Embolization of a cavernous carotid fistula through the vein of Labbé: a new alternative transvenous access route.

Endovascular treatment of carotid cavernous fistulas (CCFs) via a transvenous approach is standard, but in rare cases this approach is challenging due to absence or thrombosis of the commonly used venous routes. A 61-year-old woman presented with a symptomatic CCF with all but one of the venous access routes to the CCF thrombosed, leaving an engorged superficial middle cerebral vein (SMCV) as the only venous outflow from the cavernous sinus. Access to the CCF was made possible after careful navigation of the sigmoid sinus, the vein of Labbé and the SMCV, bypassing the need for surgical access to the SMCV or for a direct transorbital puncture. The CCF was completely occluded by coiling and Onyx embolization. The patient made an uneventful recovery, with resolution of her symptoms. To the best of our knowledge, this access route has not been previously reported in the treatment of CCFs.

Natural history, current concepts, classification, factors impacting endovascular therapy, and pathophysiology of cerebral and spinal dural arteriovenous fistulas.

Dural arteriovenous fistulas (DAVFs) may occur anywhere there is a dural or meningeal covering around the brain or spinal cord. Clinical manifestations are mostly related to venous hypertension, and may be protean, acute or chronic, ranging from minor to severe, from non-disabling tinnitus to focal neurological deficits, seizures, hydrocephalus, psychiatric disturbances, and developmental delay in pediatric patients. Although low-grade lesions may have a benign course and spontaneous involution may occasionally occur (i.e. cavernous sinus DAVFs), the risk of hemorrhage is considerable in high grade lesions. Angiographic features of DAVFs have been clarified since the 1970s when venous drainage pattern was clearly identified as the most significant risk predictor and as a major determinant of success or failure of treatment. The mainstay of therapy is interruption of arteriovenous shunting, which has traditionally been accomplished surgically. Currently, endovascular therapy is generally considered the first line of treatment, allowing elimination of the lesion in most patients, with surgery and stereotactic radiosurgery reserved for complex situations. This review discusses major aspects of DAVFs, including grading systems, clinical presentation, diagnostic evaluation, various issues impacting endovascular therapy, and pathophysiology.

Brain temperature changes during selective cooling with endovascular intracarotid cold saline infusion: simulation using human data fitted with an integrated mathematical model.

The feasibility of rapid cerebral hypothermia induction in humans with intracarotid cold saline infusion (ICSI) was investigated using a hybrid approach of jugular venous bulb temperature (JVBT) sampling and mathematical modeling of transient and steady state brain temperature distribution. This study utilized both forward mathematical modeling, in which brain temperatures were predicted based on input saline temperatures, and inverse modeling, where brain temperatures were inferred based on JVBT. Changes in ipsilateral anterior circulation territory temperature (IACT) were estimated in eight patients as a result of 10 min of a cold saline infusion of 33 ml/min. During ICSI, the measured JVBT dropped by 0.76±0.18°C while the modeled JVBT decreased by 0.86±0.18°C. The modeled IACT decreased by 2.1±0.23°C. In the inverse model, IACT decreased by 1.9±0.23°C. The results of this study suggest that mild cerebral hypothermia can be induced rapidly and safely with ICSI in the neuroangiographical setting. The JVBT corrected mathematical model can be used as a non-invasive estimate of transient and steady state cerebral temperature changes.

The gamma-subunit of ENaC is more important for channel surface expression than the beta-subunit.

The amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in fluid and electrolyte homeostasis and is composed of three homologous subunits: alpha, beta, and gamma. Only heteromultimeric channels made of alphabetagammaENaC are efficiently expressed at the cell surface, resulting in maximally amiloride-sensitive currents. To study the relative importance of various regions of the beta- and gamma-subunits for the expression of functional ENaC channels at the cell surface, we constructed hemagglutinin (HA)-tagged beta-gamma-chimeric subunits composed of beta- and gamma-subunit regions and coexpressed them with HA-tagged alphabeta- and alphagamma-subunits in Xenopus laevis oocytes. The whole cell amiloride-sensitive sodium current (DeltaI(ami)) and surface expression of channels were assessed in parallel using the two-electrode voltage-clamp technique and a chemiluminescence assay. Because coexpression of alphagammaENaC resulted in larger DeltaI(ami) and surface expression compared with coexpression of alphabetaENaC, we hypothesized that the gamma-subunit is more important for ENaC trafficking than the beta-subunit. Using chimeras, we demonstrated that channel activity is largely preserved when the highly conserved second cysteine rich domains (CRD2) of the beta- and gamma-subunits are exchanged. In contrast, exchanging the whole extracellular loops of the beta- and the gamma-subunits largely reduced ENaC currents and ENaC expression in the membrane. This indicates that there is limited interchangeability between molecular regions of the two subunits. Interestingly, our chimera studies demonstrated that the intracellular termini and the two transmembrane domains of gammaENaC are more important for the expression of functional channels at the cell surface than the corresponding regions of betaENaC.

cAMP-dependent activation of CFTR inhibits the epithelial sodium channel (ENaC) without affecting its surface expression.

The cystic fibrosis transmembrane conductance regulator (CFTR) is thought to modulate epithelial sodium channel (ENaC) function in various preparations. However, the molecular nature and (patho-)physiological significance of the CFTR/ENaC interaction is still unclear and may vary in different tissues. Co-expression experiments in Xenopus laevis oocytes are a popular approach to investigate a possible functional interaction of CFTR and ENaC but have revealed controversial results. We could confirm previous reports that in oocytes co-expressing ENaC and CFTR the amiloride-sensitive current was reduced during cAMP-mediated stimulation of CFTR. In contrast, co-expression of CFTR per se had no effect on baseline ENaC currents. ENaC with Liddle's syndrome mutation is also inhibited during activation of CFTR, suggesting that the C-terminus of the ENaC beta-subunit is not important for this functional interrelation. Single-channel patch-clamp recordings demonstrated that co-expression of CFTR does not alter the single-channel conductance of ENaC. Using a chemiluminescence assay we demonstrated that the inhibition of ENaC during cAMP-dependent activation of CFTR was not associated with a decrease in ENaC surface expression. We conclude that the inhibitory effect of cAMP-activated CFTR on ENaC is due to a decrease in channel open probability.

Regulation of the epithelial sodium channel by N4WBP5A, a novel Nedd4/Nedd4-2-interacting protein.

The amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in fluid and electrolyte homeostasis and consists of alpha, beta, and gamma subunits. The carboxyl terminus of each ENaC subunit contains a PPXY motif that is believed to be important for interaction with the WW domains of the ubiquitin-protein ligases, Nedd4 and Nedd4-2. Disruption of this interaction, as in Liddle's syndrome where mutations delete or alter the PPXY motif of either the beta or gamma subunits, has been shown to result in increased ENaC activity and arterial hypertension. Here we present evidence that N4WBP5A, a novel Nedd4/Nedd4-2-binding protein, is a potential regulator of ENaC. In Xenopus laevis oocytes N4WBP5A increases surface expression of ENaC by reducing the rate of ENaC retrieval. We further demonstrate that N4WBP5A prevents sodium feedback inhibition of ENaC possibly by interfering with the xNedd4-2-mediated regulation of ENaC. As N4WBP5A binds Nedd4/Nedd4-2 via PPXY motif/WW domain interactions and appears to be associated with specific intracellular vesicles, we propose that N4WBP5A functions by regulating Nedd4/Nedd4-2 availability and trafficking. Because N4WBP5A is highly expressed in native renal collecting duct and other tissues that express ENaC, it is a likely candidate to modulate ENaC function in vivo.

Cystic fibrosis transmembrane conductance regulator-dependent up-regulation of Kir1.1 (ROMK) renal K+ channels by the epithelial sodium channel.

The epithelial sodium channel (ENaC) and the secretory potassium channel (Kir1.1/ROMK) are expressed in the apical membrane of renal collecting duct principal cells where they provide the rate-limiting steps for Na(+) absorption and K(+) secretion. The cystic fibrosis transmembrane conductance regulator (CFTR) is thought to regulate the function of both ENaC and Kir1.1. We hypothesized that CFTR may provide a regulatory link between ENaC and Kir1.1. In Xenopus laevis oocytes co-expressing both ENaC and CFTR, the CFTR currents were 3-fold larger than those in oocytes expressing CFTR alone due to an increased expression of CFTR in the plasma membrane. ENaC was also able to increase Kir1.1 currents through an increase in surface expression, but only in the presence of CFTR. In the absence of CFTR, co-expression of ENaC was without effect on Kir1.1. ENaC-mediated CFTR-dependent up-regulation of Kir1.1 was reduced with a Liddle's syndrome mutant of ENaC. Furthermore, ENaC co-expressed with CFTR was without effect on the closely related K(+) channel, Kir4.1. We conclude that ENaC up-regulates Kir1.1 in a CFTR-dependent manner. CFTR may therefore provide the mechanistic link that mediates the coordinated up-regulation of Kir1.1 during the stimulation of ENaC by hormones such as aldosterone or antidiuretic hormone.