Renal hemodynamics and urinary excretion of 6-keto-prostaglandin F1 alpha and thromboxane B2 in newly diagnosed type I diabetic patients

We have studied the functional importance of renal eicosanoids in renal hemodynamics of seven newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients by treatment with two structurally unrelated inhibitors of cyclooxygenase (i.e., piroxicam and sulindac). Glomerular filtration rate (GFR), renal plasma flow (RPF), daily urinary excretion of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, the stable hydrolysis product of prostacyclin), and thromboxane B2 (TXB2, the stable hydrolysis product of thromboxane A2) were measured before, during, and after piroxicam (all patients) or sulindac (3 patients) treatment. Urinary excretion of 6-keto-PGF1 alpha was significantly increased (P less than .01) in diabetic patients compared with seven healthy subjects, whereas urinary excretion of TXB2 was unchanged. The baseline value of GFR was significantly (P less than .01) higher in diabetic compared with normal volunteers, whereas baseline RPF was comparable in both groups. Piroxicam (20 mg/day) reduced urinary excretion of 6-keto-PGF1 alpha and TXB2 by 65.7 +/- 26 and 64.6 +/- 33%, respectively. These biochemical changes were temporally associated with the approximately 19% decrease in GFR (P less than .01). A week after discontinuation of the drug, GFR and urinary excretion of 6-keto-PGF1 alpha were still significantly (P less than .05) reduced, whereas urinary excretion of TXB2 returned to control values. In contrast, urinary excretion of eicosanoids and renal function were not affected by sulindac (0.4 g/day) treatment. No functional changes were detected in healthy subjects despite a similar suppression of renal cyclooxygenase activity when they were treated with piroxicam.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dietary fish oil on plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha levels in septic rats

Increased mortality from sepsis is associated with high levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha). Linoleic acid, an n-6 essential fatty acid, is the usual precursor of TXB2 and PGF1 alpha, while fish oil is rich in n-3 essential fatty acid, the precursor of less active moieties. Rats were fed chow, an essential fatty acid-deficient diet, or an essential fatty acid-deficient diet supplemented with linoleic acid or fish oil for 2 weeks. The animals then underwent a sham operation or cecal ligation and puncture to induce sepsis. Six hours later, blood was obtained for analysis. The chow and linoleic acid diets produced significant (twofold to fivefold) increases in levels of both TXB2 and PGF1 alpha after sepsis. The essential fatty acid-deficient diet and fish oil diet protected against increases in levels of TXB2 or PGF1 alpha during sepsis. Dietary restriction of linoleic acid or fish oil supplementation may play an important role in altering the inflammatory mediator response to sepsis.     

Aprotinin decreases release of 6-keto-prostaglandin F1 alpha and increases release of thromboxane B2 in cultured human umbilical vein endothelial cells.

Use of the proteinase inhibitor aprotinin significantly improves hemostasis and reduces bleeding after operations in which extracorporeal circulation is used. The mechanism of action, however, has been only partially clarified. In this work we investigated whether aprotinin influenced the production and release of the eicosanoids prostacyclin, measured as the stable metabolite 6-keto-prostaglandin F1 alpha, and thromboxane A2, measured as the stable metabolite thromboxane B2, from endothelial cells. Human umbilical vein endothelial cells were incubated with different concentrations of aprotinin (5.5, 20, 55, and 100 mumol/L). The levels of 6-keto-prostaglandin F1 alpha and thromboxane B2 were measured at baseline and after thrombin stimulation. A concentration-dependent effect of aprotinin on 6-keto-prostaglandin F1 alpha synthesis was demonstrated. After incubation with 100 mumol/L of aprotinin, a 90% reduction in 6-keto-prostaglandin F1 alpha production was seen (31.69 versus 307.44 picograms per million cells; p less than 0.001). Conversely, thromboxane B2 production showed a 345% increase after incubation with aprotinin (287.80 versus 83.82 picograms per million cells; p less than 0.0001). Since 6-keto-prostaglandin F1 alpha inhibits and thromboxane B2 strongly enhances platelet aggregation, it appears that one mechanism of the clinically observed effectiveness of aprotinin lies in the altered ratio of 6-keto-prostaglandin F1 alpha: thromboxane B2 in endothelial cells, which leads to enhanced platelet aggregation and improved vessel sealing.     

Changes of endothelin concentration in cerebrospinal fluid and plasma of patients with aneurysmal subarachnoid hemorrhage

To investigate the clinical significance of endothelin (ET), a potent vasoconstrictor peptide, in subarachnoid hemorrhage (SAH) and SAH-related cerebral vasospasm, we measured the ET-like immunoreactivity (ETLI) in plasma and cerebrospinal fluid (CSF) obtained serially from patients with SAH due to ruptured cerebral aneurysm who underwent aneurysmal surgery. The normal ET–LI levels in plasma and CSF (n = 24) were 12.4±2.0 (mean±s.d.) and 9.1±1.2 pg·ml^-1, respectively. Plasma ET-LI levels in patients with SAH before surgery (16.8±7.8 pg·ml^-1, n = 8) were higher than the normal values ( P <0.05), and became further elevated after surgery (22.5±9.4 pg·ml^-1). ET-LI levels in plasma and CSF one day after surgery were 18.7±5.5 and 18.4±6.8 pg·ml^-1 ( P <0.01 vs. normal values), respectively, and declined thereafter. The plasma and CSF ET-LI levels in patients who showed symptomatic vasospasm became concomitantly elevated again. These results suggest that ET is involved in SAH-related vasospasm and raise the possibility that surgical stress influences the vasospasm.     

Ventricular cerebrospinal fluid and serum concentrations of sTNFR-I, IL-1ra, and IL-6 after aneurysmal subarachnoid hemorrhage

Postsubarachnoid hemorrhage, systemic inflammatory response syndrome and associated organ system failure are more frequently found in patients in poor neurologic condition. Since subarachnoid hemorrhage causes a profound intrathecal inflammatory response with production of proinflammatory cytokines TNFalpha, IL-1beta, and IL-6, a possible explanation for this association is that brain-derived cytokines may enter the systemic circulation in the presence of postsubarachnoid hemorrhage blood brain barrier disruption to systemically activate inflammatory cascades and thereby contribute to the development of postsubarachnoid hemorrhage systemic inflammatory response syndrome and extracerebral organ system failures. In 44 patients with aneurysmal subarachnoid hemorrhage admitted within 3 days of the initial bleed, extracerebral organ system functions were assessed individually and in aggregate using the modified Multiple Organ Dysfunction Score. Serum and cerebrospinal fluid concentrations of soluble tumor necrosis factor-alpha receptor-I, interleukin-1beta receptor antagonist, and IL-6 were determined during the first 2 weeks after subarachnoid hemorrhage and tested for correlation with (1) admission Hunt-Hess grade, (2) development of systemic inflammatory response syndrome and extracerebral organ system failures, and (3) neurologic outcome. The development of postsubarachnoid hemorrhage systemic inflammatory response syndrome and extracerebral organ system failures was paralleled by a significant increase in serum but not in cerebrospinal fluid levels of soluble tumor necrosis factor-alpha receptor-I and IL-1ra, that is, patients with and without extracerebral organ system failures did not differ in pattern and time course of cerebrospinal fluid cytokine concentrations. In contrast, increasing soluble tumor necrosis factor-alpha receptor-I and interleukin-1beta receptor antagonist serum levels correlated with a higher Multiple Organ Dysfunction score and with individual organ system dysfunctions. Postsubarachnoid hemorrhage, systemic inflammatory response syndrome and extracerebral organ system failures could therefore not be linked to changes in cerebrospinal fluid cytokine concentration profiles.     

动脉瘤性蛛网膜下腔出血患者脑脊液垂体激素含量变化的临床研究

目的　研究动脉瘤性蛛网膜下腔出血 (SAH )患者脑脊液 (CSF)促肾上腺皮质激素(ACTH)、促甲状腺激素 (TSH )、卵泡刺激素 (FSH)、黄体生成素 (LH)、泌乳素 (PRL)、生长激素 (GH)浓度的动态变化规律。方法　对 40例动脉瘤性蛛网膜下腔出血患者发病后 1～ 3d、7～ 9d、13～ 15d脑脊液ACTH、TSH、FSH、LH、PRL、GH的含量进行动态检测 ,用TCD检测大脑中动脉血流速度(VMCA)。结果　动脉瘤性蛛网膜下腔出血患者CSF中ACTH、TSH、FSH、LH、PRL、GH在发病后 1～3d、7～ 9d各均值明显高于对照组 ,尤以发病后 7～ 9d变化最明显 ;术前、术后有脑血管痉挛组和非脑血管痉挛组也有明显差异。结论　动脉瘤性蛛网膜下腔出血患者脑脊液ACTH、TSH、FSH、LH、GH、PRL含量与病情演变、脑血管痉挛 (CVS)程度有关 ,并可判断预后。     

Results of early surgical evacuation of packed intraventricular hemorrhage from aneurysm rupture in patients with poor-grade subarachnoid hemorrhage.

OBJECT: The goal of this study was to evaluate the results of early surgical evacuation of "packed" intraventricular hemorrhage (IVH) in patients with poor-grade subarachnoid hemorrhage (SAH). METHODS: The authors performed surgery within 24 hours after onset of SAH, identified on neuroimaging as a cast distending the ventricular system, in 74 patients with poor-grade SAH (World Federation of Neurosurgical Societies Grades IV and V) without intracerebral hemorrhage. Eighteen of these patients had packed IVH; in these patients the intraventricular clots were extensively evacuated via frontal corticotomy performed under microscopic view. CONCLUSIONS: Overall, 42% of the 74 patients undergoing craniotomy in the acute stage had favorable outcomes, whereas 30% died. Using multivariate analysis, variables significantly associated with favorable outcome in patients with poor-grade SAH included absence of a packed intraventricular clot on computerized tomography scanning; absence of a history of cardiac disease; and a Glasgow Coma Scale score of 11 or 12. None of the 18 patients who had packed IVH had favorable outcomes and seven of these died. In six recently treated patients with packed IVH, which was examined using fluid-attenuated inversion recovery imaging, extensive periventricular brain damage was found both immediately after surgery and during the chronic stage. Accordingly, the authors believe that irreversible periventricular brain damage is already complete immediately after packed IVH occurs.     

Levels of catecholamine in plasma and cerebrospinal fluid in aneurysmal subarachnoid hemorrhage.

Despite intensive investigation into the cause of cerebral vasospasm (focal ischemic deficit) after subarachnoid hemorrhage, the morbidity and mortality associated with this condition remain high. Various studies have shown levels of catecholamine in plasma and cerebrospinal fluid (CSF) to be increased in subarachnoid hemorrhage, and it is possible that these vasoactive substances play an important role in the subsequent vasospasm. In an attempt to elucidate this possibility, the study presented here was undertaken to investigate the relationship between catecholamine levels in plasma and CSF and focal ischemic deficit (FID); the rupture of aneurysms on blood vessels supplying the hypothalamus as compared with the rupture of aneurysms on blood vessels supplying other areas of the brain; and the clinical outcome of the patients. Concentrations of adrenaline and noradrenaline in plasma and CSF samples obtained from 21 patients who had suffered aneurysmal subarachnoid hemorrhage were determined by a radioenzymatic technique. Significantly higher levels of adrenaline were found at the time of surgery in the CSF of patients with FID. A similar trend, though not statistically significant, was also observed for plasma. Patients with a rupture of aneurysms on blood vessels supplying the hypothalamus showed a tendency towards higher catecholamine levels in plasma and CSF. Subjects with a bad clinical outcome (i.e., those who were severely disabled or had died) had significantly higher levels of catecholamine in plasma than did those with a good clinical outcome (i.e., those with moderate or no disability). Further detailed analysis of the interrelationships showed that, within the group of patients with FID, those with rupture of aneurysms on blood vessels supplying the hypothalamus had significantly higher catecholamine levels in plasma than did those with rupture of aneurysms on other cerebral vessels. Furthermore, in the group of patients with rupture of aneurysms on blood vessels supplying the hypothalamus, those with a bad clinical outcome had significantly higher catecholamine levels in plasma than did those with a good clinical outcome. These findings lend support to the possibility that damage to the hypothalamus and subsequent elevations in catecholamine levels may be associated with FID and poor clinical outcome.     

Increased concentration of atrial natriuretic factor in the cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage and raised intracranial pressure

Plasma and cerebrospinal fluid (CSF) atrial natriuretic factors/peptides (ANFs/ANPs) were measured in 26 patients with normal or raised intracranial pressure (ICP) by means of an instant radioreceptor assay. All 26 patients were suffering from aneurysmal subarachnoid hemorrhage (SAH), and 11 had also developed raised ICP (ICP greater than 20 mm Hg). In SAH patients with normal ICP, the plasma levels of ANF were 20 to 200 pg/ml (mean +/- SE, 89 +/- 68 pg/ml); in the 11 SAH patients with raised ICP, however, ANF levels were 14 to 262 pg/ml (mean 114 +/- 79 pg/ml). The difference was not statistically significant. The ANF/ANP plasma levels in 6 healthy volunteers were 15 to 167 pg/ml (mean 77 +/- 32 pg/ml). Although the ANF/ANP concentration in the CSF of patients with normal ICP did not reach the lower limit of detectability (i.e., 4 pg/ml) in any case, in those with elevated ICP it was 14 to 120 pg/ml (mean 49 +/- 37 pg/ml). This difference was statistically highly significant. The results of this preliminary study suggest that the ANF/ANP concentration in human CSF is 1 to 2 orders lower than that in the plasma and that there is no significant correlation between ANF/ANP levels in the CSF and the plasma. After SAH in patients with raised ICP, there was an accompanying increase in the ANF/ANP concentration in the CSF, but the ANF/ANP concentration in the plasma was not changed significantly. Accordingly, a central ANF/ANP release might be hypothesized to play a causative or adaptive role in the neuroendocrine regulation of ICP dynamics, although this may simply be an epiphenomenon.     

Detection of soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in both cerebrospinal fluid and serum of patients after aneurysmal subarachnoid hemorrhage

OBJECT: The aim of this study was to explore whether levels of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are elevated in the cerebrospinal fluid (CSF) and serum of patients after aneurysmal subarachnoid hemorrhage (SAH). METHODS: This prospective clinical study focused on 21 patients who had recently suffered an SAH due to aneurysmal rupture and 15 control patients with hydrocephalus who had no other central nervous system disease. Cerebrospinal fluid and serum samples obtained within the first 3 days and on the 5th and 7th days of SAH were assayed for ICAM-1 and VCAM-1 by using quantitative enzyme-linked immunosorbent assays. Levels of soluble forms of ICAM-1 (p = 0.00001) and VCAM-1 (p = 0.009) in the patients' CSF and those of ICAM-1 (p = 0.00001) and VCAM-1 (p = 0.00001) in their serum were found to be elevated after SAH compared with levels in the CSF and serum of control patients with hydrocephalus. In addition, when the authors compared the increased levels of adhesion molecules in the CSF and serum of patients after SAH, the only statistically insignificant difference that they found was between the levels of VCAM-1 in serum obtained on Days 5 and 7 after SAH (p = 0.27). CONCLUSIONS: Adhesion molecules are a group of macromolecules that may participate in the inflammatory process, a common pathway leading to vasospasm after SAH. Leukocyte adherence to the vascular endothelium, which is induced by adhesion molecules, has been believed to be the initial signal of the development of vasospasm. The authors have demonstrated the synchronized elevation of two adhesion molecules in both CSF and serum following aneurysmal SAH. Blocking of ICAM-1 as well as VCAM-1 by monoclonal antibodies post-SAH may provide a beneficial effect on vasospasm.     

Effect of hydrocephalus on prostaglandins and thromboxane B2 in ventricular cerebrospinal fluid

The concentrations of prostaglandin F2 alpha, prostaglandin E2, 6-ketoprostaglandin F1 alpha (prostacyclin metabolite), and thromboxane B2 were assayed in ventricular cerebrospinal fluid obtained from 28 patients with hydrocephalus (17 obstructive, 11 communicating). Seven patients received dexamethasone or hydrocortisone on the day of sampling. No patient received nonsteroidal anti-inflammatory compounds for 48 hours before sampling. The median values did not differ significantly between the two types of hydrocephalus or from the concentrations in lumbar cerebrospinal fluid obtained from patients without intracranial pathology during lumbar myelography for possible lumbar disc disease. Hence, there is no evidence that eicosanoids accumulate in the ventricles in hydrocephalus, and it is unlikely that they have a significant role in its symptomatology.     

Minor leak before rupture of an intracranial aneurysm and subarachnoid hemorrhage of unknown etiology.

Of 312 consecutive patients who were admitted to an emergency hospital because of subarachnoid hemorrhage (SAH), data on premonitory minor leaks were available on 303. Patients with an aneurysmal SAH had significantly (P less than 0.05) more frequently (100 of 273, or 37%) a history of symptoms consistent with a previous minor leak than those with a hemorrhage of unknown etiology (4 of 30, or 13%). Aneurysmal SAH was associated with a poorer prognosis, more frequent occurrence of repeated bleeding and cerebral ischemia compared with SAH of unknown etiology, even in the good grade patients. The possible occurrence of a minor leak in poor grade patients may be even more frequent because the history obtained from family members was quite often uncertain. The outcome did not differ according to the evidence of previous minor leaks, but those who were admitted before a major rupture had a good outcome. The median time between a minor leak and major rupture was 14 days (range, 1 day to 4 mo). The correct diagnosis of a minor leak is important because early diagnosis and management can improve the overall outcome of this disastrous disease.     

Changes in arterial thromboxane B2 and 6-keto-prostaglandin-F1 alpha levels in cirrhotic and non-cirrhotic patients after hepatectomy

Following hepatectomy, arterial concentrations of thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), which are stable metabolites of thromboxane A2(TXA2) and prostaglandin I2(PGI2), were measured by radioimmunoassay in 17 cirrhotic and 9 non-cirrhotic patients to assess the role of TXB2 and PGI2 in patients with liver dysfunction during hepatectomy. In both cirrhotic and non-cirrhotic patients, arterial TXB2 and 6-keto-PGF1 alpha levels significantly increased during hepatectomy and decreased to preoperative levels at the 1st postoperative day (1-POD). The TXB2/6-keto-PGF1 alpha ratio significantly decreased during hepatectomy and at 1-POD. There were no significant differences in changes of TXB2 and PGI2 levels between cirrhotic and non-cirrhotic patients. In cirrhotic patients with poor hepatic reserve, whose ICG K values were less than 0.08, arterial 6-keto-PGF1 alpha levels were significantly higher and the ratio were significantly lower than in cirrhotic patients with good hepatic reserve and non-cirrhotic patients before and after operation. Based on these results, it is concluded that the TXA2/PGI2 ratio becomes low after hepatectomy and the ratio is lower in cirrhotic patients with poor hepatic reserve.     

CT与脑脊液炎性细胞因子对外伤性蛛网膜下腔出血后脑血管痉挛的早期诊断意义

目的探讨CT及脑脊液炎性细胞因子对外伤性蛛网膜下腔出血后脑血管痉挛的早期诊断价值。方法50例外伤性蛛网膜下腔出血患者根据据其临床表现和TCD检查分为血管痉挛组及非血管痉挛组，对比其CT的改良Fisher分级及脑脊液中IL-6、TGF水平。结果两组脑脊液中IL-6、TGF水平差异有显著性，且血管痉挛发生率及程度与改良Fisher分级成正比。结论根据早期CT影像及脑脊液中炎性细胞因子的变化可以预测脑血管痉挛的发生，从而指导治疗。