Effects of cerebrospinal fluid from patients with Parkinson disease on dopaminergic cells

BACKGROUND: The pathogenesis of substantia nigra pars compacta neuronal injury in Parkinson disease (PD) remains unknown. Cerebrospinal fluid (CSF) has been reported to contain factors toxic to dopaminergic neurons. OBJECTIVES: To determine whether the cytotoxic effects of CSF of PD patients are specific for dopaminergic neurons, dependent on prior levodopa therapy, and mediated by the cytokine tumor necrosis factor alpha (TNF-alpha). DESIGN: Specimens of CSF were evaluated in dopaminergic (MES 23.5) and nondopaminergic (N18TG2) cell lines for cytotoxicity by viability assay and by the inhibition of tyrosine hydroxylase. After specificity and time and dose response were established, CSF specimens were assayed in a blinded manner. The TNF-alpha levels in CSF were determined by enzyme-linked immunosorbent assay. The toxicity of TNF-alpha in MES 23.5 cells was determined. SETTING: A university-based research facility. SUBJECTS: There were 4 groups of subjects: normal control subjects (n = 10), control subjects with neurologic disease (n = 8), PD patients treated with levodopa (n = 10), and untreated subjects with PD (n= 20). RESULTS: Specimens of CSF from 15 (50%) of 30 PD patients and 2 (11%) of 18 control subjects were cytotoxic to dopaminergic MES 23.5 cells and were nontoxic to the parental cell line N18TG2. There was no correlation between the degree of PD CSF cytotoxicity, levodopa therapy, or the severity and duration of PD. Terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine triphosphate nick-end labeling (TUNEL) for DNA fragmentation suggested the involvement of apoptotic mechanisms. The inhibition of tyrosine hydroxylase was an early effect of cell injury by PD CSF and correlated with the viability assay. The mean TNF-alpha level was 2.6-fold higher in CSF specimens from PD patients than in those of controls. The addition of recombinant human TNF-alpha equivalent to the highest level determined in PD CSF was not cytotoxic to MES 23.5 cultures. CONCLUSIONS: Blinded CSF specimens from PD patients, regardless of therapy, contain factors that cause specific dopaminergic neuronal cell injury. These factors are present in a substantial proportion of CSF specimens from patients with early PD, before the institution of medical therapy. Levels of TNF-alpha are elevated in the CSF of PD patients, but TNF-alpha is not responsible for the cytotoxicity.     

Protection against amyloid beta peptide toxicity by zinc

Zinc (Zn) is an essential element in normal development and biology, although it is toxic at high concentrations. Recent studies show that Zn at high concentrations accelerates aggregation of amyloid beta peptide (Abeta), the major component of senile plaques in Alzheimer's disease (AD). This study reports the effect of varying Zn concentrations on Abeta toxicity and the mechanism by which low concentrations function in a protective role. At Abeta/Zn molar ratios of 1:0.1 and 1:0.01, Zn produces significant protection against Abeta toxicity in cultured primary hippocampal neurons. At higher concentrations (1:1 molar ratio), Zn offers no protection or enhances Abeta toxicity. The protective effect of Zn against Abeta toxicity is due in part to the enhancement of Na+/K+ ATPase activity which prevents the disruption of calcium homeostasis and cell death associated with Abeta toxicity. Analysis of Na+/K+ ATPase activity in cultured rat cortical cells indicated that Zn exposure alone afforded a 20% increase in enzyme activity, although the differences were statistically insignificant. However, in cortical cultures exposed to a toxic dose of Abeta (50 microM), Zn at concentrations of 5 and 0.5 microM led to significant increases in Na+/K+ ATPase activity compared with levels in cells treated with Abeta alone. Zn at a 1:1 molar ratio (50 microM) led to a significant decrease in enzyme activity. Together, these data suggest that Zn functions as a double-edged sword, affording protection against Abeta at low concentrations and enhancing toxicity at high concentrations.     

Palmitoylation occurs at cysteine 347 and cysteine 351 of the dopamine D(1) receptor

To determine the palmitoylation sites in the human dopamine D(1) receptor, we expressed wild type and mutant receptors in which candidate cysteines in the carboxyl tail were substituted by alanines both individually (A347, A351) and together (AA). Our results showed that palmitoylation levels of A347 and A351 were reduced substantially and that AA had no detectable signal of palmitoylation. These data indicate that cysteines 347 and 351 were both palmitoylated and that they were the only sites of palmitoylation. We introduced a cAMP-dependent protein kinase site encompassing the position 351. We predicted that a functional cAMP-dependent protein kinase site would impair receptor-G protein coupling if it is not occluded by palmitoylation. Our results demonstrated that indeed, the introduction of the cAMP-dependent protein kinase site caused reduced potency of dopamine stimulation of adenylyl cyclase, and thus confirmed that when unoccluded, the cAMP-dependent protein kinase site introduced to position 351 of dopamine D(1) receptor could confer constitutive desensitization.     

氟伐他汀对自发性高血压大鼠阻力血管 功能的影响

AIM: To evaluate the effects of fluvastatin, a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor, on the alterations of structure and function of resistant vessels in spontaneously hypertensive rats (SHR). METHODS: Eight-week-old male SHR were given fluvastatin 20 mg.kg-1.d-1 by gavage. Rats were decapitated at 16 wk. Wall-to-lumen area ratios (W/L) of thoracic aorta and mesenteric arteries (3rd grade branch) were assessed by morphometric assay. The effects of fluvastatin on vascular reactivity to sodium nitroprusside (SNP) and norepinephrine (NE), were studied with rings of thoracic aorta and mesenteric arteries isolated from rats. RESULTS: After 8 wk of treatment, histological examination showed that the wall-to-lumen area ratio was lower in SHRflu than that in SHR (0.44 +/- 0.09 vs 0.79 +/- 0.09, P < 0.05). EC50 of vasodilation response was much lower in SHRflu than that in SHR [(4.9 vs 190) pmol.L-1, P < 0.05], while EC50 of mesenteric artery rings from SHRflu was somewhat lower than that of SHR [(0.02 vs 0.04) nmol.L-1, P > 0.05]. In both aortic and mesenteric artery rings, EC50 of vasoconstriction in response to NE from SHRflu was higher than that of SHR [thoracic aorta: (0.20 vs 0.02) nmol.L-1, P < 0.05; mesentric arteries: (1.46 vs 0.72) nmol.L-1, P < 0.05]. CONCLUSION: Short-term treatment with fluvastatin ameliorated the vasomotoricity of resistant vessels, enhanced the sensitivity to vasodilator and depressed the sensitivity to vasoconstrictor; fluvastatin also attenuated the resistant vascular hypertrophy during the development of hypertension in SHR.     

Electron microscopic appearance of the chronic Campylobacter jejuni enteritis of mice.

Campylobacter jejuni is a major cause of human enteritis which mimics the inflammatory bowel disease (IBD). In this study, microstructural changes on the surfaces of the murine gastrointestinal tract persistently colonized by Campylobacter jejuni, strain GJ-S131, were investigated by using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The results revealed that the appearance of the gastrointestinal mucosa in both BALB/C and KM mice resembled that in human with inflammatory bowel disease. Under SEM, the mucosa of the jejunum and ileum, with broken or distorted villi had a "worm eaten" look; crypts were irregular in shape and size, and the mucosa showed atrophy, especially in the colon. Epithelial junctions demonstrated furrows, clefts or deep crevasses, with exudates containing a large number of leukocytes. Cytologic appearances were characterized by microvilli dysplasia and/or atrophy, patchy erosions or necrosis and pelade-like appearance due to absence of microvilli, which were similar to the findings under TEM.

     

Indications for early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups

BACKGROUND AND PURPOSE: Long-term daily aspirin is of benefit in the years after ischemic stroke, and 2 large randomized trials (the Chinese Acute Stroke Trial [CAST] and the International Stroke Trial [IST]), with 20 000 patients in each, have shown that starting daily aspirin promptly in patients with suspected acute ischemic stroke also reduces the immediate risk of further stroke or death in hospital and the overall risk of death or dependency. However, some uncertainty remains about the effects of early aspirin in particular categories of patient with acute stroke. METHODS: To assess the balance of benefits and risks of aspirin in particular categories of patient with acute stroke (eg, the elderly, those without a CT scan, or those with atrial fibrillation), a prospectively planned meta-analysis is presented of the data from 40 000 individual patients from both trials on events that occurred in the hospital during the scheduled treatment period (4 weeks in CAST, 2 weeks in IST), with 10 characteristics used to define 28 subgroups. This represents 99% of the worldwide evidence from randomized trials. RESULTS: There was a highly significant reduction of 7 per 1000 (SD 1) in recurrent ischemic stroke (320 [1.6%] aspirin versus 457 [2. 3%] control, 2P<0.000001) and a less clearly significant reduction of 4 (SD 2) per 1000 in death without further stroke (5.0% versus 5. 4%, 2P=0.05). Against these benefits, there was an increase of 2 (SD 1) per 1000 in hemorrhagic stroke or hemorrhagic transformation of the original infarct (1.0% versus 0.8%, 2P=0.07) and no apparent effect on further stroke of unknown cause (0.9% versus 0.9%). In total, therefore, there was a net decrease of 9 (SD 3) per 1000 in the overall risk of further stroke or death in hospital (8.2% versus 9.1%, 2P=0.001). For the reduction of one third in recurrent ischemic stroke, subgroup-specific analyses found no significant heterogeneity of the proportional benefit of aspirin (chi(2)(18)=20. 9, NS), even though the overall treatment effect (chi(2)(1)=24.8, 2P<0.000001) was sufficiently large for such subgroup analyses to be statistically informative. The absolute risk among control patients was similar in all 28 subgroups, so the absolute reduction of approximately 7 per 1000 in recurrent ischemic stroke does not differ substantially with respect to age, sex, level of consciousness, atrial fibrillation, CT findings, blood pressure, stroke subtype, or concomitant heparin use. There was no good evidence that the apparent decrease of approximately 4 per 1000 in death without further stroke was reversed in any subgroup or that in any subgroup the increase in hemorrhagic stroke was much larger than the overall average of approximately 2 per 1000. Finally, there was no significant heterogeneity between the reductions in the composite outcome of any further stroke or death (chi(2)(18)=16.5, NS). Among the 9000 patients (22%) randomized without a prior CT scan, aspirin appeared to be of net benefit with no unusual excess of hemorrhagic stroke; moreover, even among the 800 (2%) who had inadvertently been randomized after a hemorrhagic stroke, there was no evidence of net hazard (further stroke or death, 63 aspirin versus 67 control). CONCLUSIONS: Early aspirin is of benefit for a wide range of patients, and its prompt use should be routinely considered for all patients with suspected acute ischemic stroke, mainly to reduce the risk of early recurrence.     

黄芪注射液临床应用进展

目的：对黄芪注射液临床应用及其疗效进行综述。方法：通过查阅近期国内部分期刊杂志，对黄芪注射液在肺心病、老年肺结核、脑中风、冠心病、流行性出血热、病毒性心肌炎、甲亢、肝病及肾病等临床应用新进展进行综述。结果：黄芪注射液辅助治疗上述疾病疗效满意。结论：黄芪注射液是治疗心脑血管疾病、肾病、肝病等的有效药物。     

腹腔镜与腹腔镜辅助乙状结肠代阴道术治疗MRKH综合征

目的 :总结使用全腹腔镜和腹腔镜辅助下乙状结肠阴道成形术各成功治疗1例Mayer Rokitansky Kuster Hauser综合征 (MRKH综合征 )的经验。方法 :全腹腔镜下使用腔镜闭合切割器切断乙状结肠的近端和远端。自肛门插入腔内圆型吻合器 ,将降结肠与直肠吻合。经会阴于尿道膀胱与直肠之间造穴。将带血管蒂的乙状结肠牵入穴道 ,完成阴道成形。腹腔镜辅助下阴道成形中 ,腔镜闭合切割器切断乙状结肠的远端后 ,于左下腹壁做一辅助切口 ,将近端乙状结肠经此切口拉出至腹腔外。切断乙状结肠近端 ,将乙状结肠的远端开口缝合 2层 ,使之成盲端。近侧端开口置入吻合器之钉钻 ,再行荷包缝合送回腹腔 ,用吻合器行肠吻合。其余步骤同全腹腔镜手术步骤。术后根据临床检查或磁共振成像测量新成形阴道的长度和宽度。结果 :全腹腔镜手术新成形的阴道长 18cm ,宽 4cm。腹腔镜辅助手术新形成的阴道长 19cm ,宽 4cm。两例新形成的阴道黏膜湿润 ,呈粉红色。无术中和术后并发症的发生。结论 :经腹腔镜乙状结肠移植段的长度完全能达到开腹手术的要求。与开放手术比较 ,全腹腔镜乙状结肠代阴道手术在腹壁上不留手术瘢痕 ,美容效果理想。而腹腔镜辅助下阴道成形 ,虽腹壁留有小手术疤痕 ,但操作简便 ,手术时间短 ,手术费用低     

白细胞介素6和肿瘤坏死因子—α在分泌性中耳炎渗出液中表达及…

Using enzyme-linked immunosorbant assay (ELISA), we measured levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in middle ear effusions (MEE) from patients with secretory otitis media (SOM) undergoing auripuncture to study the role of cytokines in the pathogenesis of the disease. Significant levels of IL-6 (> 62.5 ng/L) were found in 19 (86.36%) of 22 MEEs and those of TNF-alpha (> 37.5 ng/L) in 19 (70.37%) of 27 MEEs. The mean (+/- s) levels of IL-6 and TNF-alpha were 507.68 +/- 813.11 ng/L and 186.86 +/- 166.93 ng/L, respectively. It revealed that the shorter the course, the higher the concentration of IL-6 in MEE: the longer the course, the higher the concentration of TNF-alpha in MEE. These findings suggested that during the early stages of SOM, IL-6 might participate in the defensive reaction of organism, while TNF-alpha might be closely related to the persistence of SOM, resulting in an excessive inflammatory reaction with a potential for pathological changes. It is concluded that the immunological mechanisms probably play a significant role in the pathogenesis of SOM.     

再次尿道成形术治疗先天性尿道下裂术后严重并发症

目的：了解先天性尿道下裂行各种尿道成形术失败后，利用膀胱粘膜行尿道成形术的疗效。方法：将严重狭窄和（或）无法修补的尿瘘瘢痕组织彻底切除，取膀胱粘膜片形成尿道，正位开口于龟头，新尿道内置多孔硅胶支架管作引流。结果：２８例中，２３例治愈，３例有小尿瘘需作尿瘘修补，２例完全失败，再次作粘膜尿道成形术治愈。结论：各种类型先天性尿道下裂尿道成形失败后，可用膀胱粘膜移植尿道成形，效果良好