Magnitude and time course of platelet inhibition with extended release dipyridamole with or without aspirin in healthy Japanese volunteers. The AGgrenox versus Aspirin Therapy Evaluation (AGATE-Japan)

Randomized trials showed greater stroke prevention with extended release dipyridamole in combination with low dose aspirin than with either aspirin or dipyridamole alone. However, most studies with this formulation (Aggrenox) were carried out in Europe and North America. Considering potential inter-racial differences in drug response, we conducted a small randomized study in healthy Japanese volunteers to compare antiplatelet regimens with regard to the changes in the platelet biomarkers. Thirty healthy volunteers (18-40 years old, 15 male and 15 female) of Japanese descent were randomized to Aggrenox (n = 17) or aspirin 81 mg (n = 13 volunteers) for 30 days. Platelet function was assessed at baseline, and on days 15, and 30 by conventional aggregometry, whole blood flow cytometry, and cartridge-based analyzer. Both Aggrenox and aspirin provided sustained platelet inhibition at Day 15 and Day 30. Therapy with Aggrenox, however, was associated with more prominent and significant inhibition of collagen-induced aggregation (p = 0.08, Day 15), as well as prolongation of the closure time (p = 0.001, Day 30); diminished expression of platelet endothelial cell adhesion molecule-1 (PECAM-1) (p = 0.02, Day 30), glycoprotein IIb (GPIIb) antigen (p = 0.001 and 0.024 for Day 15 and Day 30), and GPIIb/IIIa activity by PAC-1 antibody (p = 0.014 and 0.03), CD62 (P-selectin) (p = 0.03 for Day 15 and Day 30), as well as inhibition of protease activated receptors (PAR-1) associated with intact WEDE-15 (p = 0.002 and 0.003) and SPAN-12 (p = 0.002 and 0.04) thrombin receptors when compared with aspirin. The magnitude and durability of platelet response after Aggrenox in healthy Japanese is similar to those effects observed in Caucasians and African-Americans. A larger study to assess drug efficacy and safety in the Japanese post-stroke patients is warranted.     

No difference in the effects of clopidogrel and aspirin on inflammatory markers in patients with coronary heart disease

Aspirin reduces several pro-inflammatory markers in patients with coronary heart disease (CHD), while limited data exists with clopidogrel. The aim of the present substudy of ASCET was to assess the influence of clopidogrel as compared to aspirin on selected circulating inflammatory markers in patients with stable angiographically verified CHD. Patients on treatment with aspirin 160 mg/day for at least seven days were randomized to either aspirin 160 mg/day (n = 105) or clopidogrel 75 mg/day (n = 101). Fasting blood samples were drawn at baseline and after one month and after one year for determination of high sensitivity C-reactive protein, tumor necrosis factor a (TNFa), interleukin 6, monocyte chemoattractant protein 1(MCP-1), CD40L, P-selectin, interleukin 10 and transforming growth factor. The groups were similar regarding demographic variables. There were no differences in any variables including changes from baseline to one month and one year between the groups. In the aspirin group we found significantly lower levels of TNFa and MCP-1 after one year; 1.00 versus 1.16 pg/ml (p < 0.001) and 245 versus 261 pg/ml (p < 0.001), respectively. Likewise, in the clopidogrel group the level of TNFa was significantly reduced after one year; 0.99 versus 1.19 pg/ml (p < 0.001). In patients with CHD we found no between-group differences in circulating markers of inflammation after one year treatment with clopidogrel 75 mg/day compared to aspirin 160 mg/day, but in both groups lower levels of TNFa were obtained. The present results indicate similar anti-inflammatory effects of the two drugs.     

Twice daily dosing of aspirin improves platelet inhibition in whole blood in patients with type 2 diabetes mellitus and micro- or macrovascular complications

The efficacy of low-dose aspirin in type 2 diabetes mellitus (T2DM) has been questioned. We tested if twice daily dosing of aspirin would be more effective in T2DM, possibly due to increased platelet turnover. A randomised cross-over study compared 75 mg aspirin OD, 75 mg BID and 320 mg OD (≥ 2 week treatment periods) in 25 patients with T2DM and micro- or macrovascular complications. Platelet responses were examined by impedance aggregometry (WBA) and the IMPACT-R aspirin test in whole blood, light transmittance aggregometry in platelet-rich plasma (LTA), and urinary 11-dehydro-thromboxane B2 (TxM). Aspirin 75 mg BID decreased arachidonic acid (AA)-induced WBA compared to 75 mg OD (9.7 ± 4.5 vs. 12.6 ± 3.5 ohm; p = 0.003) or to 320 mg OD (11.5 ± 4.2 Ohms; p = 0.049). WBA responses to collagen were similarly attenuated by BID or high dosing (by 12-14%; p = 0.02 for both). The IMPACT-R showed a better response to 75 mg BID compared to 75 mg OD (p = 0.049), but not to 320 mg OD. AA-induced aggregation by LTA was <6.5% on all occasions, with no differences between aspirin dosages. TxM was reduced after 320 mg OD (p = 0.002), but not 75 mg BID (p = 0.07). Reticulated platelets were highly correlated with mean platelet volume (MPV; r2 = 0.74, p<0.0001). Both markers for platelet turnover were correlated with AA-induced WBA, but neither identified patients who benefited from BID dosing dependably. In conclusion, twice daily dosing improved laboratory responses to aspirin in high risk T2DM patients. Studies of whether BID dosing of aspirin can improve clinical outcomes in such patients are of interest.     

Inflammation, oxidative stress and platelet activation in aspirin-treated critical limb ischaemia: beneficial effects of iloprost

Platelets critically contribute to atherothrombosis and worsening ischaemia in patients with peripheral arterial disease (PAD), eventually leading to critical limb ischaemia (CLI). Furthermore, persistent platelet activation despite antiplatelet therapy has been reported in this setting. The prostacyclin analogue iloprost is currently recommended in CLI patients for its effects in relieving symptoms by promoting local perfusion. In this study, we investigated the effects of iloprost infusion on urinary 11-dehydro-TXB? and 8-iso-PGF(?α) excretion rate, as in vivo indexes of thromboxane-dependent platelet activation and lipid peroxidation, respectively, and on platelet-derived proinflammatory sCD40L and nitric oxide bioavailability in 44 patients with CLI while on chronic treatment with low-dose aspirin. Daily iloprost infusion for one-week significantly decreased urinary 11-dehydro-TXB? [499 (277-807) vs. 380 (189-560) pg/mg creatinine, p < 0.0001] and 8-iso-PGF(?α) [533 (316-842) vs. 334 (196-540) pg/mg creatinine, p < 0.0001] as well as plasma sCD40L [1540 (1005-3015) vs. 948 (845-2030) pg/ml, p < 0.0001]. Furthermore, a significant increase in plasma nitrate plus nitrite levels has been observed [26.8 (18.8-35.9) vs. 43.7 (33.0-75.5) μM, p < 0.0001]. A significant direct correlation was also found between urinary 8-iso-PGF(?α) and 11-dehydro-TXB2 before and after iloprost treatment (Rho = 0.695, p < 0.0001). In conclusion, we report that a short-term course of iloprost is able to significantly reduce residual thromboxane biosynthesis, oxidative stress, endothelial dysfunction and platelet-derived inflammation in low-dose aspirin treated patients with CLI.     

银杏酮酯对缺血性卒中患者血浆促炎因子及认知功能的作用研究

目的研究银杏酮酯分散片对缺血性卒中后炎症反应及认知功能的影响及临床意义。方法本研究为前瞻性临床随机对照试验,选取2012年10月-2014年6月在南京鼓楼医院和扬州市第一人民医院神经内科住院的急性缺血性卒中患者,并随机分为试验组[银杏酮酯分散片(0.15 g,tid)联合阿司匹林治疗(0.1 g qd)]和对照组[阿司匹林(0.1 g qd)治疗],用药180 d。比较两组血清炎症因子白细胞介素(interleukin,IL)-1β、IL-6、IL-15、IL-17A、IL-23、肿瘤坏死因子(tumor necrosis factor,TNF-α)水平。使用美国国立卫生研究院卒中量表(National Institutes of Health Stroke Scale,NIHSS)、改良Rankin量表、简易精神状态量表(Mini-Mental State Examination,MMSE)、蒙特利尔认知量表(Montreal Cognitive Assessment,MOCA)评分评估两组治疗前及治疗后(13±1)d、(30±7)d、(90±7)d、(180±7)d的神经功能缺损和卒中后认知功能的改变,比较两组治疗前后量表评分的变化情况。结果研究纳入60例患者,因血液标本不合格脱落8例,纳入统计分析的有试验组27例,对照组25例。治疗(13±1)d时,试验组血清IL-1β([1.55±0.43)pg/ml vs(2.05±0.74)pg/ml,P0.001],IL-15([1.88±0.82)pg/ml vs(3.17±1.93)pg/ml,P0.001],IL-6([5.57±4.96)pg/ml vs(8.81±8.00)pg/ml,P=0.042],IL-17A([5.11±1.51)pg/ml vs(6.67±2.24)pg/ml,P0.001],IL-23([0.42±0.88)pg/ml vs(0.67±0.98)pg/ml,P0.001],TNF-alpha([15.12±6.97)pg/ml vs(18.31±6.61)pg/ml,P=0.009]水平较用药前有显著下降;而在对照组中仅IL-15([2.01±0.72)pg/ml vs(2.53±1.20)pg/ml,P=0.036]较用药前有显著下降。两组各随访点MMSE和MOCA评分虽无显著差异,但试验组用药后(30±7)d、(90±7)d、(180±7)d与用药前MMSE相比,比对照组改善更显著(P分别为0.036、0.012和0.048)。结论银杏酮酯分散片联合阿司匹林比单用阿司匹林能更显著降低急性缺血性卒中患者血清炎症因子水平,改善其认知功能。     

Measurement of aspirin concentrations in portal and systemic blood in pigs: effect on platelet aggregation, thromboxane and prostacyclin production

Low doses of enteric-coated aspirin were administered orally to pigs. Plasma aspirin concentrations measured in blood obtained simultaneously from permanent catheters in a systemic artery and portal vein for 6 hours after dosage showed a large variation in the plasma aspirin concentration: time profile between pigs. After 50 mg single dose the ratio of the arterial: portal area under the plasma concentration versus time curve (AUC) was 0.63 +/- 0.08 (mean +/- SE, n = 6). In three pigs which received all three dosage regimens, the arterial: portal AUC ratios were 0.48 +/- 0.05 after 50 mg single dose, 0.52 +/- 0.02 after 100 mg single dose and 0.47 +/- 0.02 after 100 mg daily for 1 week. Platelet aggregation in response to sodium arachidonate (1.65 mM) was completely abolished after chronic aspirin administration of 100 mg daily. Thromboxane production (pg/10(6) platelets) induced by this stimulus decreased from 536 +/- 117 before aspirin to 57 +/- 14 after aspirin (mean +/- SE, n = 4; p = 0.03). Aortic prostacyclin synthesis, measured as 6-keto PGF1 alpha (ng/disc after 10 min incubation), was 1.66 +/- 0.28 (mean +/- SE, n = 4) in untreated pigs and 0.95 +/- 0.25 (n = 5) in treated pigs (p = 0.07). Results from this study support the idea that a difference between aspirin concentrations in the portal and systemic circulations can be achieved. Whether this can be translated into a clinically useful differential effect on the vessel wall compared to the platelet remains to be determined.     

Dipyridamole decreases protease-activated receptor and annexin-v binding on platelets of post stroke patients with aspirin nonresponsiveness

BACKGROUND: Although controversial, the phenomenon of aspirin resistance (AR) has been correlated in some small studies with poor clinical outcomes in patients with coronary artery disease. Even less is known regarding the role of AR in the post stroke population. The reason for and the underlying mechanism of AR is unknown. We hypothesized that excessive formation of thrombin on the platelet surface may contribute to this phenomenon and assessed how dipyridamole affects multiple platelet and thrombin generation biomarkers in AR patients after ischemic stroke. METHODS: Whole blood samples from 20 post stroke AR patients were pretreated with dipyridamole, simulating the therapeutic range, and then incubated for 45 min at 37 degrees C. Platelet characteristics were assessed by aggregometry, cartridge-based analyzer, and receptor expression by flow cytometry. Markers of thrombin generation were measured in the autologous plasma by ELISA. RESULTS: Pretreatment of blood with dipyridamole resulted in 22-26% diminished expression of intact PAR-1 receptor (p=0.021 and p=0.024) and 28-31% decrease of annexin V binding (p=0.031 and p=0.02) after incubation with 2 microg/ml and 4 microg/ml of dipyridamole, respectively. Platelet aggregation and thrombin generation markers were not affected in vitro by dipyridamole. CONCLUSIONS: Dipyridamole may be capable of overcoming increased prothrombinase complex formation and be in part able to compensate for AR in patients with moderate carotid stenosis. This phenomenon may explain the clinical advantages of Aggrenox, known to reduce ischemic events in post stroke patients as proven in clinical trials, though an additional antithrombotic benefit beyond the platelet inhibition by aspirin alone.     

Prevention by NCX 4016, a nitric oxide-donating aspirin, but not by aspirin, of the acute endothelial dysfunction induced by exercise in patients with intermittent claudication

Ischemia/reperfusion damage evokes systemic inflammation and endothelial dysfunction in patients with intermittent claudication. We compared the effects of aspirin with those of a nitric oxide-donating aspirin in preventing the acute, systemic endothelial dysfunction provoked by exercise-induced ischemia of the lower limbs in patients with intermittent claudication. In a prospective, randomized, single-blind, parallel-groups trial among 44 patients with intermittent claudication we compared four weeks of aspirin (100 mg o.d.) with NCX 4016 (800 mg b.i.d.). Primary end point was the exercise-induced changes in brachial flow-mediated vasodilation (FMD) at day 28; secondary end points were effort-induced changes of markers of neutrophil (plasma elastase) and endothelial (soluble VCAM-1) activation. Baseline FMD was comparable in the two groups, both on day 1 (pre-treatment: aspirin = 3.1 +/- 0.5%, nitroaspirin = 3.9 +/- 0.7%, p = NS), and on day 28 (aspirin = 3.4 +/- 0.7%, NCX 4016 = 3.2 +/- 0.6%, p = NS). Maximal treadmill exercise induced an acute worsening of FMD in both groups at baseline (aspirin = -1.15%, nitroaspirin = -1.76%); after four weeks treatment, the impairment of FMD induced by exercise was still present in the aspirintreated group (-1.46%) while it was abolished in the NCX 4016-treated group (+0.79%, p = 0.038 vs. aspirin). Similarly, exercise induced an increase of plasma elastase and of sVCAM-1 which were not affected by aspirin while they were suppressed by NCX 4016. Maximal treadmill exercise induces a systemic arterial endothelial dysfunction in patients with intermittent claudication. A nitric oxide-donating aspirin, but not aspirin, prevents effort-induced endothelial dysfunction.     

Botulism: heart rate variation, sympathetic skin responses, and plasma norepinephrine.

BACKGROUND: Botulism may involve the autonomic nervous system. METHODS: We assessed the autonomic function of 6 botulism patients with heart rate variations, sympathetic skin responses, and plasma norepinephrine. RESULTS: Two weeks after onset, all the patients had absent sympathetic skin response in the palm and sole. Compared with controls, the heart rate variation of botulism patients was significantly decreased at rest (3.1 +/- 1.2% vs. 20.9 +/- 2.0%, p = 0.0018) and during deep breathing (4.3 +/- 2.3% vs. 29.7 +/- 2.6%, p = 0.0018). The botulism patients had significantly lower plasma norepinephrine levels (supine 29.2 +/- 10.1 pg/ml vs. 257.5 +/- 65.8 pg/ml, p = 0.0018; standing 40.3 +/- 13.1 pg/ml vs. 498.5 +/- 85.6 pg/ml, p = 0.0018). The heart rate variation and sympathetic skin response was greatly improved 6 months after onset. CONCLUSIONS: Heart rate variation, absence of sympathetic skin response, and low plasma norepinephrine are all manifestations of autonomic dysfunction in botulism patients.     

The effect of aspirin on the size of the hemostatic plug

The prolongation of the bleeding time by aspirin is presumably due to interfering with platelet function. Direct quantitative studies evaluating the effects of aspirin on the platelet component of the hemostatic plug have not been described. We measured blood loss from a standard ear injury in rabbits after treatment with either 5 mg or 200 mg/kg of aspirin (ASA) or sodium salicylate (SA), and related this observation to the number of platelets incorporated into the hemostatic plug. The high dose of aspirin was chosen since this dose inhibits PGI2 biosynthesis. Both doses of aspirin but not salicylate caused a significant increase on blood loss from the treated ear compared to the control (ASA 5 mg/kg, 0.012 +/- 0.009 ml, (m +/- SE), n = 44, p = 0.03; ASA 200 mg/kg, 0.02 +/- 0.007 ml, n = 17, p less than 0.05). Both doses of aspirin also caused a significant increase in the number of platelets incorporated into the hemostatic plug when compared to the SA treated animals (ASA 5 mg/kg, 3.52 +/- 0.34 X 10(6) platelets per incision, (m +/- SE), n = 59; SA 5 mg/kg, 1.9 +/- 0.15 X 10(6) platelets per incision, n = 54, p less than 0.001; ASA 200 mg/kg, 3.19 +/- 0.54 X 10(6) platelets per incision, n = 22; SA 200 mg/kg, 1.5 +/- 0.26 X 10(6) platelets per incision, n = 23, p less than 0.001). This study suggests that following aspirin administration hemostasis is achieved by the incorporation of a greater number of platelets into the platelet plug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Simultaneous monitoring of endothelin-1 and vasopressin plasma levels in migraine

Vasopressin levels in plasma rise during migraine attacks. Vasopressin also induces endothelin-1 synthesis in endothelial cells, suggesting a role as a mediator of elevated plasma endothelin-1 in migraine. To explore a possible relationship between endothelin-1 and vasopressin in migraine, plasma concentrations of both peptides were monitored simultaneously throughout an attack and during two migraine-free intervals (control) in 20 patients. Endothelin-1 was elevated 6 h after the onset of an attack (3.3 +/- 0.3 pg/ml vs 2.7 +/- 0.2 pg/ml during migraine-free intervals; p = 0.12) whereas vasopressin was increased over control levels (2.8 +/- 0.3 pg/ml) by 3 h (3.6 +/- 0.4 pg/ml; p < 0.05) and remained elevated at 6 h (3.9 +/- 0.5 pg/ml; p < 0.01). These data suggest that vasopressin may act as a peripheral mediator of increased plasma endothelin-1 in migraine.     

Predictors of thromboxane levels in patients with non-ST-elevation acute coronary syndromes on chronic aspirin therapy

High levels of thromboxane A2 (TxA2), a key mediator of platelet activation and aggregation, are associated with an increased risk of cardiovascular events. We aimed at assessing the predictors of higher plasma levels of TxB2, the stable metabolite of TxA2, in consecutive patients presenting with non-ST-elevation acute coronary syndrome (NSTE-ACS) on previous aspirin (ASA) treatment undergoing coronary angiography. Ninety-eight consecutive patients (age 61 ± 11, 75% males) with NSTE-ACS, on previous chronic ASA treatment, were prospectively enrolled in this study. Coronary disease extent was assessed by angiography according to the Bogaty score. In all patients, admission plasma levels of TxB2 (pg/ml) were measured by enzyme-linked immunosorbent assay, and patients showing TxB2 levels in the fourth quartile were compared to patients showing TxB2 levels in the lower quartiles. Multivariable logistic regression analysis showed that platelet count (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.02-1.63, p=0.04), multivessel coronary disease (OR 1.37, 95% CI 1.13-3.67, p=0.03), and coronary atherosclerosis extent index (OR 1.91, 95% CI 1.45-6.79, p=0.001) were independent predictors of TxB2 level upper quartile. Of note, C-reactive protein serum levels were similar in patients with TxB2 levels in the upper quartile as compared to those in the lower quartiles (p=0.49). In conclusion, NSTE-ACS patients with severe coronary atherosclerosis may have incomplete suppression of TxA2 production despite chronic ASA therapy. This finding suggests that additional efforts should be made to lower TxA2 levels in patients with widespread coronary artery disease.     

A lzheimer病患者血清IL-2、sIL-2R水平的研究

目的 :Alzheimer病 (AD)是由多种病因引起的涉及多种病理机制和出现多种病理表现的多因素性疾病。近年来研究发现 AD患者血清中细胞因子水平增高以及皮质、海马内神经炎性斑数量增加 ,表明免疫炎症机制在 AD的发生、发展中起重要作用。本研究拟通过对 AD患者血清 IL - 2、 s IL - 2 R水平的检测 ,来探讨其在 AD慢性炎症病理过程中的作用。方法 :采用双抗体酶联免疫吸附试验 (EL ISA) ,检测 10例 AD患者血清 IL 2及 s IL 2 R水平 ,并与血管性痴呆 (VD)组及正常对照组做了比较。结果 :AD组血清中 IL- 2水平为 35 2± 33.4pg/ ml,明显高于 VD组 (2 83.6± 6 2 .9pg/ ml)和正常对照组 (2 5 8.5± 49.1pg/ ml) ,差异显著 (P<0 .0 0 5 ) ;AD组 s IL - 2 R水平为 81± 37.3pmol/ L ,明显高于VD组 (5 4.1± 30 .9pmol/ L )和正常对照组 (48.3± 18.3pmol/ L ) ,差异显著 (P<0 .0 5 )。结论 :说明 AD患者脑内免疫细胞被激活 ,IL- 2、s IL- 2 R参与了 AD的慢性炎症改变过程。血清 IL- 2和 s IL- 2 R可作为检测 AD外周血的免疫标记物。     

Influence of lithium treatment on GDNF serum and CSF concentrations in patients with early Alzheimer's disease

Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer's disease (AD). One possible mechanism of action might be the induction of neurotrophins. Recently, we found a significant increase of brain-derived neurotrophic factor (BDNF) serum levels in AD patients treated with lithium and a significant decrease of ADAS Cog sum scores in comparison to placebo-treated patients. In another previous study we have shown that glial cell line-derived neurotrophic factor (GDNF) levels in CSF of patients with early AD are increased most probably due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease. Here we assessed the influence of a lithium treatment on GDNF serum and cerebrospinal fluid (CSF) concentrations in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. We found a significant negative correlation of lithium concentration in serum with GDNF concentration in CSF at the end of treatment (r = -0.585, p = 0.036) and with the difference of GDNF concentration in CSF before and after treatment (r = - 0.755, p = 0.003). However, we could not show a difference in GDNF concentrations between the patients after the treatment with lithium or placebo (serum, mean ± standard deviation: 434.3 ± 117.9 pg/ml versus 543.8 ± 250.0 pg/ml, p = 0.178; CSF, 62.3 ± 37.4 pg/ml versus 72.8 ± 43.9 pg/ml, p = 0.511). The findings of the present investigation indicated that beneficial effects of the lithium treatment might reduce the necessity of enhanced GDNF expression in the CNS in early AD.     

多发性硬化患者病情演变与血浆和脑脊液趋化因子CXCL10水平的相关性

目的 观察急性期多发性硬化(MS)患者血浆和脑脊液中趋化因子CXCL10水平的动态变化规律及其与临床神经功能障碍的相关性,探讨其对疾病活动性的判定价值.方法 收集急性期MS患者、缓解期MS患者及健康对照各53例,神经系统非炎性疾病(NIND)32例,采用酶联免疫吸附试验法检测血浆和脑脊液中CXCL10水平,并进行扩展残疾状况评分量表(EDSS)评分.结果 (1)与急性期初期相比,急性期MS组患者第2、4周血浆CXCL10水平[(601±365)、(575±297)pg/ml]明显升高(t=-2.898、-2.651,P=0.001、0.003);第4周脑脊液中CXCL10水平[(1807±803)pg/ml]与急性期初期比较差异无统计学意义.(2)急性期初期MS组血浆CXCL10水平明显高于缓解期MS组[(287±118)pg/ml,t=3.555,P=0.001]和健康对照组[(248±130)pg/ml,t=4.895,P=0.000].(3)急性期MS组脑脊液CXCL10水平[(1774±604)pg/ml]明显高于NIND组[(122±114)pg/ml,t=15.192,P=0.000].(4)急性期MS组患者血浆与脑脊液中CXCL10水平间存在相关性(r=0.792,P=0.001);脑脊液CXCL10水平与同期EDSS评分之间存在相关性(r=0.526,P=0.002).结论 (1)MS患者血浆中CXCL10水平对判断疾病活动性有一定的参考价值.(2)急性期MS患者血浆CXCL10水平能在一定程度上反映其在脑脊液中的水平.(3)检测急性期MS患者脑脊液CXCL10水平对判断临床功能障碍程度有一定的参考价值.

Abstract：

Objective To investigate the evolution of CXCL10 in blood plasma and cerebrospinal fluid (CSF) during relapses of multiple sclerosis (MS),and the correlation between these and the clinical neurological dysfunction.Methods Fifty-three patients with definite MS during relapsing state (relapsing MS group) diagnosed by the McDonald criteria;fifty-three patients with definite MS during remitting state ( remitting MS group);thirty-two patients with non-inflammatory neurologic disease ( NIND group) and fiftythree healthy controls (NC group) were enrolled in the study.Each patient clinical status was evaluated with the Expanded Disability Status Scale ( EDSS).Plasma and CSF levels were analyzed by enzyme-linked immunoassay.Results ( 1 ) The CXCL10 level in plasma in relapsing MS group elevated significantly between the 2nd ( (601 ± 365 ) pg/ml,t = - 2.898,P = 0.001) and the 4th ( (575 ± 297 ) pg/ml,t = -2.651,P=0.003) week after relapsing;GXL10 in CSF (n =32) did not changed significantly in the 4th week after relapsing( (1807 ±803) pg/ml).(2) The CXCL10 level in plasma in relapsing MS group were significantly higher than that in the healthy control group ((248±130) pg/ml,(=4.895,P=0.000) and remitting MS group ((287 ±118) pg/ml,t = 3.555,P = 0.001 ).( 3 ) The CXCL10 level in CSF in relapsing MS group (( 1774 ± 604) pg/ml) was significantly higher than that in NIND group ( ( 122 ± 114) pg/ml,t= 15.192,P =0.000).(4) The CXCL10 level in plasma in relapsing MS group had correlation with that in CSF (r=0.792,P=0.001).The CXCL10 level in CSF in relapsing MS group had correlation with EDSS scores (r = 0.526,P = 0.002 ).Conclusions The CXCL10 level in plasma might be implemented as a paraclinical marker of disease activity in MS.The CXCL10 level in plasma of MS may be relevant to that in CSF.The CXCL10 level in CSF of MS may indicate the clinical neurological dysfunction.     

Potential utility of soluble p3-alcadeinα plasma levels as a biomarker for sporadic Alzheimer's disease

Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins (α, β, γ) that share identical localization and function to the amyloid-β protein precursor (AβPP) in the brain. Alcs are proteolyzed in neurons through successive cleavages via secretases, resulting in non-aggregative p3-Alc, where p3 corresponds to the AβPP-fragment. We found p3-Alcα detected in human plasma reflected the pathological process of amyloid-β accumulation in Alzheimer's disease (AD) patients and therefore investigated the utility of p3-Alcα as a plasma biomarker in AD. We measured p3-Alcα plasma levels in 83 sporadic-AD, 18 mild cognitive impaired (MCI), and 24 control subjects using the sandwich-ELISA system. Pooled samples with previously published data (171 AD and 45 controls) were also analyzed. The plasma p3-Alcα concentrations in patients with AD and MCI were significantly higher compared with control subjects (224.7 ± 40.4, 223.3 ± 53.9, and 189.1 ± 32.9 pg/ml, respectively; p = 0.0012). In AD patients, the plasma p3-Alcα concentration significantly correlated with age (r = 0.23, p = 0.037) and serum creatinine levels (r = 0.23, p = 0.0012). Even after adjusting for confounding factors of age, gender, renal function, and ApoE-ε4, high plasma p3-Alcα levels were correlated with significant AD risk, with an odds ratio 1.47 (95% confidence interval: 1.18-1.93, p = 0.0019) for every 10 pg/ml increase. Pooled analysis further confirmed these findings. Increased plasma p3-Alcα, evident in the early stages of cognitive impairment, suggests that Alc metabolites are useful plasma biomarkers of AD.     

Brain-derived neurotrophic factor plasma variation during the different phases of the menstrual cycle in women with premenstrual syndrome

Premenstrual syndrome (PMS) is characterized by a cluster of psychological and somatic symptoms that begin during the late luteal phase of the menstrual cycle and disappear after the onset of menses. Since PMS might be caused by an alteration in the cyclical hormonal modifications and ovarian steroids are directly involved in the regulation of mood, affective and cognitive functions and influence neurotrophins expression, in particular the brain-derived neurotrophic factor (BDNF), we aimed to evaluate whether plasma BDNF levels in women with PMS differ from those of normally menstruating women without PMS. Sixty-two women were divided into two groups: one group of women (n=35) with PMS and one group (n=27) composed by normally menstruating women. Plasma samples were collected at day 7 (follicular phase) and day 21 (luteal phase) of the menstrual cycle. Plasma BDNF of the control group significantly increased (p<0.001) from the follicular phase (402.90±74.41pg/ml) to the luteal phase (1098.79±146.49pg/ml). On the other hand, in the PMS group plasma BDNF levels significantly decreased (p<0.001) from the follicular phase (412.45±78.35pg/ml) to the luteal phase (233.03±75.46pg/ml) Luteal BDNF levels of the PMS women were significantly lower than those of the control group (p<0.001). In women with PMS, plasma BDNF followed a decreasing trend during the ovarian cycle, in opposition to the increasing trend observed in women without PMS. The lower luteal BDNF levels of the PMS women might be a consequence of an altered hormonal response and might play a role in the onset of the symptoms PMS related.     

Reduced sensitivity of platelets from type 2 diabetic patients to acetylsalicylic acid (aspirin)-its relation to metabolic control

Aspirin (acetylsalicylic acid, ASA), which is recommended for primary and secondary prevention in diabetes mellitus (DM), has been shown to have a lower antiplatelet activity in diabetic patients. We conducted a crossover designed observational study to evaluate whether there is an association between the parameters relevant to metabolic control of diabetes and platelet sensitivity to aspirin in type 2 diabetic patients. Platelets' ability to adhere and aggregate was monitored with the use of platelet function analyser (PFA-100 collagen/epinephrine closure time, CT(CEPI) or collagen/ADP closure time, CT(CADP)), classical turbidimetric aggregometry and whole blood electrical aggregometry (WBEA), using collagen (WBEA(coll)), ADP (WBEA(ADP)) and arachidonic acid (WBEA(AA)) as platelet agonists, in 48 control healthy volunteers (mean age+/-S.D., 49+/-9 years) and 31 type 2 DM patients (50+/-9 years; HbA(1c) 9.4+/-1.6%). In majority of control subjects (69%) and minority of diabetic patients (29%, p=0.0006), the use of 150 mg aspirin daily for 1 week significantly reduced platelet adhesiveness and reactivity (by 14.1% in diabetes vs. 78.6% in control, p(np)=0.0035, as expressed by the relative changes in CT(CEPI)). Aspirin reduced WBEA(coll) and WBEA(AA) to a lesser extent in diabetic patients (by 2.1% vs. 8.3% in controls, p(np)=0.0397, and by 97.3+/-12.8% vs. 100% in controls, p(np)=0.0383, respectively), which corresponded to ASA-mediated decreased aggregation in platelet-rich plasma (PRP, r(S)=0.45 and r(S)=0.78 for collagen- or arachidonate-agonized platelets, p<0.01 or lower). The maximal inhibition of platelet aggregation was lower and IC(50) higher in diabetic compared to control subjects, both in the presence of arachidonic acid (71% vs. 39%, p(np)0.0001; 0.5 microg/ml vs. 1.3 microg/ml, p<0.0001) and collagen (52% vs. 35%, p<0.0004; 1.6 microg/ml vs. 2.1 microg/ml, p<0.01). The reduced response of platelets from diabetic subjects to aspirin was associated with a higher level of HbA(1c), lower concentration of HDL-cholesterol and a higher total cholesterol concentration. Overall, there is evidence that reduced platelets response to aspirin may occur more often in diabetic patients. Poor metabolic control may play a role in the reduced platelet sensitivity to aspirin in DM patients. Thus, our findings strongly support the requirements for an excellent near-normal metabolic control and may suggest a need for alternative ASA dosing schedules in DM patients.     

阿尔茨海默病患者外周血IL-6、IL-8、TNF-α水平与认知功能的相关性

目的 探讨阿尔茨海默病(AD)患者外周血白细胞介素-6(IL-6)、IL-8及肿瘤坏死因子α(TNF-α)水平与认知功能的相关性.方法 选择2015年1月~2016年1月在济宁医学院附属医院兖州院区治疗的AD患者90例作为研究组,并选择同期在我院体检的90名健康人作为对照组,采用酶联免疫吸附法(ELISA)检测两组研究对象的外周血IL-6、IL-8及TNF-α水平,并采用简易精神状态量表(MMSE)和临床痴呆评定量表(CDR)对其认知功能和日常行为能力进行评估.比较各组间炎性因子水平的差异,分析炎性因子表达水平与认知功能的相关性.结果 研究组AD患者外周血的IL-6、IL-8及TNF-α水平均明显高于对照组[(128.64±10.28)pg/ml比(103.59±8.72)pg/ml,(134.32±9.67)pg/ml比(101.45±7.32)pg/ml,(221.39±23.54)pg/ml比(109.68±18.76)pg/ml],差异均有统计学意义(P<0.05).受教育年限为AD患者认知功能的保护因素,IL-6、IL-8及TNF-α水平为危险因素(P<0.05).整体人群中IL-6、TNF-α水平与MMSE得分呈负相关(r=-0.314,-0.079;P<0.05),IL-8与MMSE无相关性.结论 外周血IL-6及TNF-α水平与轻度AD患者的认知功能相关.     

Increased plasma levels of pro- and anti-inflammatory cytokines in patients with febrile seizures

PURPOSE: Pro- and antiinflammatory cytokines regulate the febrile response during infection. Febrile seizures (FSs) conversely are associated with rapid onset of high fever. Activation of the cytokine network has been shown in previous studies of FSs and cytokines. In this study, the association between cytokines and FSs was further investigated. METHODS: Interleukin-1beta (IL-1beta), interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), interleukin-10, and tumor necrosis factor-alpha plasma levels were measured with enzyme-linked immunosorbent assay in 55 children with FSs and in 20 age-matched febrile controls immediately on arrival at the hospital. Cerebrospinal fluid cytokine levels also were measured in 16 FS children. RESULTS: The plasma IL-1RA/IL-1beta ratio (mean, 2,133 vs. 119; median, 790 vs. 105; p < 0.0001) and plasma IL-6 (mean, 41.7 pg/ml vs. 16.1 pg/ml; median, 19.6 pg/ml vs. 10.5 pg/ml; p = 0.005) were significantly higher in FS patients compared with control children. Logistic regression analysis was used to find the most significant predisposing factors for FSs. In this analysis, the high plasma IL-1RA/IL-1beta ratio was the most significant factor connected to FSs (OR, 41.5; 95% CI, 4.9-352.8), but high plasma IL-6 also was significantly associated with FSs (OR, 5.3; 95% CI, 1.4-20.3). CONCLUSIONS: Present results support the hypothesis that the cytokine network is activated and could have a role in the pathogenesis of FS.