Neuroprotective strategies in parkinson’s disease: protection against progressive nigral damage induced by free radicals

Brain undergoes neurodegeneration when excess free radicals overwhelm antioxidative defense systems during senescence, head trauma and/or neurotoxic insults. A site-specific accumulation of ferrous citrate-iron complexes in the substantia nigra dopaminergic neurons could lead to exaggerated dopamine turnover, dopamine auto-oxidation, free radical generation, and oxidant stress. Eventually, this iron-catalyzed dopamine auto-oxidation results in the accumulation of neuromelanin, a progressive loss of nigral neurons, and the development of Parkinson's disease when brain dopamine depletion is greater than 80%. Emerging evidence indicates that free radicals such as hydroxyl radicals ((.-)OH) and nitric oxide ((.-)NO) may play opposite role in cell and animal models of parkinsonism. (.-)OH is a cytotoxic oxidant whereas oNO is an atypical neuroprotective antioxidant. (.-)NO and S-nitrosoglutathione (GSNO) protect nigral neurons against oxidative stress caused by 1-methyl-4-phenylpyridinium (MPP(+)), dopamine, ferrous citrate, hemoglobin, sodium nitroprusside and peroxynitrite. MPP(+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), increases the nigral uptake of iron complexes and dopamine overflow leading to the generation of (.-)OH, protein oxidation, lipid peroxidation, and associated retrograde degeneration. In addition to GSNO, MPP(+)-induced oxidative neurotoxicity can be prevented by antioxidants including selegiline, 7-nitroindazole, 17beta-estradiol, melatonin, alpha-phenyl-tert-butylnitrone and U78517F. Similar to selegiline, 7-nitroindazole is a MAO-B inhibitor, which blocks the bio-activation of MPTP and oxidative stress. Freshly prepared but not light exposed, (.-)NO-exhausted GSNO is about 100 times more potent than the classic antioxidant glutathione. Via S-nitrosylation, GSNO also inhibits proteolysis and cytotoxicity caused by caspases and HIV-1 protease. Furthermore, in addition to protection against serum deprivation stress, the induction of neuronal NOS1 in human cells increases tolerance to MPP(+)-induced neuro-toxicity since newly synthesized (.-)NO prevents apoptosis possibly through up-regulation of bcl-2 and down regulation of p66(shc). In conclusion, reactive oxygen species are unavoidable by-products of iron-catalyzed dopamine auto-oxidation, which can initiate lipid peroxidation, protein oxidation, DNA damage, and nigral loss, all of which can be prevented by endogenous and exogenous (.-)NO. Natural and man-made antioxidants can be employed as part of preventative or neuroprotective treatments in Parkinson's disease and perhaps dementia complexes as well. For achieving neuroprotection and neuro-rescue in early clinical parkinsonian stages, a cocktail therapy of multiple neuroprotective agents may be more effective than the current treatment with extremely high doses of a single antioxidative agent.     

不同放疗靶区对食管癌疗效及安全性的影响

目的:分析不同临床靶区勾画对食管癌同步放化疗疗效及安全性的影响,探讨食管癌三维适形放疗的临床靶区范围。方法:2009年1月至2012年1月收治的60例食管癌患者随机分为非预防组和预防组,均接受同步放化疗。非预防组28例,CTV包括原发灶上下外扩3cm、周围外扩0.8-1.0cm及肿大淋巴结累及区;预防组32例,食管癌原发灶CTV外扩同非预防组,根据原发灶部位不同,给予区域淋巴结引流区的预防照射。结果:非预防组和预防组1、2年的生存率分别为67.9%、57.1%和68.8%、50.0%;1、2年局部控制率分别为71.4%、60.7%和71.9%、59.4%;野内淋巴结复发率分别为7.1%、6.3%。非预防组Ⅲ级以上放射性肺炎、放射性食管炎及骨髓抑制为3.6%、7.1%、14.3%;预防组Ⅲ级以上放射性肺炎、放射性食管炎及骨髓抑制发生率为6.3%、12.5%、15.6%。结论:预防组在提高生存率、局部控制率及降低野内淋巴结复发率方面未表现出明显优势,两组疗效相当(P>0.5)。预防组放射性肺炎、放射性食管炎及骨髓抑制发生率均高于非预防组,但两组比较无统计学意义(P>0.5)。预防组肺V10(%)、肺V20(%)、肺V30(%)三项指标均大于非预防组,两者差异有统计学意义(P<0.05)。     

针对患者调强放射治疗计划的剂量学验证

目的建立针对调强放射治疗患者的剂量学验证方法。方法对100例患者进行的剂量验证共有3个测量项目一是采用小灵敏体积的电离室在仿人形模体中测量靶区剂量参考点(一般是射野等中心点)的绝对剂量,二是采用胶片测量一个治疗计划的所有射野在仿人形模体内形成的复合剂量分布,三是采用胶片或半导体探测器阵列在干水模体中测量单个射野的强度分布。由于完成全3个测量项目占用机器的时间过长,实际操作时采用自适应的方式,即首先测量靶区剂量参考点的绝对剂量,如果剂量误差在允许范围内,则不再进行其他的测量;如果剂量误差超出允许范围,则增加两个电离室测量点,并采用胶片测量横断面的剂量分布和(或)射野强度分布。结果93%患者的计划可以顺利实施,其他患者的计划需要调整铅门位置或完全重新设计。87%患者计划的剂量误差在临床可以接受的范围内,其他患者的计划需要对射野机器跳数进行修正;修正系统误差后,有96%患者计划的剂量误差在临床可以接受的范围内。结论利用已有的设备条件建立了患者调强放射治疗计划的剂量学验证方法,这种方法随着设备条件的改善和经验的积累还会进一步完善。针对患者的计划进行剂量学验证是很有必要的。     

The involvement of PI 3-K/Akt-dependent up-regulation of Mcl-1 in the prevention of apoptosis of Hep3B cells by interleukin-6

Interleukin-6 (IL-6) is a pleitrophic cytokine that not only regulates growth and differentiation of many cell types, but also induces production of acute phase proteins (AAP) in hepatocytes. Our previous works have demonstrated that both PI 3-K/Akt and STAT3 pathways were concomitantly activated and cooperatively mediated the anti-apoptotic effect of IL-6. This investigation reports that IL-6 protected cells against apoptosis induced by a variety of agents including, TGF-beta, UV and retinoic acid (RA) in Hep3B cells, suggesting that IL-6 is a fundamental determinant of hepatic cell survival. Mcl-1, but not other Bcl-2 family members, was rapidly up-regulated by IL-6, with a peak (approximately 3-4-fold) appearing at 4 h. Transient transfection of cells with a mcl-1 antisense vector, resulting in a 50-60% reduction of the anti-apoptotic effect of IL-6, indicating that Mcl-1 is a downstream effector of IL-6. Which signaling pathway transduced by IL-6 responsible for the Mcl-1 up-regulation was further investigated. In Hep3B cells, the JAK/STAT3, ERK, and PI 3-K/Akt pathways were activated by IL-6 stimulation. Blocking JAK/STAT3 activation with a dominant-negative mutant STAT3F or a JAK inhibitor AG490 could not influence IL-6-mediated Mcl-1 up-regulation. Similarly, PD98059 treatment, a MEK specific inhibitor, also failed to inhibit Mcl-1 expression. However, the IL-6-induced Mcl-1 up-regulation was effectively attenuated in the presence of PI 3-K inhibitors, LY294002 and wortmannin. Expression of dominant-negative Akt, but not Etk, could abrogate the IL-6-induced increase of Mcl-1. In conclusion, our results suggest that the anti-apoptotic effect of IL-6 is mediated, at least in part, by Mcl-1 expression and that is mainly through the PI 3-K/ Akt-dependent pathway.     

七氟烷预先吸入对单肺通气患者肺功能及氧化应激的影响

目的：探讨七氟烷预先吸入对食管癌患者单肺通气（one lung ventilation,OLV）期间肺功能及氧化应激的影响。方法：60例拟行食管癌切除术患者,随机分为七氟烷预先吸入组（SP组）、丙泊酚静脉组（P组）及七氟烷全程吸入组（S组）。3组患者全麻诱导均为静脉注射咪达唑仑0.04 mg/kg,芬太尼3~4 μg/kg,靶控输注丙泊酚血浆靶浓度3 μg/ml,静脉注射罗库溴铵0.6~0.8 mg/kg,插入双腔管后SP组以七氟烷预先吸入维持麻醉至OLV前,OLV后与P组相同,采用丙泊酚、瑞芬太尼维持麻醉,七氟烷全程吸入组全程七氟烷吸入维持麻醉。麻醉诱导后（T1）、OLV开始前（T2）、OLV 30 min（T3）、OLV 60 min（T4）、OLV结束前（T5）及术毕（T6） 共6个时间点,采集桡动脉血和右心房血进行血气分析,计算Qs/Qt值,于T1、T3~T6时取右心房血样,测定血清超氧化物歧化酶（superoxide dismutase,SOD）活性和丙二醛（malondialdehyde,MDA）的浓度,同时记录血流动力学指标以及相关的临床数据。结果：与T1时比较,T3～T5（OLV期间）,3组Qs/Qt有明显增高（P<0.01）,PaO2明显降低（P<0.01）,T3～T6时血清SOD活性降低（P<0.05）,MDA浓度升高（P<0.05）;组间比较：与P组、S组相比,SP组在T4时Qs/Qt降低（P<0.05）,T5时血清SOD活性升高、MDA浓度降低（P<0.05）;S组与P组相比,S组在T3时Qs/Qt降低（P<0.05）,T5时Qs /Qt增加（P<0.05）,T3～T6时血清SOD活性稍降低,MDA浓度稍升高,但无统计学差异（P >0.05）;PaO2在3组各对应时点比较差异无统计学意义（P >0.05）。结论：OLV前用七氟烷预先吸入可降低食管癌患者OLV的肺内分流率,减轻OLV的氧化应激反应,对氧分压无明显改善。     

Patterns of biopsy-proven renal diseases in geriatric patients: A single medical center experience

The elderly population is expanding rapidly, and that has become a major healthcare burden in terms of chronic kidney disease. The distribution patterns of kidney diseases in these elderly patients remain largely unclear. Here, we compared biopsy-based renal disease patterns between elderly and nonelderly patients. We performed a single-center, retrospective study (1992–2008) on biopsy-proven renal diseases to compare results between geriatric patients (age ≥ 65 years; n = 254) and nongeriatric patients (18 ≤ age < 65 years; n = 2592). Renal pathology was interpreted by pathologists based on light microscopy, immunofluorescence, and electron microscopy. The ages of the geriatric and nongeriatric groups were 71.8 ± 4.5 (65.1–87.3) and 39.7 ± 17.6 (18–64.9) years, respectively, and 74% and 41% of them, respectively, were men. In the geriatric group, the most frequent diagnosis was membranous nephropathy (46.1%), followed by minimal change disease/focal segmental glomerulosclerosis (16.9%), diabetic nephropathy (8.3%), hypertensive nephrosclerosis (7.5%), and IgA nephropathy (5.9%). The geriatric group had more membranous nephropathy and less lupus nephritis and IgA nephropathy than the nongeriatric group. Furthermore, the 5-year survival rate of the geriatric group was significantly low. Our results demonstrated the different distributions of renal biopsy patterns in geriatric patients diagnosed with acute or chronic progressive kidney injury and proteinuria through renal biopsy.     

Effects of Achieving SVR on Clinical Characteristics and Surgical Outcomes in Patients Who Developed Early-Stage HCV-Related Hepatocellular Carcinoma and Received Curative Resection: Preoperative versus Postoperative SVR

The high accessibility to healthcare and increasing awareness of hepatocellular carcinoma (HCC) surveillance after sustained virologic response (SVR) to HCV treatment allow early detection of operable HCC in Taiwan. However, the effects of achieving SVR on patient characteristics and surgical outcomes after curative resection remain elusive. We aimed to compare the clinical presentation and postoperative prognosis among patients with early-stage HCV-related HCC and different viral status. We retrospectively analyzed 208 patients with BCLC stage 0 or A-HCC, including 44 patients who remained HCV viremic, 90 patients who developed HCC after achieving SVR (post-SVR HCC), and 74 patients who subsequently achieved SVR after resection. Patients with post-SVR HCC had a lower degree of hepatitis and better liver function than those who achieved SVR or remained viremic after resection. Notably, 75.6% of patients with post-SVR HCC did not have cirrhosis. Patients with post-SVR HCC and those achieving SVR after resection exhibited comparable recurrence rates and recurrence-free survival, while patients with persistent viremia had the worst surgical outcomes. We concluded that patients with post-SVR HCC had a better liver function but similar surgical outcomes compared with patients who achieved SVR after resection. The low prevalence of cirrhosis in patients with post-SVR HCC highlights the importance of regular surveillance after SVR.     

Comparison of accuracy between digital and conventional implant impressions: two and three dimensional evaluations

PURPOSEThe present study compared the accuracy between digital and conventional implant impressions.MATERIALS AND METHODSThe experimental models were divided into six groups depending on the implant location and the scanning span. Digital impressions were captured using the intraoral optical scanner TRIOS (3Shape, Copenhagen, Denmark). Conventional impressions were taken with the monophase impression material based on addition-cured silicones, Honigum-Mono (DMG, Hamburg, Germany). A high-precision laboratory scanner D900 (3Shape, Copenhagen, Denmark) was used to obtain digital data of resin models and stone casts. Surface tessellation language (STL) datasets from scanner were imported into the analysis software Geomagic Qualify 14 (3D Systems, Rock Hill, SC, USA), and scan body deviations were determined through two-dimensional and three-dimensional analyses. Each scan body was measured five times. The Sidak t test was used to analyze the experimental data.RESULTSImplant position and scanning distance affected the impression accuracy. For a unilateral arch implant and the mandible models with two implants, no significant difference was observed in the accuracy between the digital and conventional implant impressions on scan bodies; however, the corresponding differences for trans-arch implants and mandible with six implants were extremely significant (P<.001).CONCLUSIONFor short-span scanning, the accuracy of digital and conventional implant impressions did not differ significantly. For long-span scanning, the precision of digital impressions was significantly inferior to that of the traditional impressions.     

The effects of desipramine, zimelidine, electroconvulsive treatment and lithium on rat brain biogenic amines: a comparison with peripheral changes

The effects of 4 common treatments for affective disorders on total body norepinephrine (NE) and dopamine (DA) turnover and metabolism were evaluated in rats. The treatments were chronic desipramine (DMI), zimelidine (ZMI), electroconvulsion (ECT) and lithium (Li). The central effects of ECT and Li were also assessed in the brain. The results obtained were compared with the effects of these 4 treatments on total NE (Sum NE) and DA (Sum DA) turnover in depressed patients. We have also evaluated central and/or peripheral effects of these treatments on phenylethylamine, p-tyramine and serotonin metabolism. The urinary changes in Sum NE and DA observed after DMI, ZMI and Li in the rat were similar to those found in depressed patients; Sum NE was significantly reduced. In contrast to its effects on depressed patients, chronic ECT significantly increased Sum NE. Similar to depressed patients, ECT reduced the fraction of NE escaping re-uptake in the rat. Sum DA was not affected by DMI, ZMI or ECT, but was significantly reduced by chronic Li treatment. All 4 treatments significantly reduced serotonin metabolism as indicated by reduced 5-hydroxyindoleacetic acid excretion rates. DMI, ZMI and Li treatments significantly reduced phenylethylamine urinary but not p-tyramine urinary outputs. The opposite effect was observed after ECT. Consistent with their effects on Sum NE, Li reduced while ECT increased hypothalamic NE turnover as deduced from the changes in 3-methoxy-4-hydroxyphenylglycol's rate of formation. As for Sum DA, Li had no effect on 3,4-dihydroxyphenylacetic acid or homovanillic acid's rates of formation in the caudate nucleus. Chronic ECT produced a small, but significant increase in homovanillic acid's rate of formation in the caudate nucleus.     

Antioxidative and in vitro hepatoprotective activity of Bupleurum kaoi leaf infusion

The roots of Bupleurus spp. have been used in traditional Chinese herbal medicine for curing liver diseases. Although bioactive saikosaponins have been detected in the leaves as well as in the roots, the aerial parts of the plants are discarded as waste. In the present study, a leaf infusion of B. kaoi Liu, Chao et Chuang, an indigenous Bupleurus species in Taiwan, was prepared and the antioxidant properties and in vitro hepatoprotective activity were demonstrated. The results show that the leaf infusion exerted DPPH free radical scavenging activity, inhibitory capacity on superoxide anion formation and superoxide anion scavenging activity. The hepatotoxicity of acetaminophen (APAP) and carbon tetrachloride (CCl4) on the rat liver cells were also decreased by the leaf infusion.