颅脑损伤继发脑性耗盐综合征的临床研究

目的探讨颅脑损伤继发脑性耗盐综合征（CSWS）患者的相关激素水平和氢化可的松对本病的疗效。方法检测54例颅脑损伤继发CSWS患者促肾上腺皮质激素（ACTH）、皮质醇（CTS）和醛固酮（ALDO）含量。将患者分为对照组和治疗组各27例,分别采用单纯补钠和氢化可的松加补钠治疗,并比较两组治疗前后的血清钠和尿钠的变化。结果（1）颅脑损伤继发CSWS患者中,ACTH和CTS分别为（52．8±7．1）ng/L和（0．69±0．17）μmol/L,均明显高于正常值（P＜0．05）;而ALDO平均值为（0．15±0．03）nmol/L,明显低于正常值（P＜0．05）。（2）治疗后第5天和第10天,治疗组和对照组的平均血清钠分别为（127．5±4．2）mmol/L、（131．1±4．3）mmol/L和（124．4±4．5）mmol/L、（128．3±4．7）mmol/L,治疗组平均血清钠均明显高于对照组（P＜0．05）;治疗组和对照组的平均尿钠分别为（99．0±20．0）mmol/24 h、（89．8±21．6）mmol/ 24 h和（122．3±51．7）mmol/24 h、（105．2±24．7）mmol/24 h,治疗组均明显低于对照组（P＜0．05）。结论颅脑损伤继发CSWS与血浆ALDO水平下降有关,氢化可的松能提高颅脑损伤继发CSWS患者的血钠水平。     

ICU患者肠内外营养支持治疗效果对比观察

目的：对比观察肠内营养和肠外营养治疗ICU患者的临床疗效。方法采用随机分组的方式将90例ICU治疗患者分为试验组与对照组各45例。2组患者均给予常规原发病治疗、抗感染、纠正水电解质紊乱等治疗。试验组采用肠内营养支持治疗,对照组患者采用肠外营养支持治疗,检测2组患者血清白蛋白、氮平衡、血红蛋白水平,并比较2组并发症发生率及ICU治疗时间。结果试验组患者的血清白蛋白、氮平衡、血红蛋白水平明显高于对照组（P＜0．05）;试验组并发症发生率为4．44％明显低于对照组的20．00％（P＜0．05）;试验组在ICU治疗时间明显短于对照组（P＜0．05）。结论肠内营养治疗ICU患者的临床疗效优于肠外营养,能有效促进患者氮平衡,提高血清白蛋白、氮平衡、血红蛋白水平,降低并发症发生率,缩短ICU治疗时间,值得临床推广应用。     

早期肠内营养标准化治疗流程管理对重症肺炎机械通气患者血糖变异度指标及预后的影响

目的 探讨早期肠内营养（EN）标准化治疗流程管理对重症肺炎机械通气患者血糖变异度指标及预后的影响。方法 选取2019年1—12月常州市第一人民医院心胸外科收治的26例重症肺炎机械通气患者为对照组（常规的肠内营养支持管理）,选取2020年1月至2021年6月常州市第一人民医院心胸外科收治的28例重症肺炎机械通气患者为试验组（早期肠内营养标准化治疗流程管理）。观察两组治疗后平均血糖值（GLUave）及血糖标准差（GLUsd）、血糖变异系数（GLUcv）、最高血糖值（GLUmax）、最低血糖值（GLUmin）、高血糖发生率、营养支持各项指标、肺氧合呼吸功能相关指标以及预后相关指标。结果 试验组患者的首次排便时间、达目标喂养量时间短于对照组,7 d EN/[EN+全胃肠道外营养（PN）]比例和鼻肠管达标比例高于对照组,差异有统计学意义（P <0.05）。试验组血糖指标GLUave、GLUmax、GLUmin和血糖变异性指标GLUsd、GLUcv均低于对照组,高血糖发生率低于对照组,差异有统计学意义（P <0.05）。试验组呼吸机自检呼吸力学相关指标好转趋势较对照组明显,第7天试验组...     

胰岛素泵短期强化治疗初诊2型糖尿病的临床观察

目的探讨初诊2型糖尿病胰岛素泵短期强化治疗对β细胞功能及其病程的影响。方法对空腹血糖〉11．1mmol／L的36例初诊2型糖尿病患者进行2周的持续胰岛索皮下输注（CSⅡ）强化治疗，对比分析治疗前后血糖、胰岛素、C肽、糖化血红蛋白（HbAlc）、胰岛β细胞功能（HOMA—β）和胰岛素抵抗指数（HOMA-IR）等变化。随访患者血糖控制情况2年，分析临床缓解有关因素。结果2周的CSⅡ治疗后空腹及餐后2h血糖分别由（13．6±1．5）mmol／L、（20．1±4．0）mmo[／L降至（5．6±0．4）mmo[／L、（8．2±1．4）mmol／L，达到良好控制（P〈0．01），且未见明显低血糖。治疗后C肽水平（1．3±0．4）μg／L，较治疗前（0．8±0．2）μg／L明显升高（P〈0．05），HOMA-β（95±34），较治疗前（27±9）明显提高（P〈0．02），HOMA-IR（1．26±0．29），较治疗前（2．31±0．52）明显下降（P〈0．05）。随访2年，单纯饮食运动组较需加用口服药组BMI和治疗后空腹血糖低（P〈0．05），血糖达标所需时间及胰岛素平均用量少（P〈0．05，P〈0．01）。结论胰岛素泵CSⅡ强化治疗能在短期内达到理想血糖控制，有利于胰岛B细胞功能的恢复，部分患者能够获得较长时间的临床缓解。     

重组人生长激素在机械通气病人中的应用

目的 :探讨重组人生长激素 (rHGH )对外科术后需机械通气的病人的效果。方法 :6 0例术后呼吸衰竭需机械通气的病人 ,分为rHGH组和对照组各 30例 ,2组均接受ICU标准支持治疗 ,rHGH组每日肌内注射rHGH ,4～ 8IU。观察 2组机械通气时间 ,治疗期间血清清蛋白、血生化的峰值及胰岛素的用量。结果 :rHGH组机械通气时间为 (2 9±s13)d ,对照组为 (40± 14)d(P <0 .0 1)。rHGH组血清清蛋白浓度明显升高 (P <0 .0 1) ,血糖及胰岛素用量略有增加 ,血钙增加 (P <0 .0 5 )。rHGH组预测的死亡率为 4 3% ,实际死亡率 17% ,死亡率显著降低 (P <0 .0 5 )。结论 :rHGH能够显著缩短外科危重病人机械通气时间 ,撤机成功率增加 ,死亡率降低     

健脾温中方对机械通气肠内营养支持治疗患者血清蛋白及机体营养的影响研究

目的：观察健脾温中方对机械通气肠内营养支持治疗患者血清蛋白及机体营养的影响。方法将50例机械通气患者随机分为肠内营养组和联合中药组,每组25例。对照组行肠内营养治疗,联合中药组在对照组基础上加服健脾温中汤,2组均值疗10 d。以,观察2组实验室指标[血清白蛋白（ ALB）、转铁蛋白（ TFN）、总蛋白（ TP）]、人体测量指标[肱三头肌皮褶厚度（ TSF）、上臂围（ MAC）、上臂肌围（ MAMC）、大腿周经]及入住ICU时间。结果肠内营养组织过程中及治疗后第10d,ALB、TFN均无明显变化,比较差异无显著性,治疗后第10dTP较治疗后第1 d有所提高（ P ＜0．05）。而联合中药组在治疗过程中,各项指标均有明显上升的趋势,治疗第10 d ALB、TFN、TP均较治疗第1 d明显提高,差异具有显著性（ P ＜0．05）,同时也高于肠内营养组（ P ＜0．05）。联合中药组治疗后TSF、MAC、MAMC及大腿周径均较本组治疗前增加（ P ＜0．05）,且与对照组肠内营养组比较差异有统计学意义（ P ＜0．05）。肠内营养组治疗后仅大腿周径较治疗前有所增加（ P ＜0．05）,TSF、MAC、MAMC有增加的趋势,但差异无统计学意义（ P ＜0．05）。联合中药组ICU入住时间明显少于对照组（ P ＜0．05）。结论健脾温中中药可促进胃肠运动和营养吸收,修复损伤的小肠组织细胞,增强机体免疫蛋白合成,有效改善患者血清蛋白及肌肉、脂肪等营养学指标,从而提高了营养支持的疗效,体现出了中医治疗的优势。     

卡宁颗粒冲剂治疗肺癌的疗效和作用机制探讨

目的分析检测血液中代表肿瘤转移性的CD31分子用于诊断肺癌血行转移的应用价值,评价抗癌中药卡宁颗粒冲剂治疗肺癌的疗效。方法应用流式细胞仪技术检测40例肺癌（试验组）患者服用卡宁颗粒冲剂前后血CD31水平、有效率和Karnofsky（KPS）评分,并与对照组（40例）比较。结果对照组肺癌患者治疗前后CD31的平均荧光强度分别为（18．62±1．79）和（18．52±1．34）,试验组分别是（17．31±1．75）和（14．41±1．35）（P＜0．05）;试验组总有效率（CR＋PR＋SD）上升达85．0%,对照组为77．5%;KPS评分改善30%。结论卡宁颗粒冲剂有效治疗肺癌,治疗后CD31值有所下降,并同时提高疾病控制率,改善生活质量。     

胰岛素泵治疗糖尿病酮症的临床观察

目的：观察胰岛素泵持续皮下注射胰岛素（CSⅡ）治疗糖尿病酮症的疗效。方法：将2型糖尿病合并酮症患者随机分为胰岛素泵持续皮下注射胰岛素治疗组（CSⅡ组）和常规小剂量胰岛素静脉滴注治疗组（对照组）各20例，分别使用CSⅡ和小剂量胰岛素静脉滴注，观察血糖、血酮、尿酮的变化、低血糖的发生率及胰岛素用量的多少。结果：2组患者经胰岛素治疗后血酮恢复正常，但CSⅡ组血酮恢复时间（50．4&#177;7．6）h较对照组（88．6&#177;8．9）h明显缩短，差异有显著性（P〈0．05）；尿酮转阴时间CSⅡ组（20．5&#177;6．8）h较对照组（55．2&#177;15．6）h明显缩短，差异有极显著性（P〈0．01）；CSⅡ组低血糖的发生率[（0．5&#177;0．4）次／人]较对照组[（1．6&#177;0．8）次／人]明显减少，差异有极显著性（P〈0．01）；2组患者的血糖经治疗后均明显下降，但达目标血糖的时间相似，差异无显著性；胰岛素用量CSⅡ组[（38．6&#177;5．3）U&#183;d^-1]较对照组[（54．6&#177;11．0）U&#183;d^-1]减少，差异具有显著性（P〈0．05）。结论：CS治疗糖尿病酮症较小剂量胰岛素静脉滴注胰岛素疗效更安全有效。     

肠内营养治疗对机械通气患者的影响

目的：研究慢性阻塞性肺疾病（COPD）患者机械通气时营养支持治疗对患者营养状况和免疫功能的影响。方法：30例COPD机械通气患者分为肠内营养治疗组（EN组）和肠外营养治疗组（PN组）,治疗10d,观察治疗前后营养指标及血清免疫指标的变化。结果：两组患者治疗后血清白蛋白、前白蛋白、上臂肌围、肱三头肌皮褶厚度、TLC、CD4、CD4/CD8较治疗前升高（P〈0.05）,其中EN组较PN组明显升高,差异有统计学意义（P〈0.05）,而且EN组缩短机械通气时间,降低ICU住院时间,减少治疗费用。结论：肠内营养和肠外营养均能改善COPD机械通气患者的营养状况及免疫功能,肠内营养在临床疗效上优于肠外营养。     

口腔护理联合气流冲击法对气管插管机械通气患者呼吸机相关性肺炎的影响

目的 探讨口腔护理联合气流冲击法对经口气管插管机械通气患者预防呼吸机相关性肺炎（VAP）的干预效果。方法 选取2016年6月至2017年7月安徽省立医院ICU收治的96例经口气管插管患者，采用随机数字表法将患者分为对照组和试验组，每组48例。对照组予0.12%洗必泰溶液配合可冲洗式牙刷刷洗进行口腔护理，试验组先用气流冲击法清除气囊上滞留物，再采用同对照组相同的口腔护理方法进行操作，比较两组患者VAP的发生率、机械通气时间以及ICU住院时长。结果 方案数据分析（PP）显示试验组与对照组VAP的发生率分别为4.35%、18.28%，意向性分析（ITT）显示两组VAP的发生率分别为8.33%、25.00%，不同分析结果得出两组的VAP发生率差异均具有统计学意义（P<0.05）；方案数据分析（PP）显示试验组患者机械通气时间、ICU住院时长分别为（7.41±2.86）d、（11.24±3.18）d，对照组患者机械通气时间、ICU住院时长分别为（9.98±3.45）d、（12.96±4.01）d，两组比较差异具有统计学意义（P<0.05）。结论 经口气管插管患者进行口腔护理前联合气流冲击法能够降低VAP的发生率，间接减少机械通气时间与ICU入住时长。     

EDHF: spreading the influence of the endothelium

Our view of the endothelium was transformed around 30 years ago, from one of an inert barrier to that of a key endocrine organ central to cardiovascular function. This dramatic change followed the discoveries that endothelial cells (ECs) elaborate the vasodilators prostacyclin and nitric oxide. The key to these discoveries was the use of the quintessentially pharmacological technique of bioassay. Bioassay also revealed endothelium-derived hyperpolarizing factor (EDHF), particularly important in small arteries and influencing blood pressure and flow distribution. The basic idea of EDHF as a diffusible factor causing smooth muscle hyperpolarization (and thus vasodilatation) has evolved into one of a complex pathway activated by endothelial Ca(2+) opening two Ca(2+) -sensitive K(+) -channels, K(Ca)2.3 and K(Ca)3.1. Combined application of apamin and charybdotoxin blocked EDHF responses, revealing the critical role of these channels as iberiotoxin was unable to substitute for charybdotoxin. We showed these channels are arranged in endothelial microdomains, particularly within projections towards the adjacent smooth muscle, and close to interendothelial gap junctions. Activation of K(Ca) channels hyperpolarizes ECs, and K(+) efflux through them can act as a diffusible 'EDHF' stimulating Na(+) /K(+) -ATPase and inwardly rectifying K-channels. In parallel, hyperpolarizing current can spread from the endothelium to the smooth muscle through myoendothelial gap junctions upon endothelial projections. The resulting radial hyperpolarization mobilized by EDHF is complemented by spread of hyperpolarization along arteries and arterioles, effecting distant dilatation dependent on the endothelium. So the complexity of the endothelium still continues to amaze and, as knowledge evolves, provides considerable potential for novel approaches to modulate blood pressure.     

Pharmacological modulation of GABAA receptor-mediated postsynaptic potentials in the CA1 region of the rat hippocampus

1. It is unclear whether GABA_A receptor-mediated hyperpolarizing and depolarizing synaptic potentials (IPSP_As and DPSP_As, respectively) are evoked by (a) the same populations of GABAergic interneurones and (b) exhibit similar regulation by allosteric modulators of GABA_A receptor function. We have attempted to address these questions by investigating the effects of (a) known agonists for presynaptic receptors on GABAergic terminals, and (b) a range of GABA_A receptor ligands, on each response.
2. The GABA uptake inhibitor NNC 05-711 (10 μM) enhanced whereas bicuculline (10 μM) inhibited both IPSP_As and DPSP_As.
3. (−)-Baclofen (5 μM), [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (DAGO; 0.5 μM), and carbachol (10 μM) caused substantial depressions (up to 99%) of DPSP_As that were reversed by CGP 55845A (1 μM), naloxone (10 μM) and atropine (5 μM), respectively. In contrast, 2-chloroadenosine (CADO; 10 μM) only slightly depressed DPSP_As. Quantitatively, the effect of each agonist was similar to that reported for IPSP_As.
4. The neurosteroid ORG 21465 (1–10 μM), the anaesthetic propofol (50–500 μM), the barbiturate pentobarbitone (100–300 μM) and zinc (50 μM) all enhanced DPSP_As and IPSP_As.
5. The benzodiazepine (BZ) agonist flunitrazepam (10–50 μM) and inverse agonist DMCM (1 μM) caused a respective enhancement and inhibition of both IPSP_As and DPSP_As. The BZω₁ site agonist zolpidem (10–30 μM) produced similar effects to flunitrazepam.
6. The anticonvulsant loreclezole (1–100 μM) did not affect either response.
7. These data demonstrate that similar populations of inhibitory interneurones can generate both IPSP_As and DPSP_As by activating GABA_A receptors that are subject to similar allosteric modulation.

     

Characteristics of histamine-induced leukocyte rolling in the undisturbed microcirculation of the rat mesentery

1. The main objective of this study was to analyse the role and mode of action of the mast cell mediator histamine in leukocyte-endothelium interactions in small venules in vivo. For this purpose, we used a histological approach (combined with intravital microscopy) that allows studies of rapid mediator-induced venular leukocyte accumulation, reflecting leukocyte rolling, in the undisturbed microcirculation of the rat mesentery where rolling is normally absent.
2. We first examined the relative importance of histamine and 5-hydroxytryptamine (5-HT) in acute mast cell-dependent leukocyte recruitment. The mast cell secretagogue compound 48/80 (i.p. for 15 min) induced a marked venular accumulation of polymorphonuclear leukocytes (PMNL) which was almost abolished by combined histamine₁ (H₁)- and histamine₂ (H₂)-receptor blockade. In contrast, the 5-HT-receptor antagonist methysergide was inactive in this regard. Moreover, exogenous 5-HT was less active than exogenous histamine in evoking venular PMNL accumulation (histamine response dose-dependent; 5-HT response bell shaped). Prostaglandin D₂ did not cause PMNL accumulation.
3. The venular PMNL response to exogenous histamine peaked between 15 min and 1 h, was still significantly elevated at 2 h, and then returned to prechallenge values after 3 h. At all time points, the histamine-induced PMNL accumulation was nearly abolished by i.v. treatment with the polysaccharide fucoidin (which blocks rolling but not firm adhesion per se), suggesting that the PMNL response to histamine was due to rolling rather than firm adhesion over the entire 3 h period. At no time point did histamine trigger accumulation of mononuclear leukocytes (MNL).
4. To examine the role of histamine-receptors in the histamine-induced PMNL accumulation (i.e. rolling), the animals were pretreated with diphenhydramine (H₁-receptor antagonist), cimetidine, or ranitidine (H₂-receptor antagonists). Diphenhydramine alone inhibited the venular PMNL response to histamine by 52%, while both H₂-receptor antagonists were completely inactive. However, the combination of cimetidine and diphenhydramine reduced the histamine-induced PMNL rolling by 82%. Furthermore, in contrast to an H₃-receptor agonist, challenge with either the H₁-receptor agonist 2-thiazolylethylamine or two different H₂-receptor agonists (impromidine, dimaprit) was sufficient to provoke significant venular PMNL accumulation.
5. Treatment with the nitric oxide-synthase inhibitor L-NAME did not affect the histamine-induced PMNL rolling. On the other hand, 3 h pretreatment with dexamethasone reduced the PMNL response to histamine by 73%, and flow cytometric analysis showed that the dexamethasone treatment almost completely inhibited binding of soluble P-selectin to rat isolated PMNLs.
6. We conclude that initial leukocyte recruitment after mast cell activation in the rat mesentery is critically dependent on histamine release. The cellular response to histamine was specifically due to PMNL rolling, involved activation of both H₁- and H₂-receptors, and lasted for 2–3 h. Moreover, the histamine-induced PMNL rolling was not dependent on nitric oxide synthesis, but was sensitive to glucocorticoid treatment, possibly via inhibition of expression or function of leukocytic P-selectin ligand(s).

     

Preclinical studies investigating the neural mechanisms involved in the co‐morbidity of migraine and temporomandibular disorders: the role of CGRP

Background and PurposeTemporomandibular disorders (TMD) and migraine can be co‐morbid. This can be a significant factor in exacerbating and increasing the prevalence of migraine‐like symptoms. However, the underlying mechanisms involved are unknown. Our objective was to investigate these neural mechanisms and the role of CGRP as a key modulator in this co‐morbidity.Experimental ApproachWe combined experimental approaches using CGRP, which triggers a migraine‐like response in patients, with that of masseteric muscle injection of complete Freund''s adjuvant (CFA), to model myofascial TMD‐like inflammation. Using validated electrophysiological methods to assess each of the above approaches independently or in combination, we examined their effects on the response properties of migraine‐like dural‐trigeminocervical neurons.Key ResultsIndependently, in ~2/3 of animals (rats) each approach caused delayed migraine‐like activation and sensitisation of dural‐trigeminocervical neurons. The response to masseteric‐CFA was attenuated by a selective CGRP receptor antagonist. The combination approach caused a migraine‐like neuronal response in all animals tested, with somatosensory‐evoked cranial hypersensitivity significantly exacerbated.Conclusion and ImplicationsThe data demonstrate a neuronal phenotype that translates to the exacerbated clinical co‐morbid phenotype, supporting this combination approach as a relevant model to study the mechanisms involved. It provides a pathophysiological rationale for this exacerbated phenotype, strongly implicating the involvement of CGRP. The results provide support for targeting the CGRP pathway as a novel monotherapy approach for treating this co‐morbid condition. This has key implications into our understanding of this co‐morbid condition, as well as potentially addressing the major unmet need for novel and effective therapeutic approaches.     

Opportunities for the replacement of animals in the study of nausea and vomiting

Nausea and vomiting are among the most common symptoms encountered in medicine as either symptoms of disease or side effects of treatments. Developing novel anti-emetics and identifying emetic liability in novel chemical entities rely on models that can recreate the complexity of these multi-system reflexes. Animal models (especially the ferret and dog) are the current gold standard; however, the selection of appropriate models is still a matter of debate, especially when studying the subjective human sensation of nausea. Furthermore, these studies are associated with animal suffering. Here, following a recent workshop held to review the utility of animal models in nausea and vomiting research, we discuss the limitations of some of the current models in the context of basic research, anti-emetic development and emetic liability detection. We provide suggestions for how these limitations may be overcome using non-animal alternatives, including greater use of human volunteers, in silico and in vitro techniques and lower organisms.     

Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease

Animal models of Parkinson''s disease (PD) have proved highly effective in the discovery of novel treatments for motor symptoms of PD and in the search for clues to the underlying cause of the illness. Models based on specific pathogenic mechanisms may subsequently lead to the development of neuroprotective agents for PD that stop or slow disease progression. The array of available rodent models is large and ranges from acute pharmacological models, such as the reserpine- or haloperidol-treated rats that display one or more parkinsonian signs, to models exhibiting destruction of the dopaminergic nigro-striatal pathway, such as the classical 6-hydroxydopamine (6-OHDA) rat and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models. All of these have provided test beds in which new molecules for treating the motor symptoms of PD can be assessed. In addition, the emergence of abnormal involuntary movements (AIMs) with repeated treatment of 6-OHDA-lesioned rats with L-DOPA has allowed for examination of the mechanisms responsible for treatment-related dyskinesia in PD, and the detection of molecules able to prevent or reverse their appearance. Other toxin-based models of nigro-striatal tract degeneration include the systemic administration of the pesticides rotenone and paraquat, but whilst providing clues to disease pathogenesis, these are not so commonly used for drug development. The MPTP-treated primate model of PD, which closely mimics the clinical features of PD and in which all currently used anti-parkinsonian medications have been shown to be effective, is undoubtedly the most clinically-relevant of all available models. The MPTP-treated primate develops clear dyskinesia when repeatedly exposed to L-DOPA, and these parkinsonian animals have shown responses to novel dopaminergic agents that are highly predictive of their effect in man. Whether non-dopaminergic drugs show the same degree of predictability of response is a matter of debate. As our understanding of the pathogenesis of PD has improved, so new rodent models produced by agents mimicking these mechanisms, including proteasome inhibitors such as PSI, lactacystin and epoximycin or inflammogens like lipopolysaccharide (LPS) have been developed. A further generation of models aimed at mimicking the genetic causes of PD has also sprung up. Whilst these newer models have provided further clues to the disease pathology, they have so far been less commonly used for drug development. There is little doubt that the availability of experimental animal models of PD has dramatically altered dopaminergic drug treatment of the illness and the prevention and reversal of drug-related side effects that emerge with disease progression and chronic medication. However, so far, we have made little progress in moving into other pharmacological areas for the treatment of PD, and we have not developed models that reflect the progressive nature of the illness and its complexity in terms of the extent of pathology and biochemical change. Only when this occurs are we likely to make progress in developing agents to stop or slow the disease progression. The overarching question that draws all of these models together in the quest for better drug treatments for PD is how well do they recapitulate the human condition and how predictive are they of successful translation of drugs into the clinic? This article aims to clarify the current position and highlight the strengths and weaknesses of available models.

LINKED ARTICLES

This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4     

S-nitrosothiols and the nitrergic neurotransmitter in the rat gastric fundus: effect of antioxidants and metal chelation

1. The effects of the antioxidants ascorbic acid and α-tocopherol and of the metal chelator ethylenediaminetetraacetic acid (EDTA) were studied on relaxations in response to S-nitrosothiols, authentic nitric oxide (NO) and nitrergic non-adrenergic non-cholinergic stimulation of the rat gastric fundus.
2. The S-nitrosothiols S-nitrosocysteine (1–100 nM), S-nitrosoglutathione (0.01–3 μM) and S-nitroso-N-acetylpenicillamine (0.01–3 μM) induced concentration-dependent relaxations of the rat gastric fundus muscle strips, which were precontracted with prostaglandin F_2α. The relaxations to all S-nitrosothiols were concentration-dependently enhanced by the antioxidants ascorbic acid (0.1–3 μM) and α-tocopherol (3–30 μM) and inhibited by the metal chelator EDTA (26 μM).
3. Ascorbic acid and α-tocopherol alone did not induce a relaxation of the precontracted rat gastric fundus muscle strip. However, when ascorbic acid (1 μM) or α-tocopherol (1 μM) were injected in the organ bath 1 minute after S-nitrosoglutathione (0.1 μM) or after S-nitroso-N-acetylpenicillamine (0.1 μM), they induced an immediate, sharp and transient relaxation. This relaxation was inhibited by the superoxide generator pyrogallol (2 μM). Such a relaxation to ascorbic acid or α-tocopherol was not observed in the presence of S-nitrosocysteine (10 nM).
4. Electrical field stimulation (0.5–4 Hz) of the precontracted rat gastric fundus strips induced frequency-dependent nitrergic relaxations which were mimicked by authentic NO (3–300 nM) and by acidified sodium nitrite NaNO₂ (0.3–10 μM). Ascorbic acid (0.3–3 μM), α-tocopherol (3–30 μM) or EDTA (26 μM) did not affect the relaxations to nitrergic stimulation, NO or NaNO₂.
5. In summary, relaxations to S-nitrosothiols in the rat gastric fundus are enhanced by the antioxidants ascorbic acid and α-tocopherol and inhibited by the metal chelator EDTA. However, relaxations to nitrergic stimulation of the rat gastric fundus or those to authentic NO were not affected by the antioxidants or by the metal chelator. These results indicate that antioxidants and metal chelators have a different effect on the biological activity of S-nitrosothiols and on that of the nitrergic neurotransmitter. Therefore, our results suggest that S-nitrosothiols do not act as intermediate compounds in nitrergic neurotransmission in the rat gastric fundus.

     

高三酰甘油腰围表型与糖尿病前期及2型糖尿病发病风险的关系

摘要：目的探讨高三酰甘油（TG）腰围表型与糖尿病前期及2型糖尿病（T2DM）发病风险的关系。方法从参与2011年4—11月四川省泸州地区2型糖尿病患者肿瘤发生风险流行病学调查研究的基线调查者中筛选出1 722例糖耐量正常者,以血TG≥1.7 mmol/L、男性腰围≥90 cm或女性腰围≥80 cm为切点,分为TG和腰围正常组（856例）、单纯高三酰甘油血症组（133例）、单纯腹型肥胖组（518例）、高三酰甘油血症-腰围表型（HTWC）组（215例）,行5年随访观察,比较各组间糖尿病前期及T2DM发病情况。结果随访5年后,1 722例糖耐量正常者中共445例发展为糖尿病前期,67例发展为T2DM。TG和腰围正常组、单纯高三酰甘油血症组、单纯腹型肥胖组、HTWC组糖尿病前期发病率分别为20.7%（177/856）、21.1%（28/133）、30.5%（158/518）、38.1%（82/215）,T2DM发病率分别为2.9%（25/856）、3.8%（5/133）、4.4%（23/518）、6.5%（14/215）。在调整了年龄、性别、空腹血糖、餐后2 h血糖、收缩压、糖化血红蛋白后,多分类无序Logistic回归分析结果显示,HTGW表型人群的糖尿病前期及T2DM发病风险较正常组升高,其OR（95%CI）分别为1.961（1.387～2.773）与2.638（1.279～5.441）。结论HTWC表型是糖尿病前期及T2DM患病的危险因素,可作为筛选两者高风险人群的简便指标。     

Influence of the metabolic profile on the in vivo antioxidant activity of quercetin under a low dosage oral regimen in rats

BACKGROUND AND PURPOSE: Flavonoids are known to possess a broad set of pharmacological effects, some of which have been attributed to their antioxidant properties and, more recently, to cell signalling modulation. Nevertheless, flavonoids are extensively metabolized and their metabolites are the potential bioactive forms in vivo. Therefore, a first and crucial step to understand the mechanisms underlying potential health benefits of flavonoids is knowledge of their metabolites and their biological activities.EXPERIMENTAL APPROACH: To approximate a human dietary pattern of intake of flavonoids, regular rat chow was supplemented with 0.02% quercetin and fed to Sprague-Dawley rats over 3 weeks. Plasma samples were analysed by HPLC and electrospray tandem mass spectrometry, and plasma antioxidant capacity was measured by the 2,2'-azino-bis(3-ethylbenzothiazoline sulphonate) assay. KEY RESULTS: Major metabolites were 3'-methylquercetin (isorhamnetin) glucuronide sulphate conjugates, the most plausible conjugation positions being at the 3-, 5- and 7-hydroxyl positions. Isorhamnetin conjugates are methylated at the 3'-OH position, which decreases the high antioxidant activity of quercetin and its metabolites and their contribution to plasma antioxidant potential.CONCLUSIONS AND IMPLICATIONS: This metabolic pattern differs from that observed after a single high-dose administration, where the major metabolites were quercetin conjugates at 5- and 7-hydroxyl positions and a significantly increased plasma antioxidant activity was observed. These data show altogether that the different metabolic patterns obtained under a prolonged low-dosage regimen or after a single high dose, crucially affected the antioxidant potential of plasma in treated animals. Our data also allow for the establishment of structure-antioxidant activity relationships for quercetin metabolites.     

Using microdialysis to analyse the passage of monovalent nanobodies through the blood-brain barrier

BACKGROUND AND PURPOSE

Nanobodies are promising antigen-binding moieties for molecular imaging and therapeutic purposes because of their favourable pharmacological and pharmacokinetic properties. However, the capability of monovalent nanobodies to reach targets in the CNS remains to be demonstrated.

EXPERIMENTAL APPROACH

We have assessed the blood–brain barrier permeability of Nb_An33, a nanobody against the Trypanosoma brucei brucei variant-specific surface glycoprotein (VSG). This analysis was performed in healthy rats and in rats that were in the encephalitic stage of African trypanosomiasis using intracerebral microdialysis, single photon emission computed tomography (SPECT) or a combination of both methodologies. This enabled the quantification of unlabelled and ^99mTc-labelled nanobodies using, respectively, a sensitive VSG-based nanobody-detection elisa, radioactivity measurement in collected microdialysates and SPECT image analysis.

KEY RESULTS

The combined read-out methodologies showed that Nb_An33 was detected in the brain of healthy rats following i.v. injection, inflammation-induced damage to the blood–brain barrier, as in the late encephalitic stage of trypanosomiasis, significantly increased the efficiency of passage of the nanobody through this barrier. Complementing SPECT analyses with intracerebral microdialysis improved analysis of brain disposition. There is clear value in assessing penetration of the blood–brain barrier by monovalent nanobodies in models of CNS inflammation. Our data also suggest that rapid clearance from blood might hamper efficient targeting of specific nanobodies to the CNS.

CONCLUSIONS AND IMPLICATIONS

Nanobodies can enter the brain parenchyma from the systemic circulation, especially in pathological conditions where the blood–brain barrier integrity is compromised.