阴离子隙和潜在HCO3^-诊断慢性呼吸衰竭酸碱失衡的临床意义

目的探讨阴离子隙（AG）和潜在HCO3^-判断酸碱失衡类型的应用。方法同步测定动脉血气和血电解质，以酸碱失衡预计代偿公式，结合AG值和潜在HCO3^-对慢性呼吸衰竭患者进行酸碱失衡类型的判断。结果（1）代谢性酸中毒（代酸）31例次，其中高AG代酸22例次，高Cl^-代酸5例次，如不测定AG将有17例次代酸失检；（2）应用AG后，三重性酸碱失衡（TABD）从0增至14例次，在这14例次TABD中，如不应用潜在HCO3^-将有8例失检。结论（1）AG和潜在HCO3^-在提高代酸和TABD诊断率方面发挥了重要的作用，并且提出判断TABD的标准和步骤；（2）因有诸多因素影响AG值，使某些代酸患者AG值不能相应地升高，临床应用时应予注意。     

电导滴定法测定氨基化磁性微球表面氨基含量

目的建立电导滴定法测定磁性微球表面微量氨基的化学计量点选择新方法,定量分析其氨基含量,为其表面修饰及偶联奠定基础。方法观察不同因素对滴定结果准确度的影响,在此基础上采用电导滴定法对磁性微球表面氨基进行定量测定,比较曲线拟合及电导率的变化率(ΔK)确定化学计量点2种不同方法对滴定结果的影响。结果建立了更为直接、客观的电导滴定法测定磁性微球表面微量氨基的新方法。利用滴定曲线拟合计算氨基化磁性微球表面氨基含量为(35.05±14.18)μmol/g(RSD=40.47%,n=5);而用ΔK确定化学计量点计算氨基化磁性微球表面氨基含量为(51.38±2.91)μmol/g(RSD=5.66%,n=5),后者的测定精度明显高于前者。结论利用电导率的变化率(ΔK)确定滴定拐点更为直接客观,降低了主观误差,测定精度较高。     

Mental stress and gastric acid secretion

In 14 healthy male volunteers, we studied the influence of acute mental (=psychological) stress induced by performing mental arithmetic and solving anagrams against a financial reward on endogenously stimulated gastric acid output. Personality factors were determined by the Personality Research Form. Acute mental stress significantly (P<0.05) increased systolic blood pressure (+8.9±2.0 mm Hg±sem) and heart rate (+5.3±1.6 beatslmin). The mean gastric acid output during the mental stress period (17.9±2.7 mmol/32 min) did not significantly differ from pre- (16.9±2.3 mmol/32 min) and poststress (18.1±2.2 mmol/32 min) values. However, detailed analysis revealed that mental stress induced contrary changes of gastric acid output in different subjects. About half the individuals reacted with a decrease (up to 60%) and the other half with an increase (up to 60%) in acid output. In some individuals the changes of gastric acid output were very small. By multiple correlations, impulsivity was identified as the personality trait with the highest correlation coefficient (r=0.82) with changes of gastric acid output during the acute mental stress period. During the mental stress period, gastric acid output increased in subjects with high scores on the impulsivity scale, but significantly decreased in those with low scores. We conclude that (1) there is a great individual variability in gastric acid response to acute mental stress, and (2) this variability may be partly attributed to differences in personality traits.     

Simultaneous double-isotope autoradiographic measurement of local cerebral glucose metabolic rate and acid-base status in rat brain

We developed a double-isotope autoradiographic method for the simultaneous measurement of the local cerebral metabolic rate for glucose (1CMRG) and index of regional acid-base status (rABI) in single brain slices using [2-¹⁴C]deoxy-D-glucose (DG) and 5,5-dimethyl-[2-¹⁴C]oxazolidine-2,4, dione (DMO). After iv isotope administration, paper chromatography separates plasma DMO from DG activity using a methanol-methylene chloride solvent system. Initial tissue autoradiograms depict regional DMO plus DG and DG metabolite distribution. After 14 days in a well-ventilated hood, 97.5 ±0.5% of all DMO is lost from tissue sections by sublimation, and a second autoradiogram depicts DG plus DG metabolite distribution. Retention of brain lipids does not alter beta-particle self-absorption, avoiding problems associated with isotope extraction with solvents. Autoradiograms are digitized and converted to isotope-content images. The second autoradiogram is used for lCMRG computation. After subtracting the second regional isotope-content value from the first, the DMO content is obtained and used to compute rABI. Application of this method to normal animals yields expected values for lCMRG and rABI. This method is amenable to whole-slice digitization and creation of functional images of lCMRG and ABI followed by pixel-by-pixel correlations of the two variables, making this a potentially valuable tool for the investigation of the relationships between glucose metabolism and brain acid-base balance.     

高渗羟乙基淀粉(200/0.5)氯化钠注射液用于择期颅脑手术麻醉效果探讨

目的 探讨高渗羟乙基淀粉(200/0.5)氯化钠注射液用于择期颅脑手术麻醉对患者血流动力学、电解质酸碱平衡及降低颅内压效果的影响.方法 选取行择期胶质瘤切除手术患者120例,以随机抽样方法分为对照组(60例)和高渗组(60例);分别给予常规羟乙基淀粉和高渗羟乙基淀粉(200/0.5)静脉输注,比较两组患者不同时间点心率(HR),平均动脉压(MAP),中心静脉压(CVP),Na+、K+、Ca2+、pH及颅内压(ICP)等指标水平.结果 两组患者T2、T3及T4时间点HR和CVP指标均较T0时间点明显提高,差异有统计学意义(P＜0.05);两组患者T3和T4时间点MAP指标均较T0时间点显著降低,差异有统计学意义(P＜0.05);而高渗组患者T4时间点HR和MAP指标水平均明显优于对照组,差异有统计学意义(P＜0.05);两组患者T1、T2、T3及T4时间点Na+和K+指标水平与T0时间点比较差异有统计学意义(P＜0.05);两组患者T2、T3及T4时间点ICP水平较T0时间点均显著降低,差异有统计学意义(P＜0.05);高渗组患者T4时间点ICP水平显著低于对照组,差异有统计学意义(P＜0.05).结论 高渗羟乙基淀粉(200/0.5)氯化钠注射液用于行颅脑外科手术治疗患者可有效稳定血流动力学,纠正电解质酸碱平衡平衡紊乱,并抑制颅内压升高.     

Thermodynamics of clayedrug complex dispersions: Isothermal titration calorimetry and high-performance liquid chromatography

An understanding of the thermodynamics of the complexation process utilized in sustaining drug release in clay matrices is of great importance.Several characterisation techniques as well as isothermal calorimetry were utilized in investigating the adsorption process of a model cationic drug(diltiazem hydrochloride,DIL)onto a pharmaceutical clay system(magnesium aluminium silicate,MAS).X-ray powder diffraction(XRPD),attenuated total reflectance Fourier transform infrared spectroscopy(ATRFTIR)and optical microscopy confirmed the successful formation of the DIL-MAS complexes.Drug quantification from the complexes demonstrated variable behaviour in the differing media used with DIL degrading to desacetyl diltiazem hydrochloride(DC-DIL)in the 2 M HCl media.Here also,the authors report for the first time two binding processes that occurred for DIL and MAS.A competitor binding model was thus proposed and the thermodynamics obtained suggested their binding processes to be enthalpy driven and entropically unfavourable.This information is of great importance for a formulator as care and consideration should be given with appropriate media selection as well as the nature of binding in complexes.     

The SM protein Sly1 accelerates assembly of the ER–Golgi SNARE complex

Soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) and Sec1/Munc18 (SM) proteins constitute the core of an ancient vesicle fusion machine that diversified into distinct sets that now function in different trafficking steps in eukaryotic cells. Deciphering their precise mode of action has proved challenging. SM proteins are thought to act primarily through one type of SNARE protein, the syntaxins. Despite high structural similarity, however, contrasting binding modes have been found for different SM proteins and syntaxins. Whereas the secretory SM protein Munc18 binds to the ‟closed conformation” of syntaxin 1, the ER–Golgi SM protein Sly1 interacts only with the N-peptide of Sed5. Recent findings, however, indicate that SM proteins might interact simultaneously with both syntaxin regions. In search for a common mechanism, we now reinvestigated the Sly1/Sed5 interaction. We found that individual Sed5 adopts a tight closed conformation. Sly1 binds to both the closed conformation and the N-peptide of Sed5, suggesting that this is the original binding mode of SM proteins and syntaxins. In contrast to Munc18, however, Sly1 facilitates SNARE complex formation by loosening the closed conformation of Sed5.In eukaryotic cells, material is transported in vesicles that pinch off of one set of membranes and move along microtubule tracks to the next compartment, where they specifically fuse. Key players in the fusion of a vesicle with its acceptor membrane are the soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) proteins. Heterologous sets of SNARE proteins drive the fusion of two membranes by zippering into a tight four-helix bundle structure. Distinct sets of SNARE proteins carry out different vesicle fusion steps in the cell. An essential SNARE protein for transport into and across the Golgi is Sed5/syntaxin 5 (1). Besides SNARE complexes, Sed5 exists also in a 1:1 complex with the Sec1/Munc18 (SM) protein Sly1 that is essential for ER–Golgi and intra-Golgi trafficking (2). Distinct types of SM proteins are thought to function together with the respective SNARE complex, specifically its syntaxin (reviewed in refs. 3–8).The very N-terminal region, the so-called N-peptide, of Sed5 binds with nanomolar affinity to the outer surface of Sly1 (9–12). This mode of interaction is consistent with the notion that Sly1 can stay bound during SNARE complex formation and that it might even be actively involved in this reaction (13). This idea was strengthened by the observation that Sec1, the SM protein essential for secretion in yeast, interacts with the assembled SNARE complex but not with its isolated syntaxin (14). Unfortunately, for the interaction of Sec1 with its SNARE unit, no definitive structural foundation exists so far, and it remains uncertain whether Sec1 can be considered as a model for SM protein function. Fortunately, the animal counterpart of Sec1, Munc18-1, has been studied in more detail. However, the results of numerous biochemical studies on Munc18-1 appear not to fit into the concept of SM proteins being factors that promote SNARE assembly. On the contrary, initial studies found that Munc18-1 strongly interferes with the ability of its cognate syntaxin 1 to form a SNARE complex (15, 16). This inhibition is difficult to reconcile with an essential role of Munc18-1 during neurotransmitter release (17). The structure of the Munc18-1/syntaxin 1a complex revealed that the central cavity of Munc18-1 wraps around syntaxin in the so-called “closed conformation” (18). In this conformation, the three-helix bundle formed by syntaxin’s N-terminal Habc domain folds back onto its SNARE motif (19), restricting the availability of syntaxin for its SNARE partners. Thus, although they share a similar structure, Munc18-1 and Sly1 appear to bind to their cognate syntaxins in different modes.New light on this discrepancy was shed when it was discovered that Munc18-1 is able to bind simultaneously to a second, spatially separated binding site on syntaxin 1 (15). This second site involves the N-peptide region of syntaxin 1 that, similar to the Sed5 N-peptide (12), binds to the outer surface of Munc18-1. Interestingly, both binding sites are also present in the Munc18/syxtaxin 1 complex of the choanoflagellate Monosiga brevicollis (20). This suggests that the binding mode involving two different sites is evolutionarily conserved. A comparable binding mode was also described for the SM protein Vps45, which regulates trans-Golgi network trafficking. Vps45 binds tightly to the N-peptide of its cognate syntaxin Tlg2/syntaxin 16 (21). It was shown later that Vps45 is also able to interact with the remainder of its Qa-SNARE, possibly in a closed conformation (15, 22).Not all SM proteins are known to bind to the N-peptide of their cognate syntaxin. For example, in the SM protein Vps33, which plays an essential role in the degradation pathway, the N-peptide binding pocket is blocked (23, 24). Vps33 is part of a multisubunit tethering complex known as the homotypic fusion and protein sorting complex (25). Nevertheless, the structure of Vps33 is very similar to other SM protein types despite having low sequence similarity (23, 24). It would be surprising if such structures were not preserved to maintain similar molecular functions. This raises the question of whether there are missing pieces to our understanding of the molecular role of SM proteins.With the idea of a conserved molecular role of SM proteins in mind, we aimed here at a more thorough comparison of Sly1 and Munc18, which are still thought to represent two examples of SM proteins with contrasting syntaxin binding modes. So far nothing is known about a second binding site in the Sly1/Sed5 complex, but the presence of a homologous N-peptide binding site in Munc18 and Sly1 reveals a certain similarity of the two SM protein types. It is debated whether binding of Sly1 to the N-peptide of Sed5 is essential for Golgi trafficking while biochemically less is known (11, 26–28). Neither the effect of Sly1 on SNARE complex assembly has been determined rigorously, nor is it clear whether Sed5 can adopt a closed conformation that interferes with its ability to form a SNARE complex. We therefore sought to determine whether Sly1, in addition to its tight interaction with the N-peptide of Sed5, interacts with the remaining part of Sed5 and, if so, whether this interaction would have an impact on the ability of Sed5 to form a SNARE complex. We found that Sed5 adopts a closed conformation. Comparable to Munc18-1, Sly1 binds simultaneously to both the closed conformation and the N-peptide region of Sed5, although the latter is the major contributor to its affinity to the complex. Remarkably, in contrast to Munc18-1, which blocks SNARE complex assembly, Sly1 was found to assist Sed5 in forming a SNARE complex.     

电位滴定法测定尼美舒利含量能力验证结果分析

目的：设计组织尼美舒利含量测定的能力验证项目（编号NIFDC-PT093）,评价药品检测机构电位滴定法的测定能力。方法：对参加实验室的测定结果进行稳健统计分析,用Z比分数评价实验室检测能力。结果：共153家实验室反馈了结果,其中33个参加实验室（占21.6%）的结果可疑或不满意。省级以上食品药品检验机构的满意率（占92.6%）高于其他机构。结论：本次能力验证项目检测结果主要受滴定液、电极、电位滴定仪、空白试验和溶剂的影响,建议离群者可采取调整滴定液浓度、选择合适电极和滴定参数等措施以保证结果的准确。     

An open multicentre pilot study examining the safety,efficacy and tolerability of fast titrated (800 mg/day by day 4) quetiapine in the treatment of schizophrenia/schizoaffective disorder

Objective. Rapid dose escalation of quetiapine could offer prompt and effective therapy to patients requiring hospitalization for schizophrenia or schizoaffective disorder. This study evaluated the safety, tolerability, and efficacy of a rapid dose escalation of quetiapine to 800 mg/day over 4 days in patients with severe psychotic symptoms diagnosed as schizophrenia or schizoaffective disorder. Methods. In this open-label, multicenter, pilot study, 14 patients aged 18 years or older, requiring hospitalization for schizophrenia or schizoaffective disorder, received quetiapine orally twice daily for 14 days. Quetiapine was administered according to the schedule: 200, 400, 600, and 800 mg/day on the first four treatment days, followed by flexible dosing within the range 400–800 mg/day during the next 10 days. The primary endpoint was to evaluate the safety and tolerability of a fast titration of quetiapine (200, 400, 600, 800 mg/day on the first four treatment days). Effectiveness of a fast titration of quetiapine was the secondary objective of this investigation. Efficacy assessments in the intent-to-treat (ITT) population included changes in the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Severity of Illness (CGI-S) scores from Day 1 (baseline) to Day 14. Results. In 4 days 14 patients were titrated up to a dose of 800 mg/day. Ten patients were diagnosed with schizophrenia, one subject was suffering from schizoaffective disorder of the depressive type and three patients were diagnosed with schizoaffective disorder of the bipolar type. Eleven patients (79%) completed the study. Two patients discontinued the trial because of non-compliance and one patient because of a prolonged QTcB interval. Overall, 29 AEs were reported during this trial, all were considered mild or moderate in severity. During the first 7 days of the trial, 25 AEs were reported in 11 patients. The majority of AEs were considered as possibly related to the study medication. No deaths or serious adverse events were reported. Physical examination at the last trial visit revealed no clinically relevant changes versus baseline and there were no consistent changes over time in vital signs. The BARS and SAS scores indicated an improvement of EPS during the study. After 4 days of fast titration, the mean total PANSS score decreased from 92.8 at baseline to a value of 87.4, there was a further decrease to 78.2 at endpoint. This corresponds to a statistically significant decrease by 14.6 versus baseline (P<0.01). After 4 days of fast titration, the mean CGI-S score was improved from 4.7 at baseline to a value of 4.3 and improved further to 3.8 at endpoint, corresponding to a statistically significant decrease of 0.9 points versus baseline (P<0.01). Conclusion. In this study, fast titration of quetiapine to 800 mg/day over 4 days was generally well tolerated and effective in reducing psychotic symptoms in patients requiring hospitalization for schizophrenia/schizoaffective disorder.