Safety and effectiveness of risedronate in Paget's disease of bone: postmarketing surveillance study in Japan.

INTRODUCTION: We conducted an all-case postmarketing surveillance study between 2008 and 2017 to evaluate the safety and effectiveness of risedronate for Paget's disease of bone (PDB) in Japan. MATERIAL AND METHODS: This study registered all patients who received once-daily risedronate 17.5 mg for the treatment of PDB and collected data over a 48-week follow-up period per treatment cycle for each patient. RESULTS: The safety analysis set included 184 patients (mean age, 63.7 years), 81 (44.0%) of whom previously received a bisphosphonate. Of them, 41 (22.3%) experienced 72 adverse drug reactions (ADRs), and 8 (4.3%) experienced 14 serious ADRs. Common ADRs included gastrointestinal disorders (20 patients, 10.9%) and hypocalcemia (6 patients, 3.3%). The effectiveness analysis set included 182 patients, 124 of whom completed only one treatment cycle and 58 of whom completed multiple treatment cycles. The proportions of patients who normalized serum alkaline phosphatase (ALP) concentration were 71.1% (113/159 patients) and 67.3% (33/49 patients) for the first and second treatment cycles, respectively. The relapse rate according to ALP levels after the end of treatment for the first cycle was 5.0% (95% confidence interval [CI] = 2.1-11.5) at 24 weeks and 12.9% (95% CI = 7.5-21.7) at 40 weeks. Regarding pain relief, the achievement rates were 70.0% (49/70 patients) and 30.8% (4/13 patients) for the first and second treatment cycles, respectively. CONCLUSION: To conclude, risedronate 17.5 mg/day is safe and effective for treating patients with PDB in daily practice.

Effects of antiresorptive medications on tooth root formation and tooth eruption in paediatric patients.

Tooth eruption is a pivotal milestone for children's growth and development. This process involves with the formation of the tooth root, the periodontal ligament (PDL) and the alveolar bone, as the tooth crown penetrates the bone and gingiva to enter the oral cavity. This review aims to outline current knowledge of the adverse dental effects of antiresorptive medications. Recently, paediatric indications for antiresorptive medications, such as bisphosphonates (BPs), have emerged, and these agents are increasingly used in children and adolescents to cure pathological bone resorption associated with bone diseases and cancers. Since tooth eruption is accompanied by osteoclastic bone resorption, it is expected that the administration of antiresorptive medications during this period affects tooth development. Indeed, several articles studying human patient cohorts and animal models report the dental defects associated with the use of these antiresorptive medications. This review shows the summary of the possible factors related to tooth eruption and introduces the future research direction to understand the mechanisms underlying the dental defects caused by antiresorptive medications.

Microbicidal effect of 405-nm blue LED light on Candida albicans and Streptococcus mutans dual-species biofilms on denture base resin.

This study investigated: (1) the microbicidal effect of 405-nm blue LED light irradiation on biofilm formed by Candida albicans hyphae and Streptococcus mutans under dual-species condition on denture base resin, (2) the generation of intracellular reactive oxygen species (ROS) induced by irradiation, and (3) the existence of intracellular porphyrins, which act as a photosensitizer. Denture base resin specimens were prepared and C. albicans and S. mutans dual-species biofilms were allowed to form on the specimens. The biofilms were irradiated with 405-nm blue LED light and analyzed using the colony-forming unit assay, fluorescence microscopy, and scanning electron microscopy (SEM). Single-species biofilms of C. albicans and S. mutans formed on the specimens were irradiated with 405-nm blue LED light. After the irradiation, the intracellular ROS levels in C. albicans and S. mutans cells were measured. In addition, the level of intracellular porphyrins in C. albicans and S. mutans were measured. Irradiation for more than 30 min significantly inhibited the colony formation ability of C. albicans and S. mutans. Fluorescence microscopy revealed that almost all C. albicans and S. mutans cells were killed by irradiation. SEM images showed various cell damage patterns. Irradiation led to the generation of intracellular ROS and porphyrins were present in both C. albicans and S. mutans cells. In conclusion, irradiation with 405-nm blue light-emitting diode light for 40 min effectively disinfect C. albicans hyphae and S. mutans dual-species biofilms and possibly react with intracellular porphyrins resulting in generation of ROS in each microorganism.

Inhibitory effect of 405-nm blue LED light on the growth of Candida albicans and Streptococcus mutans dual-species biofilms on denture base resin.

We investigated whether irradiation with 405-nm blue LED light could inhibit the growth of not only single- but dual-species biofilms formed by Candida albicans and Streptococcus mutans on denture base resin and cause the alteration in gene expression related to adhesion and biofilm formation. C. albicans and S. mutans single-/dual-species biofilms were formed on the denture base specimens. The biofilms were irradiated with 405-nm blue LED light (power density output: 280 mW/cm2) for 0 (control) and 40 min. Dual-species biofilms were analyzed using CFU assay and fluorescence microscopy, and single-/dual-species biofilms were analyzed using alamarBlue assays and gene expression analysis. To assess the inhibitory effect of irradiation on dual-species biofilms, specimens after irradiation were aerobically incubated for 12 h. After incubation, the inhibition of growth was assessed using CFU assays and fluorescence microscopy. Data were analyzed using the Mann-Whitney U or Student's t test (p < 0.05). Irradiation produced a significant inhibitory effect on biofilms. Fluorescence microscopy revealed that almost all C. albicans and S. mutans cells were killed by irradiation, and there was no notable difference in biofilm thickness immediately after irradiation and after irradiation and incubation for 12 h. alamarBlue assays indicated the growth of the biofilms was inhibited for 12-13 h. The expression of genes associated with adhesion and biofilm formation-als1 in C. albicans and ftf, gtfC, and gtfB in S. mutans-significantly reduced by irradiation. Irradiation with 405-nm blue LED light effectively inhibited the growth of C. albicans and S. mutans dual-species biofilms for 12 h.

Antiandrogenic Effects of a Polyphenol in Carex kobomugi through Inhibition of Androgen Synthetic Pathway and Downregulation of Androgen Receptor in Prostate Cancer Cell Lines.

Prostate cancer (PC) represents the most common cancer disease in men. Since high levels of androgens increase the risk of PC, androgen deprivation therapy is the primary treatment; however this leads to castration-resistant PC (CRPC) with a poor prognosis. The progression to CRPC involves ectopic androgen production in the adrenal glands and abnormal activation of androgen signaling due to mutations and/or amplification of the androgen receptor (AR) as well as activation of androgen-independent proliferative pathways. Recent studies have shown that adrenal-derived 11-oxygenated androgens (11-ketotestosterone and 11-ketodihydrotestosterone) with potencies equivalent to those of traditional androgens (testosterone and dihydrotestosterone) are biomarkers of CRPC. Additionally, dehydrogenase/reductase SDR family member 11 (DHRS11) has been reported to be a 17ß-hydroxysteroid dehydrogenase that catalyzes the production of the 11-oxygenated and traditional androgens. This study was conducted to evaluate the pathophysiological roles of DHRS11 in PC using three LNCaP, C4-2 and 22Rv1 cell lines. DHRS11 silencing and inhibition resulted in suppression of the androgen-induced expression of AR downstream genes and decreases in the expression of nuclear AR and the proliferation marker Ki67, suggesting that DHRS11 is involved in androgen-dependent PC cell proliferation. We found that 5,7-dihydroxy-8-methyl-2-[2-(4-hydroxyphenyl)ethenyl]-4H-1-benzopyran-4-one (Kobochromone A, KC-A), an ingredient in the flowers of Carex kobomugi, is a novel potent DHRS11 inhibitor (IC50 = 0.35 µM). Additionally, KC-A itself decreased the AR expression in PC cells. Therefore, KC-A suppresses the androgen signaling in PC cells through both DHRS11 inhibition and AR downregulation. Furthermore, KC-A enhanced the anticancer activity of abiraterone, a CRPC drug, suggesting that it may be a potential candidate for the development of drugs for the prevention and treatment of CRPC.

[Gastric bezoars caused by enteral nutrient gel via gastric fistula in a patient with esophageal cancer].

A 62-year-old man presented to our hospital with difficulty in swallowing. Physical examination and subsequent diagnostic tests identified hypopharyngeal and esophageal carcinoma with tracheal invasion. The patient underwent gastric fistula placement, radiotherapy, and chemotherapy. Palliative care was initiated after recurrence. The patient was later hospitalized for neck pain, and during a routine exchange of the gastric fistula, two large bezoars were found. The enteral nutrient gel was discontinued, cola was administered, and the bezoars gradually reduced. He continued to receive home care, and later when he was hospitalized for mediastinal abscess, no bezoars were identified. This case highlights the possibility of bezoar formation as a rare complication of enteral nutrition gel administration.

Accuracy of cone beam computed tomography in evaluation of palatal mucosa thickness.

AIM: The purpose of this study was to investigate the accuracy of the measurement of palatal mucosa thickness using cone beam computed tomography (CBCT) and to create a conversion formula to evaluate palatal mucosa thickness more accurately. We then evaluated the palatal mucosa thickness in a Japanese population using CBCT and the conversion formula. MATERIALS AND METHODS: We evaluated palatal mucosa thickness in 10 healthy subjects at 15 sites using CBCT, digital impression, and K file. Multiple regression analysis was performed to create a conversion formula to measure thickness accurately. We then obtained CBCT data from 174 patients retrospectively, applied the conversion formula, and evaluated palatal mucosa thickness. RESULTS: Sites of measurement affected measurement error. Measurement using CBCT was 0.34 ± 0.04 mm smaller than actual measurement; therefore, a conversion formula was created. Male, age ≥60 years, and probing pocket depth ≥4 mm had significant and positive associations with palatal mucosa thickness; however, no association was observed between bleeding on probing and palatal mucosa thickness. CONCLUSION: CBCT is useful for the noninvasive and accurate measurement of palatal mucosa thickness.

Effectiveness of 405-nm blue LED light for degradation of Candida biofilms formed on PMMA denture base resin.

This study investigated (i) the degradation effect of 405-nm blue light-emitting diode (LED) light irradiation on Candida albicans and C. glabrata biofilms formed on denture base resin and (ii) the effects of 405-nm blue LED light irradiation on the mechanical and surface characteristics of the resin. Polymethyl methacrylate denture base resin discs were prepared, and C. albicans or C. glabrata biofilms formed on the denture base resin discs. Each biofilm was irradiated with 405-nm blue LED light under a constant output power (280 mW/cm2) for different times in a moisture chamber with 100% relative humidity. Postirradiation, each biofilm was analyzed using a colony-forming unit assay, fluorescence microscopy, and scanning electron microscopy (SEM). Parallelepiped specimens of acrylic resin were prepared, and changes in their flexural strength (FS), flexural modulus (FM), and surface roughness (Ra) preirradiation and postirradiation with 405-nm blue LED light were evaluated. Irradiation for 30 min completely inhibited colony formation in both Candida species. Fluorescence microscopy showed that almost all Candida cells were killed because of irradiation. SEM images showed various cell damage patterns, such as wrinkles, shrinkage, and cell surface damage. An increase in FS was noted postirradiation, but no significant changes were observed in FM and Ra preirradiation and postirradiation. In conclusion, irradiation with 405-nm blue LED light induces degradation of C. albicans and C. glabrata biofilms on denture base resin, even in the absence of photosensitizers, without resin surface deterioration.

Epidermal growth factor receptor/heme oxygenase-1 axis is involved in chemoresistance to cisplatin and pirarubicin in HepG2 cell lines and hepatoblastoma specimens.

PURPOSE: To investigate the possibility that the antioxidant stress protein Heme oxygenase-1 (HO-1) is involved in the acquisition of chemoresistance in cisplatin and pirarubicin (CITA) therapy. METHODS: Human hepatoblastoma-derived cell line (HepG2) was used to generate a knockdown cell line of HO-1 by small interfering RNA (siRNA). Expression of HO-1, epidermal growth factor receptor (EGFR), Akt, and extracellular signal-regulated kinase1/2 (ERK1/2) was examined by Western blot. The cytotoxic effect of cisplatin, pirarubicin, and EGFR inhibitor was examined by trypan blue staining. In human hepatoblastoma specimens (n = 5), changes of HO-1 expression were examined immunohistochemically before and after CITA therapy. RESULTS: HO-1 expression in HepG2 cells was increased by the treatment of cisplatin (CDDP) and pirarubicin (THP) dose-dependently. In HO-1 knockdown HepG2 cells, the HO-1 was not expressed and the percentage of trypan blue-positive cells (dead cells) was significantly increased after treatment of CDDP and THP. The EGFR inhibitor decreased the levels of HO-1, phospho-Akt and phospho-ERK1/2 in HepG2 cells. Combination treatment of EGFR inhibitor with CDDP and THP increased the cytotoxic effect in HepG2 cells. In human hepatoblastoma specimens, 4 of the 5 patients (80%) showed HO-1 expression changed much stronger in the viable tumor cells after CITA therapy. CONCLUSION: The cytotoxic effects of CDDP and THP were both enhanced under HO-1 knockdown conditions as well as under conditions that inhibit the activation pathway of HO-1 by EGFR inhibitors. EGFR/HO-1 axis may be involved in acquiring chemoresistance in HepG2 cell lines as well as in human hepatoblastoma.

Synthesis of 8-hydroxy-2-iminochromene derivatives as selective and potent inhibitors of human carbonyl reductase 1.

Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces anthracycline anticancer drugs to their less potent anticancer C-13 hydroxy metabolites, which are linked with pathogenesis of cardiotoxicity, a side effect of the drugs. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with a twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity. In order to search for new potential inhibitors of CBR1, we synthesized a series of des-methoxyphenyl derivatives of (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) that was developed previously as a potent inhibitor of aldo-keto reductase (AKR) 1B10 and AKR1B1. Among the newly synthesized inhibitors, 8-hydroxy-2-imino-2H-chromene-3-carboxylic acid (2-chlorophenyl)amide (13h) was the most potent competitive inhibitor of CBR1, showing a Ki value of 15 nM. 13h also showed high selectivity to CBR1 over its isozyme CBR3 and other enzymes with CBR activity (AKR1B1, AKR1B10, AKR1C1, AKR1C2, AKR1C4, DXCR and DHRS4). Furthermore, 13h inhibited the cellular metabolism by CBR1 at its concentration of 4 µM. The structure-activity relationship of the derivatives, site-directed mutagenesis of putative binding residues (Met141 and Trp229) and molecular docking of 13h in CBR1 revealed that the interactions of 13h with the substrate-binding residues (Ser139, Met141, Tyr193 and Trp229) are important for the tight binding.

Cloning and characterization of four rabbit aldo-keto reductases featuring broad substrate specificity for xenobiotic and endogenous carbonyl compounds: relationship with multiple forms of drug ketone reductases.

Multiple forms of reductases for several drug ketones were isolated from rabbit liver, but their interrelationship and physiologic roles remain unknown. We isolated cDNAs for four aldo-keto reductases (AKR1C30, AKR1C31, AKR1C32, and AKR1C33), which share high amino acid sequence identity with the partial sequences of two rabbit naloxone reductases. The four recombinant enzymes reduced a variety of carbonyl compounds, including endogenous α-dicarbonyls (e.g., isatin and diacetyl), aldehydes (e.g., farnesal and 4-oxo-2-nonenal), and ketosteroids. They differed in specificity for drug ketones and ketosteroids. Although daunorubicin and befunolol were common substrates of all of the enzymes, AKR enzymes specifically reduced naloxone (AKR1C30, AKR1C32, and AKR1C33), metyrapone (AKR1C32 and AKR1C33), loxoprofen (AKR1C31 and AKR1C32), ketotifen (AKR1C30), and naltrexone and fenofibric acid (AKR1C33). AKR1C30 reduced only 17-keto-5ß-androstanes, whereas the other enzymes were active toward 3-, 17-, and 20-ketosteroids, and AKR1C33 further reduced 3-keto groups of bile acids and 7α-hydroxy-5ß-cholestanes. In addition, AKR1C30, AKR1C31, AKR1C32, and AKR1C33 were selectively inhibited by carbenoxolone, baccharin, phenolphthalein, and zearalenone, respectively. The mRNAs for the four enzymes were ubiquitously expressed in male rabbit tissues, in which highly expressed tissues were the brain, heart, liver, kidney, intestine, colon, and testis (for AKR1C30 and AKR1C31); brain, heart, liver, kidney, testis, lung, and adrenal gland (for AKR1C32); and liver and intestine (for AKR1C33). Thus, the four enzymes correspond to the multiple drug ketone reductases, and may function in the metabolisms of steroids, isatin and reactive carbonyl compounds, and bile acid synthesis.

Probing AKR1C30 and AKR1C31 with site-directed mutagenesis: identifying the roles of residues 54 and 56 in the binding of substrates and inhibitors.

Five rabbit aldo-keto reductases (AKRs) that participate in the reduction of drug ketones and endogenous ketosteroids have recently been cloned and characterized. Among them, AKR1C30 and AKR1C31 show the highest amino acid sequence identity of 91%, but markedly differ in their substrate specificity and inhibitor sensitivity. AKR1C30 reduces two drugs (ketotifen and naloxone) and 17-keto-5ß-androstanes, whereas AKR1C31 does not reduce the two drugs, but is active towards loxoprofen and various 3/17/20-ketosteroids. In addition, AKR1C30 is selectively inhibited by carbenoxolone, valproic acid and phenobarbital. Residues A54 and R56 are located adjacent to the catalytic residue Y55 of AKR1C30. To clarify the determinants for the substrate specificity and inhibitor sensitivity of AKR1C30, we performed the mutagenesis of A54 and R56 to the corresponding residues (L and Q) of AKR1C31. The A54L mutation produced an enzyme that had almost the same substrate specificity as AKR1C31 and decreased the sensitivity to the inhibitors except for carbenoxolone. The R56Q mutation decreased the affinity for only carbenoxolone among the substrates and inhibitors. Thus, the difference in the properties between the two enzymes can be attributed to their residue difference at positions 54 and 56.

[Clinical and neuropsychological features and changes to regional cerebral blood flow in |patients with Parkinson's disease dementia].

This study aimed to clarify associations of clinical and neuropsychological features and change in regional cerebral blood flow (rCBF) on 123I-IMP-SPECT in patients with Parkinson's disease (PD) who developed dementia. Sixty-one PD patients (mean age, 65.9 ± 8.6 years; mean disease duration, 11.0 ± 11.0 years) were recruited and followed-up for two years. Clinical and neuropsychological characteristics, and rCBF from SPECT were compared between PD patients who developed dementia (PDD+) and those who remained undemented (PDD-). Thirty-eight PD patients (62.3%) were diagnosed with PD-MCI at baseline. During follow-up, 22 PD patients (36%) developed dementia (PDD+). Univariate logistic regression models showed that Hoehn and Yahr scale 4 (odds ratio [OR] 5.85; 95% confidence interval [CI] 1.35-30.75]), visual hallucination (OR 5.95; 95%CI 1.67-25.4]), and PD-MCI (OR 6.47; 95%CI 1.57-39.63]) represented a significant risk factor for PDD+. Among neuropsychological parameters, WAIS (Wechsler Adult Intelligence Scale)-III block design (OR 6.55; 95%CI 1.66-29.84), letter number sequencing (OR 7.01; 95%CI 1.65-36.64), digit-symbol coding (OR 3.90; 95%CI 1.13-14.2), Wechsler Memory Scale, revised (WMS-R) visual paired associates II (delayed recall) (OR 4.68; 95%CI 1.36-17.36), Logical memory I (immediate recall) (OR 8.30; 95%CI 1.37-90.89), Logical memory II (delayed recall) (OR 6.61; 95%CI 1.35-44.33), Visual reproduction I (immediate recall) (OR 7.67; 95%CI 2.11-31.40), and Visual reproduction II (delayed recall) (OR 5.64; 95%CI 1.62-21.47) were significant risk factors. Decreased rCBF assessed using the general linear model (two-sample t-test) by SPM8 was observed in the left precuneus (0, -66, 16), right cuneus (6, -76, 30), and left angular gyrus (-46, -74, 32) in PDD+ compared with PDD- patients. Collectively, we have here shown that clinical and neuropsychological characteristics as well as changes to rCBF in PD patients who converted to PDD+. These features should be carefully monitored to detect the development of dementia in PD patients.

Control of alveolar bone development, homeostasis, and socket healing by salt inducible kinases.

Alveolar bone supports and anchors teeth. The parathyroid hormone-related protein (PTHrP) pathway plays a key role in alveolar bone biology. Salt inducible kinases (SIKs) are important downstream regulators of PTH/PTHrP signaling in the appendicular skeleton where SIK inhibition increases bone formation and trabecular bone mass. However, the function of these kinases in alveolar bone remains unknown. Here, we report a critical role for SIK2/SIK3 in alveolar bone development, homeostasis, and socket healing after tooth extraction. Inducible SIK2/SIK3 deletion led to dramatic alveolar bone defects without changes in tooth eruption. Ablating these kinases impairs alveolar bone formation due to disrupted osteoblast maturation, a finding associated with ectopic periostin expression by fibrous cells in regions of absent alveolar bone at steady state and following molar extraction. Distinct phenotypic consequences of SIK2/SIK3 deletion in appendicular versus craniofacial bones prompted us to identify a specific transcriptomic signature in alveolar versus long bone osteoblasts. Thus, SIK2/SIK3 deletion illuminates a key role for these kinases in alveolar bone biology and highlights the emerging concept that different osteoblast subsets utilize unique genetic programs. Summary statement: SIK2/SIK3 deletion in alveolar bone reduces bone formation and mass by impairing osteoblast maturation, unlike in long bones, where it increases bone formation and mass.

Characterization of rabbit morphine 6-dehydrogenase and two NAD(+)-dependent 3α(17ß)-hydroxysteroid dehydrogenases.

Mammalian morphine 6-dehydrogenase (M6DH)(1) converts morphine into a reactive electrophile, morphinone. M6DH belongs to the aldo-keto reductase (AKR) superfamily, but its endogenous substrates and entire amino acid sequence remain unknown. A recent rabbit genomic sequencing predicts three genes for novel AKRs (1C26, 1C27 and 1C28) that share >87% amino acid sequence identity and are similar to the partial sequence of rabbit liver M6DH. We isolated cDNAs for the three AKRs, and compared the properties of their recombinant enzymes. Like M6DH, only AKR1C26 that shares the highest sequence identity with hepatic M6DH oxidized morphine. The three AKRs showed NAD(+)-dependent dehydrogenase activity towards other non-steroidal alicyclic alcohols and 3α/17ß-hydroxy-C(18)/C(19)/C(21)-steroids, and their mRNAs were ubiquitously expressed in rabbit tissues. The kinetic constants for the substrates suggest that at least AKR1C26 and AKR1C28 act as NAD(+)-dependent 3α/17ß-hydroxysteroid dehydrogenases. AKR1C27 differed from AKR1C28 in its high K(m) values for the substrates and low sensitivity towards competitive inhibitors (ikarisoside A, hinokitiol, hexestrol and zearalenone), despite their 95% sequence identity. The site-directed mutagenesis of Tyr118 and Phe310 in AKR1C27 to the corresponding residues (Phe and Ile, respectively) in AKR1C28 produced an enzyme that was similar to AKR1C28, suggesting their key roles in ligand binding.

Substrate specificity and inhibitor sensitivity of rabbit 20α-hydroxysteroid dehydrogenase.

In this study, we examined the substrate specificity and inhibitor sensitivity of rabbit 20α-hydroxysteroid dehydrogenase (AKR1C5), which plays a role in the termination of pregnancy by progesterone inactivation. AKR1C5 moderately reduced the 3-keto group of only 5α-dihydrosteroids with 17ß- or 20α/ß-hydroxy group among 3-ketosteroids. In contrast, the enzyme reversibly and efficiently catalyzed the reduction of various 17- and 20-ketosteroids, including estrogen precursors (dehydroepiandrosterone, estrone and 5α-androstan-3ß-ol-17-one) and tocolytic 5ß-pregnane-3,20-dione. In addition to the progesterone inactivation, the formation of estrogens and metabolism of the tocolytic steroid by AKR1C5 may be related to its role in rabbit parturition. AKR1C5 also reduced various non-steroidal carbonyl compounds, including isatin, an antagonist of the C-type natriuretic peptide receptor, and 4-oxo-2-nonenal, suggesting its roles in controlling the bioactive isatin and detoxification of cytotoxic aldehydes. AKR1C5 was potently and competitively inhibited by flavonoids such as kaempferol and quercetin, suggesting that its activity is affected by ingested flavonoids.

Rat model of attention-deficit hyperactivity disorder exhibits delayed recovery from acute incisional pain due to impaired descending noradrenergic inhibition.

Chronic pain and attention-deficit hyperactivity disorder (ADHD) frequently coexist. However, the common pathology is still unclear. Attenuated noradrenergic endogenous analgesia can produce acute pain chronification, and dysfunction of noradrenergic systems in the nervous system is relevant to ADHD symptoms. Noxious stimuli-induced analgesia (NSIA) is measured to estimate noradrenergic endogenous analgesia in spontaneously hypertensive rats (SHR) as an ADHD model and control. Recovery of pain-related behaviors after paw incision was assessed. Contributions of noradrenergic systems were examined by in vivo microdialysis and immunohistochemistry. The SHR showed attenuated NSIA and needed a more extended period for recovery from acute pain. These results suggest ADHD patients exhibit acute pain chronification due to pre-existing attenuated noradrenergic endogenous analgesia. Immunohistochemistry suggests abnormal noradrenaline turnover and downregulation of the target receptor (alpha2a adrenoceptor). Standard ADHD treatment with atomoxetine restored NSIA and shortened the duration of hypersensitivity after the surgery in the SHR. NSIA protocol activated the locus coeruleus, the origin of spinal noradrenaline, of both strains, but only the control exhibited an increase in spinal noradrenaline. This result suggests dysfunction in the noradrenaline-releasing process and can be recognized as a novel mechanism of attenuation of noradrenergic endogenous analgesia.

Knowledge acquisition efficacy of a remote flipped classroom on learning about removable partial dentures.

PURPOSE: Coronavirus disease 2019 has forced the use of remote education worldwide. In 2020, the authors conducted a fully digitized, remote flipped (RF) classroom focusing on removable partial dentures. This study aimed to evaluate the learning outcomes of the RF classroom and compare these with those of the on-site classroom. METHODS: The fourth-year dental students in 2017-2019 attended on-site flipped classroom (OF; n=70) or on-site lecture classroom (OL; n=67), and those in 2020 (n=58) attended the RF classroom. Lecture videos and text were provided online in the OF and RF groups, while only the text was given to the OL group. Individual and group tests were conducted to assess knowledge acquisition one week after all the classes ended. A one-way analysis of variance following Tukey's test was performed to compare individual/group test scores among the OF, OL, and RF groups. Multilevel linear regression analysis was performed to identify the factors associated with an increase in each test score. RESULTS: The mean individual test scores in the RF and OF groups were significantly higher than in the OL group (P<0.01). The mean group test score in the RF group was significantly higher than in the OF and OL groups (P<0.001). The multilevel analysis identified remote and flipped classroom styles in the individual test, and the remote style in the group test, as significant effective factors in learning (P<0.05). CONCLUSIONS: These results suggest that the RF classroom is more effective than the on-site lecture in knowledge acquisition in undergraduate prosthodontic education.

Effect of abutment tooth location on the accuracy of digital impressions obtained using an intraoral scanner for removable partial dentures.

PURPOSE: To verify the effect of abutment tooth location on the accuracy of digital impressions obtained using an intraoral scanner (IOS) for removable partial dentures (RPDs). METHODS: The target abutment teeth included the left first premolar (#34), second molar (#37), and right second premolar (#45) in a mandibular Kennedy class II model and the left and right second molars (#37, #47) in a class III model. Only #37 was isolated from the remaining teeth by the mucosal area in both models. Digital impressions were obtained using a desktop scanner (reference data) and an IOS (IOS data; scanning origin #37; n=10). The general trueness based on the entire model superimposition (TG), local trueness (TL) of an individual tooth, and dimensional accuracy (coordinate and linear accuracy) of the IOS data of the target abutment teeth were compared (α=0.05). RESULTS: In both models, #37 showed significantly inferior TG (P<0.01), superior TL (P<0.01), and mesial coordinate displacement (P<0.01 and P<0.05 in class II and III models, respectively). Intra-model comparisons showed that #45 in the class II model and #47 in the class III model had significantly inferior linear accuracy (P<0.05 and P<0.01, respectively) and buccal coordinate displacement (P<0.05 and P<0.01, respectively) compared with the other target teeth. CONCLUSIONS: In digital impressions of RPDs, isolation of abutment teeth by mucosal areas can reduce general trueness based on the entire dental arch and mesial tooth displacement, whereas increased distance from the scanning origin can adversely affect local trueness and dimensional accuracy.

Morphological Comparison of Residual Ridge in Impression for Removable Partial Denture between Digital and Conventional Techniques: A Preliminary In-Vivo Study.

Although digital impression using an intraoral scanner (IOS) has been applied for removable partial denture (RPD) fabrication, it is still unclear how the morphology of a residual ridge recorded by digital impression would differ from that recorded by conventional impression. This in vivo study investigated the morphological difference in the recorded residual ridge between digital and conventional impressions. Vertical and horizontal displacements (VD and HD) in residual ridges recorded by digital and conventional impressions were assessed in 22 participants (15 female; mean age 78.2 years) based on the morphology of the tissue surface of in-use RPD. Additionally, the mucosal thickness of the residual ridge was recorded using an ultrasound diagnostic device. VD and HD were compared using the Wilcoxon signed-rank test, and the correlation of mucosal thickness with VD and HD was analyzed using Spearman's ρ. The VD of digital impression was significantly greater than that of a conventional impression (p = 0.031), while no significant difference was found in HD (p = 0.322). Meanwhile, the mucosal thickness showed no significant correlation with the recorded morphology of the residual ridge, regardless of the impression techniques. It was concluded that the digital impression would result in a greater displacement in the height of the residual ridge from the morphology of in-use RPD than the conventional impression.