Transfer of Advances in Science into Dental Education

Diabetes Mellitus as a Modulating Factor of

Endodontic Infections
Ashraf F. Fouad, D.D.S., M.S.
Abstract: Diabetes mellitus is a chronic disease with serious health consequences. The association between diabetes and periodontal disease is well documented. However, the progression and healing of endodontic infections in diabetic patients has not
been adequately studied. In this review, diabetes mellitus is explored as a potential modulating factor of endodontic pathosis.
Recent data on the relationship between the clinical presentation of pulpal and periradicular disease, as well as the outcome of
endodontic treatment in diabetic and nondiabetic patients, are presented. Diabetics who present for endodontic treatment,
particularly those with periradicular pathosis, may have increased perioperative symptoms. Cases with preoperative periradicular
lesions are less likely to be determined successful two years or longer postoperatively if the patient reports a history of diabetes.
Studies examining the pathogenesis of periradicular lesions in mouse models with uncontrolled type 1 diabetes suggest that the
lesion size may be increased and the animals have increased serious sequelae. Preliminary findings suggest that some bacterial
species may be more prevalent in necrotic pulp of diabetic than nondiabetic patients. More studies are needed to further explore
the microbiology of endodontic infections and to determine effective treatment strategies in both diabetic and nondiabetic
patients.
Dr. Fouad is Associate Professor, Department of Endodontology, School of Dental Medicine, University of Connecticut Health
Center. Direct correspondence and requests for reprints to him at Department of Endodontology, School of Dental Medicine,
University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-1715; 860-679-2726 phone; 860-6792208 fax; fouad@nso.uchc.edu.
Key words: endodontic infections, periradicular lesions, diabetes mellitus, outcomes analysis, NOD mice

iabetes mellitus is a chronic disease with

serious long-term debilitating complications
and no known cure. The relationship between
oral health and diabetes has been extensively studied, particularly with respect to periodontal disease
and, to a lesser extent, dental caries. Endodontic infections are very prevalent and are caused by microbial factors that are very similar to those that cause
periodontal disease. However, the literature on the
pathogenesis, progression, and healing of endodontic pathosis in diabetic patients is remarkably scarce.
In this review, the epidemiology and pathogenesis of
periradicular infections will be briefly described. The
literature addressing the natural history of endodontic infections and endodontic treatment outcome in
diabetics will be discussed. Finally, recent data on
the microbiology and host response in periradicular
infections of diabetic and nondiabetic hosts will be
presented.

April 2003

Journal of Dental Education

Epidemiology and
Pathogenesis of Periradicular
Lesions
Periradicular (PR) lesions result from irritation
of the PR tissues by polymicrobial irritants from root
canals, in teeth with necrotic pulps. The prevalence of
PR lesions in the general population of the United
States has not been established. However, estimates
based on prevalence in other countries and prevalence
among dental clinic populations in this country show
that the percentage of individuals with PR lesions in
at least one tooth is 41-47 percent.1-5 This prevalence
tends to increase to 60-72 percent in older patients.6,7
In dental patient populations, the percentage
of teeth with PR lesions has been estimated to range

459

from 3 to 5 percent of all teeth examined. However,

among teeth that have been endodontically treated,
the percentage with PR lesions is 31-61 percent.5,8-10
PR lesions are, therefore, quite prevalent, especially
in relation to endodontically treated teeth.
A significant clinical complication of PR disease is acute exacerbation, which results in significant pain that may be associated with localized or
spreading swelling. This dento-alveolar infection
causes significant pain and suffering for patients and,
occasionally, can cause significant morbidity or rarely
even mortality.11-14 Exact estimates of the likelihood
of acute exacerbation or its serious sequelae are not
available. According to the American Dental
Associations 2000 Survey of Dental Practice, about
10 percent of annual visits in general dental practitioners offices are walk-in and emergency visits.15
The percentage of dental emergencies is probably
much higher among patients of dental schools and
hospital-based dental clinics. It has been shown from
mail or phone surveys that 12-14 percent of the North
American population has acute toothache at any given
time.16-17 Some of these cases involve painful pulpitis
rather than painful PR lesions. The incidence of painful pulpitis and painful apical periodontitis in emergency dental patients has been estimated to be 35
percent and 31 percent respectively.18,19 Moreover,
some cases present as asymptomatic or mildly painful PR lesions, but the patients experience flare-ups
after initial root canal instrumentation, requiring unscheduled emergency visits. It has been reported that
interappointment flare-ups occur in 2-4 percent of
all endodontic cases.20,21
Another important complication of PR lesions
is resistance to therapy. Endodontic prognosis studies have shown that success rates of teeth with preoperative lesions range from 68 to 86 percent.22-26
These and other prognosis studies demonstrate that
the presence of a preoperative lesion lowers the
chances of long-term success compared with cases
with vital pulp, where a successful outcome occurs
in more than 90 percent of cases. While the reasons
for these less successful outcomes are not fully understood, it is thought to be primarily due to the difficulty of total elimination of microorganisms from
the root canal system, and possibly the dentinal tubules, in cases with endodontic infections.27
Taken together, cross-sectional studies show a
much higher percentage of endodontically treated
teeth with PR lesions than could be extrapolated from
prognosis studies. The reasons for this are not fully

460

understood, but may be due to the long period of time

(up to three to four years) that it takes PR lesions to
show complete radiographic healing.28 Also, traditional
prognosis studies that have reported higher success
rates are performed in dental schools with closer control over asepsis and restorative aspects than is generally possible in the general population, which may
account for the relatively high success rate.
Another factor that may be an important determinant of disease severity is the preoperative size of
the lesion. Larger lesions may be associated with the
presence in the root canal of more than six cultivable
bacterial species29 and a higher number of cultivable
bacterial cells.30 Larger lesions may also be slower
to heal completely, and therefore appear to have incomplete healing in some studies.26 Numerous studies have used lesion size to examine the pathogenesis and healing of PR lesions in animal models and
have documented their findings in terms of lesion
size either histomorphometrically31-34 or radiographically.35-37 More studies are needed to determine if the
radiographic size of PR lesions in patients is related
to the virulence of root canal microorganisms and if
the rate of reduction in size correlates with the effectiveness of treatment.

Pulpal and Periradicular

Disease in Diabetic Patients
About 17 million people in the United States
(6.2 percent of the population) have diabetes.38 Close
to one third of these individuals (5.9 million or 2.2
percent) are undiagnosed, mostly type 2, diabetics.
Minorities have increased prevalence of diabetes; it
is estimated that 13 percent of non-Hispanic blacks,
10 percent of Hispanic/Latino Americans, and 15
percent of American Indians and Alaska Natives receiving care from the Indian Health Service have
diabetes. Type 1 diabetes represents about 5-10 percent of all diagnosed cases, or about 0.5-1 million
patients.
About 1 million new cases of diabetes are diagnosed every year, and in 1999 about 450,000 deaths
occurred among people with diabetes aged twentyfive years or older. Of those individuals, 68,399 had
diabetes noted as the underlying cause of death, making diabetes the sixth leading cause of death in the
United States.

Journal of Dental Education Volume 67, Number 4

There are numerous reports documenting, quite

convincingly, that diabetes mellitus (DM), especially
when poorly controlled, is associated with significant periodontal disease and tooth loss due to periodontal disease.39-44 However, in patients with DM,
very little data are available on the pathophysiology
and clinical progression of PR lesions or the prognosis of endodontic treatment. An earlier report45
proposed that healing of periapical lesions will not
occur if diabetes is not controlled and that the lesions will increase in size despite endodontic treatment. In a Swedish subpopulation, female residents
with long-duration insulin-dependant DM (IDDM)
were found to have an increased prevalence of endodontically treated teeth with PA lesions than residents
with short-duration IDDM or age- and sex-matched
nondiabetics.46 This difference was statistically significant in all individuals with more than one PR lesion. In an earlier clinical study,47 radiographic healing of PR lesions following endodontic treatment was
closely monitored in twelve patients with low plasma
glucose (70-89 mg/dL) and thirteen patients with high
glucose (90-110 mg/dL). None of the patients in either group was a known diabetic. At the endodontic
treatment visit, blood glucose measurement was done
two hours postprandially. After thirty weeks, the PR
radiolucencies in the low glucose groups were reduced by an average of 74 percent compared with a
reduction of only 48 percent for the high glucose
group. Another study reported that patients with DM
had a disproportionately high percentage of clinically
severe pulpal or periodontal infections (24 percent
of all cases), but had a much lower percentage of
moderate infections (2.3 percent).48 Taken together,
these reports provide preliminary findings that suggest some differences in the natural history of endodontic infections in the diabetic patient. Clearly, larger
scale studies performed with a more objective design are needed to test the hypotheses presented.

Outcome of Endodontic
Treatment in Diabetic and
Nondiabetic Patients
Since the mid-1990s, the Department of
Endodontology of the University of Connecticut
Health Center has developed and used an Endodontic Electronic Record (EER) system. This is a secured client/server database system that allows

April 2003

Journal of Dental Education

chairside entry of medical history and endodontic diagnosis and treatment data of all predoctoral and postgraduate student patients. The system also organizes
endodontic follow-up examinations and contains data
on treatment outcome for those cases where the patients did return for follow-up examination.
The percentage of new endodontic patients who
reported that they have diabetes in the last six years
is shown in Figure 1. These figures are close to 4
percent, which is the percentage of known diabetics
in the general population (6.2-2.2 percent, as noted
before). In the patient cohort studied, diabetics represented 4.6 percent of all patients, but had 5.2 percent of the endodontic cases.
Data on nonsurgical endodontic cases entered
from 1995 for predoctoral students and 1997 for postgraduate students through October 2001 were analyzed with respect to variables on clinical presentation, diagnosis, flare-up rates, and treatment outcome
in diabetic and nondiabetic patients.49 Treatment outcome was restricted to cases that have been followed
up for two years or longer after obturation, including all cases that failed at any time. The sample consisted of data on 7,516 endodontic cases (5,244 patients) that presented for endodontic assessment and/
or treatment, including 394 cases from 242 diabetic
patients (fifty-eight of whom were on insulin). For
diabetic patients, the designation of type 1 or type 2
was not used on older cases, since this classification
is relatively new,50 so reference was made only as to
whether the diabetic patients were managed with insulin. Of the whole cohort, 5,494 cases had endodontic treatment completed, and the rest did not need
treatment or had treatment started but not completed.
An examination of all presenting patients revealed that, in patients diagnosed with PR lesions,
diabetic patients on insulin tended to have a higher
incidence of PR pain compared with the non-insulin
dependant diabetics or the nondiabetic patients (Chisquare; p=0.058). Diabetics in general also had about
twice the rate of flare-ups compared to nondiabetics
(4.8 percent vs. 2.3 percent, Chi-square; p=0.09). No
differences were found between diabetics and
nondiabetics with PR lesions in the presence of sinus tracts, swelling, or the size of the PR lesion as
noted by the providers.
In cases that were followed up after obturation,
success was generally defined as the lack of any signs
and symptoms and the complete radiographic healing of PR lesions. Cases with no signs and symptoms that had reduction but incomplete healing of

461

Figure 1. Prevalence of diabetes mellitus in new endodontic patients of predoctoral students and postgraduate
endodontics students in 1997-2002

the lesions were classified as uncertain; any other

cases were classified as failing. Only 540 cases (including seventy-three cases from diabetic patients)
had follow-up data longer than two years postoperatively. These cases, which represented about 10 percent of the initial sample, included all cases determined to have failed at any time. Using univariate
analysis, the following individual factors were found
to significantly affect the treatment outcome in the
total recall sample: presence of preoperative PR lesion, presence of a permanent restoration at the time
of follow-up examination, length of time to recall,
primary treatment vs. nonsurgical retreatment, treatment provider (predoctoral vs. postgraduate student)
and the age of the patient. Diabetes did not affect the
treatment outcome in the total sample. However,
when only cases with preoperative PR lesions were
considered (174 cases including sixteen from diabetic patients), diabetics had a much lower percentage of successful cases compared with nondiabetics.
Therefore, a hierarchical logistic regression analysis
was performed on cases with preoperative lesions,
which considered all the significant factors mentioned previously in addition to the gender of the
patient. The results showed that diabetics with preoperative PR lesions had a significantly lower chance

462

of successful outcome at two years or longer postoperatively compared with nondiabetics (p<0.001).
There were many uncertain cases in this study, and
since a large sample of patients with longer followup periods of three or four years was not available, it
is not known whether diabetes prevents or merely
delays the healing process of preoperative PR lesions.
We are currently working on analyzing the outcome
after longer evaluation periods and with larger groups
of patients.

Pathogenesis of Periradicular
Lesions in Type 1 Diabetic
Animal Models
Animal models allow the testing of the specific hypotheses with fewer confounding variables
than can be tested in clinical studies. The pathogenesis of PR lesions can be studied in relation to standardized amounts and types of irritants, and could
be examined radiographically, histologically, and
histomorphometrically. Moreover, the expression of
certain inflammatory mediators can be examined at
the mRNA or the protein levels.

Journal of Dental Education Volume 67, Number 4

There are a number of different rodent models

for diabetes, particularly type 1 diabetes. Two models are commonly used: Streptozotocin-induced diabetes in rats and non-obese diabetic (NOD) mice.
The advantages of the Streptozotocin model is that
diabetes can be induced in a controlled manner in all
animals and the animals in the diabetes and
nondiabetes groups are of same genetic background.
However, Streptozotocin, which is selectively cytotoxic to the islet cells in the pancreas, may also be
cytotoxic to other tissues such as the liver and kidneys. Using Streptozotocin-induced hyperglycemic
rats, Kohsaka et al.51 demonstrated that induced PR
lesions were larger in size than in nondiabetic controls. No significant infections or mortality among
the animals were reported.
The NOD mouse is a closer model to human
type 1 DM.52 About 40-70 percent of these animals
(more so in females) spontaneously develop autoimmune DM, marked by glucosuria, insulitis, and
weight loss. Diabetes onset is marked by increase in
autoantibodies to insulin and glutamic acid dehydrogenase (GAD).53
We compared the pathogenesis of PR lesions
in diabetic NOD and nondiabetic BALB/c mice.54 In
this study, lesions were induced by two methods.
Either the pulp was exposed to the oral cavity for
two or five weeks, or the exposures were inoculated
with three endodontic bacterial pathogens: Fusobacterium nucleatum, Peptostreptococcus micros, and
Streptococcus intermedius, for one or five weeks. The
inoculated groups were intended to simulate a virulent endodontic infection, where the one-week group
was sealed with a dentin bonding agent and the fiveweek group received reinoculation every other week.
Significantly more NOD mice expired prematurely as a result of PR lesion induction compared
with nondiabetic controls, particularly in the oneweek sealed inoculations group. Furthermore, among
the animals that survived to their predetermined time
points, NOD mice with pulp exposures lost significantly more weight than unexposed control NOD
mice, indicating increased morbidity. Histomorphometric and immunohistochemical analyses were performed of the PR lesions of the animals that survived to their predetermined time points to determine
the lesion size and expression of the bone-modulating cytokine interleukin-6 (IL-6). These analyses did
not reveal any differences between the diabetic and
nondiabetic animals. Similar analyses among the
animals that expired could not be performed.

April 2003

Journal of Dental Education

These studies suggest that the type 1 diabetic

host, with no glycemic control, may experience an
increase in PR lesion size, as well as in morbidity
and mortality in response to endodontic pathogens.
In the latter study, one more experiment was
performed on the five-week exposed mouse molars
that were inoculated with bacteria to explore the relative difference in sensitivity of anaerobic culturing
and molecular identification techniques. The results
showed that, in the case of the two strict anaerobes
used, F. nucleatum and P. micros, identification of
the bacteria using polymerase chain reaction (PCR)based methods was significantly more sensitive than
culture-based methods.54

Microbiological Findings in
Endodontic Infections of
Diabetic and Nondiabetic
Patients
One hypothesis that may explain why the diabetic host may be more susceptible to significant infections is the presence of different root canal microbial profiles in teeth with pulp necrosis and that
diabetics harbor a more virulent microbial profile.
A number of studies have compared the bacterial flora
associated with periodontal disease in diabetic and
nondiabetic patients with no conclusive findings. For
example, when sulcular flora from children and adolescents with type 1 DM was compared with that from
their nondiabetic siblings, there were no significant
differences.55 However, when these same groups were
followed for three years, there was a statistically significant increase in P. intermedia in patients with DM
at the deepest probing sites.56 Also, significantly more
P. gingivalis was recovered from insulin-dependent
diabetic patients.57 In these studies, no other significant differences between putative periodontal pathogens or correlation to the level of metabolic control
were found.58 Only traditional culturing methods were
used, with their classic limitations in these studies.
The use of the more sensitive technique of PCR amplification of 16S rDNA may reveal differences in
the flora of diabetic and nondiabetic patients.
The differences in treatment outcome that we
have previously observed in cases with PR lesions
and the trend toward increased apical symptoms or
interappointment flare-ups may be related to the pres-

463

ence of more virulent microorganisms in root canals

with necrotic pulp of diabetic patients. It is known,
for example, that diabetic patients have increased oral
candidiasis59 and are more likely to have the symptomatic variant of this disease.48 We have started conducting studies on molecular identification of root
canal microorganisms in endodontic infections of
diabetic and nondiabetic patients. We have elected
to use molecular methods because of their increased
sensitivity compared with culturing methods as noted
before. In a recent study, we sought to identify ten
putative endodontic pathogens from symptomatic and
asymptomatic, diabetic and nondiabetic patients with
pulp necrosis and PR lesions.60 Microbial samples
were collected aseptically from necrotic pulp of
twenty-four patients including six diabetics undergoing endodontic treatment. DNA was extracted from
the specimens and subjected to PCR amplification
with universal bacterial primers for the 16S rRNA
gene, as well as primers specific to the organisms
listed in Table 1. The results showed that F. nucleatum,
P. micros, and Streptococcus spp. were the most
prevalent of the microorganisms examined. There
were highly significant associations between Streptococcus spp., Odds Ratio (OR)=13, p<0.001, and
the combination of Streptococcus spp. and F.
nucleatum (OR=11, p=0.01) and preoperative pain.
With respect to diabetes, there was a positive, yet
nonsignificant, association between diabetes and the
presence of P. endodontalis (OR=4) and P. gingivalis
(OR=3.4). The number of different microorganisms
detected per specimen was, on average, higher in the
diabetic vs. nondiabetic specimens, but the differences were not statistically significant.

In another study,61 we have analyzed these microbial specimens for the presence of another virulent endodontic bacterial pathogen, Eubacterium spp.
Primers that are specific for several species of Eubacterium, but negative with other closely related
organisms, were used to amplify extracted DNA. The
resulting amplicons were directly sequenced using
the amplification primers and then phylogenetically
analyzed to reveal the identity of the individual Eubacterium species detected. The results revealed that
sixteen of twenty-two specimens (73 percent) were
positive for Eubacterium spp. Of those, nine (56 percent) were matched to E. infirmum, an organism that
has been detected in periodontal disease,62,63 but has
not been previously reported in endodontic infections.
The association between the presence of E. infirmum
and diabetes was found to be statistically significant
(OR=9.6; p=0.04). Taken together, these two studies
provide some preliminary data on the potential increased prevalence of some virulent endodontic
pathogens in root canals of diabetic patients. Larger
studies are currently under way to ascertain if these
or other associations are consistent.

Summary and Future

Directions
Endodontic infections lead to periradicular pathosis, which is mostly asymptomatic and is remarkably prevalent. Increased PR disease severity is manifested clinically by increased size of PR radiolucency,

Table 1. Prevalence of bacterial DNA in necrotic pulp specimens from twenty-four diabetic and nondiabetic patients
undergoing endodontic treatment
Microorganism

Percent of Positive Specimens

Universal bacterial 16S rRNA gene

Fusobacterium nucleatum
Peptostreptococcus micros
Streptococcus spp.
Prevotella nigrescens
Porphyromonas endodontalis
Bacteroides forsythus
Enterococcus spp.
Treponema denticola
Porphyromonas gingivalis
Prevotella intermedia

22 positive of 24 specimens
Diabetic Patients
(n=5)

Nondiabetic Patients
(n=17)

Total Positive Specimens

(n=22)

100 percent
40 percent
40 percent
20 percent
40 percent
20 percent
0 percent
20 percent
20 percent
0 percent

76 percent
53 percent
41 percent
35 percent
12 percent
18 percent
18 percent
12 percent
6 percent
6 percent

80 percent
50 percent
41 percent
32 percent
18 percent
18 percent
14 percent
14 percent
9 percent
5 percent

Source: Fouad AF, Barry J, Caimano M, et al. PCR-based identification of bacteria in endodontic infections. J Clin Microbiol
2002;40:1491-501.

464

Journal of Dental Education Volume 67, Number 4

associated symptoms of pain or swelling, or resistance to treatment.

The information available on the pathogenesis,
progression, and healing of pulpal and periradicular
pathosis in diabetic patients remains in its infancy.
Many clinical studies that have examined factors affecting the prognosis of endodontic therapy have either not reported on the medical history of patients
or have eliminated patients with compromised medical histories, such as diabetics, to minimize variables.
This problem may have been due to the difficulty in
controlling for the degree of glycemic control of diabetic patients or the difficulty in including patients
who have not received additional precautionary treatment, such as antibiotic therapy or tooth extraction,
which would not otherwise be done.
In this review, data was presented to show the
association between preoperative PR lesions in diabetics and a reduced therapeutic success at two years
or longer postoperatively, compared with
nondiabetics. Animal studies show that the induction of PR lesions in uncontrolled type 1 diabetic
rodent models is associated with increased lesion size
or morbidity and mortality. Finally, preliminary data
reveal some associations between the presence of
diabetes and increased findings of certain pathogenic
microorganisms in root canals with necrotic pulp.
A number of important unanswered questions
should be addressed in future research in this area.
More treatment outcome studies that utilize larger
patient databases, preferably in multiple centers,
should be performed. The glycemic control of the
patients should be studied as to whether it affects the
treatment outcome. Furthermore, the differences
between type 1 and type 2 diabetics should be explored. Diabetic patients, particularly older type 2
diabetics, have a number of concomitant medical
conditions that have to be carefully assessed when
performing these studies. The concomitant use of
antibiotics or antifungal agents for oral or nonoral
conditions should also be included in the analysis. The
microbial ecology in infected root canals, particularly
in diabetic patients, needs to be examined in more
detail and with high-powered studies. Likewise, the
microbial status of failing cases should be assessed.
An important goal of these studies should be the determination of effective antimicrobial agents and treatment strategies for both diabetic and nondiabetic patients. Ultimately, the objective of this research is to
preserve a healthy dentition throughout life.

April 2003

Journal of Dental Education

Acknowledgments
I gratefully acknowledge the contributions of
my collaborators on the studies reported. These studies were also supported in part by grants from DE/
OD 12037-01A1 and DE 14476-02 from NIDCR as
well as a grant from the American Association of
Endodontists Foundation.

REFERENCES
1. Bergstrom J, Eliasson S, Ahlberg KF. Periapical status in
subjects with regular dental care habits. Community Dent
Oral Epidemiol 1987;15:236-9.
2. Odesjo B, Hellden L, Salonen L, Langeland K. Prevalence of previous endodontic treatment, technical standard and occurrence of periapical lesions in a randomly
selected adult, general population. Endod Dent Traumatol
1990;6:265-72.
3. Ainamo A, Soikkonen K, Wolf J, et al. Dental radiographic
findings in the elderly in Helsinki, Finland. Acta Odontol
Scand 1994;52:243-9.
4. Seppala B, Ainamo J. A site-by-site follow-up study on
the effect of controlled versus poorly controlled insulindependent diabetes mellitus. J Clin Periodontol
1994;21:161-5.
5. Saunders WP, Saunders EM. Prevalence of periradicular
periodontitis associated with crowned teeth in an adult
Scottish subpopulation. Br Dent J 1998;185:137-40.
6. Palmqvist S. Oral health patterns in a Swedish county
population aged 65 and above. Swed Dent J Suppl
1986;32:1-87.
7. Eriksen HM, Bjertness E. Prevalence of apical periodontitis and results of endodontic treatment in middle-aged
adults in Norway. Endod Dent Traumatol 1991;7:1-4.
8. De Cleen MJ, Schuurs AH, Wesselink PR, Wu MK. Periapical status and prevalence of endodontic treatment in
an adult Dutch population. Int Endod J 1993;26:112-9.
9. Buckley M, Spangberg LS. The prevalence and technical
quality of endodontic treatment in an American subpopulation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
1995;79:92-100.
10. Weiger R, Hitzler S, Hermle G, Lost C. Periapical status,
quality of root canal fillings and estimated endodontic
treatment needs in an urban German population. Endod
Dent Traumatol 1997;13:69-74.
11. Bonapart IE, Stevens HP, Kerver AJ, Rietveld AP. Rare
complications of an odontogenic abscess: mediastinitis,
thoracic empyema and cardiac tamponade. J Oral
Maxillofac Surg 1995;53:610-3.
12. Garatea-Crelgo J, Gay-Escoda C. Mediastinitis from odontogenic infection: report of three cases and review of
the literature. Int J Oral Maxillofac Surg 1991;20:65-8.
13. Schuman NJ, Owens BM. Ludwigs angina following dental treatment of a five-year-old male patient: report of a
case. J Clin Pediatr Dent 1992;16:263-5.
14. Stoykewych AA, Beecroft WA, Cogan AG. Fatal necrotizing fasciitis of dental origin. J Can Dent Assoc
1992;58:59-62.

465

15. The 2000 survey of dental practice: characteristics of dentists in private practice and their patients. Chicago: American Dental Association, 2000:87.
16. Lipton JA, Ship JA, Larach-Robinson D. Estimated prevalence and distribution of reported orofacial pain in the
United States. J Am Dent Assoc 1993;124:115-21.
17. Locker D, Grushka M. Prevalence of oral and facial pain
and discomfort: preliminary results of a mail survey. Community Dent Oral Epidemiol 1987;15:169-72.
18. Gibson GB, Blasberg B, Altom R. A prospective survey
of hospital ambulatory dental emergencies. Part 2: follow-up to emergency treatment. Special Care in Dentistry
1993;13:110-2.
19. Sindet-Pedersen S, Petersen JK, Gotzsche PC. Incidence
of pain conditions in dental practice in a Danish county.
Community Dent Oral Epidemiol 1985;13:244-6.
20. Imura N, Zuolo ML. Factors associated with endodontic
flare-ups: a prospective study. Int Endod J 1995;28:2615.
21. Walton R, Fouad A. Endodontic interappointment flareups: a prospective study of incidence and related factors.
J Endod 1992;18:172-7.
22. Strindberg LL. The dependence of the results of pulp
therapy on certain factors. Acta Odontol Scand
1956;14:175.
23. Kerekes K, Tronstad L. Long-term results of endodontic
treatment performed with a standardized technique. J
Endod 1979;5:83-90.
24. Sjgren U, Hagglund B, Sundqvist G, Wing K. Factors
affecting the long-term results of endodontic treatment. J
Endod 1990;16:498-504.
25. Smith CS, Setchell DJ, Harty FJ. Factors influencing the
success of conventional root canal therapya five-year
retrospective study. Int Endod J 1993;26:321-33.
26. Chugal NM, Clive JM, Spangberg LS. A prognostic model
for assessment of the outcome of endodontic treatment:
effect of biologic and diagnostic variables. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 2001;91:342-52.
27. Siqueira JF, Jr. Endodontic infections: concepts, paradigms, and perspectives. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 2002;94:281-93.
28. Orstavik D. Time-course and risk analyses of the development and healing of chronic apical periodontitis in man.
Int Endod J 1996;29:150-5.
29. Sundqvist G. Bacteriological studies of necrotic dental
pulps (odontological dissertation no. 7). Umea, Sweden:
University of Umea, 1976.
30. Bystrom A, Happonen RP, Sjogren U, Sundqvist G. Healing of periapical lesions of pulpless teeth after endodontic treatment with controlled asepsis. Endod Dent
Traumatol 1987;3:58-63.
31. Stashenko P, Yu SM. T helper and T suppressor cell reversal during the development of induced rat periapical lesions. J Dent Res 1989;68:830-4.
32. Kawashima N, Stashenko P. Expression of bone-resorptive and regulatory cytokines in murine periapical inflammation. Arch Oral Biol 1999;44:55-66.
33. Fouad AF, Acosta AW. Periapical lesion progression and
cytokine expression in an LPS hyporesponsive model. Int
Endod J 2001;34:506-13.

466

34. Fouad AF. IL-1 alpha and TNF-alpha expression in early

periapical lesions of normal and immunodeficient mice.
J Dent Res 1997;76:1548-54.
35. Fouad AF, Walton RE, Rittman BR. Induced periapical
lesions in ferret canines: histologic and radiographic evaluation. Endod Dent Traumatol 1992;8:56-62.
36. Katebzadeh N, Sigurdsson A, Trope M. Radiographic
evaluation of periapical healing after obturation of infected
root canals: an in vivo study. Int Endod J 2000;33:60-6.
37. Balto K, Muller R, Carrington DC, Dobeck J, Stashenko
P. Quantification of periapical bone destruction in mice
by micro-computed tomography. J Dent Res 2000;79:3540.
38. National Institute of Diabetes and Digestive and Kidney
Disease. National diabetes statistics fact sheet: general
information and national estimates on diabetes in the
United States, 2000. Bethesda, MD: U.S. Department of
Health and Human Services, National Institutes of Health.
2002. At: www.niddk.nih.gov. Accessed: November 2002.
39. Vernillo AT. Diabetes mellitus: relevance to dental treatment. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2001;91:263-70.
40. Soskolne WA, Klinger A. The relationship between periodontal diseases and diabetes: an overview. Ann
Periodontol 2001;6:91-8.
41. Grossi SG. Treatment of periodontal disease and control
of diabetes: an assessment of the evidence and need for
future research. Ann Periodontol 2001;6:138-45.
42. Ponte E, Tabaj D, Maglione M, Melato M. Diabetes mellitus and oral disease. Acta Diabetol 2001;38:57-62.
43. Kornman KS. Patients are not equally susceptible to periodontitis: does this change dental practice and the dental
curriculum? J Dent Educ 2001;65:777-84.
44. Taylor GW. Periodontal treatment and its effects on glycemic control: a review of the evidence. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 1999;87:311-6.
45. Bender IB, Seltzer S, Freedland J. The relationship of systemic disease to endodontic failures and treatment procedures. Oral Surg Oral Med Oral Pathol 1963;16:1102-15.
46. Falk H, Hugoson A, Thorstensson H. Number of teeth,
prevalence of caries and periapical lesionsin insulin-dependent diabetics. Scand J Dent Res 1989;97:198-206.
47. Cheraskin E, Ringsdorf WM, Jr. The biology of the endodontic patient: 3. Variability in periapical healing and blood
glucose. J Oral Med 1968;23:87-90.
48. Ueta E, Osaki T, Yoneda K, Yamamoto T. Prevalence of
diabetes mellitus in odontogenic infections and oral candidiasis: an analysis of neutrophil suppression. J Oral
Pathol Med 1993;22:168-74.
49. Fouad AF, Burleson J. The effect of diabetes mellitus on
endodontic treatment outcome: data from an electronic
patient record. J Am Dent Assoc 2003;134:43-51.
50. American Diabetes Association. Report of the Expert
Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabet Care 1997;20:1183-97.
51. Kohsaka T, Kumazawa M, Yamasaki M, Nakamura H.
Periapical lesions in rats with streptozotocin-induced diabetes. J Endod 1996;22:418-21.

Journal of Dental Education Volume 67, Number 4

52. Atkinson MA, Leiter EH. The NOD mouse model of type
1 diabetes: as good as it gets? Nat Med 1999;5:601-4.
53. Bonifacio E, Atkinson M, Eisenbarth G, et al. International workshop on lessons from animal models for human type 1 diabetes: identification of insulin but not
glutamic acid decarboxylase or IA-2 as specific
autoantigens of humoral autoimmunity in nonobese diabetic mice. Diabetes 2001;50:2451-8.
54. Fouad AF, Barry J, Russo J, Radolf J, Zhu Q. Periapical
lesion progression with controlled microbial inoculation
in a type I diabetic mouse model. J Endod 2002;28:8-16.
55. Sbordone L, Ramaglia L, Barone A, Ciaglia RN, Tenore
A, Iacono VJ. Periodontal status and selected cultivable
anaerobic microflora of insulin-dependent juvenile diabetics. J Periodontol 1995;66:452-61.
56. Sbordone L, Ramaglia L, Barone A, Ciaglia RN, Iacono
VJ. Periodontal status and subgingival microbiota of insulin-dependent juvenile diabetics: a 3-year longitudinal
study. J Periodontol 1998;69:120-8.
57. Hugoson A, Koch G, Bergendal T, et al. Oral health of
individuals aged 3-80 years in Jonkoping, Sweden in 1973,
1983, and 1993: II. Review of clinical and radiographic
findings. Swedish Dent J 1995;19:243-60.
58. Tervonen T, Oliver RC, Wolff LF, Bereuter J, Anderson L,
Aeppli DM. Prevalence of periodontal pathogens with

April 2003

Journal of Dental Education

varying metabolic control of diabetes mellitus. J Clin

Periodontol 1994;21:375-9.
59. Guggenheimer J, Moore PA, Rossie K, et al. Insulin-dependent diabetes mellitus and oral soft tissue pathologies:
II. Prevalence and characteristics of Candida and Candidal
lesions. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 2000;89:570-6.
60. Fouad AF, Barry J, Caimano M, et al. PCR-based identification of bacteria in endodontic infections. J Clin Micro 2002;40:1491-501.
61. Fouad AF, Kum KY, Clawson ML, et al. Molecular characteristics of the presence of Eubacterium spp. and Streptococcus spp. in endodontic infections. Oral Microbiol
Immunol (in press).
62. Spratt DA, Weightman AJ, Wade WG. Diversity of oral
asaccharolytic Eubacterium species in periodontitis: identification of novel phylotypes representing uncultivated
taxa. Oral Microbiol Immunol 1999;14:56-9.
63. Cheeseman SL, Hiom SJ, Weightman AJ, Wade WG. Phylogeny of oral asaccharolytic Eubacterium species determined by 16S ribosomal DNA sequence comparison and
proposal of Eubacterium infirmum sp. nov. and Eubacterium tardum sp. nov. Int J Syst Bacteriol 1996;46:957-9.

467