Impact of TLR9 and TLR7 gene polymorphisms on prognosis and survival of patients with oral squamous cell carcinoma.

Despite significant efforts in developing new diagnostic and therapeutic modalities, oral squamous cell carcinomas (OSCCs) still exhibit a high recurrence rate, a low five-year survival rate, and an increasing prevalence. Toll-like receptors (TLRs), which initiate and perpetuate immune mechanisms upon activation, have been linked to immune surveillance and the antitumor immune response. The aim of this study was to investigate the association between the polymorphisms of the TLR7 rs3853839 and TLR9 rs187084 genes and OSCC risk, clinicopathological features, and survival. Genotyping was assessed by real-time polymerase chain reaction (PCR) in 95 HPV negative OSCC patients and 107 age- and sex-matched healthy controls. Patients with lymph node metastases had higher frequencies of the TLR9 rs187084 CC variant genotype compared to the major TT genotype (P = 0.020) and to T-allele carriers (combined TT + CT genotypes, P = 0.015). A higher prevalence of advanced stage III was observed in patients with the TLR9 rs187084 variant CC genotype compared to TT (P = 0.047) and to T-allele carriers (TT + CT, P = 0.037). Kaplan-Meier analysis revealed a lower overall survival (OS) rate in patients with the TLR9 rs187084 variant CC genotype compared to the TT genotype (P = 0.010, log-rank test) and to T-allele carriers (TT + CT genotypes, P = 0.002), though it was not an independent predictor of OS. Both TLR9 rs187084 and TLR7 rs3853839 polymorphisms were associated with high alcohol consumption (P = 0.027 and P = 0.001, respectively). The investigated genetic variations were not associated with OSCC susceptibility. The variant CC genotype of the TLR9 rs187084 polymorphism might be a marker of poor survival and tumor progression in OSCC.

Effects of apical periodontitis treatment on hyperglycaemia in diabetes: A prospective cohort study.

AIM: This prospective cohort study was undertaken to evaluate the success rate of root canal treatment (RCT) in type 2 diabetes mellitus (T2DM) patients with targeted level and unachieved targeted level of glycaemic control as well as the impact of RCT on the glucose blood level in T2DM patients. METHODOLOGY: Patients needing RCT were divided into three groups: these without T2DM, that is, the control group (CG), those with targeted level of glycated haemoglobin HbA1c < 7% (TL A1c) and the third ones with unachieved targeted level (UTL A1c), that is, with HbA1c ≥ 7%. Before RCT, HbA1c and the periapical index (PAI) score were assessed, as well as 1 year later. RESULTS: Our results showed less favourable treatment results of RCT such as a reduction of radiographic lesions in T2DM patients, particularly in subjects with UTL A1c. The intergroup analysis of PAI score at the 12-month follow-up revealed a significant difference in TL A1C (p = .022) and CG (p = .001) with respect to UTL A1c. Total number of healed teeth (PAI≤2) at the 12-month after RCT in UTL A1c was significantly lower in comparison to CG (p = .008). Contrariwise, RCT may improve the glycaemic control in diabetic patients with UTL A1c after 12 months of posttreatment. Regression analysis showed that UTL A1c patients were more likely to have AP persistence after endodontic treatment (OR = 4.788; CI: 1.157-19.816; p = .031). CONCLUSIONS: T2DM retards the AP healing and conversely AP contributes to increasing the inflammatory burden in T2DM. RCT reduces the cumulative inflammatory burden in T2DM and thus may contribute to improvement of glycaemic control particularly in patients with UTL A1c.

Vesicular Messages from Dental Biofilms for Neutrophils.

The encounter between dental biofilm and neutrophils in periodontitis remains elusive, although it apparently plays a crucial role in the periodontal pathology and constitutes a key topic of periodontology. Dental biofilm and neutrophils were isolated from orally healthy persons and patients with periodontitis. We investigated biofilm and its particle-shedding phenomenon with electron microscopy and nanoparticle tracking analysis (NTA); biofilm shedding-neutrophil interactions were examined ex vivo with epi-fluorescence microscopy. For this purpose, we used acellular dental biofilm shedding, purified lipopolysaccharide (LPS), and phorbol 12-myristate 13-acetate (PMA) as activators, and the interleukin 8 receptor beta (CXCR2) inhibitor and the anti-interleukin 8 receptor alpha (CXCR1) antibody as modulators. The shedding of acellular dental biofilms overwhelmingly consists of bacterial extracellular vesicles (BEVs). The latter induced the moderate formation of neutrophil extracellular traps (NETs) in orally healthy subjects and a strong formation in patients with periodontitis. A CXCR2 inhibitor and an anti-CXCR1 antibody had a minor effect on NET formation. Neutrophils from patients with periodontitis exhibited NET hyper-responsiveness. BEVs were stronger inducers of NET formation than purified LPS and PMA. A plateau of neutrophil responsiveness is reached above the age of 40 years, indicating the abrupt switch of maladaptive trained immunity (TI) into the activated modus. Our results suggest that dental biofilms consist of and disseminate immense amounts of outer membrane vesicles (OMVs), which initiate NET formation via a non-canonical cytosolic LPS/caspase-4/11/Gasdermin D pathway. This modus of NET formation is independent of neutrophil elastase (NE), myeloperoxidase (MPO), peptidylarginine deiminase 4 (PAD4), and toll-like receptors (TLR). In periodontitis, the hyper-responsiveness of neutrophils to BEVs and the increased NET formation appear to be a consequence of TI.

Changes in pulp sensitivity across the menstrual cycle in healthy women and women with temporomandibular disorders.

BACKGROUND: Menstrual cycle may contribute to experimental pain measures in healthy women and women with chronic pain. OBJECTIVES: The present study aimed to investigate variation in pulp sensitivity across the menstrual cycle in healthy women and women with temporomandibular disorders (TMD) and to explore the effect of TMD pain and psychosocial variables on the pulp response. METHODS: This longitudinal study involved 47 regularly menstruating women aged 20-45, 24 healthy and 23 with diagnosed painful TMD. The electric and cold stimuli were performed by electric pulp tester and refrigerant spray, respectively, on mandibular lateral incisors, in five menstrual phases (menstrual, follicular, periovulatory, luteal and premenstrual). Research Diagnostic Criteria for TMD were used to assess TMD, chronic pain, depression and somatisation. Regression analysis was performed to investigate the effect of the predictor variables on the pulp sensitivity. RESULTS: Significant phase-related differences were observed for pain intensity to cold stimuli. Higher pain sensitivity was reported in menstrual in comparison with luteal phase (P = .019) among healthy women, and in menstrual in comparison with follicular (P = .033), periovulatory (P = .003) and luteal (P = .007) phases in TMD women. No significant differences were recorded for electric stimuli. Regression analysis identified depression as the determinant of cold and electric response in menstrual phase, regardless of age and presence of TMD. CONCLUSION: Menstrual phase in healthy and TMD women with regular menstrual cycle is characterised with higher pulp sensitivity to cold stimuli. Depressive symptoms independently influence pulp response in this phase.

Apolipoprotein ɛ4 Allele and Dental Occlusion Deficiency as Risk Factors for Alzheimer's Disease.

Compromised dentition has been suggested to pose a significant risk factor for dementia. It was mainly investigated through insufficient tooth number, disregarding contact between opposing teeth (dental occlusion). The ɛ4 allele of apolipoprotein (APOE4) is the primary genetic marker for the late onset of Alzheimer's disease (AD). However, APOE4 and dental occlusion have not yet been investigated as possible associated risk factors for AD. The study was aimed to examine the impact of dental status and different APOE gene variants on AD occurrence. Secondly, sociodemographic variables were investigated as factors potentially associated with AD. The case-control study included two groups: 116 patients with AD (according to the NINDS-ADRDA criteria) and 63 controls (Mini-Mental State Examination scores ≥24). The analysis of APOE gene polymorphism was conducted through PCR reaction. Dental examination included recording of number of teeth, presence of fixed or removable dentures, and number of functional tooth units (FTU). Regression analysis was used to investigate the joint effect of the clinical and genetic variables on AD. Results showed that patients with AD were more often carriers of ɛ3/ɛ4 genotype and ɛ4 allele, had lower number of teeth and FTU, and were less likely to be married, live in home, and had less chronic diseases, compared to the controls. Regression analysis showed that presence of APOE4 allele and the number of total FTU remained associated with AD, even when adjusted for age, sex, and level of education. In conclusion, deficient dental occlusion and presence of APOE4 may independently increase risk for AD.

Pulp Sensitivity: Influence of Sex, Psychosocial Variables, COMT Gene, and Chronic Facial Pain.

INTRODUCTION: The purpose of this study was to evaluate the associations of variability in pulp sensitivity with sex, psychosocial variables, the gene that encodes for the enzyme catechol-O-methyltransferase (COMT), and chronic painful conditions (temporomandibular disorders [TMDs]). METHODS: The study was composed of 97 subjects (68 women and 29 men aged 20-44 years). The electric (electric pulp tester) and cold (refrigerant spray) stimuli were performed on mandibular lateral incisors. The results were expressed as pain threshold values for electric pulp stimulation (0-80 units) and as pain intensity scores (visual numeric scale from 0-10) for cold stimulation. The Research Diagnostic Criteria for TMD were used to assess TMD, depression, and somatization. DNA extracted from peripheral blood was genotyped for 3 COMT polymorphisms (rs4680, rs6269, and rs165774) using the real-time TaqMan method. Multivariate linear regression was used to investigate the joint effect of the predictor variables (clinical and genetic) on pulp sensitivity (dependent variables). RESULTS: Threshold responses to electric stimuli were related to female sex (P < .01) and the homozygous GG genotype for the rs165774 polymorphism (P < .05). Pain intensity to cold stimuli was higher in TMD patients (P < .01) and tended to be higher in women. Multivariate linear regression identified sex and the rs165774 COMT polymorphism as the determinants of electric pain sensitivity, whereas TMD accounts for the variability in the cold response. CONCLUSIONS: Our findings indicate that sex/a COMT gene variant and TMD as a chronic painful condition may contribute to individual variation in electric and cold pulp sensitivity, respectively.

Limited Jaw Movements and Somatization (But Not Pain) May Play a Role in Salivary Flow in Female Patients with Temporomandibular Disorders.

AIMS: To explore the unstimulated salivary flow rate and subjective feeling of oral dryness in young adult women with temporomandibular disorders (TMD) and their relation to the presence of chronic pain, depression, somatization, and limited mandibular mobility. METHODS: Unstimulated whole saliva flow rate and presence of oral dryness were determined in 45 women with TMD and 30 healthy controls. The Research Diagnostic Criteria for TMD (RDC/TMD) were used for assessment of TMD, chronic pain, depression, somatization, and mandibular mobility. Factors with P < .05 in the bivariate analysis were included in multivariate modeling. RESULTS: The TMD patients showed significantly diminished unstimulated salivary flow (P = .010) in comparison to controls, but there was no difference in subjective oral dryness. Within the TMD group, patients with mandibular hypomobility and free from somatization exhibited significantly lower salivary output (P = .037; P = .015, respectively). No relationship between salivary flow and depression or TMD pain was observed. Multivariate linear regression identified somatization as the single variable contributing to salivary flow (P = .044) in the TMD patients. CONCLUSION: The present study shows a relationship between TMD and lower salivary flow but no evidence of a relationship between TMD and subjective oral dryness in young adult women. Somatization was the single variable to emerge from the evaluation of potential factors contributing to salivary output in TMD patients.

Genetic Polymorphisms of Catechol-O-Methyltransferase: Association with Temporomandibular Disorders and Postoperative Pain.

AIMS: To evaluate the association between catechol-O-methyltransferase (COMT) gene polymorphisms and temporomandibular disorders (TMD), TMD pain, psychosocial impairment related to TMD, and postoperative pain. METHODS: A total of 90 patients with a diagnosis of painful TMD and 92 matched controls were investigated for the presence of TMD, TMD pain, and psychosocial variables by the Research Diagnostic Criteria for TMD. In a prospective cohort study of 40 subjects who underwent extraction of at least one fully impacted mandibular third molar, subjects had 6 months post-surgery follow-up of postoperative pain. DNA extracted from peripheral blood was genotyped for three COMT polymorphisms (rs4680, rs6269, and rs165774) by real-time TaqMan method. The association between COMT polymorphisms and clinical variables was determined by calculating odds ratios (OR) and their 95% confidence intervals (CI). RESULTS: Homozygous AA genotype and heterozygous variant A allele carriers (genotype AG/AA) for rs165774 polymorphism were associated with increased risk of TMD compared to wild type (wt) GG genotype (OR = 9.448, P = .006; OR = 2.088, P = .017, respectively). In addition, AA genotype was associated with increased risk of arthralgia (OR = 4.448, P = .011), myofascial pain (OR = 3.543, P = .035), and chronic TMD pain (OR = 6.173, P = .006), compared to wt genotype. AA genotype for rs6269 polymorphism was related to less postoperative chronic TMD pain (P = .025) and lower postoperative acute pain at the extraction site (P = .030). No associations with depression and somatization were observed. CONCLUSION: AA genotype of rs165774 could be a significant risk factor for the development of TMD and TMD pain, while AA genotype of rs6269 presents less postoperative chronic TMD pain and acute pain at a dental extraction site.

Cephalometric analysis of the middle part of the face in patients with mandibular prognathism.

BACKGROUND/AIM: The middle part of the face, that is the maxilla, has always been mentioned as a possible etiologic factor of skeletal Class III. However, the importance of the relationship of maxillary retroposition towards the cranial base is still unclear, although it has been examined many times. The aim of this study was to conduct cephalometric analysis of the morphology of maxilla, including the whole middle part of the face in patients with divergent and convergent facial types of mandibular prognathism, as well as to determine differences betweeen them. METHODS: Lateral cephalometric teleradiograph images of 90 patients were analyzed at the Dental Clinic of the Military Medical Academy, Belgrade, Serbia. All the patients were male, aged 18-35 years, not previously treated orthodontically. On the basis of dentalskeletal relations of jaws and teeth, the patients were divided into three groups: the group P1 (patients with divergent facial type of mandibular prognathism), P2 (patients with convergent facial type of mandibular pragmathism) and the group E (control group or eugnathic patients). A total of 9 cephalometric parameters related to the middle face were measured and analyzed: the length of the hard palate--SnaSnp, the length of the maxillary corpus--AptmPP, the length of the soft palate, the angle between the hard and soft palate--SnaSnpUt, the angle of inclination of the maxillary alveolar process, the angle of inclination of the upper front teeth, the effective maxillary length--CoA, the posterior maxillary alveolar hyperplasia--U6PP and the angle of maxillary prognathism. RESULTS: The obtained results showed that the CoA, AptmPP and SnaSnp were significally shorter in patients with divergent facial type of mandibular prognathism compared to patients with convergent facial type of the mandibular prognathism and also in both experimental groups of patients compared to the control group. SnaSnp was significantly shorter in patients with divergent facial type of mandibular prognathism compared to the control group, whereas SnaSnp was significantly smaller in patients with convergent facial type of mandibular prognathism compared to the control group. Additionally, there was a pronounced incisor dentoalveolar compensation of skeletal discrepancy in both groups of patients with mandibular prognathism manifested in the form of a significant upper front teeth protrusion, but without significant differences among the groups, while the maxillary retrognathism was present in most patients of both experimental groups. A pronounced UGPP was found only in the patients with divergent type of mandibular prognathism. CONCLUSION: The maxilla is certainly one of the key factors which contributes to making the diagnosis, but primarily to making a plan for mandibular prognathism treatment Accurate assessment of the manifestation of abnormality, localization of skeletal problems and understanding of the biological potential are key factors of the stability of/the results of surgical-orthodontic treatment of this abnormality.

A cephalometric analysis of the cranial base and frontal part of the face in patients with mandibular prognathism.

BACKGROUND/AIM: The literature suggests different views on the correlation between the cranial base morphology and size and saggital intermaxillary relationships. The aim of this study was to investigate the cranial base morphology, including the frontal facial part in patients with mandibular prognathism, to clarify a certain ambiguities, in opposing viewspoints in the literature. METHODS: Cephalometric radiographies of 60 patients were analyzed at the Dental Clinic of the Military Medical Academy, Belgrade, Serbia. All the patients were male, aged 18-35 years, with no previous orthodontic treatment. On the basis of dental and sceletal relations of jaws and teeth, the patients were divided into two groups: the group P (patients with mandibular prognathism) and the group E (the control group or eugnathic patients). A total of 15 cephalometric parametres related to the cranial base, frontal part of the face and sagittal intermaxillary relationships were measured and analyzed. RESULTS: The results show that cranial base dimensions and the angle do not play a significant role in the development of mandibular prognathism. Interrelationship analysis indicated a statistically significant negative correlation between the cranial base angle (NSAr) and the angles of maxillary (SNA) and mandibular (SNB) prognathism, as well as a positive correlation between the angle of inclination of the ramus to the cranial base (GoArNS) and the angle of sagittal intermaxillary relationships (ANB). Sella turcica dimensions, its width and depth, as well as the nasal bone length were significantly increased in the patients with mandibular prognathism, while the other analyzed frontal part dimensions of the face were not changed by the malocclusion in comparison with the eugnathic patients. CONCLUSION: This study shows that the impact of the cranial base and the frontal part of the face on the development of profile in patients with mandibular prognathism is much smaller, but certainly more complex, so that morphogenetic tests of the maxillomandibular complex should be included in further assessment of this impact.

TMD in class III patients referred for orthognathic surgery: psychological and dentition-related aspects.

OBJECTIVE: To investigate temporomandibular disorders (TMD), psychosocial, and occlusal variables in class III orthognathic surgery patients with respect to the control subjects, and to compare psychosocial and occlusal features in class III patients with different Research Diagnostic Criteria for TMD (RDC/TMD) diagnoses. MATERIALS AND METHODS: The study enrolled 44 class III patients referred for orthognathic surgery and 44 individuals without a malocclusion. TMD, depression and somatization were assessed by RDC/TMD. Occlusal analysis included Helkimo's Occlusal Index items, overjet and overbite. RESULTS: In the controls, patients with class III deformities had higher prevalence of myogenic TMD, increased grade of chronic pain, and more occlusal deviations. Within the study group, TMD patients reported higher depression score (P < 0.01), myofascial pain was related to higher depression and somatization grades (P < 0.01, P < 0.05 respectively), and disc displacement showed relation with RCP-ICP slide interferences (P < 0.05). CONCLUSION: With respect to subjects without a malocclusion, TMD in class III dentofacial deformities is similar in prevalence, but differs in clinical appearance. Occlusal, but not psychosocial features deviate from those in the controls. While psychosocial variables accompanied TMD and myofascial pain, increased RCP-ICP slide was related to disc displacement in class III patients.

Temporomandibular disorders after orthognathic surgery in patients with mandibular prognathism with depression as a risk factor.

OBJECTIVE: To examine the prevalence of temporomandibular disorders (TMD) after orthodontic-surgical treatment in patients with mandibular prognathism and analyze psychosocial variables related to TMD. MATERIALS AND METHODS: The case-control study comprised 40 patients with mandibular prognathism who underwent combined orthodontic-surgical treatment (orthognathic surgery group). Forty-two patients with untreated mandibular prognathism served as a control group. Research diagnostic criteria for temporomandibular disorders was used in order to assess the clinical diagnosis of TMD (Axis I) and to estimate depression, somatization and patient's disability related to chronic pain (Axis II). RESULTS: The overall prevalence of TMD was not significantly different between the groups. Myofascial pain was significantly higher, while arthralgia, arthritis and arthrosis was significantly lower in the orthognathic group compared with the controls (90.5% vs 50.0%, 0.0% vs 27.8%, respectively) (p < 0.05). Females in orthognathic surgery group showed higher prevalence of TMD (p < 0.05) and myofascial pain (p < 0.01) and increased level of chronic pain (p < 0.05) in comparison with post-operative males. No significant difference in chronic pain, somatization and depression scores was found between investigated groups. With respect to presence of TMD within the groups depression was higher in untreated subjects with dysfunction (p < 0.05). CONCLUSION: Prevalence of TMD immediately after completion of orthodontic-surgical treatment for mandibular prognathism is similar to frequency of dysfunction in untreated subjects, is significantly higher in females and is most commonly myogenic. Furthermore, females show an increased level of chronic pain post-operatively. Somatization and depression levels do not differ between patients with corrected prognathism and untreated prognathic patients.