Microbiologic Effect of Bovine Cerebrospinal Fluid and Azithromycin Against Neisseria meningitidis,Streptococcus pneumoniae,and Haemophilus influenzae

Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of azithromycin against reference strains of Streptococcus pneumoniae ATCC 49619, Neisseria meningitidis ATCC 13090, and Haemophilus influenzae ATCC 49247 were determined by the macrodilution broth method with and without 10% bovine cerebrospinal fluid (CSF) supplementation. The MICs and MBCs were within one to two dilutions for N. meningitidis and S. pneumoniae, and no difference was observed for H. influenzae. Time-kill curves demonstrated enhanced killing by azithromycin when 10% bovine CSF was added to media for N. meningitidis. The minimum azithromycin concentration for a greater than 3 log₁₀ reduction in inoculum with bovine CSF was 0.03 μg/ml and without CSF was 0.12 μg/ml, a 3-fold difference. Killing was not significantly different for either H. influenzae nor S. pneumoniae. (Pharmacotherapy 1997;17(5);985–989)     

利奈唑胺在脑膜炎患者脑脊液中的药动学及药效学研究

目的:探讨利奈唑胺在脑膜炎患者脑脊液中的药动学及药效学参数变化。方法:10例重症神经外科患者入组,应用利奈唑胺(600 mg/次,静脉滴注,每日2次,每次静脉滴注60 min)治疗脑室外引流引起的革兰阳性球菌感染所致的脑膜炎,当药物达稳态后测定其在脑脊液中的药动学参数,结合微生物学评价其药效学指标。结果:利奈唑胺在用药2.5 h达到峰浓度(cmax)(5.5±2.5)μg/ml,其谷浓度(cmin)是在用药0和12 h时出现,分别为(3.1±1.3)μg/ml和(3.3±1.8)μg/ml;AUC0-12 h为(105±59)μg·h/ml,性别对AUC0-12 h的影响差异无统计学意义[男性:(112±58)μg·h/ml,女性:(104±49)μg·h/ml,(P>0.05)];药物对脑脊液的平均穿透率为67%;最低抑菌浓度(MIC)≤2μg/ml时,AUC0-24 h/MIC的值为112.6,浓度>2μg/ml的时间是(11.2±2.8)h,抗菌药物超MIC时间(T>MIC)占100%,90%MIC(MIC90)≤4μg/ml时,AUC0-24 h/MIC90的值为57.1,T>MIC占54%。结论:利奈唑胺对脑膜炎患者脑脊液有良好的穿透率,常规剂量能达到有效治疗浓度。     

脑脊液生物标志物辅助诊断新生儿化脓性脑膜炎研究进展

新生儿化脓性脑膜炎( neonatal purulent meningitis, NPM)是指在新生儿时期常见的中枢神经系统急性细菌 感染性疾病,由于新生儿体液、细胞免疫及吞噬细胞功 能发育不成熟,新生儿患脑膜炎的风险比其他年龄段儿 童更高;早产儿因其接受母体来源的免疫球蛋白远远低 于足月儿,也成为 NPM 的高发人群。 NPM 总体发病率 在发达国家为 0. 2‰~ 0. 3‰,在发展中国家高达 0. 8‰~ 6. 1‰[1] ;病死率在发达国家为 10% ~ 15%,在发展中国 家仍达 40% ~ 60%,是引起新生儿致死致残的主要原因 之一[2] 。 近年来,其病死率虽有明显下降,但存活新生 儿中仍有 50%遗留神经系统后遗症[3] 。 早期诊断和及 时有效应用抗菌药物治疗是降低 NPM 病死率、改善预 后 的 关 键 措 施[4] 。 NPM 诊 断 的 金 标 准 是 脑 脊 液 (cerebrospinal fluid,CSF) 微生物培养阳性,然而阳性率 通常很低[5] 。 目前仍依靠经典的 CSF 参数辅助诊断 NPM(白细胞计数、葡萄糖和蛋白,以及革兰染色),然 而,这些参数不仅随着患儿胎龄、日龄的增长而变化,还 受穿刺时损伤、抗菌药学预处理、脑室内出血以及标本 的送检时间等因素的影响[6-7] 。 近年来各种 CSF 生物标 志物成为人们的研究对象,以期早期、快速、准确地诊断 NPM,本文对这些生物标志物在 NPM 诊断中的研究进 展作一综述。     

血及脑脊液病原菌培养阴性的小儿化脓性脑膜炎121例疗效分析

目的：探讨血及脑脊液培养阴性的小儿化脓性脑膜炎121例的临床疗效,为临床经验用药提供依据。方法：回顾性分析我院2017年1月至6月收治的血及脑脊液培养阴性的化脓性脑膜炎患儿121例,根据治疗方法不同分为观察组和对照组。观察组68例,采用万古霉素联合头孢他啶治疗;对照组53例,采用头孢曲松联合青霉素常规治疗方案。观察两组患儿脑脊液的恢复、住院天数、费用及预后、药物不良反应情况。结果：观察组治疗7 d、14 d后复查脑脊液WBC均低于对照组（t=分别为-2.96、-3.72,P均<0.01）。两组患儿治疗7 d、14 d后复查脑脊液葡萄糖、蛋白水平比较差异均无统计学意义（P均>0.05）。观察组患儿的住院时间（15.16±0.47）d,短于对照组的（18.51±1.04）d（t=-2.95,P<0.01）;住院费用与对照组比较差异无统计学意义（t=0.72,P>0.05）。观察组治愈60例（88.2%）,对照组治愈38例（71.7%）,两组比较差异有统计学意义（χ2=4.52,P<0.05）。两组患儿均未出现脑室膜炎、脑积水及肝肾功能、心肌酶异常并发症,对照组出现4例出现胆囊病变,两组比较差异有统计学意义（P<0.05）。结论：万古霉素联合头孢他啶在小儿化脓性脑膜炎治疗中疗效显著,与常规治疗方法相比,强有力的抗生素可有效迅速改善脑脊液白细胞总数,缩短住院时间,减少并发症及后遗症的风险,值得临床推广应用。     

流行性脑脊髓膜炎病死率的马尔科夫预测模型

对大庆市1980~1999年流行性脑脊髓膜炎病死率数据,利用马尔可夫链来预测估计未来年份的病死率的状态,为卫生防疫提供科学的依据。     

脑脊液细胞学检查在早期结核性脑膜炎的诊断价值(附39例报告)

目的评估脑脊液细胞学在早期结核性脑膜炎的诊断价值。方法对39例颅内结核性脑膜炎的脑脊液细胞学变化进行分析。结果脑脊液细胞学早期存在二种变化的混合反应：①嗜中性粒细胞为主；②小淋巴细胞为主。结论早期结核性脑膜炎在临床症状和CT变化不明显情况下，脑脊液细胞学检查具有明显的诊断价值。     

大鼠脑脊液多次采集改良模型的建立

目的 建立大鼠多次采集脑脊液的动物模型,以进行药物在大鼠脑部的动力学研究。方法 将大鼠麻醉后,利用脑立体定位仪,通过大鼠双侧耳道与上方门齿固定大鼠头部,切开大鼠头部皮肤,暴露颅骨与颈部肌肉交界处,将采样针对准大鼠颅骨与颈部肌肉交界处的中心位置,利用脑立体定位仪的上下轴将采样针竖直缓慢向下刺入,刺入约0.6~0.9 cm（视大鼠体质量而定）后,脑脊液即可被采出。结果 脑脊液采集成功率（脑脊液成功采样1次及以上）100%（26例）,动力学采样成功率（脑脊液成功采样6次及以上）80%（10例）。结论 本模型操作简单、结果稳定、成功率高、重复性高,适合脑部作用药物进行脑脊液动力学研究。     

A Common Variant in ERBB4 Regulates GABA Concentrations in Human Cerebrospinal Fluid

The neuregulin 1 (NRG1) receptor ErbB4 is involved in the development of cortical inhibitory GABAergic circuits and NRG1-ErbB4 signaling has been implicated in schizophrenia (SCZ). A magnetic resonance spectroscopy (¹H-MRS) study has demonstrated that a single-nucleotide polymorphism in ERBB4, rs7598440, influences human cortical GABA concentrations. Other work has highlighted the significant impact of this genetic variant on expression of ERBB4 in the hippocampus and dorsolateral prefrontal cortex in human post mortem tissue. Our aim was to examine the association of rs7598440 with cerebrospinal fluid (CSF) GABA levels in healthy volunteers (n=155). We detected a significant dose-dependent association of the rs7598440 genotype with CSF GABA levels (G-allele standardized β=−0.23; 95% CIs: −0.39 to −0.07; P=0.0066). GABA concentrations were highest in A homozygous, intermediate in heterozygous, and lowest in G homozygous subjects. When excluding subjects on psychotropic medication (three subjects using antidepressants), the results did not change (G-allele standardized β=−0.23; 95% CIs: −0.40 to −0.07; P=0.0051). The explained variance in CSF GABA by rs7598440 in our model is 5.2% (P=0.004). The directionality of our findings agrees with the aforementioned ¹H-MRS and gene expression studies. Our observation therefore strengthens the evidence that the A-allele of rs7598440 in ERBB4 is associated with increased GABA concentrations in the human central nervous system (CNS). To our knowledge, our finding constitutes the first confirmation that CSF can be used to study genotype–phenotype correlations of GABA levels in the CNS. Such quantitative genetic analyses may be extrapolated to other CSF constituents relevant to SCZ in future studies.     

α1-Acid Glycoprotein Concentrations and Cerebrospinal Fluid Drug Distribution after Subarachnoid Hemorrhage

Study Objective . To test the hypothesis that changes in α₁-acid glycoprotein (AAG) concentration alter central nervous system (CNS) drug distribution after subarachnoid hemorrhage. Design . Two-phase, prospective study. Setting . University-associated medical center. Patients . Twenty-one patients with subarachnoid hemorrhage. Intervention . In phase I, serum AAG concentrations of patients with subarachnoid hemorrhage were measured serially and compared with those in 21 controls undergoing elective neurosurgical procedures. In phase II, nimodipine was the pharmacologic probe to determine the relationship between drug distribution into the CNS and changes in AAG concentration. Measurements and Main Results . Serum and cerebrospinal fluid (CSF) samples were collected from patients with subarachnoid hemorrhage treated with nimodipine and used to measure total and unbound drug concentrations. Concentrations of AAG were 39% higher in patients than in controls preoperatively. They decreased significantly by 24 hours after surgery in patients and increased in controls. In both groups the concentrations were higher than reported normal values. During the period of reduced AAG concentration, calculated unbound nimodipine concentrations were 3-fold higher (p<0.05) than at later periods, with a trend toward higher total concentrations. Overall, mean CSF nimodipine concentration was 6.4% of mean serum total concentration. The CSF concentrations decreased as AAG concentrations increased, independent of serum concentrations (r = −0.52, p<0.02). Conclusion . Concentrations of AAG change after subarachnoid hemorrhage and are transiently influenced by surgery. Unbound drug concentration increases when AAG concentrations decrease, whereas CSF concentrations decrease when AAG concentrations increase. These preliminary findings suggest that changes in AAG concentrations can alter unbound serum nimodipine concentrations and may affect CSF drug distribution.     

Elevated Concentrations of Neurofilament Light Chain in the Cerebrospinal Fluid of Bipolar Disorder Patients

Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for BD. To investigate this hypothesis, we sampled CSF from 133 patients with BD and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-type fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, although the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs.     

Dissimilar Effects of Lithium and Valproic Acid on GABA and Glutamine Concentrations in Rat Cerebrospinal Fluid

• 1.This study compared the effects of the antimanic drugs, lithium and valproic acid, on GABA and glutamine CSF concentration and on head-shakes during hyponatremia.
• 2.Hyponatremic and normonatremic rats were treated with 2 mEq/kg lithium and 360 mg/kg valproic acid. Behavioral observation was conducted for 120 min after which blood and CSF collection were performed under anesthesia.
• 3.Peritoneal dialysis with glucose induced moderate hyponatremia and doubled glutamine CSF concentrations. Both lithium and valproic acid significantly increased GABA CSF levels in normonatremic and hyponatremic animals. Valproic acid induced head-shakes and increased CSF glutamine concentration.
• 4.The results suggest that both antimanic drugs have similar effects on GABA, but lithium is preferred if the increase in glutamine concentration poses a problem, either in the presence or absence of hyponatremia.

     

流行性脑脊髓膜炎流行特征的灰色预测模型

利用灰色 GM( 1,1)模型预测大庆市流行性脑脊髓膜炎发病率和病死率 ,并对模型精度进行了检验。结果显示 ,发病率GM( 1,1)模型为 :x( k+1) =-12 1.0 449e- 0 .2 859k+181.0 0 42 ,预测平均残差为 :e=-0 .10 963,后验差的比值 C=0 .0 742 <0 .35 ,则 P>0 .95 ,拟合精度高     

颞下颌关节紊乱病关节液中NO含量变化及临床研究

目的：研究颞下颌关节上腔注射透明质酸钠治疗颞下颌关节紊乱病及治疗前后下颌关节液中一氧化氮（NO）含量变化.方法：将60例颞下颌关节紊乱病患者随机分为两组,关节腔灌洗＋透明质酸钠注射治疗组（透明质酸钠组）,单纯关节腔灌洗治疗组,10例志愿者为对照组.观察两种治疗方法治疗前后下颌关节液NO含量变化.结果：无症状志愿者1例检测出微量NO（0.17 μmol/L）,治疗前两组关节滑液NO含量差异无统计学意义（P＞0.05）,治疗后透明质酸钠组比单纯关节腔灌洗组NO含量明显降低（P＜0.05）.结论：透明质酸钠对NO有抑制作用,关节上腔注射透明质酸钠对关节盘前移位和骨关节病有较好的治疗效果.     

脑脊液置换加鞘内注药治疗结核性脑膜炎及结核性脑膜脑炎疗效研究

目的探讨脑脊液置换加鞘内注药治疗结核性脑膜炎和结核性脑膜脑炎(二者统称结脑)的临床疗效。方法将确诊的63例结脑患者随机分两组。对照组予以常规抗结核药物及激素等治疗。治疗组在此基础上采用脑脊液置换加鞘内注药治疗。观察两组患者的体温、颅压、临床体征、颅内病灶吸收情况和脑脊液(CSF)等变化,并进行比较。结果治疗组患者体温、颅压降至正常,意识恢复时间及CSF中细胞数、糖、蛋白质、氯化物等恢复时间均短于对照组(P<0.05);治疗1个月后,患者颅内病灶吸收情况及并发症改善优于对照组(P<0.05)。结论脑脊液置换加鞘内注药可缓解结脑的症状,缩短疗程,减少并发症,该方法是治疗结核性脑膜炎的一种简单、有效、安全的方法。     

神经系统疾病脑一氧化氮、一氧化氮合酶的变化

目的 通过测定癫痫患者及格林巴利综合征患者脑内NO及NOS的变化探讨NO的可能作用。方法 采集复杂部分性发作病人发作3日内及格林巴利综合征患者脑脊液测定NO及NOS的含量。结果 病性发作3日内脑内NO水平247.5000±79.6829μmol/L,NOS为1.6088±0.1831U/ml,格林巴利综合征病人NO水平为478.9024±180.2927μmol/L,NOS活性为1.2648±0.2308U/ml,均显著高于对照组。结论 NO参与了某些神经系统疾病的发病过程,在复杂部分性发作及格林巴利综合征中具有不同的作用机制。     

Plasma and Cerebrospinal Fluid Concentrations of Morphine and Morphine Glucuronides in Rabbits Receiving Single and Repeated Doses of Morphine

The pharmacokinetics of morphine in plasma and the distribution of morphine and its glucuronidated metabolites within the cerebrospinal fluid were investigated in rabbits. After single morphine dosage, the plasma AUC ratio of morphine-3-glucuronide/morphine was 11·1 compared with 0·14 for morphine-6-glucuronide/morphine. The similar elimination half-lives of morphine (107 min), morphine-3-glucuronide (122 min), and morphine-6-glucuronide (105 min) suggested the glucuronidation to be the rate-limiting step, which was substantiated by the observation that morphine-3-glucuronide becomes eliminated four times faster when applied intravenously. Both after single and repeated morphine administration, the ratios of CSF and plasma levels of the parent drug were higher than those of morphine-3-glucuronide or morphine-6-glucuronide. These data demonstrate a poor penetration of the glucuronides across the blood-brain barrier and do not support the previously postulated accumulation of morphine-6-glucuronide in the central nervous system during chronic morphine treatment.     

反相高效液相色谱法测定兔血清和脑脊液甲硝唑浓度和药代动力学参数的研究

用ＲＰ－ＨＰＬＣ测定兔血清和脑脊液甲硝唑的浓度和药代动力学参数。５只健康家兔口服０．１ｇ／ｋｇ甲硝唑后，同时采血和脑脊液，分别测得兔血清和脑脊液的药时曲线，经计算机拟合为一室模型。甲硝唑在脑脊液的达峰时比血清的达峰时滞后４５．７ｍｉｎ而两者峰浓度之比为２１：１００，表观分布容积之比为１００：１７。     

血脂康对急性冠脉综合征患者内皮功能的影响

目的观察血脂康对急性冠脉综合征患者血清一氧化氮（NO）及一氧化氮合酶（NOS）的影响。方法随机选择急性冠脉综合征病患者67例．将其随机分为血脂康治疗组35例，阿托伐他汀组32例，并对两组患者治疗前后血清NO及NOS含量水平进行对比分析。结果血脂康和阿托伐他汀均可升高急性冠脉综合征患者血清NO及NOS水平，其作用无明显差异（P〉0．05）。结论血脂康可抑制脂质过氧化反应．保护血管内皮功能，对急性冠脉综合征的防治具有重要意义。     

Dual Therapeutic Effects of an Albumin-Based Nitric Oxide Donor on 2 Experimental Models of Chronic Kidney Disease

Chronic kidney disease (CKD) is accompanied by a variety of complications, typically renal anemia and kidney fibrosis. Accordingly, it is desirable to develop the novel therapeutics that can treat these CKD conditions. Since nitric oxide (NO) has multiple functions including hypoxia inducible factor stabilizing, anti-inflammatory, anti-oxidative, and anti-apoptoic activities, the use of NO for the CKD therapy has attracted considerable interest. Here, we evaluate the therapeutic impacts of S-nitrosated human serum albumin (SNO-HSA), a long-lasting NO donor, on 2 animal models of CKD. SNO-HSA increased the expression of erythropoietin (EPO), VEGF, and eNOS by stabilizing hypoxia inducible factor–1α in HepG2 and HK-2 cells. SNO-HSA increased hematopoiesis in both healthy and renal anemia rats, suggesting the promotion of EPO production. In unilateral ureteral obstruction–treated mice, SNO-HSA ameliorated kidney fibrosis by suppressing the accumulation of renal extracellular matrix. SNO-HSA also inhibited unilateral ureteral obstruction–induced α–smooth muscle actin increase and E-cadherin decrease, suggesting that SNO-HSA might suppress the accumulation of myofibroblasts, an important factor of fibrosis. SNO-HSA also inhibited the elevations of fibrosis factors, such as transforming growth factor–β, interleukin-6, and oxidative stress, while it increased EPO production, an anti-fibrosis factor. In conclusion, SNO-HSA has the potential to function as a dual therapeutics for renal anemia and kidney fibrosis.     

Effects of Kaempferol and Myricetin on Inducible Nitric Oxide Synthase Expression and Nitric Oxide Production in Rats

Abstract: When administered as drugs or consumed as food components, polyphenolic compounds synthesized in plants interfere with intracellular signal transduction pathways, including pathways of nitric oxide synthase expression. However, effects of these compounds in vivo do not always correlate with nitric oxide synthase‐inhibiting activities revealed in experiments with cultured cells. The initial goal of this work was to compare effects of flavonoids kaempferol and myricetin on inducible nitric oxide synthase mRNA and protein expression monitored by real‐time RT‐PCR and immunohistochemistry and to evaluate the impact of these effects on nitric oxide production in rat organs measured by means of electron paramagnetic resonance spectroscopy. Kaempferol and myricetin attenuated the lipopolysaccharide‐induced outburst of inducible nitric oxide synthase gene expression; kaempferol also significantly decreased the lipopolysaccharide‐induced outburst of inducible nitric oxide synthase protein expression in the liver. Myricetin decreased nitric oxide production in intact rat liver. Kaempferol did not decrease nitric oxide production neither in intact rats nor in the lipopolysaccharide‐treated animals. Kaempferol even enhanced the lipopolysaccharide‐induced increase of nitric oxide production in blood. Myricetin did not interfere with lipopolysaccharide effects. As both kaempferol and myricetin are known as inhibitors of inducible nitric oxide synthase expression, our results suggest that modifications of nitric oxide level in tissues by these compounds cannot be predicted from data about its effects on nitric oxide synthase expression or activity.