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1.
J Dent Res ; 102(2): 170-177, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36254392

RESUMO

The aim of this study was to develop and externally validate a score for use in dental settings to identify those at risk of undiagnosed nondiabetic hyperglycemia (NDH) or type 2 diabetes (T2D). The Studies of Health in Pomerania (SHIP) project comprises 2 representative population-based cohort studies conducted in northeast Germany. SHIP-TREND-0, 2008 to 2012 (the development data set) had 3,339 eligible participants, with 329 having undiagnosed NDH or T2D. Missing data were replaced using multiple imputation. Potential covariates were selected for inclusion in the model using backward elimination. Heuristic shrinkage was used to reduce overfitting, and the final model was adjusted for optimism. We report the full model and a simplified paper-based point-score system. External validation of the model and score employed an independent data set comprising 2,359 participants with 357 events. Predictive performance, discrimination, calibration, and clinical utility were assessed. The final model included age, sex, body mass index, smoking status, first-degree relative with diabetes, presence of a dental prosthesis, presence of mobile teeth, history of periodontal treatment, and probing pocket depths ≥5 mm as well as prespecified interaction terms. In SHIP-TREND-0, the model area under the curve (AUC) was 0.72 (95% confidence interval [CI] 0.69, 0.75), calibration in the large was -0.025. The point score AUC was 0.69 (95% CI 0.65, 0.72), with sensitivity of 77.0 (95% CI 76.8, 77.2), specificity of 51.5 (95% CI 51.4, 51.7), negative predictive value of 94.5 (95% CI 94.5, 94.6), and positive predictive value of 17.0 (95% CI 17.0, 17.1). External validation of the point score gave an AUC of 0.69 (95% CI 0.66, 0.71), sensitivity of 79.2 (95% CI 79.0, 79.4), specificity of 49.9 (95% CI 49.8, 50.00), negative predictive value 91.5 (95% CI 91.5, 91.6), and positive predictive value of 25.9 (95% CI 25.8, 26.0). A validated prediction model involving dental variables can identify NDH or undiagnosed T2DM. Further studies are required to validate the model for different European populations.


Assuntos
Diabetes Mellitus Tipo 2 , Hiperglicemia , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Fatores de Risco , Medição de Risco , Odontologia
2.
J Dent Res ; 101(11): 1408-1416, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36000800

RESUMO

Genetic risk factors play important roles in the etiology of oral, dental, and craniofacial diseases. Identifying the relevant risk loci and understanding their molecular biology could highlight new prevention and management avenues. Our current understanding of oral health genomics suggests that dental caries and periodontitis are polygenic diseases, and very large sample sizes and informative phenotypic measures are required to discover signals and adequately map associations across the human genome. In this article, we introduce the second wave of the Gene-Lifestyle Interactions and Dental Endpoints consortium (GLIDE2) and discuss relevant data analytics challenges, opportunities, and applications. In this phase, the consortium comprises a diverse, multiethnic sample of over 700,000 participants from 21 studies contributing clinical data on dental caries experience and periodontitis. We outline the methodological challenges of combining data from heterogeneous populations, as well as the data reduction problem in resolving detailed clinical examination records into tractable phenotypes, and describe a strategy that addresses this. Specifically, we propose a 3-tiered phenotyping approach aimed at leveraging both the large sample size in the consortium and the detailed clinical information available in some studies, wherein binary, severity-encompassing, and "precision," data-driven clinical traits are employed. As an illustration of the use of data-driven traits across multiple cohorts, we present an application of dental caries experience data harmonization in 8 participating studies (N = 55,143) using previously developed permanent dentition tooth surface-level dental caries pattern traits. We demonstrate that these clinical patterns are transferable across multiple cohorts, have similar relative contributions within each study, and thus are prime targets for genetic interrogation in the expanded and diverse multiethnic sample of GLIDE2. We anticipate that results from GLIDE2 will decisively advance the knowledge base of mechanisms at play in oral, dental, and craniofacial health and disease and further catalyze international collaboration and data and resource sharing in genomics research.


Assuntos
Cárie Dentária , Periodontite , Cárie Dentária/genética , Cárie Dentária/prevenção & controle , Genômica , Humanos , Saúde Bucal , Fenótipo
3.
Sci Rep ; 11(1): 20672, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34667240

RESUMO

Peri-implantitis may result in the loss of dental implants. Cold atmospheric pressure plasma (CAP) was suggested to promote re-osseointegration, decrease antimicrobial burden, and support wound healing. However, the long-term risk assessment of CAP treatment in the oral cavity has not been addressed. Treatment with two different CAP devices was compared against UV radiation, carcinogen administration, and untreated conditions over 12 months. Histological analysis of 406 animals revealed that repeated CAP exposure did not foster non-invasive lesions or squamous cell carcinoma (SCCs). Carcinogen administration promoted non-invasive lesions and SCCs. Molecular analysis by a qPCR screening of 144 transcripts revealed distinct inflammatory profiles associated with each treatment regimen. Interestingly, CAP treatment of carcinogen-challenged mucosa did not promote but instead left unchanged or reduced the proportion of non-invasive lesions and SCC formation. In conclusion, repeated CAP exposure of murine oral mucosa was well tolerated, and carcinogenic effects did not occur, motivating CAP applications in patients for dental and implant treatments in the future.


Assuntos
Carcinogênese/efeitos dos fármacos , Carcinógenos/administração & dosagem , Mucosa Bucal/efeitos dos fármacos , Gases em Plasma/administração & dosagem , Animais , Antibacterianos/farmacologia , Pressão Atmosférica , Implantes Dentários/efeitos adversos , Inflamação/induzido quimicamente , Masculino , Camundongos , Osseointegração/efeitos dos fármacos , Peri-Implantite/induzido quimicamente , Propriedades de Superfície/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
4.
J Dent ; 111: 103727, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34119612

RESUMO

OBJECTIVE: The aim of this study was to assess 10-year trends in coronal caries in adults aged 20-83 years using data from the two-representative population-based Studies of Health in Pomerania (SHIP-0/SHIP-Trend-0). METHODS: Repeated cross-sectional data from 4,286 SHIP-0 and 3,913 SHIP-Trend-0 participants were analysed. Carious, filled and missing teeth/surfaces were recorded in a half-mouth design and the DMF-T/S scores and sound surfaces/teeth were calculated according to WHO criteria. Trends in DMF-T/S scores and its single components were presented stratified by age group and sex. RESULTS: A statistically significant decline in coronal caries experience (DMF-T and DMF-S) in adults aged 20 to 83 years as well as for D-T/S components was observed. The proportion of edentulous participants was almost halved from 8.7% (SHIP-0) to 5.1% (SHIP-Trend-0), while the number of M-T declined from 4.4 to 3.5 revealing an overall clear shift to a higher retention rate of teeth. In younger adults (25-34 years) 3.8 more sound teeth (17.2 sound surfaces) were found in average in the mouth and in elderly (65-74 years) a clear shift from extracted to filled teeth was observed (M-T reduced by 5.4, while F-T increased by 4). Regarding sex differences, females had consistently on average higher MF-T/S values, but lower D-T/S values than males. CONCLUSION: A clinically relevant drop in the severity of coronal caries experience in all adult age groups in Northeast Germany shows that not only reductions in caries experience in adolescence translated into adulthood but also later improvements led to long-term oral health.


Assuntos
Cárie Dentária , Perda de Dente , Adolescente , Adulto , Idoso , Estudos Transversais , Índice CPO , Cárie Dentária/epidemiologia , Feminino , Humanos , Masculino , Prevalência , Perda de Dente/epidemiologia
5.
J Dent ; 109: 103662, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33857544

RESUMO

OBJECTIVES: To predict patients' tooth loss during supportive periodontal therapy across four German university centers. METHODS: Tooth loss in 897 patients in four centers (Kiel (KI) n = 391; Greifswald (GW) n = 282; Heidelberg (HD) n = 175; Frankfurt/Main (F) n = 49) during supportive periodontal therapy (SPT) was assessed. Our outcome was annualized tooth loss per patient. Multivariable linear regression models were built on data of 75 % of patients from one center and used for predictions on the remaining 25 % of this center and 100 % of data from the other three centers. The prediction error was assessed as root-mean-squared-error (RMSE), i.e., the deviation of predicted from actually lost teeth per patient and year. RESULTS: Annualized tooth loss/patient differed significantly between centers (between median 0.00 (interquartile interval: 0.00, 0.17) in GW and 0.09 (0.00, 0.19) in F, p = 0.001). Age, smoking status and number of teeth before SPT were significantly associated with tooth loss (p < 0.03). Prediction within centers showed RMSE of 0.14-0.30, and cross-center RMSE was 0.15-0.31. Predictions were more accurate in F and KI than in HD and GW, while the center on which the model was trained had a less consistent impact. No model showed useful predictive values. CONCLUSION: While covariates were significantly associated with tooth loss in linear regression models, a clinically useful prediction was not possible with any of the models and generalizability was not given. Predictions were more accurate for certain centers. CLINICAL RELEVANCE: Association should not be confused with predictive value: Despite significant associations of covariates with tooth loss, none of our models was useful for prediction. Usually, model accuracy was even lower when tested across centers, indicating low generalizability.


Assuntos
Periodontite , Perda de Dente , Humanos , Estudos Retrospectivos , Fumar , Resultado do Tratamento
6.
J Dent Res ; 100(8): 824-832, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33655783

RESUMO

Although a potential link between periodontitis and cardiorespiratory fitness might provide a reasonable explanation for effects of tooth-related alterations seen on cardiometabolic diseases, evidence is currently limited. Thus, we investigated the association between clinically assessed periodontitis and cardiopulmonary exercise testing (CPET). Data from 2 independent cross-sectional population-based studies (5-y follow-up of the Study of Health in Pomerania [SHIP-1; N = 1,639] and SHIP-Trend-0 [N = 2,439]) were analyzed. Participants received a half-mouth periodontal examination, and teeth were counted. CPET was based on symptom limited-exercise tests on a bicycle ergometer. Associations of periodontitis parameters with CPET parameters were analyzed by confounder-adjusted multivariable linear regression. In the total sample, mean pocket probing depth (PPD), mean clinical attachment levels, and number of teeth were consistently associated with peak oxygen uptake (peakVO2) and exercise duration in both studies, even after restriction to cardiorespiratory healthy participants. Statistically significant associations with oxygen uptake at anaerobic threshold (VO2@AT), slope of the efficiency of ventilation in removing carbon dioxide, and peak oxygen pulse (VÉ/VCO2 slope) occurred. Further, interactions with age were identified, such that mainly older individuals with higher levels of periodontal disease severity were associated with lower peakVO2. Restricted to never smokers, associations with mean clinical attachment levels and the number of teeth mostly diminished, while associations of mean PPD with peakVO2, VO2@AT, VÉ/VCO2 slope, and exercise duration in SHIP-1 and SHIP-Trend-0 were confirmed. In SHIP-1, mean peakVO2 was 1,895 mL/min in participants with a mean PPD of 1.6 mm and 1,809 mL/min in participants with a mean PPD of 3.7 mm. To conclude, only mean PPD reflecting current disease severity was consistently linked to cardiorespiratory fitness in 2 cross-sectional samples of the general population. If confirmed in well-designed large-scale longitudinal studies, the association between periodontitis and cardiorespiratory fitness might provide a biologically plausible mechanism linking periodontitis with cardiometabolic diseases.


Assuntos
Tolerância ao Exercício , Periodontite , Estudos Transversais , Teste de Esforço , Humanos , Consumo de Oxigênio , Periodontite/epidemiologia
7.
J Dent Res ; 100(8): 875-882, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33655796

RESUMO

The aims of this study were to 1) determine if continuous eruption occurs in the maxillary teeth, 2) assess the magnitude of the continuous eruption, and 3) evaluate the effects of continuous eruption on the different periodontal parameters by using data from the population-based cohort of the Study of Health in Pomerania (SHIP). The jaw casts of 140 participants from the baseline (SHIP-0) and 16-y follow-up (SHIP-3) were digitized as 3-dimensional models. Robust reference points were set to match the tooth eruption stage at SHIP-0 and SHIP-3. Reference points were set on the occlusal surface of the contralateral premolar and molar teeth, the palatal fossa of an incisor, and the rugae of the hard palate. Reference points were combined to represent 3 virtual occlusal planes. Continuous eruption was measured as the mean height difference between the 3 planes and rugae fix points at SHIP-0 and SHIP-3. Probing depth, clinical attachment levels, gingiva above the cementoenamel junction (gingival height), and number of missing teeth were clinically assessed in the maxilla. Changes in periodontal variables were regressed onto changes in continuous eruption after adjustment for age, sex, number of filled teeth, and education or tooth wear. Continuous tooth eruption >1 mm over the 16 y was found in 4 of 140 adults and averaged to 0.33 mm, equaling 0.021 mm/y. In the total sample, an increase in continuous eruption was significantly associated with decreases in mean gingival height (B = -0.34; 95% CI, -0.65 to -0.03). In a subsample of participants without tooth loss, continuous eruption was negatively associated with PD. This study confirmed that continuous eruption is clearly detectable and may contribute to lower gingival heights in the maxilla.


Assuntos
Incisivo , Erupção Dentária , Adulto , Oclusão Dentária , Seguimentos , Humanos , Maxila
8.
J Dent Res ; 100(5): 487-495, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33213272

RESUMO

The long-term effectiveness of powered toothbrushes (PTBs) and interdental cleaning aids (IDAs) on a population level is unproven. We evaluated to what extent changes in PTB and IDA use may explain changes in periodontitis, caries, and tooth loss over the course of 17 y using data for adults (35 to 44 y) and seniors (65 to 74 y) from 3 independent cross-sectional surveys of the German Oral Health Studies (DMS). Oaxaca decomposition analyses assessed to what extent changes in mean probing depth (PD), number of caries-free surfaces, and number of teeth between 1) DMS III and DMS V and 2) DMS IV and DMS V could be explained by changes in PTB and IDA use. Between DMS III and V, PTB (adults: 33.5%; seniors: 28.5%) and IDA use (adults: 32.5%; seniors: 41.4%) increased along with an increase in mean PD, number of caries-free surfaces, and number of teeth. Among adults, IDA use contributed toward increased number of teeth between DMS III and V as well as DMS IV and V. In general, the estimates for adults were of lower magnitude. Among seniors between DMS III and V, PTB and IDA use explained a significant amount of explained change in the number of caries-free surfaces (1.72 and 5.80 out of 8.44, respectively) and the number of teeth (0.49 and 1.25 out of 2.19, respectively). Between DMS IV and V, PTB and IDA use contributed most of the explained change in caries-free surfaces (0.85 and 1.61 out of 2.72, respectively) and the number of teeth (0.25 and 0.46 out of 0.94, respectively) among seniors. In contrast to reported results from short-term clinical studies, in the long run, both PTB and IDA use contributed to increased number of caries-free healthy surfaces and teeth in both adults and seniors.


Assuntos
Cárie Dentária , Perda de Dente , Adulto , Estudos Transversais , Humanos , Saúde Bucal , Escovação Dentária
9.
J Dent ; 94: 103307, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32112911

RESUMO

OBJECTIVES: In this retrospective study, we compared tooth loss between patients receiving periodontal therapy (PT) in four German university centres, stratified according to periodontal treatment phase. MATERIALS AND METHODS: Overall, 896 patients (Kiel (KI) n = 391; Greifswald (GW) n = 282; Heidelberg (HD) n = 174; Frankfurt a.M. (F) n = 49) were examined initially (T0), after active periodontal therapy (APT, T1) and after supportive periodontal therapy (SPT, T2). Descriptive analyses and multivariable negative binomial regression models were performed. RESULTS: Follow-up periods differed significantly between the centres, ranging between 6.7 ±â€¯3.0 (GW) and 18.2 ±â€¯5.5 (KI) years (p < 0.001). At T0, age, gender, smoking and diabetes showed notable regional distinctions (p < 0.001). However, the number of teeth per patient was similar (between 24.0 ±â€¯4.6 (F) and 24.5 ±â€¯4.1 (HD); p = 0.27). During PT, the number of extracted teeth differed significantly between centres, with greater differences during SPT (0.9 ±â€¯1.8 (GW) to 2.3 ±â€¯2.8 (KI), p < 0.001) compared to APT (0.4 ±â€¯0.9 (F) to 1.0 ±â€¯2.1 (KI), p = 0.02). Annual tooth loss during SPT remained low in all centres (between 0.10 ±â€¯0.14 (F) to 0.15 ±â€¯0.30 (HD), p < 0.001). CONCLUSION: Within the limitation of the study, PT leads to a low risk of tooth loss in all university centres irrespective of patients' baseline characteristics. CLINICAL RELEVANCE: Within the limitations of this retrospective investigation, long-term tooth retention seems to be feasible for most patients, as long as a systematic and structured treatment approach is applied.


Assuntos
Periodontite , Perda de Dente , Seguimentos , Alemanha , Humanos , Estudos Longitudinais , Bolsa Periodontal , Estudos Retrospectivos , Resultado do Tratamento , Universidades
10.
J Dent Res ; 98(10): 1088-1095, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31361174

RESUMO

Prediction models learn patterns from available data (training) and are then validated on new data (testing). Prediction modeling is increasingly common in dental research. We aimed to evaluate how different model development and validation steps affect the predictive performance of tooth loss prediction models of patients with periodontitis. Two independent cohorts (627 patients, 11,651 teeth) were followed over a mean ± SD 18.2 ± 5.6 y (Kiel cohort) and 6.6 ± 2.9 y (Greifswald cohort). Tooth loss and 10 patient- and tooth-level predictors were recorded. The impact of different model development and validation steps was evaluated: 1) model complexity (logistic regression, recursive partitioning, random forest, extreme gradient boosting), 2) sample size (full data set or 10%, 25%, or 75% of cases dropped at random), 3) prediction periods (maximum 10, 15, or 20 y or uncensored), and 4) validation schemes (internal or external by centers/time). Tooth loss was generally a rare event (880 teeth were lost). All models showed limited sensitivity but high specificity. Patients' age and tooth loss at baseline as well as probing pocket depths showed high variable importance. More complex models (random forest, extreme gradient boosting) had no consistent advantages over simpler ones (logistic regression, recursive partitioning). Internal validation (in sample) overestimated the predictive power (area under the curve up to 0.90), while external validation (out of sample) found lower areas under the curve (range 0.62 to 0.82). Reducing the sample size decreased the predictive power, particularly for more complex models. Censoring the prediction period had only limited impact. When the model was trained in one period and tested in another, model outcomes were similar to the base case, indicating temporal validation as a valid option. No model showed higher accuracy than the no-information rate. In conclusion, none of the developed models would be useful in a clinical setting, despite high accuracy. During modeling, rigorous development and external validation should be applied and reported accordingly.


Assuntos
Modelos Dentários , Periodontite/diagnóstico , Perda de Dente/diagnóstico , Adulto , Estudos de Coortes , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade
11.
J Dent Res ; 98(10): 1096-1102, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31256728

RESUMO

The aim of the present study was to construct a biological age score reflecting one's physiologic capability and aging condition with respect to tooth loss over 10 y. From the follow-up to the population-based Study of Health in Pomerania (i.e., SHIP-2), 2,049 participants were studied for their baseline biomarker measures 10 y before (i.e., in SHIP-0). Metabolic and periodontal data were regressed onto chronological age to construct a score designated as "biological age." For either sex separately, the impact of this individualized score was used to predict tooth loss in the follow-up cohort in comparison with each participant's chronological age. Outcome data after 10 y with respect to tooth loss, periodontitis, obesity, and inflammation were shown to be better for biologically younger subjects than as expected by their chronological age, whereas for the older subjects, data were worse. Especially for tooth loss, a striking increase was observed in subjects whose biological age at baseline appeared to be higher than their chronological age. Biological age produced significantly better tooth loss predictions than chronological age (P < 0.001). Areas under receiver operating characteristic curves for tooth loss of ≥3 teeth in men during follow-up were 0.811 and 0.745 for biological and chronological age, respectively. For women, these figures were 0.788 and 0.724. For total tooth loss, areas under the curve were 0.890 and 0.749 in men and 0.872 and 0.752 in women. Biological age combines various measures into a single score and allows identifying individuals at increased risk of tooth loss.


Assuntos
Fatores Etários , Envelhecimento , Obesidade , Periodontite , Perda de Dente/diagnóstico , Adulto , Estudos de Coortes , Feminino , Alemanha , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade
12.
J Dent Res ; 98(6): 642-651, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31026179

RESUMO

Periodontitis is one of the most prevalent oral diseases worldwide and is caused by multifactorial interactions between host and oral bacteria. Altered cellular metabolism of host and microbes releases a number of intermediary end products known as metabolites. There is an increasing interest in identifying metabolites from oral fluids such as saliva to widen the understanding of the complex pathogenesis of periodontitis. It is believed that some metabolites might serve as indicators toward early detection and screening of periodontitis and perhaps even for monitoring its prognosis in the future. Because contemporary periodontal screening methods are deficient, there is an urgent need for novel approaches in periodontal screening procedures. To this end, we associated oral parameters (clinical attachment level, periodontal probing depth, supragingival plaque, supragingival calculus, number of missing teeth, and removable denture) with a large set of salivary metabolites ( n = 284) obtained by mass spectrometry among a subsample ( n = 909) of nondiabetic participants from the Study of Health in Pomerania (SHIP-Trend-0). Linear regression analyses were performed in age-stratified groups and adjusted for potential confounders. A multifaceted image of associated metabolites ( n = 107) was revealed with considerable differences according to age groups. In the young (20 to 39 y) and middle-aged (40 to 59 y) groups, metabolites were predominantly associated with periodontal variables, whereas among the older subjects (≥60 y), tooth loss was strongly associated with metabolite levels. Metabolites associated with periodontal variables were clearly linked to tissue destruction, host defense mechanisms, and bacterial metabolism. Across all age groups, the bacterial metabolite phenylacetate was significantly associated with periodontal variables. Our results revealed alterations of the salivary metabolome in association with age and oral health status. Among our comprehensive panel of metabolites, periodontitis was significantly associated with the bacterial metabolite phenylacetate, a promising substance for further biomarker research.


Assuntos
Metaboloma , Saúde Bucal , Periodontite/microbiologia , Saliva/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bactérias , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Perda da Inserção Periodontal , Perda de Dente , Adulto Jovem
13.
Br J Dermatol ; 180(1): 141-148, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30099737

RESUMO

BACKGROUND: Generalized severe epidermolysis bullosa simplex (EBS-gen sev) is a genetic blistering skin disease in which autosomal dominant mutations in either the keratin KRT5 or KRT14 genes lead to impaired function of the intermediate filament cytoskeleton in the basal epidermis. Here we present an ex vivo RNA trans-splicing-based therapeutic approach to correct the phenotype. OBJECTIVES: To correct a mutation within exon 1 of the KRT14 gene, using a 5'-trans-splicing approach, where any mutation within the first seven exons could be replaced by a single therapeutic molecule. METHODS: A therapeutic RNA trans-splicing molecule containing wild-type exons 1-7 was stably transduced into an EBS patient-derived keratinocyte line. Trans-splicing was confirmed via reverse-transcriptase polymerase chain reaction, Western blotting and immunofluorescence microscopy. Skin equivalents generated from corrected keratinocytes were grafted onto nude mice and analysed about 8 weeks post-transplantation for regular epidermal stratification, trans-splicing-induced green fluorescent protein expression and blistering. RESULTS: Transplanted skin equivalents generated from trans-splicing-corrected patient keratinocytes showed a stable and blister-free epidermis. KRT14 correction disrupted EBS-gen sev-associated proinflammatory signalling, as shown at the mRNA and protein levels. Disruption of the pathogenic feedback loop in addition to overall downregulation of KRT14 expression highlighted the effect of KRT14 correction on the EBS pathomechanism. CONCLUSIONS: Our data demonstrate that trans-splicing-mediated mRNA therapy is an effective method for the correction of dominantly inherited KRT14 mutations at the transcriptional level. This results in the rescue of the EBS-gen sev phenotype and stabilization of the epidermis in a xenograft mouse model.


Assuntos
Epidermólise Bolhosa Simples/terapia , Engenharia Genética , Terapia Genética/métodos , Queratina-14/genética , Transplante de Pele , Animais , Técnicas de Cultura de Células , Linhagem Celular , Modelos Animais de Doenças , Epidermólise Bolhosa Simples/genética , Éxons/genética , Feminino , Humanos , Queratinócitos , Camundongos , Camundongos Nus , Mutação , Transdução Genética
14.
J Dent Res ; 98(2): 171-179, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30326764

RESUMO

Evidence is limited regarding whether periodontal treatment improves hemoglobin A1c (HbA1c) among people with prediabetes and periodontal disease, and it is unknown whether improvement of metabolic status persists >3 mo. In an exploratory post hoc analysis of the multicenter randomized controlled trial "Antibiotika und Parodontitis" (Antibiotics and Periodontitis)-a prospective, stratified, double-blind study-we assessed whether nonsurgical periodontal treatment with or without an adjunctive systemic antibiotic treatment affects HbA1c and high-sensitivity C-reactive protein (hsCRP) levels among periodontitis patients with normal HbA1c (≤5.7%, n = 218), prediabetes (5.7% < HbA1c < 6.5%, n = 101), or unknown diabetes (HbA1c ≥ 6.5%, n = 8) over a period of 27.5 mo. Nonsurgical periodontal treatment reduced mean pocket probing depth by >1 mm in both groups. In the normal HbA1c group, HbA1c values remained unchanged at 5.0% (95% CI, 4.9% to 6.1%) during the observation period. Among periodontitis patients with prediabetes, HbA1c decreased from 5.9% (95% CI, 5.9% to 6.0%) to 5.4% (95% CI, 5.3% to 5.5%) at 15.5 mo and increased to 5.6% (95% CI, 5.4% to 5.7%) after 27.5 mo. At 27.5 mo, 46% of periodontitis patients with prediabetes had normal HbA1c levels, whereas 47.9% remained unchanged and 6.3% progressed to diabetes. Median hsCRP values were reduced in the normal HbA1c and prediabetes groups from 1.2 and 1.4 mg/L to 0.7 and 0.7 mg/L, respectively. Nonsurgical periodontal treatment may improve blood glucose values among periodontitis patients with prediabetes (ClinicalTrials.gov NCT00707369).


Assuntos
Diabetes Mellitus Tipo 2/sangue , Hemoglobinas Glicadas/análise , Periodontite/terapia , Estado Pré-Diabético/epidemiologia , Adulto , Idoso , Antibacterianos/uso terapêutico , Glicemia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Periodontite/sangue , Periodontite/complicações , Estado Pré-Diabético/sangue , Estudos Prospectivos , Resultado do Tratamento
15.
J Nutr Health Aging ; 22(7): 829-836, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30080228

RESUMO

BACKGROUND: Aging is associated with a decline in masticatory muscles mass and performance. The present study aims to examine the differences in the cross-sectional areas of the masseter, medial and lateral pterygoid muscles in relation to age and the present dental status in a population-based magnetic resonance imaging study. METHODS: This cross sectional study involved 747 subjects aged between 30-89 years (344 male, 403 female) who underwent both a whole body MRI and a full oral examination. The cross-sectional areas of the masseter, medial and lateral pterygoid muscles were measured from MRI images using the software Osirix. Dental and prosthetic status data from the oral examination were classified according to Eichner index. The method of generalized least squares, also called growth curve model, was used to examine the associations between the cross-sectional areas, age and tooth status. RESULTS: The cross-sectional area of the lateral pterygoid muscle decreased substantially with age in women but did not depend on age in men. The medial pterygoid muscle depended on age but an effect modification by gender was uncertain. Masseter muscle was weakly associated with age but strongly associated with the number of teeth in both genders. CONCLUSIONS: Our findings suggest that age has a heterogeneous effect on masticatory muscles. This indicates that age related changes to the masticatory muscles are muscle specific and are not consistent between the different muscles.


Assuntos
Envelhecimento/fisiologia , Músculo Masseter/fisiologia , Músculos Pterigoides/fisiologia , Músculo Temporal/fisiologia , Perda de Dente/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Músculos da Mastigação/fisiologia , Pessoa de Meia-Idade
16.
J Dent Res ; 97(5): 537-546, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29294296

RESUMO

Periodontitis is one of the most common inflammatory human diseases with a strong genetic component. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWASs) of chronic periodontitis (CP) have largely been unsuccessful in identifying common susceptibility factors. A combination of quantitative trait loci (QTL) mapping in mice with association studies in humans has the potential to discover novel risk loci. To this end, we assessed alveolar bone loss in response to experimental periodontal infection in 25 lines (286 mice) from the Collaborative Cross (CC) mouse population using micro-computed tomography (µCT) analysis. The orthologous human chromosomal regions of the significant QTL were analyzed for association using imputed genotype data (OmniExpress BeadChip arrays) derived from case-control samples of aggressive periodontitis (AgP; 896 cases, 7,104 controls) and chronic periodontitis (CP; 2,746 cases, 1,864 controls) of northwest European and European American descent, respectively. In the mouse genome, QTL mapping revealed 2 significant loci (-log P = 5.3; false discovery rate = 0.06) on chromosomes 1 ( Perio3) and 14 ( Perio4). The mapping resolution ranged from ~1.5 to 3 Mb. Perio3 overlaps with a previously reported QTL associated with residual bone volume in F2 cross and includes the murine gene Ccdc121. Its human orthologue showed previously a nominal significant association with CP in humans. Use of variation data from the genomes of the CC founder strains further refined the QTL and suggested 7 candidate genes ( CAPN8, DUSP23, PCDH17, SNORA17, PCDH9, LECT1, and LECT2). We found no evidence of association of these candidates with the human orthologues. In conclusion, the CC populations enabled mapping of confined QTL that confer susceptibility to alveolar bone loss in mice and larger human phenotype-genotype samples and additional expression data from gingival tissues are likely required to identify true positive signals.


Assuntos
Predisposição Genética para Doença/genética , Periodontite/genética , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/genética , Animais , Mapeamento Cromossômico , Modelos Animais de Doenças , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Periodontite/diagnóstico por imagem , Locos de Características Quantitativas/genética , Microtomografia por Raio-X
17.
Diabetes Metab ; 44(3): 243-249, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29249612

RESUMO

AIM: As periodontitis may contribute to the pathogenesis of diabetes, the effects of periodontitis on diabetes incidence and HbA1c change was quantified in a prospective cohort. METHODS: Data from an 11-year follow-up of the Study of Health in Pomerania were analyzed to evaluate the effects of periodontitis on incident diabetes and long-term HbA1c changes in 2047 subjects aged 20-81years. Diabetes was based on self-reported physician diagnoses, antidiabetic medication use, or HbA1c≥6.5% or non-fasting blood glucose levels ≥11.1mmol/L. To assess periodontal status, periodontal pockets were probed, and their depth and clinical attachment levels measured. For both measures, means and percentages of sites≥3mm were calculated. In addition, all probing depths≥4mm were summed (cumulative probing depth). Modified Poisson and multivariable linear models were applied, adjusted for age, gender, highest level of general education, marital status, waist circumference, physical activity, smoking status and follow-up time. RESULTS: Over a mean follow-up period of 11.1years, 207 subjects developed diabetes. Baseline mean clinical attachment levels (CAL) and probing depths (PPD) were not significantly associated with either diabetes incidence [mean CALs, fourth quartile, incidence rate ratio=0.819, 95% confidence interval (CI): 0.489-1.370; P=0.446] or long-term changes in HbA1c (mean CAL, fourth quartile, ß=-0.086, 95% CI: -0.187, -0.016; P=0.098). Sensitivity analyses using alternative exposure definitions confirmed these results. CONCLUSION: Contrary to the currently available literature, no convincing evidence was found of any potential association between periodontitis and diabetes incidence or HbA1c change.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Hemoglobinas Glicadas/análise , Periodontite/complicações , Adulto , Idoso , Glicemia , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/etiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
18.
J Dent Res ; 96(12): 1392-1399, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28732187

RESUMO

An association between periodontitis and nonalcoholic fatty liver disease (NAFLD) has been reported by experimental animal and epidemiologic studies. This study investigated whether circulating levels of serum C-reactive protein (CRP) and a weighted genetic CRP score representing markers of inflammatory burden modify the association between periodontitis and NAFLD. Data came from 2,481 participants of the Study of Health in Pomerania who attended baseline examination that occurred between 1997 and 2001. Periodontitis was defined as the percentage of sites (0%, <30%, ≥30%) with probing pocket depth (PD) ≥4 mm, and NAFLD status was determined using liver ultrasound assessment. Serum CRP levels were assayed at a central laboratory, and single-nucleotide polymorphisms previously identified through genome-wide association studies as robustly associated with serum CRP were combined into a weighted genetic CRP score (wGSCRP). Logistic regression models estimated the association between periodontitis and NAFLD within strata of serum CRP and separately within strata of the wGSCRP. The prevalence of NAFLD was 26.4% (95% confidence interval [CI], 24.6, 28.1) while 17.8% (95% CI, 16.0-19.6) had ≥30% of sites with PD ≥4 mm. Whereas the wGSCRP was not a modifier ( Pinteraction = 0.8) on the multiplicative scale, serum CRP modified the relationship between periodontitis and NAFLD ( Pinteraction = 0.01). The covariate-adjusted prevalence odds ratio of NAFLD comparing participants with ≥30% of sites with PD ≥4 mm to those with no site affected was 2.39 (95% CI, 1.32-4.31) among participants with serum CRP <1 mg/L. The corresponding estimate was 0.97 (95% CI, 0.57-1.66) for participants with serum CRP levels of 1 to 3 mg/L and 1.12 (95% CI, 0.65-1.93) for participants with serum CRP >3 mg/L. Periodontitis was positively associated with higher prevalence odds of NAFLD, and this relationship was modified by serum CRP levels.


Assuntos
Marcadores Genéticos , Hepatopatia Gordurosa não Alcoólica/genética , Periodontite/genética , Adulto , Proteína C-Reativa/genética , Feminino , Alemanha/epidemiologia , Humanos , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Periodontite/sangue , Periodontite/epidemiologia , Polimorfismo de Nucleotídeo Único , Prevalência , Inquéritos e Questionários
19.
J Dent Res ; 96(8): 945-952, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28467728

RESUMO

Periodontitis is a common dysbiotic inflammatory disease with an estimated heritability of 50%. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWAS) of chronic periodontitis (CP) have been unsuccessful in discovering susceptibility factors. A strategy that combines agnostic GWAS with a well-powered candidate-gene approach has the potential to discover novel loci. We combined RNA-seq data from gingival tissues with quantitative trait loci (QTLs) that were identified in a F2-cross of mice resistant and susceptible to infection with oral bacterial pathogens. Four genes, which were located within the mapped QTLs, showed differential expression. The chromosomal regions across the human orthologous were interrogated for putative periodontitis-associated variants using existing GWAS data from a German case-control sample of aggressive periodontitis (AgP; 651 cases, 4,001 controls), the most severe and early onset form of periodontitis. Two haplotype blocks, one upstream to the coding region of UGT2A1 (rs146712414, P = 9.1 × 10-5; odds ratio [OR], 1.34; 95% confidence interval [CI], 1.16-1.56) and one downstream of the genes PF4/PPBP/CXCL5 (rs1595009, P = 1.3 × 10-4; OR, 1.32; 95% CI, 1.15-1.52), were associated with AgP. The association of rs1595009 was validated in an independent cohort of CP of European Americans (1,961 cases and 1,864 controls; P = 0.03; OR, 1.45; 95% CI, 1.01-1.29). This association was further replicated in another sample of 399 German CP cases (disease onset <60 y of age) and 1,633 controls ( P = 0.03; OR, 1.75; 95% CI, 1.06-2.90). The combined estimates of association from all samples were P = 2.9 × 10-5 (OR, 1.2; 95% CI, 1.1-1.3). This study shows the strength of combining QTL mapping and RNA-Seq data from a mouse model with association studies in human case-control samples to identify genetic risk variants of periodontitis.


Assuntos
Periodontite Agressiva/genética , Quimiocina CXCL5/genética , Fator Plaquetário 4/genética , beta-Tromboglobulina/genética , Animais , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Camundongos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco , Software
20.
J Dent Res ; 96(3): 277-284, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28081371

RESUMO

Temporomandibular disorder (TMD) is a musculoskeletal condition characterized by pain and reduced function in the temporomandibular joint and/or associated masticatory musculature. Prevalence in the United States is 5% and twice as high among women as men. We conducted a discovery genome-wide association study (GWAS) of TMD in 10,153 participants (769 cases, 9,384 controls) of the US Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The most promising single-nucleotide polymorphisms (SNPs) were tested in meta-analysis of 4 independent cohorts. One replication cohort was from the United States, and the others were from Germany, Finland, and Brazil, totaling 1,911 TMD cases and 6,903 controls. A locus near the sarcoglycan alpha ( SGCA), rs4794106, was suggestive in the discovery analysis ( P = 2.6 × 106) and replicated (i.e., 1-tailed P = 0.016) in the Brazilian cohort. In the discovery cohort, sex-stratified analysis identified 2 additional genome-wide significant loci in females. One lying upstream of the relaxin/insulin-like family peptide receptor 2 ( RXP2) (chromosome 13, rs60249166, odds ratio [OR] = 0.65, P = 3.6 × 10-8) was replicated among females in the meta-analysis (1-tailed P = 0.052). The other (chromosome 17, rs1531554, OR = 0.68, P = 2.9 × 10-8) was replicated among females (1-tailed P = 0.002), as well as replicated in meta-analysis of both sexes (1-tailed P = 0.021). A novel locus at genome-wide level of significance (rs73460075, OR = 0.56, P = 3.8 × 10-8) in the intron of the dystrophin gene DMD (X chromosome), and a suggestive locus on chromosome 7 (rs73271865, P = 2.9 × 10-7) upstream of the Sp4 Transcription Factor ( SP4) gene were identified in the discovery cohort, but neither of these was replicated. The SGCA gene encodes SGCA, which is involved in the cellular structure of muscle fibers and, along with DMD, forms part of the dystrophin-glycoprotein complex. Functional annotation suggested that several of these variants reside in loci that regulate processes relevant to TMD pathobiologic processes.


Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Transtornos da Articulação Temporomandibular/genética , Brasil/epidemiologia , Estudos de Casos e Controles , Distrofina , Feminino , Finlândia/epidemiologia , Loci Gênicos , Predisposição Genética para Doença , Genótipo , Alemanha/epidemiologia , Hispânico ou Latino , Humanos , Masculino , Fenótipo , Prevalência , Receptores Acoplados a Proteínas G , Sarcoglicanas , Fator de Transcrição Sp4 , Inquéritos e Questionários , Transtornos da Articulação Temporomandibular/epidemiologia , Transtornos da Articulação Temporomandibular/etnologia , Estados Unidos/epidemiologia
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