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1.  Characterization of Periodontal Structures of Enamelin-Null Mice 
Journal of periodontology  2013;85(1):195-203.
Enamelin-null (ENAM−/−) mice have no enamel. When characterizing ENAM−/− mice, alveolar bone height reduction was observed, and it was hypothesized that enamel defects combined with diet are associated with the periodontal changes of ENAM−/− mice. The aim of the present study is to compare the dimension of interradicular bone of ENAM−/− (knock-out [KO]) with wild-type (WT) mice, maintained on hard (HC) or soft (SC) chow.
A total of 100 animals divided into four groups were studied at 3, 8, and 24 weeks of age: 1) KO/HC; 2) KO/SC; 3) WT/HC; and 4) WT/SC. Microcomputed tomography was performed, and the following measurements were made between mandibular first (M1) and second (M2) molars: relative alveolar bone height (RBH), crestal bone width (CBW), bone volume (BV), bone mineral content (BMC), and bone mineral density (BMD). The position of M1 and M2 in relation to the inferior border of the mandible was also determined at 24 weeks. All variables were analyzed by one-way analysis of variance and Dunnett test for pairwise comparisons. Morphologic analyses were conducted on hematoxylin and eosin–stained sections.
Radiographically, the enamel layer was absent in ENAM−/− mice. Interproximal open contacts were observed exclusively in ENAM−/− mice, and the prevalence decreased over time, suggesting that a shifting of tooth position had occurred. Additionally, in the two ENAM−/− groups, RBH was significantly lower at 8 and 24 weeks (P <0.02); CBW, BV, and BMC were significantly less (P <0.05) at 24 weeks. No differences in BMD were found among the four groups. The molars migrated to a more coronal position in ENAM−/− mice and mice on HC. Histologic findings were consistent with radiographic observations. After eruption, the junctional epithelium was less organized in ENAM−/− mice.
The interdental bone density was not affected in the absence of enamelin, but its volume was, which is likely a consequence of alternations in tooth position.
PMCID: PMC4283203  PMID: 23646854
Amelogenesis imperfecta; dental enamel; dental enamel proteins; periodontium; x-ray microtomography
2.  Practice Based Research Networks Impacting Periodontal Care: PEARL Initiative 
Journal of periodontology  2012;84(5):567-571.
In 2005, the National Institute of Dental and Craniofacial Research /National Institutes of Health funded the largest initiative to date to affect change in the delivery of oral care. This commentary provides the background for the first study related to periodontics in a Practice Based Research Network (PBRN). It was conducted in the Practitioners Engaged in Applied Research & Learning (PEARL) Network. The PEARL Network is headquartered at New York University College of Dentistry. The basic tenet of the PBRN initiative is to engage clinicians to participate in clinical studies, where they will be more likely to accept the results and to incorporate the findings into their practices. This process may reduce the translational gap that exists between new findings and the time it takes for them to be incorporated into clinical practice. The cornerstone of the PBRN studies is to conduct comparative effectiveness research studies to disseminate findings to the profession and improve care. This is particularly important because the majority of dentists practice independently. Having practitioners generate clinical data allows them to contribute in the process of knowledge development and incorporate the results in their practice to assist in closing the translational gap. With the advent of electronic health systems on the horizon, dentistry may be brought into the mainstream health care paradigm and the PBRN concept can serve as the skeletal framework for advancing the profession provided there is consensus on the terminology used.
PMCID: PMC4264584  PMID: 22702516
Comparative effectiveness research; dentistry; evidence based dentistry; periodontal disease; research subjects
3.  Localized Aggressive Periodontitis Treatment Response in Primary and Permanent Dentitions 
Journal of periodontology  2014;85(12):1722-1729.
The comparative treatment response of children and young adults with localized aggressive periodontitis (LAP) affecting primary and permanent dentition is unknown. The objective of this study was to evaluate the influence of non-surgical periodontal therapy with adjunctive systemic antibiotics on the clinical outcome of children/young adults with primary versus permanent dentition affected by LAP.
A cohort of 97 African-American participants between the ages of 5–21 (30M; 66F; 22 primary and 75 permanent dentition affected), diagnosed with LAP were included. Patients presented with no significant medical history. All patients underwent periodontal therapy, which consisted of full mouth mechanical debridement at baseline, 3, 6, and 12 month appointments. Additionally, all patients were prescribed a one-week regimen of systemic antibiotics at the initial appointment. Clinical parameters were analyzed, including probing depth (PD), clinical attachment levels (CAL), bleeding on probing (BOP) and percentage of visible plaque.
Overall, periodontal therapy was found to be effective in improving the clinical outcomes of both primary and permanent dentitions. Although baseline CAL were similar between the groups, the reductions in mean CAL at 3, 6 and 12 months as well as reduction in % Plaque at 3 months were significantly greater in primary dentition as compared to permanent dentition.
Non-surgical therapy with systemic antibiotics is effective for LAP in both primary and permanent dentitions. A greater reduction in CAL in LAP of primary dentition may suggest that younger children may carry a greater propensity for positive treatment outcomes and healing potential as compared to children/young adults with permanent dentition.
PMCID: PMC4250294  PMID: 25186780
Adolescent; aggressive periodontitis; root planing
4.  Distinctive Tooth-Extraction Socket Healing: Bisphosphonate Versus Parathyroid Hormone Therapy 
Journal of periodontology  2013;85(1):24-33.
Patients with osteoporosis who receive tooth extractions are typically on either oral bisphosphonate or parathyroid hormone (PTH) therapy. Currently, the consequence of these therapies on hard- and soft-tissue healing in the oral cavity is not clearly defined. The aim of this study is to determine the differences in the therapeutic effect on tooth-extraction wound healing between bisphosphonate and PTH therapies.
Maxillary second molars were extracted in Sprague Dawley rats (n = 30), and either bisphosphonate (zoledronate [Zol]), PTH, or saline (vehicle control [VC]) was administered for 10 days (n = 10 per group). Hard-tissue healing was evaluated by microcomputed tomography and histomorphometric analyses. Collagen, blood vessels, inflammatory cell infiltration, and cathepsin K expression were assessed in soft tissue using immunohistochemistry, quantitative polymerase chain reaction, and immunoblotting.
Both therapies significantly increased bone fill and suppressed vertical bone loss. However, considerably more devital bone was observed in the sockets of rats on Zol versus VC. Although Zol increased the numbers of blood vessels, the total blood vessel area in soft tissue was significantly smaller than in VC. PTH therapy increased osteoblastic bone formation and suppressed osteoclasts. PTH therapy promoted soft-tissue maturation by suppressing inflammation and stimulating collagen deposition.
Zoledronate therapy deters whereas PTH therapy promotes hard- and soft-tissue healing in the oral cavity, and both therapies prevent vertical bone loss.
PMCID: PMC4245052  PMID: 23688101
Parathyroid hormone; tooth extraction; wound healing; zoledronic acid
5.  The association between clinical and radiographic periodontitis measurements during periodontal maintenance 
Journal of periodontology  2012;84(10):1382-1390.
To examine the association between clinical and radiographic periodontitis measurements during two years of periodontal maintenance.
Secondary analyses were performed from a two-year, double-blind, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of subantimicrobial dose doxycycline (SDD) in 128 postmenopausal osteopenic women with moderate to severe chronic periodontitis. Relative clinical attachment level (RCAL) and probing depth (PD) measures were made. Posterior vertical bite-wings were taken for alveolar bone density (ABD) and alveolar bone height (ABH) measurements. Generalized estimating equations were used to model associations.
One-year ABD changes and one-year RCAL/PD changes did not predict two-year ABH changes and ABH/ABD changes, respectively. Baseline RCAL and PD were positively associated with baseline ABH loss (p<0.0001) and baseline probing depths were associated with subsequent ABD and ABH loss (p<0.05 for each). Among placebo (but not SDD) participants, RCAL changes were associated with concurrent ABD loss (p=0.027) when considering one- and two-year changes combined. The odds of ABH loss were higher among sites with concurrent one-year ABD loss versus no change (OR=3.15, p<0.0001) or concurrent PD increases versus no change (OR=1.88, p=0.0025) when considering one- and two-year changes combined.
In postmenopausal osteopenic women undergoing periodontal maintenance, baseline PD was associated with subsequent ABD and ABH loss. Although no longitudinal change preceded another measurement change, changes in probing depths and relative clinical attachment levels appeared to reflect changes in the underlying alveolar bone over time.
PMCID: PMC3612134  PMID: 23205917
alveolar bone loss; doxycycline; osteopenia; periodontal attachment loss; periodontitis; postmenopause
6.  Expression Profile of Human Gingival Fibroblasts Induced by Interleukin-1β Reveals Central Role of Nuclear Factor-Kappa B in Stabilizing Human Gingival Fibroblasts During Inflammation 
Journal of periodontology  2009;80(5):833-849.
Interleukin (IL)-1β is a key cytokine in the pathogenesis of periodontitis, and it induces inflammatory mediators in periodontal diseases. We developed immortalized human gingival fibroblasts (HGFs), investigated the effects of IL-1β on the gene expression using expression arrays containing ~40,000 genes, and tested the role of nuclear factor-kappa B (NF-κB) in maintaining an activated HGF population.
Total RNA was isolated from IL-1β–induced and mock-induced control cells. Gene expression analyses were performed using expression arrays and confirmed by quantitative real-time polymerase chain reaction. Western blot analysis to show inhibitor of kappa B-alpha (IκBα) phosphorylation and immunostaining of cells for NF-κB nuclear translocation were performed. Apoptosis was confirmed by assay of poly ADP-ribose polymerase (PARP) cleavage.
A total of 382 probe sets corresponding to 254 genes were differentially expressed in IL-1β–induced cells (P <0.001). A total of 215 genes were upregulated, and 39 genes were downregulated. Most notable NF-κB pathway members (NFκB1, NFκB2, IκBα, IκBε, IκBζ, REL, RELB, and TA-NFKBH) were upregulated. IκBα was phosphorylated, and NF-κB accumulated in the nucleus. An IL-1β–induced set of 27 genes was downregulated by an NF-κB inhibitor, leading to a decreased number of viable cells and suggesting an antiapoptotic role for NF-κB.
IL-1β leads to a large number of significant expression changes consistent with a pathologic role in periodontitis, including enhancement of inflammatory cytokines, chemokines, transcription factors, matrix metalloproteinases, adhesion molecules, and especially NF-κB–dependent antiapoptotic genes. NF-κB activation blocks apoptosis, thereby stabilizing the HGF population in inflammation.
PMCID: PMC4150685  PMID: 19405838
Fibroblasts; gene expression; interleukin-1 beta; microarrays; nuclear factor-kappa B; real-time polymerase chain reaction
7.  Systemic Immune Responses in Pregnancy and Periodontitis: Relationship to Pregnancy Outcomes in the Obstetrics and Periodontal Therapy (OPT) Study 
Journal of periodontology  2009;80(6):953-960.
Our previous studies reported on the obstetric, periodontal, and microbiologic outcomes of women participating in the Obstetrics and Periodontal Therapy (OPT) Study. This article describes the systemic antibody responses to selected periodontal bacteria in the same patients.
Serum samples, obtained from pregnant women at baseline (13 to 16 weeks; 6 days of gestation) and 29 to 32 weeks, were analyzed by enzyme-linked immunosorbent assay for serum immunoglobulin G (IgG) antibody to Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans), Campylobacter rectus, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia (previously T. forsythensis), and Treponema denticola.
At baseline, women who delivered live preterm infants had significantly lower total serum levels of IgG antibody to the panel of periodontal pathogens (P = 0.0018), to P. gingivalis (P = 0.0013), and to F. nucleatum (P = 0.0200) than women who delivered at term. These differences were not significant at 29 to 32 weeks. Changes in IgG levels between baseline and 29 to 32 weeks were not associated with preterm birth when adjusted for treatment group, clinical center, race, or age. In addition, delivery of low birth weight infants was not associated with levels of antibody at baseline or with antibody changes during pregnancy.
Live preterm birth is associated with decreased levels of IgG antibody to periodontal pathogens in women with periodontitis when assessed during the second trimester. Changes in IgG antibody during pregnancy are not associated with birth outcomes.
PMCID: PMC4133130  PMID: 19485826
Antibody; bacteria; periodontitis; pregnancy; preterm birth
8.  Within-Subject Variability in Repeated Measures of Salivary Analytes in Healthy Adults 
Journal of periodontology  2009;80(7):1146-1153.
Saliva contains a large number of biomolecules, some of which have putative diagnostic usefulness. A potential problem with the use of biomolecules in diagnosis is day-to-day fluctuation due to within-subject variability. This study evaluated the intraindividual variability of six salivary analytes in healthy adults and determined their normal range.
Unstimulated whole saliva (5 ml) was collected every 2 to 3 days on six occasions from 30 subjects in good oral and systemic health. Four of the samples were collected in the clinic, and two were collected by the subject at home. The concentration ranges of interleukin (IL)-1β, IL-6, matrix metalloproteinase-8, prostaglandin E2, tumor necrosis factor-alpha, interferon-alpha, and albumin were examined. Descriptive statistics were computed, and a one-way random-effects model was used to quantify within- and between-subject components of variability. Intraclass correlation coefficients (ICCs) were calculated for each subject/analyte combination.
Within-subject coefficients of variation for these analytes ranged from 67.6% to 172.1% for the in-clinic samples and from 111.9% to 201.0% for the at-home samples. The ICC for the various analytes ranged from 41% to 61% for the in-clinic samples. The at-home samples exhibited significantly more variability than did those obtained in the clinic under supervision.
There was marked within-subject variation in the salivary concentrations of these analytes. With increased interest in salivary diagnostics, the within-subject variability, normal range, and threshold levels for abnormal levels of individual salivary analytes need to be determined if these diagnostics tests are to have clinical usefulness.
PMCID: PMC4131719  PMID: 19563296
Biologic markers; diagnostic tests; reproducibility of results; saliva; statistics
9.  An Evidenced Based Scoring System To Determine The Periodontal Prognosis On Molars 
Journal of periodontology  2013;85(2):214-225.
This retrospective study evaluated and assigned scores to six prognostic factors and derived a quantitative scoring system used to determine the periodontal prognosis on molar teeth.
Data were gathered on 816 molars in 102 patients with moderate to severe periodontitis. The six factors evaluated, age, probing depth, mobility, furcation involvement, smoking, and molar type, were assigned a numerical score based on statistical analysis. The sum of the scores for all factors was used to determine the prognosis score for each molar. Only patients with all first and second molars at the initial examination qualified for the study. All patients were a minimum of 15 years post treatment.
The post treatment time ranged from 15 to 40 years and averaged 24 years. When the study was completed, 639 molars survived (78%), and of those surviving molars, 566 survived in health (89%). In molars with lower scores (1,2,and 3) the 15-year survival rates ranged from 99% to 96%. For scores 4, 5, 6 the 15 year survival rates ranged was 95% to 90% and for molars with scores of 7, 8, 9, and 10 the survival rates ranged from 86% to 67%.
Our results indicate that the periodontal prognosis on molars diagnosed with moderate to severe periodontitis can be calculated using an evidence-based scoring system.
PMCID: PMC4104765  PMID: 23725028
Prognosis; Smoking; Tooth Mobility; Periodontitis; Long-Term Care; Molar
10.  Evidence that periodontal treatment improves diabetes outcomes: a Systematic Review and Meta-analysis 
Journal of periodontology  2013;84(4 0):S153-S169.
The effect of periodontal therapy on diabetes outcomes has not been established.
This update examines the effect of periodontal treatment on diabetes outcomes.
Data Sources
Literature since October 2009 using MEDLINE.
Study eligibility criteria
Published RCTs including periodontal therapy for diabetic subjects, a metabolic outcome, an untreated control group, and follow up of 3 months.
Data Extraction
Predefined data fields, including study quality indicators were used.
Data Synthesis
A search revealed 56 publications of which 9 met inclusion criteria. Mean change of HbA1c from baseline was compared across treatment groups. Pooled analysis was based on random effects models.
A meta analysis indicated a mean treatment effect of −0.36% HbA1c (CI −0.54, − 0.19) compared to no treatment after periodontal therapy (p<0.0001). Heterogeneity tests revealed only minimal evidence of publication bias (I2 =9%).
Small sample size and high risk of bias remain problematic for studies of this type. Periodontal therapy varied considerably.
The modest reduction in HbA1c observed as a result of periodontal therapy in subjects with type 2 diabetes is consistent with previous systematic reviews. Despite this finding, multi-center trials of sufficient sample size are lacking.
PMCID: PMC4100543  PMID: 23631575
Diabetes; Diabetes Mellitus; Type 2; Periodontal Disease; Periodontitis; Glycosylated Hemoglobin; HbA1c
11.  Periodontitis in Pregnancy: Clinical and Serum Antibody Observations From a Baboon Model of Ligature-Induced Disease 
Journal of periodontology  2009;80(7):1154-1165.
Chronic oral infections that elicit host responses leading to periodontal disease are linked with various sequelae of systemic diseases. This report provides seminal information on the clinical and adaptive immunologic characteristics of a baboon model of ligature-induced periodontitis during pregnancy.
Female Papio anubis were evaluated for periodontal health at baseline. Ligatures were tied around selected teeth to initiate oral inflammation and periodontitis. Then the animals were bred. At midpregnancy (~90 days), a clinical evaluation was performed, and additional ligatures were tied on teeth in the contralateral quadrants to maintain progressing periodontitis throughout pregnancy. A final clinical evaluation was done for all experimental teeth after delivery, and ligatures were removed. Serum was collected at all sampling intervals for the determination of antibody levels to a group of 20 oral bacteria. Unligated animals served as controls.
At baseline, 16% of animals exhibited minimal plaque and gingival inflammation without periodontal disease. The remaining baboons demonstrated varying levels of inflammation/bleeding, and ~20% of the population had periodontal pocketing (>3 mm). Ligated animals expressed increased levels of inflammation and increased probing depths and clinical attachment loss (AL) and could be stratified into multiple subsets postligation based upon changes in clinical parameters at midpregnancy and at delivery. Baboons were categorized into disease susceptibility groups (periodontal disease susceptibility 1 through 4) that described the extent/severity of induced disease during pregnancy. Control animals showed minimal periodontal changes during gestation. Significant differences in serum antibody to multiple oral bacteria were found in animals presenting with periodontitis at baseline and during the 6 months of ligature-induced disease. A significant correlation to antibody to P. gingivalis, which was sustained throughout ligation and pregnancy, was observed with disease presentation.
The clinical presentation at baseline, reflecting the natural history of oral disease in these animals, suggests individual variation that is reflected in the characteristics of the adaptive immune responses to oral bacteria. The variability in the response to ligation with resulting periodontal disease provides a model to document prospectively the relationship between oral and systemic health outcomes.
PMCID: PMC4096487  PMID: 19563297
Antibody; bacteria; periodontitis; pregnancy; primate studies; serum
12.  Birth Weight of Infants of Mothers With Aggressive Periodontitis 
Journal of periodontology  2011;83(3):279-286.
It was hypothesized that if periodontal infections predispose low birth weights and premature birth, then such outcomes should be apparent when the mother has aggressive periodontitis (AgP).
Birth weight data were collected by questionnaire from females with AgP, their periodontally healthy siblings, and unrelated periodontally healthy women. Both prospective and retrospective birth outcome data were used. Because many of the periodontal evaluations were performed after the births, there were incomplete data regarding most of the risk factors for low birth weight. We determined associations between mothers’ periodontal diagnoses and clinical variables and the reported birth weights.
There were no significant differences in mean birth weights of babies born to control subjects or AgP patients. This was true whether all the births were considered or only those reported <1 or 2 years before periodontal examination. For periodontally healthy controls, 13.2% of babies born to siblings of AgP patients and 12.8% of babies born to unrelated mothers weighed <2,500 g, whereas 9.9% of those born to mothers with generalized AgP and 10.3% of those born to mothers with localized AgP weighed <2,500 g.
Because of the relative rarity of AgP in the population, and attendant difficulties in performing a prospective study of its association with pregnancy outcomes, we used a compromised approach using prospective data as well as weaker retrospective data assuming that disease onset was likely before the births. Our results, within the limitations of this approach, indicate no evidence that AgP in the mother predisposes low birth weights. AgP has many unique biologic characteristics that differentiate it from chronic forms of periodontal disease, and the possible lack of its association with birth weight may be another such characteristic.
PMCID: PMC4063275  PMID: 21819247
Aggressive periodontitis; infant, low birth weight; pregnancy; preterm birth
13.  Comparison of microbial changes in early re-developing biofilms on natural teeth and dentures 
Journal of periodontology  2012;83(9):1139-1148.
Background and objective
Surfaces and fluids can affect oral bacterial colonization. The aim of this study was to compare re-developing biofilms on natural teeth and dentures.
Supragingival plaque samples were taken from 55 dentate subjects and the denture teeth of 62 edentulous subjects before and after professional cleaning. Also, samples from 7 “teeth” in randomly selected quadrants were collected after 1, 2, 4 and 7 days of no oral hygiene. Samples were analyzed using checkerboard DNA-DNA hybridization. Counts and proportions of 41 bacterial taxa were determined at each time point and significant differences were sought using the Mann-Whitney test. Ecological succession was determined using a modified moving window analysis.
Mean total DNA probe counts were similar pre-cleaning but were higher in dentate subjects at all post-cleaning visits (p<0.01). Pre-cleaning edentate biofilms had higher counts and proportions of Streptococcus mitis, Streptococcus oralis and Streptococcus mutans, whereas dentate subjects had higher proportions of Tannerella forsythia, Selenomonas noxia and Neisseria mucosa. By 2 days, mean counts of all taxa were higher in natural teeth and most remained higher at 7 days (p<0.01). Succession was more rapid and complex in dentate subjects. Both groups demonstrated increased proportions of S. mitis and S. oralis by 1 day. N. mucosa, Veillonella parvula and Eikenella corrodens increased in both groups but later in edentate samples.
“Mature” natural and denture teeth biofilms have similar total numbers of bacteria but different species proportions. Post-cleaning biofilm re-development is more rapid and more complex on natural than denture teeth.
PMCID: PMC4041159  PMID: 22443543
microbiota; biofilms; supragingival; dental plaque; tooth; dentures
14.  Epigenetic Regulation of TNFA Expression in Periodontal Disease 
Journal of periodontology  2013;84(11):1606-1616.
Tumor necrosis factor-alpha (TNF-α) plays a central role in the molecular pathogenesis of periodontal disease. However, the epigenetic regulation attributable to microbial and inflammatory signals at the biofilm gingival interface are poorly understood. In this study, we investigated the DNA methylation alteration within the TNFA promoter in human gingival biopsies from different stages of periodontal disease, and explored the regulatory mechanism of TNFA transcription by DNA methylation.
Gingival biopsies were harvested from 17 chronic periodontitis patients and 18 subjects with periodontal health. Another 11 subjects participated in an experimentally induced gingivitis study, and gingival biopsies were collected at the baseline, induction, and resolution phase. To confirm that TNFA promoter methylation modulated TNFA transcription we treated THP.1 cells with a DNA methyltransferase inhibitor, 5-aza-2-deoxycytidine and used a RAW 294.7 cell line transfected with a TNFA promoter-specific luciferase reporter system with or without methlyaiton,
In gingival biopsies from subjects with severe chronic periodontitis two individual CpG sites within the TNFA promoter (at -163bp and -161bp) displayed increased methylation in periodontitis samples as compared to gingival health (16.1±5.1% vs. 11.0±4.6%, p=0.02, 19.8±4.1% vs. 15.4±3.6%, p=0.04, respectively). The methylation level at -163bp was inversely associated with the transcription level of TNFA (p=0.018). However, no significant difference in the TNFA promoter methylation pattern was observed in samples biopsied during the induction or resolution phase of experimentally induced gingivitis, which represented a reversible periodontal lesion. THP.1 cells treated with 5-aza-2-deoxycytidine demonstrated a time-dependent increase in TNFA messenger level. We also found that the luciferase activity decreased 2.6 fold in a construct containing an in vitro methylated TNFA promoter as compared to the unmethylated insert (p=0.03).
Although the biopsy samples represented a mixed cell population, the change in promoter methylation status in chronic periodontal disease suggested that DNA methylation may be an important regulatory mechanism in controlling TNFA transcriptional expression in disease.
PMCID: PMC3986590  PMID: 23368949
15.  Periodontal Disease as a Risk Factor for Bisphosphonate-Related Osteonecrosis of the Jaw 
Journal of periodontology  2013;85(2):226-233.
Previous case reports and animal studies suggest periodontitis is associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ). We conducted a case-control study to evaluate the association between clinical and radiographic measures of periodontal disease and BRONJ.
25 BRONJ patients were matched with 48 controls. Trained examiners measured probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP) on all teeth except third molars, and gingival and plaque indices on six index teeth. Alveolar bone height was measured from orthopantomograms. Most BRONJ cases were using antibiotics (48%) or a chlorhexidine mouthrinse (84%) at enrollment. Adjusted comparisons of cases vs. controls used multiple linear regression.
The average number of BP infusions was significantly higher in BRONJ cases compared to controls (38.4 vs 18.8, p=0.0001). In unadjusted analyses, BRONJ cases had more missing teeth (7.8 vs 3.1, p=0.002) and high average CAL (2.18 vs 1.56 mm, p=0.047) and percent of sites with CAL ≥3 mm (39.0 vs 23.3, p=0.039) than controls. Also, BRONJ cases had lower average bone height (as a fraction of tooth length, 0.59 vs 0.62, p=0.004) and more teeth with bone height under half of tooth length (20% vs 6%, p=0.001). These differences remained significant after adjusting for age, sex, smoking, and number of bisphosphonate infusions.
BRONJ patients have fewer teeth, greater CAL, and less alveolar bone support compared to controls after adjusting for number of bisphosphonate infusions. Group differences in antibiotics and chlorhexidine rinse usage may have masked differences in the other clinical measures.
PMCID: PMC3972496  PMID: 23786404
Bisphosphonates; Periodontitis; Periodontal Disease; Alveolar Bone Loss; Osteonecrosis; Bisphosphonate-related osteonecrosis of the jaw
16.  Impact of Periodontal Therapy on the Subgingival Microbiota of Severe Periodontitis: Comparison between Good Responders and “Refractory” Subjects by the Human Oral Microbe Identification Microarray (HOMIM) 
Journal of periodontology  2012;83(10):1279-1287.
This study compared the changes on the subgingival microbiota of subjects with “refractory” periodontitis (RP) or treatable periodontitis (GR) before and after periodontal therapy by using the Human Oral Microbe Identification Microarray (HOMIM).
Individuals with chronic periodontitis were classified as RP (n=17) based on mean attachment loss (AL) and/or >3 sites with AL ≥2.5 mm after scaling and root planing, surgery and systemically administered amoxicillin and metronidazole or as GR (n=30) based on mean attachment gain and no sites with AL ≥2.5 mm after treatment. Subgingival plaque samples were taken at baseline and 15 months after treatment and analyzed for the presence of 300 species by HOMIM analysis. Significant differences in taxa before and after therapy were sought using the Wilcoxon test.
The majority of species evaluated decreased in prevalence in both groups after treatment; however, only a small subset of organisms was significantly affected. Species that increased or persisted in high frequency in RP but were significantly reduced in GR included Bacteroidetes sp., Porphyromonas endodontalis, Porphyromonas gingivalis, Prevotella spp., Tannerella forsythia, Dialister spp., Selenomonas spp., Catonella morbi, Eubacterium spp., Filifactor alocis, Parvimonas micra, Peptostreptococcus sp. OT113, Fusobacterium sp. OT203, Pseudoramibacter alactolyticus, Streptococcus intermedius or Streptococcus constellatus and Shuttlesworthia satelles. In contrast, Capnocytophaga sputigena, Cardiobacterium hominis, Gemella haemolysans, Haemophilus parainfluenzae, Kingella oralis, Lautropia mirabilis, Neisseria elongata, Rothia dentocariosa, Streptococcus australis and Veillonella spp. were more associated with therapeutic success.
Persistence of putative and novel periodontal pathogens, as well as low prevalence of beneficial species was associated with chronic “refractory” periodontitis.
PMCID: PMC3971922  PMID: 22324467
Refractory Periodontal Disease; Non-surgical periodontal therapy; antimicrobials; DNA microarrays; Microbiology
17.  Blocking Pro-Inflammatory Cytokine Release Modulates Peripheral Blood Mononuclear Cell Response to Porphyromonas Gingivalis 
Journal of periodontology  2012;84(9):1337-1345.
Chronic periodontitis is an inflammatory disease in which cytokines play a major role in the progression of disease. Anti-inflammatory cytokines (IL-4 and IL-10) were reported to be absent or reduced in diseased periodontal tissues, suggesting an imbalance between the pro- and anti-inflammatory mediators. We have tested the hypothesis that there is cellular cross-talk mediated by pro- and anti-inflammatory cytokines and that blocking pro-inflammatory cytokine (TNF-α and IL-1) production will enhance anti-inflammatory cytokine (IL-4 and IL-10) production from peripheral blood mononuclear cells (PBMC) in response to P. gingivalis.
PBMC were isolated from individuals diagnosed with chronic periodontitis or healthy individuals and cultured for 24 hours. Concanavalin-A (ConA) was used as an activator of lymphocyte function. Live and heat-killed P .gingivalis or lipopolysaccharide from P. gingivalis was used as the bacterial stimulants. TNF-α and IL-1 production was neutralized by specific antibodies against TNF-α and IL-1α or β. Culture supernatants were evaluated by ELISA for TNF-α, IL-1β, IL-4, and IL-10 production.
Live P. gingivalis did not result in any significant IL-10 or IL-4 release while heat-killed P. gingivalis led to a significant increase in IL-10 levels compared to unstimulated or live P. gingivalis-stimulated cells from both healthy and periodontitis individuals. Overall, PBMC from patients with chronic periodontitis produced significantly lower IL-10 in response to ConA and P. gingivalis suggesting chronic suppression of the anti-inflammatory cytokine production. Blocking the pro-inflammatory cytokine response did not result in any substantial change in IL-10 or IL-4 response to live P. gingivalis. Blocking the pro-inflammatory cytokine response restored IL-10 production by cells from chronic periodontitis in response to P. gingivalis LPS.
These findings suggest that PBMC from patients with chronic periodontitis have suppressed anti-inflammatory cytokine production that can, in part, be restored by neutralizing pro-inflammatory cytokines. Monocytes are an important source of IL-10 production and monocyte-derived IL-10 might play a regulatory role in the pathogenesis of chronic periodontitis.
PMCID: PMC3935330  PMID: 23173823
IL-4; IL-10; monocytes; Porphyromonas gingivalis; Periodontitis
18.  Guided bone regeneration (GBR) utilizing injectable Vascular Endothelial Growth Factor (VEGF) delivery gel 
Journal of periodontology  2012;84(2):230-238.
Vascularization underlies the success of guided bone regeneration (GBR) procedures. This study evaluated the regenerative potential of GBR in combination with Vascular Endothelial Growth Factor (VEGF) delivery, via an injectable hydrogel system.
Critical-sized defects were created in rat calvariae and GBR procedures were performed with a collagen membrane either alone (control), plus bolus delivery of VEGF, or plus application of VEGF releasing hydrogels (VEGF - Alg). Four and eight weeks following treatment, defect sites were evaluated with microcomputed tomographic and histomorphometric analyses for blood vessel and bone formation.
At four weeks, relative to the control condition, the bolus addition of VEGF did not affect blood vessel density within the defect site; yet, the application of the VEGF+ Alg significantly (p< 0.05) increased blood vessel density. Though there was no difference in bone regeneration at four weeks, at eight weeks, there was a significant (p < 0.05) increase in bone regeneration in the VEGF + Alg treated defects.
These data demonstrated that the application of VEGF + Alg enhanced early angiogenesis while at a later timepoint, it enhanced bone regeneration. Controlled delivery approaches of angiogenic growth factors used adjunctively with GBR may be a promising strategy for enhancing outcomes of GBR.
PMCID: PMC3669541  PMID: 22668339
regenerative medicine; bioengineering; growth factors; hydrogel; bone; angiogenesis
19.  Modulation of phosphate/pyrophosphate metabolism to regenerate the periodontium. A novel in vivo approach 
Journal of periodontology  2011;82(12):10.1902/jop.2011.110103.
The developing periodontium is sensitive to local levels of phosphate (Pi) and pyrophosphate (PPi), as demonstrated by cementum phenotypes resulting from loss of function of protein regulators of Pi/PPi homeostasis. The progressive ankylosis protein (ANK) regulates transport of PPi, and Ank knock-out (KO) mice feature rapidly forming and thick cementum. We hypothesized that, besides affecting cementum formation, decreased extracellular PPi levels in Ank KO mice would also impact cementum regeneration.
Periodontal fenestration defects (2mm/1mm/0.5mm) were created on the buccal aspects of mandibular molars in Ank KO and wild-type (WT) mice. Mandibles were harvested at 15 and 30 days post-surgery for histology, histomorphometry, evaluation of in vivo fluorochrome labeling, and immunohistochemistry(IHC) for proteins including bone sialoprotein (BSP), osteopontin (OPN), dentin matrix protein 1 (DMP1), and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1).
A greater amount of new cementum was observed for Ank KO mice at 15 and 30 days post-surgery (p<0.05), that was confirmed by fluorochrome labeling showing a higher new cementum appositional activity in the defect areas in Ank KO vs. controls. At days 15 and 30 during healing, regenerating cementum and associated cells in Ank KO recapitulated expression patterns mapped during development, including limited BSP and positive OPN and DMP1 in the cementum matrix, as well as elevated NPP1 in cementoblasts.
Within the limits of the study, these findings suggest that reduced local levels of PPi can promote increased cementum regeneration. Therefore, local modulation of Pi/PPi may be a potential therapeutic approach for achieving improved cementum regeneration.
PMCID: PMC3884815  PMID: 21488756
cementum; periodontal regeneration; ankylosis protein; mouse; pyrophosphates; inorganic phosphates
20.  Correction of hypophosphatasia (HPP) associated mineralization deficiencies in vitro by phosphate/pyrophosphate modulation in periodontal ligament cells 
Journal of periodontology  2011;83(5):10.1902/jop.2011.110310.
Mutations in the Alpl gene in hypophosphatasia (HPP) reduce the function of tissue nonspecific alkaline phosphatase (TNAP), resulting in increased pyrophosphate (PPi) and a severe deficiency in acellular cementum. We hypothesized that exogenous phosphate (Pi) would rescue the in vitro mineralization capacity of periodontal ligament (PDL) cells harvested from HPP-diagnosed subjects, by correcting Pi/PPi ratio and modulating expression of genes involved with Pi/PPi metabolism.
Ex vivo and in vitro analyses were employed to identify mechanisms involved in HPP-associated PDL/tooth root deficiencies. Constitutive expression of PPi-associated genes was contrasted in PDL versus pulp tissues obtained from healthy subjects. Primary PDL cell cultures from HPP subjects (monozygotic twin males) were established to assay alkaline phosphatase activity (ALP), in vitro mineralization, and gene expression. Exogenous Pi was provided to correct Pi/PPi ratio.
PDL tissues obtained from healthy individuals featured higher basal expression of key PPi regulators, genes Alpl, progressive ankylosis protein (Ankh) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1), versus paired pulp tissues. A novel Alpl mutation was identified in the twin HPP subjects enrolled in this study. Compared to controls, HPP-PDL cells exhibited significantly reduced ALP and mineralizing capacity, which were rescued by addition of 1mM Pi. Dysregulated expression of PPi regulatory genes Alpl, Ankh, and Enpp1 was also corrected by adding Pi, though other matrix markers evaluated in our study remained down-regulated.
These findings underscore the importance of controlling Pi/PPi ratio toward development of a functional periodontal apparatus, and support Pi/PPi imbalance as the etiology of HPP-associated cementum defects.
PMCID: PMC3871996  PMID: 22014174
hypophosphatasia; cementum; periodontal ligament; phosphate; pyrophosphate
21.  Relationships Among IL-6, TNF-α, Adipokines, Vitamin D and Chronic Periodontitis 
Journal of periodontology  2011;83(9):1183-1191.
to explore relationships among serum adipokines, vitamin D, clinical and microbial parameters of chronic periodontitis before and after treatment.
weight, height and smoking status were recorded for 56 patients with chronic periodontitis. Plaque, gingivitis, bleeding on probing (BOP), suppuration, pocket depth (PD) and attachment level (AL) were measured at all teeth present. Subgingival biofilm samples from each tooth were analyzed for levels of 40 bacterial species using checkerboard DNA-DNA hybridization. Serum levels of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), adiponectin, leptin, resistin and vitamin D were measured at baseline. Sample collection was then performed in a subset of the population 6 months post-therapy (n=17). Serum samples were analyzed using ELISA and immunoassays. Differences in clinical, microbial and serum factors among groups were sought using the Mann-Whitney test. Correlations among factors were evaluated using regression analysis. Effects of therapy were sought using the Wilcoxon signed ranks test
There were positive correlations between adiponectin/vitamin D and between IL-6/leptin; negative correlations between IL-6/vitamin D, and leptin/vitamin D, but no associations between serum analytes and clinical or microbial parameters. Gender and BMI were associated with levels of adipokines. Periodontal therapy improved clinical and microbiological parameters, but did not influence the levels of serum analytes.
Adipokines and IL-6 levels were affected by gender and BMI. Serum analytes were not influenced by periodontal therapy.
PMCID: PMC3678944  PMID: 22181684
adipokines; cytokines; calcitriol; periodontitis; subgingival scaling; biofilm; microbiota
22.  Plasma 25-hydroxyvitamin D concentrations and periodontal disease in postmenopausal women 
Journal of periodontology  2012;84(9):1243-1256.
Vitamin D has anti-inflammatory and anti-microbial properties that, together with its influence on bone health, may confer periodontal benefit.
We investigated cross-sectional associations (1997–2000) between plasma 25-hydroxyvitamin D concentrations [25(OH)D] and periodontal measure among 920 postmenopausal women. Chronic measures of disease were defined based on: 1) alveolar crestal height (ACH) measures from intraoral radiographs and tooth loss, and the 2) Center for Disease Control and Prevention (CDC)/American Academy of Periodontology (AAP) criteria using measures of clinical attachment level (CAL) and probing pocket depth (PD). Acute oral inflammation was assessed by the % of gingival sites that bled upon assessment with a probe. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CIs) for periodontal disease among participants with adequate ([25(OH)D]≥50 nmol/L) compared to deficient/inadequate ([25(OH)D]<50 nmol/L) vitamin D status adjusted for age, dental visit frequency, and body mass index.
No association was observed between vitamin D status and periodontal disease defined by ACH and tooth loss (adjusted OR=0.96, 95% CI: 0.68–1.35). In contrast, women with adequate compared to deficient/inadequate vitamin D status had a 33% lower odds (95% CI: 5%–53%) of periodontal disease defined using the CDC/AAP definition and a 42% lower odds (95% CI: 21%-58%) of having ≥50% of gingival sites that bled.
Vitamin D status was inversely associated with gingival bleeding, an acute measure of oral health and inflammation and inversely associated with clinical categories of chronic periodontal disease that incorporated PD, an indicator of oral inflammation. However, vitamin D was not associated with chronic periodontal disease based on measures of ACH in combination with tooth loss.
PMCID: PMC3745794  PMID: 23259413
vitamin D; 25-hydroxyvitamin D; periodontal diseases; postmenopausal period; epidemiology; women
23.  Cross-sectional Study of Vitamin D and Calcium Supplementation Effects on Chronic Periodontitis 
Journal of periodontology  2009;80(9):1433-1439.
Low dietary intakes of vitamin D and calcium hasten bone loss and osteoporosis. Because vitamin D metabolites may also alter the inflammatory response and have anti-microbial effects, we studied whether use of vitamin D and calcium supplements affects periodontal disease status.
A cohort of 51 subjects receiving periodontal maintenance therapy was recruited from 2 dental clinics. Of these, 23 were taking vitamin D (≥400 international units/day) and calcium (≥1000mg/day) supplementation, and 28 were not taking such supplementation. All subjects had ≥2 interproximal sites with ≥3 mm clinical attachment loss. Daily calcium and vitamin D intakes (from food and supplements) were estimated by nutritional analysis. The following clinical parameters of periodontal disease were recorded for the mandibular posterior teeth: gingival index, probing depth, cementoenamel junction-gingival margin distance (attachment loss), bleeding upon probing, and furcation involvement. Posterior photostimulable-phosphor bitewing radiographs were taken to determine cementoenamel-junction-alveolar-crest distances (alveolar crest height loss). Data were analyzed with a repeated-measures, multivariate analysis of variance.
Relative to subjects who did not take vitamin D and calcium supplementation, supplement takers had shallower probing depths, fewer bleeding sites, lower gingival index values, fewer furcation involvements, less attachment loss and less alveolar crest height loss. The repeated-measures analysis indicated that collectively these differences for clinical parameters were borderline significant (P=0.08).
In these subjects receiving periodontal maintenance therapy, there was a trend for better periodontal health with intake of vitamin D and calcium supplementation. More expanded longitudinal studies are required to determine the potential of this relationship.
PMCID: PMC3706188  PMID: 19722793
vitamin D; calcium; chronic periodontitis; alveolar bone
24.  Depot Medroxyprogesterone Acetate Use and Periodontal Health in United States Women Ages 15-44 
Journal of periodontology  2012;83(8):1008-1017.
One sentence summary
Women who indicate DMPA use have a significantly increased risk of prevalence of periodontal conditions as compared to women who have never used DMPA.
PMCID: PMC3704052  PMID: 22309173
25.  Severe Preeclampsia and Maternal Self-Report of Oral Health, Hygiene, and Dental Care 
Journal of periodontology  2012;84(2):143-151.
Maternal periodontal disease diagnosed by a detailed oral health examination is associated with preeclampsia. Our objective was to measure the association between maternal self-report of oral symptoms/problems, oral hygiene practices, and/or dental service utilization prior to or during pregnancy and severe preeclampsia.
A written questionnaire was administered to pregnant women at the time of prenatal ultrasound, and outcomes ascertained by chart abstraction. Chi square test compared maternal oral symptoms/problems, hygiene practices, and dental service utilization between women with severe preeclampsia versus normotensive women. Multivariable logistic regression was used to calculate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for severe preeclampsia. Results: 48 (10%) of 470 women reported ≥ 2 oral symptoms/problems in the 6 months prior to pregnancy and 77 (16%) since pregnancy. 51(11%) reported prior periodontal treatment. 28 (6%) of 470 developed severe preeclampsia. Women with a history of periodontal treatment were more likely to develop severe preeclampsia (aOR, 95%CI: 3.71, 1.40-9.83) than women without a prior history of periodontal treatment. Self-reported oral health symptoms/problems, oral hygiene practices, or dental service utilization prior to or during pregnancy were not associated with severe preeclampsia when considered in the context of other maternal risk factors. Conclusion: Maternal self report of previous periodontal treatment prior to pregnancy is associated with severe preeclampsia.
PMCID: PMC3685176  PMID: 22509752
Pregnancy complications; periodontitis; epidemiology

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