Long-term enhancement of REM sleep by the pituitary adenylyl cyclase-activating polypeptide (PACAP) in the pontine reticular formation of the rat

In rats, rapid eye movement (REM) sleep can be elicited by microinjection of vasoactive intestinal polypeptide (VIP) into the oral pontine reticular nucleus (PnO). In the present study, we investigated whether this area could also be a REM-promoting target for a peptide closely related to VIP: the pituitary adenylyl cyclase-activating polypeptide (PACAP). When administered into the posterior part of the PnO, but not in nearby areas, of freely moving chronically implanted rats, PACAP-27 and PACAP-38 (0.3 and 3 pmol) induced a marked enhancement (60-85% over baseline) of REM sleep for 8 h that could be prevented by prior infusion of the antagonist PACAP-(6-27) (3 pmol) into the same site. Moreover, injections of PACAP into the centre of the posterior PnO resulted in REM sleep enhancement which could last for up to 11 consecutive days. Quantitative autoradiography using [125I]PACAP-27 revealed the presence in the PnO of specific binding sites with high affinity for PACAP-27 and PACAP-38 (IC50 = 2.4 and 3.2 nM, respectively), but very low affinity for VIP (IC50 > 1 microM). These data suggest that PACAP within the PnO may play a key role in REM sleep regulation, and provide evidence for long-term (several days) mechanisms involved in such a control. PAC1 receptors which have a much higher affinity for PACAP than for VIP might mediate this long-term action of PACAP on REM sleep.     

PACAP and PAC1 receptor in brain development and behavior

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) act through three class B G-protein coupled receptors, PAC1, VPAC1 and VPAC2, initiating multiple signaling pathways. In addition to natural peptides ligands, a number of synthetic peptides and a small molecular antagonist have been generated. Genetically modified animals have been produced for the neuropeptides and receptors. Neuroanatomical, electrophysiological, behavioral and pharmacological characterization of the mutants and transgenic mice uncovered diverse roles of PACAP-PAC1-VAPC2 signaling in peripheral tissues and in the central nervous system. Human genetic studies suggest that the PACAP-PAC1-VPAC2 signaling can be associated with psychiatric illness via mechanisms of not only loss-of-function, but also gain-of-function. For example, a duplication of chromosome 7q36.3 (encoding the VPAC2 receptor) was shown to be associated with schizophrenia, and high levels of PACAP-PAC1 signaling are associated with posttraumatic stress disorder. Whereas knockout animals are appropriate to address loss-of-function of human genetics, transgenic mice overexpressing human transgenes in native environment using artificial chromosomes are particularly valuable and essential to address the consequences of gain-of-function. This review focuses on role of PACAP and PAC1 receptor in brain development, behavior of animals and potential implication in human neurodevelopmental disorders. It also encourages keeping an open mind that alterations of VIP/PACAP signaling may associate with psychiatric illness without overt neuroanatomic changes, and that tuning of VIP/PACAP signaling may represent a novel avenue for the treatment of the psychiatric illness.     

Consumption of cranberry beverage improved endogenous antioxidant status and protected against bacteria adhesion in healthy humans: a randomized controlled trial

Consumption of polyphenol-rich foods is associated with lower risk from many chronic diseases. We hypothesized that a single dose of cranberry beverage would improve indices of oxidative stress, inflammation, and urinary antibacterial adhesion activity in healthy humans. Six males and 6 females (18-35 years; body mass index, 19-25 kg/m²) consumed placebo, cranberry leaf extract beverage, or low-calorie cranberry juice cocktail (LCJC) once in a randomized, double-blind, placebo-controlled cross-over experimental design trial. The washout period between beverages was 1 week. Blood was collected 0, 2, 4, 8, and 24 hours after beverage consumption for measuring oxidative and inflammatory biomarkers. Urine was collected at 0, 0 to 3, 3 to 6, 6 to 9, 9 to 12, and 24 hours postintervention to assess antibacterial adhesion activity. Consumption of cranberry leaf extract beverage elevated (P < .05) blood glutathione peroxidase activity, whereas LCJC consumption increased (P < .05) glutathione concentrations and superoxide dismutase activity compared with placebo. Cranberry leaf extract beverage and LCJC consumption had no effect on the inflammatory biomarkers measured as compared with placebo. At 0 to 3 hours postconsumption, urine from participants who consumed cranberry beverages had higher (P < .05) ex vivo antiadhesion activity against P-fimbriated Escherichia coli compared with placebo. An acute dose of cranberry beverages improved biomarkers of antioxidant status and inhibition of bacterial adhesion in urine.     

人工流产后服务模式在门诊手术室中的应用

目的 探讨人工流产后服务模式在门诊手术室的应用效果.方法 选择2012年6-7月行人工流产术的患者分为对照组462例和观察组425例,对照组采取给人工流产患者发术前、术后健康处方,告知相关注意事项并解答患者提出的问题的方式进行护理服务,观察组在原有流产服务模式的基础上加入人工流产后服务模式内容,即强化“立即避孕”的意识、知情选择合适的避孕方法、立即落实避孕措施及指导坚持正确的使用4个方面,比较两组患者避孕措施应用情况和术后避孕措施坚持情况.结果 患者避孕措施应用情况比较,对照组使用人数435例（94.2％）、使用口服避孕药的有32例（6.9％）,使用节育器的有25例（5.4％）,而观察组使用人数为425例（100.0％）,使用口服避孕药的有61例（14.4％）,使用节育器的有228例（53.7％）,避孕措施使用率对照组为94.2％,观察组为100％,两组比较差异有统计学意义（P＜0.01）;两组患者术后避孕措施坚持情况比较,术后1个月避孕落实人次对照组为319例（69.9％）,观察组为413例（98.5％）;术后3个月避孕落实人次对照组为195例（50.0％）,观察组为306例（81.0％）;术后半年避孕落实人次对照组为107例（36.4％）,观察组为190例（66.7％）,两组比较差异有统计学意义（P＜0.01）.结论 实施人工流产后服务模式可以促进有效避孕,降低重复流产率,是优质护理服务在门诊手术室的具体体现.     

Combination chemotherapy with paclitaxel and intraperitoneal cisplatin for ovarian cancer with disseminated lesions in the peritoneum and the diaphragm

Background: In ovarian cancer, the management of micrometastases disseminated in the peritoneal cavity is extremely important. We performed intravenous paclitaxel (PAC) infusion combined with cisplatin (CDDP) intraperitoneal infusion for progressive ovarian cancer. Methods: Twelve patients with progressive epithelial ovarian cancer (FIGO IIIc), which was resected using an optimal method at primary surgery, except for disseminated lesions in the peritoneum and the diaphragm, were studied. At primary surgery, a reservoir was placed in the peritoneal cavity. If metastases were identified in the diaphragm, then another reservoir was also placed in the subdiaphragm (double reservoirs). The basic regimen was set at 175 mg/m² with divided doses of PAC and 75 mg/m² CDDP by intraperitoneal injection. When a double reservoir was used, 30 mg/m² of subdiaphragmatic CDDP and 45 mg/m² of intraperitoneal CDDP were administered. The patients received five courses of this regimen. The response to the therapy was evaluated with tumor markers, and by using cytodiagnoses on the peritoneal washing fluid collected from the reservoirs. Results: After five courses of the chemotherapy, the tumor marker levels and cytodiagnoses of all patients became negative. With reference to adverse effects, grade 3–4 neutropenia was detected in 2 patients (16.6%), peripheral neuropathy was detected in 4 patients (33.3%), and alopecia was detected in 11 patients (91.6%). The median follow-up period was 29.2 months and median progression-free survival was 25.6 months. Conclusion: The combination chemotherapy with intravenous PAC and intraperitoneal CDDP was effective on ovarian cancer with disseminated lesions in the peritoneum and the diaphragm, having only mild adverse effects. Received: February 20, 2002 / Accepted: October 9, 2002 Correspondence to:F. Terauchi     

高血压患者服用丹芎通脉颗粒后的血小板活化水平

目的 用流式细胞仪测定高血压病人服用丹芎通脉颗粒前后血小板活化水平。方法 在服药前后,采用双注射器采集外周静脉血,3 8％枸掾酸钠抗凝,加入三种荧光素标记的单克隆抗体。分别加入FITC-PACl,PE-CD62P及PerCP-CD61单抗,室温避光孵育,1％多聚甲醛固定,上机检测。 结果 16例病人服药前后PACl ％从(12.61±3.15)％下降到(2.83±0.71)％(P<0.0001)。34例病人服药前后CD62P ％从(5.49±3.64)％下降到(2.31±1.54)％(P<0.0001)。结论 服用丹芎通脉颗粒后,病人的血小板活化水平都有显著性下降。     

PACAP promotes neural stem cell proliferation in adult mouse brain

In recent years, it has become evident that neural stem cells in the adult mammalian brain continuously generate new neurons, mainly in the hippocampus and olfactory bulb. Although different growth factors have been shown to stimulate neurogenesis in the adult brain, very little is known about the role of neuropeptides in this process. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with pleiotropic effects acting through three receptors to which it has high affinity, namely, PACAP receptor 1 (PAC1), vasoactive intestinal peptide (VIP) receptor 1, and VIP receptor 2. We show that PAC1 is expressed in the neurogenic regions of the adult mouse brain, namely the ventricular zone of the lateral ventricle and the hippocampal dentate gyrus. Cultured neural stem cells isolated from the lateral ventricle wall of adult mice express PAC1 and proliferate in vitro in response to two PAC1 agonists, PACAP and Maxadilan, but not VIP at physiologic concentrations, indicating PAC1 as a mediator of neural stem cell proliferation. Pharmacologic and biochemical characterization of PACAP-induced neural stem cell proliferation revealed the protein kinase C pathway as the principal signaling pathway, whereas addition of epidermal growth factor synergistically enhanced the proliferating effect of PACAP. Further in vitro characterization of the effect of PACAP on neural stem cells showed PACAP capable of stimulating ex novo in vitro formation of multipotent neurospheres with the capacity to generate both neuronal and glial cells. Finally, intracerebroventricular infusion of PACAP increases cell proliferation in the ventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus. We conclude that PACAP, through PAC1, is a potent mediator of adult neural stem cell proliferation.