A case of hepatitis C-associated osteosclerosis: accelerated bone turnover controlled by pulse steroid therapy.

Hepatitis C-associated osteosclerosis (HCAO), a very rare disorder in which an extremely rapid bone turnover occurs and results in osteosclerosis, was acknowledged in 1990s as a new clinical entity with the unique bone disorder and definite link to chronic type C hepatitis, although the pathogenesis still remains unknown. Affected patients suffer from excruciating deep bone pains. We report the 19th case of HCAO with diagnosis confirmed by bone biopsy, and treated initially with a bisphosphonate, next with corticosteroids and finally with direct acting antivirals (DAA: sofosbuvir and ribavirin) for HCV infection. Risedronate, 17.5 mg/day for 38 days, did not improve the patient's symptoms or extremely elevated levels of bone markers, which indicated hyper-bone-formation and coexisting hyper-bone-resorption in the patient. Next, intravenous methylprednisolone pulse therapy followed by high-dose oral administration of prednisolone evidently improved them. DAA therapy initiated after steroid therapy successfully achieved sustained virological response, but no additional therapeutic effect on them was observed. Our results strongly suggested that the underlying immunological alteration is the crucial key to clarify the pathogenesis of HCAO. Bone mineral density of lumbar vertebrae of the patient was increased by 14% in four-month period of observation. Clarification of the mechanisms that develop osteosclerosis in HCAO might lead to a new therapeutic perspective for osteoporosis. LEARNING POINTS: HCAO is an extremely rare bone disorder, which occurs exclusively in patients affected with HCV, of which only 18 cases have been reported since 1992 and pathogenesis still remains unclear.Pathophysiology of HCAO is highly accelerated rates of both bone formation and bone resorption, with higher rate of formation than that of resorption, which occur in general skeletal leading to the diffuse osteosclerosis with severe bone pains.Steroid therapy including intravenous pulse administration in our patient evidently ameliorated his bone pains and reduced elevated values of bone markers. This was the first successful treatment for HCAO among cases reported so far and seemed to propose a key to solve the question for its pathogenesis.The speed of increase in the bone mineral content of the patient was very high, suggesting that clarification of the mechanism(s) might lead to the development of a novel therapy for osteoporosis.

Evaluation of resin infiltration using quantitative light-induced fluorescence technology.

OBJECTIVES: To determine whether quantitative light-induced fluorescence (QLF) technology can be used to classify the colour of teeth specimens before and after resin infiltration (RI) treatment, and calculate the correlation between the ΔF value and colour difference (ΔE) in fluorescence images of the specimens obtained using a QLF-digital (QLF-D) device. METHODS: Sixty sound bovine permanent teeth specimens were immersed in demineralized solution. Two exposed windows were formed in each specimen, and RI treatment was applied to one of them. The ΔE values were obtained for the differences between a sound tooth surface (SS), an early dental caries surface (ECS) and an ECS treated with RI (RS) in white-light and fluorescence images obtained using QLF-D, respectively. The ΔF value was obtained from fluorescence images using dedicated software for QLF-D. The mean differences between the ΔE values obtained from the white-light and fluorescence images were analyzed by paired t-test. Pearson correlation analysis and Bland-Altman plots were applied to the differences between the ΔF value for ECS (ΔFSS-ECS) and the ΔE value between SS and ECS (ΔESS-ECS), and between the ΔF value for RS (ΔFSS-RS) and the ΔE value between SS and RS (ΔESS-RS) in fluorescence images. RESULTS: The ΔE values obtained from fluorescence images were three times higher than the ΔE values obtained from white-light images (p<0.001). Significant correlations were confirmed between ΔESS-ECS and ΔFSS-ECS (r=-0.492, p<0.001) and between ΔESS-RS and ΔFSS-RS (r=-0.661, p<0.001). CONCLUSION: QLF technology can be used to confirm the presence of RI in teeth.

Validity of screening methods for periodontitis using salivary hemoglobin level and self-report questionnaires in people with disabilities.

BACKGROUND: The aim of this study is to evaluate the validity of screening methods in predicting periodontitis in people with disabilities using the objective salivary hemoglobin level, a subjective self-report questionnaire, and a combined model of the two methods with demographic characteristics. METHODS: The participants were 195 patients with disabilities aged >18 years who were examined using the community periodontal index (CPI), salivary hemoglobin level, and answers to 10 self-report questions (n = 192). Multivariable logistic regression and receiver operating characteristic (ROC) curve analysis were performed to evaluate the validity of the methods and the combined model in predicting the prevalence of ≥CPI 3 (probing depth [PD] ≥4 mm) or CPI 4 (PD ≥6 mm). RESULTS: Overall, 75.9% of the study group (148 of 195) were diagnosed with ≥CPI 3, and 38.5% of the study group (75 of 195) were diagnosed with CPI 4. The areas under the ROC curve (AUCs) of the salivary hemoglobin level were 0.578 (sensitivity of 41% and specificity of 77%) and 0.662 (sensitivity of 53% and specificity of 75%) for predicting the prevalence of ≥CPI 3 and CPI 4, respectively. Multivariable modeling incorporating four different questions for predicting ≥CPI 3 or CPI 4 indicated higher AUCs of 0.710 and 0.732, respectively, yielding higher sensitivity (55% for ≥CPI 3 and 69% for CPI 4) than that of salivary hemoglobin level. The most useful prediction models for ≥CPI 3 or CPI 4 were combined models, which yielded AUCs of 0.773 and 0.807, respectively, with sensitivity values of 70% and specificity values >75%. CONCLUSION: The salivary hemoglobin level, self-report questionnaire, and the combined method demonstrated screening potential that could predict the population prevalence of ≥CPI 3 or CPI 4.

Ror2/Frizzled complex mediates Wnt5a-induced AP-1 activation by regulating Dishevelled polymerization.

The receptor tyrosine kinase Ror2 acts as a receptor or coreceptor for Wnt5a to mediate Wnt5a-induced activation of the Wnt/JNK pathway and inhibition of the beta-catenin-dependent canonical Wnt pathway. However, little is known about how Ror2 cooperates with another receptor component(s) to mediate Wnt5a signaling. We show here that Ror2 regulates Wnt5a-induced polymerization of Dishevelled (Dvl) and that this Ror2-mediated regulation of Dvl is independent of the cytoplasmic region of Ror2. Ror2 can associate with Frizzled7 (Fz7) via its extracellular cysteine-rich domain to form a receptor complex that is required for the regulation of Dvl and activation of the AP-1 promoter after Wnt5a stimulation. Suppressed expression of Fz7 indeed results in the inhibition of Wnt5a-induced polymerization of Dvl and AP-1 activation. Interestingly, both the DIX and the DEP domains of Dvl are indispensable for Dvl polymerization and subsequent AP-1 activation after Wnt5a stimulation. We further show that polymerized Dvl is colocalized with Rac1 and that suppressed expression of Rac1 inhibits Wnt5a-induced AP-1 activation. Collectively, our results indicate that Ror2/Fz receptor complex plays an important role in the Wnt5a/Rac1/AP-1 pathway by regulating the polymerization of Dvl.

Receptor tyrosine kinase Ror2 mediates Wnt5a-induced polarized cell migration by activating c-Jun N-terminal kinase via actin-binding protein filamin A.

The receptor tyrosine kinase Ror2 has recently been shown to act as an alternative receptor or coreceptor for Wnt5a and to mediate Wnt5a-induced migration of cultured cells. However, little is known about the molecular mechanism underlying this migratory process. Here we show by wound-healing assays that Ror2 plays critical roles in Wnt5a-induced cell migration by regulating formation of lamellipodia and reorientation of microtubule-organizing center (MTOC). Wnt5a stimulation induces activation of the c-Jun N-terminal kinase JNK at the wound edge in a Ror2-dependent manner, and inhibiting JNK activity abrogates Wnt5a-induced lamellipodia formation and MTOC reorientation. Additionally, the association of Ror2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration. We further show that Wnt5a-induced JNK activation and MTOC reorientation can be suppressed by inhibiting PKCzeta. Taken together, our findings indicate that Wnt5a/Ror2 activates JNK, through a process involving filamin A and PKCzeta, to regulate polarized cell migration.

A determination of bite force in northern Japanese children.

The bite force of 2594 school children (1248 males and 1346 females) living in northern Japan was investigated during oral health examinations in May and June 2001, using a new type of occlusal force gauge. The subjects were recruited from a variety of educational institutes and comprised: 73 nursery (3-5 years old), 1019 primary (6-11 years old), 902 junior high (12-14 years old) and 600 high (15-17 years old) school children. The measuring apparatus consisted of a hydraulic pressure gauge, with a bite element encased in a plastic tube. The bite force was measured at the first molar or second primary molar in the children presenting in the permanent and primary dentitions, respectively. The findings revealed significant variations in bite force between children of different ages. The average bite force was 186.2 N in males and 203.4 N in females of nursery school children; 374.4 N in males and 330.5 N in females of primary school children; 514.9 N in males and 448.7 N in females of junior high school children; and 545.3 N in males and 395.2 N in females of high school children. The prevalence of malocclusion in the nursery school children was found to be less than 30 per cent, which contrasted with almost 70 per cent in the high school children.

Relationship between electrical resistance measurements and microradiographic variables during remineralization of softened enamel lesions.

The purpose of this study was to investigate the relationship between electrical resistance (ECM) measurements and microradiographic variables during remineralization of softened enamel lesions. Sound bovine enamel blocks were demineralized and, subsequently, were remineralized for 3, 4, 5, 7 or 14 days. All the specimens were assessed by ECM and transversal microradiography. The mean ECM values in each group increased after remineralization. The ECM values after remineralization (ECM1), mineral loss (DeltaZ) and maximum mineral content in the surface layer (V(max)) were significantly correlated with the remineralization time. The ECM1 values were also significantly correlated with DeltaZ and V(max). It is suggested that ECM could be used as a device to monitor mineral accumulation as a result of preventive treatment in vitro. However, it may take a much longer time to follow up the remineralization changes compared with demineralization.

Two different effects of transcranial magnetic stimulation to the human motor cortex during the pre-movement period.

A single-pulse TMS to the human motor cortex (M1) influences reaction time (RT). We may summarize from previous studies where different groups of subjects participated in various types of RT tasks that TMS above motor threshold (MT) delays RT, whereas TMS below MT shortens RT and that these RT changes depends on TMS timings during RT period. However, these effects have never been systematically investigated in a single study where an identical group of subjects participated. The purpose of this study is to test previous TMS effects in a study of simple RT task. Seven subjects isometrically abducted their right index fingers as quickly as possible when a visual stimulus appeared. A single-pulse TMS was randomly delivered over the left M1 at various timings during RT period in a single trial (at 0, 40, 60, 80 or 100 ms after the visual stimulus). Motor-evoked potential (MEP) and EMG activity for response were recorded from the right finger muscles. Only the TMS above MT delivered at 80 or 100 ms, which increased MEP amplitude, significantly delayed RT and increased the size of response EMG activities that may reflect contents of central motor commands. The TMS below MT at these timings, which occasionally evoked MEP, exclusively shortened RT despite the fact that the response EMG size was unchanged. A single-pulse TMS has different effects on the ongoing neuronal processes in M1 during the pre-movement period: TMS above MT may temporally retard the processes and also affect contents of central motor commands, whereas TMS below MT may simply facilitate its processes without affecting motor commands.

Enamel fluoride uptake from mouthrinse solutions with different NaF concentrations.

OBJECTIVES: The influence on enamel fluoride uptake of reducing the NaF concentration of a mouthrinse solution by half, from 0.05-0.025%, was examined in elementary school children. METHODS: The participatory elementary school had employed school-based fluoride mouthrinse with 0.05% NaF solution since 1983, and in 1993, the NaF content was lowered to 0.025%. Dental examination and enamel biopsy of maxillary central incisors were performed just before the NaF content reduction for children who had received the daily 0.05% NaF mouthrinse for 2-5 years since 6 years of age. During 1993-95, dental examination and enamel biopsy were undertaken for newly enrolled 6-year-old children, and the same subjects were re-examined after 2 years. The same series of examinations were conducted for the control group, which consisted of children belonging to another elementary school without a fluoride program. RESULTS: The enamel fluoride concentration of 8-year-old children who used the 0.025% NaF mouthrinse for 2 years was 1810 +/- 535 ppm, reaching the same order as that in children who continued using the 0.05% NaF mouthrinse (1863 +/- 1358 ppm), and was significantly higher than that of children without fluoride programs (1113 +/- 303 ppm). There was no considerable increase of mean DMFT values due to the NaF content reduction. CONCLUSIONS: It was concluded that a daily 0.025% NaF mouthrinse provides the similar fluoride content for enamel as 0.05% NaF mouthrinse as long as the rinsing frequency is maintained.