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Hepatic uptake of organic cations is essential for the metabolism and secretion of numerous endobiotics and drugs. Several hepatic organic cation transporters have been kinetically defined, yet have not been isolated or cloned. We have isolated a complementary DNA (cDNA) from both murine liver and kidney cDNA libraries (mOct1/Slc22a1), and have functionally expressed it in Xenopus laevis oocytes. Although mOct1/Slc22a1 is homologous to previously cloned rat and human organic cation transporters, organic cation transport kinetics differed markedly. mOct1/Slc22a1-RNA injection of oocytes resulted in the saturable, time- and temperature-dependent uptake of the quaternary organic cation [14C]-tetraethylammonium ([14C]-TEA), with a Km of 38 micromol/L. TEA uptake was inhibited by several other organic cation drugs, but was not inhibited by the organic cation n-methyl-nicotinamide (NMN), being instead stimulated by it (fourfold). [14C]-TEA uptake was also stimulated by an inside-outside proton gradient. mOct1/Slc22a1-injected oocytes transported the organic cations [3H]-1-methyl-4-phenylpyridium and [3H]-choline chloride, but did not transport other classes of organic compounds. mOct1/Slc22a1 encodes for a hepatic and renal organic cation transporter which may be important for the uptake and secretion of cationic drugs and endobiotics.

J Vasc Surg 1998; 28:955-63.

Popliteal artery aneurysms rarely rupture. We treated a 91-year-old man who presented with a deep venous thrombosis and anemia; rupture of a popliteal artery aneurysm was suspected only after compartment syndrome isolated to the thigh developed as the result of bleeding. Although fasciotomy was required on the basis of the clinical examination alone, the cause of the problem, operative strategy, and definitive treatment (i.e., resection and bypass) were clarified by the preoperative computed tomography scan. Ruptured popliteal aneurysm can manifest as a massively swollen leg with anemia and should be suspected if no other cause is evident. (J Vasc Surg 1998;27:783-7.)

We would like to thank D’Alessandris and colleagues for their interest in our study. We agree that following 2 negative phase III trials of upfront bevacizumab, both with significant crossover in the placebo arms, the optimal timing of bevacizumab administration is unclear. 1,2 Our study showed that the deferred use of bevacizumab to later recurrences was not associated with diminished efficacy. Additionally, we suggested that deferring bevacizumab to later recurrences may be beneficial for some, but not all patients. D’Alessandris and colleagues observed that the time between diagnosis and initiation of bevacizumab was progressively longer in each recurrence cohort, and the overall survival (OS) from bevacizumab administration was statistically similar, which would imply that delayed bevacizumab resulted in an increase in OS. While it is true that the OS from time of diagnosis was progressively longer in each of the recurrence cohorts (first, second, and 3+ recurrences), we intentionally avoided making the conclusion that deferred use of bevacizumab led to an improved OS. Since it is likely that patients receiving bevacizumab at later recurrences were subject to selection bias enriching for those with greater OS, we strongly believe that the limitations of a retrospective study prohibit this conclusion, and suggest that a randomized prospective study is needed to answer this question. In a similar study by Hamza and colleagues, deferring bevacizumab to later recurrences did not change progression-free survival and showed a longer OS from date of surgery, but again this must be interpreted with caution. 3 In both studies, the clinician’s judgment to defer bevacizumab to later recurrences presumably selected for less aggressive disease, such as tumors with less edema, mass effect, enhancement, or steroid requirement. Moreover, this highly selected group of patients who deferred bevacizumab to later progressions may be confounded by markers of improved survival such as isocitrate dehydrogenase 1 (IDH1) mutation and methylation of O 6 -DNA methylguanine-methyltransferase (MGMT). Our study did not find a difference in MGMT methylation among the cohorts, but the percentage of IDH1 mutations increased with each recurrence cohort, suggesting a selection bias. Hamza et al also point out that data for prognostic markers were not included in their study and that the question of deferring bevacizumab to later recurrences must be examined prospectively. From our study, we conclude that delaying bevacizumab in recurrent glioblastoma patients is not associated with diminishing effectiveness. Furthermore, we identified patients who were unable to continue therapy at early progressions, and suggest this population might benefit from early bevacizumab. More work is needed to identify both the optimal timing and patient subpopulations to maximize the benefits of bevacizumab therapy.

Purpose: An increased incidence of bleeding complications has been observed after supraceliac aortic clamping (SCC). This study was performed to identify possible hemostatic abnormalities that contribute to this problem.Methods: A prospective cohort study over a 3-month period was performed by comparing hemostatic parameters in 10 consecutive patients who required elective SCC with those of eight concurrent randomly selected control subjects who required infrarenal clamping (IRC) for abdominal aortic reconstruction. Measures of coagulation, fibrinolysis, platelet function, temperature, hemodilution, and hepatic function were performed at selected times before, during, and after operation.Results: Aneurysm size, fibrinogen, D-dimers, prothrombin, partial thromboplastin time, platelet counts, bleeding times, hemodilution, and temperature were comparable in both groups. Patients in the SCC group, however, consistently developed a primary fibrinolytic state within 20 minutes after supraceliac clamping, reflected by significantly decreased euglobulin clot lysis times (ECLT; p < 0.0001), elevated tissue plasminogen activator (t-PA) levels ( p < 0.0006), elevated t-PA–to–plasminogen activator inhibitor-1 ratios ( p < 0.0001), and reduced α2-antiplasmin levels ( p < 0.002). SCC produced hepatocellular injury documented by elevations in both aspartate transaminase ( p < 0.0001) and lactate dehydrogenase ( p < 0.009).Conclusions SCC rapidly induces a primary fibrinolytic state manifested by increased circulating t-PA, reduced α2-antiplasmin, and increased fibrinolytic activator–to–inhibitor ratios. These effects may be a result of hepatic hypoperfusion caused by SCC leading to insufficient clearance of t-PA. Antifibrinolytic agents may be of benefit if bleeding develops after aortic procedures that require supraceliac clamping. (J Vasc Surg 1997;25:244-54.)

Purpose: There are excellent arguments in favor of the preferential use of prosthetic grafts above the knee for the treatment of infrainguinal occlusive disease. This approach has been popularized on the basis of the seemingly acceptable results when using polytetrafluoroethylene (PTFE). However, in many centers, knitted Dacron polyester has been used in these patients, and there are several studies that show equivalent and, in some, superior results with Dacron when compared with PTFE. The purpose of this study was to examine these results in a definitive way. Methods: A randomized prospective trial in eight clinical academic centers in the United States and Canada was initiated in 1991. Two hundred forty-four patients eligible for such a study, by virtue of criteria extant in each institution at the time, were centrally randomized. They underwent placement of either a knitted Dacron polyester graft impregnated with collagen or a thin-wall expanded reenforced PTFE graft to the above-knee popliteal artery, usually from the common femoral artery. They were frequently observed by protocol for as long as 5 years by a physical examination noninvasive hemodynamic study, including duplex scanning in many instances. Continuing patency was noted, as were other potential adverse outcome events. The data were analyzed by the log-rank test for cumulative patency and expressed as Kaplan-Meier curves. Data were further analyzed with a Cox proportional hazards model. Results: There were no differences in graft groups in demographic or comorbid factors. The procedural mortality rate was zero, and the morbidity rate was low (6.5%). The long-term patient survival rate was excellent (77% at 3 years). At the end of these years, no statistical significance in primary or secondary patency rates was observed between the two grafts (primary patency rate, 62% ± 14.4% for Dacron; 57% ± 15.5% for PTFE). No unexpected adverse outcomes on limb status were noted. Patency rates in both graft groups were inferior in patients who received small grafts (5 to 6 mm vs 7 to 8 mm; hazards ratio, 4.15) and younger (

Current randomized prospective studies suggest that the degree of carotid stenosis is a critical element in deciding whether surgical or medical treatment is appropriate. Of potential interest is the actual pressure drop caused by the blockage, but no direct non-invasive means of quantifying the hemodynamic consequences of carotid artery stenoses currently exists. The present prospective study examined whether preoperative pulsed-Doppler duplex ultrasonographic velocity (v) measurements could be used to predict pressure gradients (delta P) caused by carotid artery stenoses, and whether such measurements could be used to predict angiographic percent diameter reduction. Preoperative Doppler velocity and intraoperative direct pressure measurements were obtained, and per cent diameter angiographic stenosis measured in 76 consecutive patients who underwent 77 elective carotid endarterectomies. Using the Bernoulli principle (delta P = 4v(2), pressure gradients across the stenoses were calculated. The predicted delta P, as well as absolute velocities and internal carotid artery/common carotid velocity ratios were compared with the actual delta P measured intraoperatively and with preoperative angiography and oculopneumoplethysmography (OPG) results. An end-diastolic velocity of > or = 1 m/s and an end-diastolic internal carotid artery/common carotid artery velocity ratio of > or = 10 predicted a 50% diameter angiographic stenosis with 100% specificity. Although statistical significance was reached, preoperative pressure gradients derived from the Bernoulli equation could not predict actual individual intraoperative pressure gradients with enough accuracy to allow decision making on an individual basis. Velocity measurements were as specific and more sensitive than OPG results. Delta P as predicted by the Bernoulli equation is not sufficiently accurate at the carotid bifurcation to be useful for clinical decision making on an individual basis. However, end-diastolic velocities alone as well as internal carotid artery/ common carotid artery velocity ratios are highly specific in the prediction of clinically significant carotid stenoses. An end-diastolic velocity of > or = 1 m/s accurately identifies a 50% or greater diameter stenosis, and thus may in some cases be sufficient for operation.

Purpose: Activated protein C (APC) is a naturally occurring anticoagulant that interacts with factors V and VIII to inhibit the clotting cascade. Resistance to APC (APC-R), hypothesized to occur as a result of an abnormal factor V, has been documented in up to 40% of patients with venous thrombotic events, but its prevalence in patients with arterial disease remains ill defined. Methods: With an assay of APC resistance that expresses the ratio of the activated partial thromboplastin time with and without the addition of exogenous APC, APC resistance ratios were quantitated in 200 individuals comprising 177 patients with vascular disease and 23 control subjects. An abnormal activated partial thromboplastin time was present in four patients who were excluded from analysis. The 173 remaining patients formed the study population and were divided into diagnostic subgroups on the basis of the most symptomatic problem. Results: APC resistance was documented in 20 individuals, representing 11.6% of the study group. The highest prevalence of APC resistance was observed in patients with lower extremity occlusive disease, with the APC-R ratio below 2.0 in 13.%. Within the subgroup of individuals with lower extremity disease, 76 patients (10 with APC-R, 13.2%) underwent infrainguinal bypass and were monitored a mean of 47±8 months. Occlusion of the arterial reconstruction occurred in 22 patients (29%). Six (60%) of the patients with APC-R had failed reconstructions, versus 16 (24%) of 66 patients without APC-R (p=0.02). Conclusions: These findings suggest that APC-R is relatively common in patients with peripheral vascular disease, especially in those with lower extremity occlusive disease. APC-R appears to be a risk factor for failure of infrainguinal bypass. These observations suggest that screening for APC-R may be useful in patients with peripheral vascular disease, providing the opportunity to restore the normal thrombogenic balance with anticoagulant therapy in susceptible individuals.

The treatment of subclavian venous thrombosis due to thoracic outlet compression has been significantly altered over the past few decades due to the advent of percutaneous therapies. Most believe that the combination of venous thrombolysis followed by thoracic outlet decompression is safe and effective, and best for most patients. The only cases that thrombolysis is not used are those with subacute or chronic occlusions, those patients with limited symptoms and functional needs, and those with significant medical contraindications.

Purpose: A variety of preoperative provocative tests have been used to define the risk of cardiac morbidity and mortality after peripheral vascular procedures, including dipyridamole myocardial scintigraphy and dobutamine stress echocardiography. Although highly sensitive, these tests are time-consuming and associated with significant expense. We investigated outpatient echocardiography as a less resource-intensive means of assessing cardiac risk with operation. Methods: Over a 2-year period 250 consecutive patients underwent outpatient transthoracic echocardiography before elective peripheral vascular operation was performed. The accuracy of the Goldman, Detsky, and the American Society of Anesthesiologists' Physical Status Classification clinical indexes of cardiac risk were assessed with regard to the development of cardiac complications such as unstable angina, myocardial infarction, life-threatening ventricular arrhythmias, severe congestive heart failure, and cardiogenic shock. The accuracy of echocardiographically determined left ventricular ejection fraction was determined at threshold values between 20% and 60%. Results: Perioperative cardiac events developed in 23 (9.2%) of the patients, and nine (3.6%) of the patients died as a result of these complications. Clinical indexes lacked sensitivity in the preoperative prediction of cardiac complications. Receiver operating curve analysis defined a left ventricular ejection fraction of less than 50% as an appropriate threshold for defining patients at high risk, with a sensitivity of 78% and a specificity of 81% in the identification of patients who had cardiac morbidity. The positive predictive value was 27%, and the negative predictive value was 97%. The economic impact of outpatient echocardiography was well below that of dipyridamole myocardial scintigraphy or dobutamine stress echocardiography. Conclusions: Outpatient echocardiography appears to offer a cost-efficient compromise between clinical criteria alone and provocative cardiac testing such as dipyridamole myocardial scintigraphy and dobutamine stress echocardiography in the preoperative screening of patients undergoing peripheral vascular surgical procedures. (J VASC SURG 1995;22:671-9.)

The importance of von Willebrand factor (vWf) in the formation of platelet-fibrin thrombi on expanded polytetrafluoroethylene (ePTFE) surfaces was studied in an in vitro system, perfusing non-anticoagulated human blood over ePTFE grafts for 3 min at varying shear rates (100, 500 and 1500/s shear). Platelet (111In) and fibrin (125I) deposition was assessed on ePTFE surfaces in the presence and relative absence of vWf, achieved by use of polyclonal anti-vWf antibody (anti-vWf Ab). A total of 29 perfusions were performed. Increasing shear rate was associated with greater platelet deposition in the presence of vWf (p < 0.001). This shear-dependent rise in platelet deposition was not observed when vWf was blocked by anti-vWf Ab (P < 0.1), confirming the role of vWf in platelet deposition at high shear rates. Fibrin deposition increased with increasing shear rate in the presence of vWf (P < 0.01). Inhibiting vWf abolished the shear-dependent increase in fibrin deposition. These data suggest that vWf plays a critical role in platelet and fibrin thrombus formation on ePTFE surfaces. These effects are particularly important under conditions of high shear rate. These mechanisms may lead to the observed pathologic thrombus formation and platelet-dependent neointimal processes occurring at areas of high shear rate within the anastomotic regions of ePTFE grafts.

The advent of graft thrombolysis has provided an objective means for evaluating the etiology of graft occlusion. Over a 10-year period, intra-arterial urokinase (102 cases) or streptokinase (seven cases) was used in 109 infrainguinal conduits (30 autogenous and 79 non-autogenous) that failed 30 days or more after implantation. Thrombolysis was not achieved in 19 additional graft occlusions; these cases were excluded from study because of an inability to define the mechanism of failure. Non-invasive laboratory data were available within 6 months of graft occlusion in 82 (75%) of the cases, with Doppler segmental studies in 80 cases (73%) and duplex ultrasonography studies in 39 cases (36%). Pre-failure non-invasive laboratory abnormalities were detected more frequently in autogenous grafts (21 of 24 patients, 88%), while non-autogenous grafts usually occluded without prior hemodynamic change (11 of 58 patients had abnormalities, 19%) (P < 0.001). Thrombolysis uncovered anatomic defects responsible for thrombosis in 27 (90%) of 30 autogenous grafts compared with only 32 (41%) of non-autogenous conduits (P < 0.001). The most common lesions underlying autogenous graft failure comprised stenoses within the body of the graft (11 cases, 37%), while the most common lesions in failed non-autogenous grafts appeared to be stenoses at an anastomosis (21 cases, 27%). Thus, the mechanisms underlying the late failure of autogenous and non-autogenous grafts differ markedly; autogenous grafts most commonly fail as a result of the gradual development of lesions intrinsic to the graft, while non-autogenous grafts fail precipitously, presumably as a result of some non-anatomic mechanism.

Tumor necrosis factor-alpha (TNF alpha), a cytokine that is produced in a variety of inflammatory diseases associated with cholestasis, is believed to be the primary mediator of the systemic effects of endotoxin. Thus, we have investigated the role of TNF alpha in the pathogenesis of endotoxin-induced cholestasis in intact animals, and in the uptake of taurocholate by cultured hepatocytes. Male Sprague-Dawley rats received either intravenous (IV) endotoxin (7.5 mg/kg) or monoclonal anti-TNF alpha antibody followed by endotoxin. Basal bile flow and bile salt excretion were measured for a 2-hour period, after which all animals received an IV bolus of taurocholate (10 mumol/100 g body weight). Endotoxin decreased basal bile flow by 41% and bile salt stimulated bile flow by 38% (n = 12; P < .01). Basal bile salt excretion was decreased 86% after endotoxin administration. Passive immunization with anti-TNF alpha antibody blocked this endotoxin-associated cholestasis. In addition, rat hepatocytes were isolated and cultured in the presence of either endotoxin (10 micrograms/mL) or TNF alpha (100 ng/mL) for 24 hours. These primary hepatocyte cultures exhibited a dose- and time-dependent, noncompetitive, inhibition of taurocholate uptake. We postulate that TNF alpha is an important mediator of the cholestasis of sepsis.

Background : The value of carotid duplex analysis is well proven for the diagnosis of carotid bifurcation occlusive disease, but its use in the postoperative setting is less well defined. Patients and methods : A series of 281 carotid endarterectomies were performed in 222 patients. A protocol of serial duplex examinations was established, with tests performed at the time of the first postoperative clinic visit and every 6 months thereafter. The goal of postoperative surveillance was to identify critical restenotic carotid lesions of greater than 80% diameter reduction and determine the incidence of subsequent carotid occlusion and neurologic events. Results : Critical restenoses developed in 25 (8.9%) of the arteries and occlusions occurred in 12 (4%). Restenosis occurred with greatest frequency during the first year after operation (5%), but continued to develop with a frequency of approximately 2% per year thereafter. Postoperative carotid occlusions occurred at a rate of approximately 1% per year. Known restenotic lesions progressed to occlusion over a mean duration of 11 months. Stroke was infrequent in patients with critical restenoses (4%) until the lesions progressed to occlusion (33%). Conclusions : These observations suggest that a protocol of semiannual duplex testing into the late postoperative period may identify critical carotid restenotic lesions prior to the development of carotid occlusion and stroke.

Purpose: We sought to determine whether low-dose radiation can inhibit neointimal hyperplasia immediately after balloon injury to the common carotid artery and to assess the extent of endothelial regeneration after treatment.Methods: Sprague-Dawley rats were subjected to balloon injury to the common carotid artery. Immediately after injury rats were treated with a single dose of iridium 192 radiation at 5 gy, 10 gy, and 15 gy or received no radiation (control). Three weeks after injury and treatment, vessels were harvested and compartment areas were measured on fixed specimens. Scanning and transmission electron microscopy, along with Evans blue dye uptake into injured vessels, was used to assess the effect radiation had on endothelial regeneration.Results: Rats receiving radiation at all three doses demonstrated no intimal thickening when compared with rats that were not treated (at 5 Gy 0.01 ± 0.01 mm2; at 10 Gy 0.02 ± 0.01 mm2; at 15 Gy 0.05 ± 0.02 mm2; with balloon injury/no radiation 0.12 ± 0.02 mm2; p < 0.01). In addition, the groups that were irradiated had no medial thickening when compared with control rats (at 5 Gy 0.22 ± 0.02 mm2; at 10 Gy 0.21 ± 0.02 mm2; at 15 Gy 0.22 ± 0.07 mm2; with balloon injury/no radiation 0.37 ± 0.03 mm2; p < 0.01). Endothelial regeneration, evaluated by transmission and scanning electron micrographs along with uptake of Evans blue dye, was significantly greater in animals that received radiation compared with controls.Conclusions: Low-dose radiation prevents the occurrence of neointimal hyperplasia after balloon injury and may have a future role in vascular grafting. (J Vasc Surg 1995;22:17-24.)

Author(s): Nguyen, HuyTram N; Lie, Amy; Li, Tie; Chowdhury, Reshmi; Liu, Fei; Ozer, Byram; Wei, Bowen; Green, Richard M; Ellingson, Benjamin M; Wang, He-Jing; Elashoff, Robert; Liau, Linda M; Yong, William H; Nghiemphu, Phioanh L; Cloughesy, Timothy; Lai, Albert | Abstract: BackgroundPromoter mutation in the human telomerase reverse transcriptase gene (hTERT) occurs in ~75% of primary glioblastoma (GBM). Although the mutation appears to upregulate telomerase expression and contributes to the maintenance of telomere length, its clinical significance remains unclear.MethodsWe performed hTERT promoter genotyping on 303 isocitrate dehydrogenase 1 wild-type GBM tumors treated with standard chemoradiotherapy. We also stratified 190 GBM patients from the database of The Cancer Genome Atlas (TCGA) by hTERT gene expression. We analyzed overall and progression-free survival by Kaplan-Meier and Cox regression.ResultsWe detected hTERT promoter mutation in 75% of the patients. When included as the only biomarker, hTERT mutation was not prognostic in our patient cohort by Cox regression analysis. However, when hTERT and O6-DNA methylguanine-methyltransferase (MGMT) were included together, we observed an interaction between these 2 factors. To further investigate this interaction, we performed pairwise comparison of the 4 patient subcohorts grouped by hTERT-MGMT status (MUT-M, WT-M, MUT-U, and WT-U). MGMT methylated patients showed improved survival only in the presence of hTERT promoter mutation: MUT-M versus MUT-U (overall survival of 28.3 vs 15.9 mos, log-rank P l .0001 and progression-free survival of 15.4 vs 7.86 mo, log-rank P l .0001). These results were confirmed by Cox analyses. Analogously, the cohort from TCGA demonstrated survival benefit of MGMT promoter methylation only in patients with high hTERT expression. In addition, hTERT mutation was negatively prognostic in our MGMT unmethylated patients, while the analogous association with high expression was not observed in the cohort from TCGA.ConclusionThe prognostic influence of MGMT promoter methylation depends on hTERT promoter mutation. This interaction warrants further mechanistic investigation.

Varicose veins are a common ailment affecting more than 20 million Americans. These veins and the associated venous hypertension are associated with leg swelling, pain, dermatitis, phlebitis, and ulceration. The underlying principle of treatment of any varicosity is the removal or obliteration of pathologically functioning veins and the preservation of those with normal function. Diagnosis is obvious, but deciding whether the varicose veins are responsible for the patient's symptoms is more difficult. Often a trial of graduated compression stockings is worth-while. Treatment consists of compression, sclerotherapy, and/or operation depending on the etiology and severity of the condition.

The safety, efficacy and utility of inserting a vascular prosthesis through the femoral artery and attaching it to a native artery with stents to treat abdominal aortic aneurysms are under various stages of testing around the world. The potential of these endovascular techniques to reduce the morbidity and cost of care is enormous. Many advances in imaging, catheter techniques, delivery systems and the knowledge about aneurysm morphology are reponsible for the progress to date. The requirements of an endoprosthesis include a small and flexible delivery system that allows retrograde insertion through the iliofemoral arterial system, secure attachments to normal arterial wall, and a fabric which meets Food and Drugs Administration criteria for strength and durability. Application of this technique to large numbers of patients with aneurysms will probably require the development of a bifurcated prosthesis. The long-term behavior of the aneurysm wall after endoprosthesis insertion will not be known until clinical trials are completed. The development of these techniques will undoubtedly fuel the ‘turf battle’ between vascular surgeons and interventionalists. Although each group will lay claim to the technology, a cooperative effort to maximize patient benefit seems to be the most appropriate way to insure that the interests of the patients are best served.

The presence of horseshoe kidney in conjunction with abdominal aortic disease Significantly increases the technical difficulty of aortic reconstruction. Preservation of the renal blood supply and collecting system during the surgical procedure is the goal of operative management. The pertinent issues that remain unresolved include the need for specific preoperative studies, the optimal operative approach and the safety of isthmus division. From 1979 to 1994 eight patients with horseshoe kidney underwent operative intervention for aortic disease. Five men and three women who had a mean age of 66 years underwent seven reconstructions for aneurysmal disease and one for aortoiliac occlusive disease. All operations were elective and the transperitoneal approach was used in all cases, in the patients with aneurysmal disease the mean maximal aortic diameter was 7.3 cm. The mean preoperative serum creatinine value was 1.1 mg/dl. Preoperative identification of horseshoe kidney was accomplished in all seven patients with aneurysmal disease but not in the patient with occlusive disease. The anomaly was correctly identified by CT scan in seven of seven (100%) patients, arteriography in two of eight (25%) patients, ultrasonography in two of seven (29%) patients, and renal scan in one patient, in the three patients who underwent intravenous pyelography (IVP) the caliceal system was demonstrated to be completely separate from the isthmus. Renal artery anomalies were present in six (75%) patients; in three (50%) these anomalies could be not visualized on the preoperative arteriogram. Renal revascularization was accomplished by a variety of techniques, including reimplantation of multiple (one patient) and single (four patients) renal arteries and branch grafting to an individual renal artery (one patient). Isthmus division was required in three patients. Seven patients had no postoperative elevation in the serum creatinine level including the three patients in whom the isthmus was divided. One patient had postoperative renal failure requiring permanent hemodialysis; this patient had massive intraoperative blood loss due to technical difficulties unrelated to the horseshoe kidney. There were no perioperative deaths. Preoperative identification of horseshoe kidney is best accomplished by CT scanning. Arteriography and IVP should be performed routinely to evaluate the arterial and caliceal anatomy. Arteriography frequently fails to identify anomalous circulation; the transperitoneal approach affords the best opportunity to identify these anomalies intraoperatively. Preoperative IVP allows identification of the renal collecting system, facilitating safe division of the isthmus if necessary.

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of nonalcoholic steatohepatitis. The ER stress response is activated in the livers of mice fed a methionine- and choline-deficient (MCD) diet, yet the role of ER stress in the pathogenesis of MCD diet-induced steatohepatitis is unknown. Using chemical chaperones on hepatic steatosis and markers of inflammation and fibrosis in mice fed a MCD diet, we aim to determine the effects of reducing ER stress. C57BL/6J mice were fed a MCD diet with or without the ER chemical chaperones 4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) for 2 wk. TUDCA and PBA effectively attenuated the ER stress response in MCD diet-fed mice, as evidenced by reduced protein levels of phosphorylated eukaryotic initiation factor 2α and phosphorylated JNK and suppression of mRNA levels of CCAAT/enhancer binding protein homologous protein, glucose-regulated protein 78 kDa, and X-box binding protein 1. However, PBA and TUDCA did not decrease MCD diet-induced hepatic steatosis. MCD diet-induced hepatic inflammation, as evidenced by increased plasma alanine aminotransferase and induction of hepatic TNFα expression, was also not reduced by PBA or TUDCA. PBA and TUDCA did not attenuate MCD diet-induced upregulation of the fibrosis-associated genes tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9. ER chemical chaperones reduce MCD diet-induced ER stress, yet they do not improve MCD diet-induced hepatic steatosis, inflammation, or activation of genes associated with fibrosis. These data suggest that although the ER stress response is activated by the MCD diet, it does not have a primary role in the pathogenesis of MCD diet-induced steatohepatitis.

Carotid blowout syndrome is a rare life-threatening complication of head and neck malignancy. Current literature has focused exclusively on the carotid system and associated branches. We present a unique case of multivessel blowout in the setting of a large nonresectable neck sarcoma requiring various endovascular techniques for palliation.

The structure of infrarenal aortic aneurysm was studied as a basis for design of a transfemoral system of aneurysm repair. This information was particularly important because endovascular techniques, unlike conventional techniques, afford little opportunity for intraoperative adjustments.Three-dimensional computer reconstructions of the distal aorta, the renal arteries, the aneurysm and the iliac arteries were generated from computed tomography scanning data in 22 patients with aortic aneurysms.The proximal neck of the aneurysm was longer than 20 mm in 14 patients, and the mean length (of all 22) was 26.7 +/- 4.1 mm. In contrast, only one patient had a distal cuff longer than 20 mm and 14 of the others had no measurable distal cuff. The mean distal cuff length (of all 22) was 4.2 +/- 1.6 mm. There was no significant difference between mean aneurysm diameter in the anteroposterior direction (58.0 +/- 3.2 mm) and the transverse direction (56.4 +/- 3.3 mm), although corresponding values in individual patients were often different. Aneurysm diameter correlated with aneurysm length (r = 0.79, p0.001). The proximal right common iliac artery deviated from the axis of the distal aorta by 40.0 +/- 5.8 degrees, whereas the left deviated by 47.8 +/- 5.4 degrees. One of the iliac arteries deviated by more than 45 degrees in 12 cases. Eleven common iliac arteries in seven patients were aneurysmal. Fifteen patients had no aneurysm of the common iliac arteries, and another three had segments of nondilated common iliac artery distal to iliac aneurysms on both sides.Computerized three-dimensional reconstruction facilitated interpretation of anatomic information from computed tomography scans, particularly the length of the aneurysm neck and shape of the iliac arteries. On the basis of this information, we expect that few patients will have too short an aneurysm neck for endovascular aneurysm repair, but many will require a bifurcated graft for secure, hemostatic implantation distally.

Purpose: Despite the widespread use of intraarterial thrombolytic therapy for peripheral arterial occlusive disease, a randomized study comparing its efficacy with that of operative intervention has never been performed. This study evaluates the potential of intraarterial urokinase infusion to provide clinical benefits in patients with acute peripheral arterial occlusion. Methods: Patients with limb-threatening ischemia of less than 7 days' duration were randomly assigned to intraarterial catheter-directed urokinase therapy or operative intervention. Anatomic lesions unmasked by thrombolysis were treated with balloon dilation or operation. The primary end points of the study were limb salvage and survival. Results: A total of 57 patients were randomized to the thrombolytic therapy group, and 57 patients were randomized to the operative therapy group. Thrombolytic therapy resulted in dissolution of the occluding thrombus in 40 (70%) patients. Although the cumulative limb salvage rate was similar in the two treatment groups (82% at 12 months), the cumulative survival rate was significantly improved in patients randomized to the thrombolysis group (84% vs 58% at 12 months, p = 0.01). The mortality differences seemed to be primarily attributable to an increased frequency of in-hospital cardiopulmonary complications in the operative treatment group (49% vs 16%, p = 0.001). The benefits of thrombolysis were achieved without significant differences in the duration of hospitalization (median 11 days) and with only modest increases in hospital cost in the thrombolytic treatment arm (median $15,672 vs $12,253, p = 0.02). Conclusions: Intraarterial thrombolytic therapy was associated with a reduction in the incidence of in-hospital cardiopulmonary complications and a corresponding increase in patient survival rates. These benefits were achieved without an appreciable increase in the duration of hospitalization and with only modest increases in hospital cost, suggesting that thrombolytic therapy may offer a safe and effective alternative to operation in the initial treatment of patients diagnosed with acute limb-threatening peripheral arterial occlusion. (J VASC SURG 1994;19:1021–30.)

Treatment for newly diagnosed anaplastic oligodendroglial tumors is controversial. Radiotherapy (RT) alone and in combination with chemotherapy (CT) are the most well studied strategies. However, CT alone is often advocated, especially in cases with 1p19q codeletion. We retrospectively identified 1013 adults diagnosed from 1981-2007 treated initially with RT alone (n = 200), CT + RT (n = 528), CT alone (n = 201), or other strategies (n = 84). Median overall survival (OS) was 6.3 years and time to progression (TTP) was 3.1 years. 1p19q codeletion correlated with longer OS and TTP than no 1p or 19q deletion. In codeleted cases, median TTP was longer following CT + RT (7.2 y) than following CT (3.9 y, P = .003) or RT (2.5 y, P < .001) alone but without improved OS; median TTP was longer following treatment with PCV alone than temozolomide alone (7.6 vs. 3.3 y, P = .019). In cases with no deletion, median TTP was longer following CT + RT (3.1 y) than CT (0.9 y, P = .0124) or RT (1.1 y, P < .0001) alone; OS also favored CT + RT (median 5.0 y) over CT (2.2 y, P = .02) or RT (1.9 y, P < .0001) alone. In codeleted cases, CT alone did not appear to shorten OS in comparison with CT + RT, and PCV appeared to offer longer disease control than temozolomide but without a clear survival advantage. Combined CT + RT led to longer disease control and survival than did CT or RT alone in cases with no 1p19q deletion. Ongoing trials will address these issues prospectively.

Purpose: Vascular reconstruction alone can be insufficient for extremity salvage in some patients with severe soft-tissue wounds. We present our experience in 20 patients with vascular reconstruction for ischemic disease and free-tissue transfer for limb-threatening soft-tissue wounds. Methods: Nineteen patients underwent autogenous venous bypasses and one patient underwent an aortobifemoral bypass. Ten soft-tissue reconstructions were performed at the time of the vascular reconstruction and 10 were delayed. Free-tissue transferred included muscle, fasciocutaneous flaps, and omentum. Inflow to the flap was from the bypass graft ( n = 12) or the distal tibial artery. Results: One free flap and graft failed immediately in the same patient. One successful flap and graft required a below-knee amputation for ongoing infection in the surrounding soft tissues. Eighteen of 20 patients have had free-flap and graft patency during the mean follow-up period of 17 months (range 6 to 33 months). These 18 patients ambulate independently. Conclusions: In patients with arterial insufficiency and severe soft-tissue wounds, combined vascular reconstruction and free-tissue transfer permits extended limb salvage with excellent functional results. (J VASC SURG 1993;18:972-80.)

This study prospectively evaluated 75 consecutive patients (mean age 69 ± 9 years) undergoing major vascular surgery to test the hypothesis that dobutamine stress echocardiography can be used to predict perioperative cardiac events. A positive test was defined as 3 new or worsening wall motion abnormality in at least 2 of 18 wall segments. Up to 40 μg/kg/min of dobutamine was administered. All readings were done by physicians unaware of the patients' symptoms and electrocardiographic response. In addition, physicians caring for the patients were unaware of the test result. End points of the study were unstable angina with documented electrocardipgraphic changes, nonfatal myocardial infarction or cardiac death. The perioperative ischemic event rate was 7% (5 of 75 patients). Three patients developed unstable angina and 2 sustained nonfatal myocardial infarctions. All of these patients had positive results on dobutamine stress echocardiography (sensitivity 100%). However, 22 patients who also had positive results on dobutamine stress echocardiography did not have perioperative events (specificity 69%). The corresponding positive predictive value was 19%. None of the 48 patients who had negative results on dobutamine stress echocardiography had events (negative predictive value 100%). In conclusion, dobutamine stress echocardiography can be used to predict perioperative events with great sensitivity, but its positive predictive value in this patient population is low, likely due to the low incidence of perioperative events in patients with known coronary artery disease and the imperfect specificity of dobutamine stress echocardiography in identifying significant coronary stenosis. Dobutamine stress echocardiography is most useful in this setting when negative, because it predicts safety from complications with confidence.

Purpose: The purpose of this study was to develop an endovascular system for transfemoral placement of straight aortic grafts and bifurcated aortoiliac grafts. Methods: Both types of graft consist of barbed, self-expanding stents attached to a woven polyester fabric. Survival studies of straight-graft function were performed in six large mongrel dogs. Digital subtraction fluoroscopic equipment was used to guide insertion and record angiograms at 0, 1, and 3 months. Bifurcated grafts were inserted in an additional eight dogs, four with distal stents and four without. Straight grafts were inserted into six cadaveric aortas (five atherosclerotic and one aneurysmal; age 68.7 + 5.7 years) to assess stent attachment. Results: Angiograms obtained immediately after straight-graft insertion showed placement to be within 4.6 + 1.6 mm of the intended level. Follow-up angiograms at 1 and 3 months showed no migration, no leakage, and patency of all six grafts. After bifurcated graft insertion there were no angiographic signs of perigraft leakage, with or without distal stents. The mean force required to displace straight grafts 10 mm from their original position in cadaveric aortas was 1388 + 127 g . Conclusion: These preliminary results show that straight and bifurcated endovascular grafts can be positioned accurately and securely in the abdominal aorta. (J VASC SURG 1993;18:185-97.)

A total of 1572 carotid endarterectomies were performed at one institution between 1975 and 1987. One hundred five patients had early (

Purpose This open-label, prospective, multicenter single-arm phase II study combined bevacizumab (BV) with radiation therapy (RT) and temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma (GBM). The objectives were to determine the efficacy of this treatment combination and the associated toxicity. Patients and Methods Seventy patients with newly diagnosed GBM were enrolled between August 2006 and November 2008. Patients received standard RT starting within 3 to 6 weeks after surgery with concurrent administration of daily TMZ and biweekly BV. After completion of RT, patients resumed TMZ for 5 days every 4 weeks and continued biweekly BV. MGMT promoter methylation was assessed on patient tumor tissue. A University of California, Los Angeles/Kaiser Permanente Los Angeles (KPLA) control cohort of newly diagnosed patients treated with first-line RT and TMZ who had mostly received BV at recurrence was derived for comparison. Results The overall survival (OS) and progression-free survival (PFS) were 19.6 and 13.6 months, respectively, compared to 21.1 and 7.6 months in the University of California, Los Angeles/KPLA control cohort, and 14.6 and 6.9 months in the European Organisation for Research and Treatment of Cancer-National Cancer Institute of Canada cohort. Correlation of MGMT promoter methylation and improved OS and PFS was retained in the study group. Comparative subset analysis showed that poor prognosis patients (recursive partitioning analysis class V/VI) may derive an early benefit from the use of first-line BV. Toxicity attributable to RT/TMZ was similar, and additional toxicities were consistent with those reported in other BV trials. Conclusion Patients treated with BV and TMZ during and after RT showed improved PFS without improved OS compared to the University of California, Los Angeles/KPLA control group. Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence.

The difficult intubation is one of the most trying situations encountered in airway management. Transtracheal jet ventilation via needle cricothyroidotomy can provide temporary oxygenation in this critical situation in a minimally invasive fashion. The esophageal detector device (EDD) has been previously shown to be effective in determining the tracheal placement of endotracheal tubes. In this experiment, three commonly available EDDs are utilized to accurately identify 15 of 15 intratracheal placements of a 16-gauge IV catheter in five cadaveric domestic swine. The incorporation of EDDs in IV catheter placement for needle cricothyroidotomy is shown to be effective and merits further study. Likewise, further investigation is needed to identify a standardized apparatus for needle cricothyroidotomy in emergent situations.

The enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD) is key in tyrosine catabolism. Inhibition of HPPD results in tyrosinemia and increased urinary excretion of 3 phenylketones: 4-hydroxyphenylpyruvate (HPPA), 4-hydroxyphenyllactate (HPLA), and 4-hydroxyphenylacetate (HPAA). A previous study involving administration of a novel HPPD inhibitor to dogs resulted in detection of ketonuria in treated animals using urine dipsticks read by reflectance photometry. Dipstick-positive results were suspected to be false because high concentrations of urinary phenylketones have been reported to react with ketone test fields of urine dipsticks, but visual confirmation was not performed.The purpose of this study was to determine which of the 4- hydroxyphenolic acids produced by HPPD inhibition react with ketone test fields of 3 commercially available urine dipsticks.Canine urine samples were prepared with HPPA, HPLA, HPAA, and lithium acetoacetate (positive control) at 6 concentrations. Unmodified urine samples were used as negative controls. All samples were tested for ketones using Combur 10 Test M dipsticks read by a Miditron dipstick analyzer. Urinalysis was also performed by visually inspecting ketone test fields on the Combur 10 Test M, Multistix 10 SG, and Aution 10 EA dipsticks.Urine samples containing HPPA were positive for ketones with Combur 10 Test M dipsticks read by the Miditron analyzer and produced a red–brown color change in ketone test fields of all 3 dipsticks. Urine samples containing HPLA and HPAA were negative by all methods.The phenylketone HPPA reacts with ketone test fields of 3 commercially available urine dipsticks, producing a red–brown color change that may be misinterpreted as positive for ketones by reflectance photometry.

Background BSEP disease results from mutations in ABCB11, which encodes the bile salt export pump (BSEP). BSEP disease is associated with an increased risk of hepatobiliary cancer. Case Presentation A 36 year old woman with BSEP disease developed pancreatic adenocarcinoma at age 36. She had been treated with a biliary diversion at age 18. A 1.7 × 1.3 cm mass was detected in the pancreas on abdominal CT scan. A 2 cm mass lesion was found at the neck and proximal body of the pancreas. Pathology demonstrated a grade 2-3 adenocarcinoma with invasion into the peripancreatic fat. Conclusions Clinicians should be aware of the possibility of pancreatic adenocarcinoma in patients with BSEP disease.

Rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle is a mixed glio-neuronal neoplasm recently codified by the World Health Organization WHO Classification of Central Nervous System (CNS) Tumors (2007). To date, 43 cases have been described in the literature; most occurring in the fourth ventricle region. We report the fourth case involving the pineal region in a 16-year-old female with signs of increased intracranial pressure (ICP). A stereotactic biopsy of the mass was followed by a debulking procedure. Both specimens revealed classic RGNT histology. The patient had stable scans 7 months post-resection. The clinical, radiological and histopathologic features of the previously described 43 cases are reviewed along with our illustrative case. Mean age of patients was 30 ± 12.8 years with 1.9:1 female to male ratio. The most common presenting signs related to increased ICP and posterior fossa involvement, including: headache (62.8%), ataxia (39.5%) and vomiting and vertigo (both 16.3%). This tumor usually presents with cystic changes (54.5%) with focal enhancement (60.9%) and hydrocephalus (43.2%). Microcalcifications and satellite lesions were common radiographic observations. All reported cases had the classic biphasic pattern. Rosenthal fibers and eosinophilic granular bodies are each present in approximately two thirds of cases. Ki-67 labeling index is consistently low (mean (%): 1.8 ± 0.75 SD). The isocitrate dehydrogenase 1 or 2 mutation found in low grade diffuse gliomas is not identified in this RGNT case. Reported outcome is nearly uniformly excellent after complete or subtotal resection. A solitary report of recurrence after 10 years and the limited experience with this entity suggest that long term follow up is advisable.

The antiphospholipid syndrome was diagnosed in 19 of 1078 patients treated between 1987 and 1991. All patients with antiphospholipid syndrome had either anticardiolipin antibody (16/19) or lupus anticoagulant (10/19); three patients had thrombocytopenia, eight patients had a prolonged partial thromboplastin time, and 10 patients had an elevated erythrocyte sedimentation rate. The most common site of involvement was the cerebral circulation (nine patients), manifested by transient ischemic attacks or stroke. Eight patients had upper extremity disease, characterized by symptoms of Raynaud's phenomenon, with angiographic lesions involving the brachial, radial, ulnar, and/or digital arteries. Lower extremity disease occurred in seven patients, with clinical presentations similar to those of atherosclerosis and varying angiographic patterns. In comparison with the population having atherosclerosis, patients with arterial manifestations of antiphospholipid syndrome were more likely to be women (13 of 19 versus 411 of 1078, p less than 0.02), were significantly younger (46.2 years versus 63.6 years, p less than 0.0001), did not smoke (1 of 19 patients versus 700 of 1078, p less than 0.0001), had a higher percentage of upper extremity involvement (8 of 18 versus 13 of 1078, p less than 0.0001), and had a higher incidence of early graft failure (9 of 12 grafts versus 13 of 371 grafts, p less than 0.0001). The syndrome is associated with the repetitive failure of vascular reconstructions and occlusion of native vessels. Antiphospholipid syndrome should therefore be suspected in young, female, nonsmokers with vascular disease, especially those with involvement of the upper extremity, cerebrovascular disease with normal findings on extracranial carotid angiography, and premature graft failure.

The diameter of aortic aneurysms were standardized to measures of patient size and normal aortic size in an effort to define indexes that might be more predictive of aneurysm rupture than raw aneurysm diameter alone. Normal aortic diameters were measured in 100 patients undergoing abdominal CT scans for other reasons, and an average infrarenal aortic diameter of 2.10 ± 0.05 cm was observed. Normal aortic diameter was dependent on both age and sex, ranging from 1.71 ± 0.06 cm in women below age 40 years to 2.85 ± 0.04 cm in men above age 70 years. Overall, 11 (5.1%) of the ruptures occurred in aneurysms less than 5 cm in diameter, and four (1.9%) occurred in aneurysms less than 4.0 cm in diameter. When the CT scans of 100 patients undergoing elective aneurysm resection were compared with those of 36 patients with ruptured aneurysms, no threshold diameter value accurately discriminated between the two groups. However, standardization of the aneurysm diameter to the transverse diameter of the third lumbar vertebral body as an index of patient body size produced an accurate predictor of rupture when a threshold ratio of 1.0 was used. No aneurysm ruptured below this ratio, but 29% of elective aneurysms were smaller than the vertebral body diameter. Receiver operating characteristic curve analysis confirmed the superiority of the aneurysm to vertebral body diameter ratio as a discriminator of ruptured aneurysms. It appears that aneurysm diameter alone is not sufficiently predictive of rupture to be used as the sole indication for elective resection. ( J Vasc Surg 1992;15:12–20.)

BackgroundThe majority of acute myeloid leukaemia (AML) patients are over sixty years of age. With current treatment regimens, survival rates amongst these, and also those younger patients who relapse, remain dismal and novel therapies are urgently required. In particular, therapies that have anti-leukaemic activity but that, unlike conventional chemotherapy, do not impair normal haemopoiesis.Principal findingsHere we demonstrate the potent anti-leukaemic activity of the combination of the lipid-regulating drug bezafibrate (BEZ) and the sex hormone medroxyprogesterone acetate (MPA) against AML cell lines and primary AML cells. The combined activity of BEZ and MPA (B/M) converged upon the increased synthesis and reduced metabolism of prostaglandin D(2) (PGD(2)) resulting in elevated levels of the downstream highly bioactive, anti-neoplastic prostaglandin 15-deoxy Delta(12,14) PGJ(2) (15d-PGJ(2)). BEZ increased PGD(2) synthesis via the generation of reactive oxygen species (ROS) and activation of the lipid peroxidation pathway. MPA directed prostaglandin synthesis towards 15d-PGJ(2) by inhibiting the PGD(2) 11beta -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD(2) to 9alpha11beta-PGF(2alpha). B/M treatment resulted in growth arrest, apoptosis and cell differentiation in both AML cell lines and primary AML cells and these actions were recapitulated by treatment with 15d-PGJ(2). Importantly, the actions of B/M had little effect on the survival of normal adult myeloid progenitors.SignificanceCollectively our data demonstrate that B/M treatment of AML cells elevated ROS and delivered the anti-neoplastic actions of 15d-PGJ(2). These observations provide the mechanistic rationale for the redeployment of B/M in elderly and relapsed AML.

Diets high in trans fats are associated with an increased risk of cardiovascular disease and components of the metabolic syndrome. The influence of these toxic fatty acids on the development of nonalcoholic fatty liver disease has not been significantly examined. Therefore, we sought to compare the effect of a murine diet high in trans fat to a standard high-fat diet that is devoid of trans fats but high in saturated fats. Male AKR/J mice were fed a calorically identical trans fat diet or standard high-fat diet for 10 days, 4 wk, and 8 wk. Serum alanine aminotransferase (ALT), lipid, insulin, and leptin levels were determined and the quantitative insulin-sensitivity check index (QUICKI) was calculated as a measure of insulin resistance. Additionally, hepatic triglyceride content and gene expression of several proinflammatory genes were assessed. By 8 wk, trans fat-fed mice exhibited higher ALT values than standard high-fat-fed mice (126 ± 16 vs. 71 ± 7 U/l, P < 0.02) despite similar hepatic triglyceride content at each time point. Trans fat-fed mice also had increased insulin resistance compared with high-fat-fed mice at 4 and 8 wk with significantly higher insulin levels and lower QUICKI values. Additionally, hepatic interleukin-1β (IL-1β) gene expression was 3.6-fold higher at 4 wk ( P < 0.05) and 5-fold higher at 8 wk ( P < 0.05) in trans fat-fed mice compared with standard high-fat-fed mice. Trans fat feeding results in higher ALT values, increased insulin resistance, and elevated IL-1β levels compared with standard high-fat feeding.

Potassium bromate (KBrO3) is a well-established rodent kidney carcinogen and its oxidising activity is considered to be a significant factor in its mechanism of action. Although it has also been shown to be clearly genotoxic in a range of in vivo and in vitro test systems, surprisingly, it is not readily detected in several cell lines using the standard alkaline Comet assay. However, previous results from this laboratory demonstrated huge increases in tail intensity by modifying the method to include incubation with either human 8-oxodeoxyguanosine DNA glycosylase-1 (hOGG1) or bacterial formamidopyrimidine DNA glycosylase (FPG) indicating that, as expected, significant amounts of 8-oxodeoxyguanosine (8-OHdG) were induced. The purpose of this work, therefore, was to investigate why KBrO3, in contrast to other oxidising agents, gives a relatively poor response in the standard Comet assay. Results confirmed that it is a potent genotoxin in mouse lymphoma L5178Y cells inducing micronuclei and mutation at the tk and hprt loci at relatively non-cytotoxic concentrations. Subsequent time-course studies demonstrated that substantial amounts of 8-OHdG appear to remain in cells 24h after treatment with KBrO3 but result in no increase in frank stand breaks (FSB) even though phosphorylated histone H2AX (gamma-H2AX) antibody labelling confirmed the presence of double-strand breaks. Using bromodeoxyuracil (BrdU) incorporation together with measured increases in cell numbers, L5178Y cells also appeared to go through the cell cycle with unrepaired hOGG1-recognisable damage. Since unrepaired 8-OHdG can give rise to point mutations through G:C-->T:A transversions, it was also surprising that mutation could not be detected at the Na+/K+ATPase locus as determined by ouabain resistance. Some increases in strand breakage could be seen in the Comet assay by increasing the unwinding time, but only at highly toxic concentrations and to a much smaller extent than would be expected from the magnitude of the other genotoxic responses. It was considered unlikely that these anomalous observations were due to the inability of L5178Y cells to recognise 8-OHdG because these cells were shown to express mOGG1 and have functional cleavage activity at the adducted site. It appears that the responses of L5178Y cells to KBrO3 are complex and differ from those induced by other oxidising agents.

Objectives In the era of highly active antiretroviral therapy (HAART), liver disease has become a leading cause of morbidity and mortality in HIV-seropositive individuals. Although liver disease is commonly caused by viral co-infection, it has also been described in patients without viral hepatitis. In this study, we determined clinical factors associated with the development of cryptogenic liver disease in HIV-infected individuals. Methods HIV-seropositive and -seronegative patients undergoing evaluation for liver transplantation were selected if they met clinical criteria for cryptogenic liver disease. Clinical data were collected retrospectively, and radiological and histological data were reviewed separately. Results Nine HIV-seropositive individuals were compared with 41 HIV-seronegative patients with cryptogenic liver disease. Only one HIV-seropositive patient (11%) had cirrhosis, compared to 39 HIV-seronegative patients (93%) (Po0.001). Three HIV-infected patients (33%) had histological evidence of nodular regenerative hyperplasia. HIV-seropositive patients had significantly lower body mass indices, and lower Child‐Pugh‐Turcotte and Model for Endstage Liver Disease scores than HIV-seronegative patients (Po0.05). Conclusions Advanced cryptogenic liver disease in HIV-infected patients is infrequently caused by cirrhosis, and more frequently by nodular regenerative hyperplasia. This disease entity may become more common in the HAART era, and may contribute to an increased morbidity in HIV-infected individuals.

Objective: Bevacizumab has been shown to be effective in the treatment of recurrent glioblastoma in combination with chemotherapy compared with historic controls but not in randomized trials. Methods: We conducted a retrospective analysis of patients treated for recurrent glioblastoma with bevacizumab vs a control group of patients, comparing progression-free survival (PFS) and overall survival (OS) between the two groups, and performed subgroup analysis based on age and performance status. Expression of vascular endothelial growth factor (VEGF) based on age was examined using DNA microarray analysis. We also evaluated the impact of bevacizumab on quality of life. Results: We identified 44 patients who received bevacizumab and 79 patients who had not been treated with bevacizumab. There was a significant improvement in PFS and OS in the bevacizumabtreated group. Patients of older age (55 years) and poor performance status (Karnofsky Performance Status 80) had significantly better PFS when treated with bevacizumab, and bevacizumab-treated older patients had significantly increased OS. VEGF expression was significantly higher in older glioblastoma patients (aged 55 years). Patients treated with bevacizumab also required less dexamethasone use and maintained their functional status longer than the control group. Conclusions: Bevacizumab in combination with chemotherapy may be a more effective treatment for recurrent glioblastoma and warrants further randomized prospective studies to determine its effect on survival. Bevacizumab also has more effect in those with older age and might reflect biologic differences in glioblastoma in different age groups as seen with the expression of vascular endothelial growth factor. Neurology ® 2009;72:1217–1222

We reviewed our 12-year experience with transaxillary first rib resection in 136 patients screened by neurologists and thought to have neurologic thoracic outlet syndrome to determine what factors affected outcome. These patients represented 85% of the operative experience in a referral area of 1.2 million people. Patients were recalled every 2 years for surveillance. The mean follow-up was 60 +/- 7 months. There were no brachial plexus or vascular injuries. Secondary operations in the neck were required in 20 patients. The quality of the operative result was determined by whether the patient was able to return to preillness activities and whether the patient would undergo operation again if the same result would be obtained. The most important determinant of result was a history of trauma precipitating the neurologic symptoms, particularly in women. Only 25 of the 53 patients (47%) with a history of trauma returned to preillness activities compared to 65 of the 83 patients (78%) without such a history. Overall patient satisfaction was not affected by trauma. Thirty-eight of the 53 patients with trauma (72%) and 69 of the 83 patients (83%) without trauma were satisfied. When the men and women were analyzed separately men were found to have better results after trauma than did women. Other factors with a negative impact on operative results were the need to return to an activity that required repetitive arm movements, coverage under a worker's compensation insurance policy, and fixed joint abnormalities or neurologic findings in the upper extremity. The presence of an anatomic abnormality had no effect on operative results.(ABSTRACT TRUNCATED AT 250 WORDS)

Most early reports on the efficacy of laser angioplasty have used subjective symptoms rather than objective hemodynamic parameters to evaluate clinical results. We reviewed our experience with hot tip laser-assisted balloon angioplasty in 99 occluded or stenotic arterial segments during 80 procedures in 71 patients, ranging from the aortic bifurcation to the tibial-peroneal trunk. Initial failure to successfully recanalize occluded or stenotic segments occurred in 13 instances (16%). Forty-one procedure-related complications occurred in 31 patients (39%). Functional results were evaluated by use of life-table methods on the basis of symptomatic versus hemodynamic improvement. Cumulative patency rates for symptomatic and hemodynamic improvement were 91% and 64% at 1 month, 71% and 48% at 6 months, and 57% and 34% at 1 year, respectively. These data suggest that symptomatic improvement alone gives a misleadingly high estimate of the efficacy of laser angioplasty when compared with more objective hemodynamic criteria (p less than 0.005). Hemodynamic success was more likely in aortoiliac lesions than femoropopliteal lesions (58% vs 18% at 1 year, p less than 0.01). Hemodynamic parameters should be used to evaluate the success of laser angioplasty, which in its present form, is associated with frequent complications and poor long-term success.

Over a 5-year period 642 patients underwent 686 carotid endarterectomies with patch closure and intraoperative surveillance with continuous-wave Doppler. The perioperative stroke rate was 1.5%. Patients were screened with duplex scans immediately after operation for the presence of residual carotid lesions, and followed every 3 to 6 months for either the development of a true recurrent lesion or a change in a residual one. Five hundred thirty-nine arteries (84%) had no postoperative abnormalities. The incidence of recurrent carotid lesions in this groups was 1.5%, 3.4%, and 5.2% at 1, 2, and 3 years, respectively. The incidence of symptoms in this group was 0.2%, 0.7%, and 1.4% at 1, 2, and 3 years, respectively. The earliest recurrence or symptom occurred 8 months from operation. One hundred forty-seven arteries had residual lesions that were more common when either a temporary shunt was used or the operation was carried out above the hypoglossal nerve or below the omohyoid muscle. Sixty-one patients who had plaque proximal to the arteriotomy without a significant stenosis were followed an average of 21 months. There were no changes in plaque morphology and no proven symptoms related to the residual lesion. Fifty-six patients with both plaque and significant hemodynamic abnormalities in the carotid bulb were followed an average of 18 months. Seven of these patients (12.5%) had either a significant deterioration of the lesion or a symptom from it. Each event occurred within 6 months of operation. Thirty patients had significant flow abnormalities but no visible plaque. None of these lesions deteriorated. Although common, residual carotid lesions are benign unless the lesion is characterized by both plaque within the artery and a hemodynamically significant stenosis. These lesions should be further investigated and treated when discovered. (J VASC SURG 1991;13:112-20.)

Background Partial External Biliary Diversion (PEBD) is a surgical intervention to treat children with Progressive Familial Intrahepatic Cholestasis (PFIC) and Alagille syndrome (AGS). PEBD can reduce disease progression, and examining the alterations in biliary lipid composition may be a prognostic factor for outcome. Methods Biliary lipid composition and the clinical course of AGS and PFIC patients were examined before and after PEBD. Results Pre-PEBD bile from AGS patients had greater chenodeoxycholic/cholic acid (CDCA/CA), bile salt, cholesterol and phospholipid concentrations than PFIC patients. AGS patients, and PFIC patients with familial intrahepatic cholestasis 1 (FIC1) genotype, responded better to PEBD than PFIC patients with bile salt export protein (BSEP) genotype. After successful PEBD, AGS patients have higher biliary lipid concentrations than PFIC patients and PEBD also increases biliary phospholipid concentrations in FIC1 patients. Conclusion Both AGS and FIC1 patients can benefit from PEBD, and preserved biliary phospholipid concentrations may be associated with better outcomes post-PEBD.