A synthetic retinoic acid receptor γ antagonist (7C)-loaded nanoparticle enhances bone morphogenetic protein-induced bone regeneration in a rat spinal fusion model.

BACKGROUND CONTEXT: Bone morphogenetic proteins (BMPs) have potent osteoinductivity and have been applied clinically for challenging musculoskeletal conditions. However, the supraphysiological doses of BMPs used in clinical settings cause various side effects that prevent widespread use, and therefore the BMP dosage needs to be reduced. PURPOSE: To address this problem, we synthesized 7C, a retinoic acid receptor γ antagonist-loaded nanoparticle (NP), and investigated its potential application in BMP-based bone regeneration therapy using a rat spinal fusion model. STUDY DESIGN: An experimental animal study. METHODS: Fifty-three male 8-week-old Sprague-Dawley rats underwent posterolateral spinal fusion and were divided into the following five treatment groups: (1) no recombinant human (rh)BMP-2 and blank-NP (Control), (2) no rhBMP-2 and 1 µg 7C-NP (7C group), (3) low-dose rhBMP-2 (0.5 µg) and 1 µg blank-NP (L-BMP group), (4) low-dose rhBMP-2 (0.5 µg) and 1 µg 7C-NP (L-BMP + 7C group), and (5) high-dose rhBMP-2 (5.0 µg) and 1 µg blank-NP (H-BMP group). Micro-computed tomography and histologic analysis were performed 2 and 6 weeks after the surgery. RESULTS: The spinal fusion rates of the Control and 7C groups were both 0%, and those of the L-BMP, L-BMP + 7C, and H-BMP groups were 55.6%, 94.4%, and 100%, respectively. The L-BMP + 7C group markedly promoted cartilaginous tissue formation during BMP-induced endochondral bone formation that resulted in a significantly better spinal fusion rate and bone formation than in the L-BMP group. Although spinal fusion was slower in the L-BMP + 7C group, the L-BMP + 7C group formed a spinal fusion mass with better bone quality than the spinal fusion mass in the H-BMP group. CONCLUSIONS: The combined use of 7C-NP with rhBMP-2 in a rat posterolateral lumbar fusion model increased spinal fusion rate and new bone volume without deteriorating the quality of newly formed bone. CLINICAL SIGNIFICANCE: 7C-NP potentiates BMP-2-induced bone regeneration and has the potential for efficient bone regeneration with low-dose BMP-2, which can reduce the dose-dependent side effects of BMP-2 in clinical settings.

Risk factors for insufficient ultrasound-guided supraclavicular brachial plexus block.

PURPOSE: Ultrasound-guided supraclavicular brachial plexus block (SCBPB) is performed by surgeons for upper limb anesthesia; however, certain patients need additional local anesthesia. This study aimed to identify risk factors for additional local anesthetic injection requirements. METHODS: In total, 269 patients receiving ultrasound-guided SCBPB were enrolled. Patient age, sex, body mass index, anesthetic drug dose, surgeon expertise (hand surgeon or resident), tourniquet time, comorbidities (diabetes mellitus and mental disorders), and preoperative blood pressure representing anxiety were compared between the additional local anesthesia and no additional local anesthesia groups matched for background using propensity scores. Receiver operating characteristic analysis was performed to determine risk factor cut-off values with the highest predictive potential. RESULTS: Of 269 patients, 41 (15.2%) required additional intraoperative local anesthesia. Among surgical sites, elbow surgery showed the highest prevalence of the need for additional local anesthesia (17/41, 41%). A high body mass index and high systolic blood pressure before surgery were identified as risk factors for additional intraoperative local anesthesia requirement. Furthermore, systolic blood pressure > 170 mmHg (area under the curve, 0.66) predicted the need for intraoperative local anesthesia with 36% sensitivity, 89% specificity, 37.5% positive predictive value, and 88.6% negative predictive value. The median systolic blood pressure was significantly greater in patients requiring additional local anesthesia than in those not requiring it [151 (139-171) mmHg vs. 145 (127-155) mmHg; P = 0.026]. CONCLUSION: Elbow surgery, obesity, and high systolic blood pressure (> 170 mmHg) before surgery are predictive of additional intraoperative local anesthesia requirement. LEVEL OF EVIDENCE: Prognostic Level III.

Review of Basic Research about Ossification of the Spinal Ligaments Focusing on Animal Models.

Ossification of the posterior longitudinal ligament (OPLL) is a heterotopic ossification that may cause spinal cord compression. With the recent development of computed tomography (CT) imaging, it is known that patients with OPLL often have complications related to ossification of other spinal ligaments, and OPLL is now considered part of ossification of the spinal ligaments (OSL). OSL is known to be a multifactorial disease with associated genetic and environmental factors, but its pathophysiology has not been clearly elucidated. To elucidate the pathophysiology of OSL and develop novel therapeutic strategies, clinically relevant and validated animal models are needed. In this review, we focus on animal models that have been reported to date and discuss their pathophysiology and clinical relevance. The purpose of this review is to summarize the usefulness and problems of existing animal models and to help further the development of basic research on OSL.

Upregulation of HNF-1ß during experimental acute kidney injury plays a crucial role in renal tubule regeneration.

Hepatocyte nuclear factor-1ß (HNF-1ß) is a transcription factor expressed in the kidney, liver, pancreas, and other organs. Mutations of HNF-1ß cause maturity-onset diabetes of the young type 5 (MODY5). The aims of this study were to investigate the functional roles of the HNF-1ß/suppressor of cytokine signaling-3 (SOCS-3) pathway in tubule damage after acute kidney injury (AKI) both in vivo and in vitro and to examine the effect of HNF-1ß on renal tubule formation. To clarify the significance of the HNF-1ß/SOCS-3 pathway in AKI, we used a rat ischemia/reperfusion (I/R) AKI model and cultured renal tubular cells (NRK-52E cells). Western blot analysis showed that HNF-1ß and polycystic kidney disease 2 (PKD2) expressions were increased at 3-12 h and 12-24 h after I/R, respectively. The expression level of SOCS-3 was decreased at 3-48 h. Immunohistological examination revealed that expression of HNF-1ß was increased in proximal tubules. Overexpression of HNF-1ß resulted in decreased SOCS-3 expression, activation of signal transducer and activator of transcription 3 (STAT3) and Erk, and increased [(3)H]thymidine uptake in the presence of hepatocyte growth factor. Furthermore, tubule formation in three-dimensional gels was inhibited by dominant-negative HNF-1ß. Our study shows that HNF-1ß is upregulated after AKI in proximal tubular cells and that HNF-1ß controls cellular proliferation and tubule formation by regulating SOCS-3 expression and STAT3/Erk activation. Therefore, the current study unravels the physiological and pathological significance of the HNF-1ß pathway in AKI.