bluuebunny/crossref_metadata_2025 huggingface dataset:
Kostentreiber in Gesundheitssystemen – Ursachen für hohe Gesundheitskosten in den USA
Authors: Lichert Frank
Published: June 2018

Papanicolas I et al. Health Care Spending in the United States and Other High-Income Countries. JAMA 2018; 319: 1024–1039. doi:10.1001/jama.2018.1150

Die USA nehmen im Vergleich zu anderen Ländern mit hohem Einkommen eine Führungsposition bei den Gesundheitsausgaben ein. Dennoch lassen die
Gesundheitsversorgung und Gesundheitsoutcomes der Menschen teilweise zu wünschen übrig. I. Papanicolas et al. haben nun die Gesundheitssysteme der USA und
10 weiterer reicher Länder verglichen und die wichtigsten Kostentreiber identifiziert.
Protective but Non-Synergistic Effects of Nigella Sativa and Vitamin E against Cisplatin-Induced Renal Toxicity and Oxidative Stress in Wistar Rats
Authors: Busari Abdulwasiu , Adejare Abdullahi , Shodipe Abiodun , Oduniyi Oludaisi , Ismail-Badmus Khadijah , Oreagba Ibrahim
Published: June 2018

Background Cisplatin is an anti-cancer drug that causes nephrotoxicity and oxidative stress. Extracts of Nigella sativa is nephroprotective. Vitamin E is also a potent antioxidant. This study sought to determine a possible synergistic effect of administering the two agents prior to cisplatin use on nephrotoxicity and oxidative stress.

Methods 48 male Wistar rats were randomly divided into 6 groups of 8 rats each. Group I served as the control. Group II received cisplatin without any treatment for 6 days. Groups III, IV, V and VI received 100 mg/kg Nigella sativa (NS), 200 mg/kg NS, 100 mg/kg Vitamin E and 200 mg/kg NS+100 mg/kg Vitamin E respectively for 5 days prior to 6 days administration of cisplatin. On the last day of the experiment, all the animals were sacrificed and serum samples collected for analysis.

Results Cisplatin administration caused a significant increase in creatinine level (p<0.01), urea level (p<0.01), sodium concentration and malondialdehyde level (p<0.001). Pre-administration with NS caused a significant reduction in creatinine level (p<0.001), urea level (p<0.001), sodium concentration (p<0.001) and malondialdehyde (p<0.01) level. Pre-administration with vitamin E caused a significant reduction in creatinine level (p<0.001), urea level (p<0.01), sodium concentration (p<0.001) and malondialdehyde level. They both also caused a significant increase in superoxide dismutase, reduced glutathione and catalase (CAT) levels. The combination of NS and vitamin E however did not show significant synergistic effects.

Conclusion These results suggest that even though pre-administration of the two agents protect against renal toxicity and oxidative stress, the effects are however not collaborative.
Training Performed Above Lactate Threshold Decreases p53 and Shelterin Expression in Mice
Authors: de Carvalho Cunha Verusca , dos Santos Rosa Thiago , Sales Marcelo , Sousa Caio , da Silva Aguiar Samuel , Deus Lysleine , Simoes Herbert , de Andrade Rosangela
Published: June 2018

Telomere shortening is associated to sarcopenia leading to functional impairment during aging. There are mechanisms associated with telomere attrition, as well to its protection and repair. Physical training is a factor that attenuates telomere shortening, but little is known about the effects of different exercise intensities on telomere biology. Thus, we evaluated the effects of exercise intensity (moderate vs. high-intensity domain) on gene expression of senescence markers Checkpoint kinase 2 and tumor suppressor (Chk2 and p53, respectively), shelterin telomere repeat binding 1 and 2 (Trf1/Trf2), DNA repair (Xrcc5), telomerase reverse transcriptase (mTERT) and telomere length in middle aged mice. Three groups were studied: a control group (CTL) and two groups submitted to swimming at intensities below the lactate threshold (LI group) and above the lactate threshold (HI group) for 40 and 20 min respectively, for 12 weeks. After training, the HI group showed reduction in p53 expression in the muscle, and decreased shelterin complex expression when compared to LI group. No differences were observed between groups for mTERT expression and telomere length. Thus, exercise training in high-intensity domain was more effective on reducing markers of senescence and apoptosis. The higher intensity exercise training also diminished shelterin expression, with no differences in telomere length and mTERT expression. Such results possibly indicate a more effective DNA protection for the higher-intensity exercise training.
The Association Between the Levels of Thyroid Hormones and Peripheral Nerve Conduction in Patients with Type 2 Diabetes Mellitus
Authors: Zhu Fan-Fan , Yang Li-Zhen
Published: June 2018

Background Type 2 diabetes has an underlying pathology with thyroid dysfunction. However, few studies have investigated the association between thyroid hormones and diabetic peripheral neuropathy. Our aim was to evaluate the relationship between thyroid hormones and electrophysiological properties of peripheral nerves in type 2 diabetes.

Patients and Methods The medical records of 308 patients with type 2 diabetes were enrolled in this study. Subjects stratified by sex were divided into subgroups based on the diagnosis of nerve conduction study. The nerve conduction parameters were separately described with the spectrum of thyroid hormones. Multivariate regression models to analyze the potential links between thyroid hormones and nerve conduction parameters.

Results The serum free triiodine thyronine levels between normal and abnormal nerve conduction groups were statistically different in total (4.55±0.65 vs 4.37±0.63, P<0.05) and female diabetic patients (4.46±0.50 vs 4.14±0.57, P<0.01). Moreover, the summed amplitude and velocity Z score of female and male increased with free triiodine thyronine levels (P<0.05). Sex-specific binary logistic regression models showed that free triiodine thyronine levels were associated with decreased odds of abnormal nerve conduction diagnosis (odds ratio [95%CI]=0.151[0.047-0.186]) and low tertile of summed amplitude Z score (odds ratio [95%CI]=0.283[0.099-0.809]) in female. In total patients, free triiodine thyronine level was negatively associated with odds of abnormal nerve conduction (odds ratio [95%CI]=0.436 [0.226-0.842]), low tertile of summed velocity (odds ratio [95%CI]=0.44[0.226-0.858]) and amplitude (odds ratio [95%CI]=0.436[0.227-0.838) Z score.

Conclusions Serum free triiodine thyronine level is associated with nerve conduction in diabetes. Low free triiodine thyronine may be a potential risk for diabetic peripheral neuropathy.
Asymmetric Cycloetherification by Bifunctional Organocatalyst
Authors: Asano Keisuke , Matsubara Seijiro
Published: June 2018

Attempts to obtain enantiomerically enriched tetrahydrofuran derivatives via an intramolecular oxy-Michael addition reaction of ε-hydroxyenone is discussed. Despite previous difficulties associated with the asymmetric induction of this reaction, which can proceed even without a catalyst, a highly efficient asymmetric induction was realized using a bifunctional organocatalyst derived from a cinchona alkaloid. The reaction could be extended to ζ-hydroxyenone to yield an optically active tetrahydropyran derivative with a high ee. In these reactions, it is important for the gentle acidic and basic sites in the bifunctional organocatalyst to be arranged properly within the molecular skeleton of the catalyst. The high performance asymmetric induction relied on the affinity of the catalyst for the substrate, which played an important role. A disubstituted tetrahydropyran synthesis could be effectively performed via kinetic resolution using ζ-hydroxyenone containing a secondary alcohol moiety using a chiral phosphoric acid catalyst.
Synthesis of Lipid-Linked Oligosaccharides (LLOs) and Their Phosphonate Analogues as Probes To Study Protein Glycosylation Enzymes
Authors: Reymond Jean-Louis , Boilevin Jérémy
Published: June 2018

Here we review chemical and chemoenzymatic methods for the synthesis of lipid-linked oligosaccharides (LLOs) and their phosphonate analogues, which serve as substrates and inhibitors to investigate the structure and mechanism of protein N-glycosylation enzymes. We emphasize how to overcome the challenges pertaining to the instability and difficult physicochemical properties of this class of compounds.

1 Introduction

2 LLO Syntheses

2.1 Glycosyl Phosphate Syntheses

2.2 Glycosyl Phosphonates

2.3 Lipid Elongation

2.4 Lipid Phosphates

2.5 Coupling Reaction Strategies

3 Chemoenzymatic Synthesis of Elongated LLOs

4 Biological Properties of Synthetic LLOs

5 Conclusion
The Inhibitory Effect of Sialic Acid on Fibrinolysis
Authors: Rubin H , Ritz N. D
Published: June 2018

The inhibitory effect of N-acetylneuraminic acid and glycolyl neuramaminic acids on the hydrolysis of 51Cr tagged casein by plasmin and α-chymotrypsin has been demonstrated. N,O-diacetylneuraminic acid was ineffective. The inhibitory effect was increased by an increase in ionic strength of the reaction mixture. The two active sialic acids also inhibited the fibrinolytic action of human plasmin on heated and unheated bovine fibrin plates. The greater inhibition noted on heated plates may indicate a primary effect on plasmin rather than on activators of plasmin. The inhibitory effects of N-acetyl neuraminic acid appeared to be potentiated by normal serum inhibitors. Sialic acid did not influence the conversion of fibrin monomer to polymer.

N-acetylneuraminic acid may play an important role in preserving the integrity of fibrin deposits in the body.
Spontaneous Fibrinolysis Demonstrated by Immunological Technique
Authors: Laursen B , Gormsen J
Published: June 2018

The occurrence of spontaneous fibrinolysis has been investigated in various medical diseases, e. g. myocardial infarction, cerebral stroke, phlebothrombosis, pulmonary embolism, metastasing cancer, and others. Serum from patients has been tested for fibrinolytic break-down products by use of immunodiffusion and Immunoelectrophoresis with double-diffusion. It was anticipated that positive results might provide useful diagnostic, prognostic, and therapeutic information, particularly in patients with myocardial infarction. However, there is no apparent correlation between the occurrence of spontaneous fibrinolysis and the course of disease.

In patients with haemorrhagic diathesis the tests give useful information, but in the remaining groups tested, the significance of occurring fibrinolytic break-down products cannot yet be evaluated.
Platelet Aggregation in Mammalians (Human, Rat, Rabbit, Guinea-Pig, Horse, Dog) A Comparative Study
Authors: Sinakos Z , Caen J. P
Published: June 2018

A comparative study of mammalian (human, rat, rabbit, guinea-pig, horse, dog) platelet aggregation was done using phase contrast microscopy and photometric method and gave us the following results :

1. The animal platelets do not spread spontaneously onto glass in contrast to human ones (in their own plasma).

2. They do not aggregate in presence of adrenalin, noradrenalin, 5-HT but these amines increase the sensitivity of the platelets towards ADP.

3. Although all the platelets aggregate in presence of ADP, bovine thrombin, collagen or thimerosal, there exists some quantitative differences from one species to another.

4. Adenosine and AMP are inhibitors of ADP-induced aggregation for human, rabbit and dog platelets and not for guinea-pig and horse. As for the rat, if adenosine is not inhibitor, AMP can be inhibitor if used at strong doses.

5. There exist great differences in the ability of the various platelet-poor plasmas studied to inactivate the aggregating property of ADP, as for instance the weakest being the human one and the strongest the rat one.

6. The authors insist on the importance of ADP-inhibition by AMP and adenosine, and the ADP-inactivation by the plasmas for the mammalian platelet aggregation and almost disaggregation.
Inherited Fibrinogen Abnormality Causing Thrombophilia
Authors: Egeberg O
Published: June 2018

A family with high incidence of thrombo-embolic diseases is described. Thromboses are reported from members of 3 generations, mostly as leg vein affections, frequently complicated with pulmonal embolism. The family is also known for epileptic manifestations.

Investigations of affected members gave normal values for ordinary coagulation tests; procoagulant factor activities were found normal, and no systematic deficiencies in natural anticoagulants could be demonstrated. A tendency to short plasma thrombin times was, however, revealed. The difference between patients and normals could not be eliminated by Al(OH)3-adsorption of the plasmas, and it was still distinct when the plasmas were diluted in defibrinated normal plasma or in congenitally fibrinogen deficient plasma. Isolated fibrinogen from one of the patients gave markedly shortened thrombin times compared with normal fibrinogen. When test plasmas were heat-defibrinated and isolated normal fibrinogen added, no systematic differences in thrombin times between patients and normals could be found, while corresponding addition of patient’s fibrinogen gave shorter thrombin times.

The results strongly support the explanation that the plasmas of the affected family members contain an abnormal fibrinogen, and that this protein defect is responsible for their thrombotic tendency.

The possibility is considered that the epileptic manifestations in the family might also to some degree be precipitated by cerebral damage due to thrombo-embolic episodes.

The coagulation defect seems to be inherited as an autosomal dominant trait.
Congenital Combined Deficiency of Factor VIII (Antihaemophilic Globulin) and Factor V (Proaccelerin) in Two Siblings
Authors: Gobbi F , Ascari E , Barbieri U
Published: June 2018

Two cases of congenital combined deficiency of factor VIII (antihaemophilic globulin) and factor V (proaccelerin) in 2 sibilings (a female and a male) born of non-consanguineous parents are reported.

Mild isolate defect of factor V was demonstrated in the mother and in 2 maternal aunts, while pure factor VIII deficiency was found in a male relative on the maternal side.

Infusion of normal fresh plasma lead in both cases to a parallel rise of both factors, while infusion of haemophilic plasma lead to a rise of factor V only, thus excluding the presence in the haemophilic plasma of a common precursor to both factors.

The genetic study of the family seems to suggest that the two defects are inherited according to different patterns, two genes being responsible for the two defects. Factor V deficiency seems inherited according to an autosomal incompletely dominant type of heredity, while factor VIII deficiency is due to a sex-linked mutant gene.

Genie interaction, inversion of the dominance or early inactivation of the normal X-chromosome in a carrier are the possible explanations for the severe factor VIII deficiency in the proposita.
Effects of Clotting on the Label in Iodinated Fibrinogen in Different Species
Authors: Regoeczi E , Walton P. L
Published: June 2018

1. The behaviour of the iodine label during coagulation was investigated in 8 species using 125I-fibrinogen.

2. Guinea pig, human, monkey, ox and rabbit fibrinogen preserved the label quantitatively when converted into fibrin, but goat and sheep fibrinogen lost 5.6% and canine fibrinogen lost 11.1 % of its radioactivity.

3. Using a constant iodination technique, the fraction of radioactivity released during clotting proved to be fairly reproducible. The origin and quantity of thrombin used had no influence on the results.

4. The released activity was tentatively identified in the clot liquor of sheep as 125I-fibrinopeptide B. Based on this observation, a theory is presented which satisfactorily explains the experimental findings by the variations in the occurrence of non-esterified tyrosine residues in the fibrinopeptides of different species.
Mechanisms of Interaction between a Phosphoinositide Anticoagulant and a Phospholipid Activator in the Stypven Type Conversion of Prothrombin to Thrombin
Authors: Kahn M. J. P , Bourgain R. H
Published: June 2018

Summary and Conclusion

In the Stypven activation of prothrombin to thrombin, successive steps were investigated in order to locate more precisely the action of a phosphoinositide anticoagulant. The anticoagulant effect has been located precisety at the time of interaction of activated factors X and V, calcium ions and phospholipid material. When this interaction is completed, the phosphoinositide is no longer capable of demonstrating anticoagulant activity.
L’Action du Facteur VIII (Globuline Antihemophilique) sur la Consommation du Facteur X pendant la Coagulation
Authors: Mayer G , Mayer S , Waitz R ,   avec, la collaboration technique de Mme Bichel
Published: June 2018

1. (faits expérimentaux) Le facteur VIII bovin partiellement purifié, sous forme de fraction I de Cohn, ajouté à du plasma ou à du sérum humains, y provoque, après recalcification, une très forte consommation du facteur X.

Ce phénomène ne se produit qu’en présence de facteur IX et de phospholipides. Il ne paraît pas influencé par le facteur V. Il est plus marqué dans le sérum que dans le plasma et d’ailleurs nettement inhibé par des taux croissants de prothrombine.

Le facteur VIII humain natif, constitutif d’un plasma ou ajouté à un sérum sous forme de plasma Ba, n’a qu’un effet faible, apparent seulement pour des concentrations élevées, sur la consommation du facteur X.

2. (hypothèse de travail) La prothrombine agit sur la consommation du facteur X par la thrombine qui neutralise le facteur VIII et protège ainsi le facteur X. Aussi le facteur VIII humain, fragile, pris dans son environnement plasmatique favorable à la thrombine, rapidement détruit par elle, ne peut avoir dans nos expériences la même action que le facteur VIII bovin, robuste et débarassé de toute contamination.

Si la coagulation intrinsèque de l’homme, au contraire de celle du cobaye, ne consomme que peu de facteur X, cela tient à la neutralisation très rapide du facteur VIII par la thrombine, par diminution des stabilisateurs du facteur VIII et augmentation des accélérateurs ou potentialisateurs de la thrombine. La lenteur de la coagulation en est la conséquence. Il est vraisemblable qu’elle est une acquisition phylogénetique. Les avantages qu’elle doit procurer nous sont inconnus.
Kinetic Aspects of the Interaction of Blood-Clotting Enzymes
Authors: Hemker H. C , Siepel T , Altman R , Loeliger E. A
Published: June 2018

It is demonstrated that clotting time in a thrombotest experiment bears a linear relationship to the inverse of factor X concentration under conditions in which the ratio of factor X to the factors II and VII is equal to or smaller than the ratio in normal plasma.

A similar relationship occurs with other thromboplastins as long as factor V and fibrinogen are present in excess, i. e. when the dilutions are made with BaSO4 absorbed plasma.

Contact activation causes deviation from the observed straight-line relationship.
Effects of Thrombin on Factor VIII Activity: Stabilization of Factor VIII by Glycine Ethyl Ester
Authors: Kisker C. T
Published: June 2018

The action of purified thrombin on a preparation of antihemophilic factor with fibrinogen has been studied. In the absence of active thrombin (thrombin inactivated with DFP) polymerization of fibrin by calcium was accompanied by significant losses of AHF. In the presence of thrombin and calcium, 0.3 M glycine ethyl ester resulted in a significant reduction in the loss of AHF activity.
Activation of Chymotrypsinogen by Preparations of Thrombokinase Derived from Bovine Plasma
Authors: Milstone J. H , Milstone V. K
Published: June 2018

Activation of chymotrypsinogen by thrombokinase was observed by the use of benzoyl tyrosine ethylester, which was hydrolyzed by chymotrypsin but not by thrombokinase. Optimal pH was 7.5 to 7.7; and 0.0035 M calcium chloride was beneficial. The ratio of chymotrypsinogen to thrombokinase could reach 1,000, without evidence that the zymogen was saturating the activator. But it was convenient to use a ratio near 20, with 2 mg chymotrypsinogen/ml. The early rate of activation was proportional to the concentration of thrombokinase; and this was made the basis for an assay of activator.

The thrombokinase was a highly purified derivative of bovine plasma; but it was a weak chymotrypsinogen activator compared to trypsin. Nevertheless, activation could proceed in the presence of pancreatic trypsin inhibitor, in which case added trypsinogen caused no acceleration. Apparently, the activating effect was exerted directly on chymotrypsinogen. The ratio of activator to thrombin increased 2,000 fold during purification. Hence, activation was not due to the remaining trace of thrombin; although it could be due to some other impurity. However, it is possible that a single enzyme, namely thrombokinase, is able to split toluenesulfonylarginine methylester and also to activate prothrombin and chymotrypsinogen, respectively.
The Thrombolytic Effect of Heparin and a Heparin-Like Substance, SP 54
Authors: Gerald D. E. Fitz , Szeto Isabel L. F. , Spero Joel , Lewis Jessica H.
Published: June 2018

The intravenous administration of heparin or SP 54 produced statistically significant reductions in the weights of experimentally induced jugular thrombi, which had been allowed to grow for 48, 72, or 120 hrs before treatment. The results observed in the smaller saphenous veins were less striking.
Preparation and Properties of Anticoagulant Split Product of Fibrinogen and Its Determination in Plasma
Authors: Nanninga L. B , Guest M. M
Published: June 2018

The anticoagulant split product resulting from fibrinolytic digestion was found by two independent methods to be 83% by weight of the initial fibrinogen. Molecular weights of the fibrinogen and the two split products were determined. A method for purification of the anticoagulant split product is described and a quantitative method to estimate this product in plasma is presented. A virtual absence of this split product was found in normal plasma, while it appeared in large amounts after fibrinolytic activation. Observations on the inhibition of clotting by the split product and blocking of the inhibition by positive dyes are presented. A similarity between the inhibition of clotting by this product and by negative dyes is suggested.
Physical Factors in the Thromboplastic Activity of Phospholipids
Authors: Gobbi F , Barbieri U , Ascari E
Published: June 2018

Cephalin suspensions lose their thromboplastic activity when incubated with Tween or with sodium deoxycholate. This effect is proportional to the concentration of the surface-active substance, and to the length of its incubation with the phospholipids.

The disappearance of the thromboplastic activity of cephalin treated with surface-tension lowering substances is due to the increased dispersion of the suspensions, as demonstrated by the decrease of their optical density. The activity of sodium deoxycholate is faster than that of Tween.

The impaired thromboplastin formation in the presence of phospholipids treated with Tween or with sodium deoxycholate is not due to the formation of inhibitors.

Cephalin incubated with surface-tension lowering substances and recovered by ultracentrifugation does not show any thromboplastic activity.

Electron-microscopic studies show that incubation with surface-active substances causes the demolition of the structure of phospholipid-particle, on which the thromboplastic activity seems to depend.

The size of the particles and the electric surface-charge seem to be among the main factors responsible for the thromboplastic activity of phospholipids.
Spontaneous Hemorrhage in Anticoagulant-Treated Rats when Subjected to Excitant or Depressant Drugs
Authors: Lucas O. N , Millar G. J , Jaques L. B
Published: June 2018

Rats were given the convulsant drugs, Picrotoxin or Metrazol intraperitoneally, and then fed with food containing the anticoagulant, phenylindanedione (Danilone) for 10 days. Other rats received for 10 days food containing Phenylindanedione and depressant drugs (Nembutal, Barbitone, Librium or chlorpromazine). All combinations of drugs but not the single drugs produced a high incidence of internal hemorrhage, which was fatal to some animals.
Studies with a Preparation of Urokinase
Authors: Dubber Anne H. C. , McNicol G. P , Wilson Patricia A. , Douglas A. S
Published: June 2018

The evidence presented in this paper shows that though less coagulative than urokinase (Leo), urokinase (Abbott), both in vitro and in vivo, has coagulant activity. Further, evidence has been presented that urokinase may accelerate platelet aggregation. While it is likely that the intense fibrinolytic activity which may be produced by intravenous administration of urokinase would largely cancel out the coagulative activity in vivo, these properties in theory could predispose to thrombosis or perhaps more particularly to rethrombosis during therapy with urokinase and it would clearly be desirable, if possible, to obtain a preparation free from such coagulative properties.
Inhibitor of Blood Clotting Derived from Prothrombin
Authors: Marciniak Ewa , Murano Genesio , Seegers Walter H
Published: June 2018

Purified prothrombin was dissociated with thrombin and one of the three main degradation products was separated as a protein and found to be a competitive inhibitor of autoprothrombin C. Relatively large amounts were needed to inhibit the generation of thrombin activity. This slowing of thrombin generation occurred whether prothrombin or prethrombin was the source of thrombin. The main evidence is consistent with the view that the inhibitor originates from the prethrombin portion of prothrombin.
The Immunological Properties of Factor VIII II. The Immunoelectrophoretic Studies
Authors: Uszyński L
Published: June 2018

The results of immunoelectrophoretic studies with, the use of antisera against factor VIII preparations have been presented. When normal or hemophilic plasmas were analysed with the anti-I-0 serum 7 precipitation lines were obtained. Six of them were identified as albumin, alpha 2 macroglobulin, beta lipoprotein, fibrinogen, IgM and IgG globulins. One unidentified line found in betax globulin region seems to have some relation to factor VIII. This precipitation line was absent when plasma from one patient with anti-AHG inhibitor and normal plasma adsorbed on bentonite were studied. It was very faint in ief patterns of von Willebrand’s disease plasma. The possibility of 2 kinds of antibodies directed against 2 hypothetical sub-units of factor VIII is discussed.
Vergleichende Untersuchungen zur Darstellung von Fibrinogen und Faktor VIII durch Alkoholfällung (Cohn) und Kryopräzipitation (Pool u. Robinson)
Authors: Kalinke H , Egli U. H
Published: June 2018

Vergleichende Untersuchungen über den Fibrinogengehalt und die Faktor-VIII-Aktivität in Plasmafraktionen, die entweder nach der Methode von Cohn durch Alkoholfällung oder nach der Methode von Pool und Robinson durch Kryopräzipitation gewonnen wurden, ergaben für die ersteren signifikant höhere Aktivitätsgrade.
Uroplastin, Its Nature and Its Excretion Pattern in Health and in Certain Disease States
Authors: Joist H , Alkjaersig Norma
Published: June 2018

Experimental studies with a partially purified, potent procoagulant from human urine are reported. The material having the electrophoretic property of a â-globulin appears to functionally closely resemble tissue thromboplastin. A significant difference in the excretion of this pro coagulant between normal males and females and deviations from the normal excretion pattern in patients with impaired kidney function and certain other disease states are demonstrated. Possible pathophysiological implications of these findings are discussed.
Separation and Estimation of Split “Products” of Fibrinogen and Fibrin in Human Serum
Authors: Niléhn J. E
Published: June 2018

Pure fibrinogen and fibrinogen in plasma respectively, were digested with plasmin under various conditions. The split products obtained were afterwards separated on Sephadex G 200 and determined immunologically. The investigation showed that when plasmin digested plasma is separated by gel filtration high molecular weight split products with antigenic determinants for both D and E products occur in at least 3 different main types, which are eluted in the “19 S” and “7 S” peaks. On digestion of pure fibrinogen investigated in the same way only 2 main types of split products occurs in the same region. In the “4 S” peak D and E products occur as end degradation products.

The amount of split products formed in serum samples with fibrinolysis is larger than in those with fibrinogenolysis.

Split products in sera from patients with different diseases were identified after gel filtration on Sephadex G 200. As a rule, they were eluted together with the macro - globulins (“19 S”) but samples from patients with advanced fibrinolytic conditions were also found to have split products of lower molecular weight, which were eluted later in the “7 S” and “4 S” peaks.

With the immunologic technique used split products in the serum can be determined down to a concentration of 0.5 mg/100 ml. Split products were found in a concentration between 1 and 45 mg/100 ml in certain patients with liver disease, blood disease, cancer and thrombosis, but not in any of the healthy subjects studied.
Herstellung eines monospezifischen Antiserums gegen menschliches Fibrinogen
Authors: Karitzky D , Künzer W
Published: June 2018

Mit der Methode der Immunoadsorption kann menschliches Fibrinogen von kontaminierenden Serumproteinen gereinigt werden. Antiseren gegen dieses reine Fibrinogen sind monospezifisch und eignen sich für immunologische quantitative Bestimmungen.
Studies on Hypercoagulable State
Authors: Izak G , Galewski K , Eyal Z
Published: June 2018

The rate of disappearance of 131I-labelled, purified fibrinogen was estimated in 43 human subjects simultaneously with repeated determinations of various other constituents of the coagulation and fibrinolytic systems.

A marked shortening of theT/2 of 131I-labelled fibrinogen was observed in patients with thromboembolic disease, as well as in some patients following extensive surgical procedures, in the absence of clinical signs of occlusive vascular lesions at the time of the study. In some of the latter patients thromboembolic episodes developed subsequently.

The application of the procedures described here in the diagnosis of the so-called hypercoagulable state is discussed.
Basic Aspects of Blood Clotting: Thrombokinase and Cofactors in the Conversion of Prothrombin to Thrombin
Authors: Ferguson J. H , Wilson Ennis Ella Gray , Iatridis P. G , White Norma B
Published: June 2018

A basic biomathematical analysis of quantitative clotting test data becomes highly significant in the light of a complex logic which indicates a possible accord with certain postulated biophysical principles. Rectilinear plots are obtainable with one or other of two methods of analyzing the clotting-time data for an experimental system in which prothrombin is converted into thrombin by thrombokinase in the presence of specified cofactors.

Determinants of enzymic activity fit the postulate of Michaelis-Menten kinetics and the Lineweaver-Burk double-reciprocal rectilinear plot. This holds when the ∼ substrate variable is (a) thrombokinase (as precursor of the true prothrombin-convertor enzyme), (b) specific cation (Ca++, Sr++, or Ba++), and (c) factor V (AcG). The validated assays are particularly meaningful in the case of factor V, and suggest a new system of unit age (AcGact)- Tentative Km values are given for these “substrate” functions.

Determinants of effective thrombin (activated prothrombin) quasi-activity are studied by rectilinear log-log plots of endpoint clotting-times against the factor variable, when this is (a) prothrombin, (b) prothromboplastic phospholipid (cephalin), but (c) factor V (AcG) only to a limited extent. The discussion explains how these findings accord with certain colloidal principles that modify a basic enzyme formula based on “the inverse law.”

Evidence of complexing of both substrate and enzyme with certain factors is provided, especially by exploring effects of successive suboptimal additions. The following mechanisms could explain the facts: (a) prothrombin + phospholipid form a colloidal (micellar) substrate complex ; (b) the true activating enzyme is thrombokinase after specific activation by cation (Ca++, normally) ; (c) factor V plays a dual role (in (a) and (b)), thus acting after the manner of an amboceptor. These key reactions should be added to the current “cascade” concept of blood clotting.
Platelet Factor 3 and the Generalized Shwartzman Reaction
Authors: Müller-Berghaus G , Goldfinger D , Margaretten W , McKay D. G
Published: June 2018

The mechanism of “provocation” of the generalized Shwartzman reaction was studied in rats and rabbits. Rats were “prepared” for the reaction by epsilon-aminocaproic acid or pregnancy, rabbits by Thorotrast or endotoxin. Infusions of different preparations of platelet factor 3 activity were not capable of “provoking” the Shwartzman reaction. Purified bovine platelet factor 3, rabbit brain tissue extracts in the form of “so-called” partial thromboplastin or a soya bean phospholipid preparation were used. The results suggest that in addition to the aggregation of platelets and the release of platelet factor 3 other actions of endotoxin are essential to the production of the generalized Shwartzman reaction.
A Simple Method for Preservation of Fine Structure in Blood Cells
Authors: White J. G
Published: June 2018

A technique is described which simplifies the preparation of blood leukocytes and platelets for electron microscopy without sacrificing morphologic preservation. The method has the following advantages :

1. Simplicity of procedure without sacrifice of morphology.

2. Elimination of need for rapid processing and cumbersome ice water baths.

3. Samples may be shipped to other laboratories after initial fixation.

4. Applicable to cytochemical and immunochemical studies.

5. Fine structural preservation is excellent. Structures which are destroyed by cold are maintained by the method described.
Adenosine Diphosphate Breakdown by the Plasma of Different Species and by Human Whole Blood and White Cells
Authors: Bolton C. H , Emmons P. R
Published: June 2018

1. The breakdown rate of ADP (200 µM/ml) by the platelet-poor plasma of the animals studied (human, rabbit, cat, sheep and rat) is consistent within a species and characteristic of that species.

2. The breakdown rate of ADP is related directly to the B. M. R. of that species.

3. The platelet aggregation response to ADP is extremely variable even within a species, and bears little, if any, relationship to ADP breakdown.

4. The breakdown of ADP added to whole blood has been studied both in normal subjects and in patients with myocardial infarctions. The breakdown patterns were found to be identical.

5. The ADP-ase activity of whole blood was localised almost entirely in the white cells.
The Control of Bleeding in Splenectomized Animals by Ellagic Acid
Authors: Agostino D , Cliffton E. E
Published: June 2018

1. Blood loss after splenectomy was reduced significantly by i. v. injection of ellagic acid.

2. The duration of bleeding was also shortened significantly.

3. There were no obvious toxic manifestations and no evidence of thrombosis.
Experimentelle Grundlagen für die therapeutische Anwemcltimg von Ginkgoextrakt EGb 761
Authors: Chatterjee S. S. , Koch E.
Published: June 2018

Monoextrakte aus den Blättern des Ginkgobaumes (Ginkgo biloba L.) werden zur Behandlung von peripheren und zentralen Durchblutungsstörungen sowie bei nachlassender intellektueller Leistungsfähigkeit eingesetzt. Der Spezialextrakt EGb 761 wird in einem standardisierten, vielstufigen Produktionsverfahren gewonnen. Ziel des Herstellungsprozesses ist neben der Anreicherung aktiver Inhaltsstoffe die weitgehende Entfernung von Substanzen mit unerwünschten Eigenschaften. Die experimentellen Befunde zeigen, daß dieser Extrakt pharmakologische Effekte auf alle wesentlichen, an der Blutversorgung beteiligten Komponenten ausübt. Auf der Gefäßebene bewirkt EGb 761 eine Steigerung der lokalen Durchblutung, beeinflußt den Arterienund Venentonus, vermindert eine erhöhte Kapillarpermeabilität und stimuliert die endotheliale Prostazyklinsynthese. Die Wirkungen auf das Blut umfassen unter anderem eine Verbesserung der rheologischen Eigenschaften, eine Stabilisierung der Erythrozytenmembran und die Hemmung PAF-vermittelter Reaktionen. Im Gewebe erhöht EGb 761 die Hypoxietoleranz, besitzt antiischämische Eigenschaften, verbessert den Energiemetabolismus und schützt vor Radikalinduzierten Schädigungen durch Hemmung und Neutralisierung von freien Radikalen.
Pharmakologische Grundlagen der Prostaglandin-Therapie
Authors: Braun Marina , Schrör K.
Published: June 2018

Vasodilatierende Prostaglandine werden zur Therapie fortgeschrittener Stadien der peripheren arteriellen Verschlußkrankheit und der Thrombangiitis obliterans eingesetzt. Der klinische Nutzen liegt vor allem in der therapeutischen Anwendung in Fällen, wo chirurgische Maßnahmen nicht angezeigt bzw. erfolglos geblieben sind. Eine Reihe von klinischen Studien belegt die klinische Wirksamkeit der systemischen Anwendung von Prostaglandin E1 und lloprost. Die pharmakologischen Wirkungen dieser Substanzen betreffen nicht nur den Vasotonus, sondern auch Zellen des strömenden Blutes sowie das Fibrinolyseund Gerinnungssystem. Neuere experimentelle Befunde weisen auf eine antiatherosklerotische Wirkung der Prostaglandine hin.
Stellenwert der bildgebenden Sonographie und Duplex-Sonographie für die Diagnostik der Venenthrombose
Authors: Eichlisberger R. , Frauchiger B. , Jäger K.
Published: June 2018

Mit der Duplex-Sonographie steht eine neue, nichtinvasive Untersuchungsmethode zur Diagnose der tiefen Venenthrombose zur Verfügung. Die gezielte Venenkompression durch die Schallsonde des konventionellen Ultraschallgerätes erlaubt bereits in vielen Fällen die Diagnose, die zusätzliche Ableitung gepulster Doppler-Signale verbessert jedoch die diagnostische Aussagekraft beträchtlich. Die Einführung der farbkodierten Duplex-Sonographie hat die Untersuchungstechnik erleichtert und zur derzeitigen Beliebtheit beigetragen. 35 Studien mit insgesamt 4747 phlebographisch kontrollierten Extremitäten berichten durchwegs über eine hohe Sensitivität (Median 95%) und Spezifität (Median 97%). Bei isolierter Unterschenkelvenenthrombose sind Sensitivität (89%) und Spezifität (92%) weniger günstig. Die diagnostische Treffsicherheit ist signifikant besser als mit den konventionellen nichtinvasiven Untersuchungstechniken (Plethysmographie, CW-Doppler), ist jedoch vergleichbar mit jener der invasiven Phlebographie. Die Duplex-Sonographie ist der Phlebographie in verschiedenen klinischen Situationen, ebenso wie bei der differentialdiagnostischen Abgrenzung, überlegen. Im Gegensatz zum Einsatz bei klinischem Verdacht auf TVT hat sich die Duplex-Sonographie jedoch als ScreeningMethode noch nicht eindeutig bestätigen können.
Das Trousseausche Syndrom
Authors: Kemkes-Matthes Bettina
Published: June 2018

Patienten mit malignen Erkrankungen leiden gehäuft unter thromboembolischen Komplikationen. Die Ätiologie dieser Komplikationen ist vielfältig und hängt sowohl von Art und Ausbreitung des Tumors, dem Ausmaß der begleitenden Akute-Phase-Reaktion als auch vom Vorliegen zusätzlicher Risikofaktoren ab: Das Zusammenspiel von Strömungsveränderungen, Endothelaktivierung unter dem Einfluß von Zytokinen und Aktivierung der Gerinnungskaskade durch »Cancer Procoagulants« oder Tissue-Faktor-ähnliche Substanzen bei gleichzeitiger Verminderung von Gerinnungsinhibitoren und fibrinolytischem Potential begünstigt das Auftreten thrombembolischer Komplikationen.
Diagnose der Thrombophilie: Was läßt sich im Gerinnungslaboratorium erfassen?
Authors: Bruhn H. D.
Published: June 2018

Bei der Diagnose einer Thromboseneigung (Thrombophilie) sind die Unterschiede der Thrombogenese des arteriellen und venösen Systems zu berücksichtigen. Angeborene Störungen im Hämostasesystem können zu einer familiären Thromboseneigung führen (Mangel an Inhibitoren wie Antithrombin III, Protein C, Protein S, Heparin-Kofaktor-Il-Mangel). Weiter kommt als Thromboseursache eine verminderte fibrinolytische Aktivität in Betracht (Fibrinolyseaktivator vermindert, Plasminogenaktivator-Inhibitor erhöht). Mit Hilfe der neuen Thrombinmarker (Thrombin-Antithrombin-Ill-Komplexe, Prothrombinaktivierungspeptid F1+2’ lösliche Fibrinmonomere, Plättchenfaktor 4) kann der Zustand einer Thrombophilie biochemisch charakterisiert werden.
Tumorthrombophilie
Authors: Zurborn K.-H. , Bruhn H. D.
Published: June 2018

Die Inzidenz manifester Thromboembolien beim Tumorpatienten liegt bei 5-15%. Jede ätiologisch unklare Thrombembolie muß Anlaß zur Tumorsuche geben. Pathophysiologisch kann als zentraler Mechanismus eine Kombination aus einer Gerinnungsaktivität durch Tumoroder auch Monozyten/Makrophagen-Prokoagulanzien und einer Akute-Phase-Reaktion angenommen werden. Im Rahmen einer Tumortherapie (Operation, Zytostatika- und Strahlentherapie) kommt es zur Akzeleration der Gerinnungsstörung, welche die klinisch eindeutig nachgewiesene erhöhte Thromboseinzidenz in dieser Phase erklärt.

Therapeutische Maßnahmen werfen spezielle Probleme auf, da einerseits eine Resistenz gegen Antikoagulanzien und andererseits aber auch eine erhöhte Blutungsneigung besteht. Bei malignen Thrombozytenvermehrungen besteht sowohl eine Thromboseals auch eine Blutungsgefahr. Für die biologische Relevanz der Aktivierung des Hämostasesystems bei der Tumorerkrankung sprechen der Nachweis von Fibrin unmittelbar an vitalen Tumorzellen, die direkte mitogene Wirkung von Gerinnungsfaktoren auf Tumorzellen und die Beeinflussung der Tumorprogression im experimentellen System und in der klinischen Medizin durch antithrombotische Medikamente.
Kontrolle des individuellen antikoagulatorischen Effekts einer Behandlung mit oralen Cumarin-Derivaten in niedriger Intensität durch Messung des Prothrombinfragments F1+2
Authors: Bruhn H. D. , Zurborn K. -H.
Published: June 2018

Bei 164 Patienten wurden die Zitratplasmen unter einer stabilen oralen Antikoagulation untersucht. Verglichen mit einem Kontrollkollektiv von 47 gesunden, nichtantikoagulierten Personen zeigten die 164 Patienten unter stabiler oraler Antikoagulation eine signifikante Verminderung des Plasmaspiegels des Prothrombinfragments F1+2 (p <0,0005). Die Reduktion des Plasmaspiegels des Prothrombinfragments F1+2 ist also direkt abhängig von der Intensität der oralen Antikoagulation und daher zur Kontrolle des erreichten antikoagulatorischen Effekts geeignet. Diese Feststellung trifft besonders auch für eine orale Antikoagulanzienprophylaxe niedriger Intensität (INR <2,0) zu, die durch Analyse der Thromboplastinzeit in ihrer Wirkung nicht ausreichend erfaßt werden kann, und die derzeit zur Schlaganfallprophylaxe bei Vorhofflimmern, bei implantierten St.-Jude-Medical-Herzklappenprothesen, in der chirurgischen Thromboseprophylaxe, bei zentralen Venenkathetern und in der primären Herzinfarktprophylaxe klinisch geprüft wird.
Indikationen für Heparin in der Schwangerschaft
Authors: Harenberg J. , Heilmann L. , Schneider D.
Published: June 2018

Thrombosen und thromboembolische Komplikationen treten in der Gravidität relativ selten auf (Rate von 0,2 bis 2%). Dennoch weisen Schwangere ein fünffach höheres Thromboserisiko auf, das weiter ansteigt, wenn andere Risikofaktoren dazukommen. Zu den Indikationen für eine Thromboseprophylaxe zählen u.a. Herzerkrankungen, Lupusantikoagulans, Thrombozytose und kongenitaler AT-III-Mangel sowie eine Thrombose in einer früheren Schwangerschaft. Voraussetzung für ein Medikament zur Thromboembolieprophylaxe in der Schwangerschaft ist seine fehlende Plazentagängigkeit. Diese konnte für niedermolekulares Heparin in einer prospektiven randomisierten Doppelblindstudie an 65 Schwangeren bestätigt werden.
Medikamentöse Thromboembolieprophylaxe in der Allgemeinchirurgie
Authors: Adolf J.
Published: June 2018

Die Thromboembolieprophylaxe mit niedermolekularem Heparin ist im Bereich der Allgemeinchirurgie mindestens genauso effektiv wie die konventionelle Prophylaxe mit unfraktioniertem Heparin, sie kann aber rationeller und patientenfreundlicher durchgeführt werden.

Bei Patienten mit normalem Thromboembolierisiko ist die medikamentöse Thromboembolieprophylaxe mit unfraktioniertem oder niedermolekularem Heparin in hohem Maße effektiv. Problematisch bleibt der Patient mit erhöhtem Risiko. Hier ist eine weitere Verbesserung der Thromboembolieprophylaxe wünschenswert. Eine Dosiserhöhung ohne erhebliche Blutungskomplikationen scheint nur bei den niedermolekularen Heparinen möglich zu sein.
Ist niedermolekulares Heparin der Low-dose-Heparinprophylaxe überlegen?
Authors: Wolf H.
Published: June 2018

In einer multizentrisch durchgeführten randomisierten, kontrollierten Studie, die mehr als 10000 Patienten umfaßte, wurden niedermolekulares Heparin und Low-dose-Heparin direkt miteinander verglichen. Unter niedermolekularem Heparin traten weniger Blutungskomplikationen auf. Allergische Reaktionen wurden seltener beobachtet, und es kam seltener zu einer Thrombozytopenie als unter Heparin. Es gab Anhaltspunkte für eine geringere perioperative Mortalität. Auch bei Anwendung einer rückenmarksnahen Anästhesie hat sich die Prophylaxe mit niedermolekularem Heparin als sicher erwiesen. Anhand der vorliegenden Ergebnisse muß das Nutzen-Risiko-Verhältnis für das niedermolekulare Heparin günstiger beurteilt werden als für Low-dose-Heparin.
Chromogenes Substrat als Antidot gegen den Thrombininhibitor Ro 46-6240?
Authors: Kallsen B. , Liebsch J. , Lins M. , Steffens C. -Ch. , Zurborn K. -H. , Bruhn H. D. , Schwarzenberg H. , Sittner W. D. , Tschopp Th. B.
Published: June 2018

Anhand von In-vitro-Untersuchungen wird gezeigt, daß ein chromogenes Substrat (Chromozym TH der Firma Boehringer/Mannheim) die gerinnungshemmende Wirkung des neuen Thrombininhibitors Ro 46-6240 (Firma Hoffmann-LaRoche/ Grenzach-Wyhlen) zumindest partiell antagonisieren kann. Der hier beschriebene Antidoteffekt eines chromogenen Substrats gegenüber einem Thrombininhibitor könnte seine Erklärung darin finden, daß eine Substratkompetition des Thrombins im Testsystem gegenüber Fibrinogen, Thrombininhibitor und chromogenem Substrat vorliegt. In Tierversuchen müßte weiterhin geklärt werden, ob die beschriebene Antidotwirkung tatsächlich durch den Thrombininhibitor verursachte Blutungskomplikationen vermindern kann oder ob nur ein In-vitro-Phänomen vorliegt, das in vivo wenig Relevanz hat.