Targeted deep sequencing analyses of long QT syndrome in a Japanese population.

Long QT syndrome (LQTS) is one of the most common inherited arrhythmias and multiple genes have been reported as causative. Presently, genetic diagnosis for LQTS patients is becoming widespread and contributing to implementation of therapies. However, causative genetic mutations cannot be detected in about 20% of patients. To elucidate additional genetic mutations in LQTS, we performed deep-sequencing of previously reported 15 causative and 85 candidate genes for this disorder in 556 Japanese LQTS patients. We performed in-silico filtering of the sequencing data and found 48 novel variants in 33 genes of 53 cases. These variants were predicted to be damaging to coding proteins or to alter the binding affinity of several transcription factors. Notably, we found that most of the LQTS-related variants in the RYR2 gene were in the large cytoplasmic domain of the N-terminus side. They might be useful for screening of LQTS patients who had no known genetic factors. In addition, when the mechanisms of these variants in the development of LQTS are revealed, it will be useful for early diagnosis, risk stratification, and selection of treatment.

Prognostic factors affecting periodontal regenerative therapy using recombinant human fibroblast growth factor-2: A 3-year cohort study.

Introduction: Fibroblast growth factor-2 (FGF-2) has been reported to promote periodontal tissue regeneration. However, no study has investigated the long-term prognosis of periodontal regenerative therapy using FGF-2 to date. The aim of this study was to observe the long-term outcomes as well as to investigate the factors affecting the prognosis of periodontal regenerative therapy using FGF-2. Methods: Sixty intrabony defects were prospectively investigated for three years after periodontal regenerative therapy with recombinant human FGF-2 (rhFGF-2) by evaluating probing pocket depth (PPD) and radiographic bone defect depth (RBD). The factors influencing RBD were assessed by conducting a multivariate linear regression analysis after adjusting for confounders. Results: The mean age of the participants was 62.4 ± 13.4 years, and baseline PPD and RBD were 6.1 ± 1.9 mm and 4.5 ± 1.8 mm, respectively. At six months, one year, and three years after surgery, PPD and RBD had significantly improved to 4.2 ± 1.7, 3.7 ± 1.4, 4.0 ± 1.9 mm and to 3.08 ± 2.05, 2.73 ± 1.90, 2.51 ± 2.15 mm, respectively. At the three-year examination, a significant positive association was deteced between RBD reduction and RBD at baseline, while the association was not significant between RBD reduction and the radiographic bony angle, number of bony walls of the defect, or the furcation involvement at baseline. Conclusions: rhFGF-2 was effective for alveolar bone regeneration in patients with periodontitis and maintained the improved parameters over the three-year observation period. The radiographic bone defect depth at baseline was found to be the factor affecting the periodontal regenerative therapy using rhFGF-2 in the intrabony defects. Trial registration number: UMIN000027979.

Corrigendum: Comparison of Periodontal Bacteria of Edo and Modern Periods Using Novel Diagnostic Approach for Periodontitis With Micro-CT.

[This corrects the article DOI: 10.3389/fcimb.2021.723821.].

Comparison of Periodontal Bacteria of Edo and Modern Periods Using Novel Diagnostic Approach for Periodontitis With Micro-CT.

Ancient dental calculus, formed from dental plaque, is a rich source of ancient DNA and can provide information regarding the food and oral microbiology at that time. Genomic analysis of dental calculus from Neanderthals has revealed the difference in bacterial composition of oral microbiome between Neanderthals and modern humans. There are few reports investigating whether the pathogenic bacteria of periodontitis, a polymicrobial disease induced in response to the accumulation of dental plaque, were different between ancient and modern humans. This study aimed to compare the bacterial composition of the oral microbiome in ancient and modern human samples and to investigate whether lifestyle differences depending on the era have altered the bacterial composition of the oral microbiome and the causative bacteria of periodontitis. Additionally, we introduce a novel diagnostic approach for periodontitis in ancient skeletons using micro-computed tomography. Ancient 16S rDNA sequences were obtained from 12 samples at the Unko-in site (18th-19th century) of the Edo era (1603-1867), a characteristic period in Japan when immigrants were not accepted. Furthermore, modern 16S rDNA data from 53 samples were obtained from a database to compare the modern and ancient microbiome. The microbial co-occurrence network was analyzed based on 16S rDNA read abundance. Eubacterium species, Mollicutes species, and Treponema socranskii were the core species in the Edo co-occurrence network. The co-occurrence relationship between Actinomyces oricola and Eggerthella lenta appeared to have played a key role in causing periodontitis in the Edo era. However, Porphyromonas gingivalis, Fusobacterium nucleatum subsp. vincentii, and Prevotella pleuritidis were the core and highly abundant species in the co-occurrence network of modern samples. These results suggest the possibility of differences in the pathogens causing periodontitis during different eras in history.

Clinical comparison of an electric-powered ionic toothbrush and a manual toothbrush in plaque reduction: A randomized clinical trial.

OBJECTIVES: This study aimed to evaluate the plaque removal efficacy of a newly developed electric-powered ionic toothbrush vs. a manual toothbrush. MATERIALS AND METHODS: Manual or electric-powered ionic toothbrushes were randomly assigned to 30 healthy volunteers divided into two groups (Phase I). After 2 min of brushing, all tooth surfaces were stained with a plaque staining solution, and blinded examiners performed scoring using the Rustogi Modification of the Navy Plaque Index. Plaque removal rate was calculated at the central incisors, first premolar and first molar, as representative teeth, in the maxilla and mandibula. One week following Phase I, the same examinations were repeated in all subjects using another toothbrush (Phase II), as a crossover design. RESULTS: Electric ionic toothbrushes demonstrated a significantly higher plaque removal rate than manual toothbrushes in the premolar and molar areas (p < .05). However, in the central incisor area, no statistically significant difference was observed. CONCLUSIONS: Compared with manual toothbrushes, electric-powered ionic ones were significantly efficient in removing plaque in the premolar and molar areas.

Fretibacterium sp. human oral taxon 360 is a novel biomarker for periodontitis screening in the Japanese population.

BACKGROUND: Periodontitis is a common inflammatory disease, leading to bone destruction and tooth loss. Screening for periodontitis is important in preventing the progress of this disease. Various types of bacteria have been examined as potential screening targets, but only culturable pathogenic bacteria have been considered candidates. Recently, the various uncultivable bacteria have been identified in microbiome studies, but the value of these bacteria in periodontitis screening remains unknown. OBJECTIVES: The aim of this study was to evaluate the diagnostic use of uncultivable bacteria Fretibacterium sp. HOT 360 and TM7 sp. HOT 356 for periodontitis screening in the Japanese population. MATERIAL AND METHODS: Stimulated saliva samples were collected from 217 participants (periodontitis group, n = 157; healthy group, n = 60). The two uncultivable bacterial species selected were: Fretibacterium sp. human oral taxon 360 (Fretibacterium sp. HOT 360) and TM7 sp. human oral taxon 356 (TM7 sp. HOT 356). The levels of these two bacterial species were compared with those of Porphyromonas gingivalis (P. gingivalis), a keystone pathogen in periodontitis. These three species of bacteria were then quantified using qualitative real-time polymerase chain reaction (qPCR) with specific primers and Taqman probes. Statistical analysis was performed by SPSS 20.0 software. P value was statistically significant at .05. RESULTS: The populations of uncultivable bacterial species TM7 sp. HOT 356 and Fretibacterium sp. HOT 360 were significantly higher in periodontitis group than in healthy group. Only Fretibacterium sp. HOT 360 showed a significantly positive correlation with such periodontal parameters as probing pocket depth (PPD) and bleeding on probing (BOP). CONCLUSION: These findings indicate that uncultivable bacteria Fretibacterium sp. HOT 360 can be used as a saliva-based diagnostic bacterial biomarker for periodontitis screening.

Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data.

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.

Variants at HLA-A, HLA-C, and HLA-DQB1 Confer Risk of Psoriasis Vulgaris in Japanese.

Psoriasis vulgaris (PsV) is an autoimmune disease of skin and joints with heterogeneity in epidemiologic and genetic landscapes of global populations. We conducted an initial genome-wide association study and a replication study of PsV in the Japanese population (606 PsV cases and 2,052 controls). We identified significant associations of the single nucleotide polymorphisms with PsV risk at TNFAIP3-interacting protein 1and the major histocompatibility complex region (P = 3.7 × 10-10 and 6.6 × 10-15, respectively). By updating the HLA imputation reference panel of Japanese (n = 908) to expand HLA gene coverage, we fine-mapped the HLA variants associated with PsV risk. Although we confirmed the PsV risk of HLA-C*06:02 (odds ratio = 6.36, P = 0.0015), its impact was relatively small compared with those in other populations due to rare allele frequency in Japanese (0.4% in controls). Alternatively, HLA-A*02:07, which corresponds to the cysteine residue at HLA-A amino acid position 99 (HLA-A Cys99), demonstrated the most significant association with PsV (odds ratio = 4.61, P = 1.2 × 10-10). In addition to HLA-A*02:07 and HLA-C*06:02, stepwise conditional analysis identified an independent PsV risk of HLA-DQß1 Asp57 (odds ratio = 2.19, P = 1.9 × 10-6). Our PsV genome-wide association study in Japanese highlighted the genetic architecture of PsV, including the identification of HLA risk variants.

RpA1 ameliorates symptoms of mutant ataxin-1 knock-in mice and enhances DNA damage repair.

DNA damage and repair is a critical domain of many neurodegenerative diseases. In this study, we focused on RpA1, a candidate key molecule in polyQ disease pathologies, and tested the therapeutic effect of adeno-associated virus (AAV) vector expressing RpA1 on mutant Ataxin-1 knock-in (Atxn1-KI) mice. We found significant effects on motor functions, normalized DNA damage markers (γH2AX and 53BP1), and improved Purkinje cell morphology; effects that lasted for 50 weeks following AAV-RpA1 infection. In addition, we confirmed that AAV-RpA1 indirectly recovered multiple cellular functions such as RNA splicing, transcription and cell cycle as well as abnormal morphology of dendrite and dendritic spine of Purkinje cells in Atxn1-KI mice. All these results suggested a possibility of gene therapy with RpA1 for SCA1.

Desensitizing Agent Reduces Dentin Hypersensitivity During Ultrasonic Scaling: A Pilot Study.

BACKGROUND: Dentin hypersensitivity can interfere with optimal periodontal care by dentists and patients. The pain associated with dentin hypersensitivity during ultrasonic scaling is intolerable for patient and interferes with the procedure, particularly during supportive periodontal therapy (SPT) for patients with gingival recession. AIM: This study proposed to evaluate the desensitizing effect of the oxalic acid agent on pain caused by dentin hypersensitivity during ultrasonic scaling. MATERIALS AND METHODS: This study involved 12 patients who were incorporated in SPT program and complained of dentin hypersensitivity during ultrasonic scaling. We examined the availability of the oxalic acid agent to compare the degree of pain during ultrasonic scaling with or without the application of the dentin hypersensitivity agent. Evaluation of effects on dentin hypersensitivity was determined by a questionnaire and visual analog scale (VAS) pain scores after ultrasonic scaling. The statistical analysis was performed using the paired Student t-test and Spearman rank correlation coefficient. RESULTS: The desensitizing agent reduced the mean VAS pain score from 69.33 ± 16.02 at baseline to 26.08 ± 27.99 after application. The questionnaire revealed that >80% patients were satisfied and requested the application of the desensitizing agent for future ultrasonic scaling sessions. CONCLUSION: This study shows that the application of the oxalic acid agent considerably reduces pain associated with dentin hypersensitivity experienced during ultrasonic scaling. This pain control treatment may improve patient participation and treatment efficiency.

Thrombospondin-1 production is enhanced by Porphyromonas gingivalis lipopolysaccharide in THP-1 cells.

Periodontitis is a chronic inflammatory disease caused by gram-negative anaerobic bacteria. Monocytes and macrophages stimulated by periodontopathic bacteria induce inflammatory mediators that cause tooth-supporting structure destruction and alveolar bone resorption. In this study, using a DNA microarray, we identified the enhanced gene expression of thrombospondin-1 (TSP-1) in human monocytic cells stimulated by Porphyromonas gingivalis lipopolysaccharide (LPS). TSP-1 is a multifunctional extracellular matrix protein that is upregulated during the inflammatory process. Recent studies have suggested that TSP-1 is associated with rheumatoid arthritis, diabetes mellitus, and osteoclastogenesis. TSP-1 is secreted from neutrophils, monocytes, and macrophages, which mediate immune responses at inflammatory regions. However, TSP-1 expression in periodontitis and the mechanisms underlying TSP-1 expression in human monocytic cells remain unknown. Here using real-time RT-PCR, we demonstrated that TSP-1 mRNA expression level was significantly upregulated in inflamed periodontitis gingival tissues and in P. gingivalis LPS-stimulated human monocytic cell line THP-1 cells. TSP-1 was expressed via Toll-like receptor (TLR) 2 and TLR4 pathways. In P. gingivalis LPS stimulation, TSP-1 expression was dependent upon TLR2 through the activation of NF-κB signaling. Furthermore, IL-17F synergistically enhanced P. gingivalis LPS-induced TSP-1 production. These results suggest that modulation of TSP-1 expression by P. gingivalis plays an important role in the progression and chronicity of periodontitis. It may also contribute a new target molecule for periodontal therapy.