Development of tetracycline-modified nanoparticles for bone-targeted delivery of anti-tubercular drug.

Background: Since the poor response to existing anti-tuberculosis drugs and low drug concentration in local bone tissues, the traditional drug therapy does not result in satisfactory treatment of osteoarticular tuberculosis. Thus, we report a rifapentine release system with imparted bone targeting potential using tetracycline (TC) -modified nanoparticles (NPs). Methods: TC was conjugated to PLGA-PEG copolymer via a DCC/NHS technique. Rifapentine-loaded NPs were prepared by premix membrane emulsification technique. The resulting NPs were characterized in terms of physicochemical characterization, hemolytic study, cytotoxicity, bone mineral binding ability, in vitro drug release, stability test and antitubercular activity. The pharmacokinetic and biodistribution studies were also performed in mice. Results: Rifapentine loaded TC-PLGA-PEG NPs were proved to be 48.8 nm in size with encapsulation efficiency and drug loading of 83.3% ± 5.5% and 8.1% ± 0.4%, respectively. The release of rifapentine from NPs could be maintained for more than 60 h. Most (68.0%) TC-PLGA-PEG NPs could bind to HAp powder in vitro. The cellular studies revealed that NPs were safe for intravenous administration. In vivo evaluations also revealed that the drug concentration of bone tissue in TC-PLGA-PEG group was significantly higher than that in other groups at all time (p < 0.05). Both NPs could improve pharmacokinetic parameters without evident organ toxicity. The minimal inhibitory concentration of NPs was 0.094 µg/mL, whereas this of free rifapentine was 0.25 µg/mL. Conclusion: Rifapentine loaded TC-PLGA-PEG NPs could increase the amount of rifapentine in bone tissue, prolong drug release in systemic circulation, enhance anti-tuberculosis activity, and thereby reducing dose and frequency of drug therapy for osteoarticular tuberculosis.

Eradication and graft retention can be achieved in the treatment for acute septic arthritis after primary posterior cruciate ligament reconstruction: analysis of 1561 reconstructions.

PURPOSE: Acute septic arthritis after arthroscopic posterior cruciate ligament (PCL) reconstruction is a rare but severe complication. Optimal management has not been established. The purposes of this study were to analyze clinical findings and to retrospectively evaluate the graft-retaining treatment regimen. METHODS: From 2010 to 2021, a total of 1561 primary PCL reconstructions were performed at our institution. Seven patients with septic arthritis were identified and retrospectively analyzed with regard to incidence, clinical manifestations, treatment, postoperative clinical course and follow-up results. RESULTS: The mean interval from PCL reconstruction to the onset of symptoms was 11.0 ± 4.0 days. Staphylococcus aureus was the most commonly found pathogen. Eradication was achieved in all patients after a mean of 1.1 ± 0.4 procedures, with graft retention in all patients. The mean duration of antibiotic treatment was 5.7 ± 1.5 weeks. At the last follow-up, there was no recurrence, graft insufficiency or osteoarthritis. CONCLUSION: Arthroscopic graft-retaining treatment combined with individual antibiotic therapy, eradication and good to excellent functional results can be achieved, which might encourage surgeons to try to retain the graft as much as possible. LEVEL OF EVIDENCE: Level IV.

Robot-assisted all-epiphyseal anterior cruciate ligament reconstruction in skeletally immature patients: a retrospective study.

PURPOSE: To review a series of adolescent patients with anterior cruciate ligament (ACL) injuries surgically treated with robot-assisted all-epiphyseal ACL reconstruction (ACLR), and to compare with the traditional freehand group. METHODS: This retrospective clinical study included 16 patients with ACL injuries who underwent ACLR by robot-assisted technique or traditional freehand method from June 2018 to March 2020. All patients were divided into the robot-assisted group (6 patients) or the traditional surgery group (10 patients). The number of intra-operative fluoroscopies, operation time, accuracy of bone tunnel insertions, International Knee Documentation Committee (IKDC) subjective score and ligament laxity testing were recorded in the two groups. RESULTS: All patients returned for follow-up, at a mean of 31.6 ± 4.5 months after surgery. The average age of the robot-assisted group was 12.2 ± 1.3 years. The number of intra-operative fluoroscopies was 10.9 ± 2.8 in the traditional freehand group, whereas it was only 3.0 ± 0.6 in the robot-assisted group, which was significantly lower (P < 0.05). The operative time in the robot-assisted group was shorter than that in the traditional freehand group (87 ± 10.7 min vs. 126 ± 12.1 min, P < 0.05). The distance between the center of actual insertion and the center of the idea insertion on both femoral and tibial intra-articular bone tunnel were 1.5 ± 0.3 mm and 1.6 ± 0.3 mm for the robot-assisted group and 2.7 mm ± 0.4 mm and 2.4 ± 0.4 mm for the traditional freehand group (P < 0.05). There were no significant differences between the two groups in function recovery at the last follow-up. CONCLUSIONS: All-epiphyseal ACLR is a technically demanding procedure with a small margin of error. Robot-assisted treatment of ACL injuries in skeletally immature patients is more accurate than traditional freehand method, with shorter operation time and fewer intra-operative fluoroscopies.

Development of Rifapentine-Loaded PLGA-Based Nanoparticles: In vitro Characterisation and in vivo Study in Mice.

BACKGROUND: Tuberculosis (TB) is a leading cause of death amongst infectious diseases. The poor response to antitubercular agents necessitates the long-term use of high drug doses, resulting in low patient compliance, which is the main reason for chemotherapy failure and contributes to the development of multidrug-resistant TB. Patient non-compliance has been a major obstacle in the successful management of TB. The aim of this work was to develop and characterise rifapentine (RPT)-loaded PLGA-based nanoparticles (NPs) for reducing dosing frequency. METHODS: RPT-loaded PLGA and PLGA-PEG NPs were prepared using premix membrane homogenisation combined with solvent evaporation method. The resulting NPs were characterised in terms of physicochemical characteristics, toxicity, cellular uptake and antitubercular activity. NPs were further evaluated for pharmacokinetic and biodistribution studies in mice. RESULTS: The resulting NPs showed suitable and safe physicochemical characteristics and could be taken up by macrophages. RPT-loaded NPs were more effective against Mycobacterium tuberculosis than free RPT. In vivo studies revealed that NPs could improve pharmacokinetic parameters, particularly for RPT/PLGA-PEG NPs. Moreover, both formulations had no toxicity to the organs of mice and could reduce hepatotoxicity. CONCLUSION: The application of PLGA-based NPs as sustained-release delivery vehicles for RPT could prolong drug release, modify pharmacokinetics, increase antitubercular activity and diminish toxicity, thereby allowing low dosage and frequency.

Treatment experiences of thoracic spinal hydatidosis: a single-center case-series study.

OBJECTIVE: Spinal hydatid disease is rare and remains a serious health problem associated with high rates of recurrence. We report our experience in treating patients with thoracic spinal hydatidosis through a single-center case-series study. METHODS: Sixteen patients with thoracic spinal hydatidosis were treated in our center between 1995 and 2017. A total en bloc spondylectomy (TES) was performed in three patients. Five patients were treated with posterior decompression and stabilization after removing the involved elements. The remaining patients underwent curettage and resection of the infected bone. The therapy was completed with medical treatment or radiotherapy. RESULTS: Of the 16 patients, seven were men and nine were women; their mean age was 38.5 years (range 28-60 years). The infected area was the upper thoracic level in one patient, mid thoracic level in eight patients, and lower thoracic level in seven patients. Four patients had paraplegia and seven had paraparesis before surgery. At the last follow-up, five patients had successfully recovered from the neurological damage. During a mean follow-up of 4.75 years (range 2-12 years), eight patients had local recurrence; however, no patient who underwent TES had recurrence. CONCLUSIONS: An individualized surgical strategy should be decided carefully for each patient in the first intervention. In the early stages of the disease, TES should be considered as a treatment for suitable cases of primary thoracic spinal hydatidosis.

Development of dual delivery antituberculotic system containing rifapentine microspheres and adipose stem cells seeded in hydroxyapatite/tricalcium phosphate.

BACKGROUND: Low drug concentration in the tuberculosis (TB) lesion and bone defects or nonunion after debridement are two major problems that occur in the course of treating osteo-articular TB. Thus, the combination of drug-delivery system and bone tissue repair appears to be the most promising option for osteoarticular TB treatment. MATERIALS AND METHODS: Herein, we report a novel anti-TB dual delivery system based on rifapentine polylactic acid microspheres (RPMs) to treat infections, with the addition of adipose-derived mesenchymal stem cells (ASCs) seeded in hydroxyapatite/tricalcium phosphate (HA/TCP) to promote bone formation. Cell proliferation, osteogenesis, and apoptosis were performed to investigate the effects of rifapentine on ASCs. The RPMs were synthesized by emulsion-solvent evaporation method, and then the monolayer composite (ASC + RPM) and three-dimensional (3D) composite scaffold (ASC + RPM + HA/TCP) were constructed, respectively. The alkaline phosphatase (ALP) activity and real-time PCR were used for determining the osteogenic differentiation. The concentrations of rifapentine resulting from the composites were detected. RESULTS: The results showed that rifapentine has no influence on ASCs proliferation and osteogenesis when the drug concentration was below 20 µg/mL, which was significantly higher than minimal inhibitory concentration. The drug loading and encapsulation efficiency of RPMs were 40.56%±2.63% and 70.24%±2.18%, respectively. The proliferation of the cells in monolayer was higher than that in 3D composite, and the addition of RPMs slightly increased the proliferation. The ALP activity and gene expression of osteocalcin and osteopontin were higher in the 3D composite than those in the monolayer. Good biocompatibility was observed by microscopic image and H&E stain. The release tests revealed that the 3D composite exhibited sustained release profiles of rifapentine for 76 days. The dual delivery systems in 3D composite could moderate the burst release and extend the length of release time when compared to single delivery in monolayers. CONCLUSION: In conclusion, such dual delivery antituberculotic scaffold represents a potential new strategy for TB infections and bone defects.

The potential role of heat shock proteins in acute spinal cord injury.

PURPOSE: This study aims to investigate the differential expression proteins profile of spinal cord tissues after acute spinal cord injury (ASCI), provide preliminary results for further study and explore the secondary injury mechanisms underlying ASCI. METHODS: Using Allen's frame to establish ASCI model of Sprague-Dawley rats, then a stable isotope-labelled strategy using isobaric tags for relative and absolute quantitation (iTRAQ) coupled with two-dimensional (2D) liquid chromatography tandem mass spectrometry (2D LC-MS/MS) was performed to separate and identify differentially expressed proteins. RESULTS: A total of 220 differentially expressed proteins were identified in the spinal cord tissues of H-8 group (acute spinal cord injury after 8 h) compared with H-0 group (acute spinal cord injury after 0 h); Up to 116 proteins were up-regulated, whereas 104 proteins were down-regulated in the spinal cord tissues. Three of the differentially expressed Heat shock proteins (HSPs) namely, Hsp90ab1, Hspa4 and Hspe1 were down-regulated. CONCLUSION: The differentially expressed proteins of spinal cord tissues after ASCI will provide scientific foundation for further study to explore the secondary injury mechanism of ASCI.

Diagnostic value of alpha-L-fucosidase for hepatocellular carcinoma: a meta-analysis.

Alpha-fetoprotein (AFP) is the primary marker for detecting hepatocellular carcinoma (HCC) and has been used widely in the clinic, but AFP is a biomarker characterized by poor sensitivity and specificity. Alpha-L-fucosidase (AFU) has been proposed as a tumor marker for diagnosis of HCC in many studies. However, conclusions of its diagnostic value are inconsistent. The current review aimed to evaluate the diagnostic value of AFU for HCC. After systematic review of 12 related studies, sensitivity, specificity, and diagnostic odds ratio (DOR) were pooled using random-effect models. Summary receiver operating characteristic (sROC) curve analysis was used to summarize the overall test performance. The pooled sensitivity for AFU was 0.72 (95% confidence interval (CI) 0.69-0.76), while the pooled specificity was 0.78 (95% CI 0.74-0.81). DOR was 10.26 (95% CI 5.99-17.59), and the area under the curve (AUC) was 0.8125. AFU had great value for the diagnosis of HCC as a serum marker.

Treatment experiences of pelvic bone hydatidosis.

BACKGROUND: Hydatid diseases of the pelvic bone are rare, generally incurable, and have high rates of recurrence. METHODS: We report nine cases of osseous hydatidosis involving the pelvis. Patients were treated through different surgical options, including simple debridement, bone cement filling with or without internal fixation, reconstruction using a pedicle screw-rod system, and hemipelvic replantation after liquid nitrogen devitalization combined with femoral prosthesis replacement. The therapy was completed by medical treatment or radiotherapy. RESULTS: The average follow-up was 7.3 years (range 2-19 years). Whilst five patients were symptom-free at the last follow-up, the remaining patients suffered from hip pain or productive sinuses. CONCLUSIONS: Patients must be treated at the early stages of the disease. Total exeresis and individual reconstruction is necessary when osseous and soft tissue involvement is not extensive. Internal fixation should not be used when surgical eradication is uncertain.