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The Carney complex (CNC) is an autosomal dominant disorder characterized by endocrine and nonendocrine tumors. Loss-of-function variants of protein kinase A regulatory subunit 1 alpha (PRKAR1A) are common causes of CNC. Here, we present the case of a patient with CNC with a novel PRKAR1A missense variant. A 21-year-old woman was diagnosed with CNC secondary to acromegaly and adrenal Cushing syndrome. Genetic analysis revealed a novel missense heterozygous variant of PRKAR1A (c.176A>T). Her relatives, suspected of having CNC, also carried the same variant. RNA analysis revealed that this variant led to nonsense-mediated mRNA decay. In vitro functional analysis of the variant confirmed its role in increasing protein kinase A activity and cyclic adenosine monophosphate levels. This study broadens our understanding of the genetic spectrum of CNC. We suggest that PRKAR1A genetic testing and counseling be recommended for patients with CNC and their families.

Castleman’s disease is a rare disease of the lymph nodes and related tissues, presenting as angiofollicular or giant lymph node hyperplasia. Although various skin manifestations have been reported to occur in Castleman’s disease, a comprehensive study of cutaneous disorders in Castleman’s disease is lacking. Therefore, the aim of this study was to investigate Castleman’s disease-associated cutaneous disorders. The medical records of 57 patients with Castleman’s disease who visited our hospitals from January 2007 to May 2018 were analysed retrospectively. Patients were classified according to the presence of skin involvement. Plasma variant-type Castleman’s disease and multicentric Castleman’s disease were more commonly found in patients with Castleman’s disease with a cutaneous disorder than in those without a cutaneous disorder. In addition, the skin disorders were classified according to pathomechanisms: immune complex-related (paraneoplastic pemphigus, xanthogranulomas), cytokine-related (vasculitis-like lesion, cherry angioma, hyperpigmentation), and non-specific (pruritus). This study builds on previous case reports of cutaneous disorders in Castleman’s disease and proposes a new classification system.

Abstract Background Dalbergia odorifera T. Chen (Leguminosae) is an indigenous medicinal herb that is widely used as a popular remedy in northern and eastern Asia. However, the cellular mechanisms underlying the biological activity of D. odorifera are not fully elucidated. Methods Anti-inflammatory effect of D. odorifera extract (DOE) was determined through intraperitoneal injection in a mouse model of endotoxemia induced by lipopolysaccharide (LPS). RAW 264.7 cells, a murine macrophage, were also treated with LPS to generate a cellular model of inflammation, and investigated the anti-inflammatory activity and underlying mechanisms of DOE and its constituent isoliquiritigenin. Results DOE dose-dependently inhibited LPS-induced release of high mobility group box 1 (HMGB1), a late proinflammatory cytokine, and decreased cytosolic translocation of HMGB1 in RAW264.7 cells. This inhibitory effect of DOE on HMGB1 release was observed in cells treated with DOE before or after LPS treatment, suggesting that DOE is effective for both treatment and prevention. In addition, DOE significantly inhibited LPS-induced formation of nitric oxide (NO) and expression of inducible NO synthase (iNOS) in a dose-dependent manner. These effects of DOE were accompanied by suppression of HMGB1 release triggered by LPS, suggesting a possible mechanism by which DOE modulates HMGB1 release through NO signaling. Isoriquiritigenin, a constituent of DOE, also attenuated LPS-triggered NO formation and HMGB1 release in RAW264.7 cells, indicating that isoriquiritigenin is an indexing molecule for the anti-inflammatory properties of DOE. Furthermore, c-Jun N-terminal kinase, but not extracellular signal-regulated kinase and p38, mediated DOE-dependent inhibition of HMGB1 release and NO/iNOS induction in RAW 264.7 cells exposed to LPS. Notably, administration of DOE ameliorated survival rates in a mouse model of endotoxemia induced by LPS, where decreased level of circulating HMGB1 was observed. Conclusion These results suggest that DOE confers resistance to LPS-triggered inflammation through NO-mediated inhibitory effects on HMGB1 release.

We investigated the effect of peroxisome proliferator-activated receptor δ (PPARδ) on angiotensin II (Ang II)-triggered hypertrophy of vascular smooth muscle cells (VSMCs). Activation of PPARδ by GW501516, a specific ligand of PPARδ, significantly inhibited Ang II-stimulated protein synthesis in a concentration-dependent manner, as determined by [3H]-leucine incorporation. GW501516-activated PPARδ also suppressed Ang II-induced generation of reactive oxygen species (ROS) in VSMCs. Transfection of small interfering RNA (siRNA) against PPARδ significantly reversed the effects of GW501516 on [3H]-leucine incorporation and ROS generation, indicating that PPARδ is involved in these effects. By contrast, these GW501516-mediated actions were potentiated in VSMCs transfected with siRNA against NADPH oxidase (NOX) 1 or 4, suggesting that ligand-activated PPARδ elicits these effects by modulating NOX-mediated ROS generation. The phosphatidylinositol 3-kinase inhibitor LY294002 also inhibited Ang II-stimulated [3H]-leucine incorporation and ROS generation by preventing membrane translocation of Rac1. These observations suggest that PPARδ is an endogenous modulator of Ang II-triggered hypertrophy of VSMCs, and is thus a potential target to treat vascular diseases associated with hypertrophic changes of VSMCs.

Background The release of high mobility group box 1 (HMGB1) induced by inflammatory signals acts as a cellular alarmin to trigger a chain of inflammatory responses. Although the inflammatory actions of HMGB1 are well studied, less is known about the therapeutic agents that can impede its release. This study investigated whether the isoflavonoid formononetin can modulate HMGB1 release in cellular inflammatory responses. Methods RAW264.7 murine macrophages were exposed to lipopolysaccharide (LPS) in the presence or absence of formononetin. The levels of HMGB1 release, sirtuin 1 (SIRT1) expression, and HMGB1 acetylation were analyzed by immunoblotting and real-time polymerase chain reaction. The effects of resveratrol and sirtinol, an activator and inhibitor of SIRT1, respectively, on LPS-induced HMGB1 release were also evaluated. Results Formononetin modulated cellular inflammatory responses by suppressing the release of HMGB1 by macrophages exposed to LPS. In RAW264.7 cells, formononetin significantly attenuated LPS-induced release of HMGB1 into the extracellular environment, which was accompanied by a reduction in its translocation from the nucleus to the cytoplasm. In addition, formononetin significantly induced mRNA and protein expression of SIRT1 in a peroxisome proliferator-activated receptor δ (PPARδ)-dependent manner. These effects of formononetin were dramatically attenuated in cells treated with small interfering RNA (siRNA) against PPARδ or with GSK0660, a specific inhibitor of PPARδ, indicating that PPARδ is involved in formononetin-mediated SIRT1 expression. In line with these effects, formononetin-mediated inhibition of HMGB1 release in LPS-treated cells was reversed by treatment with SIRT1-targeting siRNA or sirtinol, a SIRT1 inhibitor. By contrast, resveratrol, a SIRT1 activator, further potentiated the inhibitory effect of formononetin on LPS-induced HMGB1 release, revealing a possible mechanism by which formononetin regulates HMGB1 release through SIRT1. Furthermore, modulation of SIRT1 expression by transfection of SIRT1- or PPARδ-targeting siRNA significantly counteracted the inhibitory effects of formononetin on LPS-induced HMGB1 acetylation, which was responsible for HMGB1 release. Discussion This study shows for the first time that formononetin inhibits HMGB1 release by decreasing HMGB1 acetylation via upregulating SIRT1 in a PPARδ-dependent manner. Formononetin consequently exhibits anti-inflammatory activity. Identification of agents, such as formononetin, which can block HMGB1 release, may help to treat inflammation-related disorders.

DJ-1 is one of the causative genes for early onset familiar Parkinson's disease (PD) and is also considered to influence the pathogenesis of sporadic PD. DJ-1 has various physiological functions which converge on controlling intracellular reactive oxygen species (ROS) levels. In RNA-sequencing analyses searching for novel anti-oxidant genes downstream of DJ-1, a gene encoding NADP+-dependent isocitrate dehydrogenase (IDH), which converts isocitrate into α-ketoglutarate, was detected. Loss of IDH induced hyper-sensitivity to oxidative stress accompanying age-dependent mitochondrial defects and dopaminergic (DA) neuron degeneration in Drosophila, indicating its critical roles in maintaining mitochondrial integrity and DA neuron survival. Further genetic analysis suggested that DJ-1 controls IDH gene expression through nuclear factor-E2-related factor2 (Nrf2). Using Drosophila and mammalian DA models, we found that IDH suppresses intracellular and mitochondrial ROS level and subsequent DA neuron loss downstream of DJ-1. Consistently, trimethyl isocitrate (TIC), a cell permeable isocitrate, protected mammalian DJ-1 null DA cells from oxidative stress in an IDH-dependent manner. These results suggest that isocitrate and its derivatives are novel treatments for PD associated with DJ-1 dysfunction.

Mechanical loading is essential to maintain normal bone metabolism and the balance between bone formation and resorption. The cellular mechanisms that control mechanotransduction are not fully defined, but several key pathways have been identified. We discuss the roles of several components of the Wnt signaling cascade, namely Lrp5, Lrp6, and β-catenin in mechanical loading-induced bone formation. Lrp5 is an important Wnt co-receptor for regulating bone mass and mechanotransduction, and appears to function principally by augmenting bone formation. Lrp6 also regulates bone mass but its action might involve resorption as well as formation. The role of Lrp6 in mechanotransduction is unclear. Studies addressing the role of β-catenin in bone metabolism and mechanotransduction highlight the uncertainties in downstream modulators of Lrp5 and Lrp6. Taken together, these data indicate that mechanical loading might affect bone regulation triggering the canonical Wnt signaling (and perhaps other pathways) not only via Lrp5 but also via Lrp6. Further work is needed to clarify the role of the Wnt signaling pathway in Lrp5 and/or Lrp6-mediated mechanotransduction, which could eventually lead to powerful therapeutic agents that might mimic the anabolic effects of mechanical stimulation.

Peroxisome proliferator-activated receptors (PPARs) are shown to modulate the pathological status of sepsis by regulating the release of high mobility group box 1 (HMGB1), a well-known late proinflammatory mediator of sepsis. Ligand-activated PPARs markedly inhibited lipopolysaccharide- (LPS) induced release of HMGB1 in RAW 264.7 cells. Among the ligands of PPAR, the effect of rosiglitazone, a specific ligand for PPARγ, was superior in the inhibition of HMGB1 release induced by LPS. This effect was observed in cells that received rosiglitazone before LPS or after LPS treatment, indicating that rosiglitazone is effective in both treatment and prevention. Ablation of PPARγ with small interfering RNA or GW9662-mediated inhibition of PPARγ abolished the effect of rosiglitazone on HMGB1 release. Furthermore, the overexpression of PPARγ markedly potentiated the inhibitory effect of rosiglitazone on HMGB1 release. In addition, rosiglitazone inhibited LPS-induced expression of Toll-like receptor 4 signal molecules, suggesting a possible mechanism by which rosiglitazone modulates HMGB1 release. Notably, the administration of rosiglitazone to mice improved survival rates in an LPS-induced animal model of endotoxemia, where reduced levels of circulating HMGB1 were demonstrated. Taken together, these results suggest that PPARs play an important role in the cellular response to inflammation by inhibiting HMGB1 release.

Introduction: This clinical study was performed to evaluate the anteroposterior and vertical displacement patterns of the maxillary teeth in sliding mechanics depending on the position of interradicular miniscrews after the extraction of premolars., Methods: Thirty-six women requiring maximum incisor retraction because of bialveolar protrusion were divided into 2 groups: group A (n = 18), miniscrew between the premolar and the molar, and group B (n = 18), miniscrew between the premolars. Cephalometric measurements for skeletal and dental changes were made before and after space closure., Results: In both groups, significant incisor retraction with intrusion of the root apex was noted, with no significant change in the first molar position. Group B displayed significantly greater intrusion at both the incisal tip (1.59 ± 1.53 mm) and the root apex (2.89 ± 1.59 mm) than did group A. In spite of the mean reduction of the vertical skeletal measurements, we failed to find significant skeletal changes., Conclusions: Miniscrews provided firm anchorage for anterior retraction. Selection of the placement site appeared to be an important determinant for the resultant displacement pattern of the incisor segment. Discriminative intrusion or retraction might be obtained via strategic miniscrew positioning., (Copyright © 2011 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)

This study evaluated the effects of blood contamination and decontamination methods during different steps of bonding procedures on the microtensile bond strength of two-step self-etch adhesives to dentin. Sixty extracted human molars were ground flat to expose occlusal dentin. The 60 molars were randomly assigned to three groups, each treated with a different two-step self-etch adhesive: Clearfil SE Bond, AdheSE and Tyrian SPE. In turn, these groups were subdivided into five subgroups (n = 20), each treated using different experimental conditions as follows: control group-no contamination; contamination group 1-CG1: primer application/ contamination/primer re-application; contamination group 2-CG2: primer application/contamination/wash/dry/primer re-application; contamination group 3-CG3: primer application/adhesive application/light curing/contamination/ adhesive re-application/light curing; contamina- tion group 4-CG4: primer application/adhesive application/light curing/contamination/wash/ dry/adhesive re-application/light curing. Composite buildup was performed using Z250. After 24 hours of storage in distilled water at 37 degrees C, the bonded specimens were trimmed to an hourglass shape and serially sectioned into slabs with 0.6 mm2 cross-sectional areas. Microtensile bond strengths (MTBS) were assessed for each specimen using a universal testing machine. The data were analyzed by two-way ANOVA followed by a post hoc LSD test. SEM evaluations of the fracture modes were also performed. The contaminated specimens showed lower bond strengths than specimens in the control group (p < 0.05), with the exception of CG1 in the Clearfil SE group and CG2 and CG3 in the Tyrian SPE group. Among the three self-etch adhesives, the Tyrian SPE group exhibited a significantly lower average MTBS compared to the Clearfil SE Bond and AdheSE (p < 0.05) groups. Based on the results of the current study, it was found that blood contamination reduced the MTBS of all three self-etch adhesives to dentin, and water-rinsing was unable to overcome the effects of blood contamination.

Introduction: The purpose of this study was to investigate the success rate of midpalatal miniscrews used for orthodontic anchorage and the factors affecting clinical success., Methods: One hundred twenty-eight consecutive patients (101 female, 27 male; mean age, 23.4 years), who received a total of 210 miniscrews in the midpalatal suture area, were examined. Success rates were determined according to 10 clinical variables., Results: The overall success rates were 88.20% for the total number of patients and 90.80% for the total number of miniscrews. There were no significant associations among success rate and sex, total period of treatment with miniscrews, diameter of miniscrews, types of tooth movements, and variables that represent sagittal and vertical skeletal relationships (ANB, FMA, and Sn-GoGn). The operator's learning curve, patient's age, area (midpalatal or parapalatal), and splinting significantly influenced the success rates. After adjusting for other variables, only 1- splinting-showed a significant effect on the success rate., Conclusions: The joining of 2 miniscrews by splinting, placement of the miniscrew in the midpalatal suture, patient's age (especially >15 years), and operator's skill were factors influencing the clinical success of orthodontic miniscrews in the palate., (Copyright 2010 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)

Many appliances are available to move maxillary molars distally. First molars have routinely been moved distally with nickel-titanium coil springs and nickel-titanium wire before the eruption of the second molars. However, when first molars are moved distally after the eruption of the second molars, they tend to move slowly, and anchorage loss increases. In adults, the midpalatal area is appropriate for placing titanium miniscrews for orthodontic anchorage. This case report demonstrates the ability of midpalatal miniscrews to control anchorage while distalizing the entire maxillary dentition in an adult, with improvements in lip profile resulting from the retraction of anterior teeth followed by a good response of the lips. This report suggests that absolute anchorage can be established by placing miniscrews in the palate and that miniscrew anchorage can serve as anchorage for the distal movement of an entire arch.

Objective: To determine the difference in the success rate for two types of oral installed mini-implants (OMIs): one type of initially installed OMI and a new implant of the same type that is reinstalled., Materials and Methods: The subjects consisted of 58 patients (19 male, 39 female; mean age = 21.78 +/- 5.85 years) who had received at least one OMI (self-drilling type, conical shape with 2.0-mm upper diameter and 5-mm length) in the attached gingiva of the upper buccal posterior regions for maximum anchorage during en masse retraction. If an OMI failed, a new one was immediately installed in the same area after 4 to 6 weeks or in an adjacent area immediately. The total number of initially installed OMIs (II-OMI) was 109 and the total number of reinstalled OMIs (RI-OMI) was 34. Statistical analysis was performed using chi2 test, Kaplan-Meier method, log-rank test, and Cox proportional hazards regression model., Results: The success rate and mean duration were 75.2% and 10.0 months, respectively, for II-OMI and 66.7% and 6.4 months, respectively, for RI-OMI. Age, vertical skeletal pattern, and site and side of implantation were not related to the success rates of II-OMI and RI-OMI. Log-rank test showed that II-OMI in males and Class III malocclusions were more prone to failure. The relative risk of II-OMI failure in Class III malocclusions as opposed to Class I malocclusions was 5.36 (95% confidence interval, 2.008 to 14.31, P = .001)., Conclusion: The success rate of the II-OMI was not statistically different from that of the RI-OMI. Sex and ANB angle might be more important factors for better II-OMI results.

Pharyngeal size and shape differences between pre- and posttrials of a mandible-protruding oral appliance were investigated using cine computerized tomography (CT). Fourteen patients diagnosed with obstructive sleep apnea whose apnea-hypopnea index was higher than 5 and arousal index higher than 20 underwent a second overnight sleep study to evaluate the effectiveness of the oral appliance. Three-dimensional changes in pharyngeal shape measured on cross-sectional CT images during two respiratory cycles after oral appliance delivery were estimated by three variables: (1) lateral dimension, (2) anterior-posterior dimension, and (3) cross-sectional area at five vertical levels. Apnea indices improved significantly when the appliance was used. During apnea, measurements at retropalatal and retroglossal levels decreased most. However, the cross-sectional area of these levels appeared to increase significantly (P < .05) with the appliance in place during wakefulness. The oral appliance appears to enlarge the pharynx to a greater degree in the lateral than in the sagittal plane at the retropalatal and retroglossal levels of the pharynx, suggesting a mechanism for the effectiveness of oral appliances that protrude the mandible.

The midpalatal suture area with thin, keratinized soft tissue and sufficient cortical bone is an optimal site for miniscrew implantation. Even though the midpalatal area has its own anatomical limitations, it can be overcome by bonding extension arms to the miniscrews. This technique also enhances screw stability, thus producing a successful outcome. Among many applications, midpalatal miniscrew implants can be effectively used for intrusion of upper molars with reduced treatment time and enhanced patient comfort.

Purpose: Recently, alveolar bone distraction has been widely used and several devices have been developed for this purpose. However, there are some disadvantages in each device, especially for distraction of posterior alveolar ridge. The purpose of this study was to develop a new device for vertical alveolar bone distraction at the molar region and to show the results of its clinical application., Materials and Methods: The mechanism of device is based on lag screw principle and the device consists of the following 4 components; distraction screw, hole implant fixture, supporting plate, and temporary short implant and/or neighboring natural teeth. The distraction screw suspended at the supporting plate is inserted into the internal thread of the hole implant fixture placed at alveolar transport segment. If the distraction screw turns at the supporting plate, the hole implant fixture with transport segment moves to the supporting plate without vertical movement of the screw at the supporting plate like a lag screw. After an animal experiment using 4 beagle dogs, the device was clinically applied in 4 patients before implant insertion., Results: The distraction of the alveolar bone could be successfully performed in all patients without any complications. The direction of distraction with this device could be adjustable, and the alveolar bone could be distracted not only vertically but also horizontally. Moreover, the surgical technique is simple with no need for a second surgery, and there is no occlusal disturbance from the device., Conclusions: The new device for alveolar bone distraction using lag screw principle can be used effectively in the molar region.

Chemiluminescence (CL) was observed during the oxidation of luminol (2 mg/L). mediated by 0.06% hydrogen peroxide (H(2)O(2)) and cytochrome c (10 mg/L). CL intensity was decreased by the presence of radical scavengers and the reduction was linearly proportional to the concentration and ability of scavengers; butylated hydroxytoluene (BHT), caffeic acid and gallic acid. The order of effectiveness as radical scavengers was gallic acid > caffeic acid > BHT, which shows that the number of hydroxyl groups (OH) in the B-ring of flavonoids plays a key role in a good radical scavenging activity. Of eight catechins obtained from green tea extracts, (-)-catechin was the least effective and (-)-epigallocatechin gallate (EGCg) showed the strongest activity. This result indicates that the stereoscopic structure between the C-3 group and the B ring of flavonoids as well as substituents at the C-3 position make a contribution to radical scavenging activity. Of the tested Chinese herbal ingredients, five species of ingredients represented more than 90% of the radical scavenging activity., (Copyright 2000 John Wiley & Sons, Ltd.)