Heterogeneously Catalyzed Selective Acceptorless Dehydrogenative Aromatization to Primary Anilines from Ammonia via Concerted Catalysis and Adsorption Control.

Although catalytic dehydrogenative aromatization from cyclohexanones and NH3 is an attractive synthetic method for primary anilines, using a hydrogen acceptor was indispensable to achieve satisfactory levels of selectivity in liquid-phase organic synthetic systems without photoirradiation. In this study, we developed a highly selective synthesis of primary anilines from cyclohexanones and NH3 via efficient acceptorless dehydrogenative aromatization heterogeneously catalyzed by an Mg(OH)2-supported Pd nanoparticle catalyst in which Mg(OH)2 species are also deposited on the Pd surface. The basic sites of the Mg(OH)2 support effectively accelerate the acceptorless dehydrogenative aromatization via concerted catalysis, suppressing the formation of secondary amine byproducts. In addition, the deposition of Mg(OH)2 species inhibits the adsorption of cyclohexanones on the Pd nanoparticles to suppress phenol formation, achieving the desired primary anilines with high selectivity.

Synthesis of unsymmetrically substituted triarylamines via acceptorless dehydrogenative aromatization using a Pd/C and p-toluenesulfonic acid hybrid relay catalyst.

An efficient and convenient procedure for synthesizing triarylamines based on a dehydrogenative aromatization strategy has been developed. A hybrid relay catalyst comprising carbon-supported Pd (Pd/C) and p-toluenesulfonic acid (TsOH) was found to be effective for synthesizing a variety of triarylamines bearing different aryl groups starting from arylamines (diarylamines or anilines), using cyclohexanones as the arylation sources under acceptorless conditions with the release of gaseous H2. The proposed reaction comprises the following relay steps: condensation of arylamines and cyclohexanones to produce imines or enamines, dehydrogenative aromatization of the imines or enamines over Pd nanoparticles (NPs), and elimination of H2 from the Pd NPs. In this study, an interesting finding was obtained indicating that TsOH may promote the dehydrogenation.

Impact of anesthesia modality and mechanical venous thromboembolism prophylaxis on the incidence of symptomatic deep venous thrombosis after TKA.

BACKGROUND: Venous thromboembolic events (VTE) are a common complication of total knee arthroplasty (TKA). Prior studies have discussed the utility of mechanical VTE prophylaxis as a monotherapy for low-risk TKA patients. We assess the incidence of clinically significant deep venous thrombosis (DVT) or pulmonary embolism (PE) in low-risk TKA patients who receive mechanical VTE prophylaxis and undergo spinal, epidural, or general anesthesia for their surgery. METHODS: A retrospective study was performed on consecutive low-risk patients who received a TKA between July 2002 and June 2015 with spinal anesthesia (n = 65), epidural and general anesthesia (n = 154), or general anesthesia alone (n = 152). Patients with spinal anesthesia had mechanical VTE prophylaxis until 15 h postoperatively, when remobilization was permitted. Patients who received epidural or general anesthesia had mechanical VTE prophylaxis for 2 h postoperatively. Notable outcomes included development of clinically symptomatic DVT or PE, patient demographics, and perioperative lab values. Statistical analysis was performed using SPSS 22, with chi-squared and Fisher's exact tests for categorical variables and the Kruskal-Wallis test with Scheffe's method for continuous variables. RESULTS: No clinically symptomatic DVT or PE was diagnosed. Patient demographics were equivocal. A statistically significant decrease in prothrombin and activated partial thromboplastin times were noted in the general anesthesia group, but all measurements were within the normal range. CONCLUSIONS: A short course of mechanical VTE prophylaxis may be appropriate for low-risk patients who can immediately mobilize.

Life expectancy of osteoarthritic patients after primary total knee arthroplasty.

BACKGROUND: Although an increased life expectancy has been previously reported in patients with osteoarthritis (OA) after undergoing total knee arthroplasty (TKA), the long-living Japanese population may provide a more accurate cohort for determining 10- and 15-year survival rates. The aims of the present study were to (1) determine the survival of patients after TKA, (2) identify the factors important for survival, and (3) compare the survival rate of the OA patients with that of the standardized general population. METHODS: The 5-, 10-, and 15-year survival rates were assessed in 326 consecutive OA patients treated with TKA from January 1998 to December 2013. Eighty-six of the cases were staged bilateral TKAs. All patients were followed until December 31, 2014 or until the time of death. The survival rate of the patients was compared with that of the standardized general population using Kaplan-Meier survival curves. RESULTS: Fifty-one of the patients died before the end of the follow-up. The cumulative 5-year patient survival was 93.5%, 10-year survival was 82.1%, and 15-year survival was 66.6%. The standardized mortality ratio was 0.916 (95% confidence interval: 0.682-1.204). A Cox proportional hazards model showed that increased age and unilateral TKA were factors related to higher patient mortality rates. CONCLUSIONS: These data suggest that patients undergoing TKA can expect similar life expectancy as the general population, with 66.6% of such patients surviving for at least 15-years. Additionally, patients undergoing bilateral TKAs may have a longer life expectancy than those undergoing unilateral TKA.

Comparing Steri-Strip and surgical staple wound closures after primary total knee arthroplasties.

BACKGROUND: Steri-Strips (3M, Two Harbors, MN, USA) have recently been employed for skin closures after orthopedic surgeries. Here we compare the performance of Steri-Strips and skin staples for wound closure after primary total knee arthroplasties (TKAs). METHODS: A total of 76 consecutive osteoarthritic knees (71 patients) that underwent a primary TKA at our facility were included in this study. Thirty-eight knees received Steri-Strips for wound closure and were evaluated prospectively. The other 38 knees were closed with skin staples (Staple group) and evaluated retrospectively. RESULTS: No deep or superficial infections developed in this series. Although Steri-Strips detached from three knees during the 10-day postoperative period, no dehiscence was observed. Thirteen knees developed blisters around the surgical incision in the Steri-Strip group compared with five knees in the Staple group. The average operative time for the Steri-Strip group was 60.6 min (SD 7.3) compared with 54.1 min (SD 6.9) in the Staple group. There were significant differences in operative time (p < 0.001) and tourniquet time (p < 0.001) between the two groups. The average time until patients were permitted to start showering was significantly shorter in the Steri-Strip group (p = 0.0496). The material cost for Steri-Strips was approximately $3.00 USD for one operation compared with $26 USD for skin staplers. CONCLUSIONS: Wound closure with Steri-Strips after a TKA does not require postoperative material removal and may have improved safety, comfort, cosmesis and cost-effectiveness compared with traditional skin closures. LEVEL OF EVIDENCE: Level II, Prognostic study.

Macroscopic evaluation of the anterior cruciate ligament in osteoarthritic patients undergoing total knee arthroplasty.

BACKGROUND: Sacrifice of the anterior cruciate ligament (ACL) is currently common practice during total knee arthroplasty (TKA). However, patients who receive an ACL-retaining TKA maintain more normal knee kinematic patterns than those without an ACL. Additionally, satisfactory survival and function more than 20 years after bicruciate-retaining TKA has recently been reported. The purpose of this study was to compare the percentage of knees with a visually intact ACL prior to TKA surgery with previously reported values. METHODS: A total of 247 knees (216 consecutive patients) that underwent TKA were retrospectively evaluated. The preoperative diagnosis for all patients was primary OA. The macroscopic appearance of the ACL at the time of surgery was retrospectively assessed using routinely recorded digital photographs and classified as normal, moderately damaged (fissured), or completely ruptured. Both normal and moderately damaged ACLs were defined as intact. RESULTS: Ninety-four percent (233/247) of the knees had an intact ACL (normal or moderately damaged). This value is higher than that found in previous reports. CONCLUSIONS: Our results show more candidates for bicruciate ligament-retaining TKA surgery than reported previously. This suggests that improved techniques for bicruciate-retaining TKA would be clinically useful and could benefit a large number of patients.

Preoperative Bone Mineral Density and Bone Turnover in Women Before Primary Knee Arthroplasty.

PURPOSE: The preoperative prevalence of osteoporosis and/or osteopenia and overall bone quality in prospective total knee arthroplasty (TKA) patients may affect the postoperative outcome after prosthetic insertion into the bone. The purpose of this study is to determine the baseline bone mineral density (BMD) and bone turnover in preoperative, female, primary TKA patients. METHODS: We prospectively measured the lumbar spine and hip BMDs using dual-energy X-ray absorptiometry (DEXA) scans in a cohort of 119 knees (107 patients) one day before surgery. We also assessed bone turnover using urinary levels of N-telopeptide (NTX), a type I collagen crosslinker, normalized to creatinine. RESULTS: The prevalence of osteoporosis by DEXA scan (T-score ≤ -2.5) among the TKAs was 12% in the spine and 10% in the hip. Eighty-three knees (70%) had osteopenia or osteoporosis of either the spine or hip. The mean T-score of the spine was -0.7 (SD 1.6), which is within normal limits, and of the hip was -1.2 (SD 1.0), which is defined as osteopenia. The mean Z-scores of 0.9 (SD 1.4) in the spine and 0.6 (SD 0.9) in the hip were positive. The median urinary NTX/creatinine ratio was elevated at 58.1 (interquartile range: 13.7 to 188.4). CONCLUSION: Based on Z-scores, the TKA patients had higher spine and hip BMDs than the age-matched general population. Elevated NTX levels may suggest a systemic or local abnormal bone turnover. Further study is needed to determine whether such turnover, as a type of patient-related medical systemic disorder, affects postoperative clinical outcomes.

Characteristics and significance of fever during 4 weeks after primary total knee arthroplasty.

PURPOSE: Most previous studies on postoperative fever (POF; ≥38 °C) after total knee arthroplasty (TKA) have reported findings from only the immediate postoperative days (PODs). The hypothesis of the current study is that 4 weeks of follow-up may reveal differences in the characteristics of POF and fever-related factors between a normal inflammatory response and an early acute infection-related response. METHODS: A total of 400 consecutive TKAs (314 patients) were retrospectively investigated. Patients were stratified into those who developed an early acute periprosthetic infection that required subsequent surgical treatment (STG; n = 5 TKAs) and those who did not (non-STG; n = 395 TKAs). RESULTS: Among the 400 knees, 149 (37 %) developed POF, with most reaching a maximum temperature (MT) on POD 0. In 13 TKA patients who had POF with a peak daily temperature ≥38 °C during postoperative weeks 2-4, the causes of POF were respiratory and urinary tract infections (n = 5 for each), superficial infection (n = 2), and periprosthetic infection (n = 1). The STG and non-STG differed significantly with regard to the rate of POF (p = 0.0205) and MT (p = 0.0003), including MTs less than 38 °C, during postoperative weeks 2-4. All five STG patients had elevated C-reactive protein levels and local symptomatic findings before the additional surgery. CONCLUSIONS: The occurrence of POF and MT along with elevated C-reactive protein and local symptomatic findings at 2-4 weeks postoperatively may indicate the need for a positive fever workup to recognize early acute periprosthetic infection.

Synthetic double-stranded RNA enhances airway inflammation and remodelling in a rat model of asthma.

Respiratory viral infections are frequently associated with exacerbations of asthma. Double-stranded RNA (dsRNA) produced during viral infections may be one of the stimuli for exacerbation. We aimed to assess the potential effect of dsRNA on certain aspects of chronic asthma through the administration of polyinosine-polycytidylic acid (poly I:C), synthetic dsRNA, to a rat model of asthma. Brown Norway rats were sensitized to ovalbumin and challenged three times to evoke airway remodelling. The effect of poly I:C on the ovalbumin-induced airway inflammation and structural changes was assessed from bronchoalveolar lavage fluid and histological findings. The expression of cytokines and chemokines was evaluated by real-time quantitative reverse transcription PCR and ELISA. Ovalbumin-challenged animals showed an increased number of total cells and eosinophils in bronchoalveolar lavage fluid compared with PBS-challenged controls. Ovalbumin-challenged animals treated with poly I:C showed an increased number of total cells and neutrophils in bronchoalveolar lavage fluid compared with those without poly I:C treatment. Ovalbumin-challenged animals showed goblet cell hyperplasia, increased airway smooth muscle mass, and proliferation of both airway epithelial cells and airway smooth muscle cells. Treatment with poly I:C enhanced these structural changes. Among the cytokines and chemokines examined, the expression of interleukins 12 and 17 and of transforming growth factor-ß(1) in ovalbumin-challenged animals treated with poly I:C was significantly increased compared with those of the other groups. Double-stranded RNA enhanced airway inflammation and remodelling in a rat model of bronchial asthma. These observations suggest that viral infections may promote airway remodelling.

RANTES expression induced by Toll-like receptor 4 ligand in rat airway smooth muscle cells.

Airway smooth muscle cells (ASMCs) have been reported to express Toll-like receptors (TLRs) and take part in the pathogenesis of asthma exacerbation. Though TLRs were found to activate epidermal growth factor receptor (EGFR) in airway epithelial cells, little is known about the association of TLR ligands with EGFR signaling pathways in ASMCs. Using primary cultured ASMCs from Brown Norway rats, TLR4, eotaxin, and RANTES mRNA were examined by real-time quantitative RT-PCR after stimulation with the TLR4 ligand, lipopolysaccharides (LPS). The concentration of RANTES protein in culture supernatant was measured by ELISA. The effect of EGFR signaling inhibitors on RANTES expression was examined as well. Phosphorylation of EGFR after stimulation was examined by Western Blotting. Rat ASMCs expressed TLR4 and eotaxin, and LPS upregulated RANTES production. The EGFR tyrosine kinase inhibitor AG1478, the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, and the matrix metalloproteinase (MMP) inhibitor GM6001 inhibited RANTES expression induced by LPS. LPS phosphorylated EGFR. TLR4 activation can induce RANTES expression via EGFR transactivation and PI3K/Akt pathway in rat ASMCs. MMP-induced EGFR proligand cleavage and ligand binding to EGFR seem to be involved in this pathway. These findings may be critical in the pathogenesis of asthma exacerbation by airway infection.

[A case of pulmonary Mycobacterium shimoidei infection].

A 68 year-old male who was ex-smoker presented with fever and cough. Chest radiograph showed infiltrative shadows in both upper lung fields. A sputum smear for acid-fast bacilli was positive. But the isolate was not identified by polymerase chain reaction method. Acid-fast bacilli were cultured from sputum, but the identification was not done by DNA-DNA hybridization method. Mycobacterium shimoidei was identified by 16S ribosomal RNA sequencing with 98.42% matching. Rifampicin, ethambutol, clarithromycin, pyrazinamide, and ciprofloxacin were administered, and the symptom and abnormal shadows on chest radiography improved. And three months later from the initiation of treatment, sputum smear for acid-fast bacilli became negative. Chest CT scan four months after treatments showed decrease of infiltrative shadows. We had treated him for six months, and after that no recurrence occurred.

Effects of ethylcellulose and 2-octyldodecanol additives on skin permeation and irritation with ethylene-vinyl acetate copolymer matrix patches containing formoterol fumarate.

Skin permeation of formoterol fumarate (FF) and irritation with ethylene-vinyl acetate (EVA) copolymer matrix patches was investigated using rat and human skin in vitro and different species of experimental animal, respectively. Skin permeation of FF increased remarkably without addition of ethylcellulose (EC) and was remarkably enhanced by incorporation of 2-octyldodecanol (OD) instead of hydrogenated rosin glycerol ester (Ester Gum H). Effects on skin permeation of FF with EVA matrix patches were similar in rat and human skin, but rat skin was 1000 times more permeable than human skin after 24 h. The primary irritation indices for matrix patches without EC and with EC (OD-0), EC and 0.5 mg OD per square centimeter (OD-0.5), and EC and 1.0 mg OD per square centimeter (OD-1) were 1.46, 1.13,1.29 and 1.38. The results suggested that the irritation induced by these patches was rather mild, but significantly greater than the 0.21 observed with the control. No significant effects were noted for either EC or OD alone. Skin irritation intensity with EVA matrix patches was observed to be in the order of rabbits, guinea pigs, rats and miniature swine.

Formulation and evaluation of ethylene-vinyl acetate copolymer matrix patches containing formoterol fumarate.

The skin permeability and stability of formoterol fumarate (FF) in matrix patches containing l-menthol as an enhancer and N-methyl-2-pyrrolidone (NMP) as the solvent were investigated. Using a total of 28 matrix patches having a similar composition, containing ethylene-vinyl acetate (EVA) as the forming polymer and hydrogenated rosin glycerol ester (Ester Gum H) as the adhesive, the skin permeation of FF was found to increase with increasing l-menthol and NMP contents. FF in the matrix patches containing NMP in the range of 4.8-7.2% was stable, but stability decreased at higher values. With a standard matrix patch containing FF, the Cmax and AUC(0-24) values were found to be 1.93 ng/ml after 4 h percutaneous application to rats and 25.6 ng x h/ml. The bioavailability after percutaneous exposure was equivalent to 15.2% of the AUC(0-24) after intravenous administration. Percutaneous application proved efficacious with regard to control of simulated asthma at dose levels lower than those with which side effects occurred. Thus an optimized matrix patch containing FF was prepared with potential advantages for control of asthma.

Effects of solvents on skin permeation of formoterol fumarate.

Effects of various chemicals applied as penetration enhancers on the permeation of formoterol fumarate (FF) across excised rat skin were investigated. Remarkable enhancement was noted with terpenes, fatty acid esters, and higher alcohols, whereas no significant influence was observed in the case of lower alcohols, pyrrolidones, and amines. At high concentration, a cineole/N-methyl-2-pyrrolidone (NMP) mixed solvent system slightly enhanced the skin permeation of FF compared with cineole alone, and a l-menthol/NMP mixed solvent system caused significant further increase. Maximum skin permeation of FF was seen when the ratio of l-menthol/NMP was 60/40 w/w. From the present results, l-menthol/NMP and isopropyl myristate (IPM)/NMP mixed solvent systems can be considered effective for augmenting skin permeation of FF, with potential applications in transdermal delivery of the drug.

[A case of pyothorax caused by Mycobacterium avium].

A 74-year-old woman was admitted to our hospital in December, 2003 because of anorexia and weight loss lasting from August, 2003. Chest CT scan showed empyema with a niveau in the right lung and infiltrative and nodular shadows in the left lung. Acid-fast bacilli were detected in pleural effusion. Polymerase chain reaction (PCR) test was negative for Mycobacterium tuberculosis (M. tuberculosis) but positive for Mycobacterium avium (M. avium). PCR test for M. avium was also positive in bronchial lavage fluid, and many colonies of M. avium complex ( MAC) were cultured from pleural effusion. After we administered 4 drugs including RFP, EB, SM, and CAM, cultured colonies of M. avium decreased, the inflammatory reaction improved, and infiltrates in the left upper lobe has disappeared. These improvements confirmed the diagnosis of empyema caused by M. avium. Since nontuberculous mycobacteria induced empyema has rarely been reported, the clinical features of this disease should further be examined.

[Penicillamine-induced bronchiolitis obliterans diagnosed by transbronchial lung biopsy].

A 57-year-old woman had been treated with penicillamine (200 mg/day) for degenerative arthritis initially misdiagnosed as rheumatoid arthritis since 2003. She presented with dyspnea and was admitted to our hospital in 2004. Pulmonary function tests revealed mixed pattern of dysfunction with severe airway obstruction. Chest computed tomography showed mosaic ground-glass opacities. Bronchoalveolar lavage fluid (BALF) demonstrated increase in total cells and lymphocytes. Since specimens of transbronchial lung biopsy (TBLB) showed lymphocytic infiltration in membranous bronchiole and occlusion of the membranous bronchiole lumen, bronchiolitis obliterans was diagnosed by TBLB. After penicillamine, which had been administered for 7 months, was stopped, she was successfully treated with steroid and macrolides.

Phototoxicity study of a ketoprofen poultice in guinea pigs.

Ketoprofen has been reported to have such side effects as photosensitive dermatitis in humans (The Ministry of Health, Labour and Welfare, 2001). In the present study, as part of a safety evaluation of Miltax, an application drug containing ketoprofen, phototoxicity of Miltax was examined in guinea pigs. In the present skin phototoxicity study, Miltax was applied for 12 hr. Ultraviolet (UV) rays were irradiated to examine whether or not Miltax elicited skin reaction. Two kinds of UV-A plus UV-B dual irradiation and UV-A single irradiation were used for the elicitation. With UV-A plus UV-B dual irradiation on the Miltax application site, no skin reaction was observed at UV irradiation side in any animals, in contrast to the case of the positive control article, 8-methoxypsoralen (8-MOP). Similar results were obtained with UV-A single irradiation. From these results, Miltax that contained ketoprofen did not show any skin phototoxicity in the guinea pig.

Tocolytic effects of formoterol are associated with local change in the progesterone/estradiol ratio.

OBJECTIVE: The aim of the study was to determine whether a beta(2)-adrenoceptor agonist, formoterol, inhibits premature delivery in connection with change in estradiol and progesterone concentrations in the amniotic fluid in ovariectomized rats. STUDY DESIGN: Pregnant rats at the 15th day of gestation were bilaterally ovariectomized and given injection of 17beta-estradiol immediately after the operation and every 24 h. An osmotic pump filled with a solution of formoterol or saline was also implanted subcutaneously into the back of each. The animals were killed by decapitation under light ether anesthesia 18, 36, 54 or 72 h after ovariectomy, and the numbers of undelivered fetuses and newborn were counted. Amniotic fluid was collected 16, 36, and 54 h after ovariectomy. RESULTS: Formoterol (0.15 mg/(kg h)) reversed the decline in premature delivered fetuses due to 17beta-estradiol 54 and 72 h after ovariectomy. Although no influence was evident regarding the progesterone and estradiol concentrations in amniotic fluid in ovariectomized rats supplemented with 17beta-estradiol, formoterol significantly inhibited the increment in the estradiol/progesterone ratio as well as the elevation in prostaglandin F2alpha concentration. CONCLUSION: These findings indicate that tocolytic effects of formoterol may be associated with suppression of uterine activity due to modulation of hormone secretion.

Comparison of poultice-type and tape-type patches containing ketoprofen on human skin irritation.

Although the patch test for visual skin observation is widely used clinically, it does not allow the mechanisms of side effects to be assessed. In this study, we examined poultice-type KP801 and tape-type KP-T patches containing ketoprofen. The parameters to measure side effects on skin were peeling intensity, amount of stripped stratum corneum, skin moisture and redness of skin color under various mechanical conditions. Since the amount of stripped stratum corneum with the tape-type KP-T patch was higher than with the poultice-type KP801 patch, the bio-adhesive strength of the latter was concluded to be lower. A clear relationship exists between the amount of stripped stratum corneum and skin moisture after tape-type patch removal, but this was not found with the poultice-type patch because of its hydration effects. Peeling intensity, one parameter to predict pain at the time of patch removal, was higher with the KP-T. As for mechanical conditions, when the patch is removed, it is important to remove it as slowly as possible and horizontally, and to avoid any rise in skin temperature. Finally, when a patch is applied to a region with little skin moisture, the amount of stripped stratum corneum may increase accordingly.

Direct analysis of indomethacin in rat plasma using a column-switching high-performance liquid chromatographic system.

We have established a robust, fully automated analytical method for the determination of indomethacin in rat plasma using a column-switching high-performance chromatographic system. The system consists of a precolumn and an analytical column connected in series via a switching valve. When a 50-microl portion of rat plasma containing a therapeutic level of indomethacin was applied directly to the system, the drug was automatically enriched in the precolumn (TSK BSA-ODS) by on-line solid-phase extraction. After elution of the plasma proteins, the analyte was automatically transferred to the analytical column (Zorbax Eclipse XDBC18) where chromatography was performed using isocratic elution and UV absorption detection at a wavelength of 254 nm. The separation mobile phase consisted of methanol-0.1% phosphoric acid (70:30, v/v) at a flow-rate of 1 ml/min. The calibration line for indomethacin showed good linearity in the range 50-10 000 ng/ml (r>0.999) with the detection quantification of 50 ng/ml (RSD=2.6%). Accuracy ranged from -0.62 to 3.22%, and the within- and between-day precision of the assay was better than 6% across the calibration range. The analytical sensitivity and accuracy of this assay is suitable for characterization of the pharmacokinetics of topical administration of imdomethacin to rats. The method has been successfully used to provide pharmacokinetic data in a large number of diverse pharmaceutical studies.