The distribution of gingival overgrowth in organ transplant patients

J Clin Periodonioi 1996; 23: S67-37I Printed in Denmark . AU rights reserved Copyright The distribution of gingival overgrowth in organ transplant patients © Munksgaard 1996 J. Mark Thomason^ Peter J. Kelly^ and Robin A. Seymour^ ^Department of Restorative Dentistry, The University ot Newcastle, Newcastle-upon-Tyne, NE2 4BW, ^Department of Medical Statistics, The University of Newcastle, Newcastle-upon-Tyne NE2 4HH, UK Thotnascm JM. Kelly PJ. Seymour RA: The distribution of gingival overgrowth in orgati transplant patient.K. J Clin Periodontol 1996; 23: 367-371. © Munksgaard, 1996, Abstract. The distributioti of gingival overgrowth was investigated in a cohort of organ transplant patients, who were tnedtcated with cyclosporin or the cotnbination of cyclosporin and a calcium channel blocking drug, Gingival overgrow th scores were significantly higher at buccal sites than lingual-palatally (/!<0,0001), There was no significant difference between upper and lower overgrowth scores (/)=O,88), The most severe overgrowth was seen in the canine region. Overgrowth between the central incisors was significantly less than in the canine region (p>0,044) and was similar to that m the molar and premolar region. Although raised overgrowth scores were associated with increased levels of plaque and gingivai infiammation. the distribution could not be explained by this observation. Cyclosporin was first used to prevent organ graft rejection in humans in 1978 (Calne et al, 1978) and is now the immunosuppressant of choice in organ transplantation. In addition, transplant patients are often concomitantly medicated with calcium channel blocking drugs (usually nifedipine), both to control the hypertension and to reduce the cyclosporin induced nephrotoxicity (Feehally et al, 1987), Gingival overgrowth has been reported in many patients medicated with cyciosporin {Rateitschak-Pluss et al, 1983. Wysocki et al, 1983. Tyldesley & Rotter 1984. Wondimu et al, 1993) and with calcium channel blocking drugs (Lederman et al, 1984, Ramon et al, 1984, Colvard et al, 1986. Miller & Damm 1992), Both the incidence and severity of gingival overgrowth in transplant patients is increased when patients are medicated with both cyclosporin and a calcium channel blocker (Thomason et al, 1993), Although cyclosporin-induced gingival overgrowth may effect all pans of the mouth (Tyldesley & Rotter 1984), it has been suggested that the gingival changes are more pronounced anteri- orly (Rateitschak-Pliiss el al, 1983. Bartold 1987, Wondimu et al, 1993). with the lesion betng most marked labially (Bencini et al, 1985. Van der Wail et al, 1985. Bartold 1987, Yusof 1989), Whilst these proposition are based on the observation from only a small number of cases. Somacarrera et al, (1994) have recently reported similar finditigs in a group of 39 patients who had been medicated with cyciosporin for a period of up to 6 months. The aim of the present study was to investigate the distribution of gingival overgrowth in a large cohort of transplant patients who had been medicated with cyclosporin for up to 13 years, and to compare this with the distribution of plaque deposits and the severity of gingival infiammation. Material and il^ettiods i94 dentate organ transplant patients participated in the study, which had received prior ethical approval from the combined Health Authority,'University Ethics Committee, Informed written consent was obtained from each patient prior to the investigation. Patients were recruited from the Car- Key words: gingival overgrowth: distribution: organ transplantation; cyciosporin Accepted tor publication 25 April t995 dio-Thoracic Unit and the Renal transplant out patient clinic of the Freeman Hospital. Newcastle, .All patients were more than 3 months posttransplant, and medicated with cyciosporin, Appro,ximately 2/3 of patients were concomitantly medicated with a calcium channel blocking drug. Patients required 6 of the 8 most anterior teeth in at least one jaw; to participate in the study, although the majority of patients had reasonably intact dentai arches. Gingivat overgrowth score Upper and lower full mouth aiginate impressions were taken for each patient. Gingival overgrowth was assessed on the plaster study models using the method described by Seymour et ai (Seymour et al, 1985), This was expanded to aliow recordings of ail interdental sites. The models were scored by one of the authors (JMT), In total. 8772 interdental sites were assessed, a little more than 75% of the maximum (1 i.64O) that would have been available in this number of patients, had they each been fuiiy dentate. The paptlla dis- 368 Thomason et at. tal to the last standing molar was not scored. At the same visit that the impressions for the models were taketi, periodontai measurements were recorded on the 8 most anterior teeth present in each arch in the order listed below. The plaque index system of Silness & Loe (1964) was used to assess the oral hygiene on the lingual, labial and interproximal stirfaces on these same teeth. The level of gingival inflammation was assessed using the papilla bleeding index of Saxer & Muhlemann (Saxer & Muhlemann 1975). Periodonta] probing depths were measured to the nearest mm using a colour-coded probe (PCP, Hu-Friedy). All measurements were taken from the crest of the gingival margin at 6 points around each tooth (Buccal; mesial, midpoint and distal; palatal/lingual; mesial, mid-point and distal). The number of sites s=4 mm in depth were recorded and expressed as a percentage of the total number of sites measured. 8/7 S/i 3/2 1/1 2/3 4/5 7/i 5M 3/2 1/1 Z/3 4/5 7/8 low«r sites Fig. I Graphic representation of mean overgrowth score (range of 0-5) for individual sites in both upper and lower jaws. tween the means overgrowth site scores was tested using one way analysis of Statistical analysis Results In total, a potential of 60 different interdental papillae were available for scoring in each patient. All papillae were classified into sites by the teeth mesially and distal to them (e.g., 18/ 17, 17/16, ... etc). These were grouped into 4 regions, viz: upper buccal. upper palatal, lower buccal and lower lingual. The mean values for each papilla in the four regions were compared using one-way ANOVA for each region. The effect of site, upper or lower, and buccal or palatal upon the overgrowth score, was assessed using analysis of variance upon the combined data from the 4 regions. Using the original scoring method described by Seymour et al (Seymour et al. 1985), the mean overgrowth score for the group was 30%. 81 of these patients (42"/.) had clinically significant overgrowth( scores ssidf'/n). The relationship between % gingival overgrim'th .score, and Yoprobing depths 94 mm. can be de- The relationship between ""/n gingival overgrowth score" (Seymour et al. 1985) and ""/a sites with a probing depth s=4 mm", for the same region, was assessed using linear regression analysis. As gingival bleeding index scores are based on the interdental site itself, the palatal and buccal papilla overgrowth scores for these were added. In a similar manner, the 2 interdental plaque scores for each interdental site were combined. The mean interdental overgrowth scores, corresponding to each of the gingival bleeding index scores and each summed interdental plaque score were calculated, along with the standard deviation of the means and 95'Mi coniidetice intervals. The differences be- 8/7 upper sites scribed by the following regression equation; % GO=2/.*-l-a50x% pd ^4, (/XO.OOOl for the slope, SE for slope= 0.048, i?^=35.1%). This equation predicts that each additional "'n site with a probing depth of 5=4 mm would equate to an increase of 0.50 in the outcome variable ""A, gingival overgrowth score". We could therefore predict that a patient with 16% of sites with a probing depth of s=4mm, would have an overgrowth score The mean gingival overgrowth site scores for each of the four regions are Table la. Mean site overgrowth scores corresponding to each of the gingival bleeding index scores Gingival bleeding index scores Mean overgrowth site score n SD 95"'l. Cl for mean 0 1 2.78 3.30 3.46 4.15 3.89 1155 434 306 150 26 1.70 1.87 1.83 1.77 1.45 2.68, 3.12. 3.25. 3.86, 3.31, 3 4 2.S8 3.48 3.67 4.44 4.47 p-value for the difference of niieans using ANOVA, ;i<0.0001. Table Ib. Mean site overgrowth scores corresponding to each of the summed interdental plaque scores Summed interdental plaque scores 0 1 2 3 4 5 6 Mean overgrowth site score 2.63 2.86 2.99 • 3.02 3.30 3.20 2.40 n SD 95'^t Cl for mean 587 247 897 209 481 35 71 .69 .88 .85 .72 .86 .64 .70 2.49, 2.62. 2.S7. 2.78, 3.13, 2.74, 2.00, /"-value for the difference of means using ANOVA, / K O . 0 0 0 1 . 2.77 3.10 3.11 3.26 3.47 3.76 2.80 The distribution of gingival overgrowth in organ transplant patients Table 2. Mean sites scores and standard deviation Site n Meai1 S,D, 8.'7 7/6 6/5 5/4 4/3 3/2 36 115 141 149 174 173 2/1 1/1 171 170 1,11 1.23 1.15 1.06 1,03 0,99 1,01 ,,,, 1/2 2/3 3/4 4/5 5/6 6/7 7/8 170 173 173 142 132 108 38 1.47 1.58 1,40 1,52 1,79 1,82 1,78 1,48 1,69 1,80 1.76 1.59 1.48 1,72 1,29 8/7 36 1 !5 141 149 174 173 171 170 170 174 173 142 131 109 39 0,69 0,87 0,89 0,93 !,12 1.19 1.11 0.9S 1.14 1,21 1,15 1,00 0.88 1,00 0,92 0,75 0,90 0,88 0,89 0,93 0,97 1.01 1.06 1.01 1.00 0.98 0,94 0,91 i,00 0,87 50 t20 151 171 193 193 190 189 187 193 194 171 158 116 44 1,30 1.39 1.26 1,36 1,68 2,17 1,92 1,38 1,85 1,95 1,49 1,35 1.19 1.41 1,20 1,02 1,09 0,87 0.91 0.88 1.12 1,11 , ,,. 1,04 1,10 1,16 0,9! 0,81 0,92 0.97 0.90 50 121 151 171 193 193 190 189 187 193 594 172 158 116 42 1,20 1,03 0,78 1,10 1,27 1,34 1,24 0,94 1.26 1.38 1,21 1,05 0,89 0,90 0,81 0.90 0,91 0,88 0,94 0,94 0,99 0,96 7,'6 6/5 5/4 4/3 3/2 2/1 I'l 1/2 2/3 3/4 4/5 5/6 6/7 7/8 S/7 7/6 6/5 5/4 4/3 3/2 2/1 1/1 1./2 2/3 3/4 4/5 5/6 bll 7/8 8/7 lib 6/5 5/4 4/3 V2 2/1 1/1 1/2 2/3 3/4 4/5 5.'6 6/7 7,'8 1,0€ 1,00 1,10 1.14 1.38 1.30 1.18 1,02 0,92 0.82 0.85 0,85 0,83 0,80 upper bruccal ^^^^^ , , "^PPei" palatal '*'*" , , , lower buceal *'^* illustrated in Fig, I, A significant difference (/>sO,002) in the mean papilla gingivai overgrowth scores was seen in each region. The highest mean overgrowth score in each of the 4 groups occurred in the canine region. The score for the papilla between the 2 centra] teeth was significantly less than the equivalent sites in the canine region (;)<0,044 in the upper arch, /;<0,0001 in the lower arch), and similar to those in the molar and premolar regions. The ANOVA upon the combined data showed a highly significant difference between site scores (/)<0,0001) and between buccal and palatal overgrowth scores (^<0,00011, but no difference between upper and lower overgrowth scores (/i=0,88). Between the 1st premolars in the upper and lower arches, 5086 (94° M) of the potential maximum number of sites (5432) were available for scoring. The lowest mean overgrowth score corresponded to a gingival bleeding index of 0, and increased for each subsequent gingival bleeding index score except the final score (4) where a small fall was seen (Table la). The differences between the mean overgrowth scores is highly significant (/)<0.0001), Again the mean overgrowth is seen to increase with increasing plaque scores until an interdental plaque score of 4 is reached (Table lb). The differences between the mean overgrowth site scores is again highly significant (/)<0,0001), The significance of the difference remains unchanged even if the overgrowth scores corresponding to the 2 highest plaque scores are ignored. Discussion , ,, lowerlmgual ^'"^^ Codes site e,g,. 8/7=papilla between 18 and 17 7/8=papilla between 27 and 28 Previous reports have suggested that drug-induced gingival overgrowth seems to have a predilection for the anterior teeth, and the labial sites are more affected than other sites (Rateitschak-Pluss et al. 19SJ. Bencini et al, 1985, Van der Wail et al, 1985. Bartold 1987. Yusof 1989, Wondimu et al, 1993. Somacarrera et al, 1994), There is no satisfactory explanation for this unusual distribution, and it affords confiicting evidence for the role of plaque and gingival inflammation in the expression of this unwanted effect. The labial aspect of the anterior teeth are more accessible to mechanical oral hygiene methods, and this is supported by the pattern of plaque distribution and tooth loss in otherwise healthy adults 369 (Lilentha! et al, 1965. Cumming & Loe 1973. Todd & Lader 1991). Our findings, in part, support this overall picture of the distribution of drug-induced gingival overgrowth. However, the more discriminating scoring method shows that the most pronounced overgrowth is on the labial gingiva in the canine region. Furthermore, the gingival tissue between the central incisors showed lower levels of overgrowth which are comparable to the levels of overgrowth seen in the premoiar and molar regions of the mouth (Fig, 1), Local anatomical features may play a role in the development and distribution of gingival overgrowth, Frenal attachments between the upper and lower central incisors could impose a physical restraint on the tissue and so impede the gingival changes. The action of the tongue in speech and mastication on the tightly bound palatal and lingual mucoperiosteum may afford some degree of resistance for these tissues against the development of excessive overgrowth. Further evidence that local factors may play a significant role in the expression of drug-induced gingival overgrowth has been supported by the observation that both nifedipine and amlodipine are sequestrated into the gingival crevictilar fluid {GCF) (Ellis et al, ^1992, Seymour et al, 1994), Such sequestration appears to be driven by local periodontal pathology. In particular, sites exhibiting inflammation show significantly greater drug sequestration when compared to non-inflamed sites (Ellis et al. (In Press)), If the local concentration of the drug does influence the severity of gitigival overgrowth, then local salivary dilution provided by the presence of the submandibular and sublingual ducts opening in the mid line, and the parotid ducts opening in the molar region, may account for the lower overgrowth scores seen at these areas. In addition, as the salivary concentration of cyclosporin is lower than that found in plaque (Keown et al, 1983. Niimi et al, 1990, Hefti et al, 1994). salivary dilution may also reduce any topical effects that plaque cyclosporin may induce in these regions. There is considerable evidence that the development and the severity of gingival overgrowth is related to the levels of oral hygiene and gingival inflammation (King et al, 1993. Pernu et al, 1993. Thomason et al, 1993), The re- 370 Thomason et al. suits illustrated in Tabies la and lb. provide further evidence to support this concept. Although the data relates oniy to the anterior teeth, there is a highly significant difference (/><0,OOOI) between the mean overgrowth scores corresponding with each of the gingivaJ index scores, A similar picture is shown for each of the summed plaque score values. Such a relationship still begs the question as to whether the gingival overgrowth is the cause or the result of the increased inflammation and pjaque ievels. At the highest index scores there is a slight tailing off of the gingival overgrowth score. This may be related to a problem of accurately recording these measures in the presence of extreme gingival distortion and the small number of sample sites with these scores (<3"'.,), In a recent study of 39 cardiac transplant patients (Somacarrera et al, 1994), the authors reported greater severity of gingival overgrowth at the front of the mouth. The individual tooth overgrowth scores (represented by the sum of the mean probing depth for each tooth at 6 months post transplant), did not suggest any difference in scores between canine and central incisor, as observed in this present study. It may be argued that the difference between these two studies simply reflects the difference in the number of patients examined in each study. In addition, the patients m the Somacarrera study had oniy been receiving cyclosporin for 6 months and so may represent a difference in the early lesion stage. Nevertheless, whilst a number of authors have used probing depths as a measure of gingivai overgrowth (Lundstrom et al, !9«2. Dahllof & Modeer i986. Wondimu et al, 1993. Somacarrera et a), 1994), this meastire only iJlustrates part of the picture, as it fails to take into account the changes in thickness seen in overgrown gingival tissue. Despite the highly significant relationship shown between the variable % sites with a probing depth 5= 4mm and the % gingival overgrowth score (/)<0,0001 for the slope) in the present study, probing depth measurements only account for 35.4% of the variability in " % gingivai overgrowth score" (the R' value). As the change in width of the gingiva is an important characteristic of the lesion, it is important that the scoring method accounts for this dimensional change. We can conclude from this study that gingival overgrowth is an extensive problem in organ transplant patients medicated with cyclosporin and calcium channel blockers. The anterior labial gingivai tissue, especially in the canine region, appears more susceptible to this unwanted effect than other parts of the mouth. Plaque and gingival inflammation are important determinants for the expression of gingival overgrowth, but the significance of the 2 factors in the development of the gingivai changes remains to be fiilly elucidated. References Bartold. P, M, 11987) Cyclosporin and gingival overgrowth, Journul of Oral Pathology 16, 463^68, Bencini, R L,, Crosti, C , Sala, F,, Montagnino, G,. Taramino. A,, Menni, S, & Piccin. no, R, (1985) Gingival hyperplasia by nifedipine. Report of a case, .4cta Dermatovenereohgica 65. 3b2-^65. Calne, R, Y,. Thiru. S,, McMaster. P.. Craddock. G, N,. White. D, J, G,, Evans. D, B,, Dunn, D, C . Pentlow. B, D & Rolles, K, (1*^78) Cyclosporin-A in patients receiving renal allografts from cadaver donors. Lancet 1, 1323-1,^27, Colvard. M, D,. Bishop. J,. Weissman, D, & Zusammenfassung Gargiulo (1986) Cardizem induced gingiDie Verteilungder gingivalen Wucherungen bei val hyperplasia: a report of 2 case.s, PeriOrgamransplaniation.ipatienten odontal Case Reports 8. 67-68, In einer Kohorte von OrgantransplantatpaCumming. B, R, & Loe. H, (1973) Consisttienten. die Cyclosporin oder eine Korabinatiency of plaque distribution in individuals on aus Cyclosporin und einem Calzium-Kawithout special home care instruction. nal-Blocker verabreicht bekamen. wurde die Journal of Periodontal Research 8, 94Verteilung von gingivalen Wucherungen tin100, ter,sucht. Die gingivalen Wucherungen Dahllof, G, & Modeer, T (19S6) The effect waren auf den hukkalen signifikant starker of a plaque control program on the develals auf den lingual'palatinalen Flachen opment of phenytoin induced gingival (/'<0,0001), Es gab keinen signifikanten Unovergrowth. Journal oj Clinical Periodonterschied zwischen den Werten fur Ober- und tology 13. 845-849, Unterkiefer (/)=0,88), Am starksten waren die Ellis, J, S,. Seymour, R, A,, Monkman. S, Wucherungen im Eckzahngebiet ausgepragt. C, & Idle. J, R, (1992) Gingival sequesDie Wucherungen zwischen den mittleren tration of nifedipine in nifedipine-induced Schneidezahnen waren signifikant geringer als gingival overgrowth. Lancet 339, 1382in der Eckzahnregion (/>3=0,044) und ahnelte 3, der im Molaren- und Pramolarengebiet, ObEllis. J, S,, Seymour, R, A,, Thomason, J, wohl die erhohten Wucherungswerte mit erM, & Idle, J, R, (1995) Periodontal factors hohten Werten fur Plaque und Gingivaentaffecting crevicular fluid sequestration of zundung verbunden waren. konnte die Verteinifedipine in drug-induced gingival overlung nicht durch diese Beobachtung erklart growth. Journal of Pcriodontat Research werden. 30, ni-llb. Feehally. J,, Walls. J,, Mislry; N,. Horsburgh. T. Taylor, J,. Vietch. P, S, & Bell. P, R, F, Resume (1987) Does nifedipine ameliorate cyclosporin A nephrotoxity? British Medical Distribution de I'hyperplasie gingivale chez les patients avant subi une transplantation d'orgaJournal 195. IW. ne Hefti. A, F. Eshenaur. A, E,. Hassell. T, La distribution de Thyperplasie gingivale a M, & Stone. C, (1994) Gingival overete etudiee dans une cohorte de patients growth in cyclosporine A treated multiple ayant subi une transplantation d'organe et sclerosis patients. Journal of Periodontotraites par cyclosporine ou par l'association logy 65. 744-749, de cyclosporine et d'un medicament bloKeown. P A,. Stiller. C, R,. Sinclair. N, R,. quant les canaus du calcium, Les scores de Carruthers. W, Howson. W. Stawecki. rhyperplasie gingivale etaient significativeM,. McMichael, J,. Koegler. J,, McKenzie, ment plus eleves dans les sites vestibulaires N, & Wall. W, (1983) The clinical relevance que du cote lingual/palatin (/J<0,O00I), H n'y of cyclosporin blood levels as measured by avait pas de difference significative entre les radioimmunoassay. Transplantation Proscores de I'hyperplasie des machoire,s supeceedings 15. 2438-41, rieures et inferieures (j) = 0,S8), L'hyperplasie King. G, N,. Fullinfaw, R,. Higgins. T, S,. la plus severe etait constatee dans ia region Walker. R, J,. Francis. D M, A, & Wiesende la canine, L'hyperplasie entre les incisives feld, D, (1993) Gingival hyperplasia in resuperieures etait significativement moins nal allograft recipients receiving cyciomarquee que dans la region canine (/is0,044) sporin-A and calcium antagonists. Journal et etait semblabie a celle de la region des mooj Clinical Periodontologv 20. 286laires et premolaires, Bien qti'il ait eu une as293, sociation entre les scores eleves d'hyperplasie Lederman. D,. Lumertnan. H,, Reuben. S, & et I'augmentation des niveaux de la plaque et Freedman. 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Journal of Oral Pathology & Medicine 19, 397^03, Pernu, H. E,, Pernu, L, M., Knuuttila, M, L, & Huttunen, K, R. (1993) Gingival overgrowth among renal transplant recipients and uraemic patients, Nephrology. Dialysis, Transplantation 8, 1254—8. Ramon, Y, Behar, S,, Kishon, Y, & Engelberg, I. S, (1984) Gingival hyperplasia caused by nifedipine - a prelinrtinary report. International Journal of Cardiology 5. 195-204. Rateitschak-Pliiss, E, M,, Hefti, A,, Lortsch. er, R, & Thiel, G, (1983) Initial observation that cyclosporm-A induces gingival enlargement in man. Journal of Clinical Periodontoiogy 10, 237-246, Saxer, U, P, & Muhlemann, H, R, (1975) Motivation und AufTciarung, Schweiz M.'ichr Zahnheiik SS. 905-919. Seymour, R, A,, Ellis, J, S,, Thomason, J, M,, Monkman, S, & Idle, J, R. (1994) Amlodipine-induced gingival overgrowth. Journal of Clinical Periodontology 21, 281283, Seymour, R. A., Smith, D. G & TurnbuU, D. N, {1985) The effect of phenytoin and sodium valproate on the penodontai health of adult epileptic patients. Journal of Clinical Periodontology 12, 4! 3-419, Silness, i. & Loe, H, (1964) Penodontai disease in pregnancy, II Correlation between oral hygiene and periodonta] condition, Acta Odontalogica Seandinavica 22, 121. Somacarrera, M, L,, Herandez, G,, ,Acero. J, & Moskow, B, S, {1994} Localisation of gingival overgrowth in heart transplant patients undergoing cyclosporin therapy. Journal of Periodontotogy 65, 666-670, Thomason, J. M,, Seymour, R, A. & Rice, N, (1993) The prevalence and severity of cyclosporin and jiifedipine-induced gingival overgrowth. Journal of Clinical Periodontology 20, 37^0. Todd, J, E, & Lader, D, (1991) Adult dental heaith 1988 United Kingdom, London: HMSO, chs. 97-111. Tyldesley, W. R, & Rotter, E. (1984) Gingival hyperplasia induced by cyclosporin-,A, British Dental Journal 157, 305-309, 371 van der Wall. E, E,, Tuinzmg, D, B, & Hes, J, {1985) Gingival hyperplasia induced by nifedipine, an arterial vasodilating drug. Oral Surgery. Oral Medicine. Oral Pathology 60, 3 8 ^ 0 , Wondimu, B,, Dahllof, G,, Berg, M. & Modeer, T, (1993) Cyclosporin-A-induced gingival overgrowth in renal transplant children. Scandinavian Journal of Dental Research 101, 282-6, Wysocki, G, P.. Gretzinger, H, A,, Laupacis, A,, Ulan. R. A, & Stiller, C. R, (1983) Fibrous hyperplasia of the gingiva: A side effect of cyclosporin A therapy. Oral Surgery Oral Medicine and Oral Pathology 55, 274-278, Yusof, W, Z, Y (1989) Nifedipine-induced Gingival hyperplasia. Journal of the Canadian Dental Association 55, 389-391, Address: J. Mark Thomason Department of Restorative Dentistry Dental School University of Newcasde-upon-Tyire Framlingion Place Nevi'castle-upon-Tyne NE2 4BW England Tel.: +44 91 222 8IS9. or -i-44 91 2574052 Fax: +44 91 222 6137 e-mail: J.M Thomason(aNewcastie.ac.uk