Older Age, Poor Preoperative Quadriceps Muscle Strength, and Residual Pain as Risk Factors for Poor Quadriceps Muscle Strength Recovery at 1 Year After ACL Reconstruction: A TMDU MAKS Study of 402 Patients.

Background: Poor postoperative quadriceps muscle strength recovery after anterior cruciate ligament reconstruction (ACLR) leads to delayed return to sports and lower patient satisfaction. Purpose/Hypothesis: The purpose of this study was to examine factors that affect quadriceps muscle strength 1 year after ACLR. It was hypothesized that older age, poor preoperative quadriceps muscle strength, and residual pain would be risk factors for poor quadriceps muscle strength recovery. Study Design: Case-control study; Level of evidence, 3. Methods: Included were patients from multiple institutions who underwent primary ACLR using autologous hamstring tendon grafts between August 1, 2013, and March 31, 2018, and who had at least 1 year of follow-up data. Patients with past ligamentous injuries in the affected knee, previous injuries or operations in the contralateral knee, accompanying ligament injuries of grade 2 or 3, or inflammatory or other types of osteoarthritis were excluded. Patients were categorized as having muscle strength ≥80% (good strength recovery) or <80% (poor strength recovery) compared with the contralateral leg at 1 year postoperatively. Multivariate logistic regression analysis was performed to investigate the factors influencing postoperative quadriceps muscle strength. In addition, a categorical analysis was conducted based on factors extracted by the multivariate logistic regression analysis. Results: A total of 402 patients were included. Multivariate logistic regression analysis revealed that age at surgery (P = .020), preoperative quadriceps muscle strength (P = .006), and postoperative Knee injury and Osteoarthritis Outcome Score (KOOS)-Pain score (P = .002) were significantly associated with quadriceps muscle strength at 1 year postoperatively. The odds of poor muscle strength recovery according to categorical analysis were 5.0-fold higher for patients aged >40 versus ≤20 years, 4.2-fold higher for those with preoperative quadriceps muscle index <60% versus ≥80%, and 7.7-fold higher for those with a postoperative KOOS-Pain score of <85 versus 100. Conclusion: Older age, poor preoperative quadriceps muscle strength, and low postoperative KOOS-Pain score were risk factors for poor quadriceps muscle strength 1 year after primary ACLR. Surgical indications, including age, preoperative active rehabilitation, and pain control, should be considered for optimization of postoperative quadriceps muscle strength recovery.

Development of Photoredox Cross-Electrophile Coupling of Strained Heterocycles with Aryl Bromides Using High-Throughput Experimentation for Library Construction.

Microscale high-throughput experimentation was used to develop a photoredox-assisted reductive cross-coupling reaction of aryl halides with strained aliphatic heterocycles facilitated via a ring-opening reaction. This methodology was found to be applicable to medicinally relevant substrates including Boc-protected strained aliphatic heterocycles and (hetero)aryl bromides and was used for compound library construction via parallel medicinal chemistry. Furthermore, the coupling reactions were shown to be scalable to the gram scale by continuous flow reaction. A possible reaction mechanism is also discussed.

Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.

Fragment-based ligand discovery was successfully applied to histone deacetylase HDAC2. In addition to the anticipated hydroxamic acid- and benzamide-based fragment screening hits, a low affinity (∼1 mM) α-amino-amide zinc binding fragment was identified, as well as fragments binding to other regions of the catalytic site. This alternative zinc-binding fragment was further optimized, guided by the structural information from protein-ligand complex X-ray structures, into a sub-µM, brain penetrant, HDAC2 inhibitor (17) capable of modulating histone acetylation levels in vivo.

Effects of different surgical procedures for meniscus injury on two-year clinical and radiological outcomes after anterior cruciate ligament reconstructions. -TMDU MAKS study.

BACKGROUND: The treatment of meniscus injuries combined with anterior cruciate ligament (ACL) reconstruction would be important to improve outcomes after ACL reconstruction. However, the effects of treatment methods for meniscus after ACL reconstruction have not been thoroughly investigated. The objective of this study was to investigate the effects of treatment methods for meniscus on clinical and radiological outcomes at 2 years after ACL reconstruction. METHODS: Three-hundred and eighteen patients with primary ACL reconstruction using autologous hamstring tendon registered in our multicenter study database and who were followed up for 2 years were included. They were then divided into 3 groups, the no meniscal lesion/untreated group (n = 149), the meniscal repair group (n = 139), and the meniscal resection group (n = 30). Patient-based subjective evaluations (Lysholm score, Knee injury and Osteoarthritis Outcome score and International Knee Documentation Committee subjective score), objective evaluations (Lachman test, pivot shift test and KT measurement), and radiological measurements (medial and lateral joint space width) were compared among the 3 groups preoperatively and at 2 years follow-up. RESULTS: All subjective scores and objective evaluations significantly improved in all groups without significant differences among the groups postoperatively. Regarding radiological findings, the medial joint space width significantly decreased only in the resection group during the 2-year period, and the medial joint space width in the resection group was significantly smaller than that of the other groups at the 2-year follow-up. Moreover, the medial joint space width significantly decreased during the 2-year period when MM was resected. CONCLUSIONS: In radiological findings, medial meniscus resection decreased medial joint space width two years after ACL reconstruction. On the other hand, treatment methods for meniscus neither significantly affected subjective nor objective findings until the 2-year follow-up. LEVEL OF EVIDENCE: Ⅱ, Cohort study.

Comparison of tissue pharmacokinetics of esflurbiprofen plaster with flurbiprofen tablets in patients with knee osteoarthritis: A multicenter randomized controlled trial.

This open-label, multicenter, prospective, randomized controlled trial aimed to determine the effectiveness of esflurbiprofen plaster (SFPP) and flurbiprofen tablets (FPTs) on knee osteoarthritis in patients scheduled for total knee arthroplasty by comparing the transfer of esflurbiprofen and flurbiprofen to tissues and fluids. Thirty-eight patients were randomly assigned in a 1:1 ratio to receive SFPP or FPT. Both groups were then divided into four subgroups, according to whether they received the final dose of SFPP or FPT at 2, 7, 12, or 24 h before planned surgery. The primary endpoints were the esflurbiprofen concentrations in synovium, synovial fluid, and plasma. Areas under concentration-time curves (AUC0-24 h ) of esflurbiprofen were calculated for each group. Pain was assessed using a numeric rating scale (NRS) 7 days before and immediately before surgery. The AUC0-24 h in the synovium were 4401.24 and 4862.70 ng·h/g in the SFPP and FPT groups, respectively. Maximum esflurbiprofen concentrations were observed in the synovium, synovial fluids, and plasma after SFPP application for 12 h. The NRS results indicated a long-lasting effect of SFPP. The AUC of the synovial esflurbiprofen concentration of SFPP indicated that the SFPP is transferred to the synovium and synovial fluid in high concentration. The efficient deep-tissue transfer of esflurbiprofen suggests that its pharmacokinetic characteristics differ from those of conventional topical NSAIDs. This study was prospectively registered in the Japan Registry of Clinical Trials (registration number: jRCTs031180228).

Lateral Collateral Ligament Repair for Hallux Metatarsophalangeal Joint Instability in a Collegiate Sumo Wrestler: A Case Report.

Although sprains of the hallux metatarsophalangeal (MTP) joint ligaments occur in barefooted martial arts athletes, few studies discuss the surgical treatments for lateral collateral ligament damage. We report herein a case of lateral collateral ligament repair for chronic hallux MTP joint instability. A 21-year-old male collegiate sumo wrestler injured his left hallux by snagging it on a sumo straw bale at 14 years of age. After entering university (4 years after the injury), he could no longer put weight on his foot at the left hallux; his athletic performance deteriorated, and he was referred to our department by his doctor. He had instability in the MTP joint of the left hallux, and magnetic resonance imaging revealed a tear in the attachment of the lateral collateral ligament to the metatarsal bone. Conservative treatment, such as taping, did not improve the symptoms; thus, surgery was performed, which consisted of passing a strong suture attached to the capsular ligament through a burr hole made in the metatarsal bone and fixing it to the burr-hole wall using an anchor. Postoperatively, the patient's joint instability improved, and he returned to competitive wrestling 4 months after surgery. He was able to put weight on his left hallux, and his athletic performance improved. The follow-up period after surgery was 2 years. In competitive sumo wrestling, hallux weakness and joint instability lead to a significant reduction in performance. Thus, ligament repair is an effective treatment for hallux MTP joint instability that cannot be treated by conservative means.

Second Anterior Cruciate Ligament Injuries After Anterior Cruciate Ligament Reconstruction in Professional Sumo Wrestlers: A Case Series.

BACKGROUND: Anterior cruciate ligament (ACL) injury is one of the most common traumatic injuries in professional sumo wrestlers. Further, ipsilateral reinjuries or contralateral ACL injuries after ACL reconstruction can occur in sumo wrestlers. The incidence of ipsilateral reinjury and contralateral ACL injury after ACL reconstruction ranges from 3% to 13% in a healthy athletic population. PURPOSE: To investigate the current status of second ACL injuries after ACL reconstruction in sumo wrestlers. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between 1988 and 2015, a total of 139 primary ACL reconstructions were performed in professional sumo wrestlers at our hospital. After exclusion of cases of multiple ligament knee reconstruction and patients in whom the contralateral ACL had been injured previously, 110 cases were included in this study. We investigated the number of second injuries, time from primary reconstruction to second injury, treatment method, and change in official sumo ranking after second injuries. The chi-square test, Student t test, and Fisher exact text were used for statistical analysis. RESULTS: Among 110 wrestlers who underwent ACL reconstruction, second injuries after primary ACL reconstruction occurred in 22 cases (20.0%). Among them, 14 cases (12.7%) entailed ipsilateral reinjury, 11 (10.0%) entailed contralateral injury, and 3 involved combined rerupture and contralateral injury. As for surgical treatment, 5 revision ACL reconstructions were performed for ipsilateral reinjury (35.7%), and 7 ACL reconstructions were performed for contralateral injury (63.6%). Surgical treatment was not performed for the remaining cases. Wrestlers who were treated by revision or contralateral ACL reconstruction after the second injury were demoted in rank for 3 to 4 tournaments but overtook the nonoperative treatment group in ranking by 2 years postoperatively; all athletes initially were demoted in rank after the second injury. CONCLUSION: This study is the first to investigate instances of ipsilateral reinjuries and contralateral ACL injuries after ACL reconstruction in professional athletes in heavyweight combat sports. The incidences of ipsilateral reinjury and contralateral ACL injury after ACL reconstruction in professional sumo wrestlers were relatively higher than those reported in previous studies.

Jones Fractures in Sumo Wrestlers: Three Case Reports.

Jones fractures sometimes occur in athletes and are known to have complications, such as nonunion, delayed union, and recurrence, even with treatment. We describe three cases of Jones fractures in sumo wrestlers with treatment-related difficulties. All patients discontinued treatment at their own discretion. The two conservative cases had nonunion or delayed union, and the operative case had a broken screw. However, all patients continued sumo wrestling, with little impact on their careers. The risk factors of Jones fractures in sumo wrestling may be heavy weight, and training or competition characteristics unique to sumo wrestling. In cases of a complete Jones fracture, operative treatment is most commonly selected, as the risk for nonunion or refractures is less than that for conservative treatment. However, in the case of sumo wrestlers, there are risks of infection and problems with treatment compliance. As taking a rest may result in a lowered rank, completing a sufficient duration of treatment is difficult. Treatment is difficult and controversial in sumo wrestlers; all three patients discontinued treatment of their own accord. These cases suggest that it is important to thoroughly inform sumo wrestlers of the treatment options, and to decide the most appropriate treatment method for each patient.

Treatment of Incomplete Jones Fractures With Low-Intensity Pulsed Ultrasound (LIPUS).

OBJECTIVE: Stress fractures of the proximal epiphysis of the fifth metatarsal bone (termed Jones fracture) frequently occur in both senior high-school-age and older contestant-level soccer players, and its incidence in Japanese soccer players is higher than that in European players. Surgery is most commonly indicated for a complete fracture, and about 3 months are required before the patient is able to return to the sport. We have performed a "Jones fracture screening" to reduce the incidence of these fractures. While surveying its frequency and promoting education on its prevalence and symptoms, we tried to discover incomplete fractures early and treat them using LIPUS without limiting their soccer practice. SUBJECTS AND METHODS: The subjects were 341 students (682 feet) from 3 senior high schools and university soccer clubs. Primary screening for tenderness and by diagnostic ultrasound imaging was performed as a Jones fracture screening. Fifty subjects (50 feet) were positive on the ultrasonic diagnosis, and secondary screening was recommended. Forty subjects underwent radiography (secondary screening rate: 80%), and 5 subjects (5 feet) were diagnosed with incomplete Jones fractures. Conservative treatment centering on LIPUS was performed in these 5 players who still continued to participate in all soccer practices. RESULTS: Bone union was achieved in 2 subjects (2 feet) after about 6 months without taking a break from soccer practice. The other 3 subjects (3 feet) are at 2 months after the diagnosis and are being followed without taking a break from soccer practice. DISCUSSION: Incomplete Jones fractures that are discovered early by an ultrasonic check-up for bone expansion with subsequent early treatment with LIPUS may heal without taking a break from practice. No preventive method has been established for Jones fractures. This check-up may serve as a useful preventative approach, and we will make an effort to suggest it as a common practice.

Outcome of Low-Intensity Pulsed Ultrasound (LIPUS) for Opening Wedge High Tibial Osteotomy.

OBJECTIVE: Opening Wedge High Tibial Osteotomy (OWHTO) for knee osteoarthritis and for osteonecrosis has reported good results. Use of low intensity pulsed ultrasound (LIPUS) after OWHTO had become an option for the treatment of OWHTO since April 2016. The purpose of this study was to examine whether LIPUS has an accelerating effect on synostosis after OWHTO. MATERIALS AND METHODS: The control subjects were 24 patients with a total of 26 knees (9 male with knees and 15 female with 17 knees treated) treated with OWHTO only. OWHTO was performed from April 2015 to March 2016 (non-LIPUS control group). The average age of the patients was 61 years. The test subjects were 25 patients with a total of 27 knees (8 male with 9 knees and 17 female with 18 knees treated) treated with OWHTO and LIPUS. OWHTO was performed from April 2016 until the present. LIPUS was started after the surgery (LIPUS + group). The average age was 64.6 years. FTA, ROM, intraoperative open angle, and the time to bone union were examined. RESULTS: There was no difference between the 2 groups in FTA, ROM, and open angle. Synostosis was obtained in 18 knees in the control group (no LIPUS) with an average duration of 8.4 months. The LIPUS + group had a short observation period with none of the patients experiencing bone union. DISCUSSION: The synostosis promoting effect of LIPUS is expected. In this study, there were no bone union cases because of the short observation period. It is necessary to extend the follow-up period, and clarify the utility of LIPUS.

Discovery and characterization of a novel potent, selective and orally active inhibitor for mammalian ELOVL6.

The elongase of long chain fatty acids family 6 (ELOVL6) is a rate-limiting enzyme for the elongation of saturated and monounsaturated long chain fatty acids. ELOVL6 is abundantly expressed in lipogenic tissues such as liver, and its mRNA expression is up-regulated in obese model animals. ELOVL6 deficient mice are protected from high-fat-diet-induced insulin resistance, suggesting that ELOVL6 might be a new therapeutic target for diabetes. We previously identified an indoledione compound, Compound A, as the first inhibitor for mammalian ELOVL6. In this study, we discovered a novel compound, Compound B, and characterized its biochemical and pharmacological properties. Compound B has a more appropriate profile for use as a pharmacological tool compared to Compound A. Chronic treatment with Compound B in model animals, diet-induced obesity (DIO) and KKAy mice, showed significant reduction in hepatic fatty acid composition, suggesting that it effectively inhibits ELOVL6 activity in the liver. However, no improvement in insulin resistance by ELOVL6 inhibition was found in these model animals. Further studies need to address the impact of ELOVL6 inhibition on pharmacological abnormalities in several model animals. This is the first report on pharmacology data from chronic studies using a selective ELOVL6 inhibitor. Compound B appears to be a useful tool to further understand the physiological roles of ELOVL6 and to evaluate the therapeutic potential of ELOVL6 inhibitors.

Discovery of novel benzoxazinones as potent and orally active long chain fatty acid elongase 6 inhibitors.

A series of benzoxazinones was synthesized and evaluated as novel long chain fatty acid elongase 6 (ELOVL6) inhibitors. Exploration of the SAR of the UHTS lead 1a led to the identification of (S)-1y that possesses a unique chiral quarternary center and a pyrazole ring as critical pharmacophore elements. Compound (S)-1y showed potent and selective inhibitory activity toward human ELOVL6 while displaying potent inhibitory activity toward both mouse ELOVL3 and 6 enzymes. Compound (S)-1y showed acceptable pharmacokinetic profiles after oral dosing in mice. Furthermore, (S)-1y significantly suppressed the elongation of target fatty acids in mouse liver at 30 mg/kg oral dosing.

Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor.

A series of 2-pyridone-containing imidazoline derivatives was synthesized and evaluated as neuropeptide Y Y5 receptor antagonists. Optimization of the 2-pyridone structure on the 2-position of the imidazoline ring led to identification of 1-(difluoromethyl)-5-[(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl]pyridin-2(1H)-one (7m). Compound 7m displayed statistically significant inhibition of food intake in an agonist-induced food intake model in SD rats and no adverse cardiovascular effects in anesthetized dogs. In addition, markedly higher brain penetrability and a lower plasma Occ90 value were observed in P-gp-deficient mdr1a (-/-) mice compared to mdr1a (+/+) mice after oral administration of 7m.

Synthesis and evaluation of a novel 2-azabicyclo[2.2.2]octane class of long chain fatty acid elongase 6 (ELOVL6) inhibitors.

A series of novel 2-azabicyclo[2.2.2]octane derivatives was synthesized and evaluated as long chain fatty acid elongase 6 (ELOVL6) inhibitors. Screening of our corporate chemical collections against ELOVL6 resulted in the identification of lead 1. Exploratory chemistry efforts were applied to lead 1 to identify the orally available, potent, and selective ELOVL6 inhibitor 28a.

Identification and characterization of a selective radioligand for ELOVL6.

ELOVL6, a member of the elongation of very long-chain fatty acids (ELOVL) family, has recently been identified as the rate-limiting enzyme for the elongation of palmitoyl-CoA. ELOVL6 deficient mice are protected from high-fat diet induced insulin resistance, suggesting that ELOVL6 might be a promising target for the treatment of metabolic disorders. Despite the increasing interest in Elovl6 as a therapeutic target, the lack of chemical tools for this enzyme has limited further elucidation of the biochemical and pharmacological properties of ELOVL6. We have identified Compound-A, a potent inhibitor for ELOVL6, by screening our company library and subsequently optimizing hit compounds. Compound-A potently inhibited human and mouse ELOVL6 and displayed >100-fold greater selectivity for ELOVL6 over other ELOVL family members. Consistent with its potent and selective inhibitory activity toward ELOVL6, [(3)H]Compound-A bound to ELOVL6 with high affinity while showing no specific binding to other ELOVL enzymes. The observation that [(3)H]Compound-A bound to ELOVL6 in a palmitoyl-CoA-dependent manner in the absence of malonyl-CoA and NADPH suggests that Compound-A might recognize an enzyme-substrate complex, e.g. an acyl-enzyme intermediate. Collectively, these observations demonstrate that Compound-A and its tritiated form are useful tools for biochemical and pharmacological characterization of ELOVL6.

Synthesis, structure-activity relationships, and biological profiles of a dihydrobenzoxathiin class of histamine H(3) receptor inverse agonists.

A series of novel dihydrobenzoxathiin derivatives was synthesized and evaluated as potent human histamine H(3) receptor inverse agonists. After systematic modification of lead 1a, the potent and selective histamine H(3) inverse agonist 1-(3-{4-[(2S,3S)-8-methoxy-3-methyl-4,4-dioxido-2,3-dihydro-1,4-benzoxathiin-2-yl]phenoxy}propyl)pyrrolidine (5k) was identified. Compound 5k showed good pharmacokinetic profiles and brain penetrability in laboratory animals. After 3mg/kg oral administration of 5k, significant elevation of brain histamine levels was observed in rats where the brain H(3) receptor was fully occupied.

Synthesis and biological evaluation of a novel 3-sulfonyl-8-azabicyclo[3.2.1]octane class of long chain fatty acid elongase 6 (ELOVL6) inhibitors.

Long chain fatty acid elongase 6 (ELOVL6) catalyzes the elongation of long chain fatty acyl-CoAs and is a potential target for the treatment of metabolic disorders. The ultrahigh throughput screen of our corporate chemical collections resulted in the identification of a novel 3-sulfonyl-8-azabicyclo[3.2.1]octane class of ELOVL6 inhibitor 1a. Optimization of lead 1a led to the identification of the potent, selective, and orally available ELOVL6 inhibitor 1w.

Development of a selective and potent radioactive ligand for histamine H(3) receptors: A compound potentially useful for receptor occupancy studies.

Radioligands are powerful tools for examining the pharmacological profiles of chemical leads and thus facilitate drug discovery. In this study, we identified and characterized 3-([1,1,1-(3)H]methyl)-2-(4-{[3-(1-pyrrolidinyl)propyl]oxy} phenyl)-4(3H)-quinazolinone ([(3)H]1) as a potent and selective radioligand for histamine H(3) receptors. Radioligand [(3)H]1 exhibited appreciable specific signal in brain slices prepared from wild-type mice but not from histamine H(3) receptor-deficient mice, demonstrating the specificity and utility of [(3)H]1 as a selective histamine H(3) receptor radioligand for ex-vivo receptor occupancy assays.

5,5-Dimethyl-3-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-1-phenyl-3-(trifluoromethyl)-3,5,6,7-tetrahydro-1H-indole-2,4-dione, a potent inhibitor for mammalian elongase of long-chain fatty acids family 6: examination of its potential utility as a pharmacological tool.

Long-chain fatty acid elongases reside in the endoplasmic reticulum and are responsible for the rate-limiting step of the elongation of long-chain fatty acids. The elongase of long-chain fatty acids (ELOVL) family 6 (ELOVL6) is involved in the elongation of saturated and monosaturated fatty acids. Increased expression of ELOVL6 in ob/ob mice suggests a role for ELOVL6 in metabolic disorders. Furthermore, ELOVL6-deficient mice are protected from high-fat diet-induced insulin resistance, which suggests that ELOVL6 might be a new therapeutic target for diabetes. As reported previously, we developed a high-throughput screening system for fatty acid elongases and discovered lead chemicals that possess inhibitory activities against ELOVL6. In the present study, we examined in detail the biochemical and pharmacological properties of 5,5-dimethyl-3-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-1-phenyl-3-(trifluoromethyl)-3,5,6,7-tetrahydro-1H-indole-2,4-dione (Compound-A), a potent inhibitor of ELOVL6. In in vitro assays, Compound-A dose-dependently inhibited mouse and human ELOVL6 and displayed more than 30-fold greater selectivity for ELOVL6 over the other ELOVL family members. In addition, Compound-A effectively reduced the elongation index of fatty acids of hepatocytes, suggesting that Compound-A penetrates the cell wall and inhibits ELOVL6. More importantly, upon oral administration to mice, Compound-A showed high plasma and liver exposure and potently reduced the elongation index of the fatty acids of the liver. This is the first study to report a potent and selective inhibitor of mammalian elongases. Furthermore, Compound-A seems to be a useful tool to further understand the physiological roles of ELOVL6 and to evaluate the therapeutic potential of an ELOVL6 inhibitor.

Synthesis and evaluation of a novel indoledione class of long chain fatty acid elongase 6 (ELOVL6) inhibitors.

Novel indoledione derivatives were synthesized and evaluated as long chain fatty acid elongase 6 (ELOVL6) inhibitors. Systematic optimization of an indole class of lead 1 led to the identification of potent ELOVL6 selective inhibitors. Representative inhibitor 37 showed sustained plasma exposure and good liver penetrability in mice. After oral administration, 37 potently inhibited ELOVL6 activity in the liver in mice.