Computational analysis followed by in vitro studies to explore cytokines (TNF-α, IL-6 and IL-1ß) inhibition potential of the new natural molecule polonilignan.

Targeting pro-inflammatory cytokines and their production is found to be of therapeutic benefit for the regulation of inflammation in various chronic autoimmune diseases. Our continued efforts to discover small molecular-weight pro-inflammatory cytokine inhibitors resulted in identifying a novel natural lignan molecule named polonilignan, isolated from the culture broth extract of an endophytic fungus Penicillium polonicum. An in silico study (molecular docking, ADME predictions, binding free energy calculation and molecular dynamics simulation) of the polonilignan over the pro-inflammatory cytokines proteins TNF-α, IL-6 and IL-1ß was performed using Schrodinger LLC software to understand the binding interactions, drug-like properties, and stability of the ligand-protein complex. Further, in-vitro testing of inhibition of TNF-α, IL-6 and IL-1ß by polonilignan was carried out using ELISA and RT-PCR on LPS-induced RAW 264.7 cell lines along with the testing of nitrite production effect (Griess assay) and cytotoxicity (MTT) analysis. Under the computational study, polonilignan revealed good docking scores, binding interactions, and stability under MDS and desirable in silico ADME results over the proteins TNF-α, IL-1ß and IL-6. Poloniligan showed significant inhibition of IL-1ß, IL-6 and TNF-α with IC50 values of 2.01 µM, 6.59 µM and 42.10 µM, respectively. Also, it reduced the translocation of the NF-κB subunit p65 to the nucleus (confocal microscopy). The mRNA expression levels of pro-inflammatory markers IL-1ß, TNF-α and IL-6 levels were lowered significantly (p < .001) by the compound, and the diminution was higher with IL-1ß. Further, the lignan was non-cytotoxic and effective in attenuating nitrite release (IC50 48.56 µM). Thus, polonilignan has been identified as a new pan-cytokine and NO inhibitor, it is recommended to optimise a method for the synthesis of this small molecular weight lignan and explore its pharmacokinetic characteristics, toxicity and therapeutic effect under various chronic inflammatory disease models.

Short-segment spinal fusion for chronic low back pain with bone marrow edema adjacent to the vertebral endplate in adult spinal deformity.

PURPOSE: Corrective long spinal fusion is a widely accepted surgical method for patients with adult spinal deformities. However, instrumented long fusion is associated with a significant risk of complications. Therefore, we aimed to assess the success of short-segment spinal fusion, particularly for bone marrow edema (BME) adjacent to the vertebral endplate, in patients with low back pain (LBP) and spinal deformity. METHODS: A prospective study was performed at multiple hospitals wherein we monitored patients with spinal deformities and accompanying LBP. Patients aged ≥ 50 years with a minimum LBP severity score of 40 mm on the visual analog scale (VAS) were included in the study. We also included patients with lumbar BME on magnetic resonance imaging. Short spinal fusion was performed on segments with BME. Clinical evaluations of LBP on VAS and Oswestry Disability Index (ODI), and radiological parameters for sagittal vertical axis (SVA), pelvic incidence (PI), lumbar lordosis (LL) and pelvic tilt (PT) were carried out. RESULTS: Overall, 35 patients (22 men and 13 women), with a mean age of 66.7 years and a mean follow-up period of 32 months, were included in the study. The mean VAS and ODI scores were 72.4 mm and 49.0% before surgery and 25.5 mm and 29.9% at the final follow-up, respectively; these parameters significantly improved after surgery. The SVA, PI-LL, and PT scores were 70.1 mm, 20.9°, and 22.8° before surgery and 85.4 mm, 13.8°, and 22.7° at the final follow-up, respectively. The spinal alignment parameters did not change significantly after surgery. CONCLUSIONS: Short-segment spinal fusion is effective for treating LBP and spinal deformity with BME adjacent to the vertebral endplate without spinal correction.

Balancing ability of patients with lumbar spinal canal stenosis.

PURPOSE: To determine the relationship between postural sway and the severity of lumbar spinal canal stenosis as well as the effect on postoperative improvement. METHODS: Stabilometry was performed before and 6 months after surgery in 52 patients (29 men and 23 women; mean age, 74.1 ± 7.8 years) who underwent decompression surgery for lumbar spinal canal stenosis. The environmental area (EA; the area surrounding the circumference of the stabilogram) and locus length per EA (L/EA) were evaluated. The patients were divided into moderate (n = 22) and severe (n = 30) groups according to the severity of canal stenosis. Patient characteristics and parameters were compared between the groups before and after surgery, including the visual analog scale (VAS) score for leg pain, Oswestry Disability Index (ODI), EA, and L/EA. In addition, factors affecting EA and L/EA were evaluated using multiple regression analysis. RESULTS: Age (p = 0.031), preoperative EA (p < 0.001), preoperative L/EA (p = 0.032), and sagittal vertical axis (p = 0.033) were significantly different between groups. The VAS score and ODI significantly improved postoperatively in both groups (p < 0.001). The EA significantly improved postoperatively only in the severe group (p < 0.001), whereas the L/EA did not significantly improve in either group. Multiple regression analysis showed that only the severity of canal stenosis was significantly associated with preoperative EA (p = 0.030), whereas age (p = 0.040) and severity of canal stenosis (p = 0.030) were significantly associated with preoperative L/EA. Diabetes was significantly associated with postoperative EA (p = 0.046) and L/EA (p = 0.030). CONCLUSION: The severity of canal stenosis affected abnormal postural sway, which improved after decompression surgery.

New natural pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß) and iNOS inhibitors identified from Penicillium polonicum through in vitro and in vivo studies.

Overexpression of pro-inflammatory cytokines and iNOS have been found to be concomitant with several chronic inflammatory diseases and hence targeting their inhibition would be a useful therapy for inflammation. In view of this, study on discovery of natural pro-inflammatory cytokines inhibitory lead molecules from Penicillium polonicum, an endophytic fungus isolated from the fresh fruits of Piper nigrum was performed. When the culture broth extract of P. polonicum (EEPP) was subjected to LPS-induced cytokines expression (ELISA in RAW 264.7 cells), it exhibited inhibition of TNF-α, IL-6 and IL-1ß and this encouraged us to do chemical investigation on EEPP to explore the bioactive components. Four compounds isolated and characterised as 3,5-di-tert-butyl-4-hydroxy-phenyl propionic acid (1), 2,4-di-tert-butyl phenol (2), indole 3-carboxylic acid (3) and tyrosol (4) were tested for their effect on the production of TNF-α, IL-1ß and IL-6 in RAW 264.7 cells (ELISA). All the compounds exhibited a highly significant (P < 0.0001) inhibition effect, particularly against IL-1ß (IC50: 4-0.91 µM, 1-2.81 µM, 3-4.38 µM, and 2-5.54 µM). Tyrosol (4) was most active with IC50 values of 0.91, 2.67 and 4.60 µM against IL-1ß, IL-6 and TNF-α, respectively. On observing the potential activity of the compounds, two compositions C1 and C2 were prepared by mixing equimolar concentrations of compounds 1, 2, 3 & 4 (C1) and compounds 1, 2, 3, 4 & piperine (C2) in equal ratio. A synergistic effect was observed with C1 exhibiting potential suppression of IL-6 secretion (IC50 1.91 µM) and C2 against IL-1ß (IC50 5.98 µM). Also, the individual compounds and C1 were effective in controlling iNOS expressions in RAW 264.7 cells (RTPCR). Further, the in vivo performance of the compounds and compositions were studied under two in vivo inflammatory models (LPS-induced endotoxaemia and carrageenan-induced paw oedema). Compounds 1, 2, 3, 4, C1 and C2 at 50 mg/kg oral dose showed a significant control over the LPS-stimulated TNF-α, IL-1ß and IL-6 levels in plasma. C1, C2 and 1 exhibited > 50% pan-cytokine inhibition effect. Under the carrageenan-induced anti-inflammatory model, a significant reduction in the paw oedema measured in terms of the difference in the paw thickness was observed. Further, attenuation of pro-inflammatory cytokines levels following ELISA and RT-PCR experiments in the paw tissue homogenate was in agreement with paw thickness results. All compounds and C1 decreased the iNOS gene expression levels, and also the MPO activity and NO production in the paw tissue homogenate with tyrosol (4) as the most active molecule. Further, the mechanism of action was explored by testing the effect of the compounds on the expression of inflammatory markers using western blot analysis (in vitro). They were found to regulate the expression of pro-form and matured-form of IL-1ß by inhibiting NFκB. Also, the compounds reduced the translocation of the NF-κB subunit p65 to the nucleus. Thus, compounds 3,5-di-tert-butyl-4-hydroxy-phenyl propionic acid (1), 2,4-di-tert-butyl phenol (2), indole 3-carboxylic acid (3) and tyrosol (4) are reported as new natural multiple pro-inflammatory cytokines inhibitory leads. The interesting results of C1 might lay a footing for the development of a new anti-inflammatory composition.

Prognostic factors of balloon kyphoplasty for osteoporotic vertebral fractures with diffuse idiopathic skeletal hyperostosis.

OBJECTIVE: The authors aimed to determine the poor prognostic factors of balloon kyphoplasty for the treatment of fractures of the most distal or distal-adjacent vertebrae in ankylosing spines with diffuse idiopathic skeletal hyperostosis (DISH). METHODS: Eighty-nine patients with fractures of the most distal or distal-adjacent vertebrae of ankylosing spines with DISH were included and divided into two groups: those with (n = 51) and without (n = 38) bone healing 6 months postoperatively. Clinical evaluation included age, sex, time from onset to surgery, the visual analog scale score for low-back pain, and the Oswestry Disability Index (ODI). The VAS scores and ODI were measured both preoperatively and at 6 months postoperatively. Radiological evaluations included bone density; wedge angles of the fractured vertebrae in the supine and sitting positions on lateral radiographs; differences in the wedge angles (change in wedge angle); and the amount of polymethylmethacrylate used. RESULTS: The preoperative ODI, vertebral wedge angles in the supine and sitting positions, change in wedge angle, and amount of polymethylmethacrylate were significantly different between the two groups and were significantly associated with delayed bone healing in univariate logistic regression analysis. Multivariate logistic regression analysis showed that only a change in the wedge angle was significantly associated with delayed healing, with a cutoff value of 10°, sensitivity of 84.2%, and specificity of 82.4%. CONCLUSIONS: Treatment with balloon kyphoplasty alone should be avoided in patients with a difference ≥ 10° in the wedge angle of the fractured vertebrae between the supine and sitting positions.

Spinous Process Fractures in Osteoporotic Vertebral Fractures: A Cross-Sectional Study.

Introduction: The purpose of this study was to assess radiological features and clinical scores of osteoporotic vertebral fracture (OVF) accompanied by spinous process fracture (SPF). Methods: We included painful patients with single-level OVF with intravertebral cleft. SPF was detected using magnetic resonance imaging (MRI) and/or computed tomography (CT). The plain radiographs of the vertebral fractures were evaluated based on the wedging angle of the fractured vertebrae and vertebral instability. We investigated the clinical parameters of age, gender, visual analog scale (VAS) score for low back pain (LBP), Oswestry Disability Index (ODI), and the period from the onset of acute fracture. Results: MRI and/or CT indicated among 195 patients of OVF with LBP, 41 patients (20.5%) had SPFs. SPFs were observed one level above the fractured vertebral body in 35 patients (85.4%) and at the same level as the fractured vertebral body in 6 patients (14.6%). The prevalence of vertebral fracture of thoracic spine in the SPF-positive group was significantly greater than that in the SPF-negative group. There were no significant differences in age, gender, VAS, ODI, the time period from the onset of acute LBP, wedging angle, and vertebral instability between the presence or absence of SPFs. Conclusions: SPFs occurred in 20.5% of patients with OVF and LBP. In addition, SPFs often occurred one level above the fractured vertebra, and SPFs with OVF tended to be located in the thoracic spine.

Radiographic Factors for Adjacent Vertebral Fractures and Cement Loosening Following Balloon Kyphoplasty in Patients with Osteoporotic Vertebral Fractures.

Introduction: Balloon kyphoplasty (BKP) is a minimally invasive surgical approach for the treatment of osteoporotic vertebral fractures (OVF). Some risks have been reported after treatment with BKP; therefore, it is necessary to determine when BKP does not work. Thus, in this study, we aim to clarify the radiographic predictors of secondary vertebral fractures and cement loosening after BKP for OVF. Methods: This study enrolled patients with single-level OVF at the thoracolumbar junction (T11-L2) who underwent BKP for the first time between January 2011 and March 2014. The clinical outcomes were evaluated using the visual analog scale (VAS) and a modified Oswestry Disability Index (ODI) at 1 week and 1, 3, 6, and 12 months after surgery. Radiographic assessments were performed preoperatively and within 1 year after BKP using plain radiography and computed tomography. Results: The 85 patients who met the inclusion criteria underwent BKP. The average age of participants (21 men, 64 women) was 77.8 years (range, 57-92 years). Postoperative VAS and ODI scores were all significantly better than preoperative scores. Polymethyl methacrylate (PMMA)-cement leakage was observed in 18 patients (21.2%) but was asymptomatic in all cases. Secondary vertebral fractures were detected in 20 patients (23.5%), including adjacent levels in 15 patients (17.6%) and non-adjacent levels in 5 patients (5.9%). Rostral bridging osteophyte formation was found to be significantly associated with the occurrence of adjacent vertebral fractures (odds ratio 12.746; p=0.010). PMMA-cement loosening was observed in three patients (3.5%). A high prevalence (100%) of bridging osteophytes, vacuum clefts, and spinous process fractures was observed in patients with PMMA-cement loosening. PMMA-cement loosening was found in 3 out of 10 patients with all three of these factors. Conclusions: Rostral bridging osteophyte formation was determined to be a risk factor for both adjacent vertebral fractures and PMMA-cement loosening.Level of Evidence: 3.

Prognostic factors for spontaneous spinal epidural hematoma: a multicenter case-control study.

BACKGROUND: To determine the optimal treatment for spontaneous spinal epidural hematoma (SSEH). The aim of this study was to identify factors associated with SSEH. METHODS: In 62 patients with SSEH, several patient-related parameters were analyzed as candidate factors associated with Frankel grade before treatment or at the last follow-up. These parameters were compared between patients with and without surgery. In addition, multivariate ordinal logistic regression analysis was used to identify factors significantly associated with Frankel's grade before treatment or at the last follow-up. RESULTS: There were significant differences in age, location of the hematoma, and Frankel grade before treatment and at the last follow-up between surgical and nonsurgical cases in all patients, but there were no significant differences in any of these parameters when comparing patients with pre-treatment Frankel grade C. The location of the hematoma was significantly associated with the severity of paralysis before treatment. In surgical cases, the time from onset to surgery and the location of the hematoma was significantly associated with the prognosis. When the time from onset to surgery was evaluated using the criteria of 12, 24, and 48 h, 24 and 48 h had a significant impact on the prognosis. In the analysis of nonsurgical cases, only the vertical size of the hematoma was significantly associated with prognosis. CONCLUSION: The time from onset to surgery and the location of the hematoma were prognostic factors in surgical cases, while the vertical size of the hematoma was a prognostic factor in nonsurgical cases.

Surgical outcomes of cervical myelopathy in patients with athetoid cerebral palsy.

PURPOSE: Surgical treatment for cervical myelopathy with athetoid cerebral palsy remains unestablished. Instrumented fusion is reported to have good clinical results; however, there are no data of decompression surgery for this pathology in recent years. This study aimed to assess the surgical outcomes of laminoplasty with or without posterior instrumented fusion for cervical myelopathy in patients with athetoid cerebral palsy. METHODS: A multi-centre surgical series of patients with cervical myelopathy and athetoid cerebral palsy were enrolled in this study. All patients showed symptoms and signs suggestive of cervical myelopathy and underwent laminoplasty with or without instrumented fusion. The Japanese Orthopaedic Association (JOA) score, Barthel index (BI), and changes in the C2-C7 sagittal Cobb angle in the lateral plain radiograph were analysed. RESULTS: There were 25 patients (16 men and 9 women; mean age, 54.4 ± 10.8 years) with cervical myelopathy and athetoid cerebral palsy who underwent surgical treatment. The mean follow-up period was 41.9 ± 35.6 months. Overall, the BI significantly improved after surgery, whereas the JOA score and C2-C7 angle did not improve postoperatively. The recovery rate of the JOA score in the laminoplasty group was significantly higher than that of the fusion group (P = 0.02). CONCLUSIONS: Cervical laminoplasty with or without instrumented fusion for treating cervical myelopathy due to athetoid cerebral palsy is effective in improving activities of daily living. Cervical laminoplasty may be an effective and less invasive surgical method for selective patients, especially for those with small involuntary movements and no remarkable cervical kyphosis nor instability.

Long-term outcome of targeted therapy for low back pain in elderly degenerative lumbar scoliosis.

PURPOSE: Treatment of low back pain (LBP) associated with elderly degenerative lumbar scoliosis (DLS) remains controversial. We have developed percutaneous intervertebral-vacuum polymethylmethacrylate injection (PIPI) targeting to the intervertebral vacuum as a minimally invasive surgery. The present study compared the long-term clinical outcomes of PIPI to that of nonoperative treatment. METHODS: Patients with de novo DLS, aged ≥ 65 years, who had LBP with visual analog scale (VAS) of ≥ 50 for ≥ 6 months with intervertebral vacuum on computed tomography and bone marrow edema (BME) on magnetic resonance imaging were included. The clinical outcomes were evaluated using VAS and the Oswestry Disability Index (ODI) at baseline, 1, 6, 12, 24 months, and at the final follow-up. The course of BME was also evaluated. RESULTS: One hundred and one patients underwent PIPI and 61 received nonoperative treatment. The mean follow-up duration after PIPI and nonoperative treatment was 63.7 ± 32.4 and 43.9 ± 20.9 months, respectively. VAS and ODI after PIPI were significantly improved compared to post-nonoperative treatment. BME decreased substantially in the PIPI group and it was significantly correlated with VAS and ODI improvement. Following PIPI, LBP recurred in 28 patients (35%). LBP recurrence was identified at the same level of PIPI in 10 patients, at the adjacent level of PIPI in 11 patients, and at the non-adjacent level of PIPI in seven patients. Eighteen patients underwent additional PIPIs, and both VAS and ODI were significantly improved after additional PIPIs. CONCLUSION: Bone marrow lesions of the endplate are strongly associated with the presence of LBP. PIPI can be considered as an effective, safe and repeatable treatment for LBP in elderly DLS patients.

New synthetic coumarinolignans as attenuators of pro-inflammatory cytokines in LPS-induced sepsis and carrageenan-induced paw oedema models.

OBJECTIVES: The aim of the study was to explore the inhibition efficacy of new synthetic coumarinolignans (SCLs) against the secretion of pro-inflammatory cytokines in two in vivo models of inflammation. METHODS: Four SCLs 1-4 were screened for their pro-inflammatory cytokine inhibitory potential through oral administration at a dose of 50 mg/kg body weight in lipopolysaccharide-induced mouse endotoxaemia and carrageenan-induced mouse paw oedema models. Levels of pro-inflammatory cytokines (IL-1ß, TNFα and IL-6) in blood and paw tissue samples were estimated using ELISA. Paw oedema was measured using a plethysmometer. Results were compared with a natural coumarinolignan, cleomiscosin A (5), and the structure-activity relationship (SAR) was interpreted. RESULTS AND DISCUSSION: Compound 2 had the greatest potential in the endotoxaemia model, exhibiting 66.41%, 62.56% and 43.15% inhibition of plasma IL-1ß, TNFα and IL-6 secretions, respectively. Further dose-dependent study revealed its anti-inflammatory potential even at dose of 10 mg/kg body weight with 24.42% decline in the level of IL-1ß. Nevertheless, SCLs 1, 3 and 4 showed marked inhibitory activity with 57.54%, 51.48% and 62.46% reduction in the levels of IL-1ß, respectively. Moreover, compound 2 decreased the plasma TNFα and IL-1ß levels to 50.03% and 36.58% along with the reduction of paw oedema volume in the local inflammation induced by carrageenan. All compounds including cleomiscosin A (5) were more effective against IL-1ß. By studying SAR, the presence of dihydroxyl groups in the phenyl ring of lignans was identified to be essential for the activity. Also, esterification of lignans and presence of a 4-methyl substituent in the coumarin nucleus were found to play some role in enhancing the activity. CONCLUSION: All four SCLs, especially compound 2, have shown vast potential to emerge out as promising anti-inflammatory drugs.

Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO) Syndrome with Destructive Spondylitis: A Case Report.

INTRODUCTION: Spinal lesions in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome generally have a good prognosis and rarely cause structural destruction or neurological deterioration. We described a surgical case of posterior instrumented surgery without anterior reconstruction and bone graft in a patient with SAPHO syndrome with destructive spondylitis and reviewed the literature on surgical treatment for this entity. CASE REPORT: We describe the case of a 73-year-old male who presented with palmoplantar pustulosis. He experienced progressive low back and leg pain for the past 3 months. Destructive spondylitis and lumbar canal stenosis were detected with magnetic resonance imaging (MRI), and aspiration biopsy was used to exclude pyogenic spondylitis and spinal tumors. He underwent posterior decompression and fixation surgery without anterior reconstruction and bone grafting. Low back and leg pain improved after surgery. Postoperative radiography and computed tomography showed boney bridge between vertebral bodies, and MRI showed the decrease of bone marrow edema. CONCLUSIONS: Posterior fusion without anterior reconstruction produced a bony bridge between the vertebral bodies. Taking the pathophysiology of SAPHO syndrome into consideration, anterior reconstructed fusion for patients with SAPHO syndrome might not be needed.

Transforaminal percutaneous endoscopic discectomy for lumbar disc herniation in athletes under the local anesthesia.

BACKGROUND: Percutaneous endoscopic discectomy (PED) has been reported to be less invasive and effective procedure for lumbar disc herniation (LDH). Damage to the back muscle is considered minimal, which is particularly important for athletes. However, the results of PED for LDH in athletes have not been reported well. The purpose of this study was to evaluate the clinical outcomes of PED for LDH in athletes. METHODS: We retrospectively analyzed 21 athlete patients with LDH who had undergone PED. All patients received athletic rehabilitation immediately after surgery. The clinical outcomes were evaluated from the visual analogue scale (VAS) for leg pain and low back pain (LBP), the Oswestry Disability Index (ODI), complications and periods of return to sport. RESULTS: There were 18 men and 3 women, and the mean age at the time of surgery was 22.9 years (range: 15-43 years). The mean VAS scores for leg pain before and after surgery were 64.3 ± 2.7 mm and 12.4 ± 1.4 mm, respectively. The mean VAS scores for LBP before and after surgery were 62.1 ± 2.2 mm and 10.5 ± 1.1 mm, respectively. The mean ODI scores before and after surgery were 31.3 ± 14.0% and 14.6 ± 7.1%, respectively. The VAS for leg pain, as well as the LBP and ODI, significantly improved after surgery. There were no complications related to the surgery. Ninety-five percent (20/21) returned to play sports at the same performance level as before the procedure by an average of 9.2 weeks after PED. CONCLUSIONS: PED is a minimally invasive and effective procedure for patients with LDH, especially in athletes. Not only the patients' leg pain but also their discogenic LBP improved. PED has the benefits of preservation of normal posterior structures and a faster return to sports.

Structure-based design and synthesis of new 4-methylcoumarin-based lignans as pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß) inhibitors.

Suppression of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6) along with nitric oxide reduction in RAW 264.7 cells by 7,8-dihydroxy-4-methylcoumarin, ethyl p-coumarate, ethyl caffeate and ethyl ferulate drove us to search structural-analogues of the aforementioned compounds through structure-based drug design. Docking studies revealed that substituted cinnamic acids and their ethyl esters (2-7c) showed higher GoldScore-fitness (GSF) and non-bonding interactions with target proteins than 7,8-dihydroxy-4-methylcoumarin (1a) and 7,8-dihydroxy-5-methylcoumarin (1b). With this background, the methylcoumarins (1a and 1b) and the cinnamic acid derivatives (2-7c) were fused in different permutations and combinations to generate sixty novel fused-cyclic coumarinolignans (FCLs) (8-13k). Docking studies on 8-13k indicated that several FCLs possess higher GSF, interesting active site interactions and distinctive π-π interactions compared to the standards (cleomiscosin A, diclofenac Na and prednisolone). Based on these findings, four novel FCLs (9d, 10d, 11d and 11e) were synthesized and tested for inhibition effect on TNF-α, IL-1ß and IL-6 expressions in LPS and oxalate crystal-induced in-vitro models. Compound 10d exhibited significant effect (P < 0.0001 at 100 µM) with an IC50 value of 8.5 µM against TNF-α. Compound 11e possessed IC50 values of 13.29 µM and 17.94 µM against IL-6 and IL-1ß, respectively. Study on SAR corroborated the requirement of C-4-methyl substituent in the coumarin moiety, dihydroxyl groups in the phenyl ring, and esterification of lignans for potent activity. Additionally, the reported excellent anti-inflammatory activity of cleomiscosin-A-glucoside was corroborated by from the higher GSF and better hydrophobic interactions than cleomsicosin A in the docking study. As an outcome, some novel and potentially active FCLs acting through NFκB and caspase 1 signaling pathways have been discovered as multiple cytokine inhibitors.

[Investigation of Clinical Outcome and Prognosis of 2nd TUR-Bt for T1 High Grade Bladder Cancer].

Second transurethral resection of bladder tumor (TUR-Bt) is a standard treatment for high grade T1 initial, non-muscle invasive bladder cancer. In our hospital from October 2008 to April 2017, 2nd TUR-Bt was performed in 51 cases of initial T1 bladder cancer. The risk factors of residual tumors on 2nd TUR-Bt and the clinical outcome were examined retrospectively. Twenty two of the 51 cases (43.1%) had residual tumors on 2nd TUR-Bt, and upstaging was not admitted. To determine the risk factor for residual tumors in 2nd TUR-Bt, we examined gender, tumor morphology (papillary/non-papillary, pedunculated/ nonpedunculated), number of tumors (single/frequent), and tumor size (≧20 mm/＜20 mm), but none of these were significant risk factors for tumor residue. The recurrence free survival (RFS) of the 51 cases was 86.0% after 1 year, and 77.0% after 3 years. There tended to be a higher RFS in the pedunculated tumor group, pT0 group on 2nd TUR-Bt, intravesical BCG therapy group, but no statistically significant difference was observed. The progression free survival (PFS) was 90.6% after 3 years, and 87.3% after 5 years. These values were similar to those reported previously.

Decrease of bone mineral density in Japanese patients with non-metastatic prostate cancer treated with androgen deprivation therapy.

The aim of this study was to conduct a cross-sectional survey of investigations related to the bone mineral density (BMD) of both non-metastatic prostate cancer (NMPC) patients who have not yet received androgen deprivation therapy (ADT) and patients receiving prolonged ADT in Japan. Japanese male patients with NMPC who received continuous ADT or who were planning to receive ADT were enrolled in this study. Lumbar spine and femoral neck BMD was measured using dual-energy X-ray absorptiometry (DEXA). To assess patient characteristics, we searched medical records and questionnaires to determine whether they had any factors that could possibly affect BMD. A total of 230 patients with a mean age of 76.6 ± 6.4 years were evaluated. Of these, 151 (65.7%) were receiving ADT, and 79 (34.4%) had not yet received ADT. The mean duration of ADT was 37.4 ± 30.7 months. DEXA showed that as the duration of ADT increased, lumbar spine and femoral neck BMD decreased gradually (p = 0.0005 and p = 0.0014, respectively). Stepwise regression analyses revealed that the duration of ADT was a significant variable of both lumbar spine and femoral neck BMD. Moreover, as the duration of ADT increased, the prevalence of osteoporosis increased statistically (p = 0.0002). This study showed that ADT negatively affected lumbar spine and femoral neck BMD. It also showed a progressive increase in the prevalence of osteoporosis in Japanese NMPC patients with ADT.

[Clinical Study of 2014 ISUP New Grade Group Classification for Prostate Cancer Patients Treated by Androgen Deprivation Therapy].

The 2014 International Society of Urological Pathology (ISUP) has proposed a new grade group (GG) classification for Gleason scores (GS). The usefulness of the new GG classification was investigated with 518 prostate cancer patients who underwent androgen deprivation therapy. According to the new GG classification, Stages B‒D and the new GG classification relapse-free rate for each stage were calculated using the Kaplan‒Meier method. The new GG classification revealed a significant difference for the relapse-free rate only between some groups. Analysis using the Cox proportional hazards model indicated that the risk of relapse was higher in GGs 4 and 5 than in GG 1. The usefulness about the relapse-free rate in androgen deprivation therapy of the 2014 ISUP new grade group classification a waits future examination.

[Investigation on Clinical Course of Patients after Cessation of Long-Term Successful Hormone Monotherapy for Prostate Cancer].

We investigated the clinical course of patients after cessation of long-term successful hormone monotherapyfor prostate cancer. Studysubjects were ten patients with prostate cancer (localized prostate cancer ; n＝8, prostate cancer with bone metastasis ; n＝2), who had hormone monotherapyfor over seven years, showed no signs of recurrence, and maintained prostatic-specific antigen (PSA) levels of less than the detection sensitivitylimit (＜0.01 ng/ml). The mean duration of hormone therapywas 101.1 months, and the mean duration of follow-up observation from cessation of the therapywas 31.1 months. PSA levels were maintained less than the detection sensitivitylimit in eight patients, and serum testosterone levels were equal to or less than the castration level in seven patients. This studydemonstrated that there were cases that maintained PSA levels of less than the detection sensitivitylimit even after cessation of long-term successful hormone monotherapyfor prostate cancer.

Bone Marrow Edema and Low Back Pain in Elderly Degenerative Lumbar Scoliosis: A Cross-Sectional Study.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: To examine whether bone marrow edema is associated with low back pain in elderly patients with degenerative lumbar scoliosis. SUMMARY OF BACKGROUND DATA: The cause of low back pain in degenerative lumbar scoliosis is unclear. METHODS: A total of 120 degenerative lumbar scoliosis patients 65 years of age or older were evaluated. Radiography, computed tomography (CT), magnetic resonance imaging (MRI), and tender point examination in the lumbar spine were performed. On MRI, coronal gadolinium-contrasted T1- or T2-weighed fat-saturated images were used to score the size of bone marrow edema. The prevalence of bone marrow edema in patients with and without low back pain was compared; in patients with low back pain, we tested whether the locations of lumbar tender point were consistent with that of bone marrow edema. RESULTS: Bone marrow edema was found in 62 of 64 (96.9%) patients with low back pain compared with 21 of 56 (37.5%) patients without it (P < 0.001). Bone marrow edema located more frequently on the concave side than on the convex side of scoliosis (P < 0.001). Among patients with low back pain, bone marrow edema score was associated with low back pain severity (r = 0.724; P < 0.001), and the location of lumbar tender point were consistent with that of bone marrow edema (κ value = 0.745; P < 0.001). CONCLUSION: Bone marrow edema on MRI was closely associated with the presence of low back pain in elderly degenerative lumbar scoliosis. LEVEL OF EVIDENCE: 4.

[A Case Report of Pyothorax Due to Pyonephrosis].

A 77-year-old woman was referred to our hospital with complaints of fever and left chest pain. Computed tomography showed left pyothorax and left pyonephrosis with left ureter calculus. After admission, drainage of the left thoracic cavity was performed and she was treated with antibiotics. On the third hospital day, debridement for pyothorax was performed because her condition had not improved. During surgery, we found perforation of the diaphragm, and abscess appeared from the perforated area. We suspected that perforation of the diaphragm from the left pyonephrosis caused left pyothorax, and performed left nephrectomy. After the operation, relapse of the pyothorax and surgical wound infection occurred, but her condition improved and she discharged on the 46 th hospital day. Relapse of the abscess has not occurred.