bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Significance of Accelerated Fibrinolysis in Liver Disease
Authors: Francis, Jr. Robert B. , Feinstein Donald I.
Published: April 2009

We compared site and severity of bleeding in 46 patients with cirrhosis of the liver and accelerated fibrinolysis (defined as a dilute whole-blood clot lysis time < 2 h) to 44 patients with cirrhosis of the liver and normal fibrinolysis (dilute whole-blood clot lysis time > 4 h). Patients with accelerated fibrinolysis had a significantly higher incidence of severe soft-tissue bleeding after trauma and a trend toward increased intracranial bleeding. Mucosal, postoperative, and gastrointestinal bleeding were equally frequent in the two groups. The median partial thromboplastin time was significantly longer, and the median bilirubin and fibrin/fibrinogen degradation product levels were significantly higher in the group with accelerated fibrinolysis, but median prothrombin time, platelet count, and levels of fibrinogen and serum albumin were comparable. The fibrinolytic inhibitor ε-aminocaproic acid successfully controlled bleeding in 4 of 6 cases used. Accelerated fibrinolysis may predispose patients with cirrhosis to soft-tissue and intracranial bleeding.
Inhibitory Effect of a New Synthetic Protease Inhibitor (FUT-175) on the Coagulation System
Authors: Hitomi Yuji , Ikari Nobuhiko , Fujii Setsuro
Published: April 2009

The inhibitory effects of 6-amidino-2-naphthyl-4-guanidinobenzoate·dimeth-anesulfonate (FUT-175) on the human Hageman factor fragment (HFf), factor Xa, thrombin, plasma kallikrein, and plasmin were studied. FUT-175 inhibited plasma kallikrein most (IC50 = 3.0 × 10-9M), followed by HFf (IC50 = 3.3 × 10-7M). FUT-175 was found to have an anticoagulant effect in the APTT and PT assay systems of human plasma. The concentration of FUT-175 for twofold increase in the clotting time in the APTT assay system was 5 × 10-7M.
Appropriate Milieu for the Assay of Alpha-2-Antiplasmin Activity with Chromogenic Substrates
Authors: Kluft C. , Wijngaards G. , Jie A.F.H. , Groeneveld E.
Published: April 2009

Inhibition reference curves for α2-antiplasmin showed a deviation from linearity at low inhibitor concentrations using the chromogenic substrate S-2251. Extrapolation of these curves to zero inhibition gave higher amidolytic activities than actually recorded with the free enzyme plasmin. It was further found that comparison of purified α2-antiplasmin and that in plasma was prevented by the deviation. The difference between calculated and measured plasmin activity could not be attributed to instability of plasmin. It was established that the observations (1) were specific for high concentrations of S-2251, (2) were not the same with another plasmin substrate, chromozym PL, and (3) were related to the addition of plasma proteins. Apparently, the problem was related to the solubility state of S-2251. A solution to this problem is the addition of nonionic detergents, notably Tween 80 (0.01%) or Triton X-100 (0.03%), which prevent all deviations.
Regulation of Blood Coagulation and Thrombosis
Authors: Briët E. , Engesser L. , Brommer E.J.P.
Published: April 2009

The syndrome of the hereditary tendency to venous thrombosis or thrombophilia has been recognized only after the discovery of regulatory mechanisms of the haemostatic system. At present, several distinct defects are known as causes of this syndrome: anti-thrombin III deficiency, protein C deficiency, protein S deficiency, dysfibrinogenaemia and dysplasminogenaemia. It is likely that several additional defects will be found in the near future. Consequently, it is important that a family history be taken in all cases of ‘spontaneous’ venous thrombosis and that laboratory studies be done to identify any underlying defect in the regulation of the blood coagulation system. We present preliminary data, which suggest that the incidence of the thrombophilia syndrome is higher than that of the haemophilias.
Inhibition of Some Activities of Thrombin by a Collagen-Derived Octapeptide
Authors: Léger Dominique , Karniguian A. , Soria J. , Soria C. , Legrand Y.
Published: April 2009

The effect of a collagen-derived octapeptide on some properties of thrombin is presented. This peptide provoked a dose- and time-dependent prolongation of the thrombin-induced plasma and fibrinogen clotting time and inhibited the polymerization of fibrin generated from fibrinogen by thrombin. It did not affect the polymerization of fibrin monomers; it was also without effect on the coagulation of plasma or fibrinogen by reptilase. The prolongation of the fibrinogen clotting time depended on the duration of the incubation of thrombin and the octapeptide and not on the duration of the incubation of fibrinogen and the octapeptide. The inhibition was therefore ascribed to an interference with thrombin, rather than with fibrinogen. A preincubation of the octapeptide with thrombin resulted in an inhibition of the thrombin-induced platelet aggregation. The effect of the octapeptide on thrombin has been related to the presence of positively and negatively charged groups, because uncharged analogue sequences were without effect on these activities of thrombin.
Do Malfunctioning Bioprosthetic Heart Valves Represent a Potential Thrombogenic Focus?
Authors: Prandoni Paolo , Pengo Vittorio , Boetto Patrizia , Zambon Giovanni , Menozzi Luciano
Published: April 2009

In vivo platelet reactivity, expressed by plasma concentration of β-thromboglobulin (βTG) and platelet factor 4 (PF4), was determined in 57 patients with bioprosthetic heart valves: 35 had well-functioning bioprostheses (WFBP), while 22 had documented malfunctioning bioprostheses (MFBP). βTG and PF4 values in patients with WFBP were not significantly different from controls, even when these determinations were repeated at monthly intervals, whereas βTG and PF4 concentration was significantly higher in patients with MFBP compared to both groups. There was a strong positive correlation between βTG and PF4 in all subjects studied. Serum lactic dehydrogenase, indirect bilirubin level and reticulocyte count were significantly higher in patients with MFBP than in those with WFBP, but no correlation was found between platelet reactivity and rate of intravascular hemolysis. Our results suggest that there is an increased platelet release in vivo of the platelet-specific proteins in patients with MFBP not related to mechanical damage, and that bioprostheses, at least in a degenerative state, may represent a potential thrombogenic focus.
Changes in Coagulation and Fibrinolysis after Total Hip Replacement and Their Relations with Deep Vein Thrombosis
Authors: Paramo J.A. , Rocha E.
Published: April 2009

Postoperative changes related to coagulation and fibrinolysis and their correlation with the incidence of deep venous thrombosis (DVT) were studied in 30 patients undergoing total hip replacement. Pre- and postoperative measurements of fibrinogen, factor Xa, VIIl·C, VIΠR:Ag and its electrophoretic mobility, antifactor Xa activity, antithrombin III (AT III) and its electrophoretic mobility in plasma and serum, fibrin monomers, euglobulin lysis time, fibrinogen degradation products (FDP), α2-antiplasmin and plasmin-antiplasmin complexes were determined. DVT was detected by 125I-fibrinogen leg scanning in 11 patients. There was a significant and progressive increase in fibrinogen, VIII:C, VIIIR:Ag, fibrin monomers, FDP and α2-antiplasmin levels after operation and likewise a prolongation of euglobulin lysis time. There were changes in electrophoretic mobility of AT III in plasma and serum in 12 patients. The presence of plasmin-antiplasmin complexes was demonstrated in 9 patients. No correlation between the changes in coagulation and fibrinolysis and the incidence of postoperative DVT was found. We conclude that important changes occur in several parameters of coagulation and fibrinolysis after total hip replacement. Such changes are not related to the development of postoperative DVT.
Platelet Function Studies during and after Infusions of ZK 36374, a Stable Prostacyclin Analogue, to Healthy Volunteers
Authors: Yardumian D.A. , Mackie I.J. , Brennan E.C. , Bull H. , Machin S.J.
Published: April 2009

ZK 36374 (Iloprost), a stable prostacyclin analogue, was administered to 6 healthy volunteers for 2-hour periods, with dose rates increasing from 0.5 to 2 ng/kg/min within that time. At these doses, which did not give troublesome side effects clinically, there was significant inhibition of ex vivo platelet aggregation responses to ADP and collagen. There was some rebound platelet hyperaggregability in all subjects, occurring between 1 and 2 h after termination of the infusion; this was of minor degree and was not associated with any clinical problems.
Evidence that the Elevated Levels of Proteinase Activity in the Plasma of Melanoma-Bearing Mice May Be of Host Origin
Authors: Hart David A.
Published: April 2009

C57B1/6 mice bearing the B16-F1 melanoma, an invasive variant (BL6) or a highly ‘metastatic’ variant (B16-F10) were found to develop elevated levels (200–300% of control) of neutral proteinase activity in their plasma during the progression of the disease. The magnitude of the level of proteinase activity detected was not dependent on tumor burden. Similar elevations in activity were detected with all 3 variants when they were transplanted either subcutaneously or intraperitoneally. However, transplantation of the B16-F10 line to the anterior chamber of the eye did not induce elevated plasma proteinase activity. Animals bearing intraocular tumors developed splenomegaly and lived the same length of time as animals bearing intraperitoneal or subcutaneous tumors. The development of increased levels of activity appeared to occur equally in male and female mice and was not dependent on the presence of a spleen, which undergoes enlargement during the disease process. These various lines of evidence support the hypothesis that the elevated level of plasma proteinase activity observed in melanoma-bearing mice is regulated by the host.
Relationship between Biological Activity and Concentration of a Low-Molecular-Weight Heparin (PK 10169) and Unfractionated Heparin after Intravenous and Subcutaneous Administration
Authors: Dawes J. , Bara L. , Billaud E. , Samama M.
Published: April 2009

The pharmacokinetics of unfractionated heparin and the low-molecular-weight (LMW) heparin PK 10169 after intravenous and subcutaneous injection were compared by crossover study in 8 healthy volunteers. The heparin concentrations in plasma were measured by a competitive binding assay, and anti-IIa and anti-Xa activities were also assayed. Unfractionated heparin was cleared after intravenous administration with a half-life of 35 min irrespective of assay method. However, the concentration of PK 10169 declined with the longer half-life of 60 min, and its anti-IIa and anti-Xa activities had half-lives of 40 and 275 min, respectively. Some of this anti-Xa activity may be mediated by a compound released by PK 10169 rather than by the LMW heparin itself. The bioavailability of PK 10169 was 3-fold greater than that of unfractionated heparin, due to more effective absorption after subcutaneous administration.
Prevention of Deep Vein Thrombosis in Elderly Medical In-Patients by a Low Molecular Weight Heparin: A Randomized Double-Blind Trial
Authors: Dahan R. , Houlbert D. , Caulin C. , Cuzin E. , Viltart C. , Woler M. , Segrestaa J.M.
Published: April 2009

Two hundred and seventy patients over 65 years were included in a placebo-controlled randomized double-blind trial to determine whether a small dose of a low molecular weight (LMW) heparin prevents the occurrence of deep vein leg thrombosis (DVT) diagnosed by 125I fibrinogen scanning. LMW heparin (60 mg daily) significantly reduced the frequency of DVT from 9 to 3 percent (p = 0.03). Adverse drug reactions did not differ significantly between the 2 groups, except for the injection site hematomas that were more frequent in the LMW heparin group. In conclusion, LMW heparin appears of value in preventing the occurrence of DVT in an unselected elderly in-patient population.
Low Molecular Weight Heparin Fraction PK10169: A New Therapeutic Means for Anticoagulant Therapy?
Authors: Huet Y. , Gouault-Heilmann M.
Published: April 2009

To test the efficacy and safety of low molecular weight heparin (LMWH) fractions in thromboembolic diseases, 2 pilot studies were performed. The aim of the first was to test the antithrombotic efficacy of the LMWH PK 10169 (Pharmuka Laboratories) in 9 patients (group I) with acute pulmonary embolism documented by pulmonary angiography and scintiscan. The second study was intended to test the safety of the same LMWH fraction in a group (group II) of 30 patients at high risk of bleeding but also requiring antithrombotic therapy. In the 2 groups, the antithrombotic efficacy of PK 10169 was found to be excellent: no recurrence of pulmonary embolism was noted in group I and no thrombotic event occurred in group II. Neither side effects nor major bleeding complications occurred in either group. However, 1 patient in group II had a moderate bleeding in relation to a transient overdosage, and 3 others exhibited minor bleeding which did not necessitate dosage adjustment. In these studies, PK 10169, at the dosage used, proved an effective antithrombotic therapy with few side effects even in a group of patients considered to be at high risk of bleeding.
γ-Glutamyl Carboxylase Activity in Experimental Tumor Tissues: A Biochemical Basis for Vitamin K Dependence of Cancer Procoagulant
Authors: Roncaglioni Maria Carla , Dalessandro Anna Paola Bolognese , Casali Bruno , Vermeer Cees , Donati Maria Benedetta
Published: April 2009

Rabbit V2 carcinoma tissues have been described to possess a procoagulant activity with specific characteristics; this material has been purified and identified as a cysteine proteinase able to directly activate coagulation factor X. We have shown here that the procoagulant activity of V2 carcinoma extracts is depressed in warfarin-treated animals, thus suggesting that cancer procoagulant could represent a new vitamin K-dependent protein. The biochemical basis for this effect is offered by the identification of γ-glutamyl carboxylase in the microsomal fraction of tumor tissues. The V2 carcinoma has a carboxylase activity which is increased in warfarin-treated animals. An endogenous substrate of tumor carboxylase, the nature of which has not been identified, has been found 5-fold increased in warfarin-treated animals. The presence of γ-glutamyl carboxylase was also described in several murine tumors including both carcinomas and fibrosarcomas. It is worth mentioning that all the tumors tested produce a procoagulant with the peculiar characteristics of that described in V2 carcinoma. It is conceivable that cancer procoagulant could represent at least one of the substrates for γ-glutamyl carboxylase in these experimental tumor tissues.
Inhibition of Platelet Thromboxane Generation by Suloctidil in Man
Authors: Bucchi Francesca , Cerletti Chiara , de Gaetano Giovanni
Published: April 2009

Oral administration of 100 or 200 mg suloctidil to healthy volunteers resulted in serum thromboxane B2 (TxB2) inhibition. This reached a maximum level between 90 min and 4 h after drug ingestion. TxB2 levels returned to 75 % of basal values 6 h after 100 mg and more than 8 h after 200 mg, reaching control values at 24 h. Different experiments were performed to define the metabolic step at which suloctidil acts to inhibit serum TxB2 generation. Suloctidil prevented TxB2 synthesis also when platelet-rich plasma was stimulated by exogenous arachidonic acid or whole blood was clotted in the presence of exogenous arachidonic acid. This rules out the possibility that it inhibits phospholipases. No rediversion of prostaglandin synthesis after suloctidil occurred concomitantly with TxB2 inhibition, suggesting that the drug is not a selective thromboxane synthase inhibitor. In contrast, a significant reduction of serum PGE2 formation was found, suggesting a mechanism of action of suloctidil involving inhibition of cyclo-oxygenase. This was supported by the finding that PGI2 production by rat smooth muscle cells stimulated with arachidonic acid was significantly prevented by suloctidil in vitro. Suloctidil, however, did not prevent aspirin-induced inhibition of serum TxB2 generation. Blockade of platelet cyclo-oxygenase activity by suloctidil is therefore exerted at a level different from that of aspirin. In conclusion, suloctidil is a relatively weak nonselective cyclo-oxygenase inhibitor whose effect on platelet TxA2 production hardly accounts for its reported inhibitory effect on platelet aggregation.
Effectiveness of Defibrotide for Prophylaxis of Deep Venous Thrombosis in Gynecological Surgery: A Double-Blind, Placebo-Controlled Clinical Trial
Authors: Ciavarella N. , Ettorre C. , Schiavoni M. , Schonauer S. , Cicinelli E. , Cagnazzo G.
Published: April 2009

Defibrotide, a new antithrombotic compound without anticoagulant activity, has been tested for prevention of deep venous thrombosis (DVT) in patients undergoing gynecological surgery (mainly hysterectomy). Eighty-nine women (mean age 48.5) were randomly allocated to defibrotide (44 patients) or placebo (45 patients). 800 mg defibrotide was given daily (200 mg intravenously 4 times a day), starting on the day before operation and then for the next 7 days. DVT were detected by the conventional 125I-fibrinogen test. The two groups were homogeneous for known risk factors (age, varicosities, obesity, neoplasia and previous thromboembolic episodes). The results showed a statistically significant reduction of DVT incidence in patients on defibrotide, as compared with those on placebo: 4/44 = 9% vs. 13/45 = 28.8% (p < 0.05). There were no side effects, including hemorrhagic complications. The numbers of units transfused were comparable for the 2 groups. In conclusion, the trial shows that defibrotide is an effective and safe drug for the prevention of DVT in gynecological surgery.
Efficacy and Safety of Two Regimens of Low Molecular Weight Heparin Fragment (Fragmin) in Preventing Postoperative Venous Thrombolism
Authors: Kakkar V.V. , Kakkar S. , Sanderson R.M. , Peers C.E.
Published: April 2009

The efficacy and safety of 2 regimens of Fragmin in preventing postoperative venous thromboembolism was compared on 206 consecutive patients, aged 40 years or more, undergoing major abdominal surgery. Ninety-four patients received a single daily injection of 2,500 U of Fragmin for at least 6 postoperative days (group I), while 112 received 5000 U per day in 2 injections of 2,500 U each (group II). In group I 7.4% of patients and in group II 2.6% of patients developed postoperative deep venous thrombosis (DVT); the difference was not statistically significant (p& < 0.05). There was no significant difference between the 2 groups in terms of numbers of patients having excessive postoperative blood loss, requiring prophylaxis to be discontinued, or measured postoperative drainage. None of the patients in group I, and 2 out of 112 in group II developed wound haematoma. These findings suggest that a single daily injection of 2,500 U of Fragmin may provide an effective prophylaxis against postoperative venous thromboembolism.
Heparin versus Low Molecular Weight Heparin K 2165 in Chronic Hemodialysis Patients: A Randomized Cross-Over Study
Authors: Borm J.J.J. , Krediet R. , Sturk A. , ten Cate J.W.
Published: April 2009

Ten patients on chronic intermittent hemodialysis treatment received either unfractionated heparin or low molecular weight (LMW) heparin K 2165 in a single-blinded randomized cross-over study to assess: (1) effects on hemostasis and ex vivo platelet functions, and (2) effectiveness, i.e. prevention of fibrin formation in the extracorporeal circuit. The 20 dialysis treatments were without untoward side effects, for both drugs used. The variation in the plasma anti-Xa activities was significantly less during K 2165 treatment than during heparinization. No differences between the drugs were observed regarding the Ivy bleeding time, platelet count and platelet aggregation (spontaneous, and induced by ADP and collagen). Plasma platelet factor 4 levels did not increase under K 2165 to such an extent as under heparin. Both drugs did not influence the plasma levels of β-thromboglobulin, thromboxane B2 and platelet serotonin content. K 2165 did not affect platelet adhesion to collagen, in contrast to heparin which substantially inhibited platelet adhesion. Under both treatments, 4 minor clots were observed in 4 artificial kidneys, despite plasma anti-Xa levels in between 0.19 and 0.46 U/ml. K 2165 may therefore be considered as effective an anticoagulant as heparin, with less effects on ex vivo platelet functions.
A Comparison of Abciximab and Small-Molecule Glycoprotein IIb/IIIa Inhibitors in Patients Undergoing Primary Percutaneous Coronary Intervention
Authors: Gurm Hitinder S. , Tamhane Umesh , Meier Pascal , Grossman P. Michael , Chetcuti Stanley , Bates Eric R.
Published: April 2009

Background—

Current guidelines recommend abciximab as the preferred agent for patients undergoing primary percutaneous coronary intervention, yet small-molecule glycoprotein IIb/IIIa inhibitors are more commonly used in clinical practice. The objective of our meta-analysis was to evaluate for differences in clinical outcome between small-molecule glycoprotein IIb/IIIa inhibitors and abciximab in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

Methods and Results—

Five randomized trials (n=2138 patients) comparing tirofiban or eptifibatide with abciximab as an adjunctive therapy to primary percutaneous coronary intervention were included in this meta-analysis. Summary odds ratios (ORs) for 30-day death, reinfarction, and major bleeding were calculated using random- and fixed-effect models. There were no differences in 30-day mortality (1.9% for small molecule versus 2.3% for abciximab; OR, 0.84; 95% CI, 0.46 to 1.55;
P
=0.58), reinfarction (1.3% versus 1.2%; OR, 1.22; 95% CI, 0.51 to 2.91;
P
=0.69), or major bleeding (1.7% versus 1.3%; OR, 1.21; 95% CI, 0.58 to 2.49;
P
=0.61) between the 2 adjunctive strategies. Similarly, there was no significant difference in the incidence of death (3.9% versus 5%; OR, 0.77; 95% CI, 0.41 to 1.46;
P
=0.43) or reinfarction on follow-up at 8 months between small-molecule glycoprotein IIb/IIIa inhibitors and abciximab.

Conclusion—

In patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction, no difference in outcome could be identified in patients treated with small-molecule glycoprotein IIb/IIIa inhibitor or abciximab.
Evaluation of the Novel Myocardial Perfusion Positron-Emission Tomography Tracer
18
F-BMS-747158-02
Authors: Nekolla S.G. , Reder S. , Saraste A. , Higuchi T. , Dzewas G. , Preissel A. , Huisman M. , Poethko T. , Schuster T. , Yu M. , Robinson S. , Casebier D. , Henke J. , Wester H.J. , Schwaiger M.
Published: April 2009

Background—

Positron-emission tomography (PET) tracers for myocardial perfusion are commonly labeled with short-lived isotopes that limit their widespread clinical use.
18
F-BMS-747158-02 (
18
F-BMS) is a novel pyridaben derivative that was evaluated for assessment of myocardial perfusion by comparison with
13
N-ammonia (
13
NH
3
) and with radioactive microspheres in a pig model.

Methods and Results—

Fourteen pigs injected with 500 MBq of
13
NH
3
or 100 to 200 MBq of
18
F-BMS underwent dynamic PET at rest and during pharmacological stress. In 8 of these pigs,
18
F-BMS was injected during stress combined with transient, 2.5-minute constriction of the left anterior descending coronary artery. Radioactive microspheres were coinjected with
18
F-BMS. Ratios of myocardial tracer uptake to surrounding tissues were determined, and myocardial blood flow was quantified by compartmental modeling. Both tracers showed high and homogeneous myocardial uptake. Compared with
13
NH
3
,
18
F-BMS showed higher activity ratios between myocardium and blood (rest 2.5 versus 4.1; stress 2.1 versus 5.8), liver (rest 1.2 versus 1.8; stress 0.7 versus 2.0), and lungs (rest 2.5 versus 4.2; stress 2.9 versus 6.4). Regional myocardial blood flow assessed with
18
F-BMS PET showed good correlation (
r
=0.88, slope=0.84) and agreement (mean difference −0.10 [25th percentile −0.3, 75th percentile 0.1 mL · min
−1
· g
−1
]) with that measured with radioactive microspheres over a flow range from 0.1 to 3.0 mL · min
−1
· g
−1
. The extent of defects induced by left anterior descending coronary artery constriction measured by
18
F-BMS and microspheres also correlated closely (
r
=0.63, slope=1.1).

Conclusions—

18
F-BMS-747158-02 is a very attractive new PET perfusion tracer that allows quantitative assessment of regional myocardial perfusion over a wide flow range. The long half-life of
18
F renders this tracer useful for clinical PET/CT applications in the workup of patients with suspected or proven coronary artery disease.
Aortic Arch Plaques and Risk of Recurrent Stroke and Death
Authors: Di Tullio Marco R. , Russo Cesare , Jin Zhezhen , Sacco Ralph L. , Mohr J.P. , Homma Shunichi
Published: April 2009

Background—

Aortic arch plaques are a risk factor for ischemic stroke. Although the stroke mechanism is conceivably thromboembolic, no randomized studies have evaluated the efficacy of antithrombotic therapies in preventing recurrent events.

Methods and Results—

The relationship between arch plaques and recurrent events was studied in 516 patients with ischemic stroke who were double-blindly randomized to treatment with warfarin or aspirin as part of the Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS), based on the Warfarin-Aspirin Recurrent Stroke Study (WARSS). Plaque thickness and morphology were evaluated by transesophageal echocardiography. End points were recurrent ischemic stroke or death over a 2-year follow-up. Large plaques (≥4 mm) were present in 19.6% of patients; large complex plaques (those with ulcerations or mobile components) were seen in 8.5%. During follow-up, large plaques were associated with a significantly increased risk of events (adjusted hazard ratio [HR], 2.12; 95% confidence interval [CI], 1.04 to 4.32), especially those with complex morphology (HR, 2.55; 95 CI, 1.10 to 5.89). The risk was highest among cryptogenic stroke patients, both for large plaques (HR, 6.42; 95% CI, 1.62 to 25.46) and large complex plaques (HR, 9.50; 95% CI, 1.92 to 47.10). Event rates were similar in the warfarin and aspirin groups in the overall study population (16.4% versus 15.8%;
P
=0.43).

Conclusions—

In patients with stroke, especially cryptogenic stroke, large aortic plaques remain associated with an increased risk of recurrent stroke and death at 2 years despite treatment with warfarin or aspirin. Complex plaque morphology confers a slight additional increase in risk.
Peripheral Arterial Disease Is Associated With Higher Rates of Hip Bone Loss and Increased Fracture Risk in Older Men
Authors: Collins Tracie C. , Ewing Susan K. , Diem Susan J. , Taylor Brent C. , Orwoll Eric S. , Cummings Steven R. , Strotmeyer Elsa S. , Ensrud Kristine E.
Published: April 2009

Background—

Peripheral arterial disease (PAD) and osteoporosis are chronic illnesses that increase in prevalence with aging and certain metabolic disorders. The association between PAD, rates of bone loss, and fracture risk in older men is uncertain.

Methods and Results—

We sought to test the hypothesis that PAD is associated with higher rates of bone loss and increased fracture risk. We analyzed data from a prospective cohort study involving 6 US centers and 5781 men at least 65 years of age. We assessed ankle-brachial index and hip bone mineral density, followed up prospectively for changes in hip bone mineral density and fractures. PAD was defined as a baseline ankle-brachial index <0.9. Hip bone mineral density was measured with dual x-ray absorptiometry at baseline and again an average of 4.6 years later. Incident nonspine fractures were ascertained by self-report and confirmed with radiography reports during an average of 5.4 years of follow-up. At baseline, the prevalence of PAD was 6.2%. After adjustment for age, race, site, and baseline bone mineral density, the mean annualized rate of bone loss at the total hip was −0.66% per year (95% confidence interval −0.78 to −0.54) in men with PAD compared with −0.34% per year (95% confidence interval −0.36 to −0.31) in men without PAD (
P
<0.001). After further adjustment for multiple potential confounders, the difference was attenuated (−0.49% in men with PAD versus −0.35% in men without PAD) but remained significant (
P
=0.02). Findings were similar at hip subregions. Twelve percent of men with PAD and 7.9% of those without PAD experienced an incident nonspine fracture (hazard ratio adjusted for age, race, and site=1.47, 95% confidence interval 1.07 to 2.04); this association was not altered substantially by further adjustment for multiple confounders.

Conclusions—

In community-dwelling older men, PAD was associated with higher rates of hip bone loss and increased risk of nonspine fractures. Further research should examine the biological mechanisms underlying the association between reduced limb blood flow and fractures.
Macrophage-Specific Expression of Mannose-Binding Lectin Controls Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice
Authors: Matthijsen Robert A. , de Winther Menno P.J. , Kuipers Dian , van der Made Ingeborg , Weber Christian , Herias M. Veronica , Gijbels Marion J.J. , Buurman Wim A.
Published: April 2009

Background—

With consideration of the central role of the innate immune system in atherogenesis and mannose-binding lectin (MBL) as an innate regulator of immunity, the role of MBL in experimental and human atherosclerosis was assessed.

Methods and Results—

With the use of immunohistochemistry and polymerase chain reaction, deposition and gene expression of MBL-A and -C were assessed in murine atherosclerosis from mice deficient for the low-density lipoprotein receptor (LDLR
−/−
) after 10 or 18 weeks of high-fat feeding. MBL was present and was produced in 10-week-old lesions, whereas deposition and gene expression were minimal after 18 weeks of high-fat feeding and absent in healthy vasculature. Interestingly, deposition of MBL-A and -C differed: MBL-A predominantly localized in upper medial layers, whereas MBL-C was found in and around intimal macrophages. To further study the role of local MBL production by monocytic cells in atherosclerosis, LDLR
−/−
mice with MBL-A and -C
−/−
monocytic cells were construed by bone marrow transplantation. Mice carrying MBL-A and -C double deficient macrophages had increased (30%) atherosclerotic lesions compared with wild-type controls (
P
=0.015) after 10 weeks of high-fat diet. Subsequently, analysis of MBL deposition and gene expression in advanced human atherosclerotic lesions revealed the presence of MBL protein in ruptured but not stable atherosclerotic lesions. Putatively in agreement with murine data, no MBL gene expression could be detected in advanced human atherosclerotic lesions.

Conclusions—

These results are the first to show that MBL is abundantly present and locally produced during early atherogenesis. Local MBL expression, by myeloid cells, is shown to critically control development of atherosclerotic lesions.
Soluble Form of the (Pro)Renin Receptor Generated by Intracellular Cleavage by Furin Is Secreted in Plasma
Authors: Cousin Christelle , Bracquart Diane , Contrepas Aurelie , Corvol Pierre , Muller Laurent , Nguyen Genevieve
Published: April 2009

The (pro)renin receptor [(P)RR] is a 35-kDa transmembrane protein that plays a pivotal role in angiotensin tissue generation and in nonproteolytic prorenin activation. We detected a soluble form of (P)RR [s(P)RR; 28 kDa] in the conditioned medium of cultured cells. The aims of our study were to identify the protease responsible for the generation of s(P)RR, the site of shedding, and to establish the existence of circulating s(P)RR in plasma. We identified furin as the protease responsible for the shedding of endogenous (P)RR based on the following: LoVo colon carcinoma cells devoid of active furin synthesize full-length (P)RR but do not secrete s(P)RR; transfection of Chinese hamster ovary cells with a plasmid coding for α1-antitrypsin Portland variant, an inhibitor of furin, completely inhibited the generation of s(P)RR, whereas addition of GM6001, an inhibitor of metalloproteases or of tumor necrosis factor-α protease inhibitor-1, an inhibitor of ADAM17, in the culture medium has no effect; when the cDNA coding for (P)RR was translated in vitro and incubated with recombinant furin or ADAM17, only furin was able to generate the 28 kDa-s(P)RR, and mutagenesis in the potential furin cleavage R275A/KT/R278A site abolished s(P)RR generation. Immunofluorescence study in glomerular epithelial cells showed that (P)RR was cleaved in the trans-Golgi, and coprecipitation experiments with renin showed that s(P)RR was present in plasma. In conclusion, our results show that s(P)RR is generated intracellularly by furin cleavage, and that s(P)RR detected in plasma is able to bind renin.
Programming of Hypertension
Authors: Reynolds Rebecca M. , Walker Brian R. , Phillips David I. , Dennison Elaine M. , Fraser Robert , Mackenzie Scott M. , Davies Eleanor , Connell John M.
Published: April 2009

Animal models suggest that explanations for the association of low birthweight with adult hypertension may include chronic activation of the hypothalamic-pituitary-adrenal or renin-angiotensin-aldosterone axes. In humans, low birthweight predicts elevated plasma cortisol, but associations with aldosterone have not been reported. We measured aldosterone in serum samples from 205 men and 106 women from 67 to 78 years of age, from Hertfordshire, UK, for whom birthweight was recorded. Participants underwent an overnight low-dose (0.25 mg) dexamethasone suppression test and a low-dose (1 μg) ACTH (corticotropin) stimulation test and were genotyped for the -344 C/T polymorphism of the
CYP11B2
gene encoding aldosterone synthase. Median aldosterone was 6.22 ng/dL (range 0.15 to 38.74) and was higher in men than women (
P
<0.0001). Higher aldosterone levels after both dexamethasone and ACTH stimulation were associated with higher blood pressure (
r
=0.20,
P
=0.001;
r
=0.33,
P
<0.0001, respectively) and with lower birthweight (
r
=−0.16,
P
=0.008;
r
=−0.21,
P
=0.001, respectively). These associations remained significant after adjusting for age, gender, obesity, and genotype. Our findings supplement previous evidence that aldosterone is an important regulator of blood pressure and suggest that factors in early life that retard fetal growth and program activation of the hypothalamic-pituitary-adrenal axis in humans result not only in higher glucocorticoid activity but also in increased mineralocorticoid activity.
Young Men and Islam in the 1990s: Rethinking an Intergenerational Perspective
Authors: Savadogo Mathias , LeBlanc Marie-Nathalie , Gomez-Perez Muriel
Published: April 2009

Interest in the question of youth and Islam in West Africa stems from the overwhelming demographic weight of youth and their relatively recent incursion into the public domain, as well a wave of Islamic revivalism that has swept across Africa from the late 1970s on. In this paper, we propose to examine the sociopolitical role of young men in Islamic revivalist movements that occurred in urban centers in Côte d'Ivoire, Burkina Faso and Senegal in the 1980-1990s. Such movements were particularly popular among secularly educated young men who attended French-speaking schools. While the role of young men in revivalist movements suggests new configurations of authority and charisma, their religious agency remains closely embedded within relationships that extend across generations. Here, we examine instances of conflicts between generations and pay attention to sites of negotiation, such as mosques and voluntary associations.
Modes of Explanation in the Aristotelian Mechanical Problems
Authors: De Groot Jean
Published: April 2009

Scholars have been puzzled by the central argument of MP 1 where the author addresses the basic principle behind the balance and lever. It is not clear what is intended to provide the explanation—the dynamic concepts of force and constraint or the geometrical demonstration. Nor is it clear whether the geometrical part of the argument carries any logical force or has value as a proof. This paper makes a case for the cogency of the argument as a kinematic, not dynamic, account. MP 1 proceeds systematically as it extends the explanatory power of the parallelogram of movements from rectilinear motion to circular motion. Euclid's Elements I.43 provides insight on the author's procedure. His general method is demonstrative, as described in Posterior Analytics I.1.
Structures of Argument and Concepts of Force in the Aristotelian Mechanical Problems
Authors: Schiefsky Mark
Published: April 2009

I argue that the main goal of the Mechanical Problems, a short treatise transmitted in the Corpus Aristotelicum, is to explain the working of technology in terms of the concepts of Aristotelian natural philosophy. The author's explanatory strategy is to reduce the thirty-five "problems" or questions that he discusses to one or more of three simple models: the circle, balance, and lever. The conceptual foundation of this reduction program is a principle concerning circular motion, viz. that a point on the circumference of a larger circle moves more quickly than one on a smaller circle, assuming that the circles turn about the same center at the same angular speed. I analyze the author's argument for this principle and his application of it throughout the text, especially to the analysis of the lever. The main conclusions are (1) that the author's justification of the circular motion principle is based on an innovative geometrical analysis of motion, not on a highly theoretical conceptualization of force; and (2) while the author is aware of a reciprocal relationship between weights and distances from the fulcrum in the case of the lever, his explanation of this fact makes no reference to the conditions for static equilibrium.
The Simple Ontology of Kalām Atomism: An Outline
Authors: Sabra Abdelhamid I.
Published: April 2009

This paper aims to present concisely the Islamic kalām atomism as an alternative philosophy to Hellenizing falsafa. Kalām is a theological-philosophical discourse which, first (in the third/ninth century) ventured to rival the falsafa represented early by al-Kindī (d.ca. 252/866), then by al-Fārābī and Avicenna in the fourth/tenth and fifth/eleventh centuries, and which eventually (in the sixth/twelfth century and after) appeared to be inclined to propose a mingling of the kalām discourse with falsafa in a series of varied "syntheses".—Focusing on the simple ontology of the basic kalām atomism, and noting the hybrid character of kalām, the aim of this paper is to help to clarify the inevitable problematic consequences of those late ventures of Islamic intellectualism.
Footprints of "Experiment" in Early Arabic Optics
Authors: Kheirandish Elaheh
Published: April 2009

This study traces the early developments of the concept of experiment with a view of extending the subject in both content and approach. It extends the content of the subject slightly backward, prior to the methodological breakthroughs of the Optics of Ibn al-Haytham (Alhazen or Alhacen, d. ca. 1040), which are credited as a "significant landmark in the history of experimental science." And it extends the approach to the subject slightly forward, from the premise that early science was "largely carried out in books," to a close examination of the books through which the footprints of 'experiment' may be traced. The point of departure is the Optics of Ahmad ibn 'Ī;sā, a revealing text for the early developments of concepts such as 'demonstration' and 'experiment', and one through which some modern discussions are examined and extended with reference to this and other historical sources.
The "Experience-Based Medicine" of the Thirteenth Century
Authors: McVaugh Michael
Published: April 2009

We should not assume that medieval physicians did not take pains to found their practice upon evidence. Academic physicians at Montpellier ca. 1300 were cautious about accepting textbook claims for the powers of drugs, and tried to verify each drug's physiological effects before using it; yet they were also flexible, ready to believe that powerful new medicines might be discovered empirically that were unknown to their authorities or superficially inconsistent with existing knowledge. Likewise, physicians were careful to observe their patients closely and to try to identify the condition from which each was suffering, and when they were unsure of the nature of an illness, they feared to administer medicines lest their known effects might be harmful to the patient. Anticipating today's "evidence-based medicine," the physician's practice involved the conscientious use of current best evidence.
The Intellect Naturalized: Roger Bacon on the Existence of Corporeal Species within the Intellect
Authors: Raizman-Kedar Yael
Published: April 2009

In this paper I challenge the claim that Bacon considered the operation of species as limited to the physical and sensory levels and demonstrate that in his view, the very same species issued by physical objects operate within the intellect as well. I argue that in Bacon the concept of illumination plays a secondary role in the acquisition of knowledge, and that he regarded innate knowledge as dispositional and confused. What was left as the main channel through which knowledge is gained were species received through the senses. I argue that according to Bacon these species, representing their agents in essence, definition and operation, arrive in the intellect without undergoing a complete abstraction from matter and while still retaining the character of agents acting naturally. In this way Bacon sets the intellect as separate from the natural world not in any essential way, but rather as it were in degree, thus supplying a theoretical justification for the ability to access and know nature.
Magic and the Physical World in Thirteenth-Century Scholasticism
Authors: Marrone Steven
Published: April 2009

The turn to modern science in the Scientific Revolution of the seventeenth century is typically characterized as dependent on the novel adoption of a mechanical hypothesis for operations in nature. In fact, the Middle Ages saw a partial anticipation of this phenomenon in the scholastic physics of the thirteenth century. More precisely, it was just the two factors, denial of action at a distance and an emphasis on the primary materiality of causation, that constituted this early mechanism—or "protomechanism." The latter's emergence can be seen most clearly where scholastic thinkers—here, William of Auvergne, Thomas Aquinas and Giles of Rome—confronted the theoretical limits of natural cause and effect in their efforts to determine the reality of magic and locate its place in the natural world.
The Debate over the Nature of Motion: John Buridan, Nicole Oresme and Albert of Saxony. With an Edition of John Buridan's Quaestiones super libros Physicorum, secundum ultimam lecturam, Book III, q. 7
Authors: Thijssen Johannes
Published: April 2009

The so-called 'Buridan school' at the University of Paris has obtained a considerable fame in the history of science. Pierre Duhem had made some bold claims about the achievements by John Buridan and his 'pupils' Nicole Oresme and Albert of Saxony in the field of medieval dynamics. Although generally, Duhem's views are no longer accepted, the idea of a 'Buridan school' has survived. This idea is, however, misleading. John Buridan, Nicole Oresme and Albert of Saxony should rather be viewed as members of an intellectual network. While interested in similar philosophical themes and understanding each other's conceptual language, they also disagreed about numerous topics. One case in point is the nature of motion, as discussed in their respective Questions on the Physics. Despite the common features of the language in which they discuss motion, the three thinkers defend different positions. This article compares the three sets of Questions on the Physics and presents a critical edition of Buridan's "ultima lectura", Book III, q. 7.
John Buridan and Critical Realism
Authors: Sylla Edith Dudley
Published: April 2009

In this paper I examine what John Buridan has to say in his Quaestiones in Analytica Posteriora relevant to the subalternate mathematical sciences, particularly astronomy. Much previous work on the scholastic background to the Scientific Revolution relies on texts that were written in the late sixteenth or seventeenth centuries. Here I am interested in texts that might reflect the context of Copernicus, and, in particular those before 1500. John Buridan and Albert of Saxony were fourteenth century authors influential in Cracow in the fifteenth century, whose conception of science may be characterized as "critical realism." Their view would support the autonomy of astronomy, as well as the idea that sciences may progress over time.
The Significance of "Chymical Atomism"
Authors: Newman William
Published: April 2009

The historical treatment of atomism and the mechanical philosophy largely neglects what I call "chymical atomism," namely a type of pre-Daltonian corpuscular matter theory that postulated particles of matter which were operationally indivisible. From the Middle Ages onwards, alchemists influenced by Aristotle's Meteorology, De caelo, and De generatione et corruptione argued for the existence of robust corpuscles of matter that resisted analysis by laboratory means. As I argue in the present paper, this alchemical tradition entered the works of Daniel Sennert and Robert Boyle, and became the common property of seventeenth-century chymists. Through Boyle, G.E. Stahl, and other chymists, the operational atomism of the alchemists was even transmitted to Antoine Laurent Lavoisier, where it became the basis of his claim that elements are simply "the final limit that analysis reaches."
Conjecture, Probabilism, and Provisional Knowledge in Renaissance Meteorology
Authors: Martin Craig
Published: April 2009

For Renaissance Aristotelian natural philosophers, ideally knowledge was certain and based on syllogistic demonstration. Many Italian scholars, such as Agostino Nifo, Pietro Pomponazzi, and Niccolò Cabeo, considered this ideal as inapplicable to the field of meteorology. Rather, because of the accidental nature of meteorological phenomena and the inherent irregularity of the weather, they believed that causal explanations of meteorology were largely conjectural, provisional, and probabilistic. Several of these natural philosophers applied the standard of "saving the appearances" to the field of meteorology because of the difficulties involved in making accurate observations. This lower epistemological standard contributed to the willingness of Aristotelians to revise meteorological theories and deviate from Aristotle's own positions.
Setting up Copernicus? Astronomy and Natural Philosophy in Giambattista Capuano da Manfredonia's Expositio on the Sphere
Authors: Shank Michael
Published: April 2009

In 1499, while Copernicus studies in Bologna, the commentary on Sacrobosco's Sphere by the Padua master Francesco Capuano da Manfredonia first appears in print. It will be revised and reprinted several times thereafter. Like Copernicus, Capuano has a high view of astronomy and mingles astronomical and physical considerations (flies moving on wheels, men on ships, impetus, comets, raptus). Also, Capuano offers a flawed argument against a two-fold (diurnal and zodiacal) motion of the Earth. Multiple thematic resonances between Capuano's commentary and De revolutionibus, I, 5-11, suggest the hypothesis that Copernicus is answering Capuano, whose work was owned by Joachim Rheticus, if not Copernicus himself.