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1.  Leukotoxic Activity of Aggregatibacter actinomycetemcomitans and Periodontal Attachment Loss 
PLoS ONE  2014;9(8):e104095.
Aggregatibacter actinomycetemcomitans is a Gram-negative periodontitis-associated bacterium that expresses a toxin that selectively affects leukocytes. This leukotoxin is encoded by an operon belonging to the core genome of this bacterial species. Variations in the expression of the leukotoxin have been reported, and a well-characterized specific clonal type (JP2) of this bacterium with enhanced leukotoxin expression has been isolated. In particular, the presence of the JP2 genotype significantly increases the risk for the progression of periodontal attachment loss (AL). Based on these findings we hypothesized that variations in the leukotoxicity are linked to disease progression in infected individuals. In the present study, the leukotoxicity of 239 clinical isolates of A. actinomycetemcomitans was analysed with different bioassays, and the genetic peculiarities of the isolates were related to their leukotoxicity based on examination with molecular techniques. The periodontal status of the individuals sampled for the presence of A. actinomycetemcomitans was examined longitudinally, and the importance of the observed variations in leukotoxicity was evaluated in relation to disease progression. Our data show that high leukotoxicity correlates with an enhanced risk for the progression of AL. The JP2 genotype isolates were all highly leukotoxic, while the isolates with an intact leukotoxin promoter (non-JP2 genotypes) showed substantial variation in leukotoxicity. Genetic characterization of the non-JP2 genotype isolates indicated the presence of highly leukotoxic genotypes of serotype b with similarities to the JP2 genotype. Based on these results, we conclude that A. actinomycetemcomitans harbours other highly virulent genotypes besides the previously described JP2 genotype. In addition, the results from the present study further highlight the importance of the leukotoxin as a key virulence factor in aggressive forms of periodontitis.
doi:10.1371/journal.pone.0104095
PMCID: PMC4122431  PMID: 25093857
2.  Prenatal Exposure to Antiepileptic Drugs and Dental Agenesis 
PLoS ONE  2014;9(1):e84420.
Objective
The aim of the study was to investigate the association between prenatal exposure to AEDs and the risk of dental agenesis and to differentiate between the possible effects of the different drugs used.
Methods
Data on 214 exposed and 255 unexposed children, aged 12–18 years, were extracted from the Prescription Database of the Central Denmark Region and North Denmark Region and the Danish Medical Birth Registry. The children's dental charts were examined for the presence of dental agenesis.
Results
Overall, children exposed to AED in utero had an increased risk of developing dental agenesis, but as a group, the difference was not significant (OR = 1.7; [95% CI: 0.8–3.6]). The risk of developing dental agenesis was three-fold increased (OR = 3.1; [95% CI: 1.3–7.4]) in children exposed to valproate in mono- or in poly-therapy with other AEDs than carbamazepine or oxcarbazepine. The risk was further increased (OR = 11.2; [95% CI: 2.4–51.9]) in children exposed to valproate and carbamazepine or oxcarbazepine in combination.
Conclusions
The present study shows that dental agenesis is a potential congenital abnormality that is related to prenatal exposure to valproate, and dental agenesis may be considered a sensitive marker for the teratogenicity of valproate.
doi:10.1371/journal.pone.0084420
PMCID: PMC3885552  PMID: 24416231
3.  Subgingival bacteria in Ghanaian adolescents with or without progression of attachment loss 
Journal of Oral Microbiology  2014;6:10.3402/jom.v6.23977.
Objective
This study describes subgingival bacterial profiles associated with clinical periodontal status in Ghanaian adolescents with or without progression of attachment loss.
Materials and methods
Among 500 adolescents included in a cohort study, 397 returned 2 years later for a periodontal re-examination, including full-mouth CAL measurements. At follow-up, a subgroup of 98 adolescents was also subjected to bacterial sampling with paper points at four periodontal sites (mesial aspect of 11, 26, 31, and 46) and analyzed with the checkerboard DNA–DNA hybridization technique against DNA-probes from nine periodontitis-associated bacterial species.
Results
The 98 Ghanaian adolescents examined in the present study were similar to the entire group examined at the 2-year follow-up with respect to age, gender, and CAL ≥3 mm. A high detection frequency of Fusobacterium nucleatum and Prevotella intermedia (>99%) using checkerboard analysis was found, while for Aggregatibacter actinomycetemcomitans the detection frequency was <50%. A strong correlation was found at the individual level between the presence of P. intermedia and the total CAL change, and P. intermedia and Porphyromonas gingivalis were strongly correlated with a change in CAL and probing pocket depth (PPD) at the sampled sites. In a linear regression model, a significant discriminating factor for the total CAL change in the dentition during the 2-year follow-up period was obtained for P. intermedia and public school.
Conclusion
This study indicates that subgingival bacterial species other than A. actinomycetemcomitans, for example, P. intermedia, have a significant association with periodontal breakdown (change in CAL) in Ghanaian adolescents with progression of periodontal attachment loss.
doi:10.3402/jom.v6.23977
PMCID: PMC4013489  PMID: 24834145
subgingival bacteria; periodontitis; attachment loss; progression; adolescent; Ghana
4.  Pathogenicity of the highly leukotoxic JP2 clone of Aggregatibacter actinomycetemcomitans and its geographic dissemination and role in aggressive periodontitis 
Journal of Oral Microbiology  2014;6:10.3402/jom.v6.23980.
For decades, Aggregatibacter actinomycetemcomitans has been associated with aggressive forms of periodontitis in adolescents. In the middle of the 1990s, a specific JP2 clone of A. actinomycetemcomitans, belonging to the cluster of serotype b strains of A. actinomycetemcomitans and having a number of other characteristics, was found to be strongly associated with aggressive forms of periodontitis, particularly in North Africa. Although several longitudinal studies still point to the bacterial species, A. actinomycetemcomitans as a risk factor of aggressive periodontitis, it is now also widely accepted that the highly leukotoxic JP2 clone of A. actinomycetemcomitans is implicated in rapidly progressing forms of aggressive periodontitis. The JP2 clone strains are highly prevalent in human populations living in Northern and Western parts of Africa. These strains are also prevalent in geographically widespread populations that have originated from the Northwest Africa. Only sporadic signs of a dissemination of the JP2 clone strains to non-African populations have been found despite Africans living geographically widespread for hundreds of years. It remains an unanswered question if a particular host tropism exists as a possible explanation for the frequent colonization of the Northwest African population with the JP2 clone. Two exotoxins of A. actinomycetemcomitans are known, leukotoxin (LtxA) and cytolethal distending toxin (Cdt). LtxA is able to kill human immune cells, and Cdt can block cell cycle progression in eukaryotic cells and thus induce cell cycle arrest. Whereas the leukotoxin production is enhanced in JP2 clone strains thus increasing the virulence potential of A. actinomycetemcomitans, it has not been possible so far to demonstrate such a role for Cdt. Lines of evidence have led to the understanding of the highly leukotoxic JP2 clone of A. actinomycetemcomitans as an aetiological factor of aggressive periodontitis. Patients, who are colonized with the JP2 clone, are likely to share this clone with several family members because the clone is transmitted through close contacts. This is a challenge to the clinicians. The patients need intense monitoring of their periodontal status as the risk for developing severely progressing periodontal lesions are relatively high. Furthermore, timely periodontal treatment, in some cases including periodontal surgery supplemented by the use of antibiotics, is warranted. Preferably, periodontal attachment loss should be prevented by early detection of the JP2 clone of A. actinomycetemcomitans by microbial diagnostic testing and/or by preventive means.
doi:10.3402/jom.v6.23980
PMCID: PMC4139931  PMID: 25206940
Virulence factors; spreading; geographical dissemination; leukotoxin; cytolethal distending toxin; host response
5.  Cytolethal Distending Toxin in Isolates of Aggregatibacter actinomycetemcomitans from Ghanaian Adolescents and Association with Serotype and Disease Progression 
PLoS ONE  2013;8(6):e65781.
Background and Objectives
The cytolethal distending toxin (Cdt) is a highly conserved exotoxin that are produced by a number of Gram negative bacteria, including Aggregatibacter actinomycetemcomitans, and affects mammalian cells by inhibiting cell division and causing apoptosis. A complete cdt-operon is present in the majority of A. actinomycetemcomitans, but the proportion of isolates that lack cdt-encoding genes (A, B and C) varies according to the population studied. The objectives of this study were to examine serotype, Cdt-genotype, and Cdt-activity in isolates of A. actinomycetemcomitans collected from an adolescent West African population and to examine the association between the carrier status of A. actinomycetemcomitans and the progression of attachment loss (AL).
Materials and Methods
A total of 249 A. actinomycetemcomitans isolates from 200 Ghanaian adolescents were examined for serotype and cdt-genotype by PCR. The activity of the Cdt-toxin was examined by DNA-staining of exposed cultured cells and documented with flow cytometry. The periodontal status of the participants was examined at baseline and at a two-year follow-up.
Results
Presence of all three cdt-encoding genes was detected in 79% of the examined A. actinomycetemcomitans isolates. All these isolates showed a substantial Cdt-activity. The two different cdt-genotypes (with and without presence of all three cdt-encoding genes) showed a serotype-dependent distribution pattern. Presence of A. actinomycetemcomitans was significantly associated with progression of AL (OR = 5.126; 95% CI = [2.994–8.779], p<0.001).
Conclusion
A. actinomycetemcomitans isolated from the Ghanaian adolescents showed a distribution of serotype and cdt-genotype in line with results based on other previously studied populations. Presence of A. actinomycetemcomitans was significantly associated with disease progression, in particular the b serotype, whereas the association with disease progression was not particularly related to cdt-genotype, and Cdt-activity.
doi:10.1371/journal.pone.0065781
PMCID: PMC3683020  PMID: 23922633
6.  Developmental Enamel Defects in Children Prenatally Exposed to Anti-Epileptic Drugs 
PLoS ONE  2013;8(3):e58213.
Objective
Some anti-epileptic drugs (AED) have well-known teratogenic effects. The aim of the present study was to elucidate the effect of prenatal exposure to AED and the risk of enamel defects in the primary and permanent dentition.
Methods
A total of 38 exposed and 129 non-exposed children, 6–10 years of age, were recruited from the Aarhus Birth Cohort and the Department of Neurology, Viborg Regional Hospital, Denmark. Medication during pregnancy was confirmed by the Danish Prescription Database. All children had their teeth examined and outcomes in terms of enamel opacities and enamel hypoplasia were recorded.
Results
Children prenatally exposed to AED have an increased prevalence of enamel hypoplasia (11% vs. 4%, odds ratio (OR) = 3.6 [95% confidence interval (CI): 0.9 to 15.4]), diffuse opacities (18% vs. 7%, OR = 3.0; [95% CI: 1.0 to 8.7, p<0.05]), and numerous (>3) white opacities (18% vs. 10%, OR = 2.2; [95% CI: 0.8 to 6.1]) in the primary dentition. In the permanent dentition, an increased risk of numerous (>3) white opacities (34% vs. 12%, OR = 3.3; [95% CI: 1.3 to 8.4]) was found.
Conclusions
The present study shows that children prenatally exposed to AED have an increased risk of developing numerous teeth with white opacities in their primary and permanent dentition. In addition, they also have an increased risk of developing diffuse opacities and enamel hypoplasia in their primary teeth.
doi:10.1371/journal.pone.0058213
PMCID: PMC3592922  PMID: 23520494
7.  Interactions of extracts from selected chewing stick sources with Aggregatibacter actinomycetemcomitans 
BMC Research Notes  2012;5:203.
Background
Aggregatibacter actinomycetemcomitans produces a leukotoxin that activates a pro-inflammatory death of human monocytes/macrophages. A specific clone of this bacterium (JP2) has a 530-base pair deletion in the leukotoxin promoter gene and significantly enhanced expression of leukotoxin. This specific clone of A. actinomycetemcomitans is common in some African populations and has a strong association with periodontal attachment loss in adolescents in these populations. Chewing sticks of plant origin are commonly used as oral hygiene tool in Africa, but their role as a therapeutic agent in periodontal disease is poorly investigated.
Results
Ethanol extracts were made from 7 common plants used as chewing sticks in West-Africa. None of the tested extracts inhibited growth of A. actinomycetemcomitans. However, extracts from Psidium guajava (Guava) completely neutralized the cell death and pro-inflammatory response of human leukocytes induced by the leukotoxin. None of the six other tested chewing stick extracts showed this effect.
Conclusions
The discovery that extracts from Guava efficiently neutralizes A. actinomycetemcomitans leukotoxicity might lead to novel therapeutic agents and strategies for prevention and treatment of aggressive forms of periodontitis induced by infections with the highly leukotoxic JP2 clone of this bacterium.
doi:10.1186/1756-0500-5-203
PMCID: PMC3393612  PMID: 22537711
8.  Development of Danish version of child oral-health-related quality of life questionnaires (CPQ8–10 and CPQ11–14) 
BMC Oral Health  2009;9:11.
Background
The Child Perceptions Questionnaire (CPQ) is a self-reported questionnaire developed to measure oral health-related quality of life in children. The CPQ aims to improve the description of children's oral health, while taking into consideration the importance of psychological aspects in the concept of health. The CPQ exists in two versions: the CPQ8–10 for children aged 8–10 years and the CPQ11–14 for those aged 11–14 years. The aim of this study was to develop a Danish version of the CPQ8–10 and the CPQ11–14 and to evaluate its validity for use among Danish-speaking children.
Methods
The instruments were translated from English into Danish in accordance with a recommended translation procedure. Afterwards, they were tested among children aged 8–10 (n = 120) and 11–14 years (n = 225). The validity was expressed by the correlation between overall CPQ scores and i) self-reported assessment of the influence of oral conditions on everyday life (not at all, very little, some, a lot, very much) and ii) the self-reported rating of oral health. Furthermore, groups of children with assumed decreased oral health-related quality of life were compared with children with healthy oral conditions. Finally, we examined the internal consistency.
Results
The correlation between overall CPQ scores and global assessments of the influence of oral conditions on everyday life showed Spearman correlation coefficients of 0.45, P < 0.001 for CPQ8–10 and 0.50, P < 0.001 for CPQ11–14. The correlation between overall CPQ scores and the self-reported rating of oral health showed Spearman correlation coefficients of 0.45, P < 0.001 for CPQ8–10 and 0.17, P = 0.010 for CPQ11–14.
The median overall CPQ8–10 scores were 7 for individuals with healthy oral conditions, 5 for individuals with cleft lip and palate, and 15 for individuals with rare oral diseases. The median overall CPQ11–14 scores were 9 for individuals with healthy oral conditions, 9 for individuals with cleft lip and palate, 17.0 for individuals with rare oral diseases, and 22.0 for individuals with fixed orthodontic appliances. There were statistically significant differences between the groups of children with healthy oral conditions and each of the subgroups, except for children with cleft lip and palate.
Chronbach'α were 0.82 for CPQ8–10 and 0.87 for CPQ11–14.
Conclusion
The results of this study reveal that the Danish CPQ8–10 and CPQ11–14, seem to be valid instruments for measuring oral health-related quality of life in children although its ability to discriminate between children with cleft lip and palate and healthy children seem to be limited.
doi:10.1186/1472-6831-9-11
PMCID: PMC2679003  PMID: 19383176
9.  Novel Loop-Mediated Isothermal Amplification Method for Detection of the JP2 Clone of Aggregatibacter actinomycetemcomitans in Subgingival Plaque▿  
Journal of Clinical Microbiology  2007;46(3):1113-1115.
We developed a loop-mediated isothermal amplification method that detects the JP2 clone of Aggregatibacter actinomycetemcomitans, which induces aggressive periodontitis in adolescents of North and West African descents. Being independent of special equipment, this specific and sensitive method offers significant advantages for screening of patients on a population basis and in clinical settings.
doi:10.1128/JCM.02107-07
PMCID: PMC2268348  PMID: 18160448
10.  Microevolution and Patterns of Dissemination of the JP2 Clone of Aggregatibacter (Actinobacillus) actinomycetemcomitans▿  
Infection and Immunity  2007;75(6):3080-3088.
The natural history, microevolution, and patterns of interindividual transmission and global dissemination of the JP2 clone of Aggregatibacter (Actinobacillus) actinomycetemcomitans were studied by population genetic analysis. The JP2 clone is strongly associated with aggressive periodontitis in adolescents of African descent and differs from other clones of the species by several genetic peculiarities, including a 530-bp deletion in the promoter region of the leukotoxin gene operon, which results in increased leukotoxic activity. Multilocus sequence analysis of 82 A. actinomycetemcomitans strains, 66 of which were JP2 clone strains collected over a period of more than 20 years, confirmed that there is a clonal population structure with evolutionary lineages corresponding to serotypes. Although genetically highly conserved, as shown by alignment of sequences of eight housekeeping genes, strains belonging to the JP2 clone had a number of point mutations, particularly in the pseudogenes hbpA and tbpA. Characteristic mutations allowed isolates from individuals from the Mediterranean area and from West Africa, including the Cape Verde Islands, to be distinguished. The patterns of mutations indicate that the JP2 clone initially emerged as a distinct genotype in the Mediterranean part of Africa approximately 2,400 years ago and subsequently spread to West Africa, from which it was transferred to the American continents during the transatlantic slave trade. The sustained exclusive colonization of individuals of African descent despite geographical separation for centuries suggests that the JP2 clone has a distinct host tropism. The colonization of family members by JP2 clone strains with unique point mutations provides strong evidence that there is intrafamilial transmission and suggests that dissemination of the JP2 clone is restricted to close contacts.
doi:10.1128/IAI.01734-06
PMCID: PMC1932881  PMID: 17353281
11.  Improved PCR for Detection of the Highly Leukotoxic JP2 Clone of Actinobacillus actinomycetemcomitans in Subgingival Plaque Samples 
Journal of Clinical Microbiology  2003;41(10):4829-4832.
The JP2 clone of Actinobacillus actinomycetemcomitans is associated with early-onset periodontitis in certain ethnic populations of African origin. Here, we describe and evaluate a set of primers for PCR to assay for the presence of A. actinomycetemcomitans and to discriminate between JP2-like strains and other genotypes in subgingival plaque samples.
doi:10.1128/JCM.41.10.4829-4832.2003
PMCID: PMC254341  PMID: 14532234

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