结直肠癌中生存素蛋白的表达与血管内皮生长因子和血管生成的关系

目的 探讨生存素(survivin)蛋白在结直肠癌组织中的表达与临床病理参数和肿瘤血管形成的关系.方法 应用免疫组织化学En Vision法检测89例结直肠癌组织中生存素和血管内皮生长因子(VEGF)的表达,同时用CD34标记肿瘤组织内的微血管密度(MVD).结果 生存素蛋白在结直肠癌组织中的阳性表达率为59.6%.随着分化程度的降低,生存素蛋白的阳性表达增高,差异有显著性(P＜0.05).生存素蛋白在伴有淋巴结转移的结直肠癌中的表达高于不伴有淋巴结转移者(P＜0.05).结直肠癌中生存素蛋白的表达与年龄、性别、部位、浸润深度、Dukes分期均无相关性(P＞0.05).VEGF蛋白的表达与肿瘤的浸润深度、淋巴结转移和Dukes分期有关(P＜0.05),而与性别、年龄、部位、分化程度无关(P＞0.05).结直肠癌中生存素蛋白表达与VEGF蛋白和MVD呈正相关(P＜0.05).结论 生存素可能直接或间接通过上调VEGF蛋白的表达促进肿瘤血管形成而参与了结直肠癌的进展.     

肝细胞癌组织中 IL-18BPc 和 VEGF 的表达及与肿瘤血管形成的关系

目的 探讨IL-18BPc和VEGF在原发性肝细胞癌组织中的表达及其与肿瘤血管形成之间的关系。方法 应用免疫组织化学SP法检测IL-18BPc和VEGF在34例肝细胞癌组织、34例癌旁肝组织及12例正常肝组织的表达,通过CD34免疫组织化学染色评价肿瘤组织MVD值,分析IL-18BPc表达与VEGF表达及MVD的关系。结果 IL-18BPc在肝癌组织中的表达阳性率高于癌旁肝组织(P＜0.01)及正常肝组织(P＜0.01),且肝癌出现侵袭转移者较未出现侵袭转移者其IL-18BPc表达阳性率高(P＜0.01);VEGF在肝癌组织中的表达高于癌旁肝组织(P＜0.01)及正常肝组织(P＜0.01);IL-18BPc和VEGF在肝细胞癌中表达呈正相关(r=0.357, P=0.037);肝癌组织MVD值与高于癌旁肝组织(P＜0.01)及正常肝组织(P＜0.01);肝癌组织中, IL-18BPc阳性表达者MVD值高于阴性表达者(P=0.004)。结论 IL-18BPc可能通过上调VEGF的表达促进肝细胞癌血管形成。     

结直肠癌微血管密度与血管内皮生长因子表达的临床研究

目的　探讨微血管密度 (MVD)与血管内皮生长因子 (VEGF)表达在结直肠癌中的变化 ,以及与结直肠癌临床病理间的关系。方法　应用免疫组化方法分析 5 2例结直肠癌、10例结直肠腺瘤、8例正常肠粘膜组织中的MVD、VEGF表达。结果　 (1)结直肠癌MVD(2 0 73± 10 16 )明显高于结直肠腺瘤 (8 5 3± 2 33)和正常肠粘膜组织 (3 5 0± 0 82 ) (P <0 0 1) ,结直肠腺瘤亦明显高于正常肠粘膜组织 (P <0 0 5 ) ;MVD与结直肠癌淋巴结转移、浆膜侵润、远处转移明显相关 ,DukeD、C期明显高于A、B期 (P <0 0 1) ,而与其肿瘤大小、病理类型无关 (P >0 0 5 )。 (2 )结直肠癌VEGF表达阳性率 6 5 4% (34/ 5 2例 )明显高于结直肠腺瘤、正常肠粘膜组织 ,后者分别为 30 % (3/ 10例 )、12 5 % (1/ 8例 ) ,P <0 0 1;VEGF表达与结直肠癌淋巴结侵犯 (P <0 0 5 )、浆膜浸润、远外转移明显相关 (P <0 0 1) ,但与病理类型、肿瘤大小无关。随肿瘤Duke分期进展 ,VEGF表达逐渐升高 ,DukeD、C期明显高于A、B期 (P <0 0 1,P <0 0 5 )。 (3)相关分析表明 ,MVD与VEGF呈正相关 (γ =0 5 34,P <0 0 5 )。结论　MVD、VEGF与结直肠癌生物学行为密切相关 ,VEGF表达与结直肠肿瘤血管生成有关。     

食管癌组织血管内皮生长因子的表达与血管生成的关系

目的 探讨血管内皮生长因子(VEGF)对食管癌血管生成的影响.方法 应用SP法对90例食管鳞癌组织和34例癌旁正常黏膜进行VEGF和CD34免疫组化染色,检测VEGF表达和微血管密度(MVD),分析VEGF的表达、MVD以及食管癌临床病理特征之间的关系.结果 食管癌组织中VEGF的阳性表达率和MVD分别为71.1%和29.70±3.82,显著高于癌旁正常黏膜的11,76%和15.10±2.38(P＜0.01).VEGF表达及MVD均值与淋巴结转移、肿瘤TNM分期有关(P＜0.05和P＜0.01),与患者年龄、性别、分化程度、以及肿瘤组织学类型、肿瘤部位均无关(P＞0.05);VEGF表达与MVD均值呈显著正相关(P＜0.01).结论 VEGF异常表达在食管癌的血管生成中起重要作用,VEGF及其诱导的血管生成与食管癌的侵袭和转移密切相关.     

血管内皮生长因子及受体FLT1在大肠癌中的表达及意义

目的探讨血管内皮细胞生长因子(VEGF)受体FLT1和血管生成及大肠癌发展的关系。方法应用免疫组织化学技术,检测102例大肠癌组织FLT1及VEGF蛋白表达和微血管密度(MVD),分析血管生成与大肠癌组织学分级、浸润深度、Dukes分期、淋巴结转移、肝转移和预后的关系。结果FLT1及VEGF阳性者MVD值显著高于阴性者(P<0.01)。FLT1、VEGF表达和MVD与大肠癌Dukes分期、淋巴结转移密切相关(P<0.01)。VEGF表达和MVD与肝转移相关(P<0.01),但FLT1与肝转移无关。FLT1及VEGF表达阳性或高MVD的大肠癌患者5年生存率较低(P<0.01)。VEGF表达与FLT1表达密切相关(P<0.01)。结论FLT1及VEGF与大肠癌的血管生成密切相关,对大肠癌的生长和浸润转移有促进作用。     

银屑病皮损中转化生长因子-α、血管内皮生长因子的表达及其与微血管密度的相关性研究

目的 探讨转化生长因子-α(TGF-α)及血管内皮生长因子(VEGF)在银屑病皮损中表达及其与血管生成的相关性.方法 采用SP免疫组化法检测寻常型银屑病患者皮损处TGF-α、VEGF及微血管密度(MVD)的表达情况,并以正常人皮肤作对照.结果 银屑病组VEGF在表皮层表达高于对照组.银屑病组皮损组织中TGF-α阳性表达率为86.7％ (26/30)与对照组的10.0％ (3/30)差异有统计学意义(x2 -16.456,P＜0.01);银屑病组皮损组织中VEGF阳性表达率为83.3％ (2/30)与对照组的13.3％ (4/30)差异有统计学意义(x2 =29.997,P＜0.01).银屑病组皮损中MVD计数(23.62±5.73)明显高于对照组的(6.84±2.57)(t=14.63,P＜0.01).银屑病组皮损中的TGF-α、VEGF表达与MVD呈正相关(r=0.672、0.735,均P＜0.01),TGF-α与VEGF的表达也呈正相关(r=0.821,P＜0.05).结论 银屑病患者皮损中TGF-α、VEGF及MVD的表达水平均增高,三者在银屑病皮损的形成发展过程中可能发挥协同促进调节作用.     

缺氧诱导因子1α对判断直肠癌预后的价值

目的 观察直肠癌病例手术后标本缺氧诱导因子1α(HIF-1α)表达水平与血管内皮生长因子(VEGF)、临床病理特征的相关性以及在判断直肠癌预后中的价值.方法 应用免疫组化技术检测30例直肠癌手术后标本HIF-1α和VEGF的表达,同时了解术后病理特征和随访治疗结果.结果 HIF-1α表达弱阳性和强阳性者分别为11例和19例,VEGF表达弱阳性和强阳性者分别为16例和14例,两者间存在显著的相关性(P＜0.01);HIF-1α的表达水平与Dukes分期和淋巴结转移情况之间也有显著的相关性(P＜0.01和P＜0.01),而与肿瘤病理分化程度之间则无明显的统计学意义(P＞0.05).3年生存率为51.0%,其中HIF-1α表达为弱阳性和强阳性者分别为90.9%和34.4%,两者间有显著差异(P＜0.01).COX多因素分析显示HIF-1α的表达水平是影响直肠癌生存率的重要预后因素(P＜0.05).结论 HIF-1α的表达水平是影响直肠癌预后的重要因素,临床上值得进一步研究.     

结肠癌中MMP-2和MMP-9蛋白表达与微血管计数的关系

目的 探讨MMP-2、MMP-9蛋白在结肠肿瘤的血管形成中的临床意义.方法 用免疫组化法检测31例结肠癌中MMP-2、MMP-9、VEGF及CD34相关抗原的蛋白表达情况,统计分析MMP蛋白与结肠肿瘤微血管密度的关系.以20例溃疡性结肠炎、21例结肠腺瘤和10例正常结肠粘膜作为对照组.结果 结肠癌中MMP-2、MMP-9、VEGF蛋白表达阳性率和微血管密度计数(MVD)明显高于正常结肠粘膜组织(P＜0.05),MMP-9各组间比较差异无统计学意义,从溃疡性结肠炎、结肠腺瘤到结肠癌中MMP-2、MMP-9、VEGF蛋白表达阳性率和MVD不同且具有递增趋势.MMP-2、MMP-9、VEGF蛋白表达和MVD与结肠癌的Duke's分期及有无淋巴结转移显著相关(P＜0.05).结肠癌中MMP-2、MMP-9表达阳性者与MMP-2、MMP-9表达阴性者相比,VEGF蛋白表达阳性率和MVD显著不同(P＜0.05).结论 MMP-2、MMP-9蛋白过度表达在结肠肿瘤的血管形成中具有重要的临床意义.     

环氧合酶-2血管内皮生长因子对食管鳞癌的影响研究

目的 研究环氧合酶-2(COX-2)和血管内皮生长因子(VECF)在食管癌发生过程中的作用和病理学意义及其与肿瘤组织中血管新生的关系.方法 采用免疫组化方法检测正常食管黏膜轻、中、重度不典型增生组织及食管鳞癌组织中COX-2和VEGF的蛋白表达和食管鳞癌组织中MVD的测定,并分析COX-2和VEGF的表达与食管癌临床病理因素的关系以及对血管生成的影响.结果 41例食管鳞癌中COX-2和VEGF的表达明显增高,表达率分别为53.7%和58.5%,两者在正常组织中均不表达.COX-2在重度不典型增生组织中表达增高,表达率为50.0%.COX-2和VEGF的表达与肿瘤的大小、分化程度、浸润深度无显著相关,而与淋巴结转移有关.COX-2和VEGF阳性组MVD值均大于阴性组(P＜0.05),两者共同阳性组的MVD值大于单一阴性组,更大于共同阴性组(P＜0.05).结论 COX-2不仅参与了食管鳞癌发生的早期过程,还和VEGF一起参与了食管鳞癌的组织生成和淋巴结转移.COX-2可能与VEGF协同参与肿瘤组织中新生血管的形成.     

血管内皮生长因子在胃癌中的表达及其意义

目的　探讨血管内皮生长因子 (VEGF)在胃癌中的表达及其与血管生成、细胞增殖关系。方法　应用免疫组织化学法检测 4 2例胃癌组织VEGF的表达、增殖细胞核抗原 (PCNA)表达和微血管密度 (MVD)。结果　VEGF表达和MVD与肿瘤大小、浸润深度、淋巴结转移有关 (P <0 0 5 ) ,PCNA表达与肿瘤分化、淋巴结转移有关 (P <0 0 5 )。VEGF阳性组MVD显著高于VEGF阴性组 (P <0 0 1) ,VEGF阳性组PCNA表达显著高于VEGF阴性组 (P <0 0 5 )。结论　VEGF与胃癌的血管生成密切相关 ,对胃癌的增殖、浸润和转移起促进作用 ,检测VEGF表达可作为胃癌的预后指标之一。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

2-(Acetoxyphenyl)-(Z)-styryl sulfides as cyclooxygenase inhibitors

2-(Acetoxyphenyl)-(Z)-styryl sulfides are described as selective cyclooxygenase-2 (COX-2) inhibitors, useful for treating inflammation and COX-2-mediated disorders including neoplasia. 2-(Acetoxyphenyl)-(Z)-styryl sulfide is claimed to be the most potent COX inhibitor in the series with a COX-2 selectivity ratio of 33. This compound is also claimed to be superior to celecoxib (Celebrex^®, Pfizer) in inhibiting cell growth of colorectal carcinoma cells. In this evaluation, the COX inhibitory activity of this compound is compared to that previously disclosed for diarylheterocycles and 2-(acetoxyphenyl)alkyl sulfides. The validity of the DLD-1 cell line in the growth inhibition studies is questioned based on recent literature reports indicating the lack of COX-2 expression in this cell line.     

Sleep-disordered breathing with chronic opioid use

Chronic opioid use for pain relief or as substitution therapy for illicit drug abuse is prevalent in our societies. In the US, retail distribution of methadone and oxycodone has increased by 824 and 660%, respectively, between 1997 and 2003. μ-Opioids depress respiration and deaths related to illicit and non illicit chronic opioid use are not uncommon. Since 2001 there has been an emerging literature that suggests that chronic opioid use is related to central sleep apnoea of both periodic and non-periodic breathing types, and occurs in ～ 30% of these subjects. The clinical significance of these sleep-related abnormalities are unknown. This review addresses the present knowledge of control of ventilation mechanisms during wakefulness and sleep, the effects of opioids on ventilatory control mechanisms, the sleep-disordered breathing found with chronic opioid use and a discussion regarding the future research directions in this area.     

Drug targets for cognitive enhancement in neuropsychiatric disorders

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimer's disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA_A α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.