Sedation outcomes for remimazolam, a new benzodiazepine.

Remimazolam is a new ultrashort-acting benzodiazepine with fast onset, quick recovery, and few side effects, such as hypotension and respiratory depression. It is expected to be safe and effective for a wide range of patients undergoing intravenous sedation for dental procedures. The aim of this literature review was to evaluate clinical and sedation outcomes for remimazolam, including method of administration, level of sedation at the dose required, and clinical adverse events. An electronic literature search of databases was conducted, and eight articles were selected for inclusion in this review. Onset time from drug administration to optimal sedation level was faster for remimazolam (around 1.5-6.4 min) than for midazolam. Recovery time was significantly shorter for remimazolam than for midazolam and propofol. A study comparing various doses of remimazolam with midazolam found no significant difference in safety. Comparison of a remimazolam group with a propofol group showed that incidences of hypotension (13.0% vs 42.9%, respectively) and respiratory depression (1.1% vs 6.9%, respectively) were significantly lower for remimazolam. Remimazolam appears to be an ideal sedative.

A deficiency of Dec2 triggers periodontal inflammation and pyroptosis.

BACKGROUND AND OBJECTIVES: Periodontal pathogens initiate various diseases and induce inflammatory host responses. The activation of inflammasomes triggers caspase-1 and interleukin (IL)-1ß-mediated pyroptosis via gasdermin D (GSDMD). Differentiated embryo chondrocyte 2 (Dec2) is a transcription repressor that controls the expression of genes involved in innate immune and inflammatory responses. However, the effects of Dec2 on inflammasome-induced pyroptosis in periodontal tissues remain elusive. This study aimed to characterize the activation of Dec2 inflammasomes that contribute to P. gingivalis lipopolysaccharide (LPS)-induced pyroptosis and its functional and regulatory importance in periodontal inflammation. MATERIALS AND METHODS: Human gingival fibroblasts (HGFs) and human periodontal ligament fibroblasts (HPDLFs) were stimulated with P. gingivalis LPS in vitro. An experimental periodontitis mouse model (wild-type (WT) and Dec2KO) was established to profile periodontal pyroptosis. RESULTS: The results demonstrate that P. gingivalis LPS activates caspase-1, caspase-11, and NF-κB in HGFs and in HPDLFs. siRNA knockdown of Dec2 stimulated the induction and further upregulated LPS-induced pyroptosis in HGFs and HPDLFs, resulting in the release of IL-1ß. Further, a deficiency of Dec2 alleviated periodontal pyroptosis via the transcriptional induction of GSDMD. In addition, P. gingivalis-induced IL-1ß expression and Dec2-deficient mice subsequently increased the inflammatory effect of P. gingivalis in HGFs and in HPDLFs, confirming the importance of Dec2 in the activation of inflammasomes and the regulation of pyroptosis. CONCLUSION: Our results demonstrate that Dec2 alleviates periodontal pyroptosis by regulating the expression of NF-κB, caspase-1 and GSDMD, suggesting that Dec2 is a crucial component of inflammasome activation and subsequent pyroptosis.

Loss of Dec1 prevents autophagy in inflamed periodontal ligament fibroblast.

Periodontal ligament fibroblasts (PDLFs) are integral to the homeostasis of periodontal tissue. The transcription factor Dec1 functions to modulate Porphyromonas gingivalis-induced periodontal inflammation. Here, we aimed to characterize the Dec1-mediated autophagy in PDLFs under inflammatory conditions. Human PDLFs were subjected to an inflammatory environment using P. gingivalis Lipopolysaccaride (LPS) along with Dec1 siRNA in vitro. Quantitative real-time polymerase chain reaction and Western blot analyses were used to evaluate the expression levels of autophagy-related genes and their upstream AKT/mTOR signaling pathways. An experimental P. gingivalis-treated Dec1 knockout (Dec1KO) mouse model was used to confirm the expression of autophagy in PDLFs in vivo. Treatment with P. gingivalis LPS induced the expression of ATG5, Beclin1 and microtubule-associated protein 1 light chain 3 (LC3) and elevated the expression of pro-inflammatory cytokine IL-1ß and Dec1 in human PDLFs. Knockdown of Dec1 partly reversed the detrimental influences of LPS on these autophagy markers in human PDLFs. The inhibition of autophagy with Dec1 siRNA suppressed the inflammatory effect of AKT/mTOR signaling pathways following treatment with P. gingivalis LPS. P. gingivalis-treated Dec1KO mice partly reduced autophagy expression. These findings suggest that a Dec1 deficiency can modulate the interaction between autophagy and inflammation in PDLFs.

MicroRNA-21 facilitates osteoblast activity.

MicroRNAs are emerging as critical post-transcriptional modulators in bone remodeling, regulating the functions of osteoblasts and osteoclasts. Intercellular crosstalk between osteoblasts and osteoclasts is mediated by miR-21 that controls the bone homeostasis response, providing potential targets for the maintenance of osteoblast function. The aim of this study was to investigate the effects of miR-21 on osteoblast function, and to explore the underlying mechanism. Increased alkaline phosphatase (ALP) activity and accelerated matrix mineralization was observed in mouse pre-osteoblast MC3T3-E1 cells compared with the non-induction (control) group. MiR-21 positively regulates osteogenic differentiation and mineralization by facilitating the expression of key osteogenic factors (ALP, Runx2, Osteopontin (OPN), Osterix (OSX) and Mef2c) in MC3T3-E1 cells. Furthermore, a deficiency of miR-21 suppresses the expression of those factors at both the mRNA and protein levels, indicating that miR-21 is a positive regulator of osteoblastic differentiation. H-E staining, Azan staining, Masson's Trichrome staining and Toluidine blue staining were performed in jaw and femur tissues of miR-21 knockout (miR-21KO) and wild-type (WT) mice. Immunohistochemical staining revealed substantially lower levels of ALP, Runx2 and OSX expression in jaw and femur tissues of miR-21KO mice. A similar trend was observed in femur tissues using quantitative real-time (RT) PCR. A total of 17 osteogenesis-related mRNAs were found to be differentially expressed in miR-21KO femur tissues using Mouse Gene Expression Microarray analysis. GeneSpring and Ingenuity Pathway Analysis revealed several potential target genes that are involved in bone remodeling, such as IL-1ß and HIF-1α. Several important pathways were determined to be facilitators of miR-21, which provides a reliable reference for future studies to elucidate the biological mechanisms of osteoblast function. Taken together, these results lead us to hypothesize a potential role for miR-21 in regulating osteoblast function, thus representing a potential biomarker of osteogenesis.

Dec2 attenuates autophagy in inflamed periodontal tissues.

INTRODUCTION: Transcriptional regulation of autophagy depends on the transcription factors coordinated inflammatory feedback mechanism. Here, we provide a comprehensive functional characterization of periodontal ligament fibroblasts (PDLFs) treated with Porphyromonas gingivalis lipopolysaccharide (LPS), aiming to reveal previously unappreciated biological changes and to investigate how a transcription factor differentiated embryonic chondrocytes 2 (Dec2)-deficient environment influences the function of autophagy in nflamed human PDLFs. METHODS: A Dec2-deficient (Dec2KO) experimental periodontal inflammation mouse model and treatment with P. gingivalis LPS were employed to examine the role of autophagy in PDLFs using hematoxylin and eosin staining and immunohistochemistry in vivo. A Dec2 small interfering RNA (siRNA) was used to modulate autophagy, and the effect of autophagy on the Dec2 pathway was explored using real-time polymerase chain reaction and western blot analysis in vitro. RESULTS: LPS-treated human PDLFs (HPDLFs) induced autophagy, as demonstrated by the enhanced levels of microtubule-associated protein 1 light chain 3-II (LC3-II) and the induction of ATG5, Beclin1, and Dec2. Compared with a scrambled siRNA, a Dec2 siRNA triggered the detrimental influences of LPS and markedly enhanced autophagy expression in inflamed HPDLFs. The expression of phosphorylated ERK was increased and levels of phosphorylated mammalian target of rapamycin (mTOR) were decreased after exposure to LPS in Dec2 siRNA transfected HPDLFs. The Dec2KO model exhibited that P. gingivalis in Dec2 deficient conditions increases the inflammation of PDLFs by regulating autophagy. CONCLUSIONS: These results demonstrate that a Dec2 deficiency can alleviate LPS-induced inflammation via the ERK/mTOR signaling pathway by regulating autophagy, conceivably delivering a novel approach for the detection of periodontal treatments.

Treatment with low-level sodium fluoride on wound healing and the osteogenic differentiation of bone marrow mesenchymal stem cells.

BACKGROUND/AIMS: Lacerations of the oral mucosa and fractures of alveolar processes commonly occur in traumatic dental injuries (TDIs). Impaired wound healing and tissue regeneration have severe consequences on the quality of life. Bone marrow mesenchymal stem cells (BMMSCs) possess the ability of self-renewal and multipotential differentiation. Treatment with low-level sodium fluoride (NaF) has emerged as a promising approach to enhance wound repair. The aim of this study was to assess the effects of low-level NaF on soft tissue healing and on the proliferation, migration and extracellular matrix synthesis of BMMSCs. MATERIAL AND METHODS: BMMSCs derived from mice were treated with 50 µM, 500 µM, or 5 mM NaF for 12, 24, and 48 hours, and cell proliferation was assessed by the MTS assay. Cell motility was detected at 12 and 24 hours by a wound healing assay, and osteoblastic differentiation for 21 days by 1% Alizarin Red S staining in 50 µM NaF-treated BMMSCs. Gene expression of Runx2 and Osteocalcin was evaluated by quantitative real-time PCR. An experimental rat skin wound model was employed, and levels of c-Myc, Ki67, fibronectin, and vimentin were assessed by immunohistochemistry. RESULTS: There was a significant induction in the proliferation and migration of BMMSCs treated with 50 µM NaF. The expression of Ki67 and c-Myc protein was increased in tissues treated with 50 µM NaF, and the expression of fibronectin and vimentin in the 50 µM NaF-treated tissues was stimulated. Alizarin Red staining revealed enhanced mineralization in 50 µM NaF-treated BMMSCs with increased expression of Runx2 and Osteocalcin, indicating their upregulated osteogenic differentiation. CONCLUSION: Low-level NaF could promote soft tissue healing and hard tissue regeneration.

Effects of 830 nm low-power laser irradiation on body weight gain and inflammatory cytokines in experimental diabetes in different animal models.

BACKGROUND AND AIMS: The present investigation was carried out to determine the levels of blood serum components and inflammatory cytokines in diabetic rat models [Goto-Kakizaki (GK), Zucker, and streptozotocin (STZ)-induced Sprague Dawley (SD) rats] which underwent abdominal Low-Power Laser Irradiation (LPLI) and compare them with non-irradiated controls. METHODS: The animals were subdivided into the following groups: diabetic control rats (GK, Zucker, STZ) and diabetic rats treated with LPLI (GK + LPLI, Zucker + LPLI, and STZ + LPLI) (n = 7). The animals were irradiated three times weekly for 12 weeks in LPLI (830 nm) at a dose of 5 J/cm2 for 500 s. RESULTS: Body weight was significantly lowered in the Zucker- LPLI group compared to control at 10 weeks and this pattern was maintained until 12 weeks of age. TNF-α, IL-1I and IL-6 levels were significantly decreased (5.1 ± 1.1 vs 3.3 ± 0.5, p < 0.01; 43.6 ± 8.8 vs 27.1 ± 3.8, p < 0.01; 98.3 ± 15.8 vs 62.2 ± 12.1, p < 0.01) in the Zucker- LPLI group compared with the control rats. The small intestinal transit rates of charcoal meals were significantly decreased (58.1 ± 10.1 vs 73.4 ± 13.3, p < 0.05) in the Zucker-LPLI group compared with the control rats. Similarly, the serum levels of glucose, cholesterol and triglycerides of LPLI groups were decreased in comparison with that of diabetic control rats. CONCLUSIONS: We suggest that abdominal LPLI can reduce body weight and LPLI could be applicable for use against diabetic-induced inflammatory factors.

A large-scale study of treatment methods for foreign bodies in the maxillary sinus.

Recently, reports regarding a foreign body in the maxillary sinus have considerably increased, with the majority being iatrogenic cases resulting from dental treatment. This study involves an extensive review of the Japanese literature, including 112 papers from 1978 to 2017. These papers documented total 407 cases of a foreign body in the maxillary sinus. Among the 392 cases for which treatment details were available, the Caldwell-Luc approach was used for 216, the alveolar approach for 116, extraction using nasal endoscopy for 15, and extraction using oral endoscopy for eight. Spontaneous passage occurred in 19 cases, follow-up with medication was used in 17, and "other" was noted in one. This study determined that surgical removal remains the most common method for treating both tooth roots and other foreign bodies and that the Caldwell-Luc approach is used in majority of the surgeries. No marked differences were noted among the removal methods used in relation to the foreign body type.

Headache attributed to temporomandibular disorders and masticatory myofascial pain.

We investigated the temporal association between temporomandibular disorders (TMD)-related symptoms and headache during TMD treatment for patients who fulfilled the diagnostic criteria for headache attributed to TMD (HATMD) specified in the Diagnostic criteria for TMD (DC/TMD) and International classification of headache disorders (ICHD)-3 beta. The study enrolled 34 patients with HATMD induced by masticatory myofascial pain but not by temporomandibular arthralgia. Facial pain intensity, the pressure pain threshold of pericranial muscles, and maximum unassisted opening of the jaw were assessed at an initial examination and before and after physical therapy. The intensity and frequency of headache episodes and tooth contact ratio were also recorded before and after the intervention. Headache intensity and frequency significantly decreased, and these reductions were temporally related to improvements in facial pain intensity, maximum unassisted opening, and pressure pain threshold during TMD treatment. Linear regression analysis showed significant correlations between facial pain intensity and headache intensity and between tooth contact ratio and pressure pain threshold. Among patients who fulfilled the DC/TMD and ICHD-3 beta diagnostic criteria for HATMD, headache improved during TMD treatment, and the improvement was temporally related to amelioration of TMD symptoms. These findings suggest that sensitization in the central and peripheral nervous systems is responsible for HATMD. (J Oral Sci 58, 195-204, 2016).

Immunolocalization of FGF-2, -7, -8, -10 and FGFR-1-4 during regeneration of the rat submandibular gland.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) play important roles in the development of the submandibular gland. Although regeneration of submandibular glands follows a similar process to their development, it is unknown how FGFs and FGFRs are distributed during regeneration of submandibular gland. The aim of this study was to determine the localization of FGFs and FGFRs during such regenerative processes. After 7 days' obstruction, the submandibular glands were collected at days 0, 1, 3, 7, 11 and 14 after duct release to study regeneration. The regenerative processes of the submandibular gland were investigated by immunohistochemistry for FGF-2, 7, 8, 10 and FGFR-1-4. Immunohistochemical staining revealed that FGF-2 was moderately expressed in the epithelial cells of duct-like structures (DLS) and newly formed acinar cells (NFAC) at days 0-7, and strongly in intercalated duct (ICD) at control gland and Day 7-14. FGF-7 was localized moderately in NFAC and DLS. FGF-8 was localized moderately in the epithelial cells of DLS during regeneration. Strong positive immunoreactions for FGF-10 were found in NFAC and the epithelial cells of DLS during regeneration, as well as the ICD and lateral surfaces of the maturing acinar cells (MAC). FGFR-1 was expressed moderately in the ICD, and weakly in the NFAC and MAC. Positive immunoreactions for FGFR-2 were not observed during regeneration. Additionally, FGFR-4 was detected strongly in the ICD and slightly in NFAC. These findings suggest that FGF-2, -7, -8 and -10 play important roles in NFAC, MAC, and DLS through FGFR-1 and -4 during regeneration of submandibular gland.

Hemicrania continua in a patient with concomitant dental disease.

BACKGROUND: There are nonodontogenic headache disorders that mimic dental pain. One such headache disorder is hemicrania continua (HC). HC is a primary headache syndrome characterized by a continuous, unilateral headache that is completely responsive to indomethacin. Patients may have signs and symptoms that the dentist should differentiate from odontogenic pain and temporomandibular disorders. These symptoms can make the diagnostic process a challenge for dentists if patients' pain has multiple causes. Dentists, thus, must have thorough knowledge of odontogenic and nonodontogenic causes of pain so they can make accurate diagnoses and prepare treatment plans. CASE DESCRIPTION: The authors describe the case of a 41-year-old woman with a six-year history of continuous headaches and a one-year history of temporomandibular dysfunction and odontogenic pain. She sought treatment from a number of dentists and received a diagnosis of right-side facial pain and headache on the basis of the results of clinical and radiologic examinations, which was followed by dental treatment. She did not experience any pain relief. Additional results of our examination led to a diagnosis of HC. CLINICAL IMPLICATIONS: Dentists must consider headache disorders in patients who have continuous headaches after undergoing dental treatment for odontogenic pain.

Alteration of the actin cytoskeleton and localisation of the α6ß1 and α3 integrins during regeneration of the rat submandibular gland.

OBJECTIVES: Actin filaments, which are regulated by signal transduction via integrins, play important roles in the regulation of cell differentiation and polarity. The aim of this study was to assess alterations in the cytoskeleton and the localisation of integrins during regeneration of the rat submandibular gland. DESIGN: After obstruction for 7 days, the regenerating glands were collected at days 0, 1, 3, 7, 14 after duct release for analysis of regeneration. Alterations in the actin filaments were examined using phalloidin, which specifically binds to filamentous actin (F-actin), and the distributions of the α6ß1 and α3 integrins were examined immunohistochemically. RESULTS: F-actin was strongly localised at the apical region in the intercalated ducts of normal and day-14 glands and in duct-like structures during the regenerative process. Thereafter, actin accumulated at the basement membrane in mature acinar cells. A temporo-spatial correlation was found between the apical distribution of F-actin and α3 integrin staining. Diffuse α6ß1 integrin staining, which occurred at a distal site in α3 integrin-positive cells, was observed in immature cells at day 3. At day 14, α6ß1 integrin was detected at the basement membrane in terminal differentiated acinar cells. CONCLUSION: These findings suggest that duct-like structures have the same properties as intercalated ducts, that alterations in α3 to α6ß1 integrins regulate the generation of acinar cells from duct-like structures, and that the α6ß1 integrin is involved in the differentiation of acinar cells during regeneration of the rat submandibular gland.

Receptor for advanced glycation end products (RAGE)-expressing endothelial cells co-express AGE and S100 in human periapical granulomas.

OBJECTIVE: The engagement of the receptor for advanced glycation end products (RAGE) by AGE or S100 perturbs homeostatic mechanisms and provides a basis for cellular dysfunction in pathological situations. To assess the mechanism of vascular immune reactions in chronic periapical periodontitis, we analysed co-expression of RAGE and AGE or S100 in periapical granulomas. METHODS: Surgically removed periapical lesions, which had been diagnosed as chronic periodontitis, were inspected histologically using paraffin-embedded sections stained with haematoxylin and eosin. Cryostat sections of the tissues, which were identified histologically as periapical granulomas, were then examined by double immunohistochemistry using polyclonal antibodies raised against human CD34 and monoclonal antibodies specific for human RAGE, AGE or S100. Dual-colour immunofluorescence image analysis was also performed to assess the co-expression of RAGE and AGE or RAGE and S100 by endothelial cells. RESULTS: Marked expression of RAGE, AGE, and S100 by CD34(+) endothelial cells was noted. Dual-colour immunofluorescence image analysis revealed that the RAGE-expressing endothelial cells co-expressed AGE and S100; however, the number of RAGE-AGE-expressing endothelial cells was significantly higher than that of RAGE-S100-expressing endothelial cells. CONCLUSIONS: Co-expression of RAGE and AGE by endothelial cells in periapical granulomas is more relevant than that of RAGE and S100. The possible engagement of RAGE and AGE may trigger cellular activation and mediate tissue injury.

Predictability of painful stimulation modulates subjective and physiological responses.

UNLABELLED: Clinical observations suggest that the perceived intensity of a painful event increases as the unpredictability of its occurrence increases. We examined the effect of varying stimulus predictability on the Somatosensory Evoked Potential (SEP), Pupil Diameter Response (PDR), Pain Report (PR), and Fear Report (FR) in 25 healthy female volunteers experiencing repeated noxious fingertip shocks. Each volunteer underwent high- and low-stimulus intensities in 4 stimulus patterns defined by stimulus sequence (SEQ) and interstimulus interval (ISI) as follows: A) serial stimulus intensity SEQ with fixed ISI; B) serial stimulus intensity SEQ with varied ISI; C) random stimulus intensity SEQ with fixed ISI; and D) random stimulus intensity SEQ with varied ISI. Results revealed that: (1) lower stimulus predictability led to higher PR and FR, greater PDR magnitude, and greater SEP amplitude; and (2) the 4 dependent measures showed the same response pattern across levels of stimulus predictability. These findings support the hypothesis that lower stimulus predictability is associated with higher reported pain and fear as well as greater physiological arousal. PERSPECTIVE: Patients undergoing painful procedures experience more distress when the occurrence of a painful event is unpredictable. Poor predictability increases pain, fear, and associated physiological arousal. Maximizing the predictability of painful events may improve the quality of patient care by minimizing associated levels of pain and fear.

Contingent negative variations associated with command swallowing in humans.

OBJECTIVE: To clarify the role of the cerebral cortex in the swallowing movement, the difference between the waveforms of contingent negative variation (CNV) for the command swallowing and movement-related cortical potential (MRCP) obtained during the volitional swallowing task in humans was investigated. METHODS: Subjects were instructed to swallow their saliva as quickly as possible in response to a sound signal 4s after the onset of a self-paced breath holding in the command swallowing task or to swallow it while holding their breath for 4s in the volitional swallowing task. RESULTS: CNV and MRCP appeared at five recording areas 1.5 and 2.0s before the onset of the suprahyoid muscle activation determined by the electromyography (EMG) during the command swallowing and volitional swallowing tasks, respectively. The CNV amplitude during the command swallowing task was significantly higher than the MRCP amplitude during the volitional swallowing task (p<0.01). However, the suprahyoid muscle activities during both tasks were not significantly different (p>0.05). CONCLUSIONS: These results indicated that CNV may reflect the activities of the prefrontal cortex, in addition to the supplementary motor area, suggesting that the processing of the cue to swallow activates brain areas more widely than the volitional swallowing itself. SIGNIFICANCE: It is possible to clarify the cognitive functions associated with command swallowing by analyzing CNV.

Pupil dilation response to noxious stimulation: effect of varying nitrous oxide concentration.

OBJECTIVE: This report examines the pain-related pupil dilation response (PDR), tracking it across mixture concentrations of nitrous oxide (N(2)O) in oxygen (O(2)) and relating its variation to change in long latency somatosensory evoked potentials (SEPs) and visual analogue scale (VAS) pain report. METHODS: We varied mixture concentrations of N(2)O in O(2) (0%, 10%, 30%, and 50%), measuring PDR, SEP and VAS responses to painful electrical fingertip stimulation at high and low intensities in 15 volunteers. RESULTS: Mixed effect model statistical analyses revealed that: (1) PDR increased significantly with stimulus intensity and constricted significantly with mixture concentration; (2) SEP and VAS decreased significantly with increasing mixture concentration; (3) PDR correlated with SEP amplitude and VAS across mixture concentrations; (4) subjects differed significantly in: (a) baseline PDR and SEP amplitudes, (b) rate of change of these measures across mixture concentrations; and (5) VAS increased significantly with stimulus intensity and decreased significantly with mixture concentration without significant individual differences. CONCLUSIONS: The findings support the hypothesis that the pain-related PDR is a complex brain-mediated response rather than a simple sympathetic reflex. SIGNIFICANCE: PDR may provide a useful indicator for studying the central processing of noxious stimuli and the effects of analgesic interventions.