Two dimensional echocardiographic evaluation of patients with mitral insufficiency

One hundred forty patients with clinical mitral insufficiency were studied with two dimensional echocardiography. Cardiac catheterization was performed in 51 patients; all had mitral insufficiency. Thirty-three patients were surgically treated. An etiologic diagnosis was made in 133 patients. Mitral valve prolapse (41 patients) was the most common cause of mitral insufficiency; the amount of valve insufficiency did not correlate with the leaflet involved or the severity of the prolapse. Patients with rheumatic disease either had combined mitral stenosis and insufficiency (27 patients) or pure mitral insufficiency (10 patients). Echocardiographic measurement of the mitral valve area separated patients with combined lesions from those with pure insufficiency. Fourteen patients had ruptured chordae tendineae; surgical findings were confirmatory in each patient who had valve replacement. Nineteen patients had left ventricular dysfunction; angiographie findings were confirmatory in each patient who underwent cardiac catheterization. Two dimensional echocardiographic findings reliably differentiated mitral insufficiency secondary to valve disease from that secondary to ventricular or papillary muscle dysfunction. Other causes of mitral insufficiency included mitral anular calcification (11 patients), idiopathic hypertrophic subaortic stenosis (5 patients), cleft anterior mitral leaflet (5 patients) and atrial myxoma (1 patient).     

Isolated cleft mitral valve: a variety of congenital mitral regurgitation identified by 2-dimensional echocardiography

Nine children with isolated cleft mitral valve, aged 1 day to 12 years, were studied. The electrocardiogram showed a normal QRS axis in 5 subjects. Cardiac catheterization was performed in 4 patients and demonstrated severe mitral insufficiency in 3 but failed to clearly demonstrate a cleft mitral valve or gooseneck deformity. The mitral cleft was confirmed at operation in 2 patients. Two-dimensional echocardiography demonstrated a cleft dividing the anterior mitral leaflet into 2 portions in each patient. The mitral anulus was normally positioned and the atrioventricular septum present. Atrial and ventricular septa were intact. Features similar to anatomic studies such as accessory chordae and thickening of the edges of the cleft with increasing age were also seen. Two-dimensional echocardiography is the only method available to reliably diagnose isolated cleft of the mitral valve.     

Color Doppler echocardiography of isolated cleft mitral valve. Roles of the cleft and the accessory chordae.

To study the mechanism of altered mitral function in the presence of an isolated cleft mitral valve (ICMV) with regard to the relative roles of the cleft and of the accessory chordae, seven patients with ICMV were studied with color Doppler echocardiography. Mitral insufficiency ranging from mild to severe was demonstrated in six cases. The regurgitant jet originated in each case from the site of the cleft: in five patients the regurgitant jet had a narrow base originating exactly from the cleft; in the sixth patient, the regurgitant flow presented as a broad-based jet suggesting that accessory chordae restricted the motion of the anterior mitral leaflet. Turbulent flow in the left ventricular outflow tract, starting at the level of the accessory chordae, was found in one patient in whom a pressure drop of 44 mm Hg was detected with continuous-wave Doppler imaging. The altered function of the mitral valve cleft stems from two elements, the cleft itself and the accessory chordae. Color Doppler flow imaging showed that the cleft was the main factor causing mitral insufficiency. The accessory chordae played an additional pathogenetic role in two patients by causing restricted mitral motion or left ventricular outflow tract obstruction.     

Angiocardiographic/pathologic correlations in congenital mitral valve anomalies.

The angiocardiographic findings were reviewed in 21 patients with congenital mitral valve disease in whom the exact anotomic diagnosis was known independently. Patients with discordant (1)transposition and simple atrioventricular canal defects were excluded. No precise diagnosis was made in five patients (24%), all of whom had a cleft anterior leaflet or congenital short chordae. In the remainder, the specific diagnosis could have been made by injection of constrast medium downstream to the mitral valve alone in 15 (71%). Upstream injection was performed in 13 of these but would have made the precise diagnosis in only three (23%). In one patient both upstream and downstream injections were necessary. Anomalies giving characteristic angiocardiographic appearances were parachute valve, atresia, annular hypoplasia, dysplasia, anomalous arcade and anomalies associated with subaortic stenosis. Thus injection downstream to the valve is preferable to upstream injection, because it gives information about its patency, competence, tensor apparatus, and annular dimensions.     

Cleft of the mitral valve in patients with Down's syndrome

Differentiation between a cleft of the mitral valve and the cleft of the left side of an atrioventricular septal defect--a lesion commonly found in patients with Down's syndrome--is surgically important since the distribution of the conduction tissue varies between the 2 lesions. We sought to determine if cleft of the mitral valve occurs also in patients with Down's syndrome. We studied 5 patients with Down's syndrome and cleft of the mitral valve followed in our institution. Echocardiography showed in all 5 patients a cleft dividing the anterior (aortic) leaflet of mitral valve with normal papillary muscle position, mural leaflet size, and ratio of the inlet/outlet dimension of the left ventricle. Associated cardiac lesions were present in all 5 patients: perimembranous ventricular septal defect in 3, ostium secundum atrial septal defect in 2 and patent ductus arteriosus in 2 patients. During the 5.6 years (0.2-11) of the follow-up period, surgical repair of the cleft was never indicated since the mitral regurgitation through the cleft remained mild or absent in all the patients. Two patients underwent closure of a ventricular septal defect, with atrial septal defect closure in one and ductal ligation in 2. One patient died suddenly at home, without evidence of a cardiac cause. In conclusion, a cleft of the mitral valve has important developmental and morphologic differences with atrioventricular septal defect and may occur in patients with Down's syndrome. If surgical repair of the cleft or of associated cardiac lesion is indicated, it is necessary to distinguish it from atrioventricular septal defect where the conduction axis is displaced posteriorly and may be exposed during surgery.     

Chordal transfer in rheumatic mitral regurgitation: early experience

Chordal transfer and chordal replacement techniques have been quite successful for repair of anterior mitral leaflet prolapse in degenerative disease, but largely unexplored in rheumatic patients. To extend the scope of valve repair, we assessed the chordal transfer technique for correction of anterior mitral leaflet prolapse in 57 patients with rheumatic mitral regurgitation, who were treated between October 2008 and March 2010. There were 36 women and 21 men with a mean age of 25 ± 7.4 years. Normal chordae and a strip of leaflet tissue were transferred from the posterior leaflet to the free edge of the anterior leaflet; the posterior leaflet was repaired in the same manner as after quadrangular resection. Additional procedures were commissurotomy in 19 patients, aortic valve replacement in 1, tricuspid repair in 5, and cryo maze operations in 21. There was no hospital mortality. One (1.7%) patient had acute renal failure but recovered fully. There was moderate regurgitation in one patient who had undergone simultaneous aortic valve replacement. At a mean follow-up of 6.2 ± 2 months, 56/57 (98.2%) patients were asymptomatic with no significant mitral regurgitation.     

Mitral insufficiency due to an isolated anterior-leaflet cleft: correction with an autologous pericardial patch supported by artificial chordae

Congenital clefts of the mitral valve without an associated atrioventricular canal defect are rare, and they may cause mitral insufficiency that requires surgical correction. Repair is typically by direct suture; however, if the cleft is especially wide, the use of this technique may distort the valve leaflet and cause poor coaptation with valvular insufficiency.Herein, we present the case of a 39-year-old woman who had severe mitral valve insufficiency secondary to a wide isolated cleft of the anterior mitral leaflet. The valve was reconstructed with an autologous pericardial patch supported by polytetrafluoroethylene neochordae and an implanted annuloplasty ring. Echocardiographic examination 1 year postoperatively showed excellent competence of the mitral valve and good coaptation of the leaflets. To our knowledge, this is the 1st report that describes the use of artificial neochordae to support an autologous pericardial patch in the repair of a cleft in the anterior mitral valve leaflet.     

Mitral regurgitation with an isolated anterior mitral leaflet cleft: a case report.

A 20-year-old man was admitted to hospital because of general fatigue during exercise. He had had a heart murmur since the age of 6 years. Echocardiography showed severe mitral regurgitation (MR, IV), probably caused by an anterior leaflet cleft or tendon rupture. During surgery, a cleft measuring 9 mm in length was found in the center of the anterior leaflet of the mitral valve. The cleft was closed directly, together with annuloplasty using the bilateral Kay's method. A Cosgrove ring (32 mm) was added because the mitral valve annulus was dilated. The patient's postoperative course was uneventful and echocardiography after surgery demonstrated no MR. An isolated cleft of the anterior mitral leaflet is a rare cause of MR and in this case, direct closure of the cleft with additional annuloplasty gave a good functional result.     

二尖瓣成形治疗小儿二尖瓣关闭不全

目的 总结小儿二尖瓣关闭不全外科矫治经验。方法 回顾近12年我院收治75例小儿二尖瓣关闭不全患,其中男31例,女44例,年龄1．5－12岁,平均7．1岁。单纯二尖瓣关闭不全8例,合并其它心血管畸形67例。二尖瓣关闭不全轻度7例,中度47例,重度21例。二尖瓣脱垂24例,瓣叶裂38例,瓣叶发育不良2例,单纯二尖瓣环扩大11例。手术在中低温体外循环心内直视下进行,行腱索缩短13例（含多根腱索缩短4例）,乳头肌缩短1例,腱索移植3例,瓣叶修复41例,瓣环成形25例,二尖瓣置换2例。同时矫正合并心血管畸形。结果 全组无手术死亡。完全矫正二尖瓣关闭不全54例（71．2％）,残留少量反流17例（23．3％）,中度反流4例（5．5％）。术后随访1．5－13年（平均7．8年）,1例术后4．5年因急性左心衰再次行人工瓣置换术,1例合并严重肺动脉高血压术后5年死于右心衰竭,1例人工瓣置换术后失访。其余患发育良好,心功能均恢复正常。结论 二尖瓣成形术治疗小儿二尖瓣关闭不全可取得良好的效果。     

Congenital mitral valve anomalies in transposition of the great arteries

In 165 hearts with transposition of the great arteries, including 16 with a ventricular septal defect and overriding pulmonary trunk and 5 with a so-called posterior transposition, the left ventricle was studied with emphasis on the morphology of the mitral valve. Distinct mitral valve anomalies were found in 36 cases (22 percent), and four categories of anomalies could be identified. Group A Included 16 specimens with a cleft anterior mitral valve leaflet. The cleft was complete or partial. Partial clefts continued as a fibrous cord within the leaflet. In eight cases the cleft was situated posterior or lateral to the pulmonary ostlum; in these cases the left ventricular outflow tract was not narrowed. Severe outflow tract stenosis was present in another eight cases in which the cleft was located anterior to the pulmonary ostlum, usually in combination with a ventricular septal defect, and in four of these specimens there was straddling of the mitral valve.

Group B included eight hearts with an abnormal size or position of the mitral valve, or both, the valve being hypoplastic or rotated clockwise, or both. Group C comprised seven hearts showing redundant left ventricular structures involving the mitral valve, among which were anomalous tissue strands, subpulmonary rings and redundant valve tissue. Group D included five specimens with deficient papillary muscles.

It is concluded that an abnormal mitral valve is not unusual in hearts with transposition of the great arteries. The findings are notably Important for those patients for whom anatomic surgical correction of the transposition is considered. In comparison with the venous baffle procedure, this operation makes greater demands on the structure of the mitral valve because the pressure in the left ventricle remains at systemic level. Thorough Investigation of mitral valve anatomy and function is necessary before anatomic correction is considered.     

Isolated cleft posterior mitral valve leaflet: an uncommon cause of mitral regurgitation

A 53-year-old woman with a history of hypertension was referredfor an echocardiogram by her primary care physician after anunspecified abnormal ECG. The echocardiogram showed normal leftventricular size and function; however, an isolated cleft posteriormitral valve leaflet was identified with concomitant bileafletprolapse and mild mitral regurgitation. She was subsequentlyreferred to a cardiologist for clinical evaluation. Cleft mitralvalve leaflet (CMVL) is an uncommon congenital cause of mitralregurgitation. Clefts, defined as slit-like holes or defects,are hypothesized to be a result of incomplete expression ofan endocardial cushion defect which most commonly involves theanterior mitral valve leaflet with a paediatric incidence of1:1340. Clefts affecting only the posterior mitral valve leafletare extremely rare with only four cases being reported in themedical literature. Important co-existing anomalies with eitherposterior and/or anterior CMVL include counterclockwise rotationof the papillary muscles, the presence of an accessory papillarymuscle or mitral valve leaflet, atrial septal defects, and mitralvalve prolapse. Regurgitation from CMVL can lead to importantphysiological and anatomical changes within the cardiac system.Regurgitation results from blood flow directly through the cleftitself or from malcoaptation from accessory chordae with orwithout papillary muscle distortion. Significant chronic mitralregurgitation elevates left atrial filling pressures and leadsto chamber enlargement and eccentric left ventricular hypertrophy.Early detection through two-dimensional echocardiography canprovide accurate anatomical images of the various mitral valvestructures and identify associated congenital anomalies. Earlysurgical correction is preferred before mitral regurgitationcauses unfavourable remodelling. Most mitral valve cleft defectscan easily be repaired by suturing the edges of the cleft. Ifa cleft resection leads to limited residual valve tissue, theleaflet of the mitral valve can be reconstructed using an autologouspericardial patch pre-treated with buffered glutaraldehyde.Posterior CMVL is an uncommon but clinically important causeof mitral insufficiency. Early recognition of this rare clinicalentity and possible co-existent anomalies can identify the patientswho would benefit from surgical intervention before compensatoryleft ventricular remodelling and contractile dysfunction develop.     

Transfer of the posterior leaflet of the tricuspid valve to the mitral valve

BACKGROUND AND AIM OF THE STUDY: Coverage of large commissural defects may present a surgical challenge in mitral valve repair, for which the transfer of posterior tricuspid valve leaflet tissue is an attractive approach. METHODS: Five patients aged between 35 and 55 years underwent this procedure. After wide excision of the diseased mitral commissures, the posterior leaflet of the tricuspid valve was carefully checked, removed with its subvalvular apparatus, and transferred to the commissural area of the mitral valve. The stress on the papillary muscle suture was relieved by reinforcement of the free edge of the transferred leaflet by natural or artificial chordae. The tricuspid valve was repaired using either a sliding plasty or an annuloplasty. RESULTS: One patient who had no reinforcement of the subvalvular apparatus had a papillary muscle rupture and required mitral valve replacement during the early postoperative period. The four remaining patients remained asymptomatic and had no or trivial mitral regurgitation after a median of 13 months (range: 3-18 months), with excellent result at transesophageal echocardiography. CONCLUSION: We conclude that transfer of the tricuspid valve leaflet allows coverage of large commissural defect, and deserves a place among the surgeon's arsenal of reconstructive techniques for mitral valve repair.     

Valve repair for mitral insufficiency secondary to idiopathic juvenile polyarthritis

A female patient in whom idiopathic rheumatoid polyarthritis was diagnosed at the age of 8 years required surgery for severe mitral valve insufficiency 16 years later. Intraoperative analysis revealed a fibrotic endocarditis involving mainly the posterior leaflet. Granulomatous vegetations as well as a large thrombus which filled the left ventricular apex and simulated endomyocardial fibrosis were noted. Valve repair was achieved using an anterior leaflet augmentation with a patch of mitral homograft associated with a prosthetic ring annuloplasty. Postoperatively, a severe pericardial effusion required surgical drainage. Eight years later, the patient had no cardiac symptoms and echocardiography confirmed a normally functioning mitral valve.     

Transesophageal echocardiography as predictor of mitral valve repair

BACKGROUND AND AIM OF THE STUDY: Mitral valve repair has recently emerged as the treatment of choice in patients presenting with insufficiency due to valve prolapse. The study aims were to evaluate: (i) the clinical presentation in a consecutive series of patients with mitral valve prolapse undergoing surgical repair; (ii) the correlation between pre- and intraoperative echocardiographic features and surgical findings in these patients; and (iii) whether clinical and echocardiographic data may predict surgical outcome. METHODS: Between March 1997 and May 2000, 152 patients (110 men, 42 women; mean age 59+/-13 years) were recruited into the study. All patients had myxomatous mitral valve disease causing severe regurgitation and underwent systematic examination by transesophageal echocardiography (TEE) for clear delineation of the three scallops of the posterior leaflet and juxtaposed segments of the anterior leaflet. RESULTS: In 119 patients (78%) a flail valve was documented by TEE and confirmed on surgical inspection; an anterior leaflet chordal rupture was not visualized by TEE in one case. In 15 cases (10%) there was flail of the anterior leaflet, and in 105 cases (69%) flail of the posterior leaflet. A bileaflet complex prolapse without chordal rupture was found in 32 cases. On the basis of TEE evaluation, mitral valve replacement was performed electively in 10 patients (7%); the other 142 (93%) underwent mitral valve repair. Adequate repair was obtained in 93% of cases; residual mitral regurgitation (eight cases; grade 3+) and mitral stenosis (one case) were documented by intraoperative TEE, and nine patients (6%) underwent valve replacement. CONCLUSION: The majority of patients with myxomatous mitral valve prolapse and severe regurgitation undergoing valve repair have chordal rupture of the posterior mitral leaflet, a condition in which results of valve repair are excellent. TEE provides a powerful means to define the mechanisms of mitral regurgitation and to identify the suitability of patients for valvuloplasty.     

Mitral clefts and interatrial septum defects: 15-year results

Between 1985 and 2002, 60 patients (58% female) with a mean age of 20.3 +/- 12.1 years (range, 2-55 years) were treated for anterior mitral leaflet cleft. There was a primum atrial septal defect in 52 patients (87%) and a secundum type in 8 (13%). Concomitant cardiac defects were patent foramen ovale in 6 patients, cleft tricuspid valve in 3, ventricular septal defect in 2, cor triatriatum in 1, and persistent left superior vena cava in 1. Mean grade (1-4) of mitral insufficiency was 2.28 +/- 0.74. Atrial septal defects were closed with a pericardial patch in 45 patients, with a prosthetic patch in 11, and primarily in 4. Mitral leaflet clefts were repaired using interrupted sutures. There was no early or late mortality. Two patients (3%) needed a permanent pacemaker. Postoperatively, severe (> or =grade 3) mitral insufficiency developed in 2 patients; valve replacement was performed in one, cleft recurrence and leakage from the patch were treated in the other. Freedom from reoperation was 92.2% +/- 5.6% at 15 years. Surgical intervention can be performed for congenital anterior mitral leaflet cleft and interatrial septal defect with good results in both pediatric and adult age groups.     

Cleft anterior leaflet of the mitral valve with intact septa. A study of 20 cases

Twenty pathologic specimens of heart, each with a cleft in the anterior leaflet of the mitral valve not associated with septal defects of persistent common atrioventricular canal (isolated cleft of the mitral valve), were studied. In 9 cases, there were either no associated anomalies or ones not of functional significance. In each of the other 11 cases there were other significant associated cardiac anomalies, including ventricular septal defect and d-transposition of the great arteries. Functional consequences of the mitral anomaly were mitral insufficiency, subaortic stenosis, or both. Mitral insufficiency was related principally to the width of the cleft. Subaortic stenosis, when present, was due to the position of insertion of accessory chordae in the ventricular septum in a position under the commissure, between the left and right aortic cusps or under the right aortic cusp.     

Replacement of chordae tendineae with polytetrafluoroethylene (PTFE) sutures in mitral valve repair: early and long-term results

BACKGROUND AND AIM OF THE STUDY: A variety of reliable techniques are now available for chordal disease management and repair of the anterior mitral valve leaflet prolapse. The study aim was to review the authors' experience with polytetrafluoroethylene (PTFE), using a standardized technique for length adjustment, and to analyze the long-term results in patients who underwent mitral valve repair. METHODS: A total of 111 patients (mean age 56.2 +/- 16.1 years) underwent mitral valve repair with PTFE neochordae, in addition to a variety of other surgical procedures. Etiologies were degenerative in 82 patients (73.9%), Barlow disease in 13 (11.7%), rheumatic in 10 (9%), and infection in six (5.4%). Prolapse of the anterior leaflet was present in 78 patients (70.3%), of the posterior leaflet in 15 (13.5%), a bileaflet prolapse was present in 12 (10.8%), and a commissural prolapse in six (5.4%). In all cases the anterior annulus was used as the reference level in order to assess the appropriate length of the PTFE neochordae. RESULTS: The mean number of PTFE neochordae used was 6 +/- 4 per patient. In-hospital mortality was 1.8% (n = 2); mean follow up was 36.8 +/- 25.6 months (range: 12-94 months). There were no late deaths. At five years postoperatively the patient overall survival was 98.2 +/- 1.8%, freedom from reoperation rate 100%, and freedom from grade 1+ mitral regurgitation rate 97.2 +/- 2.8%. There were no documented thromboembolism or hemorrhagic events. CONCLUSION: In degenerative and myxomatous mitral valve disease, leaflet prolapse can be successfully repaired by implantation of PTFE neochordae. Both immediate and long-term results proved the versatility, efficiency and durability of this technique.     

Mid-term follow up of mitral valve reconstruction due to active infective endocarditis

BACKGROUND AND AIM OF THE STUDY: Mitral valve reconstruction in patients with acute endocarditis (AE) is a challenging operation which prompts the surgeon into immediate action. This report summarizes the mid-term results of 22 patients who required mitral valve reconstruction due to AE. METHODS: Mean patient age was 46 years (range: 20-79 years); mean follow up was 46 months (range: 1-90 months). Preoperatively, >70% of patients had severe mitral regurgitation and were in NYHA functional class III. Surgical techniques used were annuloplasty (n = 16; 10 with Carpentier ring, five Wooler-Kay and one Frater); suture closure of the perforation (n = 1), patch closure of the perforation (n = 5), leaflet resection with primary closure (n = 2), leaflet resection with patch closure (n = 8), and chordal transfer (n = 3). Additional surgery included CABG (n = 3) and De Vega plasty (n = 4). Aortic valve replacement or reconstruction (n = 9) included one mechanical valve, one bioprosthesis, one reconstruction and six homografts. Patients were followed up annually in our outpatient department and/or by questionnaires. RESULTS: Two patients died perioperatively due to either low output syndrome or uncontrolled sepsis. There were three reoperations; two of these were successful, and one patient subsequently died. In addition, one patient died six years after operation due to prostatic cancer, and one seven years later due to progressive heart failure. At the last follow up, 15 patients were in NYHA class I (68%) and five in class II (23%); no or only mild mitral insufficiency was seen on transthoracic echocardiography (91%). The estimated survival rate at 60 months was 87 +/- 12.7%, and 12 patients were followed up for >60 months. No incidence of recurrent valve infection occurred. CONCLUSION: Mitral valve reconstruction in patients with AE shows a low incidence of valve-related complications with promising postoperative functional results and mid-term survival. On this basis, mitral valve reconstruction for mitral insufficiency secondary to AE may be recommended as a valve salvage treatment, when it is technically possible.     

Leaflet escape in a TRI bileaflet rotatable mitral valve

Acute prosthetic valve dysfunction is a critical condition for any patient, and is associated with a high mortality. A 24-year-old man who had undergone mitral valve replacement with a TRI bileaflet valve four months previously at another center was admitted with acute-onset left ventricular failure. Echocardiography showed massive mitral insufficiency which was suggestive of a stuck valve. Emergency surgery was carried out, at which the cranial leaflet was found to be stuck open. There was no tissue impingement and thrombosis, the caudal leaflet was absent, and there were no signs of endocarditis or pannus formation. The TRI valve was removed and a replacement 25 mm bileaflet mechanical valve inserted. The embolized leaflet was found in the terminal aorta, but the patient died on day 66 after surgery due to sepsis which had developed from aspiration pneumonia. This is the first report of leaflet escape and terminal aortic embolization with the TRI bileaflet rotatable mitral valve. Acute deterioration of a patient with a prosthetic heart valve should suggest valve dysfunction for which appropriate treatment is rapid relief of the failing left ventricle and replacement of the defective valve with a functioning prosthesis.     

Repair of the anterior mitral leaflet*

Background: Repair rather than replacement of the diseased mitral valve has been the goal of the cardiac surgeon. Although well accepted for posterior leaflet pathology, a diseased anterior leaflet was believed by some to be irreparable.
Aims: To assess the result of reconstructive mitral valve surgery involving the anterior mitral leaflet in a selected group of patients.
Methods: Twenty consecutive patients with degenerative (19), ischaemic (one) and congenital/ calcific mitral regurgitation were evaluated. There were five females and 15 males with a mean age of 62 ± 12 years (41–75 years). The technique used to repair these valves included chordal transposition, leaflet plication commissuroplasty and a new technique we call leaflet repositioning.
Result: There were no deaths, follow-up is complete with mean follow-up of 31 ± five months (two-102) months. All patients have had 2DE and 13 TOE as well. There have been no reoperations due to failure of the repair, 95% of patients are in NYHA Class HI post operative, while 15% have significant residual regurgitation. (Aust NZ J Med 1993; 23: 279–284.)