bluuebunny/crossref_metadata_2025 huggingface dataset:
FUNCTIONAL CHARACTERIZATION OF HUMAN β-THROMBIN
Authors: Bezeaud A , Guillin M C
Published: August 2018

Autolysis or tryptic hydrolysis converts β-thrombin (α-T) t β-thrombin ( β -T), and subsequently β-T to y-thrombin (γ-T). Human β-T differs from native α-T by the loss of a unique ll-re-sidues peptide arising from the B chain. Unlike its bovine counterpart, human β-Tisa transient intermediate and its enzymatic properties had not yet been investigated using purified materiaL After 3 min incubation of human β-T with trypsin-sepharose, the resulting β-T was separated from α- and γ-T by chromatography on Biorex 70 with a gradient from 10 mM to 500 mM phosphate at pH 8. No major differences were found between human α- and β-T regarding the kinetic parameters (Km, kcat, kcat/Km) on S 2238, nor the rate of inactivation by TLCK. In contrast, inhibition of β-T by DFP was slower (k = 426 ±[; 10.8 M-1 min−1) compared to α-T (764.5 ± 19.5 M−11min−1and the inhibition constant for benzami-dine was higher with β-T (Ki = 11.2 ± x00B1;.2 10−4 M) compared to α-T (Ki = 2.86± 0,06 10−4 M). The drastic reduction in the clotting activity of β-T (25 u mg−1 versus 3000 u mg−1 for α-T) was further explored by measuring the affinity of β-T for fibrinogen and fibrin. Human fibrinogen was used as a competitor in the inactivation of thrombin by DFP : 10 μM fibrinogen prevented the inhibition of α-T by DFP but failed to modify the inactivation rate of α-T. Binding of thrombin to fibrin was studied using fibrin monomers covalently linked to sepharose 4B, equilibrated in 50mM Tris, pH 7.5, 50 mM NaCl : β -T did not bind to the resin, whereas α-T was retained and eluted upon application of a NaCl gradient.

In conclusion, the loss of the peptide extending from lie (63) to Arg (73) in the thrombin B chain is responsiblefor multiple defects in thrombin enzymatic activity. Although, the three active site residues Ser (205), His (43), Asp (99) remain in an active configuration, subtle changes are induced in the microenvironment of the catalytic Ser (205), and in particular, in the primary binding pocket. In addition, the results presented in this study indicate thatthe loss of clotting activity is mainly the result of a decreased affinity for fibrinogen and fibrin, suggesting that the structural changesaffect both the fibrinopeptide groove and the anionic binding site involved in fibrinogen/fibrin recognition.
EVIDENCE FOR MULTIPLE BINDING SITES OF HIRUDIN IN THROMBIN
Authors: Villanueva German B , Sensuke Konno , Fenton John
Published: August 2018

A highly purified hirudin with a specific activity of 13, 950 AT units/mg was used in these studies. Investigation of the circular dichroism of hirudin and thrombin showed that the CD spectrum of the thrombin-hirudin complex deviates significantly from additivity towards a less organized structure (i.e. loss of a-helix).A sigmoidal curve, rather than a hyperbolic curve, is generated when the deviation from additivity is plotted against hirudin concentration. This suggests cooperativity of the binding process. At low concentation, aScatchard plot of the data fits intoa straight line clearly indicating one binding site per mole of thrombin.This site binds hirudin with a dissociation constant of 500 nM. However, the data cannot be fitted to a straight line at higher concentration ofhirudin suggesting that hirudin binds also to another site with a different affinity. These results agree with the findings of Stone and Hofsteenge (Biochemistry 25, 4622-4628, 1986) and support the idea that initially hirudin binds at a site distinct from the active site, which then rearranges through a conformational change (detected by CD) to form a tigher complex in which hirudin is also bound to the active site.
RISK FACTORS FOR AIDS AND ARC IN MULTITRANSHJSED HAEMOPHILIACS: ASSOCIATION OF A WEAK GAG P 18 IN WESTERN BLOT (WB) AND IMMUNE THROMBOCYTOPENIA?
Authors: Kos M , Hainz F X , Assmann I , Kundi M , Pabinger I , Panzer S , Korninger Ch , Kunz Ch , Lechner K
Published: August 2018

Lymphocyte subsets, platelet counts, immune globulin levels and antibody to HIV (Elisa, WB) were determined in 87 multitransfused asymptomatic haemophiliacs in 1982/83. Between 1982 and 1987 6 patients developed AIDS and 5 ARC (3 immune thrombocytopenia and 2 lymphadenopathy). AIDS or ARC developed in seropositive patients only (11/49). Patients who subsequently developed AIDS or ARC showed significantly lower numbers of T helper lymphocytes (378/mm3 versus 605/mm3; p 0.01), lower platelet counts (157x109 versus 194x109; p 0.05) and higher levels of IgG (2528 mg/dl versus 1992 mg/dl; p 0.01). AIDS or ARC occured in 4 of 7 patients(57.1%) with a low HIV antibody level ( 2000), but only in 7 of 42 (16.6%) with a high level of antibody to HIV ( 2000). A weak gag p 24 in WB was found in 4 of 11 patients (36.3%) who subsequently acquired AIDS or ARC , while none of the patients whq remained asymptomatic displayed this reactivity pattern in WB. 9 patients showed a weak gag p 18 in WB. 8 of them (88.8%) have platelet counts below 120x109 /1, 3 developed imiruine thrombocytopenia with platelet counts of less than 50xl09. Oily 6 of 40 patients (15%) without this reactivity pattern in WB have platelet counts lower than 120x109 and none below 50xl09.We conclude that a weak gag p 24 in WB has a strong positive predictive power for the development of AIDS or ARC in seropositive haemophiliacs. A weak gag p 18 in WB could possibly be associated with the occurence of immune thrombocytopenia in these patients.
THE FIBRINOLYTIC, FACTOR VIII:C, VON WILLEBRAND FACTOR AND HEMODYNAMIC RESPONSES TO DDAVP IN PATIENTS WITH HEREDITARY NEPHROGENIC DIABETES INSIPIDUS
Authors: BRINK K , DERKX F , BROMMER E , STIBBE J , KOLSTEE H , SCHALEKAMP M
Published: August 2018

The pressor response of vasopressin (AVP) is mediated by a calcium-dependent mechanism (VI-receptor), whereas its antidiuretic effect depends on c-ANP (V2-receptor). DDAVP (1-desamino-8-D-arginine vasopressin) is a synthetic V2 analog of AVP. AVP and DDAVP also increase FVIII:C vWF:Ag and tissue-type plasminogen activator (t-PA) in plasma. The mechanism by which AVP and DDAVP elevate these factors is unclear. Patients with X-linked nephrogenic diabetes insipidus (NDI) are resistant to the V2-mediated antidiuretic action of AVP and DDAVP. We therefore have studied the effect of DDAVP (0.4 ug/kg iv infusion in 10 min) in 2 brothers with NDI, their mother and an unrelated patient.

In control subjects (n=12) FVIII:C rose 122 (6) % ,mean (SEM), vWF:Ag 104 (4) % and t-PA 115 (7) % over basal levels. This rise was associated with a fall in diascolic blood pressure -11 (3) mmHg and an increase in heart rate from 62 (4) to 91 (5) bpm. Plasma noradrenaline rose from 262 (34) to 590 (84) pg/ml and renin from 16 (3) to 42 (6) uU/ml. Ten out of 12 controls showed facial flusning. The patients with NDI had normal basal FVIII:C, vWF:Ag and t-PA levels. Plasma noradrenaline and renin were within the nor mam range. Tne patients with NDI were also resistant to the stimulatory effect of DDAVP on the release of FVIII:C, vWF:Ag and t-PA. They also showed no change in blood pressure, nearc rate, plasma noradrenaline and renin and had no facial flushing. The carrier had normal responses to DDAVP.

Tne increase in FVII:C, vWF:Ag and t-PA and the hemodynamic responses after DDAVP infusion probably appear to depend on extrarenal V2-receptor activation. DDAVP cannot be used in identifying carriers in families at risk.
IMMUNE TOLERANCE INDUCTION IN HEMOPHILIA A WITH INHIBITOR
Authors: Kasper C K , Sanders N L , Ewing N P
Published: August 2018

Factor VIII (FVIII), 50 U/Kg/day, was given without immunosuppressive drugs to 11 patients with hemophilia A and inhibitor. Interval since inhibitor diagnosis was 4-6 years (yr) in 3 cases and 12-27 yr in others. Six had received no FVIII since inhibitor diagnosis. Intervals since last FVIII use were 2 months (mo) in 3 cases and 3-15 yr in others. Historic peak inhibitor levels were 3,8,9,10,25,27,64,375,809,1100 and 2780 Bethesda units (BU). Levels at start of protocol (baseline) were under one BU in 7 cases and 2,42,265 and 398 in others. Evidence of HIV. infection exists in 10 patients: 8 of 9 tested have HIV antibody, 7 of 11 tested have low T4 cell counts and 4 currently have AIDS-related complex. Results after 4-31 mo (median 10) are as follows. Peak inhibitor levels on protocol exceeded baseline in only 6 cases and exceeded historic peaks in only 2 cases. All peaks occurred during the first mo and levels fell markedly by the second. All patients but one had levels below baseline by the third mo. Among 7 patients with one BU or less baseline, no inhibitor was detected after one mo in 4 cases and after 3 mo in 2 cases; another child still has trace inhibitor after 8 mo. A child with baseline 2 BU had no inhibitor after 4 mo. Three older patients have not responded completely. In 2 adults who began the protocol 2 mo after intense FVIII use for hemorrhages, baselines of 275 and 398 BU fell rapidly in the first 4 mo but then plateaued around 20-30 BU despite 9 and 26 mo further therapy. In a teenager who began the protocol 4 yr after intense FVIII use, the baseline of 42 BU has not fallen in 4 mo of therapy. Thus, rapid induction of immune tolerance was achieved in 7 of 8 patients with low baselines; the program was less useful in patients with high baselines. Of 4 patients resistant to full induction of immune tolerance, all have evidence of HIV infection; 3 were tested and have HIV antibody, 2 have low T4 counts and 2 have ARC. Thus, the immune suppression of HIV infection may not potentiate induction of FVIII tolerance. All patients achieving FVIII tolerance remain of FVIII prophylaxis. In some, low-level inhibitors emerged on attempts at withdrawal. Induction of immune tolerance with FVIII is advised for patients with currently-low inhibitor levels because of the high success rate.
PERTURBATION OF ENDOTHELIAL CELLS INDUCES THROMBIN FORMATION IN FLOWING BLOOD RESULTING IN PLATELET AGGREGATION ON THEIR MATRIX
Authors: Zwaginga Jaap Jan , IJsseldijk Martin J W , de Groot Philip G , Sixma Jan J
Published: August 2018

Studies which try to measure the contribution of the vessel wall to thrombin formation in flowing blood and the consequences of the formed thrombin for thrombus formation can not be performed with native blood because the perfusion system itself causes thrombin formation. Therefore, we have collected blood into^a solution of low molecular weight heparin (20 U/ml, Fragmin , Kabi Vitrum) and used this blood for perfusion studies over endothelial cells (EC) and their extracellular matrix (ECM) in a flat perfusiqn chamber (J.Lab.Clin.Med. 1983, 102, 522-532).Cells (2 x 105 ) and matrices (3.2 cm2) wetje perfused with 12 ml blood for 5 min at a shear rate of 1300 s . No fibrinopeptide A (FPA) generation in the perfusate was seen after perfusion over EC, ECM or empty coverslips. Treatment of EC for 4 hours with 4-phorbol 12-myristate 13-acetate (PMA 20 µg/ml) caused a strong increase in FPA generation (50 ng/ml) which was decreased again after a 16 hour incubation (25 ng/ml). ECM of EC's treated for 4 h with PMA showed a comparable FPA generation as their EC's (40 ng/ml), however, the FPA generation increased with prolonged incubation with PMA. FPA generation was completely blocked by hirudin and with a specific antibody against FVIIa (Dr. Mertens, CLB). By incubation of the matrix with an antitissue factor serum (Dr. Bertina, AZL), FPA generation could be blocked. The effect of the locally formed thrombin on platelet adhesion to ECM of 16 h PMA treated EC was evaluated and showed that 47.1 ± 9.3 (SD)% of the surface was covered with platelets of which 22.0 ± 9.3% consisted of small (< 5 µm) and 3.1 ± 3.4% of larger (5-10 µm) aggregates. EM studies showed degranulation of platelets and fibrin formation around the aggregates. ECM of untreated EC showed a similar coverage 41.5 ± 5.5% but only 6.7% small aggregates. Anti FVIIa and anti tissue factor decreased aggregate height and number to the values found with untreated ECM; adhesion remained unchanged. These data indicate that PMA perturbation of EC induces a tissue factor dependent thrombin formation which is associated with the induction of local thrombus formation. This system may serve as an in vitro model for thrombosis.
MEMBRANE SIGNAL TRANSDUCTION IN PLATELETS WITH ALTERED RELEASE REACTION
Authors: Rendu F , Hovig T , Marche P , Lebret M , Tenza D , Maclouf J , Caen J P , Levy-Toledano S
Published: August 2018

The process of signal transduction during thrombin-induced activation was studied in pathological platelets characterized by a defect in a specific storage granule, i.e. from Hermansky-Pudlak syndrome (HPS) and from Grey-Platelet Syndrome (GPS). HPS platelets exhibited an apparently normal ultrastructure except for a decreased number of dense bodies. Grey platelets showed marked vacuolization and an almost total absence of alpha-granules. During thrombin stimulation both types of platelets showed the same tendency of centralization of the organelles present indicating that neither type of granule is a prerequisite for this ring-like structure.However this granule centralization was clearly delayed in GPS where it occurred 15 sec after thrombin addition instead of 5 sec in normal platelets. The transducing system involving phosphoinositides specific phospholipase C was observed in platelets lacking dense bodies (HPS) but the phosphatidyl 4,5 bisphosphate(PIP2 )breakdown in 32P-prelabelled platelets was measurable at 202 sec instead of 10 sec in normal platelets. No ch activity was detectable at any time in grey platelets. 32P-phosphatidate (PA) formation was subnormal in HPS platelets and normal in grey platelets. Phosphorylation pattern of myosin light chain (P20) and of 43K protein (P43) were normal in HPS platelets and markedly reduced in grey platelets, being less than half of the normal during the first 15 sec and remaining subnormal even after complete aggregation. The release of constituents from the present granules and the thromboxane formation were lower than in normal platelets in all cases. In conclusions, (i) alpha-granules but not dense bodies may play a key role in the activation of the PIP2 specific phospholipase C,(ii) PA formation does not always correlate with phosphoinositide metabolism and could originate from another pool of diacylglycerol,(iii) complete phosphorylations of both P20 and P43 may not be sufficient to stimulate a normal release, and (iv) end products such as thromboxanes and released ADP accelerate and reinforce platelet responses.
AIDS 1987
Authors: Desmyter J
Published: August 2018

AIDS virus (HIV) transmission by transfusions and blood products has been essentially halted in industrialized countries which haye introduced systematic anti-HIV screening of donations in 1985. New anti-HIV screening assays, based in part on the replacement of disrupted HIV virions by defined DNA recombinant HIV antigens, have improved specificity; sensitivity has been improved as to dectect seroconversion at an earlier stage. Confirmatory assays and (self-)exclusion of risk groups from blood donation do remain mandatory. HIVAg can be detected in some infections before antibody conversion, and HIVAg is more likely to be found in those anti-HIV positives who proceed to disease. However, there is no justification so far for routine parallel HIVAg and anti-HIV screening. There is continued uncertainty how many HIV carriers have not (yet) developed antibody, but their numbers may have been overestimated. Studies to determine how many HIV transmitters have escaped blood bank detection, and why, need to be undertaken in spite of formidable logistic difficulties.

The risk of developing AIDS is now estimated at 25-50 % within 10 years after the infectious contact. It is not clear whether the risk should be estimated differently in different groups or persons. In cities in Central Africa, 5-20 % of men and women are confirmed anti-HIV positives. At least 75 % of this HIV carrier rate is due to heterosexual transmission. Heterosexual transmission has been slower in Western countries, but factors precluding slow evolution to high figures by the same route outside Africa have not been identified. Therefore, countries have no choice in advocating behaviour changes in the general population, and not only in the classical risk groups. Initial hesitations toward extended voluntary and confidential screening are dwindling. Well-conceived confidential screening may be the only way to avoid strong-armed government intervention. The latter is certain to be divisive, and is likely to be counterproductive on balance.

An efficacious vaccine remains remote, but an antiviral which prolongs life by at least several months in AIDS patients, but not all of them, is now available. Zidovudine (AZT), however, is toxic and mere prolongation of life without cure will impose an additional burden on AIDS economics.

A novel virus (HIV-2) has been identified and is already widespread in West-Africans. It causes AIDS, but the present ratio of AIDS cases in those infected seems lower than with HIV(-l); this feature may be transient. HIV-2 antibodies are either detected or missed by anti-HIV-1 screens; if found, they can be distinguished from anti-HIV-1 only by special confirmatory technique. New screening assays showing equal sensitivity for HIV-1 and HIV-2 in a single test should be devised. At present, HIV-2 is very rare in Western countries compared to HIV-1.
DIRECTED MUTAGENESIS IN THE STUDY OF THE REQUIREMENTS FOR FACTOR VIII ACTIVITY IN VITRO AND IN VIVO
Authors: Kaufman Randal J , Pittman Debra D , Wasley Louise C , Foster W Barry , Amphlett Godfrey W , Giles Alan R
Published: August 2018

Factor VIII is a high molecular weight plasma glycoprotein that functions in the blood clotting cascade as the cofactor for factor DCa proteolytic activation of factor X. Factor VIII does not function proteolytically in this reaction hut itself can be proteolytically activated by other coagulation enzymes such as factor Xa and thrombin. In the plasma, factor VIII exists as a 200 kDa amino-terminal fragment in a metal ion stabilized complex with a 76 kDa carboxy-terminal fragment. The isolation of the cENA for human factor VIII provided the deduced primary amino acid sequence of factor VIIT and revealed three distinct structural domains: 1) a triplicated A domain of 330 amino acids which has homology to ceruloplasmin, a plasma copper binding protein, 2) a duplicated C domain of 150 amino acids, and 3) a unique B domain of 980 amino acids. These domains are arranged as shown below. We have previously reported the B domain is dispensible far cofactor activity in vitro (Toole et al. 1986 Proc. Natl. Acad 5939). The in vivo efficacy of factor VIII molecules harboring the B domain deletion was tested by purification of the wildtype and modified forms and infusion into factor VIII deficient, hemophilic, dogs. The wildtype and the deleted forms of recombinant derived factor VIII exhibited very similar survival curves (Tl/2 = 13 hrs) and the cuticle bleeding times suggested that both preparations appeared functionally equivalent. Sepharose 4B chromatography indicated that both factor VIII molecules were capable of binding canine plasma vWF.

Further studies have addressed what cleavages are necessary for activation of factor VIII. The position of the thrombin, factor Xa, and activated protein C (AFC) cleavage sites within factor VIII are presented below, site-directed ENA medicated mutagenesis has been performed to modify the arginine at the amino side of each cleavagesite to an soleucine. In all cases this modification resulted in molecules that were resistant to cleavage by thrombin at the modified site. Modification of the thrombin cleavage sites at 336 and 740 and modification of the factor Xa cleavage site at 1721 resulted in no loss of cofactor activity. Modification of the thrombin cleavage site at either 372 or 1689 destroyed oofactor activity. Modification of the thrombin cleavage site at 336 resulted in a factor VIII having an increased activity, possibly due to resistance to inactivation. These results suggest the requirement of cleavage at residues 372 and 1689 for cofactor activity.
THE INTERACTION BETWEEN FACTOR VIII AND VON WILLEBRAND FACTOR
Authors: Koedam Joost A , Hamer Rob J , Beeser-Visser Nel H , Tjoen San Etienne Jap , Schippers Kees , Sixma Jan J
Published: August 2018

Factor VIII (FVIII) circulates in plasma as a non-covalent complex with von Willebrand factor (VWF), a large multimeric adhesive glycoprotein. VWF serves as a carrier for FVIII and is thought to stabilize FVIII. The interaction between the two proteins was studied by binding purified human 125I-FVIII to VWF which was coated on a solid matrix. Experiments employing isolated heavy and light chains of FVIII and monoclonal antibodies indicated that binding occurred through the carboxyterminal 80kDa light chain of factor VIII. Treatment of VWF-bound 125I-FVIII with thrombin resulted in the release of a light chain-derived 70kDa fragment and a heavy chain-derived 50kDa fragment. A 42kDa heavy chain-derived fragment was found in the fraction which remained bound to VWF. Treatment with factor Xa (FXa) resulted in the release of 63, 50, 45, and 42kDa fragments. No phospholipids were required for proteolysis of FVIII by either of these enzymes. In solution, the activation of FVIII by FXa, but not by thrombin, was inhibited by VWF. Neither activation, nor cleavage or release from VWF were observed when FVIII was incubated with factor IXa. Activation of FVIII was parallelled by its release from VWF. We conclude that the thrombin-activated form of FVIII consists of a complex between the 70kDa and 50kDa fragments. Inactivation of FVIII by activated protein C (APC) was inhibited when FVIII was complexed to VWF. This protective effect of VWF was abolished upon activation of FVIII and its subsequent release from VWF.

In order to locate the binding site for FVIII on the VWF molecule, we digested VWF with Staphylococcal V8 protease (Sp). Digestion products were isolated with Mono Q ion-exchange chromatography and identified as Spl (39 kDa), SpII dimers (220 kDa) and Spill dimers (a triplet ranging from 210-280 kDa) by their molecular weight and chromatographic behaviour (J.-P. Girma et al.. Biochemistry 1986, 25:3156-3163). Purified VWF or digestion products were spotted on nitrocellulose paper, followed by blocking with an albumin solution. Binding of FVIII was studied by incubating the filters with 125I-FVIII, followed by autoradiography. Fifty ng of VWF was sufficient in order to detect FVIII binding. No binding was observed to partially reduced dimeric undigested VWF. Of the isolated digestion products, only the SpIII dimer was able to bind 125I-FVIII. After Western blotting of VWF-fragments from SDS-polyacrylamide gels, 125I-FVIII bound only to the bands which represented SpIII. Therefore, the domain on VWF responsible for the binding of FVIII seems to be located on its aminoterminal SpIII fragment. The integrity of internal disulfide bonds and dimerisation of VWF are required for FVIII binding.
CHANGES IN PGE2 AND TXB2 FORMATION BY PLATELETS OF ATHEROSCLEROTIC RABBITS
Authors: Laekeman G M , Van Hoydonck A , Van Diest M , Herman A G
Published: August 2018

The synthesis of thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) were studied in groups of 9 rabbits fed a normal diet or a diet containing 0.3 % of cholesterol. After 16 weeks, a platelet rich suspension containing 300.000 platelets/mm3 was prepared. Portions were incubated at 37°C with arachidonic acid (AA). Biosynthesis of PGE2, TXA2 and TXB2 was evaluated by the bioassay cascade system (rabbit coeliac and mesenteric artery and rat fundus strip) and by radioimmunoassay (RIA) :

No significant differences were recorded for TXB2 after 1 or 10 minutes incubation

A small portion of blood without EDTA was allowed to clot at 37°C during 1 hour. TXB2 was measured in the serum by RIA. The mean ± SEM obtained for the atherosclerotic rabbits (82.70 ± 9.28 ng/ml) was significantly higher than the one for the normal group (42.66 ± 11.45 ng/ml) (P < 0.02, n = 9 for both groups. From these results it can be concluded that platelets of atherosclerotic rabbits apparently synthetize less PGE2 when incubated with AA, and more TXB2 during a standardized clotting process
EFFICACY OF INTRAVENOUS PENTOXIFYLLINE IN THE MANAGEMENT OF PATIENTS WITH CRITICAL LEG ISCHEMIA
Authors: Zahavi J , Schafer R , Zelikos-ki A , Firsteter E , Zahavi M , Avrahami E
Published: August 2018

The xantine derivative pentoxifylline (P) can promote blood flow in the macro-and-micro circulation of ischemic tissues by improvement of red cell rigidity and by enhancing PGI2 release from the vascular endothelium. 35 patients (mean age 71±1.2 1SE years) suffering from critical leg ischemia due to advanced peripheral vascular disease (PVD) were treated by continuous I.V. drip of P (mean dose 22.2 g. during a mean period of 22.2 days). 19 patients were diabetics and 16 non-diabetics. Severity of PVD was assessed by the walking distance (WD), the presence of ischemic rest pain (IRP), leg ulcers or gangrene (doccumented photographically), hemodynamic evaluation using Doppler auscultation andby an arteriography of the lower limbs. The most common lesion on arteriography was occlusion or severe stenosis of the superficial femoral artery. All the patients suffered from IRP, 20 of them from leg ulcers and or gangrene. Following treatment of the diabetics, the WD was considerably improved (p≺0.01) in 7patients, the IRP disappeared in 11 and was milder in another 4 patients. Leg ulcers were healed in 5.out of 11 patients and gangrene subsided in 2 out of 9 patients. It was partially healed in another3 patients. Thus only in 4 patients the leg ischemia was worse and required bellow-knee amputation. In the non-diabetics, WD was improved considerably in 12 patients, the IRP disappeared in 11 and was milder in another 4 ' patients. Gangrene subsided in 2 out of 4 patients andwasimproved in the remaining 2 patients. None of these patients underwent amputation. The resting ankle pressure index(on Doppler auscultation) values were similar in the 2 groups and were increased after treatment (p≺0.01).

Our results indicate that P ia a useful drug in the management of patients with advanced PVD and critical leg ischemia particularly in non-diabetics. It should be considered in inoperable patients in whom leg amputation is imminent. P can induce both subjective and objective improvement in the WD and the hemodynamicprofile of these patients and promote the blood flow in the microcicul-ation of the ischemic tissues in the lower limbs.
LIPOXYGENASE PRODUCTS CHANGES IN ‘IN VITRO’ AND ‘IN VIVO’ ASPIRINISED PLATELETS UNDER THE INFLUENCE OF PAF AND EPINEPHRINE
Authors: Makris P E , Papadopoulos A , Tsakiris D A
Published: August 2018

We aimed to investigate the changes of lipoxygenase products in platelets and the simultaneous behaviour of ‘in vivo’ or ‘in vitro’ aspirinised platelets, stimulated by two agonists, PAF and epinephrine (EPI). 12 healthy were included. 6 received 20mg of aspirin (ASA) per os for 7 days (group A), and in 6 (group B) platelets were aspirinised ‘in vitro’ (5 or lOmin incubation at 37°C with ASA 1M). In group A blood was drawn once at the beginning and once at the end of the trial, while in group B just ome. First, platelet aggregation was studied using two agonists simultaneously (0.6 ¼M EPI and 20 nM PAF). We incubated then all platelet samples with 0.5 M of the substance BW755C (kind offer of Dr Moncada) far 3 min at 37°C. Second we measured PL0 products according to Takayama et al (1980), in platelets with or without ASA, and in platelets with ASA and after treatment with BW755C, always after addition of both agonists. Our results showed: a) Irreversible aggregation was slightly enhanced by the simultaneous addition of PAF and EPI in both groups and in non-aspirinised platelets. After ASA treatment, each agonist alone did not induce irreversible aggregation, whereas their combination overcame this inhibition, a fact not noticed under BW755C (a known PLO inhibitor). b) PLO products were measured in nmol TBRS/10 platelets:

Our results agree with Cerletti et al (1986) and confirm that the two agonists combined are capable of overcoming the inhibition caused by ASA, possibly by activating the PLO pathway (Cerletti et al, 1986). Respectively the quantitative determination of PLO products (about which we did not notice any other report insofar) confirm the above assumption, since inhibition by BW755C coincides with the steep fall of PLOlevels, which for group A is statisticallysignificant (p≺0.01, paired t-test) and for group B entirely significant (p ≺0.001).
POST-OPERATTVE CHANGES IN PROIEINASE INHIBITORS IN NORMAL AND IMPAIRED WOUND HEALING
Authors: Reitz M , Sauer H , Witzke G , Neher M
Published: August 2018

Tissue trauma after surgery activates blood coagulation. This results in a change and in the consumption of important inhibitors.We investigated the oonoentraticn of antithrorfoin III (AT III), ∝ 1-antitrypsin (∝l-AT), ∝ 2- macrogloublin (∝ 2-M) and Cl-inactivator (Cl-INH) in the blood plasma by means ofradial iirmunodiffusicn in 16 patients before surgery, after surgery and cn the 1st, 3rd and 7th days after surgery. In 11 patients normal wound healing wasobserved (group A), while in 5 patients amplicationsoccurred (group B). AT III: Fall in concentration upto the 3rd day after surgery, then a rise in concentration. In the patients with impaired wound healing there was a particularly marked reduction in AT III cn the 3rd day.

∝ 1-AT: Fall in concentration after surgery, followed by a rise in concentration. In impaired wound healing a lower mean value was determined on the 3rd day after surgery than in normal wound healing. ∝ 2-M: Fall in concentration up to the 3rd day after surgery, followed by a slight increase in concentration. No striking difference between the normal group and the group with complications. Cl-INH: Fall in concentration after surgery, followed by arise in concentration; in the patients with impaired wound healing there was adelayed rise in concentration.
Induction of plasminogen activator inhibitor (PAI) by lipopolysaccharide (LPS)
Authors: DOSNE A M , DUBOR F , CHEDID L
Published: August 2018

It has been shown that, under culture conditions, human endothelial cells synthetize plasminogen activator inhibitor (PAI) which neutralize urokinase and tissue plasminogen activator.

Treatment of human endothelial cells with LPS (50 ngto 10 μg/ml) from S. enteritidis resulted in a dose-dependent increase in PAI production.Fibrinoenzymographic analysis showed that incubation of supernatantfrom LPS-treated cells with urokinase of low and high mol. w. (33.000 and 55.000) led to disappearance of the two urokinase lytic bands and formation of high mol. w. complexes (Mr 93.000 and 107.000). The mol. w. of the urokinase binding factor was calculated to be near 50.000. Polymyxin B and colimycin could suppress this effect of LPS. Injection of LPS (30 ng-30 yg/kg in the rat led to a considerable decrease in the fibrinolytic activity of plasma euglobulins which clot lysis time was prolonged from 55 up to morethan 240 min. This hypofibrinolytic state was associated with PAI detected in euglobulins and in plasma.Large complexes (Mr 80.000-105.000) were formed between exogenous urokinase of low and high mol. w. mixed with post LPS plasma or euglobulins. Polymyxin B and Colimycin could prevent the hypofibrinolytic response to low doses of LPS. These results suggest thatPAI generation in endotoxemia could be due in part to the direct effect of LPS on endothelium.
WINE CONSUMMATION AND PLATELET AGGREGATION
Authors: Seigneur M , Bonnet J , Dorian B , Hourdille P , Gouverneur G , Larrue J , Crockett R , Boisseau M , Ribereau-Gayon P , Bricaud H
Published: August 2018

To compare the effects of ethanol and wine on factors inducing thrombosis, 16 healthy male volunteers had to drink3 kinds of beverage according to the following regimen :

Ethanol reference is hydroethanolic solution at PH and ethanolic titre of wine.

White wine is the reference of all wine cofactors excepting phenolics.

Red wine is the reference all wine cofactors.

At the beginning and at the end of each period, aggregation was measured with ADP 2 umole, Adrenaline 0,75 mg/1, Arachidonic Acid 0,5 mg/1.

Results show statistically significant hyperaggregation with the 3 aggregation inductors during the ethanol period, no variation during white wine period and statistically significant hypoaggre-gation with adrenaline and ADP during red wine period.

In contrast of ethanol, red wine seems to induce antiaggregant properties that could explain low incidency of CAD in countries of south of Europa.
Expanding Human Computer Interaction Methods to Understand User Needs in the Design Process of Personal Health Systems
Authors: Siek Katie
Published: August 2018

Objectives: To review innovative human computer interaction methods researchers utilize to identify stakeholders' needs that inform the design of personal health systems outside of clinical environments.

Methods: A selective review of recent literature.

Results: Summaries of exemplar needs analysis papers showing how researchers utilize novel methods to surface the lived experiences of users.

Conclusions: The medical informatics community is encouraged to ensure that we are designing health technology for all individuals - including underrepresented and underserved populations — by investigating the complex needs of target users. This paper summarizes the novel ways researchers have explored target populations via social media and engaged populations as part of the design team. Medical informaticians should continue investigating the soundness of these methods by comparing the design outcomes with currently utilized user-centered methods and to report on unintended consequences
The Omics Revolution Continues: The Maturation of High-Throughput Biological Data Sources
Authors: Mathé Ewy , Hays John , Stover Daniel , Chen James
Published: August 2018

Objective: The aim is to provide a comprehensive review of state-of-the art omics approaches, including proteomics, metabolomics, cell-free DNA, and patient cohort matching algorithms in precision oncology.

Methods: In the past several years, the cancer informatics revolution has been the beneficiary of a data explosion. Different complementary omics technologies have begun coming into their own to provide a more nuanced view of the patient-tumor interaction beyond that of DNA alterations. A combined approach is beneficial to the patient as nearly all new cancer therapeutics are designed with an omics biomarker in mind. Proteomics and metabolomics provide us with a means of assaying in real-time the response of the tumor to treatment. Circulating cell-free DNA may allow us to better understand tumor heterogeneity and interactions with the host genome.

Results: Integration of increasingly available omics data increases our ability to segment patients into smaller and smaller cohorts, thereby prompting a shift in our thinking about how to use these omics data. With large repositories of patient omics-outcomes data being generated, patient cohort matching algorithms have become a dominant player.

Conclusions: The continued promise of precision oncology is to select patients who are most likely to benefit from treatment and to avoid toxicity for those who will not. The increased public availability of omics and outcomes data in patients, along with improved computational methods and resources, are making precision oncology a reality.
Numeracy and Understanding of Quantitative Aspects of Predictive Models: A Pilot Study
Authors: Weissman Gary , Yadav Kuldeep , Madden Vanessa , Courtright Katherine , Hart Joanna , Asch David , Schapira Marilyn , Halpern Scott
Published: August 2018

Background The assessment of user preferences for performance characteristics of patient-oriented clinical prediction models is lacking. It is unknown if complex statistical aspects of prediction models are readily understandable by a general audience.

Objective A pilot study was conducted among nonclinical audiences to determine the feasibility of interpreting statistical concepts that describe the performance of prediction models.

Methods We conducted a cross-sectional electronic survey using the Amazon Mechanical Turk platform. The survey instrument included educational modules about predictive models, sensitivity, specificity, and confidence intervals (CIs). Follow-up questions tested participants' abilities to interpret these characteristics with both verbatim and gist knowledge. Objective and subjective numeracy were assessed using previously validated instruments. We also tested understanding of these concepts when embedded in a sample discrete choice experiment task to establish feasibility for future elicitation of preferences using a discrete choice experiment design. Multivariable linear regression was used to identify factors associated with correct interpretation of statistical concepts.

Results Among 534 respondents who answered all nine questions, the mean correct responses was 95.9% (95% CI, 93.8–97.4) for sensitivity, 93.1% (95% CI, 90.5–95.0) for specificity, and 86.6% (95% CI, 83.3–89.3) for CIs. Verbatim interpretation was high for all concepts, but significantly higher than gist only for CIs (p < 0.001). Scores on each discrete choice experiment tasks were slightly lower in each category. Both objective and subjective numeracy were positively associated with an increased proportion of correct responses (p < 0.001).

Conclusion These results suggest that a nonclinical audience can interpret quantitative performance measures of predictive models with very high accuracy. Future development of patient-facing clinical prediction models can feasibly incorporate patient preferences for model features into their development.
Psychosoziale und berufliche Folgen der Depression
Authors: Lang A. , Hamann J. , Brieger P.
Published: August 2018

Depressionen gehören zu den häufigsten Formen psychischer Erkrankungen in unserer Gesellschaft und gehen mit einer hohen Krankheitslast einher. Für die Betroffenen führt dies zu Beeinträchtigungen in allen Aspekten ihrer Lebensführung. Auf psychosozialer Ebene äußert sich dies u. a. in familiären Schwierigkeiten sowie einer Verarmung der sozialen Situation. Auf beruflicher Ebene kommt es zu Einbußen in der Leistungsfähigkeit bis hin zur Arbeitsunfähigkeit und Frühverrentung. Die Wiederherstellung der psychosozialen sowie beruflichen Leistungsfähigkeit gilt daher als wichtiges Ziel der Behandlung. Den psychosozialen Beeinträchtigungen kann mit unterschiedlichen psychotherapeutischen Interventionen entgegengewirkt werden. Der Klärung der beruflichen Perspektiven und der Rückkehr an den Arbeitsplatz wird jedoch in der Versorgung noch zu wenig Beachtung geschenkt. Dies sollte stärker in den Fokus gesetzt werden, um die verschiedenen Möglichkeiten zur Unterstützung der beruflichen Wiedereingliederung ausschöpfen zu können.
Economic shifts in agricultural production and trade due to climate change
Authors: Porfirio Luciana L. , Newth David , Finnigan John J. , Cai Yiyong
Published: August 2018

In addition to expanding agricultural land area and intensifying crop yields, increasing the global trade of agricultural products is one mechanism that humanity has adopted to meet the nutritional demands of a growing population. However, climate change will affect the distribution of agricultural production and, therefore, food supply and global markets. Here we quantify the structural changes in the global agricultural trade network under the two contrasting greenhouse gas emissions scenarios by coupling seven Global Gridded Crop Models and five Earth System Models to a global dynamic economic model. Our results suggest that global trade patterns of agricultural commodities may be significantly different from today’s reality with or without carbon mitigation. More specifically, the agricultural trade network becomes more centralised under the high CO2 emissions scenario, with a few regions dominating the markets. Under the carbon mitigation scenario, the trade network is more distributed and more regions are involved as either importers or exporters. Theoretically, the more distributed the structure of a network, the less vulnerable the system is to climatic or institutional shocks. Mitigating CO2 emissions has the co-benefit of creating a more stable agricultural trade system that may be better able to reduce food insecurity.
Improving the magnetodynamical properties of NiFe/Pt bilayers through Hf dusting
Authors: Mazraati Hamid , Zahedinejad Mohammad , Åkerman Johan
Published: August 2018

We investigate the effect of hafnium (Hf) dusting on the magnetodynamical properties of NiFe/Pt bilayers using spin-torque-induced ferromagnetic resonance measurements on 6 μm wide microstrips on high-resistive Si substrates. Based on two series of NiFe(tNiFe)/Hf(tHf)/Pt(5) stacks, we first demonstrate that the zero-current magnetodynamic properties of the devices benefit from Hf dusting: (i) the effective magnetization of the NiFe layer increases by 4%–8% with Hf present and (ii) the damping α decreases linearly with tHf by up to 40%. The weaker anisotropic magnetoresistance (AMR ≃ 0.3%–0.4%) of the 3 nm NiFe series is largely unaffected by the Hf, while the stronger AMR of the 5 nm NiFe series drops from 0.7% to 0.43% with increasing tHf. We find that the spin Hall efficiency ξSH is independent of the NiFe thickness, remaining unaffected (ξSH = 0.115) up to tHf = 0.4 nm and then decreasing linearly for higher tHf. The different trends of α and ξSH suggest that there is an optimum Hf thickness (≃0.4 nm) for which the threshold current for auto-oscillation should have a minimum, while the much lower damping should improve mutual synchronization. Our results also indicate that the spin-orbit torque is entirely damping-like with no field-like torque component. Finally, the internal spin Hall angle of Pt is estimated to be θSH = 0.22 by calculating the transparency of the interface.
Diamond photovoltaic radiation sensor using pn junction
Authors: Shimaoka Takehiro , Koizumi Satoshi , Tanaka Manobu M.
Published: August 2018

Because of its heat resistance and radiation hardness, diamond is a suitable semiconductor material for use in radiation sensors operating under harsh environments. To date, diamond radiation sensor designs have been constrained to Metal–Insulator–Metal structures. Instead of this structure, the pn junction offers several advantages for radiation sensors such as high built-in bias, electric field control, and depletion layer thickness control through doping profile design. We formed diamond pn diodes with ideal electric properties. A large built-in bias of 4.7 eV was obtained. The diode represented less than 10−11 A of low leakage current up to nearly 1 MV/cm of a high electric field. We detected alpha particles at zero-bias voltage using the pn diode, which opens the possibility of realizing compact radiation sensors.
Upgrade of the ECE diagnostic on EAST
Authors: Zhao Hailin , Zhou Tianfu , Liu Yong , Ti Ang , Ling Bili , Austin M. E. , Houshmandyar Saeid , Huang H. , Rowan W. L. , Hu Liqun
Published: August 2018

The electron cyclotron emission (ECE) diagnostic on the experimental advanced superconducting tokamak (EAST) was upgraded recently to provide electron temperature profile measurement with wider radial coverage and better precision. The lower limit of the ECE detection frequency band was extended from 104 GHz to 97 GHz by adding a new 8-channel heterodyne radiometer, which ensures capability for the measurement of the second harmonic ECE with toroidal magnetic field down to 1.75 T. Also, the existing 32-channel heterodyne radiometer has been upgraded, with the frequency interval for the lower frequency range up to 120 GHz reduced from 2 GHz to 1 GHz by introducing eight channels in the intermediate frequency part. In addition, a plan is presented to incorporate tunable yttrium iron garnet filters into the existing heterodyne radiometer to obtain detailed measurements of the electron temperature gradient scale length as well as finer spatial pinpointing of magnetohydrodynamic modes. Examples from DIII-D are provided where similar ECE diagnostic allowed precise measurement of the center and width of neoclassical tearing modes.
Gaussian optimizers for entropic inequalities in quantum information
Authors: De Palma Giacomo , Trevisan Dario , Giovannetti Vittorio , Ambrosio Luigi
Published: August 2018

We survey the state of the art for the proof of the quantum Gaussian optimizer conjectures of quantum information theory. These fundamental conjectures state that quantum Gaussian input states are the solution to several optimization problems involving quantum Gaussian channels. These problems are the quantum counterpart of three fundamental results of functional analysis and probability: the Entropy Power Inequality, the sharp Young’s inequality for convolutions, and the theorem “Gaussian kernels have only Gaussian maximizers.” Quantum Gaussian channels play a key role in quantum communication theory: they are the quantum counterpart of Gaussian integral kernels and provide the mathematical model for the propagation of electromagnetic waves in the quantum regime. The quantum Gaussian optimizer conjectures are needed to determine the maximum communication rates over optical fibers and free space. The restriction of the quantum-limited Gaussian attenuator to input states diagonal in the Fock basis coincides with the thinning, which is the analog of the rescaling for positive integer random variables. Quantum Gaussian channels provide then a bridge between functional analysis and discrete probability.
Experimental and numerical investigation of a flow induced by a pulsed plasma column
Authors: Koroteeva E. , Znamenskaya I. , Doroshchenko I.
Published: August 2018

The paper studies, both experimentally and numerically, a high-speed transient flow induced by a pulsed volume discharge in still air at low pressure. It is shown that, in the constricted mode, the discharge is capable of producing uniform deposition of the electrical energy into a long (24 mm in length), thin (less than 2 mm in radius) plasma column. Flow visualization experiments using particle image velocimetry (PIV) and high-speed shadow imaging indicate that this pulsed localized energy deposition generates a highly symmetrical cylindrical shock wave expanding at an average speed of 550 m/s within the first 40 μs after the discharge. Three-dimensional computational fluid dynamics (CFD) simulations successfully reproduce the experimentally observed flow structures and provide better insight into the complex discharge-induced flow. Modeling the trajectories of “virtual” particles within the CFD-predicted flow yields excellent agreement between numerical and PIV flow velocity profiles, and this comparison is used to quantify the rates of “rapid” energy thermalization in the pulsed discharge.
Variational approach to dynamic contact angles for thin films
Authors: Peschka Dirk
Published: August 2018

This paper investigates a modeling approach for viscous flows with dynamic contact angles based on variational energy-dissipation principles. A corresponding Stokes free boundary problem is reduced to a thin-film equation and its variational structure is constructed. The usefulness of this abstract modeling approach is demonstrated by providing numerical schemes for the Stokes flow and the thin-film model and by computing numerical solutions for the problem of gravity-driven thin droplets. Some implications of the contact angle model and properties of the numerical scheme are highlighted in this setting.