Lysine 117 on ataxin-3 modulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3.

Ataxin-3 (Atxn3) is a deubiquitinase with a polyglutamine (polyQ) repeat tract whose abnormal expansion causes the neurodegenerative disease, Spinocerebellar Ataxia Type 3 (SCA3; also known as Machado-Joseph Disease). The ubiquitin chain cleavage properties of Atxn3 are enhanced when the enzyme is itself ubiquitinated at lysine (K) at position 117: in vitro, K117-ubiqutinated Atxn3 cleaves poly-ubiquitin markedly more rapidly compared to its unmodified counterpart. How polyQ expansion causes SCA3 remains unclear. To gather insights into the biology of disease of SCA3, here we posited the question: is K117 important for toxicity caused by pathogenic Atxn3? To answer this question, we generated transgenic Drosophila lines that express full-length, human, pathogenic Atxn3 with 80 polyQ with an intact or mutated K117. We found that mutating K117 mildly enhances the toxicity and aggregation of pathogenic Atxn3. An additional transgenic line that expresses Atxn3 without any K residues confirms increased aggregation of pathogenic Atxn3 whose ubiquitination is perturbed. These findings suggest that Atxn3 ubiquitination is a regulatory step of SCA3, in part by modulating its aggregation.

Lysine 117 on ataxin-3 modulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3.

Ataxin-3 (Atxn3) is a deubiquitinase with a polyglutamine (polyQ) repeat tract whose abnormal expansion causes the neurodegenerative disease, Spinocerebellar Ataxia Type 3 (SCA3; also known as Machado-Joseph Disease). The ubiquitin chain cleavage properties of Atxn3 are enhanced when it is ubiquitinated at lysine (K) at position 117. K117-ubiqutinated Atxn3 cleaves poly-ubiquitin more rapidly in vitro compared to its unmodified counterpart and this residue is also important for Atxn3 roles in cell culture and in Drosophila melanogaster . How polyQ expansion causes SCA3 remains unclear. To gather insight into the biology of disease of SCA3, here we posited the question: is K117 important for toxicity caused by Atxn3? We generated transgenic Drosophila lines that express full-length, human, pathogenic Atxn3 with 80 polyQ with an intact or mutated K117. We found that K117 mutation mildly enhances the toxicity and aggregation of pathogenic Atxn3 in Drosophila . An additional transgenic line that expresses Atxn3 without any K residues confirms increased aggregation of pathogenic Atxn3 whose ubiquitination is perturbed. These findings suggest Atxn3 ubiquitination as a regulatory step of SCA3, in part by modulating its aggregation.

Accessing the common bile duct after Roux-en-Y gastric bypass.

We report on the clinical course of 2 patients who underwent laparoscopic Roux-en-Y gastric bypass for obesity and subsequently presented with biliary complications of choledocholithiasis in 1 case and sphincter of Oddi dysfunction in the other. The approach to these complex problems is described. Both patients underwent percutaneous transhepatic access to the common bile duct (CBD) for balloon sphincteroplasty. In 1 patient, percutaneous choledochoscopy was used for endoluminal visualization of the CBD. A literature review of the management of biliary problems after gastric bypass is presented. Although access to the CBD is limited, the options include percutaneous transhepatic instrumentation of the CBD, percutaneous or laparoscopic transgastric endoscopic retrograde cholangiopancreatography (ERCP), transenteric endoscopic cholangiopancreatography, ERCP using specialized endoscopes, and laparoscopic or open CBD exploration. Bile duct pathology after laparoscopic gastric bypass can be safely and effectively managed using a variety of techniques.

Percutaneous therapy to maintain dialysis access successfully prolongs functional duration after primary failure.

The role of endovascular therapy for thrombosed dialysis access has grown despite the paucity of data on its viability. The purpose of this study was to characterize the outcomes of a universal endovascular dialysis declot policy at a tertiary medical center. A database of patients undergoing endovascular treatment of thrombosed dialysis access between 1997 and 2003 was maintained. A two-puncture, combined percutaneous mechanical and pharmacologic thrombectomy technique was used. Data were collected on the success rate, complication rate, long-term patency, and presence and location of stenosis. Fistulograms were reviewed in all cases to assess lesion characteristics and pre- and postprocedure results. Results were standardized to current Society of International Radiology and Society for Vascular Surgery criteria. Failure was considered as either an anatomic defect requiring therapy or loss of functionality of the fistula. Life-table analyses were performed to assess time-dependent outcomes. Cox's proportional hazard analyses were performed to identify factors associated with outcomes. Values are the mean +/- standard error of the mean. There were 114 patients (50% male; average age 58 years, range 21-78) who presented with 174 thrombosed grafts. Therapy was performed for 237 thrombotic events (median 2, range 1-5 thrombotic events per hemodialysis access). After successful declot, anastomotic venous stenoses were encountered in 72% and central venous stenoses in 18% of cases; no cause was found in 10%. All stenoses were treated with balloon angioplasty. The technical failure rate was 4.6%. The 30-day all-cause mortality rate was 1.7%, and major morbidity rate was 2.4%. There were 413 interventions (236 percutaneous transluminal angioplasty and/or 183 declot) performed to maintain patency, which amounted to 2.3 interventions per patient. Average primary functional dialysis life span was 6.7 months up to the primary thrombotic event. Aggressive endoluminal therapy added a further average of 12 months of functionality (defined as continued dialysis access). A universal policy of endovascular therapy for occluded dialysis access results in reestablishment of function in the majority of patients and will triple functional longevity. Furthermore, while this approach remains procedure-intensive, it carries low morbidity and mortality and preserves future sites of access.

Catheter thrombolysis of thrombosed hepatic arteries in liver transplant recipients: predictors of success and role of thrombolysis.

Hepatic artery thrombosis is an uncommon complication of liver transplantation. However, it is a major indication for re-transplantation. The use of transcatheter thrombolysis and subsequent surgical revascularization as a graft salvage procedure is discussed. Four of 5 cases (80%) were successful in re-establishing flow and uncovering underlying arterial anatomic defects. None were treated definitively by endoluminal measures due to an inability to resolve the underlying anatomic defects. However, 2 of 5 cases (40%) went on to a successful surgical revascularization and represent successful long-term outcome of transcatheter thrombolysis followed by definitive surgical revascularization. We conclude that, definitive endoluminal success cannot be achieved without resolving associated, and possibly instigating, underlying arterial anatomical defects. However, reestablishing flow to the graft can unmask underlying lesions as well as asses surrounding vasculature thus providing anatomical information for a more elective, better planned and definitive surgical revision.

Incidence of arterial injuries detected by arteriography following percutaneous right-lobe ultrasound-guided core liver biopsies in human subjects.

PURPOSE: To determine the incidence and significance of arterial injuries detected by angiography subsequent to ultrasound-guided random core liver biopsies in normal healthy adults. MATERIALS AND METHODS: Retrospective analysis of 55 potential living related liver donors who underwent an ultrasound-guided random liver biopsy and a visceral angiogram was performed (January, 1999 to May, 2002). All liver biopsy samples (obtained by 2-3 18-gauge needle passes) were re-evaluated prospectively by a transplant pathologist for adequacy (defined: >or=5 complete portal triads). Subjects who underwent angiograms before the biopsy or >7 days after the biopsy were excluded from the arterial injury evaluation. Angiograms were reviewed by two angiographers. Arterial injuries were identified and classified by consensus into contusions, active bleeding, arterial-venous fistulae, and pseudoaneurysms. RESULTS: Mean needle pass was 2.1. No major complications were encountered. All samples were deemed pathologically adequate. Forty-eight potential donors were included for the arterial injury evaluation. Three arterial injuries (two arterioportal fistulae, 4.2%) were found in 48 angiograms (6.3%). None of the three injuries required intervention. CONCLUSION: The incidence of arterioportal fistulae following core liver biopsies has not changed over the past three decades despite improvement in biopsy needle technology, reduction of needle caliber, and the use of image guidance.

Inadvertent discontinuation of percutaneous nephrostomy catheters in adult native kidneys: incidence and percutaneous management.

PURPOSE: To evaluate the incidence and consequences of complete inadvertent percutaneous nephrostomy catheter discontinuation in native kidneys of adults. In addition, this study evaluated the success rate of nephrostomy tract recannulation. MATERIALS AND METHODS: Retrospective analysis was performed in adult patients who underwent percutaneous nephrostomy between January 2000 and December 2005. Patients' conditions were evaluated for complete inadvertent discontinuation of use of the nephrostomy catheters and success of subsequent recannulation procedures. Habitual discontinuation was defined by three catheter discontinuation episodes in one patient. Conditions of patients with inadvertent discontinuation were assessed for major complications before and after the recannulation, including the need for de novo nephrostomy to reestablish clinically needed access. The incidences of inadvertent discontinuation and primary assisted recannulation tract maintenance were calculated according to the Kaplan-Meier method. Successful versus unsuccessful recannulation procedures were compared for tract age, length of time the drain was out of the tract, and catheter diameter with use of the Mann-Whitney U test. RESULTS: A total of 283 patients underwent 325 percutaneous nephrostomies. The inadvertent catheter discontinuation rates at 6, 12, 24, and 36 months were 26%, 36%, 53%, and 62%, respectively. For the same time intervals, the primary recannulation assisted tract maintenance rates were 94%, 86%, 77%, and 72%, respectively. Habitual discontinuation was seen in 3.2% of the total population and 19.1% of discontinuation cases. The technical success rates of all and first-time recannulations were 85% and 74%, respectively. Tract maturity was the only variable that was statistically significant between successful and unsuccessful recannulations (P < .0001). A total of 3.5% of patients required new nephrostomies. CONCLUSION: Despite the high incidence of inadvertent discontinuation of nephrostomy catheters, the major complication rate was only 3.5%, indicating the efficacy of tract recannulation, especially in mature tracts.

Safety and efficacy of fluoroscopic versus ultrasound guidance for core liver biopsies in potential living related liver transplant donors: preliminary results.

PURPOSE: To describe and evaluate the safety and efficacy of fluoroscopically guided percutaneous liver biopsies in comparison with ultrasound (US)-guided percutaneous liver biopsies in potential living related liver donors. MATERIALS AND METHODS: Retrospective analysis of 133 consecutive preoperative workups of potential living related liver donors was performed. The subjects were treated from January 1999 through May 2002. Subjects were divided into those who underwent US-guided subcostal 18-gauge core liver biopsies (group I) and those who underwent fluoroscopically guided intercostal 18-gauge core liver biopsies (group II). Group II biopsies were performed in a manner similar to percutaneous transhepatic cholangiography. All samples obtained during the study period were reevaluated prospectively by a transplant pathologist blinded to guidance modality for sample adequacy (defined as >or=5 complete portal triads). Subjects were followed for 4 hours before discharge and afterward in the transplant clinic until donation. Subjects who did not donate organs were followed for at least 1 month. RESULTS: One hundred thirty-three potential donors were evaluated (55 for group I, 78 for group II). Mean follow-up was 1.7 months, and 77% of subjects donated. The mean numbers of needle passes were 2.1 and 2.3 for groups I and II, respectively. No major complications were encountered, and all subjects were discharged in 4 hours. Incidences of minor complications were 3.6% (vasovagal reactions) and zero for groups I and II, respectively. Sample adequacy rates were 100% and 99% for groups I and II, respectively. One case (1.8%) in group I, although pathologically adequate, had additional renal tissue. CONCLUSION: Fluoroscopically guided liver biopsy shows encouraging initial safety results and is as effective as US-guided liver biopsy in normal subjects.

Elective transjugular intrahepatic portosystemic shunt creation for portal decompression in the immediate pretransplantation period in adult living related liver transplant recipient candidates: preliminary results.

PURPOSE: To evaluate (i) the efficacy of purposeful creation of transjugular intrahepatic portosystemic shunts (TIPS) before transplantation to optimize potential living related liver transplantation (LRLTx) and (ii) the efficacy of TIPS creation in this setting in reducing perioperative resource utilization. MATERIALS AND METHODS: Retrospective review was performed of the records of patients who underwent adult LRLTx with or without preoperative TIPS creation from October 2003 through April 2005. Patients were evaluated for preoperative parameters (Child-Pugh class, Model for End-stage Liver Disease score, Acute Physiology and Chronic Health Evaluation [APACHE] II score, and coagulation parameters), intraoperative parameters (blood transfusion requirements and operative time), and postoperative parameters (intensive care unit stay, hospital stay, and 30-day repeat operation and mortality rates). Comparison between the two treatment groups was made with the Mann-Whitney U test. Within the TIPS group, comparison of blood transfusion requirements was performed by one-way analysis of variance based on the degree of portosystemic gradient reduction after TIPS creation. RESULTS: Sixteen patients were included in the TIPS group, and 12 patients were included in the group without TIPS. Median time between TIPS and transplantation was 2 days. There was no statistical difference in the preoperative, intraoperative, and postoperative parameters between groups except for the APACHE II score (P<.002), which was higher in the TIPS group. Despite this, the outcome and postoperative hospital resource utilization were similar between groups. Intraoperative blood transfusion based on the degree of portosystemic gradient reduction after TIPS creation was not significantly different between groups. CONCLUSIONS: Newly created TIPS do not interfere with the intraoperative technical and perioperative clinical aspects of adult LRLTx. Preoperative TIPS creation before transplantation may reduce the postoperative morbidity and mortality seen in liver transplant recipients who have a greater APACHE II score at the outset of treatment.

Transhepatic dilation of anastomotic biliary strictures in liver transplant recipients with use of a combined cutting and conventional balloon protocol: technical safety and efficacy.

PURPOSE: To determine the safety and technical efficacy of a transhepatic dilation protocol involving the use of a combined cutting and conventional balloon protocol in the management of anastomotic biliary strictures in adult liver transplant recipients. MATERIALS AND METHODS: Retrospective review of adult transplant recipients undergoing transhepatic cutting balloon dilation for anastomotic biliary strictures was performed over a period of 8 months. Cutting balloon dilation was followed by conventional balloon dilation with use of a balloon with a diameter at least as large as that of the initial cutting balloon. Technically successful dilation was defined by improvement of the biliary stricture. A technically successful regimen was defined by a residual stenosis less than 30% after a maximum of three sessions. The technical results were stratified according to lesions treated for the first time and those with restenosis. Comparison among institutions in terms of published methods and technical results were made. RESULTS: Twenty-two patients with liver transplants underwent 49 cutting balloon dilation sessions as part of 27 regimens (1.8 sessions per regimen): 12 cases of primary treatment, 10 cases of restenosis, four for intraprocedural failures of conventional balloon dilation, and one for the latter two indications. Technical success rates of regimens for primary stenoses, restenoses, and all cases were 100%, 90%, and 93%, respectively. These results compare favorably with historic intrainstitutional results, which are 89%, 73%, and 85% for primary stenoses, restenoses, and all cases, respectively. In addition, no biliary ruptures or cases of major hemobilia were encountered. Minor hemobilia was encountered in 10% of cases. CONCLUSIONS: The use of commercially available cutting balloons augmented subsequently with larger conventional balloons is safe for transhepatic balloon dilation and can increase the technical success rate of percutaneous management of transplant biliary strictures.

Endoluminal management of arterioportal fistulae in liver transplant recipients: a single-center experience.

Transcatheter embolization of arterioportal fistulae in liver transplant recipients is restricted to symptomatic arterioportal fistulae. Angiograms of liver transplant recipients from a single university medical center were retrospectively reviewed. Hemodynamically significant arterioportal fistulae were defined as those exhibiting opacification of the main portal vein of the transplanted hepatic graft or its first order branch with or without portal venous changes by Doppler ultrasound imaging. Six arterioportal fistulae were found. Doppler ultrasound imaging detected 50% of all arterioportal fistulae and all 3 hemodynamically significant arterioportal fistulae. Three successful embolizations were performed. Follow-up (37 to 67 months) demonstrated patent hepatic arteries and no parenchymal ischemic changes with graft preservation. High-throughput arterioportal fistulae may require larger intrahepatic artery branch embolization. There is a window of opportunity for embolizing significant arterioportal fistulae before their progression to large symptomatic, high through-put arterioportal fistulae with their added risk of ischemic changes before and after embolization.

Transhepatic balloon dilation of anastomotic biliary strictures in liver transplant recipients: the significance of a patent hepatic artery.

PURPOSE: To determine the significance of hepatic artery steno-occlusive disease on the patency of anastomotic biliary strictures in liver transplant recipients after transhepatic balloon dilation. MATERIALS AND METHODS: A retrospective review of records of all patients undergoing transhepatic balloon dilation for anastomotic biliary strictures after orthotopic liver transplantation was performed over an 8-year period. Patency of the anastomosis was based on subsequent cholangiography. The presence of hepatic artery steno-occlusive disease was determined by Doppler ultrasound and/or angiography. The anastomotic biliary stricture patency rates were calculated by the Kaplan-Meier method. RESULTS: Thirty-eight patients who had undergone liver transplants underwent 53 balloon dilations for anastomotic biliary strictures (nine patients for arterial disease, 26 patients had patent arteries and three patients had arteries of indeterminate patency). Eight of the 53 strictures treated (15%) were refractory to balloon dilation: 10.5% of first comers and 27% of restenotic lesions. Two of the 53 strictures treated (4%) had significant complications: hemobilia requiring blood transfusion and ductal rupture. One-year cumulative primary patency rates for anastomotic biliary strictures for patients with arterial disease, patent hepatic arteries, and all-comers were: 0%, 45% (P = .01), and 36%, respectively. One-year cumulative primary patency rates for choledocho-choledocal and choledocho-jejunal anstomoses in patients with patent arteries were 43% and 48%, respectively (P = .10). CONCLUSIONS: In the presence of hepatic artery disease there is a lower patency of anastomotic biliary strictures after balloon dilation. Imaging of the hepatic artery should be considered to stratify patients who will have a successful outcome.

Hepatic artery stenosis in liver transplant recipients: primary treatment with percutaneous transluminal angioplasty.

PURPOSE: To evaluate the efficacy of hepatic artery percutaneous transluminal angioplasty (PTA) in the treatment of hepatic artery stenosis (HAS). MATERIALS AND METHODS: A retrospective analysis was performed of all cases of HAS documented by angiography from January 1995 to June 2003 at the authors' institution. Management was evaluated and long-term patency was documented by Doppler ultrasonography. The patency, restenosis, and hepatic artery thrombosis (HAT) rates were determined by the Kaplan-Meier method. The technical success of hepatic artery PTA was stratified according to the location of the stenoses relative to the anastomosis, as well as by the presence of associated hepatic arterial kinks. RESULTS: Thrombosis was seen in 65% +/- 13% of untreated HAS cases within 6 months. Stenotic lesions without associated arterial kinks had an improved technical success rate and a reduced complication rate of 94% and 10%, respectively, compared with lesions with associated hepatic arterial kinks treated with hepatic artery PTA (14% and 29%, respectively). The 1-year primary and primary assisted patency rates of hepatic artery PTA for all lesions were 44% +/- 12% and 60% +/- 11%, respectively, and were 65% +/- 10% and 80% +/- 8%, respectively, for lesions not associated with hepatic arterial kinks. The 1-year HAT rate and restenosis rate after hepatic artery PTA were 19% +/- 10% and 32% +/- 11%, respectively. The 1-year primary assisted patency rate for hepatic artery PTA with repeat PTA performed for restenosed lesions and surgical revascularization performed for failed PTA was 74% +/- 10%. CONCLUSIONS: Untreated HAS carries a high morbidity rate. Hepatic artery PTA can play a large role in the management of HAS by reducing the HAT rate more than threefold. With appropriate lesion selection, hepatic artery PTA will have better patency rates than those associated with hepatic artery stent placement.

Transjugular intrahepatic portosystemic shunt in a living donor left lateral segment liver transplant recipient: technical considerations.

The technical aspects of placing transjugular intrahepatic portosystemic shunts (TIPS) in liver transplant recipients with full allografts have well been described. In the era of live related hepatic donors, and the growing population of their recipients, it is likely that TIPS shunts will be placed in failing transplant lobes/segments. Growing allografts that are initially undersized can have an unconventional orientation of the hepatic and portal veins, which may also change with remodeling and rotation of the graft during their growth. The authors review the technical differences for TIPS procedures in transplants, particularly split grafts. They describe a technically successful TIPS procedure in an undersized and remodeled left lateral segment liver recipient and the additional difficulty this may pose.