Dasatinib, a selective tyrosine kinase inhibitor, prevents joint destruction in rheumatoid arthritis animal model.

AIM: We aimed to evaluate the preventive role of the tyrosine kinase inhibitor dasatinib in an animal model of rheumatoid arthritis (RA). METHODS: DBA/1J mice were injected with bovine type II collagen to induce arthritis (collagen-induced arthritis [CIA]). There were four experimental groups of mice, namely negative control (non-CIA), vehicle-treated CIA, dasatinib-pretreated CIA, and dasatinib-treated CIA. After collagen immunization, arthritis progression in the mice was clinically scored twice weekly for 5 weeks. Flow cytometry was used to evaluate in vitro CD4+ T-cell differentiation and ex vivo mast cell/CD4+ T-cell differentiation. Osteoclast formation was evaluated using tartrate-resistant acid phosphatase (TRAP) staining and by estimating the resorption pit area. RESULTS: We found that the clinical arthritis histological scores were lower in the dasatinib pretreatment group than in the vehicle and dasatinib post-treatment groups. Flow cytometry showed that FcεR1+ cells were downregulated and regulatory T cells were upregulated in splenocytes of the dasatinib pretreatment group compared with those in the vehicle group. Additionally, there was a decline in IL-17+ CD4+ T-cell differentiation and an increase in CD4+ CD24high Foxp3+ T-cell differentiation with in vitro dasatinib treatment of human CD4+ T cells. The number of TRAP+ osteoclasts and the area of the resorption were decreased in the bone marrow cells derived from dasatinib-pretreated mice compared with those derived from vehicle group. CONCLUSION: Dasatinib protected against arthritis in an animal model of RA by regulating the differentiation of regulatory T cells and IL-17+ CD4+ T cells and inhibiting osteoclastogenesis, indicating the therapeutic potential of dasatinib in the treatment of early RA.

Comparison between oxaliplatin therapy and capecitabine monotherapy for high-risk stage II - III elderly patients with colon cancer.

PURPOSE: 45% of colon cancer patients are elderly, yet they are often deviated from standard cancer management. The MOSAIC trial favored FOLFOX over FL with superior oncologic outcomes; however, which regimen is most beneficial in elderly population remains unclear. This study aimed to compare the efficacy of oxaliplatin-added chemotherapy and capecitabine monotherapy in high-risk stage II/stage III elderly colon cancer patients. METHODS: Colon cancer patients ≥70 years of age who received adjuvant chemotherapy at Inje University Busan Paik Hospital between February 2009 to April 2016 were included. Patients were separated into the oxaliplatin-added group and capecitabine monotherapy group. The primary outcomes were CSS and OS. RESULTS: Of 74 patients, 45 received oxaliplatin-added chemotherapy and 29 received capecitabine monotherapy. There was no difference between the two groups in CSS or OS (p = 0.9670 and p = 0.6801, respectively). The N stage was significantly associated with CSS in both uni/multivariate analysis (p = 0.0565 and p = 0.0347, respectively). The oxaliplatin-added group had more stage III patients, so we performed a subgroup analysis of CSS and OS based on stage, which also showed no significant difference. CONCLUSIONS: Capecitabine monotherapy is an oncologically safe regimen compared to oxaliplatin-added regimens in elderly patients with high-risk stage II/stage III colon cancer.

Microscale Physiological Events on the Human Cortical Surface.

Despite ongoing advances in our understanding of local single-cellular and network-level activity of neuronal populations in the human brain, extraordinarily little is known about their "intermediate" microscale local circuit dynamics. Here, we utilized ultra-high-density microelectrode arrays and a rare opportunity to perform intracranial recordings across multiple cortical areas in human participants to discover three distinct classes of cortical activity that are not locked to ongoing natural brain rhythmic activity. The first included fast waveforms similar to extracellular single-unit activity. The other two types were discrete events with slower waveform dynamics and were found preferentially in upper cortical layers. These second and third types were also observed in rodents, nonhuman primates, and semi-chronic recordings from humans via laminar and Utah array microelectrodes. The rates of all three events were selectively modulated by auditory and electrical stimuli, pharmacological manipulation, and cold saline application and had small causal co-occurrences. These results suggest that the proper combination of high-resolution microelectrodes and analytic techniques can capture neuronal dynamics that lay between somatic action potentials and aggregate population activity. Understanding intermediate microscale dynamics in relation to single-cell and network dynamics may reveal important details about activity in the full cortical circuit.

Regulation of Th17 Cytokine-Induced Osteoclastogenesis via SKI306X in Rheumatoid Arthritis.

This study aimed to investigate the regulatory effect of SKI305X, a mixed extract of three herbs, in T helper (Th)17 cytokine-induced inflammation and joint destruction in rheumatoid arthritis (RA). Synovial fibroblasts were isolated from RA patients and cultured with Th17 cytokines including interleukin (IL)-17, IL-21, and IL-22 and SKI306X, and tumor necrosis factor (TNF)-, IL-1, and receptor activator of nuclear factor kappa-Β ligand (RANKL) expression and production were investigated using real-time PCR and ELISA of culture media. After peripheral blood (PB) cluster of differentiation (CD)14+ monocytes were cultured in media supplemented with Th17 cytokines and SKI306X, tartrate-resistant acid phosphatase positive (TRAP+) multinucleated giant cells (mature osteoclasts) were enumerated and gene expression associated with osteoclast maturation was assessed via real-time PCR analysis. After PB monocytes were co-cultured with IL-17-stimulated RA synovial fibroblasts in the presence of SKI306, osteoclast differentiation was assessed. When RA synovial fibroblasts were cultured with IL-17, IL-21, and IL-22, TNF-, IL-1, and RANKL expression and production were increased; however, SKI306X reduced cytokine expression and production. When PB monocytes were cultured in media supplemented with Th17 cytokines, osteoclast differentiation was stimulated; however, SKI306X decreased osteoclast differentiation and osteoclast maker expression. When PB monocytes were co-cultured with IL-17-stimulated RA synovial fibroblasts, osteoclast differentiation was increased; however, SKI306X decreased osteoclast differentiation and osteoclast maker expression. SKI306X reduced Th17 cytokine-induced TNF-, IL-1, and RANKL expression and osteoclast differentiation, providing novel insights into adjuvant therapy for regulating inflammation and joint destruction in RA.

Quercetin, a Plant Polyphenol, Has Potential for the Prevention of Bone Destruction in Rheumatoid Arthritis.

We investigated the immune-regulatory function of quercetin, in interleukin (IL)-17-produced osteoclastogenesis in rheumatoid arthritis (RA). RA fibroblasts-like synoviocytes (RA-FLS) were stimulated with IL-17, and the mRNA expression and secretion of receptor activator of nuclear factor kappa-B ligand (RANKL) were detected by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. CD14+ monocytes (osteoclast precursors) were stimulated with IL-17, RANKL, with/without quercetin, and tartrate-resistant acid phosphatase activity was evaluated to assess osteoclast differentiation. Osteoclast differentiation was investigated after coculturing IL-17-stimulated RA-FLS and Th17 cells with monocytes. CD4+ T cells were cocultured with quercetin under Th17-inducing conditions, and their differentiation to Th17 cells and Treg cells was determined by flow cytometry analysis. We found that IL-17 stimulated RA-FLS to produce RANKL and quercetin decreased the IL-17-induced RANKL protein levels. Quercetin decreased the IL-17-produced activation of mammalian target of rapamycin, extracellular signal-regulated kinase and inhibitor of kappa B-alpha. When monocytes were stimulated with IL-17, macrophage colony-stimulating factor or RANKL, mature osteoclasts were formed, and quercetin decreased this osteoclastogenesis. When monocytes were cultured with IL-17-prestimulated RA-FLS or Th17 cells, osteoclasts were produced, and quercetin decreased this osteoclast differentiation. In Th17-differentiation conditions, quercetin suppressed Th17 cell and the production of IL-17, but quercetin did not affect Treg cells. Quercetin inhibits IL-17-stimulated RANKL production in RA-FLS and IL-17-stimulated osteoclast formation. Quercetin reduces Th17 differentiation. Quercetin could be an additional therapeutic option for bone destructive processes in RA.

N-acetyl-l-cysteine controls osteoclastogenesis through regulating Th17 differentiation and RANKL production in rheumatoid arthritis.

BACKGROUND/AIMS: This study aimed to determine the regulatory role of N-acetyl-l-cysteine (NAC), an antioxidant, in interleukin 17 (IL-17)-induced osteoclast differentiation in rheumatoid arthritis (RA). METHODS: After RA synovial fibroblasts were stimulated by IL-17, the expression and production of receptor activator of nuclear factor κ-B ligand (RANKL) was determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). Osteoclastogenesis was also determined after co-cultures of IL-17-stimulated RA synovial fibroblasts, Th17 cells and various concentrations of NAC with monocytes. After human peripheral CD4+ T cells were cultured with NAC under Th17 condition, IL-17, interferon γ, IL-4, Foxp3, RANKL, and IL-2 expression and production was determined by flow cytometry or ELISA. RESULTS: When RA synovial fibroblasts were stimulated by IL-17, IL-17 stimulated the production of RANKL, and NAC reduced the IL-17-induced RANKL production in a dose-dependent manner. NAC decreased IL-17-activated phosphorylation of mammalian target of rapamycin, c-Jun N-terminal kinase, and inhibitor of κB. When human peripheral blood CD14+ monocytes were cultured with macrophage colony-stimulating factor and IL-17 or RANKL, osteoclasts were differentiated, and NAC reduced the osteoclastogenesis. After human peripheral CD4+ T cells were co-cultured with IL-17-pretreated RA synovial fibroblasts or Th17 cells, NAC reduced their osteoclastogenesis. Under Th17 polarizing condition, NAC decreased Th17 cell differentiation and IL-17 and RANKL production. CONCLUSION: NAC inhibits the IL-17-induced RANKL production in RA synovial fibroblasts and IL-17-induced osteoclast differentiation. NAC also reduced Th17 polarization. NAC could be a supplementary therapeutic option for inflammatory and bony destructive processes in RA.

A self-determination theory-based self-myofascial release program in older adults with myofascial trigger points in the neck and back: A pilot study.

PURPOSE: To examine the effectiveness and adherence to a self-determination theory (SDT)-based self-myofascial release (SMR) program in older adults with myofascial trigger points (MTrPs), and to investigate the factors that influence participant behavioral change while conducting the program in a home setting. METHODS: An explanatory mixed-method design was used to evaluate a 12-week SDT-based SMR program, including a 4-week group-based education and practice (EP) phase and an 8-week home-based self-management (SM) phase. Pain intensity on palpation and sensitivity to pain were assessed at baseline and the post EP and post SM phase. Focus group interviews were conducted at the post SM phase. FINDINGS: Fifteen participants completed the study. Pain intensity and sensitivity to pain significantly improved at the post SM phase compared with the baseline. Adherence increased during the SM phase compared with that during the EP phase. Four main themes emerged as factors that influenced participant behavioral change: 1) "awareness of the effectiveness"; 2) "a sense of duty to perform the exercise"; 3) "obedience to expert instruction"; and 4) "lack of friendship." CONCLUSIONS: These results support the effectiveness of an SDT-based SMR program for the treatment of MTrPs and in motivating older adults to participate in the program.

Preclinical efficacy and safety assessment of nano-oxaliplatin oral formulation prepared by novel Fat Employing Supercritical Nano System, the FESNS®.

BACKGROUND: It is expected that oral cancer drug will provide ease of administration with decreased unwanted events to the patients. The purpose of this study is to prepare oral formulation of nano-oxaliplatin and examine the anticancer efficacy and safety. Nano-oxaliplatin was prepared utilizing our proprietary technology, the Fat Employing Supercritical Nano System (FESNS(®)). RESULT: It showed regular nanoparticles with a mean diameter of around 212 nm. When nano-oxaliplatin was orally administered in rats, the relative bioavailability of nano-oxaliplatin oral formulations was about 25-31% compared to the Eloxatin(®) administered intravenously (i.v.). For antitumor activity in xenograft model, nano-oxaliplatin oral formulation (20 mg/kg, once daily) presented superior inhibition of tumor growth against Eloxatin(®) (5 mg/kg, i.v. once a week). In single-dose toxicity, dead animals were observed at or above 1000 mg/kg (LD(50): 888.38 mg/kg for male; 725.43 mg/kg for female rats). In repeated dose toxicity, there were hematological changes observed in rats, which is a common finding in the class of cancer drugs. It was thought that the expected dose level that has cytotoxic effect without death would be 30 mg/kg in rats, which is double the dose level of Eloxatin(®). CONCLUSION: Nano-oxaliplatin oral formulation changed the pharmacokinetic behavior of crude oxaliplatin, thus increasing oral bioavailability as well as its anticancer activity. In addition, single and repeated dose toxicity studies indicated that oral nano-oxaliplatin is superior in toxicity at the pharmacologically active doses compared to Eloxatin(®) in rats. Nano-oxaliplatin oral formulation has potential as a novel anticancer therapy.

[Involvement of splenic hemangioma and rectal varices in a patient with klippel: trenaunay syndrome].

Klippel - Trenaunay syndrome (KTS) is characterized by a cutaneous vascular nevus of the involved extremity, bone and soft tissue hypertrophy of the extremity and venous malformations. We present a case of KTS with splenic hemangiomas and rectal varices. A 29-year-old woman was referred for intermittent hematochezia for several years. She had history with a number of operations for cutaneous and soft tissue hamangiomas since the age of one year old and for increased circumference of her left thigh during the last few months. Abdominal CT revealed multiple hemangiomas in the spleen, fusiform aneurysmal dilatation of the deep veins and soft tissue hemangiomas. There was no evidence of hepatosplenomegaly or liver cirrhosis. Colonoscopy revealed hemangiomatous involvement in the rectum. There were rectal varices without evidence of active bleeding. Upon venography of the left leg, we also found infiltrative dilated superficial veins in the subcutaneous tissue and aneurysmal dilatation of the deep veins. The patient was finally diagnosed with KTS, and treated with oral iron supplementation only, which has been tolerable to date. Intervention or surgery is not required. When gastrointestinal varices or hemangiomatous mucosal changes are detected in a young patient without definite underlying cause, KTS should be considered.

Intervertebral disc degeneration-induced expression of pain-related molecules: glial cell-derived neurotropic factor as a key factor.

BACKGROUND: Discogenic low back pain has been shown to develop into chronic intractable pain due to an unknown pathogenesis. To study the mechanism of discogenic pain, we analyzed the serial expression of pain-related molecules in the dorsal root ganglia (DRG) and thalamus using a newly developed rat model of disc degeneration. METHODS: Ten microliters of complete Freund's adjuvant was injected into the L5-6 disc of male Sprague-Dawley rats for 10 minutes using a 26-gauge needle. Using a behavioral test, rats with significant pain were selected and subsequently serial gene expression of pain-related molecules in the DRG and the thalamus was analyzed by reverse transcriptase polymerase chain reaction. RESULTS: The expression of tumor necrosis factor-α and interleukin-1ß significantly increased at 4 and 8 weeks in the DRG of rats with pain. Furthermore, interleukin-6 was significantly increased at 4 weeks in the DRG; however, these cytokines did not show a significant change in the thalamus. Calcitonin gene-related peptide and substance P were significantly increased in DRG at 4 and 8 weeks and in the thalamus at 2 and 4 weeks. The level of nerve growth factor-ß did not significantly increase in the DRG or thalamus, whereas glial cell line-derived neurotropic factor (GDNF) was significantly increased at 2 weeks and was sustained through 8 weeks in both the DRG and thalamus. CONCLUSIONS: The disc degeneration rat model described herein led to significant pain of a chronic nature. The gradual and persistent increase of GDNF in both the thalamus and DRG suggests that GDNF might be a key factor in the development of intractable, chronic discogenic pain.

Kinematic analysis of the lumbar spine by digital videofluoroscopy in 18 asymptomatic subjects and 9 patients with herniated nucleus pulposus.

OBJECTIVES: The purpose of this study was to use digital videofluoroscopy to identify motion patterns of the lumbar spine during coronal movement in asymptomatic (normal) subjects and patients with herniated nucleus pulposus (HNP). METHODS: Videofluoroscopic lumbar coronal motion was recorded in 18 asymptomatic volunteers and 9 patients with HNP. Measurements were made while patients bent laterally and rotated toward the right and left from a sitting position and then returned to their original position. Direction and degree of extension in the coronal plane at each motion segment and sacral descent were measured. Through the motion analysis software, the coupled pattern with lateral bending and rotation was analyzed in the asymptomatic subjects and patients with HNP. RESULTS: Lateral flexion movement was coupled with contralateral extension and ipsilateral sacral descent but with a different rotation pattern. Rotation movement was coupled with ipsilateral extension, ipsilateral sacral descent, and ipsilateral spinous process rotation. Patients with HNP and asymptomatic subjects had similar coupled patterns but differences in amount of motion. CONCLUSIONS: Digital videofluoroscopy showed coupled patterns during the lateral bending and rotation movements.

The efficacy of two electrodes radiofrequency technique: comparison study using a cadaveric interspinous ligament and temperature measurement using egg white.

BACKGROUND: One technique in radiofrequency neurotomies uses 2 electrodes that are simultaneously placed to lie parallel to one another. Comparing lesions on cadaveric interspinous ligament tissue and measuring the temperature change in egg white allows us to accurately measure quantitatively the area of the lesion. METHODS: Fresh cadaver spinal tissue and egg white tissue were used. A series of samples were prepared with the electrodes placed 1 to 7 mm apart. Using radiofrequency, the needle electrodes were heated in sequential or simultaneous order and the distance of the escaped lesion area and temperature were measured. RESULTS: Samples of cadaver interspinous ligament showed sequential heating of the needles limits the placement of the needle electrodes up to 2 mm apart from each other and up to 4 mm apart when heated simultaneously. The temperature at the escaped lesion area decreased according to the distance for egg white. There was a significant difference in temperature at the escaped lesion area up to 6 mm apart and the temperature was above 50 degrees celsius up to 5 mm in simultaneous lesion and 3 mm in the sequential lesion. LIMITATIONS: The limitations of this study include cadaveric experimentation and use of intraspinous ligament rather than medial branch of the dorsal ramus which is difficult to identify. CONCLUSION: Heating the 2 electrodes simultaneously appears to coagulate a wider area and potentially produce better results in less time.

Synergistic effects of the combination of 20-hydroxyecdysone with ampicillin and gentamicin against methicillin-resistant Staphylococcus aureus.

The emergence of methicillin-resistant of Staphylococcus aureus (MRSA) has led to an urgent need for the discovery and development of new antibacterial agents. As part of an ongoing investigation into the antibacterial properties of the natural products, 20-Hydroxyecdysone (20E), isolated from the roots of Achyranthes japonica Nakai, was found to be active methicillin-resistant Staphylococcus aureus (MRSA), either alone or in combination with ampicillin (AM) or gentamicin (GM), vis checkerboard assay. This study investigated the antibacterial activity of 20E, which exhibited poor antibacterial activity (MIC=250-500 microg/mL) against all the bacterial strains tested. The combined activity of ampicillin (AM), gentamicin (GE) plus 20E against MRSA resulted in fractional inhibitory concentrations (FICs) ranging from 4.00 to 0.031 microg/mL, respectively. Meanwhile, the FIC index ranged from 0.16-4.50, indicating a marked synergistic relationship between AM, GE and 20E against MRSA with enterotoxin gene. Time-kill assays also showed a decrease remarkably between the combination and the more active compound. Therefore, this study demonstrated that AM, GE, and 20E can act synergistically in inhibiting MRSA in vitro.

Transient receptor potential V2 expressed in sensory neurons is activated by probenecid.

Temperature-activated transient receptor potential ion channels (thermoTRPs) are known to function as ambient temperature sensors and are also involved in peripheral pain sensation. The thermoTRPs are activated by a variety of chemicals, of which specific activators have been utilized to explore the physiology of particular channels and sensory nerve subtypes. The use of capsaicin for TRPV1 is an exemplary case for nociceptor studies. In contrast, specific agents for another vanilloid subtype channel, TRPV2 have been lacking. Here, we show that probenecid is able to activate TRPV2 using electrophysiological and calcium imaging techniques with TRPV2-expressing HEK293T cells. Five other sensory thermoTRPs-TRPV1, TRPV3, TRPV4, TRPM8 and TRPA1-failed to show a response to this drug in the same heterologous expression system, suggesting that probenecid is a specific activator for TRPV2. Probenecid-evoked responses were also reproduced in a distinct subset of cultured trigeminal neurons that were responsive to 2-aminoethoxydiphenyl borate, a TRPV1-3 activator. The probenecid-sensitive neurons were mainly distributed in a medium to large-diameter population, in agreement with previous observations with TRPV2 immunolocalization. Under inflammation, probenecid elicited nociceptive behaviors in in vivo assays. These results suggest that TRPV2 is specifically activated by probenecid and that this chemical might be useful for investigation of pain-related TRPV2 function.

A factor analysis of lumbar intradiscal electrothermal annuloplasty outcomes.

BACKGROUND CONTEXT: Intradiscal electrothermal annuloplasty (IDET) is a minimally invasive procedure for managing chronic discogenic low back pain (LBP). Although there have been numerous reports of IDET outcome rates, few have dissected the detailed factors affecting those outcomes. PURPOSE: To evaluate how heating variables and the number of catheters used affect the outcomes and pain flare-up in LBP patients treated with IDET. STUDY DESIGN/SETTING: Retrospective analysis. PATIENT SAMPLE: Data were gathered on the basis of chart records from January 6, 1999 to January 6, 2000. Twenty-five cases treated at a single level with disc protrusion < or = 2 mm, nonfocal neurological abnormalities, and positive discogram with annular tear were studied. Six patients were unavailable for follow-up at 16 months. OUTCOME MEASURES: All assessments were incorporated into our own evaluation sheet, completed before the procedure and at follow-up. Assessments included the following: 1) Visual Analog Scale (VAS) and 2) Back Pain Improvement Scales (BPI) preoperatively and at 8 and 16 months post-procedure. Post-procedure flare-up of the pain was defined as the pain aggravation after the IDET procedure from the pre-procedure baseline pain. It was evaluated by a 10-point numeric rating scale, ranging from no aggravated pain "0" to the worst aggravated pain "10". METHODS: Patients were partitioned into a single-catheter group and a double-catheter group. In these two groups, statistical analyses were done to compare the outcomes and flare-up duration and intensity. In each catheter group, the correlation coefficients were analyzed between heating variables such as heating duration/temperature and two outcome scales. Then, two outcome scales relative to intensity and duration of post-IDET flare-up were analyzed with Pearson's correlation. Also the combined effect of the heating duration and temperature was evaluated as a thermal dosage, which is the total amount of heat developed during the procedure. It was calculated by multiplying the temperature and its heating duration above a starting temperature of 65 degrees C. RESULTS: Comparing the single- and double-catheter groups, patients placed in the single-catheter group showed significantly shorter flare-up duration (11.00+/-19.17 vs. 24.89+/-20.84 days, p < .05). In the single-catheter group, the flare-up duration manifested moderate linear correlation with heating variables (0.580 with temperature, 0.519 with thermal dosage, p < .05). Also, the improvements of pain with VAS displayed moderate reverse correlation with heating variables at 8 months (-.436 with temperature, -0.439 with thermal dosage, p < .1). In the double-catheter group, the Back Pain Improvement% had strong reverse correlations with temperature and thermal dosage at 8 months (-.735 and -.729, p < .05). The correlation between the improvement of VAS and temperature yielded a moderate reverse relationship (-.619, p < 0.1). These correlations were not, however, observed at 16 months in either the single- or double-catheter groups. CONCLUSIONS: Higher temperatures and larger total heating doses during IDET procedures with catheters placed in the outer annulus may increase the duration of post-procedure pain flare-ups and lead to less favorable outcomes at 8 months follow-up. The long-term outcomes at 16 months may, however, not be affected by these heating variables.

Percutaneous disc decompression in the management of chronic low back pain.

Although there has not yet been a percutaneous intradiscal procedure developed with the superior therapeutic efficacy of open surgery, these procedures are less invasive and avoid the complications of open surgery. All of these procedures have limitations, but their therapeutic effect increases substantially given careful patient selection and proper technique. New appliances and techniques to treat LBP or sciatica continue to evolve, and numerous controlled studies are underway. With tremendous technologic advances, use of minimally invasive techniques to treat chronic back pain continues to expand.