Heparin-induced hyperkalemia in chronic hemodialysis patients: comparison of low molecular weight and unfractionated heparin

Aldosterone suppression and subsequent hyperkalemia are well described reversible side effects of prolonged treatment with heparin. This study was designed to examine whether the discontinuous use of heparin three times a week to prevent thrombosis formation during hemodialysis sessions could also induce hypoaldosteronism and might contribute to increased predialysis kalemia in hemodialysis patients. Two different heparinization regimens were prospectively compared in a crossover study of 11 chronic hemodialysis patients. During 2 consecutive weeks, the patients were dialyzed each week with either their usual doses of unfractionated heparin (UH) (6,160 IU +/- 1,350 IU) or low molecular weight heparin (LMWH) (15 anti-Xa activity [aXa] U/kg + 5 aXa U/kg/h). In all but 2 patients, the predialysis level of plasma K+ was higher with UH than with LMWH, and the mean value was higher (5.66+/-0.83 versus 5.15+/-0.68 mM, p = 0.01) while no differences in the predialysis plasma concentrations of creatinine, phosphate, urea, and bicarbonate were observed, excluding the potential role of differences in diet and dialysis efficacy in explaining the higher plasma K+ concentration with UH. The mean plasma aldosterone to plasma renin activity (pRA) ratio was higher with LMWH than with UH (149.54+/-123.1 versus 111.91+/-86.22 pg/ng/ h, p < 0.05). Individual plasma aldosterone values were found to be correlated to pRAs both during the UH period and the LMWH period, and the slope of the positive linear relation between plasma aldosterone and pRA was lower during the UH treatment period (63 versus 105 pg/ng/h). Finally, a negative linear correlation was found between the differences in individual predialysis plasma K+ observed during the 2 protocols and the differences in the corresponding plasma aldosterone levels, suggesting a link between the higher kalemia and the lower aldosterone responsiveness to angiotensin with unfractionated heparin. Although it cannot be concluded whether or not LMWH inhibits aldosterone synthesis, should LMWH decrease aldosterone production, this side effect is 33% less marked than that of UH so that the predialysis plasma K+ levels are 10% lower. This property makes LMWH use preferable to that of UH in patients with elevated predialysis kalemia.     

Inhibition of repetitive thrombus formation in the stenosed canine coronary artery by enoxaparin, but not by unfractionated heparin

Experiments were designed to compare the antithrombotic efficacy of enoxaparin and unfractionated heparin (UH) in a model of platelet-dependent cyclic flow reductions (CFRs) in the stenosed canine circumflex coronary artery. Low-molecular-weight heparins (LMWHs) are safe and effective in the prevention and treatment of venous thromboembolism. The present experiments were designed to evaluate the potential use of LMWHs in arterial thrombotic indications by comparing the antithrombotic effect of an LMWH with that of UH in an animal model of unstable angina. After establishment of consistent CFRs by experimentally induced vascular stenosis and damage, vehicle (saline), enoxaparin, or UH was administered intravenously as a loading dose plus a continuous infusion for 1 hour. The inhibition of CFRs was taken as an indicator of antithrombotic efficacy. Enoxaparin inhibited repetitive platelet thrombus formation in a dose-dependent manner, with significant inhibition of CFRs achieved at 0.5 mg/kg + 5 microg/kg per minute. This dose of enoxaparin resulted in anti-Xa levels of 0.9 to 1.0 IU/mL, anti-IIa levels of 0.2 to 0.3 IU/mL, activated partial thromboplastin time (APTT) of 1.3-fold over baseline, and a 1.4-fold increase (NS) in template bleeding time. Near-complete abolishment of CFRs was achieved with enoxaparin at 1.0 mg/kg + 10 microg/kg per minute. This dose of enoxaparin produced anti-Xa levels of 2 to 2.2 IU/mL, anti-IIa levels of 0.5 to 0.6 IU/mL, an increase in APTT of 1.4- to 1.5-fold over baseline, and a 1.9-fold increase (P<0.05) in template bleeding time. In contrast, UH had no significant effect on CFRs at a dose (100 U/kg + 10 U/kg per minute) that resulted in anti-Xa levels of 1.2 to 1.6 IU/mL, anti-IIa levels of 1.8 to 2.4 IU/mL, an increase in APTT greater than 10-fold over baseline, and a 2.5-fold increase (P<0.05) in template bleeding time. Compared with the vehicle group, circulating platelet count and hematocrit were not changed significantly by any dose of enoxaparin or UH tested. Enoxaparin, unlike UH, prevented repetitive platelet-dependent thrombus formation in the dog, thereby supporting the potential use of enoxaparin as a replacement for heparin in the treatment of arterial thrombotic disorders such as unstable angina.     

Comparative effects of enoxaparin and unfractionated heparin in healthy volunteers on prothrombin consumption in whole blood during coagulation, and release of tissue factor pathway inhibitor

In a randomized crossover study twelve healthy male volunteers (23.5 +/- of 4.8 years, 73.0 +/- 6.4 kg, 180.8 +/- 5.7 cm) received one subcutaneous injection of either enoxaparin (EN) at 40 mg or 1 mg kg-1, or unfractionated heparin (UH) at 5,000 IU at one week intervals. Area under curves (AUC) of Anti-Xa and Anti-IIa activities correlated with EN dose. The relative effectiveness of EN versus UH 5,000 U as assessed by AUC ratio (EN/UH) was 7 and 15 for Anti-Xa activity, 1.3 and 3.1 for Anti-IIa activity after sc injection of EN 40 mg (4,000 Anti-Xa IU and 1,200 Anti-IIa U) and 1 mg kg-1 (7,300 +/- 640 Anti-Xa IU and 2,190 +/- 290 Anti-IIa IU) respectively. In volunteers receiving EN, a dose dependent inhibition of thrombin generation rate in platelet depleted plasma (PDP), measured with a new and simple chromogenic thrombin generation assay, was observed when compared with baseline values. Similarly, intrinsic prothrombin activation in whole blood, evidenced by measuring residual factor II in serum 2 hours after clotting (prothrombin consumption test: PC), was inhibited in a dose dependent manner. In UH treated volunteers, although the inhibition of thrombin generation rate in PDP was similar to that observed with EN 40 mg, prothrombin consumption in whole blood was not significantly modified. Tissue factor pathway inhibitor (TFPI) activity release was increased similarly for UH and EN 40 (1.4 fold increase above baseline values) and 1.9 fold for the higher dose of EN. The discrepancy between prothrombin consumption in whole blood and inhibition of thrombin generation rate in PDP in the UH and not in the EN group strongly suggests that UH and not EN is influenced by the presence of a platelet component. This could be formed during thrombin induced platelet activation. Platelet factor 4 is a possible candidate. Another hypothesis involves the role of TFPI-UH complex anticoagulant activity which might be inhibited more during whole blood coagulation than the TFPI-EN complex.     

Inhibitory effect of low molecular weight heparin on the bronchoconstriction in ovalbumin-sensitized guinea pigs after antigen exposure

To elucidate the effect of low molecular weight heparin (LMWH) on the bronchoconstriction, we examined the serial changes of the resistance of respiratory system (Rrs) in ovalbumin (OA)-sensitized guinea pigs after antigen exposure. After sensitization of guinea pigs with repeated OA inhalation, Rrs was measured at immediate asthmatic response (IAR) and late asthmatic response (LAR) with or without LMWH inhalation. Alteration in the number of inflammatory cells of the lung by LMWH inhalation was examined in the broncholaveolar lavage fluid (BALF) and in the histological sections of airway walls. Peak Rrs at 1 min up to 9 min, except 8 min, after antigen exposure significantly decreased by the pretreatment with LMWH inhalation as compared with saline inhalation. Peak Rrs at LAR (after 4 hours up to 24 hours, except 6 hours) also showed a significant decrease in the pretreatment with LMWH inhalation. Pretreatment of LMWH exhibited a decrease of eosinophil percentage in BALF (5.5 +/- 1.2% from 8.2 +/- 0.4% in saline inhalation) and a decrease of infiltrated eosinophil count in airway walls (71.0 +/- 7.3 from 155 +/- 15.8 in saline inhalation). These data show LMWH might play an important role as an inhibitory factor to bronchial asthma.     

Low molecular weight heparin and unfractionated heparin for prevention of thrombo-embolism in general surgery: a meta-analysis of randomised clinical trials

Low molecular weight heparin (LMWH), unfractionated heparin (UFH) and warfarin were compared with respect to efficacy and safety in the prevention of thrombo-embolism in general surgery. Meta-analysis (MA) with a priori definition of the MA protocol was used to combine the results from randomised trials with patients who underwent general surgery and deep-vein thrombosis (DVT) prophylaxis with LMWH, UFH or warfarin. Forty-four studies were identified for assessment and 33 were included, however, none for warfarin. For efficacy (DVT and pulmonary embolism) and major bleeding, no significant difference between the LMWH- and UFH-treated groups was demonstrated. The relative risk of minor bleedings for LMWH versus UFH was 0.75 (0.64-0.88; 95% confidence interval) and is significant (p < 0.05). Within the limitations of the MA, LMWH and UFH did not differ significantly in terms of prevention of thrombo-embolism, but LMWH had a significantly better safety profile. On this basis, LMWH may be preferable to UFH in the prevention of thrombo-embolism in general surgery.     

Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience

BACKGROUND: The Quebec Neuroblastoma Screening (QNS) Project completed a 5-year program for measuring urinary vanillylmandelic acid (VMA)/homovanillic acid (HVA) levels at age 3 weeks and/or 6 months in 89% of 476,603 Quebec-born infants from 1989-1994; 45 screening positive preclinical cases (S-positive cases) and 20 congenital/neonatal (C/N) cases were identified. As of April 1997, an additional 59 cases in the same birth cohort were diagnosed clinically; these neuroblastomas developed after screening verified normal VMA/HVA levels (S-negative cases). METHODS: Pathology specimens from 45 of 59 S-negative cases were reviewed centrally and classified according to the Shimada system. Results were compared with clinical data and also with S-positive and C/N cases. RESULTS: Of 45 S-negative cases, 27 tumors had favorable histology (FH) and 18 had unfavorable histology (UH). Approximately 52% of FH tumors were diagnosed before age 1 year, whereas UH tumors were nearly exclusively (94%) diagnosed after age 1 year (P < 0.01). Approximately 89% of FH tumors were Stage I, II, or IV-S, whereas 72% UH tumors were Stage III or IV (P < 0.001). All children with FH tumors were alive at last follow-up (range of follow-up period: 9-79 months; median, 35 months), whereas 8 children with UH tumors died of disease even after limited follow-up (range of follow-up period: 0-60 months; median, 20 months). By contrast, S-positive and C/N cases were predominantly (97%) FH tumors, often (76%) Stage I, II, or IV-S, with excellent clinical outcome (survival rate of 98%). CONCLUSIONS: The majority of the UH neuroblastomas that developed in the birth cohort of the QNS Project were included in the group of S-negative cases and could not be detected by the screening at age 3 weeks and/or 6 months.     

Efficacy of a low molecular weight heparin administered intravenously or subcutaneously in comparison with intravenous unfractionated heparin in the treatment of deep venous thrombosis. Certoparin-Study Group

BACKGROUND: The main objective of the study presented was to test if thrombus regression can be improved by treatment with an intravenously or subcutaneously administered low molecular weight heparin (LMWH). Patients with acute deep vein thrombosis were randomly assigned to receive either intravenous UFH (131 patients), intravenous (i.v.) LMWH (128 patients), or 8000 IU of the same LMWH bid subcutaneously (s.c.) (128 patients). All patients were treated with heparin for 14 to 16 days. Vitamin-K-antagonist prophylaxis was started between Day 12 and Day 14 after enrollment into the study. METHODS: Phlebographies and perfusion/ventilation lung scans were performed at baseline and on Days 12 to 16. Primary endpoint of the study was a reduction of the phlebographic Marder score. Secondary endpoints were recurrent thrombosis and pulmonary embolism (PE), major and minor bleedings and the rate of PE at inclusion and at the end of the study assessed by ventilation/perfusion scans. RESULTS: The Marder score improved by at least 30% in 32.4% (95% CI: 22.6 ... 42.2) of the patients receiving UFH, in 34.0% (95% CI: 24.9 ... 44.0) receiving LMWH i.v. and in 42.6% (95% CI: 32.8 ... 52.8) treated with the low molecular weight heparin s.c. The difference between LMWH s.c. and UFH was 10.2% (95% CI: -3.7% ... +24.5%) (p = 0.11). PE with clinical signs confirmed by objective methods occurred in three patients of the UFH group, one of whom died and was not observed in patients of the i.v. or s.c. LMWH-groups. During the first 15 days no patient receiving UFH or i.v. LMWH, and one patient on s.c. LMWH had a recurrent thrombosis. Major bleedings were observed in four patients receiving i.v. UFH compared to nine patients on i.v. LMWH (one of these patients died) and one patient on s.c. LMWH. Perfusion ventilation lung scans were obtained from 287 patients at baseline and from 246 patients on Days 12-16. PE, defined according to PIOPED-criteria as intermediate or high probability scans, was observed in 38.0% of the patients entering the study and in 18.3% on Days 12 to 16. New asymptomatic PE occurred less frequently in the groups on LMWH (7.1%, 7.5%, respectively) than in the UFH-group (12.6%) (not significant). CONCLUSIONS: S.c. treatment with a LMWH (certoparin) (b.i.d.) is at least as effective as UFH i.v. The hypothesis of increased efficacy of subcutaneous LMWH in resolving venous thrombi will have to be confirmed by an independent study comparing s.c. LMWH with UFH. The i.v. continuous infusion of the LMWH for 12 to 16 days does not result in a higher venous re-opening rate than intravenous standard heparin.     

Low-molecular-weight heparin: an antithrombotic agent whose time has come

LMWH (enoxaparin) should be used in combination with aspirin in the early phase of non-Q wave MI and in patients with unstable angina. The benefit of LMWH in acute coronary syndromes has been validated in several clinical trials. In addition, the use of LMWH is cost-effective when compared with use of UFH. The incidence of minor bleeding may be greater with LMWH than with UFH, most frequently due to ecchymosis at the injection site. However, the frequency of major bleeding did not differ between the two heparins. LMWH has been used successfully for the past 4 years by orthopedic surgeons in the prevention of pulmonary emboli. LMWH should replace UFH in the management of acute coronary syndromes.     

Posttreatment with low molecular weight heparin reduces brain edema and infarct volume in rats subjected to thrombotic middle cerebral artery occlusion

Low molecular weight heparin (LMWH) has similar efficacy to unfractionated heparin with less hemorrhagic complications. We studied the neuroprotective effect of LMWH on a rat model of focal-ischemia. Our results revealed that treatment with LMWH at 1 and 3 h following thrombotic MCA occlusion reduced brain edema and infarct size and improved clinical outcome. Treatment with LMWH initiated at 6 h after thrombin injection only partially ameliorated brain damage.     

Assessing protein coding region integrity in cDNA sequencing projects

BACKGROUND: Low molecular weight heparin (LMWH) provides a safe and effective alternative for hemodialysis anticoagulation. While unfractionated (UF) heparin has been implicated in hyperlipidemia, the effect of LMWH on the lipid profile in nondiabetic patients is controversial in chronic hemodialysis. The effect of LMWH in diabetic patients, a high risk group of hyperlipidemia, has not been studied. METHOD: LMWH was tested for its safety and efficacy in 10 nondiabetic Taiwanese patients. To evaluate influence of lipid profile, a crossover study was carried out in 10 type II diabetic patients with poor blood sugar control associated with high triglyceride (430.4 +/- 101.1 mg/dl) and total cholesterol levels (219.2 +/- 12.7 mg/dl) using UF heparin for more than 1 year. These patients were subjected to Fraxiparine, an LMWH, for 6 months and then switched back to UF heparin for another 6 months. Lipid profiles were measured every 2 months without prescribing lipid-lowering agents and the blood sugar was maintained at stationary levels. RESULTS: LMWH is safe and effective in Taiwanese patients as a single bolus injection and maintains a 9.4% higher platelet count immediate postdialysis compared to UF heparin. With high HbA1c levels (9.6 +/- 0.6%), mean triglyceride and VLDL levels started to decrease at the 4th month after LMWH treatment and reached a 34% reduction in triglyceride, a 26.2% reduction in VLDL, and a 19% reduction of total cholesterol/HDL ratio at the 6th month. Increments of triglyceride levels were found at the 6th month after a switch back to UF heparin. The levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, apolipoprotein A-1 and B remained unchanged. CONCLUSION: LMWH may be beneficial to lipid control in hyperlipidemic diabetic patients on hemodialysis.     

Ulcerative colitis complicated by gastroduodenal lesions

The glycosylated multivalent three-domain Kunitz inhibitor TFPI is a natural inhibitor of tissue factor-FVIIa complex in the presence of FXa. TFPI has an experimental antithrombotic capacity indistinguishable from LMWH in a prophylactic dose, regardless of glycosylation and of the third domain. An inherited equilibrium between antithrombosis and haemorrhage exists. The aim of the study was to evaluate whether a two-domain non-glycosylated TFPI (117QTFPI1-161) has a bleeding potential in a rat gastric mucosa model. Groups; placebo, LMWH (tinzaparin) 60 and 250 anti-Xa IU/kg and 117 QTFPI1-161 1.0 and 10.0 mg/kg, given i.v. (bolus injection), randomised double dummy design. All actively treated groups significantly prolonged both the bleeding volume (493-984 microliters) and the bleeding time (10-20 min) compared to placebo (41 microliters, 2 min). It was not possible to distinguish a difference between the lower dose of LMWH and 117QTFPI1-161 in either parameter (p = 0.23-0.71). The two doses of 117QTFPI1-161 caused elevation of plasma-TFPI, 18 and 150 times baseline value. Both LMWH doses (0.6-3.2 anti-Xa IU/ml) and both 117QTFPI1-161 doses (0.2-2.7 anti-Xa IU/ml), caused significant effect in the anti-Xa assay, however 117QTFPI1-161 significantly less. Only the largest dose of 117QTFPI1-161 caused significant prolongation in the APTT assay (34 s). Both doses of LMWH caused significant prolongation (60-300 s). LMWH was the only substance to prolong the dilute-PT assay. Non-glycosylated two-domain 1.0 mg/kg TFPI, yielding supraphysiological plasma concentration, has an experimental haemorrhagic potential indistinguishable from LMWH in a prophylactic dose. The effect mediated by this type of TFPI could primarily be due to an inhibition of FXa.     

Low molecular weight heparin and unfractionated heparin in thrombosis prophylaxis after major surgical intervention: update of previous meta-analyses

BACKGROUND: Previous meta-analyses comparing low molecular weight heparin (LMWH) and unfractionated heparin for thrombosis prophylaxis after surgical interventions need updating. METHODS: This is a publication-based meta-analysis of 36 double-blind studies including 16583 patients. Main outcome measures are incidence of deep vein thrombosis (efficacy) and wound haematoma (safety). RESULTS: In general surgery there is no increased efficacy in favour of LMWH (odds ratio (OR) 0.88, 95 per cent confidence interval (c.i.) 0.60-1.30) but there exists a higher incidence of bleeding complications (OR 1.47, 95 per cent c.i. 1.07-2.01). Low-dose LMWH is equally efficacious (OR 1.03, 95 per cent c.i. 0.85-1.26) but safer than unfractionated heparin (OR 0.68, 95 per cent c.i. 0.56-0.82). In orthopaedic surgery there is a trend towards an increased efficacy for LMWH (OR 0.83, 95 per cent c.i. 0.68-1.02) with equivalent safety (OR 0.96, 95 per cent c.i. 0.68-1.36). CONCLUSION: A superiority of LMWH is suggested but heterogeneity might make generalizability to future patients questionable. A meta-analysis on individual patient data should be the next step before randomizing additional patients in future trials.     

Improvement of Stainless Steel Making Operation Adapting Instable Raw Material Price

Sumikin Iron and Steel Corporation (SISC) is the main manufacturing base of seamless tube materials in Sumitomo Metals group, and stainless steel making plant is in charge of semi‐manufactured special steel products such as stainless and high alloy steel. Total manufacturing costs of these special steels are heavily dependent on the price of raw material. Therefore, reduction of its usage and optimizing operation process in order to absorb influence of its unstable price are important issues. In this report, we introduce three cases as following: yield improvement in order to reduce raw material usage, optimization of the steel dust usage, and active use of low‐price raw material through dividing refining process.     

Increased kidney xanthine oxidoreductase activity in salt-induced experimental hypertension

OBJECTIVES: To assess the efficacy and safety of low molecular weight heparin (LMWH) as deep venous thrombosis (DVT) prophylaxis following total knee arthroplasty. DATA SOURCES: Medline 1986 to June 1997, Embase, and manufacturers were used to identify randomized controlled trials. REVIEW METHODS: Trials included were randomized studies of LMWH with routine radiological screening for DVT. Placebo or active controls were included. Two reviewers independently screened trials for inclusion, and assessed their quality. Pooled relative risk estimates of DVT and proximal DVT rates were calculated using a DerSimonian and Laird random effects model. Sensitivity of the results to the type of control used and the quality of the trial was assessed. RESULTS: The relative risk of DVT for a patient given LMWH is 0.73 (95% CI 0.66 to 0.80) when compared with patients treated with adjusted dose heparin or warfarin controls. The relative risk for proximal DVT is 0.58 (95% CI 0.38 to 0.90). The relative risk of pulmonary emboli in the LMWH group was 0.55 (95% C.I. 0.20 to 1.57). No excess of bleeding was recorded in the LMWH group. CONCLUSIONS: Low molecular weight heparin is more efficacious than either adjusted dose heparin or adjusted dose warfarin, when used to prevent DVT and proximal DVT following total knee arthroplasty.     

Postoperative activation of the haemostatic system--influence of prolonged thromboprophylaxis in patients undergoing total hip arthroplasty

Tissue injury during hip surgery results in the activation of the haemostatic system. The aim of this study was to detect markers of haemostatic activity, i.e. prothrombin fragment 1 and 2 (F1+2), thrombin-antithrombin (TAT) complexes, fibrin degradation products (FbDP), and soluble fibrin monomers (SF), preoperatively, and on days 1, 7 and 35 in plasma of patients undergoing total hip arthroplasty. The study was part of a multicentre study in which the patients were randomized to receive a subcutaneous injection of low molecular weight heparin (LMWH, dalteparin, Fragmin) once daily for 5 weeks or placebo following a 1-week LMWH treatment (once daily). Bilateral phlebography was performed between days 33 and 35 or before if patients had clinical symptoms of deep vein thrombosis. A lung scan was performed in patients with clinical symptoms of pulmonary embolism. Levels of the markers were significantly increased on day 35 in the patients receiving LMWH for 7 days compared to patients receiving LMWH for 35 days. In patients receiving LMWH for 5 weeks, levels of FbDP and SF were significantly higher during the entire study period, but TAT and F1+2 were normalized on day 35. The markers were increased two to five times on the 1st postoperative day in patients with diagnosed venous thromboembolism.     

A new chronometric assay to determine plasma antifactor Xa activity which is insensitive to the antithrombin activity of low molecular weight heparins

Some commercially available chronometric assays are influenced by the residual antithrombin activity of low molecular weight heparins (LMWH) and they underestimate the ex vivo anti Xa activity. We have evaluated a new kit (Staclot-Heparin) highly specific for the anti Xa activity of LMWH. A comparison with the results given by a reference chromogenic method (Stachrom-Heparin) indicates a very good correlation between the 2 assays (r = 0.95, n = 59). This new assay is not influenced by vitamin K antagonist treatments. Clinical biologists now have the possibility of determining the anti Xa activity generated by LMWH easily and accurately, using a chronometric assay.     

Treatment of deep venous thrombosis at home: evolution from ideas to medical practice

The diagnosis of Deep Venous Thrombosis (DVT) by duplex ultrasound is absolutely possible out of specialized centers. Low Molecular Weight Heparins (LMWH) allow to obtain a greater efficacy and safety compared to Unfractionated Heparin (UFH). The control of LMWH is very reduced. Two studies have just been published on the topic of treatment of DVT at home. The group of patients treated at home with LMWH is not presenting more complications than the group of patients initially treated at the hospital with UFH. Nevertheless, these studies concern a very selective population of patients. Our center has been proceeding to a study for 4 years (1993-1997) in comparing the treatment at home of proximal DVT by LMWH then oral anticoagulant, to the initial treatment (10 days) in hospital by also using LMWH then oral anticoagulant. The first results show that there is no difference between both groups in terms of end-points: death, extension or recurrence of the thrombus, pulmonary embolism, bleeding. Therefore, the treatment of some type of proximal DVT is possible at home. Nevertheless, it is necessary to be very cautions as the population studied so far is a selected one. Etiologies of DVT are a constant obsessive fear. DVT or pulmonary embolism represents a real general disease which is going to progress along life. The intervention of a specialized center is always necessary. It is a work in team which must get the upper hand compared to an isolated medical action.     

(R)-5-fluoro-5,6-dihydrouracil: kinetics of oxidation by dihydropyrimidine dehydrogenase and hydrolysis by dihydropyrimidine aminohydrolase

The biologically active isomer of 5-fluoro-5,6-dihydrouracil [(R)-5-fluoro-5,6-dihydrouracil, R-FUH2] was synthesized to study the kinetics of its enzymatic oxidation and hydrolysis by homogeneous dihydropyrimidine dehydrogenase (DPDase) and dihydropyrimidine aminohydrolase (DPHase), respectively. DPDase catalyzed the slow oxidation of R-FUH2 at pH 8 and 37 degrees with a Km of 210 microM and a kcat of 0.026 sec-1 at a saturating concentration of NADP+. The catalytic efficiency (kcat/Km) of DPDase for R-FUH2 was 1/14th of that for 5,6-dihydrouracil (UH2). In the opposite direction, DPDase catalyzed the reduction of 5-fluorouracil (FU) with a Km of 0.70 microM and a kcat of 3 sec-1 at a saturating concentration of NADPH. Thus, DPDase catalyzed the reduction of FU 30,000-fold more efficiently than the oxidation of R-FUH2. In contrast to the slow oxidation of R-FUH2 by DPDase, R-FUH2 was hydrolyzed very efficiently by DPHase with a Km of 130 microM and a kcat of 126 sec-1. The catalytic efficiency of DPHase for the hydrolysis of R-FUH2 was approximately twice that for the hydrolysis of UH2. Because R-FUH2 is hydrolysis of R-FUH2 was approximately twice that for the hydrolysis of UH2. Because R-FUH2 is hydrolyzed considerably more efficiently than it is oxidized and because the activity of DPHase was 250- to 500-fold greater than that of DPDase in bovine and rat liver, the hydrolytic pathway should predominate in vivo.     

Large Block,High Density,Low Weight Loss Rate and Excellent Plating Process for High Grade NdFeB Magnet

In order to produce N44SH and N40UH high-grade magnet, both strip casting and hydrogen decrepitation processes were adopted, and the subsequent milling, sintering and heat-treatment processes were improved. The density of N40UH magnet is risen up to 7.65 g/cm^c. Weight loss rate after the Highly Accelerated Stress Test (HAST) for 48 hours is less than 0.2 mg/cm^b. The microstructure of magnet shows that the grain size is between 5 to 8 μm. The rich-Nd phase is fine and uniform, the pinhole is very few, such magnet can be used for wind power generator after phosphoruster treatment directly, and it can also be used in hydrogen atmosphere of hybrid car after surface treatment.     

Low molecular weight heparin: a critical analysis of clinical trials

LMWHs are an important new class of antithrombotic agents. They differ from UFH in having relatively more anti-Xa activity, greater bioavailability at low doses, longer half-life, and more predictable anticoagulant response when administered in fixed doses. These properties allow LMWHs to be administered QD or at most BID and without laboratory monitoring. The incidence of heparin-induced thrombocytopenia also appears to be lower with an LMWH than with heparin. Given their favorable pharmacological profile, it was of interest to critically appraise clinical trials of thromboprophylaxis and treatment with these new agents. In orthopedic trials, it was noted that LMWH provided safe and effective thromboprophylaxis for patients undergoing major orthopedic surgery of the lower limb. In those having hip arthroplasty, LMWH was as effective as low-intensity warfarin therapy, but its use was associated with more wound hematomas. In those having total knee arthroplasty, LMWH was more effective than warfarin and did not increase bleeding. However, the prevalence of DVTs complicating this procedure as well as acute hip fracture remains unacceptably high, and additional studies of LMWH in combination with other prophylactic methods, such as external pneumatic compression, are needed. Only one adequately designed trial found less bleeding resulted from LMWH prophylaxis administered at an equivalent antithrombotic dose to UFH. In general medical patients, LMWH appeared to be as effective as UFH and had the advantages of less frequent injections and fewer injection site hematomas. In general surgical patients, there was a lower risk of thromboembolism but a trend toward an increase in bleeding events. Subjects with strokes and spinal cord injuries benefited from fewer thrombotic events, and the latter had fewer bleeding complications. Other potential indications for LMWH, such as cardiopulmonary bypass, hemodialysis, and preservation of graft patency, are presently under study. Perhaps the most impressive benefits of LMWH will be realized when it is used for the treatment of venous thromboembolism. The meta-analysis presented in this review showed a trend toward greater efficacy with LMWH and fewer major bleeding events in comparison with adjusted-dose intravenous UFH. Also, during the months following the thrombotic event, there was significantly less mortality in patients receiving LMWH. A further advantage was the subcutaneous route of administration and lack of requirement for laboratory monitoring. Additional treatment trials are presently in progress and may establish LMWH as the treatment of choice for patients with thromboembolic disorders.