bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atropisomerism in the 2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine Nucleus: Effects of Central Chirality at C3 on the N-Mesylation Reaction
Authors: Tabata Hidetsugu , Takahashi Hideyo , Natsugari Hideaki , Tsuji Yuka , Yoneda Tetsuya , Tasaka Tomohiko , Oshitari Tetsuta 
Published: July 2018

The mesylation reaction of the 1,3-dimethyl-2,3,4,5-tetra­hydro-1H-1,5-benzodiazepine nucleus was investigated in detail. Two diastereomers (A and B) of 5-mesyl-1,3-dimethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines, originating from chirality at C3 and at the Ar–N(SO2) axis were formed, among which isomers of the derivative with a methyl group at C6 (R = CH3) were separable at room temperature. A and B had chair-like and boat-like conformations, respectively, in which the C3-methyl group adopts a pseudoequatorial arrangement. Furthermore, A and B were shown to be the thermodynamically and ­kinetically controlled products, respectively.
Capturing Waste Heat Energy with Charge-Transfer Organic Thermoelectrics
Authors: Dimitrov Vladimir , Woodward Simon 
Published: July 2018

Electrically conducting organic salts, known for over 60 years, have recently demonstrated new abilities to convert waste heat directly into electrical power via the thermoelectric effect. Multiple opportunities are emerging for new structure–property relationships and for new materials to be obtained through synthetic organic chemistry. This review highlights key aspects of this field, which is complementary to current efforts based on polymeric, nanostructured or inorganic thermoelectric materials and indicates opportunities whereby mainstream organic chemists can contribute.1	What Are Thermoelectrics? And Why Use Them?2	Current Organic and Hybrid Thermoelectrics3	Unique Materials from Tetrathiotetracenes4	Synthesis of Tetrathiotetracenes5	Materials and Device Applications6	Future Perspectives
Plasma Measurement of D-Dimer as Diagnostic Aid in Suspected Venous Thromboembolism: An Overview
Authors: Bounameaux H , de Moerloose P , Perrier A , Reber G 
Published: July 2018

SummaryThis paper reviews the published experience with plasma measurement of D-dimer (DD), a specific degradation product of crosslinked fibrin, in the diagnostic approach of venous thromboembolism (VTE). Pooling 11 studies (with weighting of the figures according to sample size) with a total of 1337 patients clinically suspected of deep venous thrombosis (DVT) (prevalence of DVT 35%) disclosed an average weighted sensitivity of 96.8% (95% CI: 95.2–98.4) and specificity of 35.2% (95% Cl: 32.0–38.4) for the presence of DVT when the ELISA technique was used. In 908 patients suspected of pulmonary embolism (PE) from 9 trials (prevalence of PE 38%), the ELISA technique was associated with a weighted sensitivity of 96.8% (95% Cl: 95.0–98.6) and specificity of 45.1% (95% Cl: 40.8–49.4) for the disease. Figures obtained with latex assays were definitely lower, precluding their use in the diagnostic approach of VTE.These results show that a low concentration of plasma DD measured by the ELISA technique (usually less than 500 μg/1) might be used to rule out VTE in clinically suspected patients. Increased plasma concentrations are of no utility because of the low specificity of this test result.The clinical usefulness of the DD ELISA test should now be assessed in management trials under routine conditions, in the frame of clinical decision-making diagnostic processes. Lastly, the promising data obtained in a small number of asymptomatic, postoperative patients at risk of VTE deserve confirmation before the test can be recommended for initial screening in thrombo-prophylactic trials.
Comparison of Subcutaneous Unfractionated Heparin with a Low Molecular Weight Heparin (Fragmin®) in Patients with Venous Thromboembolism and Contraindications to Coumarin
Authors: Monreal M , Lafoz E , Olive A , del Rio L , Vedia C 
Published: July 2018

SummaryIntravenous heparin followed by oral anticoagulant therapy (e. g. with coumarin) is still the most widely used treatment for deep venous thromboembolism. Self-administered subcutaneous injections of heparin have been thought of as a promising alternative to coumarin, but the high doses required for ongoing prophylaxis have raised concerns about the possible development of bone disease. Certainly, long-term heparin therapy has been reported to cause osteoporosis in both laboratory animals and humans.This study aimed to compare the efficacy and safety of unfractionated (UF) heparin with that of a low molecular weight heparin (Fragmin®, Kabi Pharmacia) in the prevention of recurrent deep venous thrombosis (DVT) and pulmonary embolism (PE) in a consecutive series of patients with contraindications to coumarin therapy. The patients comprised 40 men and 40 women, aged between 19 and 92 years (mean age, 68 years). They had all previously been diagnosed as having acute DVT and had been treated with conventional doses of heparin while in hospital. All patients had at least one of the following conditions: recent blood loss (either spontaneous or during admission while receiving heparin therapy); active gastroduodenal ulcer disease; psychological or physical inability or unwillingness to understand and accept the need for regular laboratory monitoring during coumarin treatment; chronic alcoholism; dementia; pregnancy; recent neurosurgery, and pericardial effusion; or were over 80 years of age. They were randomly allocated to receive either UF heparin, 10,000 IU s.c. b.d., or Fragmin®, 5000 IU anti-Factor Xa s. c. b. d., for a period of 3-6 months.Two patients taking UF heparin were readmitted to hospital 2 and 3 months after discharge, owing to symptomatic, scintigraphically proven recurrent PE. No patients receiving Fragmin® had recurrent PE. There were 10 reports of minor bleeding: six in patients receiving UF heparin and four in patients on Fragmin®. Furthermore, there were seven cases of spinal fracture: six in patients on UF heparin, and one in a patient taking Fragmin®.We conclude that fixed doses of both UFH and Fragmin® appear to be quite effective and safe for use in patients with a high risk of bleeding. In our experience, however, UF heparin is associated with an unacceptably high incidence of spinal fracture.
Blood Fibrinolysis and the Response to Desmopressin in Glomerulonephritis
Authors: Brommer E J P , Van den Wall Bake A W L , Dooijewaard G , Potter van Loon B J , Emeis J J , Weening J J 
Published: July 2018

SummaryFibrinolytic parameters and von Willebrand factor (VWF) antigen were measured in 22 patients with glomerulonephritis (GN) who underwent renal biopsy after desmopressin (DDAVP) infusion. Blood was collected immediately before and after DDAVP infusion, after one week, and 3–6 months later. The main abnormalities on admission were the following: the mean baseline levels of t-PA antigen and VWF were significantly higher in GN patients than in 22 healthy controls; the median t-PA activity and the mean scu-PA level were significantly lower than normal . The t-PA response to DDAVP was impaired in 7 patients (32%), the response of VWF in 9 patients (41%), and the u-PA: Ag response in 11 patients (50%). When the patients were stratified according to creatinine clearance rate, significant differences between the subgroups with severely and moderately impaired renal function were noted: the baseline levels of PAI activity and VWF were higher in patients with severe renal failure and the VWF response to DDAVP was significantly lower. The response of u-PA (not of t-PA or VWF) to DDAVP appeared to correlate with urine flow during the first 24 h, suggesting the dependence of u-PA release on intact nephrons. A series of 18 patients with adult-type polycystic kidney disease (APKD) with creatinine clearance rates in the same abnormal range as the GN patients, had lower mean PAI and a significantly higher mean scu-PA level. Normalization of scu-PA and t-PA:Ag levels during follow-up despite impaired renal function in GN, and the absence of depressed scu-PA levels in APKD suggest that the fibrinolytic abnormalities are independent of the impaired renal function per se, but associated with the acute stage of nephritis.
Antiplatelet Effects of Ticlopidine Are Reduced in Experimental Hypercholesterolemia
Authors: Hohlfeld Thomas , Scharnowski Frank , Braun Marina , Schrör Karsten 
Published: July 2018

SummaryThis study determines the antiplatelet effects of oral ticlopidine (100 mg/kg × day) in experimental hypercholesterolemia. Rabbits were fed either a standard diet or a cholesterol-enriched diet (0.5% for 3 months, 1% for 1 month). In normocholesterolemic controls ADP-, but not collagen-induced platelet aggregation was inhibited by ticlopidine treatment. This was accompanied by a significantly enhanced inhibition of ADP-induced platelet aggregation and stimulation of cyclic AMP accumulation by iloprost. Hypercholesterolemia considerably attenuated the inhibition of ADP-induced aggregation by ticlopidine but did not change its effect on the iloprost-induced inhibition of platelet function and cyclic AMP formation. ADP-induced platelet-derived Llnumbuxane formation was considerably greater in hypercholesterolemic rabbits and not reduced by ticlopidine. Ticlopidine did also not significantly influence the extent and severity of atherosclerotic plaque formation although a tendency for improvement was observed in a subgroup of animals. The data suggest that hypercholesterolemia attenuates the inhibitory effect of ticlopidine on A DP-induced platelet aggregation. This might be related to the stimulation of thromboxane formation by ADP in hypercholesterolemia. The maintained protection from ADP-induced inhibition of cAMP accumulation suggests a minor role of this mechanism in the progression of hypercholesterolemia-induced vessel disease in this model.
Attenuating Effect of Antithrombin III on the Fibrinolytic Activation and Microvascular Derangement in Rat Gastric Mucosa
Authors: Kurose Iwao , Miura Soichiro , Fukumura Dai , Suzuki Masayuki , Nagata Hiroshi , Sekizuka Eiichi , Morishita Tetsuo , Tsuchiya Masaharu 
Published: July 2018

SummaryThe roles for the fibrinolytic activation and disorder of coagulation in formation of gastric ulcer induced by microvascular derangement were investigated. The rat stomach was exposed and repeated electrical stimuli (RES) were applied on the small arterial wall close to the lesser curvature to induce mucosal microcirculatory disturbances. The level of tissue-type plasminogen activator (t-PA), a key enzyme for fibrinolytic activity, in the regional blood of the stomach was significantly elevated immediately after RES. At 5 min after RES, the leakage of FITC-labeled albumin and thrombus formation in the mucosal microvasculature were visually demonstrated by using an intravital microscopic system. At 30 min, hemorrhagic erosions and linear ulcers were observed in the gastric mucosa. Pretreatment with human anti-thrombin-III (AT-III) in the range of 0.1–10 U/kg dose-dependently attenuated both the fibrinolytic activation and microvascular alteration promoted by RES. Human AT-III also prevented RES-induced gastric mucosal injury. Thrombin inhibitory activity in the gastric vein decreased (69.0 ± 2.1%) just after RES, and further reduced at 30 min (47.7 ± 5.3%). The present study suggests a hypothesis that human AT-III has a preventive effect on the gastric mucosal hemorrhagic changes via attenuating the fibrinolytic activation and subsequent microcirculatory disturbances.
Prevalence and Induction of Circulating Antibodies against Recombinant Staphylokinase
Authors: Declerck P J , Vanderschueren S , Billiet J , Moreau H , Collen D 
Published: July 2018

SummaryStreptokinase (SK) is a routinely used thrombolytic agent but it is immunogenic and allergenic; staphylokinase (STA) is a potential alternative agent which is under early clinical evaluation. The comparative prevalence of antibodies against recombinant STA (STAR) and against SK was studied in healthy subjects and their induction with intravenous administration in small groups of patients.Enzyme-linked immunosorbent assays, using microtiter plates coated with STAR or SK and calibration with affinospecific human antibodies, revealed 2.1 to 65 μg/ml (median 11 μg/ml) anti-STAR antibodies and 0.9 to 370 μg/ml (median 18 μg/ml) anti-SK antibodies (p <0.001 vs anti-STAR antibodies) in plasma from 100 blood donors, with corresponding values of 0.6 to 100 μg/ml (median 7.1 μg/ml) and 0.4 to 120 μg/ml (median 7.3 μg/ml), respectively, in 104 patients with angina pectoris. Three out of 17 patients with Staphylococcus aureus bacteremia had significantly increased anti-STAR antibody levels (150, 75 and 75 μg/ml), and STAR neutralizing activities (2.2, 3.6 and 4.1 μg STAR neutralized per ml plasma, respectively). In 6 patients with acute myocardial infarction, given 10 mg STAR intravenously over 30 min, median anti-STAR antibody levels were 3.5 μg/ml at baseline, 2.9 μg/ml at 6 to 8 days and 1.2 μg/ml at 2 to 9 weeks, with median corresponding titers of STAR neutralizing activity at 2 to 9 weeks of 42 μg/ml plasma. Conversely, in 5 patients treated with 1,500,000 units SK over 60 min, median anti-SK antibodies increased from 2.9 μg/ml at baseline to 360 μg/ml at 5 to 10 days, with corresponding median SK neutralizing activities of 13 μg/ml. Antibodies against STAR did not cross-react with SK and vice versa.Plasma from human subjects contains low levels of circulating antibodies against recombinant staphylokinase, and intravenous administration of this compound boosts antibody titers. These antibodies do however not cross-react with streptokinase, whereby the use of these two immunogenic thrombolytic agents would not be mutually exclusive.
Expression and Characterization of Clustered Charge-to-Alanine Mutants of Low Mr Single-Chain Urokinase-Type Plasminogen Activator
Authors: Ueshima S , Holvoet P , Lijnen H R , Nelles L , Seghers V , Collen D 
Published: July 2018

SummaryIn an effort to modify the fibrinolytic and/or pharmacokinetic properties of recombinant low M
r single-chain urokinase-type plasminogen activator (rscu-PA-32k), mutants were prepared by site-directed mutagenesis of clusters of charged amino acids with the highest solvent accessibility. The following mutants of rscu-PA-32k were prepared: LUK-2 (Lys 212, Glu 213 and Asp 214 to Ala), LUK-3 (Lys 243 and Asp 244 to Ala), LUK-4 (Arg 262, Lys 264, Glu 265 and Arg 267 to Ala), LUK-5 (Lys 300, Glu 301 and Asp 305 to Ala) and LUK-6 (Arg 400, Lys 404, Glu 405 and Glu 406 to Ala).The rscu-PA 32k moictic3 were expressed in High Five Ttichoplasiani cells, and purified to humugciicily from the conditioned cell culture medium, with recoveries of 0.8 to 3.7 mg/1. The specific fibrinolytic activities (220,000 to 300,000 IU/mg), the rates of plasminogen activation by the single-chain moieties and the rates of conversion In lwo chain moieties by plasmin were comparable for mutant and wild-type rscu PA 32k moieties, with the exception of LUK-5 which was virtually inactive. Equi-effective lysis (50% in 2 h) of 60 pi 125I-fibrin labeled plasma clots submerged in 0.5 ml normal human plasma was obtained with 0.7 to 0.8 μg/ml of wild-type or mutant rscu-PA-3?.k, except with LUK-5 (no significant lysis with 16 pg/ml). Following bolus injection in hamsters, all rscu-PA-32k moieties had a comparably rapid plasma clearance (1.3 to 2.7 ml/min), as a result of a short initial half-life (1.4 to 2.5 min). In hamsters with pulmonary embolism, continuous intravenous infusion over 60 min at a dose of 1 mg/kg, resulted in 53 to 72% clot lysis with the mutants, but only 23% with LUK-5, as compared to 36% for wild-type rscu-PA-32k.These data indicate that clustered charge-to-alanine mutants of rscu-PA-32k, designed to eliminate charged regions with the highest solvent accessibility, do not have significantly improved functional, fibrinolytic or pharmacokinetic properties.
Immunofluorescence Study on Thrombolysis with Special Reference to the Patterns of Distribution and the Contents of Fibrin, Plasminogen, α2-Macroglobulin and Urokinase in Artificial Thrombi
Authors: Hisano Shuusuke 
Published: July 2018

SummaryBy the immunofluorescence technique, fibrin, plasminogen and α2-macroglobulin demonstrated a similar basic pattern of distribution in the artificial thrombi, rimming the platelet aggregates in the white part and forming a network structure in the red part. The content of plasminogen seemed to be higher in the red part than in the white part. After superfusion with urokinase solution, urokinase was found in a similar pattern of distribution to that of fibrin. The content of urokinase seemed to be higher in the red part, especially in its outer area, than in the white part. It is concluded that urokinase diffused into the artificial thrombi can convert plasminogen, trapped onto fibrin threads to plasmin. Poor lysibility of the white part might be due to thick strands of fibrin, a low content of plasminogen and a low diffusibility of plasminogen activator, in addition to the antifibrinolytic activity of platelets.
Biochemical Changes Noted during Intermittent Administration of Streptokinase
Authors: Verstraete M , Vermylen J , Schetz J 
Published: July 2018

SummaryAn intermittent dosage scheme of streptokinase (standard initial dose 600,000 units SK infused over 30 min and repeated injections of 250,000 units SK at 24 hr intervals) was applied during 4 days in 9 patients with chronic obliterative arterial disease and in 8 patients with venous occlusion.Each dose of streptokinase produced an immediate fall in plasminogen to 17 % (SEM 5.1) of the initial value, the level then rose to 50 % (SEM 5.4) within 24 hr. Lowered levels of antiplasmin and fibrinogen (both less than 40% of the initial values) were maintained. This safe level of fibrinogen was maintained despite brief but high peaks of plasmin activity after each injection of SK. A parallel increase of the thrombin time and the fibrin(ogen) degradation products was obtained following each infusion. No bleeding was observed. The relative therapeutic effect of intermittent infusions of streptokinase has still to be compared with the continuous administration of streptokinase in controlled clinical trials.
Clinical and Laboratory Aspects of Disseminated Intravascular Coagulation (DIC): A Study of 118 Cases
Authors: Siegal Tali , Seligsohn Uri , Aghai Esther , Modan Michaela 
Published: July 2018

SummaryThe medical records of 118 cases who met laboratory criteria of DIC were studied. The most frequent etiologies were: Generalized infection (39.8%), trauma (16.9%), malignancy (6.8%) and surgical cases (6.8%). The main clinical manifestations which appeared to be related solely to DIC were (in a decreasing order of frequency): Bleeding (64.4%), renal dysfunction (24.6%), liver dysfunction (18.6%), respiratory dysfunction (16.1%), shock (14.4%), thromboembolic phenomena (6.8%) and central nervous system involvement (1.7%). In 26 patients none of these manifestations were observed. In patients with infection, liver and renal dysfunction were frequent and respiratory dysfunction rare, whereas in trauma cases, liver and renal dysfunctions were rare and respiratory dysfunction frequent. This variability indicates that the clinical manifestations are affected not only by the process of intravascular coagulation but also by the underlying clinical disorders.The most impaired coagulation tests were prothrombin time, partial thromboplastin time, platelet count and thrombin time. The degree of abnormality of these coagulation tests was found to be related to the extensiveness of organ involvement.The mortality (overall 54.7%) increased independently with age, with the number of clinical manifestations and with the degree of abnormality of the above-mentioned four most impaired coagulation tests. In addition, older patients were more likely to have an increased number of clinical manifestations and more impaired coagulation tests. Mortality was similar in the various etiologies except for trauma patients in whom it was lower (30%).
Ultrastructural Changes of the Tissue Thromboplastin after Intravenous Injection in Rabbits
Authors: Hasegawa Hiroshi , Nagata Hiroshi , Murao Makoto 
Published: July 2018

SummaryAttempts were made to demonstrate ultrastructural changes of the tissue thromboplastin after intravenous injection, as a model experiment on the pulmonary microthrombi formation induced by the tissue thromboplastin circulating from venous return.Concentrically arranged membrane structures of the injected thromboplastin disappeared in extremely short time after the injection of the thromboplastin in rabbits. The long sheet membrane of the injected thromboplastin was frequently seen as adhered to the vascular endothelium or to the surface of blood corpuscles. Furthermore, fibrin fibres were formed in contact with the long sheet membrane of the thromboplastin. Membrane structures were not found anywhere in the control rabbits.
Factor XI (PTA) Deficiency in an English-American Kindred
Authors: Zacharski Leo R , French E Elizabeth 
Published: July 2018

Summary2 sisters of English-American descent had a mild bleeding syndrome due to marked deficiency (less than 1 % activity) of factor XI. This defect was transmitted in an autosomal recessive manner. Although factor XI deficiency was previously thought to occur largely, if not exclusively in Jews, extensive review of geneologic records and analysis of family names failed to disclose Jewish ancestry. These findings, together with the existence of several definite and presumed consanguineous English-American ancestors, the fact that family members had resided in a restricted geographic area for many generations, and analysis of English and Jewish immigration patterns lead to the conclusion that this defect is not likely to be of Jewish derivation. Should this mutation have occurred in the distant past it is conceivable that the gene pool for this defect is substantial, particularly in certain areas in New England.
Spontaneous Platelet Aggregation in Cerebrovascular Disease
Authors: Ten Cate J W , Vos J , Oosterhuis H , Prenger D , Jenkins C S P 
Published: July 2018

Summary50 patients from a group of 130 patients with transient ischaemic attacks or cerebral infarction were found to demonstrate in vitro spontaneous platelet aggregation (SPA) while 80 normal subjects tested never showed this phenomenon.The following additional findings point towards a possible platelet abnormality:1. Platelets from 10 patients with SPA when isolated and resuspended in normal plasma still demonstrated SPA while isolated normal platelets resuspended in patient’s plasma did not.2. Platelets demonstrating SPA showed an increased aggregation tendency upon incubation with ADP while normal platelets developed the expected refractory state.SPA was found to be dependant upon the presence of divalent cations and could further be inhibited by phentolamine and adenosine. Aspirin effectively abolished SPA in 50 patients and relieved the clinical symptoms of patients with recurrent complaints of transient blindness and paraesthesia.