Early carotid endarterectomy after ischemic stroke: the results of a prospective multicenter Italian study.

OBJECTIVES: To evaluate safety of early carotid endarterectomy (CEA) in patients with acute brain ischemia presenting to the emergency department stroke units (EDSU). METHODS: The neurologists, neuroradiologists and vascular surgeons on duty in emergency departments enrolled 96 patients who underwent very early CEA according to a predefined protocol within two years. The protocol included evaluation of neurological status by National Institute of Health Stroke Scale (NIHSS), neuroimaging assessment, ultrasound of the carotid arteries and Transcranial Doppler. Patients with NIHSS>22 or whose neuroimaging showed brain infarct >2/3 of the middle cerebral artery territory were excluded. All eligible patients underwent CEA as soon as possible. Primary end points of the study were mortality, neurological morbidity by NIHSS and postoperative hemorrhagic conversion on neuroimaging. Statistical analysis was performed by univariate analysis. RESULTS: The mean time elapsing between the onset of stroke and endarterectomy was 1.5 days (+/-2 days). The overall 30-day morbidity mortality rate was 7.3% (7/96). No neurological mortality occurred. On hospital discharge, three patients (3%) experienced worsening of the neurological deficit (NIHSS score 1 to 2, 1 to 3 and 9 to 10 respectively). Postoperative CT demonstrated there were no new cerebral infarcts nor hemorrhagic transformation. At hospital discharge 9/96 patients (9%) had no improvement in NHISS scores, 37 were asymptomatic and 45 showed a median decrease of 4.5 NIHSS points (range 1-18). By univariate analysis none of the considered variables influenced the clinical outcome. CONCLUSION: Our protocol selected patients who can safely undergo very early (<1.5 days) surgery after acute brain ischemia. Large randomized multicenter prospective trials are warranted to compare very early CEA versus best medical therapy.

What is the best management for abdominal aortic aneurysm in patients at high surgical risk? A single-center review.

AIM: To determine the best treatment for high-risk patients with abdominal aortic aneurysms (AAA). METHODS: We reviewed a prospective database of all patients who underwent conventional (OPEN) or endovascular aneurysm repair (EVAR) between January 1998 and December 2002. Patients were preoperatively classified according to the American Society of Anesthesiology (ASA). Comorbidities and medical risk factors were categorized according to the Ad Hoc Committee on Reporting Standards. Perioperative mortality and morbidity rates were analyzed according to the type of surgical procedure (OPEN vs EVAR) and ASA class. Patients in ASA classes I and II were excluded. Continuous data were expressed as mean +/- standard deviation. All data were calculated using the cumulated actuarial method of event outcome probability. Kaplan-Meier curves were constructed and the log-rank statistic and chi squared test were used for comparative data. P values less than 0.05 were considered to indicate statistical significance. RESULTS: Of the total 375 patients who underwent AAA repair, 168 (45%) belonged in ASA classes III and IV (85 submitted OPEN and 83 EVAR to repair). Among general risk factors only coronary artery disease differed significantly between the 4 groups (P = 0.04). The Bonferroni correction identified a statistically significant difference between ASA classes III and IV for the OPEN technique and for EVAR (P = 0.007 and P = 0.012). Neither 30-day morbidity or mortality differed significantly according to ASA class and surgical technique. The median follow-up was 19 months (range 5-60 months). The overall survival was 78% at 60 months. Survival rates during follow-up differed significantly in the 2 risk classes (ASA III 5/123, 4% vs ASA IV 9/38, 24%), (P = 0.0001). The deaths in the ASA class 4 patients (12/14; 86%) were caused by preexisting medical comorbidities (in 9 patients cardiovascular, in 1 cancer and in 2 cirrhosis). CONCLUSIONS: Except patients with small aneurysms (< 6 cm), in whom the risk of death at 1-year due to comorbidities exceeds the risk of a ruptured aneurysm, all patients at high surgical risk (ASA class IV) benefit from AAA repair. Patients with small aneurysms must undergo strict surveillance to assess growth and aneurysmal wall changes to prevent unexpected rupture.

[Atheroembolic syndrome due to isolated infrarenal abdominal aorta stenosis and endovascular treatment: case report and review of literature]. / Ateroembolia da lesione stenosante isolata dell'aorta addominale sottorenale e trattamento endovascolare: caso clinico e revisione della letteratura.

One of the most common source of lower extremity atheroembolization is the aorta and particularly the infrarenal segment. Complex atherosclerotic plaque can lead the patient to gangrene and major amputation. When the origin of embolization is a focal lesion, endoluminal methods could be an alternative to surgical treatment. Although the experience with aortic stent is limited, the results obtained so far seem to be encouraging. The case of a mid-age heavy smoker woman with a history of the abrupt onset of painfull cyanotic toes in the left foot and subsequent complete gangrene of the first digit in the same foot is herein reported. Angiography and CT scan revealed an high-grade calcified aortic infrarenal plaque. Because of the discrete characteristic of the lesion, an endovascular approach with a Palmaz stent was elected. The stenosis was successfully treated: the patient experienced the complete resolution of the toe painfull cyanosis within 3 months, the stent remained patent through a 24 months follow-up and no subsequent embolic episodes were observed.

Dysregulated apoptosis in primary varicose veins.

OBJECTIVE: Programmed cell death plays a critical role in various physiological processes. To investigate its possible pathogenic role in primary varicose veins we studied histological changes in surgical specimens from human varicose veins. In varicose and healthy veins, we also determined the number of cells in apoptosis, and investigated mediators regulating the intrinsic apoptotic mitochondrial pathway (Bax and caspase 9). METHODS: A total 23 varicose veins were obtained from 18 patients undergoing lower-extremity varicose vein surgery for primary varicose disorders. We used nine healthy veins obtained from nine patients undergoing distal arterial bypass grafting surgery as controls. The venous segment analysed was the distal part of the greater saphenous vein. Specimens for histological examination were stained with hematoxylin and eosin, trichromic and Victoria blue. Cell apoptoses and mediators of the mitochondrial pathway were detected in the media by immunohistochemistry using antibodies to peroxidase in situ apoptosis, Bax and caspase 9. Results were expressed as indexes for the three antibodies tested. The Mann-Whitney test was used to compare the results obtained in the two groups. RESULTS: Varicose vein specimens exhibited a more disorganised architecture than healthy veins and showed an increased number of collagen fibres and a decrease in the density and size of elastic fibres. All anti-apoptotic antibodies tested detected significantly fewer immunoreactive cells in tissue sections from the media of varicose veins than of healthy veins (peroxidase in situ, varicose veins (VV) median 2.4% (inter-quartile range 1.6-3.9) versus control (C) 14% (IQR 8.8-19); Bax, VV 1.4% (IQR 0.36-2.4) versus C 11% (IQR 7.6-15); and caspase 9, VV 1.7% (IQR 0.06-3.4) versus C 10% (IQR 9.1-12), P=0.0001 (Mann-Whitney test). CONCLUSION: Apoptosis is down regulated in the medial layer of varicose veins. This dysregulation of the cellular mechanism that maintains normal tissue integrity is mediated through the intrinsic apoptotic pathway and may be among the causes of primary varicose veins.

Interposition vein cuff and intimal hyperplasia: an experimental study.

OBJECTIVE: There is some evidence to suggest that prosthetic distal bypass graft patency can be improved, and the risk of intimal hyperplasia diminished, by interposing a distal vein cuff. We studied intimal remodeling in an end-to-side distal prosthetic anastomosis constructed with and without a vein cuff. METHODS: Twenty-four prosthetic bypasses were constructed with (N=12) or without (N=12) a distal vein cuff in 12 pigs. At 10 weeks, the 20 anastomoses and adjacent arteries from the surviving 10 pigs were studied by histology, immunohistochemistry and morphometry. RESULTS: Intimal hyperplasia was significantly less on all zones of the arterial floor and all suture zone of arteries anastomosed with a vein cuff than within arteries anastomosed without a vein cuff (0.11 versus 0.34; p=0.001 and 0.35 versus 1.19; p=0.0001, respectively). Intimal hyperplasia was also more prominent within the vein cuff than within the recipient artery, with or without a vein cuff (1.35 versus 0.38; p=0.0001). CONCLUSION: An interposition vein cuff at the distal anastomosis between a prosthesis and an artery alters the distribution of intimal hyperplasia. By acting as an expansion chamber where intimal hyperplasia can develop harmlessly, the vein cuff may protect the arterial anastomosis from stenosis.

Aneurysm of the pancreaticoduodenal arteries with a celiac trunk lesion: current management.

OBJECTIVE: We report a ruptured aneurysm of the pancreaticoduodenal arteries without acute or chronic pancreatitis but associated with a median arcuate ligament division that compressed the celiac trunk, an exceptional event, thus far described in only 11 patients. We also conducted a targeted review to seek information about clinical presentation, to hasten diagnosis and assist in therapeutic management. METHODS: A 54-year-old man with retroperitoneal hemorrhage associated with an arcuate ligament division, documented on computed tomographic scans, underwent diagnostic arteriography and embolization to treat the bleeding aneurysm. In a second elective operation the causative arcuate ligament was sectioned to decompress the celiac artery, to prevent aneurysm recurrence. RESULTS: Embolization stopped the aneurysmal bleeding, and arteriograms showed that surgical sectioning resolved the celiac trunk stenosis. At 1-year follow-up the patient had no signs of complications or recurrence of disease. CONCLUSION: Ruptured aneurysm of the pancreaticoduodenal arteries associated with stenosis of the celiac trunk is a surgical emergency. Although a literature review disclosed no significant difference between outcomes after open surgery and radiologic arterial embolization, our experience in this case suggests immediate embolization during arteriography as the most effective treatment. Later, to prevent recurrence, the arcuate ligament should be surgically sectioned and the celiac artery stenosis treated.

Patency and limb salvage after distal prosthetic bypass associated with vein cuff and arteriovenous fistula.

OBJECTIVE: To assess the usefulness of vein cuff with or without arteriovenous fistula interposition as adjuvant techniques for improving patency and limb salvage in patients undergoing femorodistal bypass surgery using prosthetic grafts. METHOD: We undertook a retrospective study of 65 consecutive patients treated over a 5-year period with 67 prosthetic femorodistal bypasses with vein cuff, in whom an arteriovenous fistula was constructed at the distal anastomosis in 35. Patients were followed for a median time period of 23 months. RESULTS: Primary patency rates were 68, 53 and 44% at 1, 2 and 3 years, respectively. The corresponding figures for secondary patency, limb survival and patients' survival were 73, 64 and 58% for 1 year, 78, 76 and 73% for 2 years and 72, 66 and 63% for 3 years. None of the criteria analyzed influenced patency or limb salvage on prosthetic bypasses using adjuvant techniques. No statistical differences were found between patency and limb salvage rates in patients for whom the vein cuff was constructed with or without an arteriovenous fistula. But patients who managed with a supplementary arteriovenous fistula had significantly fewer distal residual arteries in the limb (p=0.001). CONCLUSION: Although results in patients treated with adjunctive techniques differed little from those in patients treated with direct prosthetic bypasses procedures, those who eventually had an adjunctive procedure had inferior runoff. This indicates that an arteriovenous fistula might be a valuable supplement in patients with poor runoff who have distal revascularisation using a prosthetic graft.

Popliteal artery entrapment associated with cannabis arteritis.

OBJECTIVE: To report popliteal artery entrapment in a patient with distal necrosis and cannabis-related arteritis, two rare or exceptional disorders never described in association. To conduct a targeted review and especially to seek information on the clinical presentation with characteristics specific to each disorder so as to hasten the diagnosis and choose appropriate management. MATERIAL AND METHODS: A 19-year-old man who presented with plantar claudication associated with necrosis in a toe underwent diagnostic arteriography and surgery for popliteal artery entrapment type III. RESULTS: Surgical clearance resolved the popliteal artery entrapment but left the clinical symptoms unchanged. Closer questioning disclosed a history of cannabis consumption and intravenous vasodilatory therapy was started. After the 21-day course of vasodilator agents the pain disappeared and the toe necrosis regressed. The patient stopped taking cannabis and had no signs of recurrence. CONCLUSION: Whereas a popliteal artery entrapment, albeit a rare event, is well described and responds to standardized treatment, popliteal artery entrapment associated with cannabis-induced arteritis is an exceptional event that could confuse management. Because young people-the age group mainly at risk for popliteal artery entrapment-increasingly use cannabis, cannabis arteritis could become a more frequent event associated with other arterial disorders that may confuse the diagnosis and complicate management. Our experience in a young patient suggests that coexisting popliteal artery entrapment and distal necrosis in a young patient should raise a strong suspicion of an associated vascular disorder possibly related to cannabis consumption. Intravenous vasodilatation treatment is successful provided that cannabis use is discontinued.

Emergency and early carotid endarterectomy in patients with acute ischemic stroke selected with a predefined protocol. A prospective pilot study.

AIM: The appropriateness of early carotid endarterectomy (CEA) in patients with acute ischemic stroke is still unsettled. The aim of this study was to verify the safety and feasibility of early CEA in a consecutive series of patients with acute ischemic stroke observed in an emergency Department Stroke Unit. METHODS: During a 24-month study, out of 756 patients with acute ischemic stroke 33 (4.4%) were scheduled for early CEA. Endarterectomy procedures were distinguished according to the time between the onset of stroke and operation as emergency (within 8 hours), early CEA (1-18 days). Patients with impaired consciousness or an infarct larger than 2.5 cm on computed tomographic (CT) or magnetic resonance (MR) scans or both were excluded from surgery. All patients underwent spiral CT, echo-color-Doppler (ECD) sonography, transcranial Doppler (TCD) sonography and, when necessary, MR angiography within 6 hours of admission. No patient underwent conventional angiography. Most patients were operated on under cervical block (CB) anesthesia; general anesthesia (GA) was used only for those with an unstable neurological deficit. Selective shunting was used on the basis of intra-operative transcranial Doppler in patients under GA and the onset or worsening of neurological deficit under CB anesthesia. RESULTS: Of the 6 patients operated on within a median 6 hours after the onset of stroke, 1 (16.5%) had a fatal hemorrhagic transformation of the infarct, while the remaining 5 (83.5%) stopped fluctuating or progressing and had a favourable neurological outcome. Of the 16 patients operated on within a median 36 hours and of the 11 patients operated on within 7 days, none deteriorated after operation. CONCLUSION: Emergency CEA is feasible for acute ischaemic stroke provided that strict selection criteria are applied and the door-to-surgery interval is kept short (within 8 hours). Early CEA for secondary prevention is feasible and safe, confirming that a delayed operation is in most cases unwarranted. Large randomized trials are warranted before implementing emergent and early CEA in routine clinical practice.

[Role of aortofemoral bypass in the management of unilateral iliac occlusive disease. A follow-up study of 95 patients over a 25-year period]. / Terapia endoscopica del sanguinamento non varicoso del tratto digestivo superiore.

BACKGROUND: To evaluate the results in a series of patients submitted to aortofemoral bypass due to an unilateral iliac occlusion. METHODS: Retrospective follow-up study. A total of 95 patients underwent, between 1975 and 2000, aortofemoral bypass because of unilateral iliac occlusion. Most of them (71 patients) were claudicants, Fontaine stage II b, while 12 complained rest pain and 12 suffered ischemic ulcers. Mean follow-up was 128 months (min 2.5 - max 292). RESULTS: Immediate success was obtained in 88 cases (92.6%), 7 patients were submitted to early redo with restored patency in 6 cases. One month global patency was gained in 98.9% (94 cases). The mean Ankle-brachial index (ABI) improvement was 0.35. At a mean follow-up of 128 months the cumulative patency was 90.8%. During the follow-up, 15 graft occlusions were observed, followed by 9 successful reoperations achieving a 5-year secondary patency of 92.1%. The contralateral iliac artery evolved toward an occlusion in 10 patients (10.5%) during a long time observation (104 months average). CONCLUSIONS: The unilateral aortofemoral bypass confirmed an excellent long term outcome regarding effectiveness and graft related complications. The low contralateral occlusion rate, in our series, does not justify a more aggressive approach as first surgical option.

The role of preoperative Tc-99m HMPAO-labeled leukocyte total-body scans in aortic prosthetic reconstruction.

PURPOSE: This study was performed to evaluate the utility of Tc-99m HMPAO-labeled leukocyte total-body scans (TBLS) for detecting remote septic foci before operation in patients undergoing aortofemoral vascular surgery. MATERIALS AND METHODS: Fifty-eight patients were screened before operation for inflammatory or infective disease, and a clinical score was assigned to each patient. Each patient had TBLSs. The relation between the clinical score and the TBLS result was determined. Patients with positive results of the TBLSs were examined, and the causes of these findings were treated before surgery. RESULTS: Ten of the 58 (17%) patients had a positive result of TBLSs. Of 31 patients with a clinical score of zero, 3 had positive findings of TBLS. No TBLS was positive in the 13 patients with a clinical score of 1. TBLS findings were positive in 7 of 14 of the combined patients with clinical scores of 2, 3, or 4. None of the patients showed signs of prosthetic vascular graft infection during the postoperative follow-up period. CONCLUSIONS: In conclusion, TBLSs can be used before aortofemoral vascular surgery, but only in patients with high clinical scores for inflammatory or infective disease to identify relevant infective foci that could cause vascular graft infection.

Somatosensory evoked potentials versus locoregional anaesthesia in the monitoring of cerebral function during carotid artery surgery: preliminary results of a prospective study.

OBJECTIVE: to relate changes in somatosensory-evoked potentials (SEPs) with onset of neurological deficits in patients having carotid endarterectomy (CEA) under locoregional anaesthesia. METHODS: a prospective study of 50 consecutive patients. RESULTS: SEPs yielded an accuracy of 98%, specificity 100%, and sensitivity 89%. In all concordant cases the onset of a neurological deficit in awake patients corresponded to a 30--40% reduction in amplitude of N20-P25 waveforms. After shunting, the N20-P25 took 2--3 min to return to normal. CONCLUSIONS: SEPs are associated with a 2% false negative rate. Their threshold for detecting cerebral ischaemia is lower than the currently reported value for patients under general anaesthesia. The time needed for evoked potentials (2--3 min) to return to normal after shunting limits their usefulness in verifying effective shunting.

Inflammatory aneurysms of the abdominal aorta involving the ureters: is combined treatment really necessary?

PURPOSE: Peri-aneurysmal fibrosis complicating inflammatory aneurysm of the abdominal aorta may involve the ureters, causing urological complications. We assessed patient anatomical and clinical outcomes after conservative ureteral management. MATERIALS AND METHODS: From the operative records of 1,271 consecutive patients who underwent surgical repair of abdominal aortic aneurysms from 1980 to 1999 we identified 77 (6%) who had inflammatory aneurysms, which were complicated in 19 (24.6%) by dense peri-aneurysmal and ureteral fibrosis. Of these 19 patients 15 (78.9%) had coexisting monolateral hydronephrosis, 3 (15.7%) had bilateral hydronephrosis and 1 (5.2%) had renal atrophy. In 14 cases (73.6%) the fibrotic reaction severely impaired renal function. Only 1 patient underwent an emergency operation, while the others underwent elective repair. Only 2 patients (10.5%) underwent a specific urological procedure, including bilateral nephrostomy in 1 and ureterolysis plus ureterolithotomy in 1. Most ureteral complications were treated conservatively by aneurysmectomy only. RESULTS: Immediate postoperative mortality was 7% (1 of 14 cases). Median followup was 48 months. In 1 of the 13 cases (7.7%) a ureteral stent was placed during followup. After aneurysmectomy in 9 of the 12 patients (75%) with renal dysfunction periaortic fibrosis disappeared or decreased as well as associated hydronephrosis. In 11 of the remaining 12 patients (91%) of the 14 with renal failure preoperatively kidney function returned to normal or improved. In the 2 patients who underwent a specific urological procedure renal function improved but did not return to normal. CONCLUSIONS: Inflammatory abdominal aortic aneurysms involving the ureters and compressing the urinary structures respond well to aneurysmal resection only without a urological procedure.

The haemodynamic effect of internal carotid artery stenosis on cerebral perfusion during aortic surgery.

OBJECTIVES: to determine the impact of the extracranial internal carotid stenosis on cerebral perfusion during aortoiliac surgery. DESIGN: prospective study. MATERIAL AND METHODS: of 432 consecutive patients undergoing aortoiliac reconstruction, 16/86 (18%) with >70% internal carotid artery stenosis, underwent inverted surgical timing (aortic reconstruction first and carotid endarterectomy second). Preoperative Transcranial Doppler (TCD) with and without acetazolamide was used to evaluate cerebrovascular reserve capacity (CRC). Intraoperatively, middle cerebral artery flow velocity (mean MCAv) and systemic blood pressure (SBP) were recorded. RESULTS: preoperatively, all 16 patients had good CRC (increase in mean MCAv: 66% right and 72% left). Intraoperatively, the mean MCAv (from 49+/-13 to 45+/-14 cm/s p=0.0249) and SBP decreased (from 127+/-25 to 113+/-22 mmHg p=0.0016). In patients with unilateral carotid disease, declamping had no effect on left mean MCAv despite a significant decrease of SBP (129+/-44 to 113+/-21 mmHg p=0.0211). In those with bilateral disease, declamping decreased both mean MCAv: from (48+/-12 to 39+/-10 cm/s p=0.011) and SBP (123+/-26 to 111+/-25 mmHg p=0.0479). No perioperative neurological deficit occurred. CONCLUSIONS: if CRC is normal or still effective, aortoiliac reconstruction does not impair cerebral perfusion.

Non-atherosclerotic saccular aneurysmal degeneration of a saphenous-vein graft inserted for repair of a popliteal aneurysm.

The Authors describe a case of a saccular aneurysm formation in a femoropopliteal autologous saphenous vein graft, inserted 12 years before. The patient was initially treated for a popliteal aneurysm. The graft revealed no microscopic signs of atherosclerosis. In spite of the widespread use of the autologous saphenous vein as arterial substitute, this complication is extremely rare.

Mechanisms of DNA topoisomerase I-induced cell killing in the yeast Saccharomyces cerevisiae.

DNA topoisomerase I (Top1) catalyzes the relaxation of supercoiled DNA by a mechanism of transient DNA strand cleavage characterized by the formation of a phosphotyrosyl bond between the DNA end and active site tyrosine. Camptothecin reversibly stabilizes the covalent enzyme-DNA intermediate by inhibiting DNA religation. During S-phase, collisions with advancing replication forks convert these complexes into potentially lethal lesions. To define the DNA damage induced by alterations in Top1p catalysis and the cellular processes that mediate the repair of such lesions, the yeast Saccharomyces cerevisiae was used. Substitution of conserved residues N-terminal to the active site tyrosine (Tyr-727) produced alterations in the camptothecin sensitivity or catalytic cycle of DNA Top1. For example, substituting Ala for Thr-722 in Top1T722A increased the stability of the covalent enzyme DNA intermediate. As with camptothecin, Top1T722A-induced cytotoxicity was ascribed to a reduction in DNA religation. By contrast, enhanced covalent complex formation by Top1N726H resulted from a relative increase in the rate of DNA cleavage. Conditional yeast mutants were also selected that exhibit temperature-sensitive growth only in the presence of the self-poisoning Top1T722A enzyme. Subsequent analyses of these tah mutants identified 9 genes whose function suppresses the cytotoxic action of camptothecin and Top1T722A. These include genes encoding essential DNA replication proteins (CDC45 and DPB11) and proteins involved in SUMO- or ubiquitination (UBC9 and DOA4).

Domain interactions affecting human DNA topoisomerase I catalysis and camptothecin sensitivity.

DNA topoisomerase I (Top1p) relaxes supercoiled DNA by the formation of a covalent intermediate in which the active site tyrosine is transiently bound to the severed DNA strand. The antineoplastic agent camptothecin (Cpt) specifically targets Top1p and several mutations have been isolated that render the enzyme Cpt resistant. The mutated residues, although located in different regions of the enzyme, may constitute part of the Cpt binding site. To begin identifying the structural features of DNA Top1p important for Cpt-induced cytotoxicity, we developed a novel yeast genetic screen to isolate catalytically active, yet Cpt-resistant enzymes from a pool of human top1 mutants. Among the mutations isolated were substitutions of Ser or Val for Gly363, which like the Gly363 to Cys mutation previously reported by us, suppressed the Cpt sensitivity of Top1p. In contrast, each amino-acid substitution differed in its ability to suppress the lethal phenotype and catalytic activity of a human top1 mutant top1T718A that resembles Cpt by stabilizing the covalent intermediate. Biochemical analyses and molecular modeling support a model where interactions between two conserved domains, a central "lip" region containing residue Gly363 and the residues around the active site tyrosine (Tyr723), directly affect the formation of the Cpt-binding site and enzyme catalysis.

CDC45 and DPB11 are required for processive DNA replication and resistance to DNA topoisomerase I-mediated DNA damage.

The antitumor agent camptothecin targets DNA topoisomerase I by reversibly stabilizing a covalent enzyme-DNA intermediate. The subsequent collision of DNA replication forks with these drug-enzyme-DNA complexes produces the cytotoxic DNA lesions that signal cell cycle arrest and ultimately lead to cell death. Despite intense investigation, the character of the lesions produced and the repair processes that resolve the damage remain poorly defined. A yeast genetic screen was implemented to isolate conditional mutants with enhanced sensitivity to DNA topoisomerase I-mediated DNA damage. Cells exhibiting temperature-sensitive growth in the presence of the DNA topoisomerase I mutant, Top1T722Ap, were selected. Substitution of Ala for Thr722 increases the stability of the covalent Top1T722Ap-DNA intermediate, mimicking the cytotoxic action of camptothecin. Two mutants isolated, cdc45-10 and dpb11-10, exhibited specific defects in DNA replication and a synthetic lethal phenotype in the absence of DNA damaging agents. The accumulation of Okazaki fragments under nonpermissive conditions suggests a common function in promoting processive DNA replication through polymerase switching. These results provide a mechanistic basis for understanding the cellular processes involved in the resolution of DNA damage induced by camptothecin and DNA topoisomerase I.