bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Prekallikrein and Endotoxemia in Liver Cirrhosis
Authors: Vliet A C M van , Vliet H H D M van , Džoljić-Danilović G , Wilson J H P
Published: July 2018

In liver disease low prekallikrein levels may be found which has been suggested to be due to diminished synthesis. However, it may also be due to endotoxemia accompanying liver disease. To study the last possibility prekallikrein, endotoxins and Normotest were determined in 18 cirrhosis patients. The relation between the prekallikrein concentration (after 15 min activation) and the Normotest was significant (r = +0.72, P <0.001). Endotoxemia was only found in the more severe forms of liver disease (Normotest below 60%). During endotoxemia the prekallikrein levels were significantly lower than when no endotoxins were present in the blood of the same patients. The Normotest did not differ significantly in these patients in relation to the presence or absence of endotoxins. The activation of prekallikrein was slower in the more severe forms of liver disease. This might be due to reduced levels of factor XII and high molecular weight kininogen.
Altered Serum Factor Vlll-Related Antigen (VIII: AGN)/von Willebrand Factor (VIII: vWf) in Haemophiliacs with Inhibitors to Factor VIII Procoagulant Activity (VIII: C)
Authors: Ballard J O , Sanders J C , Eyster M E
Published: July 2018

Inhibitors to factor VIII (anti-F VIII) developing in patients with classic haemophilia have apparent specificity for the factor VIII procoagulant activity (VIII: C), rather than the factor VIII-related antigen (VIII :AGN) and von Willebrand factor (VIII :vWf) regions of the factor VIII complex.

Since procoagulant function is absent following in vitro clotting, but serum retains VIII: AGN/vWf properties, we searched for differences in VIII :AGN and VIII :vWf of inhibitor serum that might relate to the presence of anti-F VIII.

Rocket immunoelectrophoresis and the washed platelet ristocetin assay were performed on the plasma and serum of nine haemophiliacs with inhibitors, 23 non-inhibitor haemophiliacs and six normal subjects. Unlike normal and non-inhibitor haemophilic sera, that from five of nine inhibitor patients demonstrated absent VIII : vWf and significantly lower VIII: AGN (p <0.05). Furthermore, VIII: AGN of faster mobility was detected on crossed immunoelectrophoresis of the sera of three inhibitor patients. Thrombin clotting of plasma from haemophiliacs with high titer anti-F VIII was associated with a greater loss of VIII: vWf than seen with non-inhibitor haemophilic plasma. This effect was independent of the presence of platelets.

These data indicate that in vitro clotting is associated with alteration in the serum VIII: AGN/vWf of some haemophiliacs with anti-F VIII.
Purification and Characterization of the Sand Crab (Ovalipes bipustulatus) Coagulogen (Fibrinogen)
Authors: Madaras F , Chew M Y , Parkin J D
Published: July 2018

From the coagulocytes (amoebocytes) coagulogen (fibrinogen) was isolated, and purified on Sephacryl S-200.

The cell homogenate contained one major protein species with a minimum molecular weight of 70,000. This protein clotted in the presence of human thrombin, human factor XIII and Ca++.

The coagulogen contained no free thiol groups, however these were detectable in the reduced protein. Using the cyanoethylation procedure, it was estimated that one coagulogen molecule contained two lysine residues which participated in the cross-linking reaction. The total amino add composition of the crab coagulogen and coagulin (fibrin) was estimated and compared with the amino acid composition of the Limulus polyphemus, lobster (Panulirus interruptus) and porcine fibrinogen.
Effects of Prostaglandins, Derivatives of Cyclic 3':5'-AMP, Theophylline, Cholinergic Agents and Colchicine on Clot Retraction in Dilute Platelet-Rich Plasma and Gel-Separated Platelet Test Systems
Authors: Moake J. L , Cimo P. L , Widmer K , Peterson D. M , Gum J. R
Published: July 2018

In dilute suspensions of platelet-rich plasma (PRP) or gel-separated platelets (GSP), dibutyryl-cAMP (DBcAMP) and monobutyryl-cAMP inhibited platelet-mediated fibrin clot retraction in concentrations of 2–3 × 10–6M, with complete inhibition at 1–3 × 10–4M. Prostaglandin E1 (PGE1), which inhibited fibrin clot retraction in concentrations greater than 1.5–3 × 10–8M, was a more effective inhibitor than either PGE2 or PGF2α. In the presence of theophylline (10–4M), concentrations of DBcAMP, PGE1 PGE2 and PGF2α necessary to inhibit fibrin clot retraction were reduced 50-fold for DBcAMP and 2.5 to 20-fold for the prostaglandins. In dilute PRP or GSP, inhibition of fibrin clot retraction does not result from inhibition of thrombin-induced platelet aggregation. Thus, compounds which increase platelet cAMP levels result in the inhibition of platelet-mediated fibrin clot retraction, and this inhibitory effect may be mediated, at least in part, through suppression of platelet contractility. Cyclic GMP, dibutyryl-cGMP and carbamylcholine-Cl (which stimulates guanylate cyclase) did not influence fibrin clot retraction, and did not prevent inhibition of fibrin clot retraction by DBcAMP and PGE?. Colchicine, in concentrations known to disrupt platelet microtubules (2.5 × 10–6M to 2.5 x 10–3M), had little inhibitory effect on either fibrin clot retraction or platelet (3H)-serotonin release.
Influence of Cardiac Output on Peak t-PA Plasma Levels in Patients Receiving Thrombolytic Therapy with Recombinant Tissue-Type Plasminogen Activator – Correlation with Patency Rate
Authors: Huber Kurt , Beckmann Renate , Probst Peter , Rauscha Friedrich , Kaindl Fritz , Binder Bernd R
Published: July 2018

We studied 35 consecutive patients with short onset of myocardial infarction who underwent thrombolytic therapy with rt-PA at a standard dosage regimen of 100 mg rt-PA total (10 mg given as a bolus followed by 50 mg, 20 mg and 20 mg per hour for 3 hours). These patients were monitored for t-PA antigen and t-PA activity and PAI-1 activity plasma levels during rt-PA infusion. Success or failure of thrombolytic therapy was evaluated by non-invasive criteria (early plasma creatine kinase peaks, early peak plasma myoglobin values, and electrocardiographic criteria) as well as by means of coronary angiography at the fourth day after thrombolytic treatment. In 24 (68.6%) of these patients a success of thrombolytic therapy could be established by these criteria, while 11 patients did not respond to thrombolytic therapy. Fifteen patients (14 responders and one non-responder) had to be excluded from the further evaluation because in these patients clinical laboratory data obtained upon admission before initiation of thrombolytic therapy were not complete. Therefore, 20 patients (10 responders and 10 non-responders) could further be analysed. The two groups of patients were not significantly different in body weight, body weight index, age, gender, liver or kidney functional parameters as determined before initiation of the thrombolytic therapy. Furthermore, PAI-1 plasma levels before initiation of thrombolytic therapy were not significantly different in the two groups, as were rt-PA dosage per body weight or body weight index. Only heart rate and calculated cardiac output and cardiac index were significantly higher in the group of patients not responsive to thrombolytic therapy. t-PA values, however, at 30, 60 and 90 min after initiation of rt-PA infusion were significantly higher in the group of responders as compared to the group of non-responders. From these data we conclude that cardiac output which in turn determines liver blood flow might lead to different t-PA plasma levels following the same rt-PA dosage and the resulting t-PA plasma level might determine success or failure of thrombolytic therapy in respect to reopening of the infarct-related vessel.
A Hybrid Plasminogen Activator Binds to the u-PA Receptor and Has a Reduced Thrombolytic Potency In Vivo
Authors: Asselbergs Fred A M , Bürgi Rolf , Hamerman Jessica , Heim Jutta , van Oostrum Jan , Agnelli Giancarlo
Published: July 2018

Fibrinolytic properties of four hybrids of u-PA and t-PA, all containing the u-PA growth factor domain and binding to recombinant human u-PA receptor expressed in CHO cells, were compared. Highest fibrin stimulation was observed with uK2tPA which when compared to t-PA in the rabbit system, had a considerably prolonged circulatory half-life in vivo. Compared to an equimolar dose of t-PA, 0.4 mg/kg uK2tPA caused a similar consumption of α2-antiplasmin and fibrinogen and a considerably greater prolongation of the ex-vivo blood clotting time. Nevertheless, this dose of uK2tPA was inactive in the jugular vein thrombosis assay. This lack of thrombolytic activity is presumably due to the presence of a functional u-PA growth factor domain, which in binding uK2tPA to cellular blood elements possibly retards its penetration into the blood clot and in this manner could neutralize the potential thrombolytic activity of the t-PA kringle 2 and protease domains in uK2tPA.
Application of GPIIIa Gene Taq I Polymorphism to Determination of Carrier Status in Glanzmann’s Thrombasthenia Families of Chinese Origin
Authors: Ruan Changgeng , Gu Jianming , Wang Xiaodong , Chu Xiaohong , Pan Junliang
Published: July 2018

Glanzmann’s thrombasthenia is a bleeding disorder caused by qualitative and/or quantitative defects of platelet membrane glycoprotein (GP) IIb/IIIa complex. The disease is inherited in an autosomal recessive manner. In this paper, cDNA probes were used to study restriction fragment length polymorphisms (RFLPs) in GPIIIa gene. A Taq I polymorphism was identified and this RFLP was composed of variant bands of 6.5 Kb/4.0 and 2.5 Kb with a frequency of 0.46/0.54 in Chinese population. The Taq I polymorphism was further localized by polymerase chain reaction (PCR) method to exon VIII of the GPIIIa gene. In two Glanzmann’s thrombasthenia families, the Taq I RFLP studied by both Southern blotting and PCR methods identified the defective GPIIIa gene inherited by patients, and determined the genotype of asymptomatic subjects. Analysis of this Taq I polymorphism by PCR method should be potentially useful in future for the carrier detection and prenatal diagnosis in Glanzmann’s thrombasthenia families.
Treatment of Anti-Factor VIII Antibodies
Authors: Blatt Philip M. , White Gilbert C. , McMillan Campbell W. , Roberts Harold R.
Published: July 2018

Bleeding episodes in patients with hemophilia A with anti-factor VIII antibodies are frequently difficult to treat. Factor VIII concentrates administered by continuous infusion or prothrombin complex concentrates (PCC) have been used for treatment. Hemophilia A patients with inhibitors who respond to factor VIII concentrates generally have low to moderate inhibitor titers (generally less than 20 Bethesda units). Those patients who receive PCC are quite difficult to evaluate but promising clinical responses have clearly been observed. This paper describes our experience with both modalities of therapy and will offer specific guidelines for such therapy.
Preparation (Agar Zone Electrophoresis) and Immunological Characterisation of Urokinase
Authors: Andrassy K , Ritz E
Published: July 2018

Urokinase was highly purified by electrophoretical and immunological methods starting with a commercial urokinase preparation (UK-Leo). Contaminating serum proteins and enzyme activities migrated into opposite directions in agar gel electrophoresis which proved to be a valuable preparative method. The final purification achieved was 80,000 Ploug units/mg protein. Traces of albumin, α2 HS-glycoprotein and α2-macroglobulin migrated towards the cathode together with UK in a multimolecular complex. Urokinase antibodies (rabbit) gave with the cathodic fraction 2 precipitation lines (Ouchterlony technique): the one precipitation line corresponded to urokinase (molecular weight on gel chromatography 32,000 daltons), the other corresponded to UK complexed with serum proteins. Urokinase antibodies completely suppressed UK activity in various commercial preparations. All these preparations showed immunological identity; on disc electrophoresis pure urokinase (32,000 daltons, 80,000 Ploug units/mg protein) still gave 2-3 bands suggesting the presence of isoenzymes.

This paper is dedicated to Professor G. Schettler on behalf of his 60th birthday
Chronic Effect of Smoking on Platelet Count and “Platelet Adhesiveness” in Presumably Healthy Middle-Aged Men
Authors: Erikssen Jan , Hellem Arvid , Stormorken Helge
Published: July 2018

In 386 men aged 40–49 years the number of platelets was related to differences in smoking habits. “Platelet adhesiveness” (retention) was estimated by a glass bead filter method in 376 of these men. The estimation of “adhesiveness” was performed in native blood without anticoagulants at least 12 hr after the last cigarette smoked. A small but statistically highly significant increase in platelet count, in number of “adhesive platelets” and percentage of “adhesive platelets” was found in smokers as compared with non-smokers, the highest values being found in the heaviest smokers and vice versa. Such smoking-related changes in platelet count and reactiveness might unfavourably influence the tendency towards coronary thrombosis, and might in part explain the deleterious effects of smoking on coronary heart disease morbidity and mortality.
Megakaryocytes in the Giant Platelet Syndrome
Authors: Kass Lawrence , Leichtman David A. , Beals Theodore F. , Schnitzer Bertram
Published: July 2018

When compared to normal megakaryocytes, those from a patient with the giant platelet syndrome exhibited numerous cytochemical abnormalities. These reflected disturbances in the metabolism of RNA, glycogen, arginine-rich histone, and various glycolytic enzymes. Ultrastructural studies of the abnormal megakaryocytes also showed decreased glycogen and RNA (ribosomes) as well as aberrations of nuclear lobulation.
Degradation Pathway of Fibrinogen by Plasmin
Authors: Budzynski Andrei Z. , Marder Victor J.
Published: July 2018

The molecular weights of derivatives obtained from chemical and enzymatic degradation of fibrinogen and fibrin support a model in which the two halves of the fibrinogen molecule are covalently linked by a set of disulfide bonds at the amino-terminal region. The 2 asymmetric cleavages caused by plasmin in the fibrinogen molecule occur according to the reactions:

X → Y + D

Y → E + D

The quantitative analysis of the amino-terminal amino acids in fragments D (from fibrinogen) and DD (from crosslinked fibrin) yields a total of 3.0 and 6.9 moles of amino acids per mole of protein, indicating three and six polypeptide chain structures, respectively. The data on molecular weights, polypeptide chain composition and immunologic properties of fibrinogen degradation products support the hypothesis on the asymmetric pathway of fibrinogen degradation by plasmin and the formation of two fragment D and one fragment E molecules from each molecule of fibrinogen.
Studies on the Biochemistry of Urokinase
Authors: Ong Eng Bee , Soberano Mercedes E. , Johnson Alan J. , Schoellmann Guenther
Published: July 2018

Direct evidence for an active center histidine residue in urokinase (UK) was obtained with use of newly synthesized peptide chloroketones Ac-Gly-Lys-CH2C1 and Nle-Gly-Lys-CH2C1. Stoichiometric inactivation by DFP provided further evidence that UK is a serine protease. Essential histidine and serine residues were both located in the heavy chain of the 47,0 M. W.UK. The high M.W. form can be converted (catalytically) to the low M. W. form.

9 partially purified human urinary UK preparations (5 with predominantly high M. W. UK), varying in purity and proportion of high and low M. W. forms, were found to be heterogeneous by a number of acrylamide electrophoretic procedures. 7 preparations had strikingly similar molar activities at excess substrate, except for the lower values found in 2 predominantly high M. W. UK preparations from the same supplier. 2 high M. W. UK preparations from another supplier showed a definite increase in activity when assayed at low plasminogen concentration, but this effect was abolished after gel filtration (Sephadex G-25), by further purification with affinity chromatography, or when assayed with excess plasminogen.

The high and low M. W. forms of UK (47,000 and 33,400 M. W.), isolated and purified by Sepharose-EACA-agmatine affinity chromatography were shown to be homogeneous by Coomassie Blue staining after SDS-polyacrylamide gel electrophoresis (PAGE) and by 14C-DFP and 14C-NPGB incorporation before SDS-PAGE. Comparative properties of the high M. W. vs low M. W. forms were as follows: specific activity (104,000 IU/mg vs 226,000) ; 2 chains (33,100 and 18,600 M.W.) linked by disulfide(s) vs a single chain; pi 8.60 (major subform) and pi 8.90 (minor subform) vs pi 8.35, 8.60, 8.70 (major subform) and pi 8.05 (minor subform); and second order kinetics for DFP inactivation (400 vs 770 M−1 min−1). The molar activities were similar (9.6 × 109 and 10.2 × 109IUm/mole) for each form.
Catabolism of Fibrinogen and its Derivatives
Authors: Sherman Laurence A.
Published: July 2018

Although the site and manner of normal catabolism of most of the fibrinogen pool is uncertain, certain pathways have been defined for various fibrinogen derivatives. Several organs, including the kidneys and reticuloendothelial system (RES) have been directly implicated as catabolic sites for various fibrinogen derivatives. The catabolic sites are not the same for different derivatives. These differences in catabolism are probably in part related to biochemical differences between fibrinogen and its various derivatives. Fibrinogen itself may be catabolized in endothelial cells, although little experimental data is available. RES uptake of intact fibrinogen does not occur, and removal of sialic acid does not result in the rapid hepatic uptake seen with other desialop rote ins. In contrast, a variety of studies have shown that fibrin is taken up by the RES by at least 2 mechanisms. The first is phagocytosis of microparticulate fibrin. The second involves a RES cell membrane binding of soluble fibrin which remains soluble in the blood, when complexed to fibrinogen or degradation products. Fibrinogen degradation products alone may in part also be cleared in the RES. Fragments D and E appear to be catabolized in the kidney, although both the intrarenal site of catabolism and the means of cellular uptake is unknown. It is clear that normally there is no urinary excretion of D and E. Another fibrinogen derivative, low molecular weight clottable fraction 1–8, is derived in vivo from intact fibrinogen. 1–8 is found normally in the blood and has a shorter t ½ than fibrinogen although much longer than D and E. While originally thought to be the result of limited plasmin degradation, 1–8 may be the result of another type of proteolysis. The sites of both 1–8 formation and degradation are unknown. Catabolism via fibrin, 1–8, or D and E appears to be only a small percent of normal turnover, albeit of much greater significance in disease. The relationship of these pathways to the as yet unknown catabolic site for the bulk of normal fibrinogen remains to be determined.
Factors Influencing Leukocyte Adherence in Microvessels
Authors: Harvey Mayrovttz N. , Mary Wiedeman P. , Tuma Ronald F.
Published: July 2018

In vivo studies of the microcirculation of an untraumatized and unanesthetized animal preparation has shown that leukocyte adherence to vascular endothelium is an extremely rare occurrence. Induction of leukocyte adherence can be produced in a variety of ways including direct trauma to the vessels, remote tissue injury via laser irradiation, and denuding the epithelium overlying the observed vessels. The role of blood flow and local hemodynamics on the leukocyte adherence process is quite complex and still not fully understood. From the results reported it may be concluded that blood flow stasis will not produce leukocyte adherence but will augment pre-existing adherence. Studies using 2 quantitative measures of adherence, leukocyte flux and leukocyte velocity have shown these parameters to be affected differently by local hemodynamics. Initial adherence appears to be critically dependent on the magnitude of the blood shear stress at the vessel wall as evidenced by the lack of observable leukocyte flux above some threshold value. Subsequent behavior of the leukocytes as characterized by their average rolling velocity shows no apparent relationship to shear stress but, for low velocities, may be related to the linear blood velocity.
The Intravascular Generation of Fibrinogen Derivatives and the Blood Vessel Wall in Venous Thrombosis and Disseminated Intravascular Coagulation
Authors: Stewart Gwendolyn J.
Published: July 2018

Both deep venous thrombosis and DIC are intermediate mechanisms of disease – both are a consequence of the deposition of fibrin-rich material in blood vessels some distance from the primary site of tissue destruction. The great difference in the sites of fibrin deposition may depend on the extent and site of activation of the clotting mechanism. DIC likely occurs in the fluid phase of the blood as a consequence of massive fibrin formation while thrombosis results from limited fibrin formation at the interface between blood and vessel wall. Leukocytes may be essential for attaching thrombi to the vessel wall in many places.
Characterization and Origin of Fibrinogen in Blood Platelets
Authors: James Harold L. , Ganguly Pankaj , Jackson Carl W.
Published: July 2018

The discovery of thrombin-clottable protein in platelet homogenates initiated studies on the location, properties, and origin of such material, the ultimate aim of which has been to define its physiologic role. It was established that fibrinogen is present both on the platelet membrane as well as in the cytoplasmic α-granules. The membrane-bound material is apparently fibrinogen adsorbed from plasma, while the intracellular fibrinogen appears to have unique biochemical and functional properties. Differences in properties observed between platelet fibrinogen and plasma fibrinogen are not due to in vitro modifications during handling. Whether the intracellular fibrinogen is synthesized in the platelet (or megakaryocyte) or whether it is derived through uptake and limited modification of plasma fibrinogen in vivo has remained an open question. Thus, to investigate the aspect of origin of platelet fibrinogen, radioactively-labelled fibrinogen was injected into rats, blood was collected at time intervals and the radioactivity in the subcellular fractions of platelets was examined. A part of the injected fibrinogen became associated with the platelets, but very little was found in the granule fraction. Previous findings on human platelet fibrinogen, together with the present data obtained using rats, suggest that platelet fibrinogen may not be derived from plasma fibrinogen in vivo. It thus is apparent that the intracellular fibrinogen is synthesized by a unique genetic mechanism. Molecular properties of fibrinogen derived from rat platelet granules were shown analogous to the properties of fibrinogen from human platelet granules. Fibrinogen of intracellular origin is less stable than its plasma counterpart. The results obtained by others in which identity of platelet and plasma fibrinogens was reported may be explained on the basis of recovery of only the fibrinogen component bound to the platelet membrane, which is adsorbed plasma fibrinogen. It is suggested that the term platelet fibrinogen may be used to denote that present in the α-granules, with the membrane-bound component being referred to as platelet-associated fibrinogen.
Platelets and Fibrinolysis
Authors: Joist J. Heinrich
Published: July 2018

Blood platelets play a crucial role in the response of blood to vascular injury through adherence to exposed subendothelial vessel wall structures, the subsequent release of substances which trigger platelet aggregation, and release-associated changes in platelet surface properties which facilitate the interaction of coagulation factors, leading to the formation of fibrin necessary for stabilization of the initial hemostatic plug. There is substantial evidence from in vitro studies to suggest that platelets may also affect the fibrinolytic plasminogen-plasmin system thought to be one of the important hemostatic regulatory mechanisms preventing inappropriate extension of the hemostatic plug which may lead to thrombotic vessel occlusion. In this paper, the published experimental evidence concerning the effects of platelets and platelet-associated factors on the activation and function of the plasminogen-plasmin system is reviewed. The experimental findings indicate that platelets may contribute to fibrin clot stabilization through the release of substances from their storage organelles which inhibit both plasminogen activation and the action of plasmin. The physiologic and pathophysiologic significance of platelet-mediated inhibition of fibrinolysis by plasmin, as well as other potentially important plasma and cellular fibrinolytic enzymes, is still largely subject to speculation and appears to be an important area for future investigation.
Thrombin-Stimulated Myosin Phosphorylation in Intact Platelets and its Possible Involvement Secretion
Authors: Daniel James L. , Holmsen Holm , Adelstein Robert S.
Published: July 2018

A 20,000 dalton polypeptide, which is phosphorylated in intact platelets pre-incubated with 32P-P04, has been identified as a platelet myosin light chain. Stimulation of intact platelets with thrombin produced a 5-fold increase in the amount of radioactive phosphate incorporated into the light chain. Myosin phosphorylation preceeded acid hydrolase secretion and occurred concomitantly with adenine nucleotide secretion. These results are suggestive of participation of contractile mechanisms in platelet secretion.
Malondialdehyde Production by Platelets during Secondary Aggregation
Authors: Macfarlane D. E , Gardner Sheila , Lipson Carol , Mills D. C. B
Published: July 2018

A method is described for increasing the sensitivity of the thiobarbiturate assay for malondialdehyde by concentrating the coloured reaction product. The basal level of malondialdehyde-like material in plasma was found to be about 0.03 μM. Platelets synthesized malondialdehyde when stimulated by collagen or thrombin and also during the second phase of aggregation induced by ADP or adrenaline.
Depletion of Platelet Amine Storage Granules by the Antithrombotic Agent, Suloctidil
Authors: Mills David C. B. , Macfarlane Donald E.
Published: July 2018

Suloctidil, a compound with antithrombotic properties in animal models, causes depletion of human platelet serotonin stores during 1–5 hr incubation with platelet-rich plasma in vitro. This effect is not attended by leakage of cytoplasmic nucleotides or by alterations in cyclic AMP metabolism, malondialdehyde production or energy balance. 5HT uptake was also inhibited but uptake of adenine was not. 5HT released by suloctidil appeared in the supernatant as oxidation products, though the amine also accumulated when re-uptake was blocked by imipramine.
Apparent Lack of Synergism between Heparin and Dihydroergotamine in Prevention of Deep Vein Thrombosis after Elective Hip Replacement: a Randomised Double-Blind Trial Reported in Conjunction with an Overview of Previous Results
Authors: Gallus Alexander S , Cade John F , Mills K W , Murphy Wendy
Published: July 2018

We report the results of a double-blind, randomised trial of venous thrombosis (VT) prevention in 117 patients having elective hip replacement where low dose heparin alone (5,000 IU sodium heparin given subcutaneously [sc] 8 hourly until the seventh postoperative day) was compared with low dose heparin plus dihydroergotamine (DHE; 0.5 mg, given 8 hourly by sc injection). The trial end point consisted of VT discovered through bilateral ascending venography done routinely on the seventh postoperative day. VT developed in 34% of patients given heparin/DHE (95% confidence interval = 22% – 47%) compared with 24% in those given low dose heparin alone (95% confidence interval = 14% – 37%; p = 0.34), difference = 10% (95% confidence interval = –7% to +26%). Corresponding figures for the incidence of proximal (above-knee) thrombosis were 17% and 14% (95% confidence intervals = 8% – 29% and 6% – 25% respectively). These results are discussed in the context of a detailed overview of published evidence concerning VT prevention with heparin/DHE after hip replacement and we conclude it is unlikely that heparin/DHE is markedly superior to low dose heparin alone in this clinical setting.
Effect of Stimulation on the Stabilization of Platelet-Fibrinogen Interactions
Authors: Peerschke Ellinor I B
Published: July 2018

The interaction between fibrinogen and stimulated platelets is a multiphasic process that culminates in the stabilization of ligand binding and reduced accessibility of bound fibrinogen to exogenous antibody. The present study was designed to further explore platelet-fibrinogen interactions by examining the effect of agonist on bound fibrinogen expression and interaction with stimulated platelets as a function of time after ligand binding. Two agents were identified, Zn2+ and phorbol myristate acetate (PMA), which support progressive decreases in bound fibrinogen expression on platelets, but fail to support the stabilization of fibrinogen binding. Sixty min after binding to platelets, approximately 80% of bound fibrinogen remained reversibly associated with Zn2+- or PMA-treated platelets and failed to associate with the Triton X-100 insoluble cytoskeleton. In contrast, polyclonal anti-fibrinogen antibody binding decreased by more than 66%. Over the same time course, fibrinogen binding to control platelets, stimulated with thrombin or ADP, was not only accompanied by a 70% decrease in antifibrinogen antibody binding, but also an inability of EDTA or excess exogenous fibrinogen to dissociate more than half of platelet-associated fibrinogen, as well as the progressive association of bound fibrinogen with the platelet cytoskeleton. Costimulation of platelets with ZnCl2 and thrombin or ZnCl2 and ADP enhanced overall fibrinogen binding but not the EDTA-resistant component, and prevented the recovery of irreversibly bound fibrinogen with the Triton X-100 insoluble cytoskeleton. Costimulation of PMA- or Zn2+-treated platelets with low doses of A23187, however, restored the stabilization of platelet-fibrinogen interactions. These data suggest that modulation of bound fibrinogen expression on stimulated platelets can occur independently of the development of EDTA-resistant fibrinogen binding, and that stabilization of platelet-fibrinogen interactions is sensitive to stimulation-specific intracellular signal transduction.
Trade Liberalization and Constraints on Moves to Protectionism: Multilateralism vs. Regionalism
Authors: Sheldon Ian M. , Chow Daniel C.K. , McGuire William
Published: July 2018

In this article, two key questions are asked: why has the General Agreement on Tariffs and Trade (GATT) and its predecessor the World Trade Organization (WTO) worked in terms of multilateral tariff reduction and promotion of global trade, and to what extent will it act as a constraint on economic nationalism? To answer these two questions, three themes are laid out in the article: first, the seminal economic model rationalizing the economic logic of the GATT/WTO is assessed; second, the perceived relevance of the GATT/WTO in a world of increasing regionalism is discussed; and third, the robustness of the GATT/WTO legal framework and dispute resolution mechanism is evaluated. The key conclusion is that the underlying economic logic of the GATT/WTO is still relevant, but that enforcement of the cooperative agreement will likely be placed under significant strain with the threat of increased protection, and even a potential trade war.
The joint lasso: high-dimensional regression for group structured data
Authors: Dondelinger Frank , Mukherjee Sach ,   The Alzheimer’s Disease Neuroimaging Initiative
Published: July 2018

We consider high-dimensional regression over subgroups of observations. Our work is motivated by biomedical problems, where subsets of samples, representing for example disease subtypes, may differ with respect to underlying regression models. In the high-dimensional setting, estimating a different model for each subgroup is challenging due to limited sample sizes. Focusing on the case in which subgroup-specific models may be expected to be similar but not necessarily identical, we treat subgroups as related problem instances and jointly estimate subgroup-specific regression coefficients. This is done in a penalized framework, combining an $\ell_1$ term with an additional term that penalizes differences between subgroup-specific coefficients. This gives solutions that are globally sparse but that allow information-sharing between the subgroups. We present algorithms for estimation and empirical results on simulated data and using Alzheimer’s disease, amyotrophic lateral sclerosis, and cancer datasets. These examples demonstrate the gains joint estimation can offer in prediction as well as in providing subgroup-specific sparsity patterns.
Methylphenidate Attenuates the Cognitive and Mood Alterations Observed inMbnl2Knockout Mice and Reduces Microglia Overexpression
Authors: Ramon-Duaso Carla , Gener Thomas , Consegal Marta , Fernández-Avilés Cristina , Gallego Juan José , Castarlenas Laura , Swanson Maurice S , de la Torre Rafael , Maldonado Rafael , Puig M Victoria , Robledo Patricia
Published: July 2018

Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting muscle and central nervous system (CNS) function. The cellular mechanisms underlying CNS alterations are poorly understood and no useful treatments exist for the neuropsychological deficits observed in DM1 patients. We investigated the progression of behavioral deficits present in male and female muscleblind-like 2 (Mbnl2) knockout (KO) mice, a rodent model of CNS alterations in DM1, and determined the biochemical and electrophysiological correlates in medial prefrontal cortex (mPFC), striatum and hippocampus (HPC). Male KO exhibited more cognitive impairment and depressive-like behavior than female KO mice. In the mPFC, KO mice showed an overexpression of proinflammatory microglia, increased transcriptional levels of Dat, Drd1, and Drd2, exacerbated dopamine levels, and abnormal neural spiking and oscillatory activities in the mPFC and HPC. Chronic treatment with methylphenidate (MPH) (1 and 3 mg/kg) reversed the behavioral deficits, reduced proinflammatory microglia in the mPFC, normalized prefrontal Dat and Drd2 gene expression, and increased Bdnf and Nrf2 mRNA levels. These findings unravel the mechanisms underlying the beneficial effects of MPH on cognitive deficits and depressive-like behaviors observed in Mbnl2 KO mice, and suggest that MPH could be a potential candidate to treat the CNS deficiencies in DM1 patients.
Interrogating the Relationship Between Schizotypy, the Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism, and Neuronal Oscillatory Activity
Authors: Steiner Genevieve Z , Fernandez Francesca M , Coles Madilyn , Karamacoska Diana , Barkus Emma , Broyd Samantha J , Solowij Nadia , Watson Owen T , Chiu Christine L , Lind Joanne M , Barry Robert J
Published: July 2018

The COMT Val158Met polymorphism affects the availability of synaptic dopamine in the prefrontal cortex and has been widely studied as a genetic risk factor for psychosis. Schizotypy is associated with an increased risk of psychosis, with some studies implicating similar neurobiological mechanisms to schizophrenia. The present study sought to interrogate the link between the COMT Val158Met polymorphism and schizotypy using electroencephalogram (EEG) to identify neurophysiological mechanisms underpinning psychosis risk. Neurotypical (N = 91) adults were genotyped for the COMT Val158Met polymorphism, completed the Schizotypal Personality Questionnaire (SPQ), and had eyes open resting-state EEG recorded for 4 min. SPQ suspiciousness subscale scores were higher for individuals homozygous for Val/Val and Met/Met versus Val/Met genotypes. Delta, theta, alpha-2, beta-1, and beta-2 amplitudes were lower for Val/Val than Met/Met individuals. Lower theta amplitudes were correlated with higher total SPQ scores (P = 0.050), and multiple regression revealed that higher delta, and lower theta and beta-2 amplitudes (but not COMT genotype) best predicted total SPQ scores (P = 0.014). This study demonstrates the importance of COMT genotype in determining trait suspiciousness and EEG oscillatory activity. It also highlights relationships between dopaminergic alterations, EEG and schizotypy that are dissimilar to those observed in schizophrenia.
Artificial light in baited pots substantially increases the catch of cod (Gadus morhua) by attracting active bait, krill (Thysanoessa inermis)
Authors: Humborstad Odd-Børre , Utne-Palm Anne Christine , Breen Michael , Løkkeborg Svein
Published: July 2018

The use of pots in the north Atlantic finfish fisheries is negligible because this fishing method typically has a low capture efficiency. Large numbers of individuals encounter baited pots, but the proportions of fish that enter the pot and become caught are low. Krill, which constitutes an important prey for cod (Gadus morhua), is attracted by light. The catching efficiency of baited cod pots with three light sources with different colours and intensities (white: 9744 mW m−2, white: 23 mW m−2, green: 8 mW m−2) were tested in coastal waters in northern Norway. Pots with the light source of highest intensity gave a 17 times higher catch rate of cod than that of control pots (with bait only). The light source of medium intensity gave about a five times higher catch rate, whereas the weakest light did not influence the catch. Cod caught in pots with light had more krill and arrowworms in their stomach and were observed feeding on these preys inside the pot. We concluded that light sources of increasing intensity attract more krill, and that cod were attracted into the pot by the dense swarms of prey and not the light per se.
Analysis of medication therapy discontinuation orders in new electronic prescriptions and opportunities for implementing CancelRx
Authors: Yang Yuze , Ward-Charlerie Stacy , Kashyap Nitu , DeMayo Richelle , Agresta Thomas , Green James
Published: July 2018

Objective

To illustrate the need for wider implementation of the CancelRx message by quantifying and characterizing the inappropriate usage of new electronic prescription (NewRx) messages for communicating discontinuation instructions to pharmacies.

Materials and Methods

A retrospective analysis on a nationally representative random sample of 1 400 000 NewRx messages transmitted over 7 days to identify e-prescriptions containing medication discontinuation instructions in NewRx text fields. A vocabulary of search terms signifying cancellation instructions was formulated and then iteratively refined. True-positives were subsequently identified programmatically and through manual reviews. Two independent reviewers identified incidences in which these instructions were associated with high-alert or look-alike-sound-like (LASA) medications.

Results

We identified 9735 (0.7% of the total) NewRx messages containing prescription cancellation instructions with 78.5% observed in the Notes field; 35.3% of identified NewRxs were associated with high-alert or LASA medications. The most prevalent cancellation instruction types were medication strength or dosage changes (39.3%) and alternative therapy replacement orders (39.0%).

Discussion

While the incidence of prescribers using the NewRx to transmit cancellation instructions was low, their transmission in NewRx fields not intended to accommodate such information can produce significant potential patient safety concerns, such as duplicate or inaccurate therapies. These findings reveal the need for wider industry adoption of the CancelRx message by electronic health record (EHR) and pharmacy systems, along with clearer guidance and improved end-user training, particularly as states increasingly mandate electronic prescribing of controlled substances.

Conclusion

Encouraging the use of CancelRx and reducing the misuse of NewRx fields would reduce workflow disruptions and unnecessary risks to patient safety.
Islām – Midrashic Perspectives on a Quranic Term
Authors: Kister Menahem
Published: July 2018

The article examines several Quranic passages which contain the verb aslama and the noun islām in light of Jewish parallels. It is argued that these passages (Q 2:124–33; Q 37:84, 101-3; Q 27:29-44; Q 6:125) reflect midrashic traditions, and that the Arabic aslama and islām in these passages parallel the Hebrew be-lev shalem or hishlim. The latter term accrued two meanings: (1) to worship the Lord wholeheartedly (i.e., exclusively), and (2) to deliver one’s soul (to God) while accepting his authority and surrendering to him.

The article also examines the Hebrew terms mentioned above and their antonyms ḥaluq, maḥăloqet (denoting monotheistic versus polytheistic worship), and the implications of these terms for the textual history of the Palestinian Targums.
Civil Jurisdiction and Judgments in Europe: The Brussels I Regulation, the Lugano Convention, and the Hague Choice of Court Convention - Online Update, January 2018
Authors: Trevor C Hartley
Published: July 2018

This supplement complements Civil Jurisdiction and Judgments in Europe: The Brussels I Regulation, the Lugano Convention, and the Hague Choice of Court Convention by Trevor Hartley. It discusses updates to various chapters of the main work. These include updates to chapters on Special Jurisdiction, Protective Jurisdiction, Choice of Court Agreements, and Specific Exclusions.
1 General: Meaning of ‘Court’ under Brussels 2012
Authors: Trevor C Hartley
Published: July 2018

This section of the noter-up to Civil Jurisdiction and Judgments in Europe: The Brussels I Regulation, the Lugano Convention, and the Hague Choice of Court Convention by Trevor Hartley discusses the meaning of ‘Court’ under Brussels 2012.
2 Update to Chapter 4: Subject-Matter Scope: Civil and Commercial Matters
Authors: Trevor C Hartley
Published: July 2018

This section of the noter-up to Civil Jurisdiction and Judgments in Europe: The Brussels I Regulation, the Lugano Convention, and the Hague Choice of Court Convention by Trevor Hartley discusses civil and commercial matters. These include payment for parking in a public car park under Brussels 2012.
3 Update to Chapter 5: Subject-Matter Scope: Specific Exclusions
Authors: Trevor C Hartley
Published: July 2018

This section of the noter-up to Civil Jurisdiction and Judgments in Europe: The Brussels I Regulation, the Lugano Convention, and the Hague Choice of Court Convention by Trevor Hartley discusses specific exclusions. These include bankruptcy and rights in property arising out of a matrimonial relationship.
4 Update to Chapter 8: Special Jurisdiction
Authors: Trevor C Hartley
Published: July 2018

This section of the noter-up to Civil Jurisdiction and Judgments in Europe: The Brussels I Regulation, the Lugano Convention, and the Hague Choice of Court Convention by Trevor Hartley discusses special jurisdiction. This includes defamation and invasion of privacy, and when Article 7(1) applies to matters relating to a contract.
6 Update to Chapter 11: Protective Jurisdiction
Authors: Trevor C Hartley
Published: July 2018

This section of the noter-up to Civil Jurisdiction and Judgments in Europe: The Brussels I Regulation, the Lugano Convention, and the Hague Choice of Court Convention by Trevor Hartley discusses protective jurisdiction. This includes insurance, consumer contracts, and individual contracts of employment.
7 Update to Chapter 12: Exclusive Jurisdiction
Authors: Trevor C Hartley
Published: July 2018

This section of the noter-up to Civil Jurisdiction and Judgments in Europe: The Brussels I Regulation, the Lugano Convention, and the Hague Choice of Court Convention by Trevor Hartley discusses exclusive jurisdiction. This includes intellectual property.
8 Update to Chapter 13: Choice of Court Agreements
Authors: Trevor C Hartley
Published: July 2018

This section of the noter-up to Civil Jurisdiction and Judgments in Europe: The Brussels I Regulation, the Lugano Convention, and the Hague Choice of Court Convention by Trevor Hartley discusses choice of court agreements. These include asymmetric choice-of-court agreements.
9 Update to Chapter 14: Submission
Authors: Trevor C Hartley
Published: July 2018

This section of the noter-up to Civil Jurisdiction and Judgments in Europe: The Brussels I Regulation, the Lugano Convention, and the Hague Choice of Court Convention by Trevor Hartley discusses submission. These includes Brussels 2012, Article 26(1).
Definitions
Authors: Krähenmann Sandra
Published: July 2018

The United Nations Set of Principles for the Protection and Promotion of Human Rights Through Action to Combat Impunity define at the outset a variety of key terms that are repeatedly used in the document, namely: ‘impunity’, ‘serious crimes under international law’, ‘restoration of or transition to democracy and/or peace’, ‘truth commissions’, and ‘archives’. The definitions delimit the scope of the updated Principles and emphasise two things: that the Principles are addressed to states and do not provide guidance for investigative mechanisms and archives by international organisations and non-governmental organisations. Compared to the Joinet Principles, the updated Principles adopt a broader notion of ‘serious crimes under international law’ so as to take into account any future developments. The updated Principles also acknowledge the broader role to be played by truth commissions, complementary and distinct from criminal proceedings.
Guarantees to Give Effect to the Right to Know
Authors: Unger Thomas
Published: July 2018

Principle 5 outlines guarantees that States must take to give effect to the right to know, including judicial and non-judicial mechanisms. This principle focuses on courts, truth commissions and archives, and gives a privileged position to criminal justice. It follows a clear human rights understanding on how guarantees should look like in the fight against impunity. This chapter first provides a contextual and historical background on Principle 5 before discussing its theoretical framework and some practical trends regarding the guarantees designed to give effect to the right to know. It highlights a number of limitations of Principle 5 and proposes a revised version, calling for a more dynamic functional approach that creatively looks at what kind of existing and new interventions could take on the function of guarantees to give effect to the right to know.
The Establishment and Role of Truth Commissions
Authors: Nuzov Ilya , Freeman Mark
Published: July 2018

Principle 6 is concerned with the establishment and role of truth commissions, outlined in two paragraphs. The Principle recommends criteria that can be applied ‘to the greatest extent possible’. The first paragraph encompasses three different aspects of the issue: the preliminary ‘decision to establish a truth commission’, the subsequent creation of its ‘terms of reference’, and the related determination of its ‘composition’. In the second paragraph, the term ‘role’ refers to the functional end-goal that a commission is expected to serve: ‘securing recognition of such parts of the truth as were formerly denied’. After providing a historical and contextual background on Principle 6, this chapter discusses its theoretical framework and the ways in which the Principle is exercised in practice.