Neuroendocrine,epigenetic, and intergenerational effects of general anesthetics

The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs.     

Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.     

Melatonin induces apoptosis of colorectal cancer cells through HDAC4 nuclear import mediated by CaMKII inactivation

Melatonin induces apoptosis in many different cancer cell lines, including colorectal cancer. However, the precise mechanisms involved remain largely unresolved. In this study, we provide evidence to reveal a new mechanism by which melatonin induces apoptosis of colorectal cancer LoVo cells. Melatonin at pharmacological concentrations significantly suppressed cell proliferation and induced apoptosis in a dose‐dependent manner. The observed apoptosis was accompanied by the melatonin‐induced dephosphorylation and nuclear import of histone deacetylase 4 (HDAC4). Pretreatment with a HDAC4‐specific siRNA effectively attenuated the melatonin‐induced apoptosis, indicating that nuclear localization of HDAC4 is required for melatonin‐induced apoptosis. Moreover, constitutively active Ca²⁺/calmodulin‐dependent protein kinase II alpha (CaMKIIα) abrogated the melatonin‐induced HDAC4 nuclear import and apoptosis of LoVo cells. Furthermore, melatonin decreased H3 acetylation on bcl‐2 promoter, leading to a reduction of bcl‐2 expression, whereas constitutively active CaMKIIα(T286D) or HDAC4‐specific siRNA abrogated the effect of melatonin. In conclusion, the present study provides evidence that melatonin‐induced apoptosis in colorectal cancer LoVo cells largely depends on the nuclear import of HDAC4 and subsequent H3 deacetylation via the inactivation of CaMKIIα.     

146例女性不孕症的病因分析

目的 分析女性不孕的病因。方法 收集1990-2000年我院女性不孕症146例，不孕时间2年以上。结果 不孕症的主要原因是子宫因素，感染因素及内分泌失调，原发性不孕以子宫因素为主，继发性不孕则以感染因素为主。结论 女性不孕症的原因常是多因素的，必须采用综合治疗，才能提高妊娠率。     

Microtubule dynamics in axons and dendrites.

We have investigated the stability, alpha-tubulin composition, and polarity orientation of microtubules (MTs) in the axons and dendrites of cultured sympathetic neurons. MT stability was evaluated in terms of sensitivity to nocodazole, a potent anti-MT drug. Nocodazole sensitivity was assayed by quantifying the loss of MT polymer as a function of time in 2 micrograms/ml of the drug. MTs in the axon and the dendrite exhibit striking similarities in their drug sensitivity. In both types of neurites, the kinetics of MT loss are biphasic, and are consistent with the existence of two types of MT polymer that depolymerize with half-times of MT polymer that depolymerize with half-times of approximately 3.5 min and approximately 130 min. We define the more rapidly depolymerizing polymer as drug-labile and the more slowly depolymerizing polymer as drug-stable. The proportion of MT polymer that is drug-stable is greater in axons (58%) than in dendrites (25%). On the basis of current understanding of the mechanism of action of nocodazole, we suggest that the drug-labile and drug-stable polymer observed in both axons and dendrites correspond to two distinct types of polymer that differ in their relative rates of turnover in vivo. In a previous study, we established that in the axon, these drug-stable and drug-labile types of MT polymer exist in the form of distinct domains on individual MTs, with the labile domain situated at the plus end of the stable domain (Baas and Black, J Cell Biol 111:495-509, 1990). Because of the great difference in drug sensitivity between the drug-labile and drug-stable MT polymer, we were able to dissect them apart by appropriate treatments with nocodazole. This permitted us to evaluate the drug-labile and drug-stable polymer in terms of polarity orientation and relative content of alpha-tubulin variants generated by posttranslational detyrosination or acetylation. In both the axon and the dendrite, the modified as well as unmodified alpha-tubulins are present in both drug-labile and drug-stable polymer, but at different levels. Specifically, the modified forms of alpha-tubulin are enriched in the drug-stable MT polymer compared to the drug-labile MT polymer. In studies on MT polarity orientation, we demonstrate that in axons, MTs are uniformly plus-end-distal, whereas in dendrites, MTs are non uniform in their polarity orientation, with roughly equal levels of the MTs having each orientation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Integrinα4在骨肉瘤中的表达与意义

Objective： To investigate the expression of integrin α4 in osteosaxcoma and significance. Methods- Forty-six patients with osteosarcoma （Enneking Ⅰ-Ⅲ） were analyzed for the expression of α4 integrin subunit using immunohistochemical method. Results： Twenty-nine （63.04%） of 46 samples demonstrated positive （＋-＋＋） integrin α4 expression. Loss expression of integrin α4 was observed in the patients with advanced Enneking stage （P=0.0040） and with metastatic disease at presentation （P=0.0158）. Integrin α4 expression correlated with cell differentiation, the level of malignancy and the invasive behavior of osteosaxcoma. Conclusion： The loss expression of integrin α4 subunit might be a predictor indicating the invasive potential of osteosarcoma and play a role in metastasis of osteosaxcoma patients.     

颅咽管瘤切除术后水钠代谢紊乱机制研究

目的探讨颅咽管瘤术后水钠代谢紊乱的原因和最佳处理方式。方法对102例经胼胝体切开穹窿间入路切除巨大颅咽管瘤的病人，记录术后尿量、血电解质、抗利尿激素（ADH）、醛固酮（ALD）、皮质醇水平，比较术后激素水平变化与水、钠代谢紊乱的关系。结果本组均出现水、钠代谢紊乱，术后2周完全恢复52例，4周基本恢复33例，6周恢复12例，需长时间人工调整电解质水平5例。术后ADH、ALD和皮质醇的不足是导致术后水钠代谢紊乱的主要原因。结论颅咽管瘤切除术后水、钠代谢紊乱与手术损伤下丘脑有关，紊乱类型与ADH、ALD和醛固酮的缺乏情况有关；及时给予相应激素及对症治疗，可获满意疗效。     

侯江红教授治疗小儿慢性湿疹亚健康状态的经验

侯江红教授擅长运用调脾和胃法调治处于亚健康状态的小儿，治疗小儿慢性湿疹，注重从“健脾和胃、消食清热”法入手，每获良效。     

大学生篮球运动员集训期间部分淋巴细胞亚群和Th1/Th2细胞因子mRNA表达变化分析

目的:探讨大负荷体能训练对大学生篮球运动员细胞免疫功能的影响。方法:14名男子大学生篮球运动员进行为期16周的集训,在训练期间分次对运动员外周血淋巴细胞亚群(CD3+、CD4+/CD8+淋巴细胞比值、NK细胞比例)和Th1/Th2细胞因子 mRNA表达进行检测。结果:在两次分别持续了6周的训练期后,运动员外周血CD3+淋巴细胞数于增加后出现显著下降,从第7周的峰值(59.74±7.18)下降至第16周的最低值(52.02±7.92)(P<0.001);CD8+细胞数第16周(31.15±6.25)与第3周(37.98±7.05)相比显著下降(P<0.05);NK细胞数从第7周的最高值(19.62±5.21)下降至第14周的最低值(14.41±7.93)(P<0.05);IL-4 mRNA表达训练后与基础值(6.56±0.71)相比显著增加,从第7周的7.04±0.35和第14周的7.30±0.25,直至第16周达到最大值7.36±0.45(P<0.05),其他指标的变化不具有统计学意义。结果提示,大负荷训练使运动员细胞免疫功能削弱,Th1/Th2平衡向Th2方向漂移。     

肺性脑病与多器官功能障碍临床分析

目的：分析43例肺性脑病与多器官功能障碍的关系，以便早期采取预见性防治措施。方法：把43例肺性脑病时伴发的功能障碍器官个数与死亡率的关系及酸碱、电解质测定进行统计列表分析，结果：肺性脑病100％并发器官功能障碍，最常受损器官：肺、心、脑、肝或肾，受损器官数目越多，病情越严重，肺性脑病时，呼酸代酸，低钠，低氯血症明显增多。结论：肺性脑病100％伴发多器官功能障碍，随功能障碍器官数目的增加，死亡率亦增加，酸碱失衡及电解质紊乱与多器官功能障碍有关。