Type 1 plasminogen activator inhibitor binds to fibrin via vitronectin

Type 1 plasminogen activator inhibitor (PAI-1), the primary inhibitor of tissue-type plasminogen activator (t-PA), circulates as a complex with the abundant plasma glycoprotein, vitronectin. This interaction stabilizes the inhibitor in its active conformation. In this report, the effects of vitronectin on the interactions of PAI-1 with fibrin clots were studied. Confocal microscopic imaging of platelet-poor plasma clots reveals that essentially all fibrin-associated PAI-1 colocalizes with fibrin-bound vitronectin. Moreover, formation of platelet-poor plasma clots in the presence of polyclonal antibodies specific for vitronectin attenuated the inhibitory effects of PAI-1 on t-PA-mediated fibrinolysis. Addition of vitronectin during clot formation markedly potentiates PAI-1-mediated inhibition of lysis of 125I-labeled fibrin clots by t-PA. This effect is dependent on direct binding interactions of vitronectin with fibrin. There is no significant effect of fibrin-associated vitronectin on fibrinolysis in the absence of PAI-1. The binding of PAI-1 to fibrin clots formed in the absence of vitronectin was characterized by a low affinity (Kd ~ 3.5 μM) and rapid loss of PAI-1 inhibitory activity over time. In contrast, a high affinity and stabilization of PAI-1 activity characterized the cooperative binding of PAI- 1 to fibrin formed in the presence of vitronectin. These findings indicate that plasma PAI-1-vitronectin complexes can be localized to the surface of fibrin clots; by this localization, they may modulate fibrinolysis and clot reorganization

Surgical therapy for testicular cancer metastatic to the liver

In recent years improved cure rates have been achieved for testicular cancer. A better understanding of the biology of subtypes of testicular cancer and the introduction of surgical intervention has contributed greatly to how we currently approach a young man with testicular cancer. We describe here experience at our institution of the treatment, results and prognostic factors for testicular cancer metastases to the liver. Careful diagnostic work-up and planning of the therapy are required, in cooperation with an experienced team

Adult Cyclic Vomiting Syndrome Successfully Treated with Intranasal Sumatriptan

Cyclic vomiting syndrome is an increasingly recognized cause of nausea and vomiting in adults. We report the case of a 47-year-old man with recurrent episodes of intractable nausea and vomiting for one year. His symptoms persisted for 4–7 days and then resolved spontaneously, only to return after periods of time ranging from one week up to a month. After an extensive workup, which failed to determine any causative explanation for his symptoms, he was diagnosed with cyclic vomiting syndrome. His episodes of vomiting were successfully terminated with the use of intranasal sumatriptan. In this case, we highlight that sumatriptan effectively aborted symptoms in an adult patient with cyclic vomiting syndrome. Increasing physicians’ awareness of adult cyclic vomiting syndrome may improve care of patients suffering from this debilitating condition

Spectroscopic and Reactivity Comparisons of a Pair of bTAML Complexes with Fe^VO and Fe^IVO Units

In this report we compare the geometric and electronic structures and reactivities of [Fe^V(O)]⁻ and [Fe^IV(O)]^2– species supported by the same ancillary nonheme biuret tetraamido macrocyclic ligand (bTAML). Resonance Raman studies show that the FeO vibration of the [Fe^IV(O)]^2– complex <b>2</b> is at 798 cm^–1, compared to 862 cm^–1 for the corresponding [Fe^V(O)]⁻ species <b>3</b>, a 64 cm^–1 frequency difference reasonably reproduced by density functional theory calculations. These values are, respectively, the lowest and the highest frequencies observed thus far for nonheme high-valent FeO complexes. Extended X-ray absorption fine structure analysis of <b>3</b> reveals an FeO bond length of 1.59 Å, which is 0.05 Å shorter than that found in complex <b>2</b>. The redox potentials of <b>2</b> and <b>3</b> are 0.44 V (measured at pH 12) and 1.19 V (measured at pH 7) versus normal hydrogen electrode, respectively, corresponding to the [Fe^IV(O)]^2–/[Fe^III(OH)]^2– and [Fe^V(O)]⁻/[Fe^IV(O)]^2– couples. Consistent with its higher potential (even after correcting for the pH difference), <b>3</b> oxidizes benzyl alcohol at pH 7 with a second-order rate constant that is 2500-fold bigger than that for <b>2</b> at pH 12. Furthermore, <b>2</b> exhibits a classical kinteic isotope effect (KIE) of 3 in the oxidation of benzyl alcohol to benzaldehyde versus a nonclassical KIE of 12 for <b>3</b>, emphasizing the reactivity differences between <b>2</b> and <b>3</b>