. METHODS: The faces of 10 healthy fetuses aged from 28 to 34 weeks were recorded continuously for 15 min with a 4-D ultrasonographic machine performing up to 25 frames per second. The occurrence rates of blinking, mouthing, yawning, tongue expulsion, smiling, scowling, and sucking were evaluated. RESULTS: Mouthing was the most frequent facial expression (median, 6.5; range, 2-19) whereas the least frequent were scowling (median, 1; range, 0-9) and sucking (median, 1; range, 0-2). Mouthing was evident in all fetuses and significantly more frequent than any other movement (P<.05). Yawning (median, 3; range, 0-6), smiling (median, 2; range, 0-9), and blinking (median, 1.5; range, 0-6) were observed in most cases. Tongue expulsion (median, 1.5; range, 0-5), scowling, and sucking were each observed in 6 cases. CONCLUSION: 4-D sonography provides a means of evaluating fetal facial expression early in the third trimester. It may be a key to predicting fetal brain function and well-being and an important modality in future fetal neurophysiologic research.