Dose-Dependent Effect of Aprotinin on Aggravated Pro-Inflammatory Cytokines in Patients with Pulmonary Hypertension Following Cardiopulmonary Bypass

Background: To investigate the dose dependent effect of aprotinin on aggravated pro-inflammatory cytokines in patients with pulmonary hypertension (PH) after cardiopulmonary bypass (CPB). Methods: Thirty-two patients with pulmonary arterial pressure (PAP) above 60 mmHg were recruited. They were assigned randomly to control (Group A, n = 8), and treated groups (Group B with aprotinin = 0.5 × 10⁵ KIU/Kg, and Group C with aprotinin = 1.0 × 10⁵ KIU/Kg, n = 12 each group). Blood samples were collected at various intervals of time and analyzed, from 0 hour (before CPB as baseline), at the completion of CPB, 4 hours and 24 hours after CPB, to measure the concentrations of interleukin 1 (IL-1), interleukin-8 (IL-8), interleukin-10 (IL-10) and tumor necrosis factor- (TNF-). Results: All the biomarkers significantly increased after CPB. There was no significant difference in cytokine levels between Group A and group B after CPB. But IL-1, IL-8 and TNF- of Group C were not only significantly lower than Group A (p < 0.05), but also lower than Group B at various time points after CPB (p < 0.05). IL-10 of group C was significantly higher than Group A and Group B after CPB (p < 0.05). Conclusions: High dose aprotinin can suppress the release of pro-inflammatory cytokines IL-1, IL-8 and TNF-, and enhance the release of IL-10 in patients with PH after CPB. For patients having PH, there exists a simple and potential way to reduce the inflammatory response by applying high dose aprotinin.     

Southern copperhead venom enhances tissue-type plasminogen activator induced fibrinolysis but does not directly lyse human plasma thrombi

In addition to degrading fibrinogen as a source of consumptive coagulopathy, purified fractions of southern copperhead (Agkistrodon contortrix contortrix; A. c. contortrix) venom has been demonstrated to enhance fibrinolysis. The goal of this investigation was to characterize the kinetic fibrinolytic profile of A. c. contortrix venom in the absence and presence of tissue-type plasminogen activator (tPA) to determine if intact venom had tPA independent fibrinolytic properties. Utilizing thrombelastographic methods, the coagulation and fibrinolytic kinetic profiles of human plasma exposed to A. c. contortrix venom (0–6 μg/ml) were determined in the absence or presence of tPA (0–100 IU/ml). Then, plasma was exposed to 0–6 μg/ml of venom without tPA added and coagulation observed for 3 h. Venom significantly prolonged the onset of coagulation, decreased the velocity of thrombus growth but did not significantly decrease clot strength. In the presence of tPA, venom significantly decreased clot strength, shortened the time of onset of fibrinolysis, decreased clot lysis time but did not significantly affect the maximum rate of lysis. Lastly, while venom exposure in the absence of tPA significantly prolonged the onset of coagulation and decreased the velocity of clot growth, venom exposure did not result in detectable fibrinolysis over the 3 h observation period. A. c. contortrix venom enhances tPA mediated fibrinolysis by degrading plasma coagulation kinetics. Intact A. c. contortrix venom does not possess sufficient fibrinolytic activity to cause fibrinolysis in human plasma at the concentration tested.     

Venous thrombosis and tissue plasminogen activator release deficiency: a family study

Thrombotic events are often due to fibrinolytic defects such as impaired tissue plasminogen activator (tPA) synthesis and/or release or increased plasminogen activator inhibitor (PAI) levels. In this report we describe four members of a family with a history of recurrent venous thrombosis, who demonstrated defective tPA release after dynamic tests. Two symptomatic patients and one asymptomatic individual showed absent or abnormally low tPA antigen (tPA:Ag) and activity (PA) increases after DDAVP infusion and/or 20 min of venous occlusion. In these patients PAI values were slightly higher than controls. A satisfactory tPA:Ag release was found in the fourth asymptomatic patient. All other coagulation tests were within the normal ranges. This familial defect of the fibrinolytic system seems to be inherited as an autosomal trait.     

Interleukin 12 induces activation of fibrinolysis and coagulation in humans

Interleukin 12 (IL-12) has potential efficacy in malignant, infectious and allergic diseases. Its side-effects include activation of coagulation and fibrinolysis, as documented in chimpanzees. We assessed the coagulative and fibrinolytic response in 18 patients with renal cell carcinoma after subcutaneous injection of 0.5 microg/kg recombinant human IL-12. IL-12 induced a fibrinolytic response in 17 patients (94%): plasmin-alpha2-anti-plasmin complexes (PAPc) increased from 11.8 +/- 6.6 nmol/l (mean +/- SD) to a maximum of 18.8 +/- 7.4 nmol/l at 72 h. Baseline levels of tissue plasminogen activator (tPA) and plasminogen-activator inhibitor-I (PAI) were elevated in eight and 14 patients respectively. tPA increased from 12.6 +/- 5.2 ng/ml to a maximum of 19.0 +/- 6.7 ng/ml at 72 h. PAI decreased from 111 +/- 69 ng/ml to a minimum of 65 +/- 53 ng/ml at 8 h, thereafter remaining below baseline. Elevation of PAPc correlated with elevation of tPA and reduction of PAI. A coagulative response occurred in nine patients (50%): thrombin-anti-thrombin III complexes increased from 29 +/- 53 ng/ml to a maximum of 460 +/- 322 ng/ml at 12 h. Patients with and without a coagulative response had similar levels of recombinant human IL-12, interferon-gamma or tumour necrosis factor-alpha. We conclude that IL-12 can activate both fibrinolysis and coagulation in a significant proportion of patients with cancer. The time-frame and sequence of these activation processes differ from those known for other cytokines.     

氯沙坦对高血压病患者尿白蛋白及纤溶活性的影响

目的　探讨尿白蛋白排泄率与纤溶活性的关系及氯沙坦对其影响。方法　选择 6 2例高血压病伴轻、中度肾功能损害 (肌酐清除率 <70mL/min ,但≥ 30mL/min)患者 ,经随机分为两组分别予氯沙坦 5 0～ 10 0mg/d或卡托普利75～ 15 0mg/d降压治疗 12周。同时选择 2 4例高血压病伴肾功能完全正常 (肌酐清除率≥ 80mL/min)患者作为对照组 ,降压治疗前后分别测定尿白蛋白排泄率 (UAE)、纤溶酶原激活剂活性 (tPA)、纤溶酶原激活抑制剂活性 (PAI)。结果　肾功能异常组UAE、PAI均升高 (P <0 0 1) ,tPA降低 (P <0 0 5 ) ;UAE与tPA ,PAI,PAI/tPA相关系数分别为 0 2 0 (P >0 1)、0 32 (P <0 0 5 )、0 34(P <0 0 1) ,UAE与纤溶活性降低正相关 ;降压治疗后两组均降低UAE、PAI(P <0 0 1) ,卡托普利组还升高tPA(P <0 0 5 )。结论　肾功能异常时纤溶活性降低 ,肾功能损害与纤溶降低有关 ,氯沙坦及卡托普利改善肾功能 ,也改善纤溶活性。     

Mechanisms of thrombin generation during surgery and cardiopulmonary bypass [see comments]

Although in vitro studies have been invaluable in revealing the complex biochemistry of the blood coagulation system, the mechanisms involved during the in vivo response to hypercoagulable stimuli are still unclear. We have used plasma-based enzyme-linked immunosorbent assays (ELISAs) to study the mechanisms by which the coagulation system is activated in vivo during human cardiopulmonary bypass (CPB) surgery (n = 8). A novel immunoassay for factor XIIa was used to detect activation of the contact system, factor IX activation peptide (FIXAP) was used as a marker for activation of factor IX, and prothrombin fragment F1 + 2 (F1 + 2) was used as a marker for thrombin generation. The ELISA for FIXAP is described for the first time herein. F1 + 2 levels increased early in response to surgical intervention: from a baseline of 38.7 +/- 9.7 ng/mL (mean +/-SE), levels increased rapidly during surgery and bypass to a maximum of 448.5 +/- 92.0 ng/mL. A modest yet significant increase in factor XIIa levels from 3.47 +/- 0.54 ng/mL to 4.33 +/- 0.85 ng/mL was evident during surgery before bypass, but no further significant increase was detected on establishing extracorporeal circulation. FIXAP levels demonstrated a small and late increase during surgery from 4.98 +/- 0.55 ng/mL to a maximum of 10.20 +/- 1.23 ng/mL, the increase beginning at the time of near maximal F1 + 2 levels. There was no association between activation of the contact system (factor XIIa levels) and the generation of thrombin (F1 + 2 levels). However, a strong association (r = .705) was apparent between the generation of thrombin (F1 + 2 levels) and activation of factor IX (FIXAP levels), despite the delay between the activation of prothrombin and factor IX. The data do not support the established view that contact activation resulting from exposure of blood to foreign surfaces is the major procoagulant stimulus in CPB. Instead, the results suggest that the main trigger to coagulation during CPB surgery was provided via the tissue factor-factor VIIa mechanism in response to the cutting of blood vessels, which directly activated factor X and then prothrombin. The late activation of factor IX, which presumably also contributed to maximal prothrombin activation, could have arisen due to direct tissue factor-factor VIIa action, or by secondary feedback action of thrombin on the intrinsic system.     

Relationship between elevated cerebrospinal fluid levels of plasminogen activator inhibitor 1 and neuronal destruction in patients with neuropsychiatric systemic lupus erythematosus

Objective

A homeostatic imbalance between coagulation and fibrinolysis might occur intrathecally in neuropsychiatric systemic lupus erythematosus (NPSLE). However, there are no published data on levels of fibrinolytic factors in the cerebrospinal fluid (CSF) of patients with NPSLE. The present study was undertaken to assess CSF levels of fibrinolytic molecules, including urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), D‐dimer, and plasminogen activator inhibitor 1 (PAI‐1), in SLE patients with clinically verified neuropsychiatric involvement and to compare these levels with those in SLE patients without neuropsychiatric involvement and in healthy subjects.

Methods

Levels of uPA, tPA, and PAI‐1 were assessed in CSF from 94 patients with SLE (33 who had NPSLE, 56 who did not have NPSLE, and 5 who were positive for antiphospholipid antibody [not included in the NPSLE or non‐NPSLE group]) and from 53 age‐matched controls. Patients were evaluated clinically, with magnetic resonance imaging of the brain, analyses of neuronal/glial degradation products in CSF, and neuropsychiatric testing.

Results

In the group of patients with NPSLE, intrathecal PAI‐1 levels were significantly elevated compared with levels in SLE patients without overt neuropsychiatric involvement (P < 0.05) and in healthy controls (P < 0.001). In contrast, intrathecal levels of uPA did not differ significantly. Intrathecal levels of PAI‐1 correlated significantly with CSF levels of interleukin‐6 (IL‐6) (r = 0.34, P < 0.001) and IL‐8 (r = 0.33, P < 0.001). Importantly, increased PAI‐1 and D‐dimer levels were observed in SLE patients who had pathologically elevated levels of glial fibrillary acidic protein, neurofilament triplet protein, and tau protein in CSF.

Conclusion

Intrathecal release of PAI‐1 is increased in patients with NPSLE. This results in impaired fibrinolysis, which might contribute to neuronal and astrocytic damage in NPSLE.

     

Effect of laparoscopic and conventional colorectal resection on peritoneal fibrinolytic capacity: a prospective randomized clinical trial

BACKGROUND AND AIMS: Reduced fibrinolytic activity of the peritoneum seems to be the main cause of postoperative adhesions. This prospective randomized trial compared the peritoneal fibrinolytic activity between laparoscopic and conventional colorectal resection. METHODS: Parietal peritoneal biopsy specimens were taken in standardized elective laparoscopic ( n=14) and conventional ( n=16) colorectal resections at the beginning and at the end of surgery. Activities and concentrations of tissue-plasminogen activator (tPA), plasminogen activator (PAI) type 1, and tPA/PAI complex were determined by ELISA kits. RESULTS: There was no difference in age, sex, or body mass index between the two groups. Perioperative tPA activity decreased in both groups without differences between the groups. Concentrations and activities of tPA, PAI-1, and tPA/PAI complex did not differ between the groups at any time. CONCLUSION: Peritoneal concentrations and activities of tPA, PAI-1, and tPA/PAI complex are similar during laparoscopic and conventional colorectal resections. A capnoperitoneum of 12 mmHg over 3 h did not affect the peritoneal fibrinolytic activity     

Increased levels of tPA antigen and tPA/PAI-1 complex in myotonic dystrophy

Abstract. Johansson Å, Boman K, Cederquist K, Forsberg H, Olsson T (Umeå University Hospital, Umeå, Skellefteå County Hospital, Skellefteå, and Boden Hospital, Boden, Sweden). Increased levels of tPA antigen and tPA/PAI‐1 complex in myotonic dystrophy. J Intern Med 2001; 249 : 503–510. Objective. To assess the fibrinolytic system in myotonic dystrophy (DM1), a disease connected to features of the metabolic syndrome, including a prominent insulin resistance, increased body fat mass, and hypertriglyceridaemia. We hypothesized that abnormalities in the fibrinolytic system are linked to metabolic dysfunction in DM1. Design. Circulating morning levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI‐1) antigens, tPA/PAI‐1 complex, lipids and insulin were determined. Genetic analyses, including calculation of allele size, were performed in all patients. Body fat mass was estimated with bioelectrical impedance analysis. Setting. Out‐patient clinic in collaboration with Umeå University Hospital. Subjects. A total of 42 otherwise healthy patients with DM1 (22 men, 20 women; median age 41.5 years) and 50 controls (27 men, 23 women; median age 42.0 years). Main outcome measures. The tPA and PAI‐1 antigens, tPA/PAI‐1 complex, blood lipids and body fat mass. Results. The tPA antigen and tPA/PAI‐1 complex levels were significantly increased in DM1 patients (P < 0.001 and P < 0.05, respectively) whilst levels of PAI‐1 did not differ from controls. Triglyceride levels were increased (P < 0.001) whereas HDL cholesterol levels were lower in DM1 patients (P < 0.05). Body fat mass was increased in DM1 patients (P < 0.001). Conclusions. The fibrinolytic system is disturbed in DM1 patients, with increased levels of tPA and tPA/PAI‐1 complex but paradoxically unaltered levels of PAI‐1, in spite of a severely increased body fat mass. This may imply an abnormal function of adipose tissue in DM1, and calls for further studies of the fibrinolytic system in this disease.     

组织型纤溶酶原激活物及其抑制剂与动脉粥样硬化的关系

组织型纤溶酶原激活物（tPA）和纤溶酶原激活物抑制剂（PAI）是纤溶系统外激活途径的重要活性物质,绝大多数由小血管内皮细胞合成。内皮细胞损伤和功能紊乱是动脉粥样硬化形成的重要始动环节。文章综述了内皮细胞产生的tPA和PAI与动脉粥样硬化和缺血性脑血管病之间的关系。     

Increased plasminogen activator inhibitor antigen levels in diabetic patients with stable angina.

PAI-1 antigen, tPA antigen and thrombin - antithrombin III complexes (TAT) levels were measured in 10 males with stable angina and type-II diabetes mellitus and in 16 males with stable angina without diabetes or other risk factors (hyperfibrinogenaemia, hyperlipidaemia, diabetes, hypertension, smoking and obesity) known to increase PAI levels. Ten healthy men of equivalent age served as controls. Because only diabetics with coronary artery disease (CAD) showed a decreased fibrinolytic capacity, a second study was performed on the 16 non-diabetic CAD patients to determine whether submaximal workload induces significant changes of tPA and PAI levels. TAT levels were increased in CAD, and significantly so in the diabetic group. tPA levels were increased only in the CAD patients without diabetes. PAI levels were significantly increased in diabetic CAD patients (5.26 +/- 1.96 ng/ml) but not in the stable angina patients without diabetes (2.97 +/- 1.44 ng/ml). Immunologically-reactive tPA released after exercise was higher in the 16 CAD patients without diabetes than in controls. Our data could indicate that in stable angina without diabetes there is no chronic latent activation of the clotting system, with no impairment of fibrinolytic activity. On the other hand, the presence of diabetes mellitus seems to influence the fibrinolytic capacity in CAD, particularly increasing PAI levels.     

Noninvasive Transthoracic Low Frequency Ultrasound Augments Thrombolysis in a Canine Model of Acute Myocardial Infarction – Evaluation of the Extent of ST-Segment Resolution

Background: Recently it has been demonstrated that transcutaneous delivery of ultrasound combined with tissue plasminogen activator (tPA) is more effective than tPA alone in recanalizing acutely thrombosed canine coronary arteries. In the present study, we investigated the incidence of partial (50%) and complete (70%) ST-segment elevation resolution in the precordial leads of dogs with experimental acute myocardial infarction that were treated with tissue plasminogen activator (tPA) alone or in combination with noninvasive transcutaneous delivery of high-intensity low frequency (27[emsp3 ]kHz) ultrasound. Methods: Thrombotic coronary occlusions were induced in the midportion of left anterior descending (LAD) coronary artery by electrical injury in 24 dogs. All dogs were given intravenous heparin and tPA. Dogs were randomized to tPA alone (n=12) or combined tPA and adjunctive transcutaneous ultrasound (US) delivery (n=12). Electrocardiograms were recorded at 1) baseline, 2) after coronary occlusion just before initiation of therapy, 3) when coronary angiography showed recanalization of the coronary artery (or at 90 minutes after initiation of therapy if reperfusion did not occur before then) and 4) 90 minutes later. ST amplitude was measured in all 6 precordial leads. Results: ST-segment amplitude at baseline was comparable between the tPA and the US group. Before initiation of therapy, sum of ST-segment elevationtended to be higher in the US group. At reperfusion and 90 minutes thereafter, sum of ST-segment amplitude tended to be smaller for the US group than in the tPA group (p<0.001 for the time effect; p=0.118 for the time × group interaction). Up to 90 minutes after initiation of therapy 50% resolution of the sum of precordial ST elevation was detected in 7 out of 11 dogs (63.6%) in the tPA group versus 10 out of 11 dogs (90.9%) in the US group. Ninety minutes thereafter, 3 out of 7 dogs in the tPA group (42.9%) versus 9 of 11 dogs in the US group (81.8%) had 50% resolution of the sum of precordial ST elevation. Conclusions: The combination of tPA with noninvasive transcutaneous delivery of low frequency high-intensity ultrasound resulted in greater resolution of ST-segment elevation when reperfusion occurs and 90 minutes thereafter, as well as a higher rate of epicardial coronary artery reperfusion. Abbreviated abstract. We investigated the incidence of partial (50%) and complete (70%) ST-segment elevation resolution in the precordial leads of dogs with experimental acute myocardial infarction that were treated with tissue plasminogen activator (tPA) alone or in combination with noninvasive transcutaneous delivery of high-intensity low frequency (27[emsp3 ]kHz) ultrasound. The combination of tPA with noninvasive transcutaneous delivery of low frequency high-intensity ultrasound resulted in greater resolution of ST-segment elevation when reperfusion occurs and 90 minutes thereafter, as well as a higher rate of angiographic epicardial coronary artery reperfusion.     

The effects of parabiosis on serum and kidney glycosidase activities in spontaneously diabetic mice

Summary Spontaneously diabetic non-obese mice of the ICR strain were newly inbred in Shionogi laboratory, Japan. Animals became diabetic suddenly, more frequently and severely in females. Blood glucose levels were 452±73 mg/100 ml with serum insulin levels of < 1.0 U/ml in the fed state. Parabiosis with normal control ICR mice for 2 weeks decreased the blood glucose level to 260±51 mg/ 100ml (P<0.01) and resulted in serum insulin levels of 46.0±18.0 U/ml (P<0.01). Kidney homogenate -N-acetylglucosaminidase and -galactosidase activities were reduced in diabetic mice (42% and 44% decrease respectively) (P<0.025 and P<0.001), and restored almost to normal after 2 weeks of parabiosis. Renal -mannosidase activity was decreased 43% (P<0.001) in the diabetic mice but unaffected by parabiosis. Serum -N-acetylglucosaminidase, -galactosidase and -glucosidase activities were significantly increased in diabetic mice (179%; 233% and 58% increase respectively) (P<0.005, P<0.001 and P<0.001), and returned to normal with parabiosis.     

Plasminogen activators in dextran sulfate-activated euglobulin fractions: a molecular analysis of factor XII- and prekallikrein- dependent fibrinolysis

To elucidate the mechanism by which activation of the contact system of blood coagulation leads to expression of fibrinolytic activity, we have determined the molecular characteristics of the plasminogen activators present in dextran sulfate-treated euglobulin fractions by electrophoretic-zymographic analysis and specific immunoadsorption. In addition to free and protease inhibitor-bound tissue-type plasminogen activator (t-PA), dextran sulfate precipitates of euglobulins contained the complex formed between plasma kallikrein and C1-inhibitor, an indicator of prekallikrein activation. These precipitates also contained substantial fibrinolytic activity related to urinary-type plasminogen activator (u-PA). Autoradiographic analysis was then used to evaluate the cleavage of 125I-single-chain u-PA (prourokinase) in dextran sulfate euglobulins as well as after exposure to kallikrein or beta-factor XIIa. This analysis supported the conclusion that plasma kallikrein-mediated cleavage and activation of single-chain u-PA is the mechanism operative for the development of lytic activity in euglobulin precipitates following activation of the contact system.     

凝血纤溶指标的变化与缺血性心脏病的关系

目的：探讨缺血性心脏病患者的凝血、纤溶变化及其临床意义，并对部分患者跟踪观察。方法：用高效液相色谱仪测定２６例急性心肌梗死患者，２６例不稳定性心绞痛患者，以及２０例正常人的尿纤维蛋白肽Ａ（ＦＰＡ）；并用相应方法同步测定了血浆Ｄ－二聚体（Ｄ－ｄｉｍｅｒ）含量、组织型纤溶酶原激活物（ｔＰＡ）及其抑制剂（ＰＡＩ）活性。结果：急性心肌梗死、不稳定性心绞痛患者较正常对照组尿纤维蛋白肽Ａ值增高，血浆Ｄ－二聚体水平、ＰＡＩ活性升高，ｔＰＡ活性降低。且急性心肌梗死与不稳定性心绞痛患者之间上述指标也存在显著性差异。结论：研究结果提示凝血纤溶系统的变化在缺血性心脏病的发生、发展中起着重要作用，研究凝血、纤溶指标对探讨其发病机制及判断预后可能有一定帮助。     

Direct Evidence of Gonadotropin-Releasing Hormone (GnRH)-Stimulated Nitric Oxide Production in the LβT-2 Clonal Gonadotropes

An immortal cell line (LT-2) with characteristics of gonadotropes, such as LH-containing secretory granules, and LH release responsiveness to GnRH, was used to investigate the effect of GnRH stimulation on nitric oxide (NO) production. RT-PCR analysis showed that mouse nNOS mRNA was expressed in cultured LT-2 cells. LT-2 cells were treated with the calcium ionophore, A23187, and NO levels were measured as nitrite using the Griess assay. The data clearly showed that NO production was increased dose-dependently by A23187 treatment (0–10^-5 M). Next, changes in the intracellular concentration of ionized calcium ([Ca²⁺]_i) in LT-2 cells induced by GnRH were analyzed by quantitative fluorescence microscopy, and [Ca²⁺]_i was found to be increased markedly by GnRH treatment. In fact, exposure of LT-2 cells to increasing concentrations of GnRH from 0 to 10^-6 M was found to enhance NO production in a dose dependent manner, with maximal augmentation at 10^-6 M. However, the stimulation of NO production by GnRH at this concentration was significantly attenuated by pretreatment with N^G-nitro-L-arginine methyl ester hydrochloride (L-NAME), a NO synthase inhibitor.Taken together, the present results suggest that GnRH treatment results in increased NO production in LT-2 clonal gonadotropes, and intracellular calcium augmentation produced by GnRH may be participate in this process. Our findings also indicate that the LT-2 cell line is a useful tool for in vitro studies of the autocrine and paracrine roles of NO in the anterior pituitary gland.     

Pyruvate carboxylase deficiencies: Complementation studies between “French” and “American” phenotypes in cultured fibroblasts

Pyruvate carboxylase (PC) deficiencies (McKusick 26615) are heterogeneous clinically and biochemically. We performed a complementation study with fibroblast strains from seven patients, (four patients with French phenotype, two patients with American phenotype, one patient with biotin responsive multiple carboxylase deficiency, MCD). The six isolated pyruvate carboxylase mutants (two cross-reacting material CRM –ve and four CRM +ve) failed to complement each other, but did complement a form of biotin responsive MCD.     

Coagulation activation and organ dysfunction following cardiac surgery

STUDY OBJECTIVES: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with major inflammatory triggers that cause marked activation of the microcirculation. This inflammatory response is associated with significant organ dysfunction. How this response causes organ dysfunction is not well understood; consequently, few interventions exist to prevent or treat it. In other acute inflammatory conditions, such as sepsis, increased coagulation activation in the microcirculation may be a cause of organ injury. We documented the association between coagulation activation and organ dysfunction to investigate whether coagulation activation also plays a role in organ injury following cardiac surgery with CPB. DESIGN: Prospective study of 30 patients undergoing cardiac surgery with CPB. Prothrombin fragment (PTF) 1 + 2 and plasminogen activator inhibitor (PAI) activity were measured, and levels correlated with postoperative measures of organ function including the left-ventricular stroke work index, the Pao(2)/fraction of inspired oxygen (Fio(2)) ratio, and creatinine levels. RESULTS: PTF levels increased eightfold (p < 0.05), and PAI activity increased threefold (p < 0.05) over the first 4 h after CPB. PTF levels were correlated with deteriorations in the left-ventricular stroke work index (p = 0.04), the Pao(2)/Fio(2) ratio (p = 0.02), and creatinine levels (p = 0.02). CONCLUSIONS: Levels of coagulation activation are associated with markers of postoperative organ dysfunction. Additional studies are warranted to investigate whether strategies that limit coagulation activation are associated with reductions in postoperative organ dysfunction.     

Ultrastructural changes in A-cells exposed to diabetic hyperglycaemia. Observations made on pancreas of chinese hamsters

Summary Pancreatic A-cells of chinese hamsters with diabetes of varying severity and duration were examined by electron microscopy. Two predominant changes were observed: 1. Lysosomal digestion of secretory granules (granulolysis, crinophagy) occurred in practically all A-cells of diabetic animals but was rarely observed in those of normoglycemic controls. This is considered a response of A-cells to the cessation of glucagon release secondary to hyperglycemia. 2. In relatively degranulated A-cells of ketotic diabetic animals, dilatation of the cisternae of the RER was seen together with accumulation of pale, flocculent material, possibly reflecting persisting or enhanced glucagon synthesis. In addition, numerous maturing secretory granules were seen in the cisternae of the Golgi complex. Since these apparently contradictory phenomena may be seen in the same cell, it is suggested that granulolysis may not only result from decreased hormone release secondary to hyperglycemia but that different and independent stimulatory signals may exist for glucagon synthesis, for glucagon release, and for the initiation of granulolysis.Supported in part by the Fonds national suisse de la Recherche scientifique (Grants. No. 4848.3 and 3.154.69).     

脑梗塞早期患者血纤溶系统活性状态分析

为明确血纤溶系统活性状态与脑梗塞发病的关系，采用病例对照研究方法，对３０例皮质动脉区脑梗塞（ＣＡＣＩ）患者、３２例穿通动脉区脑梗塞（ＰＡＣＩ）患者及３０名无心脑血管病等的对照者，以发色底物分解产色法测定血浆组织型纤溶酶原激活物（ｔＰＡ）活性、纤溶酶原激活物抑制物（ＰＡＩ）活性及血管内皮ｔＰＡ释放能力和ＰＡＩ／ｔＰＡ比值，以综合判定其血纤溶系统活性，结果表明两种类型脑梗塞患者发病３天内血纤溶系统活性均显著低于对照者，为脑梗塞早期行溶栓治疗提供了理论依据。同时提出，再次脑梗塞可能与血浆ＰＡＩ活性高有关。