HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Stephen J. Rooney Domenico Pagano Victor T. Tsang Robert K. Lamb James L. Monro Robert S. Bonser Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Langley, S. M. Articles by Bonser, R. S. Search for Related Content PubMed PubMed Citation Articles by Langley, S. M. Articles by Bonser, R. S.

J Thorac Cardiovasc Surg 1999;118:1014-1020
© 1999 Mosby, Inc.

SURGERY FOR ACQUIRED CARDIOVASCULAR DISEASE

REPLACEMENT OF THE PROXIMAL AORTA AND AORTIC VALVE USING A COMPOSITE BILEAFLET PROSTHESIS AND GELATIN-IMPREGNATED POLYESTER GRAFT (CARBO-SEAL): EARLY RESULTS IN 143 PATIENTS

From the Wessex Cardiothoracic Centre,^a Southampton General Hospital, Southampton, United Kingdom, Cardiothoracic Surgical Unit,^b Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom, and Medical Statistics and Computing,^c University of Southampton, Southampton General Hospital, Southampton, United Kingdom.

Address for reprints: Stephen M. Langley, Wessex Cardiothoracic Centre, Southampton General Hospital, Southampton, United Kingdom, SO16 6YD (E-mail: StephenLangley{at}dial.pipex.com ).

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

 
Objective: We report the combined early results from two centers in the United Kingdom using a composite conduit consisting of a bileaflet mechanical valve incorporated into a gelatin-impregnated, ultra-low porosity, woven polyester graft (Carbo-Seal; Sulzer Carbomedics, Inc, Austin, Tex).
Methods: Between August 1992 and March 1997, 143 patients underwent aortic root replacement with the Carbo-Seal composite prosthesis. The indication for surgery was acute type A dissection in 31 (22%), chronic type A dissection in 9 (6%), ascending aortic aneurysm without dissection in 100 (70%), and false aneurysm of the ascending aorta in 3 (2%). Twenty-seven patients (19%) had undergone previous sternotomy, and 40 (28%) were seen as emergencies. Concomitant procedures were performed in 38 (27%), including 18 aortic arch or hemiarch replacements. Total follow-up is 270 patient-years. Follow-up is 100% complete.
Results: The early (30-day) mortality was 7% (10 patients). Permanent neurologic events occurred in 2%. At a mean follow-up of 23 months, 94% of survivors were in New York Heart Association functional class I. Freedom from reoperation was 97.2% ± 1.6% (1 standard error [1 SE]) at 12 months and 95.7% ± 2.2% at 48 months. Including early mortality, survival was 90.1% ± 2.6% at 12 months and 83.1% ± 3.5% at 48 months.
Conclusions: Aortic root replacement with use of the Carbo-Seal prosthesis can be undertaken with a relatively low early mortality and morbidity. A low reoperation rate and high intermediate-term survival can be expected, but continued follow-up is needed to determine the long-term efficacy of this prosthesis.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
Since Bentall and De Bono’s first description of the use of a composite graft and valve for the complete replacement of an ascending aortic aneurysm and aortic valve, ¹ both the techniques of implantation and the types of valve and graft used have evolved. The currently preferred implantation technique, a modified Bentall procedure, involves excision of the aneurysm, implantation of a composite valve graft with direct attachment of the coronary arteries as buttons into the aortic graft and anastomosis of the graft distally to the divided aorta. ² Woven polyester has become the material of choice for most surgeons for prosthetic aortic replacement. Bleeding through the earlier porous grafts was a particular problem, and the classic inclusion technique was specifically designed to cope with this by making use of the aneurysm sac as a wrap-around to tamponade graft leakage. Grafts that required preclotting with albumin or blood have now been superceded by woven polyester impregnated with either collagen or gelatin, ^3,4 resulting in a prosthesis resistant to blood leakage through its interstices, one described as having ultra-low porosity.

More recently, composite prostheses for replacing the aortic root have become commercially available, and one such composite conduit is the Carbo-Seal ascending aortic prosthesis (Sulzer Carbomedics, Inc, Austin, Tex). The prosthesis combines a bileaflet CarboMedics prosthetic heart valve with a gelatin-impregnated, woven polyester graft. There is minimal tapering between the valve and the graft, which facilitates coronary implantation, especially where coronary mobilization is difficult (eg, in redo cases). The graft is retained by the titanium stiffening ring of the valve (Fig 1). The impregnation of the graft with gelatin confers ultra-low porosity and apart from simple washing, the graft needs no special treatment before implantation. The aim of this study was to retrospectively review the cases of all patients who underwent aortic root replacement with the Carbo-Seal prosthesis at two surgical centers in the United Kingdom and to determine risk factors for early mortality and the prevalence of early morbid events, as well as the intermediate term survival and freedom from reoperation.

View larger version (108K): [in this window] [in a new window]   Fig. 1. Incorporation of the graft into the valve housing.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

Operative details
A total of 143 patients underwent aortic root replacement with the Carbo-Seal ascending aortic prosthesis by a modification of the Bentall technique. ¹ Tight wrapping of the aortic aneurysm sac around the graft was not done owing to its association with late complications, ⁵ but loose wrapping was used occasionally as an aid to hemostasis. Redundant aortic tissue was excised, and the distal anastomosis was made to the divided aorta. Coronary reimplantation was performed by using the button technique ⁶ for 140 patients, by the inclusion technique for 2 patients, and by the Cabrol technique for 1 patient. ⁷ The prosthesis has an adequate sewing cuff as well as a graft that is easy to suture and does not fray when the coronary ostia are fashioned with a battery-operated cautery device.

The diameter of the aortic anulus determines the size of the prosthesis implanted. For valve sizes 21 to 31, the graft inner diameter is 3 mm larger than the valve size, and for a prosthesis with a valve size of 33 mm, the graft size is 34 mm. In this series a prosthesis with valve size of 23 mm was implanted in 27 patients (19%), size 25 was used in 54 patients (38%), size 27 in 30 patients (21%), and size 29 in 32 patients (22%). Gelatin-resorcin-formaldehyde tissue glue was used in 78 (55%) of cases. It was used in all patients with acute aortic dissection to facilitate apposition of layers of the dissected aorta at the distal anastomosis and in other cases to cover the anastomotic suture lines as determined by the individual surgeon’s preference. The mean duration of cardiopulmonary bypass was 129 ± 49 minutes, the mean ischemic time was 88 ± 29 minutes, and a variety of perfusion techniques were used. The femoral artery was cannulated in 127 patients (89%), the distal ascending aorta in 16 (11%). Venous return was established via the right atrium in 125 patients (87%) and the femoral vein in 18 (13%). Cold crystalloid potassium cardioplegic solution was given antegradely in 137 (96%) and retrogradely in 6 patients. Moderate hypothermia (28°C) was used in 84 patients (59%). Deep hypothermia (15°C-18°C) with circulatory arrest was used in 59 patients (41%). It was always used in patients undergoing repair of acute dissection or aortic arch surgery. The mean duration of circulatory arrest was 26 ± 14 minutes. Retrograde cerebral perfusion was used in 45 of these patients, with a mean duration of 23 ± 14 minutes. Aprotinin was used in 57 cases (40%).

All patients received anticoagulation with warfarin. This was commenced on the evening of the first postoperative day. The international normalized ratio (INR) was maintained between 2.5 and 3.5. If the INR had not reached the therapeutic range by day 3 postoperatively, then intravenous heparin was commenced and the activated partial thromboplastin ratio was also maintained between 2.5 and 3.5. Anti-platelet medication was not routinely prescribed. After patients were discharged from the hospital, their clinical status was obtained either from outpatient clinic visits to the hospital or by directly contacting the patient’s family doctor by letter and questionnaire. The total follow-up was 270 patient-years. Follow-up was 100% complete.

Statistical analysis
All continuous data are expressed as mean ± 1 SD or median ± interquartile range; categorical variables are reported as a percentage; a commercial statistical software package (SPSS for Windows, version 8.0, SPSS Inc, Chicago, Ill) was used for data analysis. A total of 26 preoperative and operative variables were analyzed for their possible influence on early mortality (defined as occurring within 30 days of operation or anytime before discharge). The preoperative variables were age, sex, previous cardiac surgery, preoperative NYHA class, cardiac rhythm, creatinine, presence of a pericardial effusion, left ventricular function, urgency of surgery, and indication for surgery. Operative variables included the operating surgeon, arterial and venous cannulation sites, type of cardioplegia, valve size implanted, use of tissue glue, aprotinin, lowest temperature, use of circulatory arrest, retrograde cerebral perfusion, concomitant procedure, aortic crossclamp and cardiopulmonary bypass time, use of an intra-aortic balloon pump, blood loss in the first 24 hours, and length of stay on the intensive care unit. Variables were first tested individually in a univariate logistic regression analysis. Subsequently, covariates found to be either significant (P < .05) or possibly significant (P < .2) were then entered into a multivariable logistic regression model. Survival and freedom from reoperation probability estimates were determined by Kaplan-Meier actuarial analysis; variability was expressed as ± 1 SEM.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

 
Early mortality
The early (30-day) mortality was 7% (10 patients). The causes of death are detailed in Table II. Of these 10 patients, 6 had undergone emergency surgery for acute type A dissection, 6 had undergone previous aortic or cardiac surgery, 7 had a concomitant procedure, and 6 were in NYHA class IV preoperatively. Three patients had acute myocardial infarction, resulting in early death. In no case was this related to technical problems with the coronary anastomoses. Two of these patients had severe underlying coronary artery disease. One had an acute infarction peroperatively and could not be weaned from cardiopulmonary bypass. The other had an unheralded MI 19 days postoperatively. The patient’s INR on the previous day was 3.2. The third patient who died of an acute myocardial infarction had received 5 g of tranexamic acid peroperatively, and acute coronary ostial thrombosis developed 12 hours postoperatively. The patient presented in cardiac arrest, and despite rapid institution of resuscitation, including commencement of cardiopulmonary bypass and coronary artery bypass grafting, the patient died. Six factors were found to be significantly associated (P < .05) with early death (Table III). By multiple logistic regression, however, only cardiopulmonary bypass time was found to be associated with increased early mortality in the presence of the other factors (P = .03). The odds ratio for cardiopulmonary bypass time was 1.0236 (95% confidence interval 1.0022 to 1.0456).

View larger version (14K): [in this window] [in a new window]   Fig. 2. Kaplan-Meier survival curve.

View larger version (15K): [in this window] [in a new window]   Fig. 3. Freedom from reoperation.

1. A 30-year-old man had infective endocarditis develop 117 days postoperatively and underwent a homograft aortic root replacement. He is currently alive and well and in NYHA class I.
   
2. A 71-year-old woman in whom a false aneurysm developed at the distal aortic suture line 153 days postoperatively, which necessitated repair on cardiopulmonary bypass though the prosthesis, did not need a replacement prosthesis. She is currently alive and in NYHA class II.
   
3. A 76-year-old man had endocarditis, including a large aortic root abscess, 256 days after aortic root and hemiarch replacement. Homografts were used to replace the root and arch, but the patient died of multisystem failure 29 days later.
   
4. A 26-year-old man with Marfan syndrome who had undergone a classical Bentall operation had a false aneurysm arising from the right coronary ostium. At 687 days postoperatively, a Carbo-Seal prosthesis was used with the button technique for the coronary anastomoses. He is currently well and in NYHA class I.
   

With regard to nonfatal valve-related complications, there were 2 patients who underwent reoperation for endocarditis, as discussed above. In addition, 3 patients had amaurosis fugax and began low-dose aspirin therapy and had no recurrence. There was no other reported incidence of valve-related complications during follow-up—no valve dysfunction, valve thrombosis, thrombotic embolism, or bleeding event.

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

 
Composite valve and graft replacement of the aortic root has become the generally accepted surgical technique for treatment of a variety of proximal aortic conditions, including aneurysm with aortic valve incompetence, aortic dissection, and infective endocarditis. Controversy exists, however, in the case of both aortic dissection and aneurysmal dilatation, particularly in patients with Marfan syndrome. Some favor aortic root replacement ^8,9; others advocate the sparing of the aortic valve leaflets, even when aortic insufficiency is present, because they believe the valve dysfunction is caused by dilatation of the sinotubular junction, distortion of the sinuses of Valsalva, or annuloaortic ectasia. ¹⁰ Currently, we elect to replace the entire aortic root, including the valve, in such patients. No patients in this series underwent root replacement for treatment of endocarditis where a homograft would be our choice.

The Carbo-Seal prosthesis was chosen because of the surgeons’ familiarity with CarboMedics prosthetic heart valves (Sulzer Carbomedics, Inc). A meta-analysis of CarboMedics prosthetic aortic valves has revealed excellent functional characteristics in combination with 5-year freedoms from thrombosis, thromboembolism, endocarditis, and reoperation of 100%, 94%, 98%, and 97%, respectively. ¹¹ The woven polyester Carbo-Seal graft is impregnated with cross-linked mammalian gelatin. The gelatin biodegrades by hydrolysis within 14 days. In collagen-coated grafts, however, the collagen is enzymatically metabolized and the rate of removal of collagen has been shown to be slower than that of gelatin. ³ Previous studies have shown the gelatin to be nonpyrogenic and to exhibit low thrombogenicity. In addition, no inflammatory reaction was induced, as determined by plasma C—reactive protein and ₁-acid glycoprotein. ^3,12 Collagen-coated grafts, however, have been shown to stimulate an increased inflammatory response arising from the incompletely absorbed collagen coating. ¹³ Six patients (4%) had a fever of unknown origin postoperatively, which resolved in all of them within 2 weeks. Although this may be related to an inflammatory response produced by the gelatin, experimental evidence suggests that this is not the case, ³ and these fevers may reflect mediastinal collections of blood around the graft.

The early mortality in this series of 7% compares with that of between 5% and 13% in other similar series. ^2,6,14-19 Direct comparison between these series is difficult, however, as the patient groups vary between the series. The number of emergencies, dissections, reoperations, and patients with Marfan’s syndrome all vary, as do the surgical techniques and prostheses used. On initial inspection, the incidence of early morbid events may seem high. In part, this probably reflects the thorough nature of this study and, in part, the relatively high-risk nature of the surgery itself. The most important complications from the patient’s standpoint, however, are those with long-term effects. These include a permanent pacemaker (8 patients), permanent neurologic deficit (3 patients), and omental transfer for sternal dehiscence in a patient with methicillin-resistant S. aureus infection.

Late complications were infrequent, given the complex nature of the surgery. Two patients had endocarditis develop, necessitating replacement of the prosthesis with a homograft. Two patients had a false aneurysm, 1 at the distal anastomosis, which was repaired without replacing the aortic root, and 1 from the right coronary artery button, after a classic Bentall procedure. This has been reported by others and seems to be associated with Bentall’s inclusion technique ⁵—probably the result of tension on the coronary ostial anastomoses resulting from the wrapping, particularly when blood accumulates within the wrap. ¹⁴ Our results give further support to other series advocating the button technique ^6,17 as no pseudoaneurysms have developed in the proximal aortic area when this technique has been used.

Actuarial survival of 83.1% ± 4.4% at 4 years compares very favorably with other series, ^2,6,18,19 including those in which higher risk patients, such as with emergency cases, have been excluded. ¹⁶ Our series, however, has relatively few patients reaching 4 years’ follow-up at present. Thromboembolism may occur more frequently after prosthetic aortic root replacement when compared with simple aortic valve replacement. Gott and associates ²⁰ found the incidence of minor thromboembolic and hemorrhagic events to be low (0.42% per 100 patient-years in a study of 270 patients), whereas Peigh and associates ²¹ reported a very high incidence of scotoma (50%) in a small group of patients with valve-conduit replacements. Amaurosis fugax was reported to us in 3 cases. None of the 4 patients whose cause of death was given as CVA underwent autopsy.

In conclusion, aortic root replacement using the Carbo-Seal ascending aortic prosthesis is effective treatment for aortic aneurysms and dissections involving the aortic root, both as a primary procedure and in patients undergoing a redo operation. The technique of aortic resection and direct coronary button implantation results in a relatively low operative mortality and morbidity, together with a high freedom from reoperation. In that the current study only addresses early and intermediate outcome, continued follow-up will be needed to determine the long-term efficacy of this prosthesis.

	References

Top Abstract Introduction Patients and methods Results Discussion References

 

1. Bentall H, De Bono A. A technique for complete replacement of the ascending aorta. Thorax 1968;23:338-9. [Medline]
   
2. Hilgenberg AD, Akins CW, Logan DL, Vlahakes GJ, Buckley MJ, Madsen JC, et al. Composite aortic root replacement with direct coronary artery implantation. Ann Thorac Surg 1996;62:1090-5. [Abstract/Free Full Text]
   
3. Drury JK, Ashton TR, Cunningham JD, Maini R, Pollock JG. Experimental and clinical experience with a gelatin impregnated Dacron prosthesis. Ann Vasc Surg 1987;1:542-7. [Medline]
   
4. Westaby S, Parry A, Giannopoulos N, Pillai R. Replacement of the thoracic aorta with collagen-impregnated woven Dacron grafts: early results. J Thorac Cardiovasc Surg 1993;106:427-33. [Abstract]
   
5. Kouchoukos NT, Marshall WG, Jr, Wedige-Stecher TA. Eleven-year experience with composite graft replacement of the ascending aorta and aortic valve. J Thorac Cardiovasc Surg 1986;92:691-705. [Abstract]
   
6. Svensson LG, Crawford ES, Hess KR, Coselli JS, Safi HJ. Composite valve graft replacement of the proximal aorta: comparison of techniques in 348 patients. Ann Thorac Surg 1992;54:427-39. [Abstract]
   
7. Cabrol C, Pavie A, Gandjbakhch I, Villemot JP, Guiraudon G, Laughlin L, et al. Complete replacement of the ascending aorta with reimplantation of the coronary arteries: new surgical approach. J Thorac Cardiovasc Surg 1981;81:309-15. [Abstract]
   
8. Bachet JE, Termignon JL, Dreyfus G, Goudot B, Martinelli L, Piquois A, et al. Aortic dissection: prevalence, cause, and results of late reoperations. J Thorac Cardiovasc Surg 1994;108:199-206. [Abstract/Free Full Text]
   
9. Fann JI, Glower DD, Miller DC, Yun KL, Rankin JS, White WD, et al. Preservation of aortic valve in type A aortic dissection complicated by aortic regurgitation. J Thorac Cardiovasc Surg 1991;102:62-75. [Abstract]
   
10. David TE, Feindel CM, Bos J. Repair of the aortic valve in patients with aortic insufficiency and aortic root aneurysm. J Thorac Cardiovasc Surg 1995;109:345-52. [Abstract/Free Full Text]
    
11. Akins CW. Results with mechanical cardiac valvular prostheses. Ann Thorac Surg 1995;60:1836-44. [Abstract/Free Full Text]
    
12. Vohra R, Drury JK, Shapiro D, Shenkin A, Pollock JG. Sealed versus unsealed knitted Dacron prostheses: a comparison of the acute phase protein response. Ann Vasc Surg 1987;1:548-51. [Medline]
    
13. Jonas RA, Schoen FJ, Levy RJ, Castaneda AR. Biological sealants and knitted Dacron: porosity and histological comparisons of vascular graft materials with and without collagen and fibrin glue pretreatments. Ann Thorac Surg 1986;41:657-63. [Abstract]
    
14. Aoyagi S, Kosuga K, Akashi H, Oryoji A, Oishi K. Aortic root replacement with a composite graft: results of 69 operations in 66 patients. Ann Thorac Surg 1994;58:1469-75. [Abstract]
    
15. Coselli JS, Crawford ES. Composite valve-graft replacement of aortic root using separate Dacron tube for coronary artery reattachment. Ann Thorac Surg 1989;47:558-65. [Abstract]
    
16. Jault F, Nataf P, Rama A, Fontanel M, Vaissier E, Pavie A, et al. Chronic disease of the ascending aorta. Surgical treatment and long-term results. J Thorac Cardiovasc Surg 1994;108:747-54. [Abstract/Free Full Text]
    
17. Kouchoukos NT, Wareing TH, Murphy SF, Perrillo JB. Sixteen-year experience with aortic root replacement: results of 172 operations. Ann Surg 1991;214:308-20. [Medline]
    
18. Lewis CT, Cooley DA, Murphy MC, Talledo O, Vega D. Surgical repair of aortic root aneurysms in 280 patients. Ann Thorac Surg 1992;53:38-46. [Abstract]
    
19. Lytle BW, Mahfood SS, Cosgrove DM, Loop FD. Replacement of the ascending aorta: early and late results. J Thorac Cardiovasc Surg 1990;99:651-8. [Abstract]
    
20. Gott VL, Gillinov AM, Pyeritz RE, Cameron DE, Reitz BA, Greene PS, et al. Aortic root replacement: risk factor analysis of a seventeen-year experience with 270 patients. J Thorac Cardiovasc Surg 1995;109:536-45. [Abstract/Free Full Text]
    
21. Peigh PS, DiSesa VJ, Cohn LH, Collins JJ Jr. Neurological and ophthalmological phenomena after aortic conduit surgery. Circulation 1990;82(5 Suppl):IV47-50.
    

This article has been cited by other articles:

				M.-H. Song, Y. Tokuda, T. Nakayama, and K. Hattori A Simple Method of Inspection of Proximal Bleeding in Bentall Procedure Asian Cardiovasc Thorac Ann, August 1, 2008; 16(4): 329 - 330. [Abstract] [Full Text] [PDF]

				Z. S Meharwal, S. N Khanna, A. Choudhary, M. Mishra, Y. Mehta, and N. Trehan Ascending aortic aneurysm resection: 15 years' experience. Asian Cardiovasc Thorac Ann, August 1, 2006; 14(4): 300 - 305. [Abstract] [Full Text] [PDF]

				D. K. Harrington, J. P. Lilley, S. J. Rooney, and R. S. Bonser Nonneurologic morbidity and profound hypothermia in aortic surgery Ann. Thorac. Surg., August 1, 2004; 78(2): 596 - 601. [Abstract] [Full Text] [PDF]

				K. Kirali, D. Mansuroglu, S. N. Omeroglu, V. Erentug, I. Mataraci, G. Ipek, E. Alcinci, O. Isik, and C. Yakut Five-year experience in aortic root replacement with the flanged composite graft Ann. Thorac. Surg., April 1, 2002; 73(4): 1130 - 1137. [Abstract] [Full Text] [PDF]

				A. Panos, B. Amahzoune, J. Robin, G. Champsaur, and J. Ninet Influence of technique of coronary artery implantation on long-term results in composite aortic root replacement Ann. Thorac. Surg., November 1, 2001; 72(5): 1497 - 1501. [Abstract] [Full Text] [PDF]

				C. Alexiou, S. M. Langley, P. Charlesworth, M. P. Haw, S. A. Livesey, and J. L. Monro Aortic root replacement in patients with Marfan's syndrome: the Southampton experience Ann. Thorac. Surg., November 1, 2001; 72(5): 1502 - 1507. [Abstract] [Full Text] [PDF]

				G. Michielon, L. Salvador, U. Da Col, and C. Valfre Modified button-Bentall operation for aortic root replacement: the miniskirt technique Ann. Thorac. Surg., September 1, 2001; 72(3): S1059 - 1064. [Abstract] [Full Text] [PDF]

				P. P. Urbanski, M. Wagner, M. Zacher, and R. W. Hacker Aortic root replacement versus aortic valve replacement: a case-match study Ann. Thorac. Surg., July 1, 2001; 72(1): 28 - 32. [Abstract] [Full Text] [PDF]

				C. Yakut A new modified Bentall procedure: the flanged technique Ann. Thorac. Surg., June 1, 2001; 71(6): 2050 - 2052. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Stephen J. Rooney Domenico Pagano Victor T. Tsang Robert K. Lamb James L. Monro Robert S. Bonser Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Langley, S. M. Articles by Bonser, R. S. Search for Related Content PubMed PubMed Citation Articles by Langley, S. M. Articles by Bonser, R. S.