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[Image: see text] The onset of neurodegenerative disorders (NDs), such as Alzheimer’s disease, is associated with the accumulation of aggregates of misfolded proteins. We previously showed that chemical knockdown of ND-related aggregation-prone proteins can be achieved by proteolysis targeting chimeras (PROTACs). However, hetero-bifunctional PROTACs generally show poor permeability into the central nervous system, where NDs are located. Here, we document the conversion of one of our PROTACs into hydrophobic tags (HyTs), another class of degraders bearing hydrophobic degrons. This conversion decreases the molecular weight and the number of hydrogen bond donors/acceptors. All the developed HyTs lowered the level of mutant huntingtin, an aggregation-prone protein, with potency comparable to that of the parent PROTAC. Through IAM chromatography analysis and in vivo brain penetration assay of the HyTs, we discovered a brain-permeable HyT. Our results and mechanistic analysis indicate that conversion of protein degraders into HyTs could be a useful approach to improve their drug-like properties.

Osteomyelitis remains one of the most challenging disorders for orthopedic doctors despite the advancement of therapeutic techniques. The purpose of this study was to investigate the feasibility of local antibiotic administration using hydroxyapatite/collagen (HAp/Col) as a drug delivery system. We hypothesized that higher adsorbability of antibiotics onto HAp/Col will result in more efficacious activity and therefore, treatment of osteomyelitis. Eight antibiotics were examined in this study: amikacin, cefazolin, cefotiam, daptomycin, minocycline, piperacillin, teicoplanin, and vancomycin. Aligning with their adsorbability onto HAp/Col, minocycline, teicoplanin, and vancomycin showed antibacterial effects up to 14 days after subcutaneous implantation in Wistar rats; while antibiotics with reduced adsorbability (cefazolin, cefotiam, piperacillin) had diminished antibacterial effects. Furthermore, when implanted into a rat femur, vancomycin levels from the Hap/Col were detected in the medullary space above the minimum inhibitory concentration for Staphylococcus aureus for 7 days, while cefazolin levels were undetectable. Aligning with these results, implantation of Hap/Col impregnated with vancomycin to the femur in an acute osteomyelitis rat model had a greater therapeutic effect than cefazolin, as measured by the number of bacteria, the extent of bone destruction, and bone regeneration. These results indicated that the adsorbability of antibiotics onto their carrier is important when locally administered and that HAp/Col scaffolds might be a useful antibiotic delivery system for osteomyelitis. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 38:843‐851, 2020, This study aimed to investigate the feasibility of local antibiotic administration using hydroxyapatite collagen (HAp/Col) composite as a drug delivery system. Minomycin, teicoplanin, and vancomycin showed antibacterial effects up to 14 days after subcutaneous implantation in rats with HAp/Col owing to their adsorbability. The implantation of HAp/Col impregnated with vancomycin for an acute osteomyelitis model revealed a significant therapeutic effect because of longitudinal antibacterial activity. These results indicated that the adsorbability of antibiotics onto the carrier is important when locally administered.

Prospective observational single-center study.To evaluate anterior decompression and fusion (ADF) or posterior surgery (PS) for patients with cervical spondylotic myelopathy (CSM) using the modified K-line (mK-line) and to compare clinical and radiologic outcomes between these 2 techniques.The authors have previously reported that insufficient posterior decompression is often seen after laminoplasty for CSM in patients with preoperative anterior clearance of the spinal cord4 mm on the basis of the mK-line. However, to our knowledge, no study has investigated the role, if any, of the mK-line in surgical decision making for patients with CSM.A total of 87 patients were enrolled who underwent surgery for treatment of CSM between 2011 and 2015 at our hospital and who could be followed up for at least 2 years. ADF was selected as a more favorable procedure than PS in patients with anterior spinal clearance of4 mm on preoperative midsagittal magnetic resonance imaging. On the basis of the Japanese Orthopedic Association (JOA) scoring system for cervical myelopathy, the rate of recovery of the JOA scores at 2 years after surgery was investigated as a clinical outcome to compare these 2 groups.Mean age was 65.1 (±12.9) years in the ADF group (n=26) and 70.5 (±8.6) years in the PS group (n=61). In the PS group, 10 patients underwent posterior decompression with fusion. Mean preoperative and postoperative JOA scores were 10.5 and 14.1 points in the ADF group and 9.8 and 13.1 points in the PS group, respectively, showing no significant difference in recovery rate of JOA score between the ADF (58.9%) and PS (47.1%) groups. However, patients with a minimum interval between the mK-line and the anterior compression factor on the midsagittal image (minimum interval of the spinal cord)4 mm tended to have unsatisfactory outcomes (recovery rate 29.6%) compared with patients with minimum interval of the spinal cord4 mm (53.6%, P=0.07) in the PS group.Preoperative intervention using the mK-line is useful to predict residual cord compression and might homogenize postoperative clinical outcomes in both anterior surgery and PS.

Introduction Patients treated with revision surgery after lumbar decompression with fusion typically have persistent low back pain and lower extremity numbness compared with patients treated with only primary surgery. No well-designed study has investigated the persistence and degree of pain after revision surgery following instrumented operation. The purpose of this study is to compare residual pain among patients who underwent reoperation and those who underwent only primary surgery for lumbar degenerative disorder using patient-based evaluation. Methods We reviewed 350 consecutive patients (143 men, 207 women, mean age 63 years) treated with primary lumbar instrumented surgery between October 2010 and February 2014 at our institution and followed up for ≥2 years postoperatively. Patients were categorized into three groups based on number of levels fused: 1-segment, 2-segment, and ≥3-segment fusion (1F, 2F, and ≥3F groups, respectively). We used the Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ) and visual analog scales (VASs) for low back pain and lower extremity pain to evaluate pain intensity pre- and postoperatively. Results Salvage surgery for late-phase complications was required in 5 cases (2.4%), 6 cases (11.3%), and 11 cases (12.1%) in the 1F, 2F, and ≥3F groups, respectively. In the 1F and 2F groups, patients treated with revision surgery had unsatisfactory improvement in the pain domain of JOABPEQ and VASs for low back pain and lower extremity pain compared with patients with only primary short fusion surgery. The ≥3F group showed no significant differences between patients who underwent reoperation and those who underwent only primary surgery. Conclusion Low back pain and lower extremity pain often persist after revision surgery in patients treated with short fusion (≤2-segment) operation. We need to follow pain states in such patients.

In fracture treatment, biological bone union generally depends on the bone's natural fracture healing capacity, even in surgically treated cases. Hydroxyapatite/collagen composite (HAp/Col) has high osteoconductivity and stimulates osteogenic progenitors. Furthermore, it has the potent capacity to adsorb bone morphogenetic proteins (BMPs). In this study, we prepared an injectable HAp/Col paste and evaluated its augmentation of bone union. Furthermore, the effect of HAp/Col paste combined with BMP-2 was also evaluated. We used a rat femur osteotomy model with a defect size of 1 mm. Male Wistar rats were assigned to one of the following four groups; a control group without any implant, a HAp/Col implant group, a group that received an absorbable collagen sponge (ACS) implant impregnated with BMP-2 (1 μg), and a group that received a HAp/Col implant impregnated with BMP-2 implant. Micro-CT analysis, three-point bending tests, and histological evaluation were performed. Bone union was achieved in two of eight cases in the HAp/Col group, five of eight cases in the ACS + BMP-2 group, and all cases in the HAp/Col + BMP-2 group at 8 weeks post-surgery. The control group did not achieve bone union. In addition, in the HAp/Col + BMP-2 group, the biomechanical strength of the fused femurs was comparable to that of the contralateral intact femur; the ratio of the mechanical load at the breaking point of the osteotomy side relative to that of the contralateral side was 1.00 ± 0.151 (SD). These results indicate that HAp/Col paste with or without BMP-2 augments bone union. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:129-137, 2018.

In fracture treatment, biological bone union generally depends on the bone's natural fracture healing capacity, even in surgically treated cases. Hydroxyapatite/collagen composite (HAp/Col) has high osteoconductivity and stimulates osteogenic progenitors. Furthermore, it has the potent capacity to adsorb bone morphogenetic proteins (BMPs). In this study, we prepared an injectable HAp/Col paste and evaluated its augmentation of bone union. Furthermore, the effect of HAp/Col paste combined with BMP-2 was also evaluated. We used a rat femur osteotomy model with a defect size of 1 mm. Male Wistar rats were assigned to one of the following four groups; a control group without any implant, a HAp/Col implant group, a group that received an absorbable collagen sponge (ACS) implant impregnated with BMP-2 (1 μg), and a group that received a HAp/Col implant impregnated with BMP-2 implant. Micro-CT analysis, three-point bending tests, and histological evaluation were performed. Bone union was achieved in two of eight cases in the HAp/Col group, five of eight cases in the ACS + BMP-2 group, and all cases in the HAp/Col + BMP-2 group at 8 weeks post-surgery. The control group did not achieve bone union. In addition, in the HAp/Col + BMP-2 group, the biomechanical strength of the fused femurs was comparable to that of the contralateral intact femur; the ratio of the mechanical load at the breaking point of the osteotomy side relative to that of the contralateral side was 1.00 ± 0.151 (SD). These results indicate that HAp/Col paste with or without BMP-2 augments bone union. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:129-137, 2018.