Cutaneous papillomatous hyperplasia in cyclosporine-A treated beagles.

All twelve Beagle dogs undergoing long-term therapy (26 weeks) with the immunosuppressive drug cyclosporine-A (30 mg/kg), developed cutaneous papillomatous hyperplasia. By week 7 all dogs developed generalized lesions distributed over the entire body. These occurred as irregular, oval, sessile, unpigmented, firm masses. The incidence and severity of the skin lesions varied among dogs and anatomic site, with no correlation to the blood level of cyclosporine. Microscopic analysis revealed that the epidermis formed short papillary folds on broad fibrovascular stalks and was hyperkeratotic and acanthotic. Mild hyperplasia of hair follicles and sebaceous glands was also evident. A mild diffuse infiltrate of lymphocytes and plasma cells was present in the papillary dermis. No histopathologic changes typical of papillomavirus infection were identified, nor were papillomavirus group-specific antigens or viral DNA detected. Other cutaneous side effects included hyperkeratosis of footpads, increased growth of hair and nails, and hyperkeratinization of the haired skin of the prepuce. All cutaneous lesions regressed spontaneously within 8 weeks following termination of cyclosporine administration. The hyperplastic lesions may have resulted from the action of cyclosporine via the T-lymphocyte system. Conversely a direct action of this drug on epithelial cells may have stimulated proliferation and keratinization.

Gingival overgrowth in cyclosporine A treated multiple sclerosis patients.

Correlations have been reported between cyclosporine A (CsA)-induced gingival overgrowth (OG) and plaque-induced gingivitis, duration of CsA therapy, and blood and tissue drug levels. We evaluated the relative importance of such factors using data from a 2-year, double-blind study of CsA therapy in multiple sclerosis (MS) patients. Ninety subjects (40 taking CsA; 50 placebo) were evaluated for plaque, calculus, gingivitis, probing depths, attachment levels, and CsA levels in blood and saliva. OG was determined by a panel of 11 calibrated examiners from standardized clinical photographs taken at the end of the study. Logistic regression was used to determine which factors were associated with occurrence of OG. Four (17%) out of 23 CsA patients with CsA trough blood levels < 400 ng/ml exhibited OG. In contrast, 10 (59%) out of 17 CsA patients with CsA trough blood levels > or = 400 ng/ml were affected with OG. Logistic regression analysis resulted in odds ratios of 0.74 (P = 0.009), 17.3 (P = 0.024) and 10.1 (P = 0.030) for the associations between OG and age, CsA trough blood levels > or = 400 ng/ml, and the interaction "color x tone," respectively. In conclusion, the incidence of CsA induced OG appears to be higher with CsA trough blood levels greater than 400 ng/ml.

Evidence that healthy human gingiva contains functionally heterogeneous fibroblast subpopulations.

Six mass cultures of human fibroblasts derived from a single biopsy of a normal gingival papilla tip were studied with regard to their protein, collagen and glycosaminoglycan synthesis in vitro, using incorporation of radiolabelled substances. The proliferation rates, replicative life-spans and cell-size distributions of these mass cultures were determined. There were significant differences among the 6 cultures and these differences persisted throughout numerous cell replications in vitro. It is suggested that functional heterogeneity exists among phenotypically stable fibroblast subpopulations or subpopulation mixtures from normal tissue. The concept of participation of fibroblast subpopulations in disease pathogenesis is supported by these preliminary findings.

Enhancement by extracts of mineralized tissues of protein production by human gingival fibroblasts in vitro.

Non-confluent cell cultures were exposed to both guanidine and guanidine-EDTA extracts of cementum, dentine and alveolar bone, at concentrations from 2 to 50 micrograms/ml for 48 h. The cells were radioactively labelled during the last 24 h. Total protein production was measured via incorporation of radioactive proline; collagen production was estimated by digestion of the radioactive protein mixture with bacterial collagenase. All guanidine-EDTA extracts elicited statistically-significant increases in total protein production when compared to controls. At 50 micrograms/ml of extract, the increase in protein production was 340, 143 and 338 per cent for bone, cementum and dentine, respectively. Similar results were obtained for collagen production. Guanidine-EDTA extracts also stimulated an increase in the production of specific proteins, as ascertained by gel electrophoresis. In contrast, the guanidine extracts had no effect on either protein or collagen production. Thus the functions of gingival fibroblasts can be altered by proteins from associated mineralized tissues. Identification of such proteins and their biological functions would enhance knowledge of the mechanisms that regulate connective-tissue regeneration.

Valproic acid: a new antiepileptic drug with potential side effects of dental concern.

Although the exact mechanism by which valproic acid acts on hemostasis is unknown, an association between the agent and defective blood clotting and spontaneous hemorrhage is evident. This side effect should be considered in the management of dental patients taking the drug for whom treatment involves surgery of the soft tissues.

Summary of an International Symposium on phenytoin-induced teratology and gingival pathology.

Phenytoin has been the preferred drug for treating grand mal epilepsy for more than 40 years. The metabolism of this drug, its teratogenic potential, and its role in the pathogenesis of gingival overgrowth are discussed.

Osseointegrated dental implants as alternative therapy to bridge construction or orthodontics in young patients: seven years of clinical experience.

Young patients often require fixed bridgework or orthodontic therapy in cases of traumatic tooth loss or congenitally missing teeth. Dental implants represent an alternative to the more conventional treatment methods. We report positive experience over a seven-year period with 42 titanium Ha-Ti implants in 34 patients aged 9 to 18 years. Fourteen implants were placed into prepared tooth sockets immediately after traumatic luxation of anterior teeth in 12 patients aged 9 to 18 years (median age 16). An additional 22 patients (median age 15.5, range 11 to 18) also received implants (N = 28), but these were placed only after healing of extraction sites, or as substitutes for congenitally missing teeth. Implants remained in situ for an average of 7.7 months before loading. During the healing period, three implants were lost due to additional trauma and one became infected. The 38 remaining implants osseointegrated and since have been loaded for five to 79 months in successful function. There was no difference between immediate and delayed implants in clinical success. These experiences demonstrate that appropriate, versatile, osseointegrated implants can provide a successful treatment method for young patients, without damaging adjacent teeth.

Effects of chlorhexidine spray on plaque and gingival health in institutionalized persons with mental retardation.

In this study, eight institutionalized males received a 0.12% chlorhexidine gluconate spray twice daily. A second group of eight males received a placebo spray in the same manner. The results indicated that pump-administered chlorhexidine spray can effectively reduce plaque and gingivitis in patients with mental retardation who are unable to brush their own teeth.

Evidence for production of an inactive collagenase by fibroblasts from phenytoin-enlarged human gingivae.

When measured by radioimmunoassay, fibroblasts derived from the overgrown gingivae of phenytoin-treated epileptic individuals synthesize and release elevated amounts of collagenase in vitro, as compared to similar-appearing fibroblasts from normal, non-phenytoin-treated persons. However, it appears that much of the immunoreactive enzyme is unable to degrade reconstituted collagen in culture. This preliminary finding in 9 different strains of cells indicates that reduced collagenase activity by a subpopulation of cells may contribute to the development of phenytoin-induced gingival overgrowth.

Phenytoin sensitivity of fibroblasts as the basis for susceptibility to gingival enlargement.

A side effect of long-term administration of the anti-epileptic drug phenytoin is overgrowth of the connective tissues surrounding the teeth. In this in vitro study of protein and collagen synthesis by diploid fibroblasts from 17 nonepileptic young persons with healthy gingivae, only seven strains of cells responded to phenytoin in culture medium. Because not all phenytoin-treated individuals develop gingival overgrowth, we suggest that susceptibility is predicated upon the presence of a (genetically determined) phenytoin-sensitive subpopulation of gingival fibroblasts. The concept of the participation of sensitive cell subpopulations in other connective tissue disorders is supported by these findings.

Hemophilic dog model for evaluating therapeutic effectiveness of plasma protein fractions.

Therapeutic effectiveness of factor VIII inhibitor bypassing materials has been evaluated in dogs with hemophilia A. A standardized template gingival biopsy was performed using local anesthesia. Hemophilic dogs bled extensively from the biopsy site, whereas in normal dogs the wound was sealed within 5 + /- 2 min. If untreated, the hemophilic dogs frequently bled for several days. Factor VIII infusion stopped the bleeding promptly. Some experimental preparations of factor VIII inhibitor bypassing materials were shown to be therapeutically effective, whereas others were not. Intravascular thrombi could not be demonstrated histologically. The model should prove useful for evaluating factor VIII inhibitor bypassing materials and also for evaluating their mechanism of action.

Characterization of collagens in phenytoin-enlarged human gingiva.

The collagen content and composition of human gingivae enlarged due to phenytoin medication were compared to normal and inflamed gingival tissues. Phenytoin-enlarged gingiva contained significantly higher amounts of collagen. The ratio of type I to type III collagen was different in enlarged tissue, with less type I and an elevated amount of type III collagen present. The amount of type V collagen did not differ among normal, inflamed and phenytoin-enlarged gingivae.

Genetic influences in caries and periodontal diseases.

Deciphering the relative roles of heredity and environmental factors ("nature vs. nurture") in the pathogenesis of dental caries and diseases of the periodontium has occupied clinical and basic researchers for decades. Success in the endeavor has come more easily in the case of caries; the complex interactions that occur between host-response mechanisms and putative microbiologic pathogens in periodontal disease have made elucidation of genetic factors in disease susceptibility more difficult. In addition, during the 30-year period between 1958 and 1987, only meager resources were targeted toward the "nature" side of the nature/nurture dipole in periodontology. In this article, we present a brief history of the development of genetic epistemology, then describe the three main research mechanisms by which questions about the hereditary component of diseases in humans can be addressed. A critical discussion of the evidence for a hereditary component in caries susceptibility is next presented, also from a historical perspective. The evolution of knowledge concerning possible genetic ("endogenous", "idiotypic") factors in the pathogenesis of inflammatory periodontal disease is initiated with an analysis of some foreign-language (primarily German) literature that is likely to be unfamiliar to the reader. We identify a turning point at about 1960, when the periodontal research community turned away from genetics in favor of microbiology research. During the past five years, investigators have re-initiated the search for the hereditary component in susceptibility to common adult periodontal disease; this small but growing body of literature is reviewed. Recent applications of in vitro methods for genetic analyses in periodontal research are presented, with an eye toward a future in which persons who are at risk--genetically predisposed--to periodontal disease may be identified and targeted for interventive strategies. Critical is the realization that genes and environment do not act independently of each other; the appearance or magnitude of heritability may differ with various environments.

Synthetic activities of mass cultures and clones of human gingival fibroblasts.

The percentage of synthesis dedicated to collagen is elevated in low-density cultures of human gingival fibroblasts, as is per-cell total protein synthetic activity and glycosaminoglycan accumulation. These observations can be explained, in part, by a decrease in membrane transport of precursor substance in high-density cultures. Synthetic activity by human fibroblasts can be reliably assayed in vitro using as few as 500 cells sparsely seeded. Such low-cell number assay is essential for study of single-cell clones, where replicative life span is limited.

Phenytoin metabolism in the cat after long-term oral administration.

The metabolism of sodium phenytoin (PHT) in the cat was studied by gas-liquid chromatographic analyses of the drug and its metabolites extracted from plasma, urine, and feces during a 5-month course of daily oral administration. Plasma PHT levels of 15-18 micrograms/ml were observed. Urine contained 5-(4-hydroxyphenyl)-5-phenylhydantoin, 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin, 1-deoxy-1-(5,5-diphenylhydantoin-3-yl)-beta-D-glucopyranuronate, and unmetabolized PHT. Large quantities of PHT (32-63% of the daily dose) were observed in feces. We suggest that gastrointestinal malabsorption, extensive N-glucuronidation, and limited hydroxylation determine the fate of orally administered PHT in the cat. This is not the case in humans.

Cyclosporine-induced gingival overgrowth in beagle dogs.

Development of gingival overgrowth during daily long-term cyclosporine A treatment was studied in 2-yr-old beagles. Gingival enlargement developed in five of 12 dogs (42%), primarily in the mandibular anterior area. The earliest gingival changes occurred by 3 wk as an increase in the size of the interdental papillae. The lesions progressively became more severe, in some cases obscuring portions of teeth by wk 6. The redundant tissue exhibited an increase in connective tissue components and an inflammatory infiltrate primarily of plasma cells. Severity of the overgrowth varied in responding animals; both incidence and severity were related to the CSA concentration in blood. The mean CSA blood levels of responders were significantly greater than nonresponders at wk 3, 6 and 10. Since beagles develop gingival overgrowth similar to humans, they provide an excellent model to investigate the roles of local and systemic factors in the induction of gingival overgrowth.

Diphenylhydantoin (dilantin) gingival hyperplasia: drug-induced abnormality of connective tissue.

Various degrees of gingival overgrowth may occur in individuals taking diphenylhydantoin, a drug used widely in the treatment of epilepsy. The tissue overgrowth is made up predominantly of collagen, and may therefore be a useful model for analysis of fibrosis and some other connective tissue abnormalities. Fibroblasts derived from the overgrown tissue exhibit a level of protein synthetic activity approximately twice that of comparable cells obtained from nonepileptic control individuals and from the gingiva of age-matched epileptics taking the drug but not exhibiting gingival enlargement. In addition, 20% of the protein synthesized by cells from the affected tissue is collagen, whereas collagen accounts for only about 11% of the total protein produced by control cells of both types. The drug appears to induce or select for fibroblasts characterized by enhanced levels of protein synthesis and collagen production. This alteration persists through several cell replications in vitro in the absence of drug.