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Biological disease-modifying antirheumatic drugs (bDMARDs) have become more popular for treating rheumatoid arthritis (RA). Whether or not bDMARDs increase the postoperative risk of surgical site infection (SSI) has remained controversial. We aimed to clarify the effects of bDMARDs on the outcomes of elective orthopedic surgery. We used multivariate logistic regression analysis to analyze risk factors for SSI and delayed wound healing among 227 patients with RA (mean age, 65.0 years; disease duration, 16.9 years) after 332 elective orthopedic surgeries. We also attempted to evaluate the effects of individual medications on infection. Rates of bDMARD and conventional synthetic DMARD (csDMARD) administration were 30.4 and 91.0 %, respectively. Risk factors for SSI were advanced age (odds ratio [OR], 1.11; P = 0.045), prolonged surgery (OR, 1.02; P = 0.03), and preoperative white blood cell count >10,000/μL (OR, 3.66; P = 0.003). Those for delayed wound healing were advanced age (OR, 1.16; P = 0.001), prolonged surgery (OR, 1.02; P = 0.007), preoperative white blood cell count >10,000/μL (OR, 4.56; P = 0.02), and foot surgery (OR, 6.60; P = 0.001). Risk factors for SSI and medications did not significantly differ. No DMARDs were risk factors for any outcome examined. Biological DMARDs were not risk factors for postoperative SSI. Foot surgery was a risk factor for delayed wound healing.

Objectives: The deformed rheumatoid forefoot may be treated with resection of lesser metatarsal heads combined with arthrodesis or resection of the first metatarsophalangeal joint. Recurrent hallux valgus deformity has been reported by resection. We performed a prospective, randomized, internal-controlled study to compare results between arthrodesis and resection., Methods: We resected the lesser metatarsal heads bilaterally and performed arthrodesis of the first metatarsophalangeal joint on one side and resection on the opposite side. We investigated 26 patients (52 feet) who were followed at least one year. Patients were assessed for clinical score, hallux valgus angle (HVA), angle between first and second metatarsals, and angle between first and fifth metatarsals preoperatively, postoperatively and at final follow-up. We evaluated callosities, claw toes, recurrences, and procedure preferences., Results: The mean follow-up period was 4.1 years. No significant differences between arthrodesis and resection were seen, with the exception of HVA. That was significantly less on arthrodesis side (11.5°) than on resection side (17.0°, p < 0.05). Seven callosities on resection side and four on arthrodesis side were observed. On resection side, hallux valgus deformity often recurred (15.3%). Patients expressed a significant preference for arthrodesis over resection (p = 0.008)., Conclusions: Arthrodesis provides better results for maintaining HVA.

We investigated the effects of biologics for rheumatoid arthritis (RA) patients on bone mineral density (BMD) and bone metabolic markers (BMM), retrospectively, and also clarified the effects of bisphosphonates (alendronate or risedronate 35 mg/week) and glucocorticoids. Participants in this study comprised 219 patients with RA, including 117 patients treated with biologics (infliximab, n = 90; etanercept, n = 27) and 102 patients with conventional disease-modifying anti-rheumatic drugs (DMARDs) for 1 year. Changes in BMD at the lumbar spine and total hip and BMMs [urinary type I collagen cross-linked N-telopeptide (NTX) and bone-specific alkaline phosphatase] were measured. BMD of the lumbar spine in both groups and total hip BMD in the biologics group were unchanged during treatment with biologics. However, BMD of the total hip was significantly decreased in the DMARDs group (from 0.731 ± 0.135 to 0.706 ± 0.135 g/cm2). Patients receiving glucocorticoids without bisphosphonates showed significant decrease in BMD of the total hip compared with patients not receiving glucocorticoids or receiving glucocorticoids with bisphosphonates in both biologics and DMARDs groups. Furthermore, BMD of the lumbar spine increased (p < 0.05) for patients in the biologics group who received bisphosphonates. NTX was significantly decreased only in the biologics group. Multiple regression analysis showed that BMD and bone metabolic marker levels correlated positively with bisphosphonate and biologics use and negatively with glucocorticoid use. BMD of the total hip was maintained in the patients using biologics without glucocorticoids or with bisphosphonates, but it was not maintained in the DMARDs patients, even without glucocorticoids or with bisphosphonates. Even if biologics have protective effect against bone loss of RA patients, we should consider reducing the dose of glucocorticoids and adding bisphosphonates for the treatment of osteoporosis.

Study Design: A cross-sectional study., Objective: This study was aimed to quantify the extent of lumbar endplate and facet joint erosion in patients with rheumatoid arthritis (RA) using magnetic resonance imaging, to calculate the prevalence of erosion, and sought correlated factors., Summary of Background Data: Few studies have examined the lumbar spine in RA, especially the relationship between endplate and facet joint erosions and lumbar lesions induced by RA., Methods: A total of 201 patients with RA were enrolled. Lumbar endplate and facet joint erosion were defined as irregularities and low-intensity change on magnetic resonance imaging, and graded utilizing the Rheumatoid Arthritis Magnetic Resonance Imaging Score. Lumbar lesions were defined as scoliosis, spondylolisthesis, and vertebral fracture on plain x-ray. Multivariable logistic regression analysis was used to seek correlations between the erosion and spinal level, RA-related factors and x-ray findings., Results: Lumbar endplate and facet erosion were detected in 70.6% and 76.6% of individuals, respectively, and at 33.8% and 38.7% of lumbar intervertebral levels, respectively. The severity of erosion in individual patients correlated with lumbar lesions. Endplate and facet erosion at each level correlated with high disease activity, and were most common at mid-lumbar and lower-lumbar levels. Strong correlations were observed between endplate erosion and adjacent vertebral body fracture or disk degeneration, and between facet erosion and spondylolisthesis., Conclusions: Lumbar endplate and facet erosion are common in RA, and are observed more frequently at mid-low levels and when RA is poorly controlled. This pattern of erosion may play a crucial role in the generation of lumbar lesions in RA.

There are few reports of the Oxford unicompartmental knee arthroplasty (UKA) survival rate in Asia. This study describes outcomes of 1279 Oxford UKAs for Japanese patients. The mean follow-up was 5.2 years. We divided patients into two groups based on preoperative indications (extended indications group and strict indications group). The Oxford knee score improved from 22.3 to 40.8 (P=0.041). The 10-year survival rate using revision was 95%. A total of 25 UKAs (2.0%) required revision. The most common reason was subsidence of tibial component. The 5-year cumulative survival rate of the strict indications group was significantly higher than that of the extended indications group (99.1% vs. 93.8%, P<0.001). When we followed inclusion criteria strictly, good clinical results were achieved in Asia., (© 2013 Elsevier Inc. All rights reserved.)

Objective: To evaluate the prevention of joint destruction and clinical efficacy of low-dose etanercept (ETN) (25 mg/week) compared with standard-dose ETN (50 mg/week) in RA., Methods: In this prospective, randomized, open-label study, 70 patients were assigned to receive ETN at either 50 or 25 mg/week for 52 weeks. The primary endpoint was the variation in modified total Sharp score (mTSS), and secondary endpoints were variations in disease activity score in 28 joints (DAS-28), modified HAQ and adverse event rate. Values of mTSS were calculated at baseline and after 52 weeks. Non-progression was estimated as ΔmTSS ≤0.5, and the non-progression rate was compared between groups., Results: Mean values at baseline were as follows: disease duration 9.2 years; DAS-28 5.45; and annual progression of mTSS 26.1. No significant differences in background were seen between groups. At 52 weeks, the non-progression rate was significantly less in the 25 mg/week group (36.7%) than in the 50 mg/week group (67.7%) (P = 0.041). Mean ΔmTSS was higher at 25 mg/week (1.03) than at 50 mg/week (-0.13). DAS-28 was significantly improved at 4 weeks, and the effect of treatment lasted for 52 weeks in both groups. No differences in adverse event rates were seen between groups., Conclusion: Low-dose ETN is not inferior to standard-dose ETN in terms of effects on clinical manifestations. However, in terms of the radiographic non-progression rate, the effects of low-dose ETN may be inferior to the effects of standard-dose ETN., Trial Registration: UMIN Clinical Trials Registry, http://www.umin.ac.jp/ctr/, UMIN000001798.

Objectives: Rheumatoid arthritis (RA) patients with high body mass index (BMI) show lower mortality than thinner patients, indicating a paradoxical effect of body mass on mortality in RA. We considered that leptin might play some part in this mechanism. Leptin regulates not only body weight, but also inflammatory processes. Furthermore, hyperleptinemia decreases sensitivity to leptin (leptin resistance). This study examined whether high-fat diet-induced hyperleptinemic obese mice with acquired leptin resistance show reduced inflammation induced by collagen antibody-induced arthritis (CAIA)., Methods: Diet therapies were induced in mice by exposure to 50% fat to obesity for 6 weeks. We examined serum leptin concentrations and leptin responses after 6 weeks and induced CAIA. Leptin effects were examined by intraperitoneal (IP) or intracerebroventricular (ICV) leptin administration after CAIA. Hindpaw swelling was monitored daily. Histopathological features were also determined at sacrifice., Results: Serum leptin concentrations were approximately 5-fold higher than in normal mice. IP leptin did not inhibit food intake, but ICV leptin did. Obese mice thus acquired peripheral leptin resistance. Arthritis was reduced approximately 30% compared with normal controls and was not exacerbated by IP leptin injection, but ICV leptin injection exacerbated arthritis to levels equal to normal controls. Histopathological assessment showed that cartilage damage was reduced by 76% compared to normal controls., Conclusions: High-fat diet-induced obese mice acquired peripheral leptin resistance reducing the development of CAIA. Leptin sensitivity was associated with severity of arthritis. These results suggest that RA patients with high BMI who acquire leptin resistance may show reduced inflammation. However, the real function of leptin in the immune system remains partly unclear.

Pyoderma gangrenosum (PG) is characterized by ulcerative skin lesions. Infliximab (IFX) may promote PG healing in patients with inflammatory bowel disease, but whether IFX is effective for treating PG in patients with rheumatoid arthritis (RA) has not reported. We report the case of a 53-year-old woman with PG complicated by RA who was treated using IFX therapy. This case suggests that IFX therapy might offer effective treatment for such patients.

Natural catechol, quinone and quinone methide diterpenes with abietane (15-deoxyfuerstione, taxodione) and totarane (dispermone, 12,13-dihydroxy-8,11,13-totaratriene-6-one), and podocarpane (nimbidiol, deoxynimbidiol) skeletons were synthesized using ortho-oxidation of phenol with meta-chlorobenzoyl peroxide. Minimum inhibitory activities of these diterpenes and previously synthesized natural diterpenes were measured against methicillin-resistant Staphylococcus aureus (MRSA) and Propionibacterium acnes, which cause serious skin infection associated with acne. Abietaquinone methide and 8,11,13-totaratriene-12,13-diol showed potent activities against S. aureus (MRSA) and P. acnes, and no serious toxicity by oral dose to mice.

Carnosic acid (2), a major anti-oxidant in rosemary (Rosmarinus officinalis), was synthesized from pisiferic acid (1), the major constituent of Sawara (Chamaecyparis pisifera), via ortho-oxidation of the phenol using meta-chlorobenzoyl peroxide (mCBPO), chloroacetyl meta-chlorobenzoyl peroxide (CAMCBPO) or 2-iodoxybenzoic acid (IBX). Carnosol (3), another anti-oxidant in rosemary, was synthesized from carnosic acid by oxidation with silver oxide. Potent antibacterial activities against Propionibacterium acnes (ATCC 6919) (minimum inhibitory concentration (MIC) mug/ml) and Staphylococcus aureus ME/GM/TC Resistant (ATCC 33592) (MIC mug/ml) of carnosic acid and carnosol were reported.

The syntheses of four totarane diterpenes-totarol, 8,11,13-totaratriene-12,13-diol, 6-deoxymaytenoquinone and maytenoquinone-are described. Totarol was synthesized via cyclization of a modified polyene. 8,11,13-Totaratriene-12,13-diol was prepared from natural totarol by ortho-oxidation with mCBPO (m-chlorobenzoyl peroxide). Maytenoquinone and 6-deoxymaytenoquinone were synthesized from 8,11,13-totaratriene-12,13-diol. 1H-NMR analysis showed that tautomeric isomerization between 6-deoxymaytenoquinone (2-hydroxy-4-quinone methide) and the ortho-quinone was very slow.

A stable symmetric diacyl peroxide, m-chlorobenzoyl peroxide (mCBPO), and an asymmetric diacyl peroxide, chloroacetyl m-chlorobenzoyl peroxide (CAMCBPO), were synthesized from m-chloroperbenzoic acid. Both peroxides oxidized phenols selectively at the ortho position predominantly. CAMCBPO gave para-oxidized compounds as minor products from some phenols. The improvement of the yield of ortho-oxidation of phenols with mCBPO was also reported.

Since irinotecan, S-1, docetaxel, and paclitaxel were approved, therapeutic options for chemotherapy in the treatment of gastric cancer have increased. It is suggested that the efficient use of the primary drugs prolongs life in the treatment of progressive colorectal cancer. Also, physicians have discussed ways to take full advantage of the drugs in the treatment of gastric cancer. In first-line treatment in other countries, combination therapy usually includes the administration of two drugs, while in Japan, where therapies based on S-1 have been developed, the most appropriate strategy must be determined after reporting the results of phase III trials in 2007. In the clinic, treatment must be selected on the basis of solid evidence in consideration of the organ dysfunction associated with progressive gastric cancer. The timing of any changes in the treatment should be considered because the cancer easily metastasizes to the peritoneum. Throughout the world, various regimens have been developed that replace cisplatin with oxaliplatin or mainly use oral fluoropyrimidine. Molecular target drugs, now being evaluated in phase II trials, will also be used in the treatment of gastric cancer in the near future. Novel therapies will be developed in Asia and Japan where the incidence of gastric cancer is high.

A quinone methide diterpene: abietaquinone methide, which possesses potent anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-vancomycin-resistant Enterococcus (VRE) activities, was synthesized via efficiently ortho-oxidation of ferruginol derived from industrially available dehydroabietic acid. ortho-Oxidation of phenols was developed to give mono esters of catechols using a stable diacyl peroxide, bis(4-chlorobenzoyl) peroxide (m-chlorobenzoyl peroxide: mCBPO) which was synthesized from meta-chlorobenzoic acid. Efficient one pot ortho-oxidation reaction of phenol with an adduct of meta-chloroperbenzoic acid (mCPBA) with dicyclohexylcarbodiimide (DCC) was also reported.

Capecitabine, an oral fluoropyrimidine carbamate, is adopted worldwide. As the treatment for metastatic colorectal cancer, capecitabine showed at least comparable efficacy with a favorable safety profile to bolus 5-FU/LV. In a large phase III trial (Xeloda Adjuvant Chemotherapy Trial: X-ACT), as the adjuvant treatment of patients with resected stage III colon cancer, capecitabine showed at least comparable disease-free survival, overall survival, and relapse-free survival with a favorable safety profile to bolus 5-FU/LV. Additionally, capecitabine-based combination regimens with oxaliplatin or irinotecan are now under evaluation. In phase II studies, capecitabine has shown the promising results in combination therapy. In Japan, capecitabine has been evaluated since 1994. In a recent phase II study, which evaluated the global dose as first-line treatment for metastatic colorectal cancer, the response rate was 35% (95% CI 23.1-48.4). The median time to disease progression was 169 days and the median overall survival was 617 days. Hand-foot syndrome (HFS), a characteristic adverse event of capecitabine, was observed in 73.3% of the patients, but the grade 3/4 was observed in 13.3% of the patients and only one patient discontinued the treatment due to HFS. An immediate approval of capecitabine in Japan is expected.

Objective: To investigate the effects of electrical pulses on the ability of methotrexate (MTX) to attenuate inflammation and subsequent joint destruction in rats with adjuvant-induced arthritis (AIA)., Methods: Rats in the experimental group received an intraperitoneal injection of MTX (0.125 mg/kg body weight), followed 30 minutes later by application of direct electrical pulses (50V, 8 Hz) to their left hind paws with an electroporation apparatus (M+/E+ group; n = 8). The procedure was repeated twice weekly for 3 weeks. Three control groups received the following treatments, respectively: MTX without electrical treatment (M+/E- group; n = 9), electrical treatment but no MTX (M-/E+ group; n = 10), or no electrical treatment and no MTX (M-/E- group; n = 9). Progression of AIA was monitored by joint swelling and radiologic and histologic changes in the ankle joint., Results: Three weeks after injection of the adjuvant, and at the height of the arthritic reaction, the swelling and radiologic and histologic changes in the left hind paws in the M+/E+ rats were significantly reduced, as compared with changes observed in the control groups., Conclusion: These results demonstrate that application of electrical pulses in combination with use of systemic low-dose MTX can ameliorate local arthritic reactions. This response probably occurs because electrical stimulation promotes transient passage of MTX through pores in the cell membranes, with a resultant local increase in the concentration of the drug within the cells. These results point to a potential use of electrochemotherapy to increase the efficacy of MTX or other drugs in an arthritic joint that is refractory to treatment, without increasing the dose of the drug.

Ten novel isocyanocyclohexane compounds that possess an oxygenic functional group at the 4-position were synthesized and evaluated for their antifouling activity against the larvae of the barnacle Balanus amphitrite with the aim of exploring the structure-activity relationships further. The anti-barnacle effect of the synthesized compounds was in the EC50 range of 0.0096-17.0 microg ml(-1). Some ester derivatives exhibited extremely high antifouling activities, and none of the synthesized isocyanocyclohexane compounds showed significant toxicity. The results suggest that the ester function is one of the important groups in the expression of potent antifouling activity in isocyano compounds.

An antifouling active natural compound, 3-isocyanotheonellin, and its analogues were synthesized and evaluated for antifouling activity against the larvae of the barnacle Balanus amphirite in order to explore structure-activity relationships. The anti-barnacle effect of the 3-isocyanotheonellin analogues was in the EC50 range 0.18-7.20 micrograms ml-1. Some synthesized analogues exhibited potent antifouling activity as high as 3-isocyanothoenllin, and none of the synthesized isocyano compounds showed significant toxicity. The results of the present study suggest that an isocyano group and a hydrophobic site at a suitable position are important for potent antifouling activity without toxicity.

[reaction: see text] N-Acyliminium cation of prolines was efficiently generated to accumulate in an undivided cell at 0 degrees C by an anodic oxidation of N-acylprolines or alpha'-phenylsulfanylated N-acylproline derivatives in a lithium perchlorate/nitromethane solution. The iminium cation intermediates gave modified prolines by a reaction with nucleophiles under mild conditions.

Combinations of typical organic solvents composed of cyclohexane and qualified aprotic polar organic solvents were found to realize an effective, biphasic thermomorphic system in arbitrary ratios of upper and lower phases that enable a practical application of a liquid-phase peptide synthesis.