Uncoupling fibrin from integrin receptors hastens fibrinolysis at the platelet-fibrin interface

A well-characterized in vitro model system composed of thrombin- stimulated gel-filtered human platelets, fibrin-(ogen), plasminogen, and recombinant tissue plasminogen activator (rt-PA) was used to examine the relationship between platelet-fibrin adhesive interactions and the lytic resistance of a platelet-rich thrombus. Laser light scattering kinetic experiments demonstrated that the ligand-mimetic peptide D-RGDW and an anti-alpha IIb beta 3 monoclonal antibody both inhibited clot retraction, but neither integrin-targeted reagent affected the overall delay in lysis of "bulk" fibrin caused by thrombin- stimulated platelets. However, lysis of the model platelet-rich thrombus did proceed some 30% more quickly when treated with a plasminogen activator inhibitor (PAI)-resistant t-PA variant. Taken together, these results confirm that platelet-released PAI-1 is a major determinant of global lytic resistance. Next events occurring during fibrinolysis in the unique microenvironment near the platelet surface were monitored by scanning electron microscopy and quantitative fluorescence microscopy. Scanning electron micrographs of the partially lysed model thrombus in the presence of 200 mumol/L of D-RGDW showed no platelet aggregates, and fibrin was attached by fewer strands to the platelets. Quantitative fluorescence microscopy, using fluorescein- labeled fibrin, showed that fibrin adherent to the surface of thrombin- stimulated platelets lysed 20% to 50% more slowly than bulk fibrin (monitored in parallel by laser light scattering). Furthermore, this microspectroscopic technique showed that D-RGDW reduced the quantity of platelet-bound fibrin, and accelerated lysis near the platelet surface with both native rt-PA and the PAI-resistant variant. These observations suggest that the dense network of fibrin bound to the platelet surface is protected from fibrinolysis by tissue-type plasminogen activators. Further, uncoupling fibrin from its platelet receptors uniquely hastens fibrinolysis at the cell/fibrin interface.     

A comparative study of the iron-clearing properties of desferrithiocin analogues with desferrioxamine B in a Cebus monkey model

A comparative study of the iron-clearing properties of subcutaneously administered desferrioxamine B (DFO) with those of orally administered desferrithiocin sodium salt (1), desmethyl desferrithiocin (2), desazadesmethyl desferrithiocin sodium salt (3), desazadesmethyl desferrithiocin pivaloyloxymethyl ester (4), and desazadesmethyl-5,5- dimethyl desferrithiocin (5) in an iron-loaded Cebus monkey model and a non-iron overloaded bile duct-cannulated rat model is presented. All six drugs, which performed well in rodent studies, demonstrated increased efficiency in the Cebus monkey model. When administered to rodents at a daily dosage of 384 mumol/kg over a period of 10 days, drug 1 demonstrated severe renal toxicity. whereas drugs 3, 4, and 5 exhibited severe gastrointestinal (GI) toxicity. Under the same experimental protocol, drug 2 did not show significant toxic side effects. In addition, to further evaluate the iron-clearing properties of analogue 2, a dose-response study was performed in the primates that showed that iron excretion increased in a dose-dependent fashion.     

无神经损伤的胸腰椎骨折体位复位、塑形背托及早期活动处理的疗效

目的　报告 2 8例无神经损伤的、胸腰椎楔形压缩型及爆裂型骨折 ,用体位复位方法治疗的疗效。方法　对这类病人进行回顾性研究 ,观察项目包括 :工作能力、整体满意程度、疼痛程度、功能性结果及X线检查。结果　 90 %的病人经治疗后完全无痛或仅有微痛。 75 %的病人能恢复工作 ,其中包括全部楔形压缩型骨折的病人和 6 5 %的爆裂骨折病人。 90 %的病人日常生活仅受到极小的影响。结论　虽然所采用的体位复位方法及治疗步骤不能长期矫正脊柱后凸畸形 ,但整体的临床效果还是令人鼓舞 ,病人满意程度也很高。     

Relative antithrombotic effects of monoclonal antibodies targeting different platelet glycoprotein-adhesive molecule interactions in nonhuman primates

The relative antithrombotic effectiveness of targeting glycoprotein (GP) Ib-dependent versus GPIIb-IIIa-dependent platelet interactions has been determined in baboons by measuring thrombus formation after infusing comparable antihemostatic doses of anti-von Willebrand factor (vWF) monoclonal antibody (MoAb) BB3-BD5, anti-GPIb MoAb AP1, and anti- GPIIb-IIIa MoAb LJ-CP8 under conditions of arterial and venous flow (shear rates of 750 to 1,000 seconds-1 and 100 seconds-1, respectively). Thrombus formation was quantified as 111In-platelet deposition and 125I-fibrin accumulation on segments of collagen-coated tubing interposed in chronic exteriorized arteriovenous (AV) shunts for 40 minutes. In vitro, anti-vWF MoAb BB3 BD5 (IgG) and anti-GPIb MoAb AP1 [IgG or F(ab)2 fragments] inhibited ristocetin-induced platelet aggregation (IC50 50 nmol/L and 1 mumol/L, respectively), but neither of these MoAbs blocked platelet aggregation induced by adenosine diphosphate (ADP) (P > .5). Conversely, anti-GPIIb-IIIa MoAb LJ-CP8 inhibited platelet aggregation induced by ADP (IC50 1 mumol/L, but failed to block ristocetin-induced platelet aggregation (P > .5). In vivo, the intravenous infusion of anti-vWF MoAb BB3 BD5 or anti-GPIIb- IIIa MoAb LJ-CP8 into baboons at doses that abolished corresponding agonist-induced aggregation ex vivo (bolus injections of 0.5 mg/kg and 10 mg/kg, respectively) prolonged template bleeding times from baseline values of 4.0 +/- 0.3 minutes to > 27 +/- 4 minutes, and to > 26 +/- 4 minutes, respectively (P < .001 in both cases), without affecting the peripheral platelet count (P > .5). However, injection of anti-GPIb MoAb AP1 [10 mg/kg as IgG or 1 mg/kg as F(ab)2 fragments] produced immediate irreversible thrombocytopenia (< 40,000 platelets/microL). Anti-GPIIb-IIIa MoAb LJ-CP8 abolished platelet deposition and fibrin accumulation on collagen segments under both arterial and venous flow conditions (P < .01 in all cases), whereas MoAb BB3 BD5 produced minimal inhibition of platelet deposition and no decrease in fibrin accumulation at arterial shear rates and undetectable antithrombotic outcomes at low shear. Thus, inhibiting GPIIb-IIIa-dependent platelet recruitment abrogates both thrombus formation and platelet hemostatic function at both venous and arterial shear rates. By contrast, interfering with GPIb-vWF-dependent platelet interactions abolishes platelet hemostatic function without producing corresponding antithrombotic effects.     

Cardiac function: evaluation with fast-echo MR imaging

Magnetic resonance (MR) imaging of the heart has, to date, been limited in its ability to evaluate cardiac function. The authors have implemented a technique for functional assessment of the heart using shorter echo times than those generally used for conventional spin-echo imaging. With these short echo times, multiple images can be obtained in a multisection mode approximately within the isovolumetric phases of the cardiac cycle. This permits a pair of image stacks to be obtained, one in end systole and the other in end diastole. With the use of a modified Simpson rule, left ventricular volume and ejection fraction were calculated and compared with results obtained from contrast material-enhanced ventriculography. Preliminary results indicate that this method has promise for the evaluation of a variety of functional parameters in the heart. The short acquisition times for this functional study permit it to be combined with a tissue characterization study within the time constraints of a clinical MR imaging session.     

Enterovenous fistula: unusual complication of Crohn disease

An unusual complication in a patient with Crohn enterocolitis is presented. Ultrasound and computed tomographic studies showed stationary gas in the portal vein, and a presumptive diagnosis of septic ascending portal thrombophlebitis was made. Emergency laparotomy was performed and the terminal ileum was excised for recurrent Crohn disease. Pathologic examination showed a fistula from the lumen of the inflamed segment to the superior mesenteric venous system. Autopsy 1 month later showed organizing thrombi and fecal debris in the portal venules.     

Neuroendocrine carcinomas of the lung: clinical, radiologic, and pathologic correlation

Neuroendocrine carcinomas of the lung are characterized by differentiation toward Kulchitsky cells and are classified as Kulchitsky-cell carcinoma (KCC) I (classic carcinoid), KCC II (atypical carcinoid), and KCC III (small-cell carcinoma). The clinical, computed tomographic (CT), and pathologic findings in 31 patients with KCC were reviewed. KCC I lesions generally occurred in younger (56 years +/- 18) nonsmoking women, were small (1.8 cm +/- 0.7 in diameter on CT scans), and were associated with lymphadenopathy in one of ten patients. KCC II tumors were found predominantly in older (66 years +/- 12) smoking men and were larger (3.9 cm +/- 1.3 in diameter, P less than .001); four of ten patients had CT evidence of lymphadenopathy. KCC III tumors occurred in older (66 years +/- 8) smoking men and were large (4.2 cm +/- 1.0); 11 of 11 patients had massive lymphadenopathy. Clinical, radiologic, or pathologic overlap was noted in three patients. Sputum cytologic and fine-needle and bronchoscopic biopsy findings were often nondiagnostic or misleading, particularly for KCC II lesions. CT of the chest provides additional discriminating information in the preoperative diagnosis of neuroendocrine lung carcinomas.