Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine

The involvement of dopamine (DA) receptor subtypes in the behavioral effects of CNS stimulants was studied in rats trained to discriminate occaine from saline. In substitution tests, the stimulus effects of 10mg/kg of this substance generalized tod-amphetamine (0.25–1.0 mg/kg) and the selective D₂ against LY-171555 (0.05–0.25 mg/kg); but not to the D₁ agonist SKF-38393 (5.0–15.0 mg/kg); in combination tests, the D₁ antagonist Sch-23390 (0.0625–0.5 mg/kg) significantly blocked, and the D₂ antagonist spiperone (0.25–0.5 mg/kg) partially blocked the cocaine cue. These data suggest that the involvement of DA systems in the behavioral effects of cocaine is more complex than either D₁ or D₂ receptor activation; for example, the stimulus properties of this substance might involve both D₁ and D₂ receptor activation.Some of these results were presented at the meeting of the Society for Neuroscience, Toronto, 1988     

Inhaled allergen-driven CD1c up-regulation and enhanced antigen uptake by activated human respiratory-tract dendritic cells in atopic asthma

Background Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory‐tract DC (hRTDC) in atopic asthma remains poorly defined. Recent data suggest that CD1 antigen presentation by hRTDC may contribute to asthma pathogenesis. Objective To investigate the influence of hRTDC on the balance between atopy and allergic asthma in human subjects and to determine whether CD1 expression by hRTDC is modulated during asthmatic inflammation. Methods Sputum cells were induced from steroid‐naïve, allergen‐challenged and allergen‐naïve subjects (atopic asthmatics, atopic non‐asthmatics and non‐atopic controls). hRTDC were identified using monoclonal antibody labelling and analysis by flow cytometry. Results hRTDC stained HLA‐DR⁺ (negative for markers of other cell lineages) were predominantly myeloid and comprised ∼0.5% of viable sputum cells. Sputum cells were potent stimulators of allogeneic CD4⁺ naïve T cells and enrichment/depletion experiments correlated stimulatory potency with DC numbers. Sputum contained cells that exhibited typical dendritic morphology when analysed by electron microscopy. Myeloid hRTDC were endocytically active, but uptake of FITC‐dextran was enhanced in cells from asthmatics (P<0.001). Despite their increased endocytic capacity, asthmatic myeloid hRTDC appeared mature and expressed increased levels of maturation markers (P<0.05–P<0.001), CD1c, CD1d and langerin (P<0.05). CD1c expression by asthmatic myeloid hRTDC was enhanced upon in vivo allergen challenge (three to ninefold within 24 h; P<0.05). CD11c⁻CD123^high hRTDC were only detected in asthmatic sputum and were increased in number following allergen challenge. Conclusion Despite limited cell numbers, it proved possible to analyse human RTDC in induced sputum, providing evidence that increased antigen uptake and enhanced CD1 presentation by activated hRTDC may contribute to allergic airway disease. CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies.     

The discriminative stimulus and subjective effects of d-amphetamine,phenmetrazine and fenfluramine in humans

The discriminative stimulus (DS) and subjective effects of d-amphetamine (AMP), phenmetrazine (PMT) and fenfluramine (FFL) were studied in a group of normal healthy adults. Subjects (N=27) were trained to discriminate between placebo and 10 mg AMP (PO). Fourteen of the subjects (discriminators) reliably learned the discrimination, whereas the other 13 did not. Nearly all discriminators labelled AMP as a stimulant, and AMP, relative to placebo, increased ratings of drug liking and general activity level, and produced typical stimulant-like subjective effects, as measured by the Profile of Mood States, the Addiction Research Center Inventory, and a series of visual analog scales. The discrimination accuracy of discriminators increased as a function of hour after drug ingestion, as did analog ratings of how certain subjects were that their discrimination responses were correct. Discriminators were tested with doses of PMT (25 and 50 mg) and FFL (20 and 40 mg) to determine whether the DS properties of these drugs would substitute for those of AMP. Both doses of PMT consistently substituted for AMP, and PMT produced subjective effects very similar to those of AMP. Conversely, neither dose of FFL consistently substituted for AMP, and FFL produced essentially no subjective effects. These findings are consistent with results from discrimination studies with other species, and provide further evidence of the validity of this procedure for studying the DS properties of drugs in humans. Offprint requests to: L.D. Chait     

Temporal trends of aeroallergen sensitization over twenty-five years

BACKGROUND: Little is known about time trends of allergic respiratory disease in adults, in particular in older adults. Furthermore, few trend studies have used objective measurements of IgE sensitization against inhalant allergens. OBJECTIVES: To investigate time trends of aeroallergen sensitization in adults over a 25-year period. METHODS: The study includes a total of 7820 persons, aged 30, 40, 50, and 60 years, who participated in three repeated cross-sectional studies of the general population of Copenhagen, Denmark, in 1976-1977, 1982-1984, and 1999-2001, respectively. Respiratory allergy was assessed by determination of specific IgE aeroallergen sensitization in stored serum samples. RESULTS: Over this 25-year period, a marked and statistically significant increase in the prevalence of aeroallergen sensitization had occurred. This increase was seen in all age-groups challenging the notion that the allergy epidemic only affects generations born 1960 onwards. For example, in 40-year-olds the prevalence (with 95% confidence intervals) of aeroallergen sensitization was 14.9% (12.7-17.1), 19.7% (17.1-22.3), and 27.6% (25.1-30.1) in 1976-1977, 1982-1984, and 1999-2001, respectively. CONCLUSIONS: Our results support that the allergy epidemic has spread to older adults resulting in a continuing increase in the overall prevalence of aeroallergen sensitization and an increase in the mean age of allergic patients.     

Graves甲亢多种治疗方法对Graves眼病影响的系统评价

目的 通过榆索、分析文献系统评价131I、手术、抗甲状腺药物(ATD)治疗Graves病(GD)对Graves眼病(GO)的影响.方法 检索了MEDIJNE(1966年-2006年3月)、EMBASE(1984-2005年)、The Cochrane Library(2006年第1期)、中国生物医学文献光盘数据库(EBMdisc,1978年1月-2006年4月)和中国学术期刊全文数据库(CNKI,1994-2006年)所收录的有关不同GD治疗方法对GO影响的文献,同时从参考文献中追溯文献.对纳入研究的方法学质量进行评价,根据是否采取预防甲状腺功能低下(简称甲低)发生的措施对纳入研究进行亚组分析,结果采用RevMan4.2软件进行统计学分析.结果 最终纳入随机对照研究5项,非随机对照研究2项,病例对照研究1项,共1625例患者.Meta分析显示:如GD治疗后早期未采取措施预防甲低,131I与手术治疗、131I与ATD治疗GD在诱发或加重GO以及减轻GO症状方面莘异有统计学意义[检验值分别为2.31,5.97,3.70,5.55;P均＜0.05];如GD治疗后早期采取措施预防甲低,手术与ATD治疗GD在诱发或加重GO以及减轻GO症状方面差异无统计学意义(检验值分别为0.27,0.99;P均＞0.05),尚无研究涉及131I治疗GD后早期采取甲低预防措施时131I对GO的影响.结论 若未及时采取甲低预防措施,131I较ATD、手术治疗GD更容易诱发或加重GO,减轻GO的症状却不如后两者,对于治疗前已有活动性GO的患者,应慎用131I.     

低剂量奥沙利铂并氟脲嘧啶对晚期复发直肠癌放疗增敏作用的临床观察

目的：观察奥沙利铂（L-OHP）并5-氟脲嘧啶、甲酰四氢叶酸钙（5-Fu／LV）配合放疗治疗晚期复发直肠癌患者的增效作用与毒性反应。方法：23例无法手术的晚期复发直肠癌患者进行盆腔放疗，在放疗的第1、5同前一天开始给予L-OHP30mg／m。静滴0．5h，LV100mg／m^2和5-Fu375mg／m^2静滴4h，连用4d。25例单纯放疗者为对照组。结果：放疗结束时，观察组局部症状缓解率较对照组高，尤其对会阴区下坠疼的改善明显（P〈0．05），且转移症状亦有所缓解。两组有效率分别为78．3％、48％（P〈0．05），完全缓解分别为8．7％、4．0％。主要毒副反应是消化道反应、神经毒性、静脉炎，骨髓抑制。结论：利用低剂量L-OHP并5-Fu／LV的增敏作用配合放疗治疗晚期、复发直肠癌可提高近期疗效，改善症状，尤其对于伴远外转移者，为理想、安全的治疗手段。     

RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature

During the past decade, RGD-peptides have become a popular tool for the targeting of drugs and imaging agents to alphavbeta3-integrin expressing tumour vasculature. RGD-peptides have been introduced by recombinant means into therapeutic proteins and viruses. Chemical means have been applied to couple RGD-peptides and RGD-mimetics to liposomes, polymers, peptides, small molecule drugs and radiotracers. Some of these products show impressive results in preclinical animal models and a RGD targeted radiotracer has already successfully been tested in humans for the visualization of alphavbeta3-integrin, which demonstrates the feasibility of this approach. This review will summarize the structural requirements for RGD-peptides and RGD-mimetics as ligands for alphavbeta3. We will show how they have been introduced in the various types of constructs by chemical and recombinant techniques. The importance of multivalent RGD-constructs for high affinity binding and internalization will be highlighted. Furthermore the in vitro and in vivo efficacy of RGD-targeted therapeutics and diagnostics reported in recent years will be reviewed.     

儿童呼吸道苛养菌分离培养及药敏分析

目的：分析儿童呼吸道苛养菌的感染率及常用抗生素的耐药状况。方法：采用儿童呼吸道2050份咽拭子及痰标本进行苛养菌分离培养与鉴定，并对其中617株苛养菌做了药敏试验，结果：显示275株肺炎链球菌，耐药率较高的有红霉素81.1%，苯唑西林76.9%，复方磺胺甲恶唑76.9%，四环素65.4%；104株流感嗜血杆菌、184株副流感嗜血杆菌、54株卡他莫拉菌对氨苄西林耐药率分别为17.6%,28.9%,64.9%，对亚胺培南/西司他丁耐药率分别为16.4%，16.5%，0，同时复方磺胺甲恶唑的耐药率也分别高达56.7%，56.7%，64.9%。结论：提示苛养菌在儿童呼吸道感染中占有重要的地位，及时掌握这类细菌的耐药动态，对合理使用抗生素，延缓耐药株的产生有极其重要的临床意义。     

Oral administration of an edible-mushroom-derived protein inhibits the development of food-allergic reactions in mice

BACKGROUND: Food allergy is a common disease without effective treatment. Since strict elimination of food allergens may be difficult, strategies for effective intervention are urgently needed. OBJECTIVE: The aim was to investigate the prophylactic use of orally administrated FIP-fve, an immunomodulatory protein isolated from the edible mushroom Flammulina velutipes, in a murine model of food allergy. METHODS: BALB/c mice were immunized twice intraperitoneally with ovalbumin (OVA), at an interval of 2 weeks. Before and during each period of immunization, FIP-fve (200 microg per mouse) or phosphate-buffered saline was given orally every other day with a total of five doses. Then OVA-specific antibodies and cytokine profiles were determined. Subsequently, the mice were orally challenged with OVA. Symptoms of anaphylaxis, levels of plasma histamine, and histology of intestines were examined. RESULTS: Mice receiving oral FIP-fve treatment during sensitization to OVA had an impaired OVA-specific IgE response with a Th1-predominant cytokine profile. These mice were protected from systemic anaphylaxis-like symptoms induced by subsequent oral challenge with OVA. CONCLUSION: Oral administration of FIP-fve has a Th1-skewing effect on the development of the allergen-specific immune response, and may serve the purpose of immunoprophylaxis for food allergy and other allergic diseases.     

Allergen microarray: comparison of microarray using recombinant allergens with conventional diagnostic methods to detect allergen-specific serum immunoglobulin E

BACKGROUND: The availability of recombinant allergens and recent advances in biochip technology led to the development of a novel test system for the detection of allergen-specific IgE. OBJECTIVE: To test the performance of this allergen microarray in a serological analytical study. METHODS: Standard allergens contained in grass pollen (Phl p 1, Phl p 2, Phl p 5 and Phl p 6) and tree pollen (Bet v 1 and Bet v 2) were used as a model system. The detection of allergen-specific serum IgE using microarrays was compared with standard test systems: CAP/RAST and an in-house ELISA. In order to test the analytical sensitivity of the assays, geometric dilutions of a serum pool containing high levels of pollen-specific IgE from allergic individuals were tested in each system. To assess the analytical specificity, the sera of 51 patients with presumptive allergic symptoms were collected before diagnosis. Thereafter, the results for grass/tree-pollen-specific IgE were compared. RESULTS: The microarray has a good dynamic range similar to the CAP/RAST system. Microarray and ELISA showed comparable analytical sensitivity exceeding the CAP/RAST system. With respect to the analytical specificity, no significant cross-reactivity of the allergens was observed. For two of the allergens tested, weak positive signals were detected in the microarray test system, whereas they were not detectable by CAP/RAST. CONCLUSION: A good correlation of presently used methods to detect serum IgE and the novel microarray test system was observed. As a next step, a careful validation of this method for a multitude of allergens and a thorough clinical evaluation has to be provided. Microarray testing of allergen-specific IgE can be presumed to be the method of choice for a prospective component-resolved diagnosis of Type I allergy, and the basis for the design and monitoring of a patient-tailored specific immunotherapy in the future.