There is currently no universally accepted method to monitor circuit function or guidelines for circuit replacement during continuous renal replacement therapies (CRRT). The objectives of this study were to diagnose the causes of circuit failure, identify factors responsible for circuit clotting and determine a predictive monitor of circuit function. The CRRT technique used in this study was continuous venovenous haemodialysis (CVVHD). Continuous monitoring of circuit pressures (pre- and post-haemofilter and their difference: the transfilter pressure gradient) was used to diagnose the causes of circuit failure. In circuits ceasing due to clotting, the factors thought to contribute, anticoagulation, haematocrit and platelet count, were measured at the commencement of CVVHD and every eight hours thereafter until circuit failure. Monitors of circuit function, creatinine clearance and plasma to diafiltrate urea ratio were measured every eight hours and compared to the transfilter pressure gradient. During a three-month period data was collected on five consecutive patients (41 consecutive haemofilters). Clotting of the haemofilter (63%) and air detection chamber (7.5%) were the most common identifiable causes of circuit failure. The duration of their circuit life was described using multiple regression analysis, i.e. hours of filter life = -82.8 + (Δ platelet count x 0.25) + (Δ haematocrit x 3.6) + (circuit flow [ml/min] x 4) R2 = 0.77. A rise in transfilter pressure gradient and a fall in haemofilter function discriminated clotted filters with falling function (decrease in creatinine clearance and urea ratio) from unclotted filters. In any circuit an increase of 26 mmHg or more in the transfilter pressure gradient accurately predicted circuit failure due to clotting and imminent cessation of function. Increases in platelet count, haematocrit, and low circuit flows are important determinants of haemofilter life. The measurement of transfilter pressure gradient across the haemofilter is an accurate bedside monitor of circuit function.

Stone JD, Holt AW, Vuncannon JR, Brault JJ, Tulis DA. AMP-activated protein kinase inhibits transforming growth factor-␤-mediated vascular smooth muscle cell growth: implications for a Smad-3-dependent mechanism.

Coronary artery disease (CAD) accounts for over half of all cardiovascular disease-related deaths. Uncontrolled arterial smooth muscle (ASM) cell migration is a major component of CAD pathogenesis and efforts aimed at attenuating its progression are clinically essential. Cyclic nucleotide signaling has long been studied for its growth-mitigating properties in the setting of CAD and other vascular disorders. Heme-containing soluble guanylyl cyclase (sGC) synthesizes cyclic guanosine monophosphate (cGMP) and maintains vascular homeostasis predominantly through cGMP-dependent protein kinase (PKG) signaling. Considering that reactive oxygen species (ROS) can interfere with appropriate sGC signaling by oxidizing the cyclase heme moiety and so are associated with several CVD pathologies, the current study was designed to test the hypothesis that heme-independent sGC activation by BAY60-2770 (BAY60) maintains cGMP levels despite heme oxidation and inhibits ASM cell migration through phosphorylation of the PKG target and actin-binding vasodilator-stimulated phosphoprotein (VASP). First, using the heme oxidant ODQ, cGMP content was potentiated in the presence of BAY60. Using a rat model of arterial growth, BAY60 significantly reduced neointima formation and luminal narrowing compared to vehicle (VEH)-treated controls. In rat ASM cells BAY60 significantly attenuated cell migration, reduced G:F actin, and increased PKG activity and VASP Ser239 phosphorylation (pVASP.S239) compared to VEH controls. Site-directed mutagenesis was then used to generate overexpressing full-length wild type VASP (FL-VASP/WT), VASP Ser239 phosphorylation-mimetic (FL-VASP/ 239D) and VASP Ser239 phosphorylation-resistant (FL-VASP/239A) ASM cell mutants. Surprisingly, FL-VASP/239D negated the inhibitory effects of FL-VASP/ WT and FL-VASP/239A cells on migration. Furthermore, when FL-VASP mutants were treated with BAY60, only the FL-VASP/239D group showed reduced migration compared to its VEH controls. Intriguingly, FL-VASP/239D abrogated the stimulatory effects of FL-VASP/WT and FL-VASP/239A cells on PKG activity. In turn, pharmacologic blockade of PKG in the presence of BAY60 reversed the inhibitory effect of BAY60 on naïve ASM cell migration. Taken together, we demonstrate for the first time that BAY60 inhibits ASM cell migration through cGMP/PKG/VASP signaling yet through mechanisms independent of pVASP.S239 and that FL-VASP overexpression regulates PKG activity in rat ASM cells. These findings implicate BAY60 as a potential pharmacotherapeutic agent against aberrant ASM growth disorders such as CAD and also establish a unique mechanism through which VASP controls PKG activity.

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We describe a case of giant cavernous haemangioma of the liver with disseminated intravascular coagulopathy (Kasabach-Merritt syndrome) which was cured by orthotopic liver transplant.A 47 year old man presented with bleeding and tender massive hepatomegaly after tooth extraction.Investigations showed disseminated intravascular coagulopathy and a giant hepatic haemangioma involving both lobes of the liver. Initial treatment failed to resolve the coagulopathy and liver resection was attempted. At laparotomy the turnout was unresectable and the only option for cure was to offer a liver transplantation. The orthotopic liver transplant was performed 20 days after initial laparotomy. Subsequently, all coagulation parameters returned to normal and the patient remains well after 12 months. Orthotopic liver transplant can be considered for giant hepatic haemangioma with Kasabach-Merritt syndrome when resection is necessary and a partial hepatectomy is not technically feasible.

TCVC is more commonly used in long-term HPN. Our analysis of comparative studies showed a lower rate of CRBSI in HPN patients using PICC compared with TCVC; however, analysis of single-arm studies showed that the rate of CRBSI was comparable in PICC and TCVC use. The decision to which type of catheter is most suited for HPN patients should hence be based on the duration of treatment, level of care, patients' dexterity, as well patients' underlying comorbidities that may potentially contribute to other catheter-related complications.

In cardiovascular research, translation of benchtop findings to the whole body environment is often critical in order to gain a more thorough and comprehensive clinical evaluation of the data with direct extrapolation to the human condition. In particular, developmental and/or pathophysiologic vascular growth studies often employ in vitro approaches such as cultured cells or tissue explant models in order to analyze specific cellular, molecular, genetic and/or biochemical signaling factors under pristine controlled conditions. However, validation of in vitro data in a whole body setting complete with neural, endocrine and other systemic contributions provides essential proof-of-concept from a clinical perspective. Several well-characterized experimental in vivo models exist that provide excellent proof-of-concept tools with which to examine vascular growth and remodeling in the whole body. This article will examine the rat carotid artery balloon injury model, the mouse carotid artery wire denudation injury model, and rat and mouse carotid artery ligation models with particular emphasis on minimally invasive surgical access to the site of intervention. Discussion will include key scientific and technical details as well as caveats, limitations, and considerations for practical use for each of these valuable experimental models.

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