Background and Purpose-Cerebral venous thrombosis is a rare entity that can be difficult to manage. Intrasinus thrombolysis is an increasingly applied intervention, but this modality carries an increased risk of hemorrhage. We describe for the first time an option with a potentially lower incidence of intracranial bleeding, the combination of the AngioJet rheolytic thrombectomy catheter with intra-arterial thrombolysis, in 2 patients with extensive dural sinus thromboses, preexisting intracranial hemorrhage, and severe progressive neurological deficits despite heparin therapy. Methods-Four procedures were performed in 2 patients with thromboses in the superior sagittal and transverse sinuses (right in 1 patient and bilateral in 1 patient) and cortical veins. Rheolytic thrombectomy was performed in the sigmoid, transverse, straight, and superior sagittal sinuses; this technique involves the use of the Bernoulli effect to create a vacuum that fragments and aspirates thrombus. For associated persistent cortical vein thromboses, low-dose intra-arterial thrombolysis was used. Results-Both patients had excellent angiographic results with sinus reopening after rheolytic thrombectomy and cortical vein reopening after intra-arterial thrombolysis. Follow-up CT showed no change in 1 patient and increased preexisting intracranial hemorrhage in the other. One patient had a negative hypercoagulable workup, and the other patient had probable anti-phospholipid antibody syndrome. At 6 months, both patients had excellent clinical outcome with no neurological deficits except mild short-term memory loss in 1 patient. Conclusions-The combination of rheolytic thrombectomy with intra-arterial thrombolysis is a treatment modality that allows accelerated recanalization of occluded dural sinuses and cerebral veins with lower doses of thrombolytic agents.

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Ventricular arrhythmias are common in both cardiac hypertrophy and failure; cardiac failure in particular is associated with a significant increase in the risk of sudden cardiac death. We studied the electrophysiologic changes in a guinea pig model with aortic banding resulting in cardiac hypertrophy at 4 weeks and progressing to cardiac failure at 8 weeks using whole-cell patch-clamp and biochemical techniques. Action potential durations (APDs) were significantly prolonged in banded animals at 4 and 8 weeks compared with age-matched sham-operated animals. APDs at 50% and 90% repolarization (APD(50) and APD(90) in ms) were the following: 4 week, banded, 208+/-51 and 248+/-49 (n = 15); 4 week, sham, 189+/-68 and 213+/-69 (n = 16); 8 week, banded, 197+/-40 and 226+/-40 (n = 21); and 8 week, sham, 156+/-42 and 189+/-45 (n = 22), respectively; P<0.05 comparing banded versus sham-operated animals. We observed no significant differences in the K(+) currents between the 2 groups of animals at 4 and 8 weeks. However, banded animals exhibited a significant increase in Na(+) and Na(+)-Ca(2+) exchange current densities compared with controls. Furthermore, we have found a significant attenuation in the Ca(2+)-dependent inactivation of the L-type Ca(2+) current in the banded compared with sham-operated animals, likely as a result of the significant downregulation of the sarcoplasmic reticulum Ca(2+) ATPase, which has been documented previously in the heart failure animals. Our data provide an alternate mechanism for APD prolongation in cardiac hypertrophy and failure and support the notion that there is close interaction between Ca(2+) handling and action potential profile.

Objectives: Upon completion of this article, the reader will be able to (1) explain the incidence and potential complications of bullet embolization, and (2) recall the challenge of diagnosing this entity and the therapeutic possibilities available including endovascular retrieval. Accreditation: Tufts University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit: Tufts University School of Medicine designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Case PresentationA 46-year-old man presented to a local level 2 trauma center after sustaining a single gunshot wound to the right upper quadrant of the abdomen. The patient was hemodynamically unstable and was taken emergently to the operating room for exploration of the abdomen. He was found to have a through and through injury to the liver, small intestinal injury at two locations, and a single injury to the infrarenal vena cava. The Keywords ► penetrating trauma ► bullet embolization ► endovascular retrieval ► interventional radiology AbstractBullet embolization after penetrating trauma is an infrequent but important phenomenon. It presents an unexpected sequelae to the otherwise predictable injury pattern of penetrating missile injury mechanism and poses a challenging diagnostic and therapeutic dilemma. Bullets from penetrating wounds can gain access to the vasculature and migrate to nearly every large vascular bed. Patients can be asymptomatic, but the potential complications can be devastating including limb-threatening ischemia, sepsis, endocarditis, cardiac valvular incompetence, pulmonary embolism, stroke, and even death. The exact incidence of bullet embolization is unknown, but it was estimated to be 0.3% during the Vietnam War and 1.1% in the recent conflict in Afghanistan and Iraq. The scarcity of the condition and the lack of concentrated experience at any single institution contribute to the controversies pertaining to the management approach. Traditionally, surgical extraction of embolized bullets may involve difficult and invasive surgical exposures. Recent advancement in endovascular techniques provides an additional option in this treatment algorithm. In this article, we describe a case of venous bullet embolization from the left iliac vein treated by a combined endovascular and surgical approach.

The properties of several components of outward K(+) currents, including the pharmacological and kinetics profiles as well as the respective molecular correlates, have been identified in mouse cardiac myocytes. Surprisingly little is known with regard to the Ca(2+)-activated ionic currents. We studied the Ca(2+)-activated transient outward currents in mouse ventricular myocytes. We have identified a 4-aminopyridine (4-AP)- and tetraethyl ammonium-resistant transient outward current that is Ca(2+) dependent. The current is carried by Cl(-) and is critically dependent on Ca(2+) influx via voltage-gated Ca(2+) channels and the sarcoplasmic reticulum Ca(2+) store. The current can be blocked by the anion transport blockers niflumic acid and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid. Single channel recordings reveal small conductance channels (approximately 1 pS in 140 mM Cl(-)) that can be blocked by anion transport blockers. Ensemble-averaged current faithfully mirrors the transient kinetics observed at the whole level. Niflumic acid (in the presence of 4-AP) leads to prolongation of the early repolarization. Thus this current may contribute to early repolarization of action potentials in mouse ventricular myocytes.

Peritoneal and pleural ports offer a convenient and relatively safe alternative to frequent paracenteses/thoracenteses in the management of refractory ascites and pleural effusions. This approach can improve the QOL for patients with end-stage disease.

Abstract-We directly tested the effects of nitric oxide (NO) on Na ϩ channels in guinea pig and mouse ventricular myocytes using patch-clamp recordings. We have previously shown that NO donors have no observed effects on expressed Na ϩ channels. In contrast, NO (half-blocking concentration of 523 nmol/L) significantly reduces peak whole-cell Na ϩ current (I Na ) in isolated ventricular myocytes. The inhibitory effect of NO on I Na was not associated with changes in activation, inactivation, or reactivation kinetics. At the single-channel level, the reduction in macroscopic current was mediated by a decrease in open probability and/or a decrease in the number of functional channels with no change in single-channel conductance. Application of cell permeable analogs of cGMP or cAMP mimics the inhibitory effects of NO. Furthermore, the effects of NO on I Na can only be blocked by inhibition of both cGMP and cAMP pathways. Sulfhydryl-reducing agent does not reverse the effect of NO. In summary, although NO exerts its action via the known guanylyl cyclase (GC)/cGMP pathway, our findings provide evidence that NO can mediate its function via a GC/cGMP-independent mechanism involving the activation of adynylyl cyclase (AC) and cAMP-dependent protein kinase. Key Words: nitric oxide Ⅲ cardiac Na ϩ current Ⅲ protein kinase A Ⅲ protein kinase G N itric oxide (NO) is a uniquely diffusible and reactive molecular messenger, which is found in abundance and plays important regulatory roles in different systems throughout the body. 1 In the cardiovascular system, NO is the major endothelium-derived relaxing factor (EDRF) and causes vasodilation and reduces blood pressure. 2 In addition, NO functions as an important endogenous inhibitor of vascular lesion formation. 3 The coronary endothelium is responsible for the bulk of the endogenous, physiological production of NO. 4 However, NO can also be produced within the cardiac myocytes themselves by the constitutive NO synthase. 5 NO modulates cardiac contractility both in vitro and in vivo. 6 More recently, it was shown that NO can regulate both adenylyl cyclase (AC) and guanylyl cyclase (GC) in cardiac myocytes. High levels of NO induce large increases in cGMP and a negative inotropic effect, whereas low levels of NO increase cAMP and induce a positive contractile response. 7 We have previously shown using heterologous expression systems that although Ca 2ϩ channel can be directly modulated by NO, Na ϩ channels are unaffected by direct NO modulation. 8 Here, we show that NO modulates Na ϩ channels in native cardiac myocytes. In addition, we provide evidence to demonstrate that NO modulates Na ϩ channels via second messenger pathways through activation of protein kinase G (PKG) and protein kinase A (PKA). Materials and MethodsSingle left ventricular myocytes were isolated from guinea pigs and mice (Charles River Laboratories, Wilmington, Mass) as previously described. 9 See further details in the expanded Materials and Methods section that can be found in the online data supplement av...

Abstract. Glypican-3 (GPC3), a membrane-associated heparan sulfate proteoglycan, is frequently upregulated in hepatocellular carcinoma (HCC). However, how GPC3 contributes to the progress of HCC is largely unclear. The present study investigated the association between GPC3 expression and HCC clinicopathological characteristics, and particularly focused on the role and underlying mechanisms of GPC3 in HCC epithelial-mesenchymal transition (EMT). Remarkably elevated expression of GPC3 was demonstrated in HCC tumor tissues compared with paired non-tumor tissues in 45 patients with HCC by quantitative real-time PCR, immunohistochemistry, and western blotting, respectively. Furthermore, the tissue expression of GPC3 was increased during HCC progression from Barcelona Clinic Liver Cancer stage A or B to stage C. The enhanced levels of GPC3 in HCC tumor tissues were tightly correlated to the expression of the EMT-associated proteins and tumor vascular invasion. Patients with GPC3-high expression in tumor tissues displayed significantly shorter survival time than those with GPC3-low expression (P=0.001). Consistent with the findings in patients, HepG2 cells, which expressed high levels of GPC3, showed stronger capacity of migration and significant EMT-like changes when compared to those HCC cells with low levels of GPC3, e.g., Hep3Band Huh7 in scratch, Transwell assays and western blotting. Furthermore, administration with exogenous GPC3 in HCC cells activated extracellular signal-regulated kinase (ERK) and significantly enhanced cell migration and invasion. The behavior was significantly inhibited by the ERK inhibitor PD98059. Together, our studies show that GPC3 contributes to HCC progression and metastasis through impacting EMT of cancer cells, and the effects of GPC3 are associated with ERK activation.