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After deep venous thrombosis (DVT), many patients have impaired quality of life (QOL). We aimed to assess whether pharmacomechanical catheter-directed thrombolysis (PCDT) improves short-term or long-term QOL in patients with proximal DVT and whether QOL is related to extent of DVT.The Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial was an assessor-blinded randomized trial that compared PCDT with no PCDT in patients with DVT of the femoral, common femoral, or iliac veins. QOL was assessed at baseline and 1 month, 6 months, 12 months, 18 months, and 24 months using the Venous Insufficiency Epidemiological and Economic Study on Quality of Life/Symptoms (VEINES-QOL/Sym) disease-specific QOL measure and the 36-Item Short Form Health Survey (SF-36) physical component summary (PCS) and mental component summary general QOL measures. Change in QOL scores from baseline to assessment time were compared in the PCDT and no PCDT treatment groups overall and in the iliofemoral DVT and femoral-popliteal DVT subgroups.Of 692 ATTRACT patients, 691 were analyzed (mean age, 53 years; 62% male; 57% iliofemoral DVT). VEINES-QOL change scores were greater (ie, better) in PCDT vs no PCDT from baseline to 1 month (difference, 5.7; P = .0006) and from baseline to 6 months (5.1; P = .0029) but not for other intervals. SF-36 PCS change scores were greater in PCDT vs no PCDT from baseline to 1 month (difference, 2.4; P = .01) but not for other intervals. Among iliofemoral DVT patients, VEINES-QOL change scores from baseline to all assessments were greater in the PCDT vs no PCDT group; this was statistically significant in the intention-to-treat analysis at 1 month (difference, 10.0; P .0001) and 6 months (8.8; P .0001) and in the per-protocol analysis at 18 months (difference, 5.8; P = .0086) and 24 months (difference, 6.6; P = .0067). SF-36 PCS change scores were greater in PCDT vs no PCDT from baseline to 1 month (difference, 3.2; P = .0010) but not for other intervals. In contrast, in femoral-popliteal DVT patients, change scores from baseline to all assessments were similar in the PCDT and no PCDT groups.Among patients with proximal DVT, PCDT leads to greater improvement in disease-specific QOL than no PCDT at 1 month and 6 months but not later. In patients with iliofemoral DVT, PCDT led to greater improvement in disease-specific QOL during 24 months.

Pharmacomechanical thrombolysis (PMT) and catheter-directed thrombolysis (CDT) are commonly used for the treatment of iliofemoral deep venous thrombosis (DVT). The purpose of this study was to examine the short- and long-term venous patency and venous valvular function as well as clinical outcomes of patients treated for iliofemoral DVT by PMT and CDT.A retrospective review of all patients with symptomatic DVT treated between 2006 and 2011 with PMT or CDT was performed. All patients were treated by local tissue plasminogen activator delivered with PMT or CDT. Patients were divided into two groups on the basis of initial treatment modality: patients treated by PMT alone (group 1), and those who underwent PMT and CDT or CDT alone (group 2). Group comorbidities, initial presenting symptoms, and Clinical, Etiologic, Anatomic, and Pathologic (CEAP) classification scores were compared. Postprocedural duplex ultrasound was used to assess valve function and treated vein patency rates. At all visits, Villalta and CEAP scores were recorded and compared. Group demographic and procedural results were analyzed by Fisher exact test for dichotomous variables and Kruskal-Wallis equality-of-populations rank test for the ordinal and continuous data. Kaplan-Meier survival estimates were used to assess preserved valve function as well as primary and secondary patency rates.There were 79 patients with 102 limbs treated for extensive iliofemoral DVT (median age, 51.5 years; range, 16.6-83.8 years). There were 18 patients in group 1 and 61 patients in group 2 (PMT + CDT [n = 54] or CDT alone [n = 7]). There were no differences in demographics or comorbidities between groups aside from malignant disease, which was more common in group 1 (35.3% vs 11.5%; P = .03). A total of 102 limbs were analyzed, 24 in group 1 and 78 in group 2. Patients in group 1 had a shorter symptom duration compared with group 2 (7 days vs 16 days; P = .011). The median number of procedures in group 1 was lower than in group 2 (P .001). At last clinical follow-up, there was no significant difference between the Villalta and CEAP scores or the rate of clinical improvement in symptoms between groups. By Kaplan-Meier analysis, there was no difference in primary patency, secondary patency, and treated valve function at 48 months.This study suggests that PMT as a stand-alone therapy is as effective as CDT with or without PMT in preserving valve function and preventing postthrombotic syndrome. Long-term physiologic and functional outcomes are comparable between the modalities, with preserved venous valve function in the majority of patients.

Objective Aortic sources of peripheral and visceral embolization remain challenging to treat. The safety of stent graft coverage continues to be debated. This study reports the outcomes of stent coverage of these complex lesions. Methods Hospital records were retrospectively reviewed for patients undergoing aortic stenting between 2006 and 2013 for visceral and peripheral embolic disease. Renal function, method of coverage, and mortality after stent grafting were reviewed. Results Twenty-five cases of embolizing aortic lesions treated with an endovascular approach were identified. The mean age was 65 ± 13 years (range, 45-87 years), and 64% were female. Sixteen (64%) patients presented with peripheral embolic events, six with concomitant renal embolization. Five patients presented with abdominal or flank pain, and two were discovered incidentally. Three patients had undergone an endovascular procedure for other indications within the preceding 6 months of presentation. Nineteen patients had existing chronic kidney disease (stage II or higher), but only three had stage IV disease. Of the eight patients tested, four had a diagnosed hypercoagulable state. Eight of the patients had lesions identified in multiple aortic segments, and aortic aneurysm disease was present in 24%. Coverage of both abdominal and thoracic sources occurred in eight patients, whereas 17 had only one segment covered. Minimal intraluminal catheter and wire manipulation was paired with the use of intravascular ultrasound in an effort to reduce embolization and contrast use. Intravascular ultrasound was used in the majority of cases and transesophageal echo in 28% of patients. Two patients with stage IV kidney disease became dialysis-dependent within 3 months of the procedure. No other patients had an increase in their postoperative or predischarge serum creatinine levels. No embolic events were precipitated during the procedure, nor were there any recurrent embolic events detected on follow-up. The 1-year mortality rate was 25%. Conclusions Endovascular coverage of atheroembolic sources in the aorta is feasible and is safe and effective in properly selected patients. It does not appear to worsen renal function when performed with the use of specific technical strategies.

Thoracic stent graft collapse is a rare complication of thoracic endovascular aortic repair that is mostly asymptomatic and occurs ≤ 3 months of the procedure. We describe the case of a 36-year-old man who presented with symptomatic endograft collapse 38 months after an initial thoracic endovascular aortic repair that was performed for traumatic aortic transection. He had sudden and complete loss of bilateral lower extremity motor and sensory functions (spinal cord ischemia) and anal sphincter tone. The patient was successfully treated with redo thoracic endovascular aortic repair, followed by open conversion and device explantation.

BackgroundGallstones appear more frequently in patients with cirrhosis and open cholecystectomy in this patient population is associated with higher morbidity and mortality. The aim of the present study was to evaluate experience with laparoscopic cholecystectomy in patients with cirrhosis and to provide recommendations for management.MethodsRetrospective review of laparoscopic cholecystectomy in patients with cirrhosis from March 1999 to May 2008 was performed. Peri-operative characteristics and subgroup analysis were performed in patients with Child–Pugh's classes A, B and C cirrhosis.ResultsA total of 68 patients were reviewed in this study. In all, 69% of the patients were Child's class A. The most common indication for cholecystectomy was chronic/symptomatic cholelithiasis (68%). Compared with patients with Child's class B and C, laparoscopic cholecystectomy in patients with Child's class A was associated with significantly decreased operative time (P= 0.01), blood loss (P= 0.001), conversion to open cholecystectomy (P= 0.001) and length of hospital stay (P= 0.001).ConclusionsLaparoscopic cholecystectomy in patients with cirrhosis is feasible with no mortality and low morbidity, especially in patients with Child's class A cirrhosis.

Introduction Current radiofrequency ablation (RFA) techniques require invasive needle placement and are limited by accuracy of targeting. The purpose of this study was to test a novel non invasive radiowave machine that uses RF energy to thermally destroy tissue. Gold nanoparticles were designed and produced to facilitate tissue heating by the radiowaves. Methods A solid state radiowave machine consisting of a power generator and transmitting/receiving couplers which transmit radiowaves at 13.56 MHz was used. Gold nanoparticles were produced by citrate reduction and exposed to the RF field either in solutions testing or after incubation with HepG2 cells. A rat hepatoma model using JM-1 cells and Fisher rats was employed using direct injection of nanoparticles into the tumor to focus the radiowaves for select heating. Temperatures were measured using a fiber-optic thermometer for real-time data. Results Solutions containing gold nanoparticles heated in a time- and power-dependent manner. HepG2 liver cancer cells cultured in the presence of gold nanoparticles achieved adequate heating to cause cell death upon exposure to the RF field with no cytotoxicity attributable to the gold nanoparticles themselves. In vivo rat exposures at 35 W using direct gold nanoparticle injections resulted in significant temperature increases and thermal injury at subcutaneous injection sites as compared to vehicle (water) injected controls. Discussion These data show that non invasive radiowave thermal ablation of cancer cells is feasible when facilitated by gold nanoparticles. Future studies will focus on tumor selective targeting of nanoparticles for in vivo tumor destruction.

Inferior vena cava (IVC) thrombosis may occur in patients with iliofemoral deep venous thrombosis (DVT), and its impact on thrombolysis outcomes is poorly defined. This study compared outcomes of patients undergoing thrombolysis for acute iliofemoral DVT with and without IVC involvement.Patients who underwent thrombolysis for iliofemoral DVT between May 2007 and March 2014 were identified from a prospectively maintained database and divided into two groups: those with IVC involvement and those without. End points were technical and clinical success (≥50% lysis or freedom from 30-day DVT recurrence), long-term DVT recurrence, and post-thrombotic syndrome (PTS; Villalta score ≥5). Multivariate regression models were used to determine predictors of anatomic and clinical failures.There were 102 patients (127 limbs) treated with various combinations of catheter-directed or pharmacomechanical thrombolysis. In 46 patients, thrombus extended into the IVC (54.3% extended up to the renal veins; 87% had ≥50% luminal reduction; 50% occurred in association with an indwelling thrombosed IVC filter). The caval group had fewer women and more previous DVTs but otherwise was similar to the noncaval group. Pharmacomechanical thrombolysis was used more frequently in the caval thrombus group (97.8% vs 82.1%; P = .011), and iliac vein stenting was used more often in the noncaval group (41.3% vs 62.5%; P = .033). Clinical success was similar between the two groups (88.7% for caval vs 89.3% for noncaval; P = .921). All failures in the caval group occurred in patients with an indwelling thrombosed IVC filter. Primary patency at 2 years for the caval and noncaval groups was 76.7% and 78.0%, respectively (P = .787). Valve reflux and PTS at 2 years were higher in the noncaval group (50.8% and 34.3% vs 23.3% and 11.5% in the caval group; P = .013 and P = .035). On multivariate analysis, incomplete lysis was predictive of recurrence (hazard ratio [HR], 22.7; P .001) and PTS (HR, 5.59; P = .010), whereas caval involvement (HR, 0.22; P = .005) was protective from PTS.IVC thrombosis does not have an impact on the technical success of thrombolysis in patients with iliofemoral DVT; the presence of a thrombosed IVC filter, though, may make failure more likely. Caval thrombosis may not affect primary patency but is associated with a lower incidence of PTS after successful lysis.

Ischemic tissues require mechanisms to alert the immune system of impending cell damage. The nuclear protein high-mobility group box 1 (HMGB1) can activate inflammatory pathways when released from ischemic cells. We elucidate the mechanism by which HMGB1, one of the key alarm molecules released during liver ischemia/reperfusion (I/R), is mobilized in response to hypoxia. HMGB1 release from cultured hepatocytes was found to be an active process regulated by reactive oxygen species (ROS). Optimal production of ROS and subsequent HMGB1 release by hypoxic hepatocytes required intact Toll-like receptor (TLR) 4 signaling. To elucidate the downstream signaling pathways involved in hypoxia-induced HMGB1 release from hepatocytes, we examined the role of calcium signaling in this process. HMGB1 release induced by oxidative stress was markedly reduced by inhibition of calcium/calmodulin-dependent kinases (CaMKs), a family of proteins involved in a wide range of calcium-linked signaling events. In addition, CaMK inhibition substantially decreased liver damage after I/R and resulted in accumulation of HMGB1 in the cytoplasm of hepatocytes. Collectively, these results demonstrate that hypoxia-induced HMGB1 release by hepatocytes is an active, regulated process that occurs through a mechanism promoted by TLR4-dependent ROS production and downstream CaMK-mediated signaling.

Background Although the accumulation of hydrophobic bile acid (e.g., glycine conjugated chenodeoxycholic acid, GCDC) is considered to be an important factor contributing to cholestatic liver dysfunction, its pathogenesis is poorly understood. The purpose of this study was to examine the effect of the bile salt GCDC on the regulation of iNOS expression, a key immune modulator during liver inflammation. Materials and methods GCDC significantly decreased cytokine-stimulated iNOS promoter activity, and both iNOS mRNA and protein expression. GCDC decreased iNOS promoter activity by preventing IκB degradation and inhibiting NF-κB DNA-binding activity. To explore the role of iNOS in bile salt induced apoptosis, we also examined the effect of NO on caspase-3 activity. Results GCDC strongly induced caspase-3 activity, and this increase was abrogated by both exogenous NO exposure and endogenous NO synthesis. Furthermore, adenoviral iNOS (AdiNOS) pre-treatment decreased acute cholestatic-induced liver injury in a rat bile duct ligation model. Conclusions These findings indicate a novel signaling pathway where potentially toxic bile salts down-regulate hepatic iNOS expression. This blockade of the iNOS mediated antiapoptotic phenotype may have important implications in certain liver disorders.

Objective With the increase in retrievable inferior vena cava (IVC) filter use, a higher than expected reported rate of pericaval tine penetration is observed. Symptomatic gastrointestinal (GI) complications associated with retrievable IVC filters have been documented; however, their management remains controversial. We describe a series of GI complications of retrievable IVC filters, detailing the spectrum of presenting symptoms and multiple treatment options, including the safety of endovascular retrieval. Methods A retrospective chart review was performed to describe the presentation, diagnosis, and treatment of patients with symptomatic GI complications associated with retrievable IVC filters from 2008 to 2014. Results Nine patients had symptomatic GI complications associated with a retrievable IVC filter (two G2 Recovery [Bard Peripheral Vascular, Tempe, Ariz], seven Celect [Cook Medical, Bloomington, Ind]; six women; age range, 17-81 years). All patients had small bowel perforation on computed tomography scan, four confirmed by esophagogastroduodenoscopy. Concomitant aortic and vertebral penetration occurred in seven and five patients, respectively. Patients presented with various abdominal complaints; one patient presented in acute sepsis. Two patients underwent laparotomy without complications. The remaining seven patients had attempted endovascular retrieval, six of which were successful. One patient's IVC filter was unable to be retrieved, and he was managed medically. Of the six patients who had successful endovascular retrieval, all had resolution of their symptoms with no complications, except for transient sepsis in a single patient who was not receiving periprocedural antibiotics. A follow-up computed tomography scan was performed 48 to 72 hours after endovascular retrieval and ruled out duodenal leak in all patients. Long-term follow-up demonstrated continued resolution of GI symptoms without further episodes of deep venous thrombosis or pulmonary embolism. Conclusions GI complications of retrievable IVC filters are manifested with a wide spectrum of symptoms and frequent concomitant aortic and vertebral penetration. Endovascular retrieval can be safely used as a first-line therapy even in the setting of small bowel and aortic penetration.

Lymphangiography and thoracic duct embolization are well-described techniques for the diagnosis and treatment of thoracic lymphatic leaks refractory to conservative treatment. However, thoracic duct embolization is not an option in patients with abdominal chylous leaks. The present report describes a 68-year-old man who underwent an aortomesenteric bypass complicated by a high-output postoperative chylothorax (>2,000 ml/day) and chylous ascites (>7,000 ml/paracentesis). Ultrasound-guided intranodal lymphangiography demonstrated a retroperitoneal lymphatic leak tracking along the vascular graft into the peritoneal cavity. Computed tomography-guided lymphatic duct occlusion with N-butyl cyanoacrylate glue was performed, resulting in successful treatment of both chylothorax and chylous ascites.

Purpose To describe a unique instance of cranial nerve injury related to uncomplicated carotid artery stenting (CAS). Case report A 74-year-old woman with a history of expressive aphasia and right upper/lower extremity weakness underwent staged CAS procedures under local anesthesia and conscious sedation. After routine predilation with a 4-mm balloon, a tapered 7 x 10 x 30-mm Acculink stent was placed and dilated with a 5-mm balloon. At 1 month after the second procedure, the carotid stents were patent bilaterally, but the patient reported voice fatigue and hoarseness along with dysphagia to liquids that started 2 days after her second procedure. Brain scans ruled out stroke. Direct laryngoscopy showed left vocal cord paralysis and a mobile right vocal cord; computed tomography revealed adduction of the left vocal cord consistent with a left recurrent laryngeal nerve injury. Radiography did not show any evidence of stent fracture. Electromyography was suggestive of right recurrent laryngeal nerve paralysis and only mild abnormalities on the left. A repeat laryngoscopy performed 4 months after the initial evaluation revealed persistent left vocal fold paralysis and no abnormalities on the right. The patient was referred for voice therapy; at 18 months, the stents were patent, and her vocal symptoms had significantly improved. Conclusion While minimally invasive endovascular techniques evolve for management of vascular disease, the anatomical structures at risk during open procedures may be injured with endovascular approaches as well.

Hepatic preconditioning has emerged as a promising strategy of activating natural pathways to augment tolerance to liver ischemia-reperfusion (IR) injury. Liver-resident natural killer T (NKT) cells play an important role in modulating the local immune and inflammatory responses. This work was aimed to investigate whether preactivation of NKT cells could provide a beneficial “preconditioning” effect to ameliorate the subsequent hepatic IR injury. To selectively activate NKT cells, C57BL/6 mice were treated intraperitoneally with the glycolipid antigen α-galactosylceramide (α-GalCer) 1 h prior to hepatic ischemia. Significantly reduced liver IR injury was observed in mice pretreated with α- GalCer, and this protective effect was specifically abrogated by a CD1d blocking antibody. Serum TNF-α, IFN-γ, and IL-13 levels were markedly increased shortly after α-GalCer injection. Pretreatment with a neutralizing antibody against TNF-α or IFN-γ did not influence the protective effect of α-GalCer preconditioning, whereas preadministration of an IL-13 neutralizing antibody completely abolished the effect. Treatment with α-GalCer also led to an increased expression of adenosine A2Areceptor (A2AR) in the liver, and blockade of A2AR by SH58261 diminished α-GalCer pretreatment-mediated attenuation of liver IR injury. In contrast, administration of the selective A2AR agonist CGS21680 reversed the counteracting effect of the IL-13 neutralizing antibody on α-GalCer preconditioning. Additionally, α-GalCer pretreatment was associated with a decreased neutrophil accumulation in the ischemic liver. These findings provide the first evidence that hepatic preconditioning by preactivation of NKT cells with α-GalCer protects the liver from IR injury via an IL-13 and adenosine A2AR-dependent mechanism.

Liver ischemia reperfusion (I/R) injury is associated with profound arginine depletion due to arginase release from injured hepatocytes. Nitric oxide (NO), shown to have protective effects in I/R, is produced by nitric oxide synthase (NOS) from the substrate arginine. The purpose of this study was to determine if nor-NOHA, a novel arginase inhibitor, would be able to increase circulating arginine levels and decrease hepatic damage following warm I/R.C57BL/6 mice underwent partial liver warm I/R and were treated intraperitoneally with either nor-NOHA (100mg/kg) or saline. Serum and tissue samples were collected to measure liver enzyme levels, amino acids, and inflammatory mediators. The agent nor-NOHA (100mg/kg) was administered 15 min before ischemia and immediately after reperfusion. Serum amino acid analysis was performed using HPLC.Arginase activity after hepatic I/R peaked at 3-6h after reperfusion and resulted in a 10-fold drop in circulating arginine levels. Treatment with nor-NOHA inhibited arginase activity and reversed the arginine depletion after I/R while simultaneously increasing serum nitric oxide. In addition, circulating citrulline, a product of NOS activity, was increased in nor-NOHA-treated animals compared to controls. Inhibition of arginase also resulted in protection from hepatic I/R-induced damage in association with markedly lower hepatic TNF, IL-6, and inducible NOS mRNA levels compared to controls.Arginase blockade represents a potentially novel strategy to combat liver injury under conditions of arginine deficiency. This protection may be mediated through the arginine-NO pathway.

Background. Thoracic surgeons are frequently called upon to provide exposure to the anterior cervicothoracic, thoracic, and proximal lumbar spine. We reviewed our surgical experience and the perioperative outcomes of these spinal approaches. Relevant technical and anatomic considerations of each procedure are highlighted. Methods. A total of 213 patients (116 female, 97 male) undergoing anterior thoracic spinal exposures over an 11-year period at a single institution were analyzed. Primary endpoints include morbidity, mortality, and perioperative outcomes. Results. Mean age was 53.7 years. Surgical approaches were determined based on the location and length of spinal involvement, and included cervicothoracic (5), thoracotomy (117), and thoracoabdominal (91) techniques. Malignant etiologies were associated with the highest perioperative mortality (6.7%, p 0.08). Procedures for infection were associated with a significantly higher complication rate (p 0.041) and length of stay (p 0.033). Correction of scoliosis required longer operative times (p < 0.001) and resulted in a trend toward higher blood loss (p 0.16). Thoracoabdominal approaches were associated with increased operative times (386 vs 316 minutes) and length of stay (8 vs 6 days) compared with thoracotomy. Conclusions. The increased use of anterior approaches to spinal pathology necessitates greater involvement by thoracic surgeons. Familiarity with the anatomic and technical features of the anterior spinal exposure is required by thoracic surgeons to optimize surgical outcomes.

Liver ischemia-reperfusion (I/R) injury is associated with profound arginine depletion due to arginase release from injured hepatocytes. The purpose of this study was to determine whether arginase inhibition with Nω-hydroxy-nor-l-arginine (nor-NOHA) would increase circulating arginine levels and decrease hepatic damage during liver I/R injury. The effects of nor-NOHA were initially tested in normal animals to determine in vivo toxicity. In the second series of experiments, orthotopic syngeneic liver transplantation (OLT) was performed after 18 h of cold ischemia time in Lewis rats. Animals were given nor-NOHA (100 mg/kg) or saline before and after graft reperfusion. In normal animals treated with nor-NOHA, there were no histopathological changes to organs, liver enzymes, serum creatinine, or body weight. In the OLT model, animals treated with saline exhibited markedly elevated serum transaminases and circulating arginase protein levels. Nor-NOHA administration blunted the increase in serum arginase activity by 80% and preserved serum arginine levels at 3 h after OLT. Nor-NOHA treatment reduced post-OLT serum liver enzyme release by 50%. Liver histology (degree of necrosis) in nor-NOHA-treated animals was markedly improved compared with the saline-treated group. Furthermore, use of the arginase inhibitor nor-NOHA did not influence polyamine synthesis owing to the decrease in ornithine levels. Arginase blockade represents a potentially novel strategy to combat hepatic I/R injury associated with liver transplantation.

High mobility group box 1 (HMGB1) is a NF released extracellularly as a late mediator of lethality in sepsis and as an early mediator of inflammation following injury. Here we demonstrate that in contrast to the proinflammatory role of HMGB1, preconditioning with HMGB1 results in protection following hepatic ischemia/reperfusion (I/R). Pretreatment of mice with HMGB1 significantly decreased liver damage after I/R. The protection observed in mice pretreated with HMGB1 was associated with a higher expression of IL-1R-associated kinase-M, a negative regulator of TLR4 signaling, compared with controls. We thus explored the possibility that HMGB1 preconditioning was mediated through TLR4 activation. HMGB1 preconditioning failed to provide protection in TLR4 mutant (C3H/HeJ) mice, but successfully reduced damage in TLR4 wild-type (C3H/HeOuj) mice. Our studies demonstrate that in contrast to the role of HMGB1 as an early mediator of inflammation and organ damage in hepatic I/R, HMGB1 preconditioning can be protective.

Hepatic ischemia occurs in the settings of trauma, transplantation, and elective liver resections. The initiating events that account for local organ damage are only partially understood. Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that regulates the expression of a number of genes involved in both innate and acquired immunity; however, its function in liver injury is unknown. Therefore, the purpose of this study was to investigate the role of IRF-1 in hepatic ischemia-reperfusion (I/R) injury. In C57BL/6 mice undergoing 60 min of hepatic ischemia, IRF-1 protein expression increased as early as 1 h after reperfusion. IRF-1 knockout mice were significantly protected from hepatic I/R-induced damage compared with their wild-type controls. Hepatic I/R injury resulted in marked activation of the MAP kinase c-Jun NH2-terminal kinase (JNK) in wild-type mice but not IRF-1 knockout mice. IRF-1 knockout mice also exhibited significantly lower hepatic expression of TNF-α, IL-6, ICAM-1, and inducible nitric oxide synthase (iNOS) mRNA. Adenoviral delivery of IRF-1 into C57BL/6 mice resulted in increased liver damage even without an ischemic insult. This injury was associated with increased JNK activation and hepatic iNOS expression. Because IRF-1 contributed to liver injury, we also examined for inflammatory signals that regulated IRF-1 gene expression in cultured hepatocytes. Whereas IFN-γ and IFN-β were strong inducers of IRF-1 mRNA (>10-fold) in a time- and dose-dependent manner, TNF-α and IL-1β also induced IRF-1 mRNA to a lesser extent (2- to 3-fold). IL-6 and lipopolysaccharide had no effect on IRF-1 expression. This study demonstrates that IRF-1 exerts a harmful role in hepatic I/R injury by modulating the expression of multiple inflammatory mediators. We further show that IRF-1-mediated injury involves the activation of JNK and that hepatocellular IRF-1 expression itself is regulated by specific cytokines.

Platelet-derived serotonin mediates liver regeneration. Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA. Platelet-derived serotonin mediates liver regeneration. The liver can regenerate its volume after major tissue loss. In a mouse model of liver regeneration, thrombocytopenia, or impaired platelet activity resulted in the failure to initiate cellular proliferation in the liver. Platelets are major carriers of serotonin in the blood. In thrombocytopenic mice, a serotonin agonist reconstituted liver proliferation. The expression of 5-HT2A and 2B subtype serotonin receptors in the liver increased after hepatectomy. Antagonists of 5-HT2A and 2B receptors inhibited liver regeneration. Liver regeneration was also blunted in mice lacking tryptophan hydroxylase 1, which is the rate-limiting enzyme for the synthesis of peripheral serotonin. This failure of regeneration was rescued by reloading serotonin-free platelets with a serotonin precursor molecule. These results suggest that platelet-derived serotonin is involved in the initiation of liver regeneration. [Abstract reproduced by permission of Science 2006;312:104–107].

ObjectiveThis study was conducted to review contemporary results of elective open infrarenal abdominal aortic aneurysm (IAAA) and pararenal abdominal aortic aneurysm (PAAA) repairs and determine predictors of death and acute and 1-year renal dysfunction (RD).MethodsA retrospective review identified 432 consecutive patients undergoing open IAAA (233 patients) or PAAA (184 patients) repair between January 2000 and December 2007. Demographic, preoperative, intraoperative, and postoperative variables were collected. RD was defined as an increase in creatinine of ≥0.5 mg/dL from baseline. Multiple logistic regression models were used to identify predictors of mortality and RD.ResultsMortality rates were similar between the groups (3.9% IAAA and 6.0% PAAA). Preoperative coronary artery disease (CAD), postoperative myocardial infarction, or pulmonary complications were all strong predictors of operative mortality in patients undergoing repair of PAAAs and IAAAs. However, neither PAAA nor baseline renal insufficiency was an independent predictor of death. Postoperative RD occurred in 32% of patients after PAAA repairs compared with 13% of patients after IAAA repairs (P < .001). The presence of PAAA, baseline hypertension, and hyperlipidemia all correlated positively with postoperative RD, while a trend was noted with baseline renal insufficiency (P = .09). At the 1-year follow-up, 5.1% of patients in the PAAA group had RD compared with none in the IAAA group. Similarly, the serum creatinine level was significantly higher in the PAAA group (1.4 mg/dL vs 1.2 mg/dL, PAAA and IAAA, respectively; P = .02) at 1 year. However, there were no instances of new-onset hemodialysis dependence at 1 year. Mean follow-up was 2.2 years overall.ConclusionOpen PAAA repair can be performed without a significant increase in mortality compared to open IAAA repair. Although the incidence of renal function deterioration after open PAAA repairs remains higher than with open IAAA repairs, the overall incidence remains low at 1-year follow-up.

Objective The presence of popliteal or tibial vein clot is thought to adversely affect thrombolysis for iliofemoral deep vein thrombosis (DVT). We examined the effect of inflow thrombosis on functional and anatomic outcomes. Methods Data for 44 patients treated for symptomatic iliofemoral DVT between 2006 and 2009 were retrospectively reviewed. All patients were treated by pharmacomechanical thrombectomy with local lytic therapy. Catheter-directed lysis and vena cava filters were used sparingly. Univariate and multivariate logistic regression analyses were used. The independent variable used in the logistic regression model was symptom relief. Results Forty-four patients (mean age, 52.1 ± 15.8 years) presented with symptoms averaging 13.4 ± 9.9 days in duration. Twenty (45.4%) had symptoms for >14 days. Seventeen patients were treated in one session, but 27 patients required lytic infusion for residual thrombus. Iliac stenting was required in 49% of limbs. Successful lysis (>50%) was achieved in 91% of patients, and symptom resolution or improvement in 91%. All patients became ambulatory, with no or minimal limitation. No major systemic bleeding complications occurred. Freedom from DVT recurrence and reintervention was 84% at 24 months by life-table analysis. Preoperative ultrasound imaging showed 89% had popliteal and tibial clots. A thrombosed popliteal vein was accessed for treatment and was corroborated by venographic findings. One patient required simultaneous tibial lysis. At a mean follow up of 8.7 ± 6.3 months, 41 patients (93%) had no symptom recurrence, 82% had preserved valve function and no reflux on duplex imaging, with a mean CEAP class of 1.4 and Villalta score of 3.3. Inflow thrombus had no adverse effect on symptom relief, treatment duration, patency, CEAP class, or valve reflux. Interestingly, 90% of patients with initial popliteal thrombus had a patent popliteal vein on postlysis ultrasound imaging, and the presence of tibial thrombus on presentation was predictive of symptom relief with thrombolysis (odds ratio, 13.03; 95% confidence interval, 1.02-165.58; P = .048). Conclusions Inflow thrombosis is common and does not preclude successful thrombolysis of iliofemoral DVT. Valve function is preserved on midterm follow-up, with maintained CEAP class and symptom relief.