De novo versus recurrent metastatic breast cancer affects the extent of brain metastases.

PURPOSE: We aimed to identify factors associated with the extent of brain metastases in patients with breast cancer to help distinguish brain oligometastases (1-4 brain metastases) from extensive metastases (5 or more brain metastases). METHODS: This retrospective observational study included 100 female patients diagnosed with brain metastases from breast cancer at a single institution between January 2011 and April 2022. Patient demographics and tumor characteristics were compared between the brain oligometastases group and the extensive metastases group. Multivariable logistic regression analysis was performed to determine the independent factors, including age at initial diagnosis, initial stage, breast cancer subtype, detection time of brain metastases, and de novo or recurrent status of the metastatic disease. In a subgroup analysis of patients with brain oligometastases, demographic and tumor characteristics were compared between patients with single and two-four brain metastases. RESULTS: Of the 100 patients, 56 had brain oligometastases, while 44 had extensive brain metastases. The multivariable logistic regression analysis revealed that only the de novo/recurrent status of metastatic breast cancer was significantly associated with the extent of brain metastasis (p = 0.023). In the subgroup analysis of 56 patients with brain oligometastases, those diagnosed at an earlier stage were more likely to have a single brain metastasis (p = 0.008). CONCLUSION: Patients with de novo metastatic breast cancer are more likely to develop extensive brain metastases than those with recurrent metastatic breast cancer. This insight could influence the development of tailored approaches for monitoring and treating brain metastases, supporting the potential advantages of routine brain screening for patients newly diagnosed with stage IV breast cancer.

Nigrosome 1 visibility and its association with nigrostriatal dopaminergic loss in Parkinson's disease.

BACKGROUND: Nigrosome 1 (NG1), a small cluster of dopaminergic cells in the substantia nigra and visible in the susceptibility map-weighted magnetic resonance image (SMwI), is severely affected in Parkinson's disease (PD). However, the degree of nigrostriatal degeneration according to the visibility of NG1 has not yet been well elucidated. METHODS: We consecutively recruited 138 PD and 78 non-neurodegenerative disease (non-ND) patients, who underwent both 18 F-FP-CIT positron emission tomography (PET) and SMwI. Three neurologists and one radiologist evaluated the visibility of NG1 in SMwI. The participants were thereby grouped into visible, intermediate, and non-visible groups. Nigrostriatal dopaminergic input was calculated using the specific binding ratio (SBR) of the 18 F-FP-CIT PET. We determined the threshold of regional SBR for discriminating NG1 visibility and the probability for NG1 visibility according to regional SBR. RESULTS: Visual rating of NG1 showed excellent interobserver agreements as well as high sensitivity and specificity to differentiate the PD group from the non-ND group. NG1 was visible in seven patients (5.1%) in the PD group, who had relatively short disease duration or less severe loss of striatal dopamine. The threshold of putaminal SBR reduction on the more affected side for the disappearance of NG1 was 45.5%, and the probability for NG1 visibility dropped to 50% after the reduction of putaminal SBR to 41% from the normal mean. CONCLUSIONS: Almost half loss of nigrostriatal dopaminergic input is required to dissipate the hyperintensity of NG1 on SMwI, suggesting its utility in diagnosing PD only after the onset of the motor symptoms.

Contrast-Enhanced Fluid-Attenuated Inversion Recovery in Neuroimaging: A Narrative Review on Clinical Applications and Technical Advances.

While contrast-enhanced fluid-attenuated inversion recovery (FLAIR) has long been regarded as an adjunct sequence to evaluate leptomeningeal disease in addition to contrast-enhanced T1-weighted imaging, it is gradually being used for more diverse pathologies beyond leptomeningeal disease. Contrast-enhanced FLAIR is known to be highly sensitive to low concentrations of gadolinium within the fluid. Accordingly, recent research has suggested the potential utility of contrast-enhanced FLAIR in various kinds of disease, such as Meniere's disease, seizure, stroke, traumatic brain injury, and brain metastasis, in addition to being used for visualizing glymphatic dysfunction. However, its potential applications have been reported sporadically in an unorganized manner. Furthermore, the exact mechanism for its superior sensitivity to low concentrations of gadolinium has not been fully understood. Rapidly developing magnetic resonance technology and unoptimized parameters for FLAIR may challenge its accurate application in clinical practice. This review provides the fundamental mechanism of contrast-enhanced FLAIR, systematically describes its current and potential clinical application, and elaborates on technical considerations for its optimization. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 5.

The role of apparent diffusion coefficient as a predictive factor for tumor recurrence in patients with cerebellopontine angle epidermoid tumor.

Intracranial epidermoid tumors are slowly growing benign tumors, but due to adjacent critical neurovascular structures, surgical resection is challenging, with the risk of recurrence. The apparent diffusion coefficient (ADC) has been used to evaluate the characteristics of brain tumors, but its utility for intracranial epidermoid tumors has not been specifically explored. This study analyzed the utility of preoperative ADC values in predicting tumor recurrence for patients with intracranial epidermoid tumors. Between 2008 and 2019, 21 patients underwent surgery for cerebellopontine angle (CPA) epidermoid tumor, and their preoperative ADC data were analyzed. The patients were divided into two groups: the recurrence group, defined by regrowth of the remnant tumor or newly developed mass after gross total resection on magnetic resonance imaging (MRI); and the stable group, defined by the absence of growth or evidence of tumor on MRI. Receiver operating characteristic (ROC) analysis was used to obtain the ADC cutoff values for predicting tumor recurrence. The prognostic value of the ADC was assessed using Kaplan-Meier curves. The minimum ADC values were significantly lower in the recurrence group than in the stable tumor group (P = 0.020). ROC analysis showed that a minimum ADC value lower than 804.5 × 10-6 mm2/s could be used to predict higher recurrence risk of CPA epidermoid tumors. Non-total resection and mean and minimum ADC values lower than the respective cutoffs were negative predictors of recurrence-free survival. Minimum ADC values could be useful in predicting the recurrence of CPA epidermoid tumors.

Interpretation of fluid-attenuated inversion recovery vascular hyperintensity in stroke.

Fluid-attenuation inversion recovery (FLAIR) vascular hyperintensity (FVH) is a common presentation on brain magnetic resonance images of patients with acute ischemic stroke. This sign is known as a sluggish collateral flow. Although FVH represents the large ischemic penumbra and collateral circulation, the clinical significance of FVH has not been established. Varying protocols for FLAIR, treatment differences, and heterogeneity of endpoints across studies have complicated the interpretation of FVH in patients with acute stroke. In this review article, we describe the mechanism of FVH, as well as its association with functional outcome, perfusion-weighted images, and large artery stenosis. In addition, we review the technological variables that affect FVH and discuss the future perspectives.

Intracranial Aneurysms Are Associated With Marfan Syndrome: Single Cohort Retrospective Study in 118 Patients Using Brain Imaging.

BACKGROUND AND PURPOSE: The association between intracranial aneurysms (IAs) and Marfan syndrome (MFS) is controversial. We aimed to evaluate the prevalence and characteristics of IAs in patients with MFS using brain imaging and compare it with the general population. METHODS: Between 2007 and 2020, 118 patients with confirmed MFS who underwent brain imaging were enrolled and classified into 2 groups; IA group versus non-IA. Demographic data were acquired from their medical records, including age, sex, comorbidities, and aortic diseases. Two readers reviewed all brain images independently regarding the presence, morphology, size, and location of IAs. All data were compared between both groups, and IA characteristics in MFS were analyzed using a database of controls with IAs. RESULTS: The prevalence of IAs was 11.9% in patients with MFS. IA group were significantly older in age (44.6±12.1 years in IA versus 36.8±14.0 years in non-IA, P=0.039) and had female predominance (71.4% in IA versus 43.3% in non-IA, P=0.047). All IAs were unruptured, and there was no subarachnoid hemorrhage during the follow-up period (mean; 53.5±43.3 months). The mean diameter of IAs was significantly larger (4.23±1.80 mm in MFS versus 3.04±1.57 mm in control, P=0.004). IAs with MFS were frequently located in the vertebrobasilar artery (33.3% in MFS versus 2.1% in control, P=0.002) and more common in fusiform morphology (13.3% in MFS versus 1.1% in control, P=0.048). CONCLUSIONS: This large-cohort study demonstrated a high prevalence and differential features of IAs in MFS, which may support the association between IAs and MFS.

Diffusion tensor and postcontrast T1-weighted imaging radiomics to differentiate the epidermal growth factor receptor mutation status of brain metastases from non-small cell lung cancer.

PURPOSE: To assess whether the radiomic features of diffusion tensor imaging (DTI) and conventional postcontrast T1-weighted (T1C) images can differentiate the epidermal growth factor receptor (EGFR) mutation status in brain metastases from non-small cell lung cancer (NSCLC). METHODS: A total of 99 brain metastases in 51 patients who underwent surgery or biopsy with underlying NSCLC and known EGFR mutation statuses (57 from EGFR wild type, 42 from EGFR mutant) were allocated to the training (57 lesions in 31 patients) and test (42 lesions in 20 patients) sets. Radiomic features (n = 526) were extracted from preoperative MR images including T1C and DTI. Radiomics classifiers were constructed by combinations of five feature selectors and four machine learning algorithms. The trained classifiers were validated on the test set, and the classifier performance was assessed by determining the area under the curve (AUC). RESULTS: EGFR mutation status showed an overall discordance rate of 12% between the primary tumors and corresponding brain metastases. The best performing classifier was a combination of the tree-based feature selection and linear discriminant algorithm and 5 features were selected (1 from ADC, 2 from fractional anisotropy, and 2 from T1C images), resulting in an AUC, accuracy, sensitivity, and specificity of 0.73, 78.6%, 81.3%, and 76.9% in the test set, respectively. CONCLUSIONS: Radiomics classifiers integrating multiparametric MRI parameters may have potential in differentiating the EGFR mutation status in brain metastases from NSCLC.

Significance of hyperintense arteries on Gd-enhanced 3D T1W black-blood imaging in acute stroke.

OBJECTIVES: To elucidate the pathogenesis of hyperintense arteries on Gd-enhanced 3D T1W BB FSE and their clinical significance in acute middle cerebral artery (MCA) stroke. METHODS: We retrospectively reviewed 20 patients with MCA infarction. We measured the contrast-to-noise ratio between hyperintense artery and adjacent grey matter on T2-FLAIR and Gd-enhanced 3D T1W BB FSE and compared them by using Student's t test. The agreement of positive hyperintense artery between T2 FLAIR and Gd-enhanced 3D T1WI BB FSE was estimated with intraclass correlation coefficient. Our cohort was dichotomised into two groups depending on hyperintense artery scores, and clinical data were compared between two groups by using Student's t test and chi-square test. RESULTS: The contrast between hyperintense artery and grey matter on Gd-enhanced 3D T1W BB FSE was significantly higher than that on T2-FLAIR (2.27 ± 1.65 versus 0.94 ± 0.86, p = 0.01). Overall, agreement of hyperintense arteries on T2-FLAIR and Gd-enhanced 3D T1W BB FSE was excellent (ρ = 0.76, p < 0.01). Patients with higher hyperintense artery scores had higher perfusion deficits that those with lower hyperintense artery scores (196.7 ± 41.4 vs 100.1 ± 130.1, p = 0.03). CONCLUSION: Hyperintense arteries on Gd-enhanced 3D T1W BB FSE in acute MCA stroke may be associated with slow collateral flows. Their territories corresponded to those of FLAIR, but had a better contrast. The patients with hyperintense arteries in a wider territory showed larger perfusion deficit than those with hyperintense arteries in a narrower territory. KEY POINTS: • Hyperintense arteries on Gd-enhanced 3D T1W BB FSE are slow collateral flows. • Hyperintense arteries on Gd-enhanced 3D T1W BB FSE are well matched with FLAIR hyperintense vessels. • Hyperintense arteries are associated with perfusion deficit in stroke patients.

Ecchordosis physaliphora: typical and atypical radiologic features.

Ecchordosis physaliphora (EP) is a distinct clinical entity defined as a notochordal remnant found on the dorsal surface of the clivus, occurring in about 2 % of autopsies. The aim of this study is to introduce typical and atypical imaging features of EP, which can be confused with those of clival chordoma. Forty-one patients with clinical suspicion for clival chordoma visited the outpatient clinic from June 2007 to August 2015. A retrospective review was performed with magnetic resonance imaging (MRI) and computed tomography (CT) studies to revise the diagnosis to EP. Eight of 41 patients (19.5 %) manifested lesions on the dorsal surface of the clivus that were well circumscribed and homogenous, with no septations or osteolysis. The lesions were all hypointense on T1, hyperintense on T2-weighted MRI, and had no enhancement with gadolinium. A distinct T2-hypointense pedicle, which is the hallmark of EP, was seen in five patients (62.5 %) and defined as typical EP. A characteristic T2-hypointense rim was observed in three patients and defined as atypical EP (37.5 %). The mean largest diameter of the lesions was 1.1 cm (0.6-1.8 cm). Lesion size did not change in all the patients who were followed for a mean of 3.6 years (1.4-8.2 years) by separate MRI scans performed every 6 months to 1 year. EP and clival chordoma represent different spectra of the same pathology. As the two lesions have completely different prognoses, precise knowledge of the imaging features of EP is very important. Accurate diagnosis is essential for proper treatment planning.

Niclosamide suppresses RANKL-induced osteoclastogenesis and prevents LPS-induced bone loss.

Niclosamide (5-chloro-salicyl-(2-chloro-4-nitro) anilide) is an oral anthelmintic drug used for treating intestinal infection of most tapeworms. Recently, niclosamide was shown to have considerable efficacy against some tumor cell lines, including colorectal, prostate, and breast cancers, and acute myelogenous leukemia. Specifically, the drug was identified as a potent inhibitor of signal transducer and activator of transcription 3 (STAT3), which is associated with osteoclast differentiation and function. In this study, we assessed the effect of niclosamide on osteoclastogenesis in vitro and in vivo. Our in vitro study showed that receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast differentiation was inhibited by niclosamide, due to inhibition of serine-threonine protein kinase (Akt) phosphorylation, inhibitor of nuclear factor-kappaB (IκB), and STAT3 serine(727). Niclosamide decreased the expression of the major transcription factors c-Fos and NFATc1, and thereafter abrogated the mRNA expression of osteoclast-specific genes, including TRAP, OSCAR, αv/ß3 integrin (integrin αv, integrin ß3), and cathepsin K (CtsK). In an in vivo model, niclosamide prevented lipopolysaccharide-induced bone loss by diminishing osteoclast activity. Taken together, our results show that niclosamide is effective in suppressing osteoclastogenesis and may be considered as a new and safe therapeutic candidate for the clinical treatment of osteoclast-related diseases such as osteoporosis.

MR imaging features that distinguish spinal cavernous angioma from hemorrhagic ependymoma and serial MRI changes in cavernous angioma.

Cavernous angiomas of the spinal cord exhibit imaging characteristics that may overlap with those of hemorrhagic ependymoma. In the present study, we aimed to identify specific magnetic resonance imaging (MRI) findings that could be used to differentiate cavernous angioma from hemorrhagic ependymoma, and to evaluate serial MRI changes in cases of cavernous angioma. We retrospectively evaluated MR images of spinal cord tumors collected at our hospital from 2007 to 2015. From this cohort of images, 11 pathologically confirmed cavernous angiomas and 14 pathologically confirmed hemorrhagic ependymomas were compared with respect to the size of the tumor, longitudinal location, axial location, enhancement pattern, syrinx, edema, tumor margin, signal intensity of T2WI, signal intensity of T1WI, and longitudinal spreading of the hemorrhage. Serial MR images of seven spinal cavernous angiomas were reviewed. Small size, eccentric axial location, minimal enhancement, and absence of edema were more frequently observed on images of cavernous angioma compared to those of hemorrhagic ependymoma (p < 0.01). Serial MRI changes in cases of cavernous angioma included increased longitudinal spreading of the hemorrhage (6/7, 86 %) and emergence of high signal intensity on T1WI (1/7, 14 %). Small size, eccentric axial location, minimal enhancement, and absence of edema are significant MRI findings that may be used to distinguish Type I and Type II spinal cavernous angiomas from hemorrhagic ependymomas. Furthermore, longitudinal spreading of the hemorrhage may be observed on follow-up MRIs of cavernous angiomas.

What is the impact of child abuse on gray matter abnormalities in individuals with major depressive disorder: a case control study.

BACKGROUND: Patients with major depressive disorder (MDD) present heterogeneous clinical symptoms, and childhood abuse is associated with deepening of psychopathology. The aim of this study was to identify structural brain abnormalities in MDD and to assess further differences in gray matter density (GMD) associated with childhood abuse in MDD. METHODS: Differences in regional GMD between 34 MDD patients and 26 healthy controls were assessed using magnetic resonance imaging and optimized voxel-based morphometry. Within the MDD group, further comparisons were performed focusing on the experience of maltreatment during childhood (23 MDD with child abuse vs 11 MDD without child abuse). RESULTS: Compared with healthy controls, the MDD patient group showed decreased GMD in the bilateral orbitofrontal cortices, right superior frontal gyrus, right posterior cingulate gyrus, bilateral middle occipital gyri, and left cuneus. In addition, the patient group showed increased GMD in bilateral postcentral gyri, parieto-occipital cortices, putamina, thalami, and hippocampi, and left cerebellar declive and tuber of vermis. Within the MDD patient group, the subgroup with abuse showed a tendency of decreased GMD in right orbitofrontal cortex, but showed increased GMD in the left postcentral gyrus compared to the subgroup without abuse. CONCLUSIONS: Our findings suggest a complicated dysfunction of networks between cortical-subcortical circuits in MDD. In addition, increased GMD in postcentral gyrus and a possible reduction of GMD in the orbitofrontal cortex of MDD patients with abuse subgroup may be associated with abnormalities of body perception and emotional dysregulation.

Can FLAIR hyperintense vessel (FHV) signs be influenced by varying MR parameters and flow velocities? A flow phantom analysis.

BACKGROUND: Fluid-attenuated inversion recovery (FLAIR) hyperintense vessels (FHVs) have been used to assess leptomeningeal collateral flow in acute ischemic stroke. However, prior FHVs studies showed inconsistent results, which may be ascribable to different magnetic resonance (MR) parameters used. PURPOSE: To evaluate whether FHVs could be influenced by varying MR parameters and flow velocities, using a flow phantom. MATERIAL AND METHODS: A total of 512 sets of FLAIRs were performed with varying parameters and flow velocities, using a flow phantom. Flow phantom was manufactured with 3.5% agarose solution, an 8-mm inner diameter silicone tube and non-pulsatile pump. Varying MR parameters were repetition time (TR)/inversion time (TI), echo time (TE), flip angle (FA) of refocusing pulse, and periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER). The signal intensity of flow were measured and regarded as the degree of FHVs. Simple and multiple linear regression analyses were applied to evaluate the association between the degree of FHVs and varying MR parameters as well as flow velocities. RESULTS: On univariate analysis, PROPELLER technique (R(2 )= 0.448) demonstrated strongest correlation with the degree of FHV, followed by flow velocities (R(2 )= 0.204), FA (R(2 )= 0.126), and TE (R(2 )= 0.031), whereas TR/TI showed no significant correlations. On multivariate analysis, TE, FA, PROPELLER technique, and flow velocities were independent factors influencing the degree of FHVs (<0.001). CONCLUSION: Flow velocities, FA of refocusing pulse, TE, and PROPELLER technique significantly affected the degree of FHVs. Optimized MR parameters should be used consistently in future studies, which may provide more reliable results.

Ethanolic extract of Schizonepeta tenuifolia attenuates osteoclast formation and activation in vitro and protects against lipopolysaccharide-induced bone loss in vivo.

BACKGROUND: Excessive osteoclast activity is a major cause of metabolic bone disorders, such as osteopenia, rheumatoid arthritis, and osteoporosis. Thus, discovery of agents targeting osteoclast differentiation and bone resorption is important for development of novel treatments for bone diseases. It has been demonstrated that ethanolic extract of schizonepeta tenuifolia (EEST) has potent anti-oxidant and anti-inflammatory activities. However, the beneficial effects of EEST on bone metabolism have not been studied. Therefore, we intend to investigate the effects of EEST on osteoclast differentiation. METHODS: We examined the effects and mechanisms of action of the EEST on osteoclastogenesis in vitro in bone marrow macrophages (BMMs) stimulated with receptor activator of nuclear factor kappa-B ligand (RANKL) and in vivo using a mouse model of lipopolysaccharide (LPS)-induced bone destruction. RESULTS: We found that EEST inhibited phosphorylation of Akt and IkB at early stages of RANKL-induced osteoclastogenesis. Furthermore, EEST negatively controlled the transcription and translation levels of nuclear factor of activated T cells c1 (NFATc1) and the translation level of c-Fos at the final stage of osteoclast differentiation. Reflecting these effects, EEST blocked both filamentous actin (F-actin) ring formation and bone resorbing activity of mature osteoclasts in vitro. The inhibitory effects of EEST on osteoclast formation and activity were observed in an LPS-mediated bone erosion mouse model using micro-CT and histological analysis. CONCLUSIONS: EEST is a potential agent that is able to treat osteoclast-related bone diseases, such as osteoporosis.

Protocatechuic Acid Attenuates Osteoclastogenesis by Downregulating JNK/c-Fos/NFATc1 Signaling and Prevents Inflammatory Bone Loss in Mice.

Protocatechuic acid (PCA) plays a critical role in nutritional metabolism; it is a major metabolite of anthocyanins, which are flavonoids with a range of health benefits. PCA has a variety of biological activities including anti-oxidant, antiinflammatory, anti-apoptosis, and anti-microbial activities. However, the pharmacological effect of PCA, especially on osteoclastogenesis, remains unknown. We examined the effect of PCA on receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation and bone resorption. PCA dose-dependently inhibited RANKL-induced osteoclast differentiation in mouse bone marrow macrophages (BMMs) and suppressed the bone-resorbing activity of mature osteoclasts. At the molecular level, PCA suppressed RANKL-induced phosphorylation of JNK among MAPKs only, without significantly affecting the early signaling pathway. PCA also suppressed RANKL-stimulated expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1) at the mRNA and protein levels, without altering c-Fos mRNA expression. Additionally, PCA down-regulated the expression of downstream osteoclastogenesis-related genes including ß3-integrin, DC-STAMP, OC-STAMP, Atp6v0d2, CTR, and CtsK. Mice treated with PCA efficiently recovered from lipopolysaccharide-induced bone loss in vivo. Thus, PCA inhibits RANKL-induced osteoclast differentiation and function by suppressing JNK signaling, c-Fos stability, and expression of osteoclastic marker genes. These results suggest that PCA could be useful in treatment of inflammatory bone disorders.

Dendrobium moniliforme Exerts Inhibitory Effects on Both Receptor Activator of Nuclear Factor Kappa-B Ligand-Mediated Osteoclast Differentiation in Vitro and Lipopolysaccharide-Induced Bone Erosion in Vivo.

Dendrobium moniliforme (DM) is a well-known plant-derived extract that is widely used in Oriental medicine. DM and its chemical constituents have been reported to have a variety of pharmacological effects, including anti-oxidative, anti-inflammatory, and anti-tumor activities; however, no reports discuss the beneficial effects of DM on bone diseases such as osteoporosis. Thus, we investigated the relationship between DM and osteoclasts, cells that function in bone resorption. We found that DM significantly reduced receptor activator of nuclear factor kappa-B ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation; DM directly induced the down-regulation of c-Fos and nuclear factor of activated T cells c1 (NFATc1) without affecting other RANKL-dependent transduction pathways. In the later stages of osteoclast maturation, DM negatively regulated the organization of filamentous actin (F-actin), resulting in impaired bone-resorbing activity by the mature osteoclasts. In addition, micro-computed tomography (µ-CT) analysis of the murine model revealed that DM had a beneficial effect on lipopolysaccharide (LPS)-mediated bone erosion. Histological analysis showed that DM attenuated the degradation of trabecular bone matrix and formation of TRAP-positive osteoclasts in bone tissues. These results suggest that DM is a potential candidate for the treatment of metabolic bone disorders such as osteoporosis.

Esculetin attenuates receptor activator of nuclear factor kappa-B ligand-mediated osteoclast differentiation through c-Fos/nuclear factor of activated T-cells c1 signaling pathway.

Esculetin exerts various biological effects on anti-oxidation, anti-tumors, and anti-inflammation. However, the involvement of esculetin in the bone metabolism process, particularly osteoclast differentiation has not yet been investigated. In the present study, we first confirmed the inhibitory effect of esculetin on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation. We then revealed the relationship between esculetin and the expression of osteoclast-specific molecules to elucidate its underlying mechanisms. Esculetin interfered with the expression of c-Fos and nuclear factor of activated T cell c1 (NFATc1) both at the mRNA and protein level with no involvement in osteoclast-associated early signaling pathways, suppressing the expression of various transcription factors exclusively expressed in osteoclasts such as tartrate-resistant acid phosphatase (Trap), osteoclast-associated receptor (Oscar), dendritic cell-specific transmembrane protein (Dcstamp), osteoclast stimulatory transmembrane protein (Ocstamp), cathepsin K, αvß3 integrin, and calcitonin receptor (Ctr). Additionally, esculetin inhibited the formation of filamentous actin (F-actin) ring-positive osteoclasts during osteoclast differentiation. However, the development of F-actin structures and subsequent bone resorbing activity of mature osteoclasts, which are observed in osteoclast/osteoblast co-culture systems were not affected by esculetin. Taken together, our results indicate for the first time that esculetin inhibits RANKL-mediated osteoclastogenesis via direct suppression of c-Fos and NFATc1 expression and exerts an inhibitory effect on actin ring formation during osteoclastogenesis.

Herniated Lumbar Disks: Real-time MR Imaging Evaluation during Continuous Traction.

PURPOSE: To assess the morphologic changes in herniated lumbar intervertebral disks and surrounding structures during lumbar traction by using real-time magnetic resonance (MR) imaging. MATERIALS AND METHODS: This prospective study was approved by the institutional review board, and written informed consent was obtained from all participants. Forty-eight consecutive patients with lumbar disk herniation (13 men and 35 women) were treated with continuous lumbar traction by using a nonmagnetic traction device. Real-time MR imaging of the lumbar spine was performed before the initiation of traction and at 10-minute intervals during 30 minutes of 30 kg of continuous traction. Sagittal and axial MR images were analyzed to determine qualitative changes during lumbar traction. Quantitative changes caused by traction on the lumbar spine were determined by measurement of lumbar vertebral column elongation and the disk reduction ratio. RESULTS: Continuous traction on herniated lumbar disks and surrounding structures resulted in change in disk shape, disk reduction with opening in the intervertebral disk, reduction of herniated disk volume, separation of the disk and adjoining nerve root, and widening of the facet joint. Both the mean lumbar vertebral column length (elongation of 1.45% after 30 minutes, P < .001) and the mean disk reduction ratio (8.57%, 15.24%, and 17.94% after 10, 20, and 30 minutes of traction, respectively) increased with time of traction. CONCLUSION: The results of this study demonstrated that the real-time effects of continuous traction on herniated lumbar intervertebral disks and their surrounding structures can be visualized by using MR imaging.

Cerebral computed tomography angiography using a 70 kVp protocol: improved vascular enhancement with a reduced volume of contrast medium and radiation dose.

OBJECTIVES: To determine the feasibility of using a 70-kVp protocol compared with a 120-kVp protocol for cerebral CT angiography. An additional target was to investigate a possible reduction in the volume of contrast medium (CM) using the 70-kVp protocol. METHODS: Attenuation value and CNR for iodine were determined at various tube voltage settings using a phantom. Sixty-nine volunteers were randomly assigned to one of three protocols: group A (120-kVp and CM 64 mL), group B (70-kVp and CM 64 mL), or group C (70-kVp and CM 40 mL). The attenuation value, SNR, and CNR of cerebral arteries, subjective image quality, and radiation dose were compared among the groups. RESULTS: The vascular attenuation, SNR, and CNR of group B were significantly higher than those of group A. Group C had a significantly higher vascular attenuation than group A. Groups B and C were significantly better than group A with respect to subjective image quality. An effective dose of 70-kVp was 10 % lower than that of 120-kVp. CONCLUSIONS: Using 70-kVp improved arterial enhancement, SNR, and CNR, and provided better subjective image quality, using a 10 % lower effective dose. Furthermore, the 70-kVp protocol may both reduce volume of CM by 37.5 % and improve arterial enhancement. KEY POINTS: • Cerebral CT angiography at 70-kVp substantially improved vascular enhancement • Subjective image quality was better at 70-kVp, with lower radiation dose • The volume of contrast media can be substantially reduced at 70-kVp.

Stauntonia hexaphylla (Lardizabalaceae) leaf methanol extract inhibits osteoclastogenesis and bone resorption activity via proteasome-mediated degradation of c-Fos protein and suppression of NFATc1 expression.

BACKGROUND: Natural plants, including common vegetables and fruits, have been recognized as essential sources for drug discovery and the development of new, safe, and economical medicaments. Stauntonia hexaphylla (Lardizabalaceae) is widely distributed in Korea, Japan, and China, and is a popular herbal supplement in Korean and Chinese folk medicine owing to its analgesic, sedative, and diuretic properties. However, the exact pharmacological effects of S. hexaphylla extract, particularly its effect on osteoclastogenesis, are not known. METHODS: Osteoclast differentiation and function were identified with tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assay, and the underling mechanisms were determined by real-time RT-PCR and western blot analysis. RESULTS: S. hexaphylla was found to inhibit early-stage receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-mediated osteoclast differentiation in bone marrow macrophages (BMMs) without cytotoxicity and bone-resorbing activity in mature osteoclasts in a dose-dependent manner. This S. hexaphylla-mediated blockade of osteoclastogenesis involved abrogation of the NF-κB, ERK, and c-Src-Btk-PLCγ2 calcium signal pathways. Interestingly, we found that S. hexaphylla down-regulated RANKL-associated c-Fos protein induction by suppressing its translation. Furthermore, ectopic overexpression of c-Fos and NFATc1 rescued the inhibition of osteoclast differentiation by S. hexaphylla. Furthermore, S. hexaphylla inhibited the c-Fos- and NFATc1-regulated expression of genes required for osteoclastogenesis, such as TRAP, OSCAR, ß3-integrin, ATP6v0d2, and CtsK. CONCLUSIONS: These findings suggest that S. hexaphylla might be useful for the development of new anti-osteoporosis agents.