Augmented Cornus officinalis Levels in Liuwei Dihuang Decoction Inhibits Nucleus Pulposus Cell Pyroptosis to Enhance Therapeutic Efficacy Against Intervertebral Disc Degeneration.

Background: Intervertebral disc (IVD) degeneration (IVDD) is highly prevalent among the elderly population and stands as a leading cause of low back pain. Our prior studies have highlighted the therapeutic potential of Liuwei Dihuang decoction (LWDHD) and its component Cornus officinalis (CO)-derived compounds in alleviating IVDD and osteoarthritis, suggesting beneficial effects of CO in treating degenerative osteoarthropathies. However, uncertainty remains regarding the optimal CO dosage within LWDHD and its potential mechanism for effectively treating IVDD. Objective: To ascertain the optimal dosage of CO within LWDHD for enhancing its therapeutic efficacy in treating IVDD, through a comparison of its effects across varied dosages using a mouse IVDD model. Methods: Eight-week-old male C57BL/6J mice were subjected to a lumbar spine instability surgery to induce an IVDD model and received a modified LWDHD formulation containing varied dosages of CO (original dose of CO, or 5- or 10-time dose of CO (referred to as 1 × CO, 5 × CO, and 10 × CO)) for 8 weeks. The therapeutic efficacy on IVDD was evaluated through changes in lumbar spine function, histopathological morphology, extracellular matrix metabolism, nucleus pulposus cell viability, sensory nerve ingrowth, and nucleus pulposus (NP) cell pyroptosis. Results: Augmenting CO levels in LWDHD led to a dose-dependent increase in the levels of CO-sourced active compounds in the plasma of mice. The modified LWDHD formulations, particularly the 5 × CO, exhibited a favorable pharmacological effect on lumbar function, structural integrity, ECM composition, NP cell viability, and sensory nerve ingrowth. Importantly, all 3 formulations notably mitigated NP cell pyroptosis by activating NRF2/KEAP1 pathway, with the 5 × CO formulation exhibiting superior efficacy. Additionally, a comprehensive score analysis indicated that 5 × CO formulation achieved the highest score. Conclusion: These data underscore that elevating the dosage of CO to a specific threshold can enhance the effectiveness of LWDHD in treating IVDD.

AR/PCC herb pair inhibits osteoblast pyroptosis to alleviate diabetes-related osteoporosis by activating Nrf2/Keap1 pathway.

Osteoporosis is a prevalent complication of diabetes, characterized by systemic metabolic impairment of bone mass and microarchitecture, particularly in the spine. Anemarrhenae Rhizoma/Phellodendri Chinensis Cortex (AR/PCC) herb pair has been extensively employed in Traditional Chinese Medicine to manage diabetes; however, its potential to ameliorate diabetic osteoporosis (DOP) has remained obscure. Herein, we explored the protective efficacy of AR/PCC herb pair against DOP using a streptozotocin (STZ)-induced rat diabetic model. Our data showed that AR/PCC could effectively reduce the elevated fasting blood glucose and reverse the osteoporotic phenotype of diabetic rats, resulting in significant improvements in vertebral trabecular area percentage, trabecular thickness and trabecular number, while reducing trabecular separation. Specifically, AR/PCC herb pair improved impaired osteogenesis, nerve ingrowth and angiogenesis. More importantly, it could mitigate the aberrant activation of osteoblast pyroptosis in the vertebral bodies of diabetic rats by reducing increased expressions of Nlrp3, Asc, Caspase1, Gsdmd and IL-1ß. Mechanistically, AR/PCC activated antioxidant pathway through the upregulation of the antioxidant response protein Nrf2, while concurrently decreasing its negative feedback regulator Keap1. Collectively, our in vivo findings demonstrate that AR/PCC can inhibit osteoblast pyroptosis and alleviate STZ-induced rat DOP, suggesting its potential as a therapeutic agent for mitigating DOP.

Development and Evaluation of a Rat Model of Full-Thickness Cartilage Defects.

Cartilage defects of the knee joint caused by trauma are a common sports joint injury in the clinic, and these defects result in joint pain, impaired movement, and eventually, knee osteoarthritis (kOA). However, there is little effective treatment for cartilage defects or even kOA. Animal models are important for developing therapeutic drugs, but the existing models for cartilage defects are unsatisfactory. This work established a full-thickness cartilage defects (FTCD) model by drilling holes in the femoral trochlear groove of rats, and the subsequent pain behavior and histopathological changes were used as readout experiments. After surgery, the mechanical withdrawal threshold was decreased, chondrocytes at the injured site were lost, matrix metalloproteinase MMP13 expression was increased, and type II collagen expression decreased, consistent with the pathological changes observed in human cartilage defects. This methodology is easy and simple to perform and enables gross observation immediately after the injury. Furthermore, this model can successfully mimic clinical cartilage defects, thus providing a platform for studying the pathological process of cartilage defects and developing corresponding therapeutic drugs.

Intra-articular injection of placental mesenchymal stromal cells ameliorates pain and cartilage anabolism/catabolism in knee osteoarthritis.

Background: Knee Osteoarthritis (kOA), the most common joint degenerative disorder, lacks effective therapeutics. Placenta-derived mesenchymal stromal cells (PMSCs) are effective in tissue repairing and generation, which have potential in treating kOA. This study aimed to determine the anti-kOA efficacy of PMSCs and to explore its action mode. Methods: Flow cytometry and three-line differentiation were performed for identification of PMSCs. In vivo, a rat kOA model established by anterior cruciate ligament transection (ACLT) surgery was used to evaluate the efficacy of PMSCs. Histopathological HE and SO staining with Osteoarthritis Research Society International scoring were conducted, and cartilage expressions of MMP13 and Col2 were measured by immunohistochemistry. Pain behavior parameters by mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL), were measured. In vitro, wound healing and cell immunofluorescence assays were conducted to detect the proliferation and migration ability of chondrocytes treated with PMSCs conditioned medium (PMSCs-CM). Quantitative real-time PCR (qRT-PCR) and Western blot (WB) assays were applied to explore the molecular action of PMSCs on chondrocytes. Results: The results of flow cytometry indicated that the surface markers of PMSCs (CD73 > 95%, CD90 > 95%, and CD34 < 2%) were consistent with the typical mesenchymal stromal cells. The in vivo data showed that PMSCs significantly reversed the kOA progression by protection of cartilage, regulation of anabolic (Col2) and catabolic (MMP13) expressions, and relief of pain symptoms. The in vitro data showed that PMSCs promoted chondrocyte proliferation and migration and significantly restored the IL-1ß-induced abnormal gene expressions of Col2, Mmp13, Adamts4, Adamts5 and Sox9 and also restored the abnormal protein expressions of Col2, Mmp13 and Sox9 of chondrocytes. The molecular actions of PMSCs on chondrocytes in nested co-culture way or in conditioned medium way were similar, confirming a paracrine-based mode of action. Conclusion: This study demonstrated PMSCs' anti-kOA efficacy and its paracrine-based action mode, providing novel knowledge of PMSCs and suggesting it as a promising cell therapy for treatment of kOA.

Aberrant spinal mechanical loading stress triggers intervertebral disc degeneration by inducing pyroptosis and nerve ingrowth.

Aberrant mechanical factor is one of the etiologies of the intervertebral disc (IVD) degeneration (IVDD). However, the exact molecular mechanism of spinal mechanical loading stress-induced IVDD has yet to be elucidated due to a lack of an ideal and stable IVDD animal model. The present study aimed to establish a stable IVDD mouse model and evaluated the effect of aberrant spinal mechanical loading on the pathogenesis of IVDD. Eight-week-old male mice were treated with lumbar spine instability (LSI) surgery to induce IVDD. The progression of IVDD was evaluated by µCT and Safranin O/Fast green staining analysis. The metabolism of extracellular matrix, ingrowth of sensory nerves, pyroptosis in IVDs tissues were determined by immunohistological or real-time PCR analysis. The apoptosis of IVD cells was tested by TUNEL assay. IVDD modeling was successfully produced by LSI surgery, with substantial reductions in IVD height, BS/TV, Tb.N. and lower IVD score. LSI administration led to the histologic change of disc degeneration, disruption of the matrix metabolism, promotion of apoptosis of IVD cells and invasion of sensory nerves into annulus fibrosus, as well as induction of pyroptosis. Moreover, LSI surgery activated Wnt signaling in IVD tissues. Mechanical instability caused by LSI surgery accelerates the disc matrix degradation, nerve invasion, pyroptosis, and eventually lead to IVDD, which provided an alternative mouse IVDD model.

Complications in operative fixation of calcaneal fractures.

OBJECTIVE: The purpose of this study focused on a number of factors that have been implicated in calcaneal complications and find the incidence of wound complications. METHODS: This was a retrospective study. A total of 162 patients (176 feet) who underwent calcaneal fractures between 2007 and 2012 were included. The patient's personal details, age, time from injury to surgery, cause of injury, type of fracture, operative details, operating and tourniquet times were collected from hospital computers and paper records. Evidence of complications including wound infection, wound necrosis, pain, malunion, nonunion, impingement, loss of fixation, ect were studied. RESULTS: Forty-seven of one hundred and seventy-six fractures (26.704%) had complications, wound infection was noted in seven fractures (3.977%), twelve fractures developed necrosis (6.818%), 14 fractures (7.955%) developed pain. Malunion was found in five fractures (2.841%), nonunion in two fractures (1.136%) and loss of fixation in four fractures (2.272%). Three neurologic injury was also seen in our study (1.705%). Operating time, time from injury to surgery and type of fracture had some association with complications in operative fixation of calcaneal fractures, which showed a statistically significant improvement (P=0.000, 0.031, 0.020, respectively), but there were no evidence that age and tourniquet time affect the incidence of complication after calcaneal fracture surgery (P=0.119, 0.682, respectively). CONCLUSIONS: Despite developments in the surgical treatment of calcaneal fracture, wound complications still remain inevitable. Advanced imaging techniques, less invasive surgical procedures, wealth of anatomical knowledge, surgical experience and better postoperative care should be ensured.

[Application of improved submental island flap in hypopharyngeal cancer reserved laryngeal function surgery].

OBJECTIVE: This study aimd to evaluate the application and clinical effect of improved submental island flap in hypopharyngeal cancer reserved laryngeal function surgery. METHOD: A retrospective review of clinical data was performed on 38 patients of hypopharyngeal cancer reserved laryngeal function using sumental island flaps, by the way of improving in design of vascular pedicle, reconstructive mode of laryngeal and hypopharyngeal function and closing of wound of neck following hypopharyngeal cancer resection. Meanwhile, the effect and prognosis was comprehensively assessed on patients with hypopharyngeal cancer reserved laryngeal function using improved submental island flaps. RESULT: The submental flaps kept alive in all 38 cases. During the follow-up period, 18 cases were dead, and of them, 7 cases died of the second primary carcinoma, included 4 cases of esophagus cancer, 1 case of cancer of soft palate, 2 cases of nasopharyngeal carcinoma; and 5 cases died of cervical or parapharyngeal lymph nodes recurrence; 2 cases died of hepatic metastasis; and 4 cases died of pulmonary metastasis. The overall 5-years survival rate was 52.6%. CONCLUSION: Improved submental island flap repairing postoperative defect of hypopharyngeal cancer reserved laryngeal function has many advantages including higher success rate, more security, easy and simple to operate as well as good clinical effects, and is worth to widespread using.

[Modified pectoralis major myocutaneous flap in reconstruction of head and neck defects].

OBJECTIVE: To report the experience of use of modified pectoralis major myocutaneous (PMMC) flaps in reconstruction of head and neck postoperative defects. METHODS: A total of 107 patients who underwent head and neck defect reconstruction using modified PMMC flaps after tumor rescetion between Jan 2008 and Dec 2013 were analyzed retrospectively. RESULTS: The success rate of reconstruction with modified PMMC flaps was 94.4% (101/107). Five patients had partial flap necrosis and their wounds healed with dressing change. One patient (0.9%) had total flap necrosis, followed by the second reconstruction using contralateral PMMC flap. CONCLUSIONS: The modified falcate PMMC flap can obtain optimum quantity of the skin in the chest and decreasing the closing tension of the donnor site in favor of wound healing. The pedicle without muscle will not only maintain the partial function of the pectoralis major, but also help to avoid pressing the vascular pedicle within the subclavian tunnel. The muscular element the pedicled muscles of the PMMC flap can increase the ability of the flap to resist infection, which can use for covering an exposed carotid artery and improving the neck fibrosis of irradiated patients.

[Analysis of the causes of flap necrosis after head and neck reconstruction].

OBJECTIVE: To analyze the causes of the vascular crisis and necrosis of free flaps used for reconstruction of defects following head and neck cancer resection and the managements of these issues. METHODS: A total of 850 cases with head and neck tumors who underwent free flap reconstruction from October 2010 to April 2014 were studied retrospectively. The risks for vascular crisis and necrosis were analyzed with one-factor analysis and multivariate analysis. RESULTS: The total success rate of 95.1% (808/850) for the free flap reconstruction was obtained. Twelve flaps due to poor blood supply indicated during operation were replaced by other free flaps. Among 73 flaps with vascular crisis, 31 flaps were salvaged by surgical exploration and subcutaneous injection of low molecular heparin calcium. Obesity, smoking, preoperative radiotherapy and surgeon's experience, rather than age, hypertension and diabetes, were the risk factors of skin flap necrosis. Two-vein anastomosis had a higher success rate than one-vein anastomosis. CONCLUSIONS: The necrosis rate of free flaps can be reduced by the choice of suitable flaps, subtly preparation of flaps, carefully vascular anastomosis, and prompt perioperative managements. The two-vein anastomosis is recommended. Diabetes, hypertension and elderly patients are not the contraindications for free flap reconstruction.

Clinical application of the combined radical operation without breaking lower lip and mandible for tongue and lingual root carcinoma / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To investigate the clinical applicability and outcomes of the combined radical operation without breaking the lower lip and mandible with one-stage reconstruction using free anterolateral thigh flap for tongue and lingual root carcinoma.</p><p><b>METHODS</b>The operation with or without breaking lower lip and mandible was performed respectively in 245 patients (experimental group) and 120 patients (control group).</p><p><b>RESULTS</b>Removal of tumor and neck dissection were conducted successfully in all patients of two groups with no serious postoperative complication. With the follows-up of 6 to 36 months, in the patients of experimental group there was no recurrence for primary sites but 3 cases with neck lymphnode recurrence, the functions of chewing, swallowing and speaking were good, there was no damage to appearance, and no osteoradionecrosis occurred in the lymphnode positive cases after radiotherapy; in the patients of experimental group there was no recurrence for primary sites but 4 cases with neck lymphnode recurrence, the functions of chewing, swallowing and speaking were good, but there was apparent scar in neck and face, and osteoradionecrosis occurred in 11 of lymphnode positive cases.</p><p><b>CONCLUSIONS</b>The combined radical operation without breaking the lower lip and mandible with one-stage reconstruction using free anterolateral thigh flap is feasible for tongue and lingual root carcinoma (T2-T3), which reduces the risk for osteoradionecrosis in lymphnode positive cases after radiotherapy and keeps good appearance for patients.</p>

[Surgical treatment of tremendous neurogenic tumors in the root of neck].

OBJECTIVE: To evaluate surgical treatment outcomes in 6 cases with tremendous neurogenic tumors in the root of neck. METHODS: Neck-chest-axil-arm "T" incision was used to remove huge tumor in the root of neck. RESULTS: The tumors in the root of neck in 6 patients were removed successfully and no serious complication occurred. With postoperative follows-up for 2-6 years(median 4.5 years), only 1 case died due to the recurrence of lesion in vertebral canal in 11 months after surgery and the other cases survived with satisfying therapeutic outcomes. CONCLUSION: Surgery is an effective method to remove advanced tumor in the root of neck and to improve the quality of life for the patients.

[Surgical management for residual or recurrent diseases in the neck after radiotherapy in nasopharyngeal carcinoma].

OBJECTIVE: To investigate the surgical managements for residual or recurrent diseases in the neck after radiotherapy in nasopharyngeal carcinoma. METHODS: Seventy-eight cases of neck masses (39 cases for unilateral residual diseases, 9 for bilateral residual diseases and 30 for recurrent diseases) after radiotherapy in nasopharyngeal carcinoma who were treated surgically between January 1990 and December 2005 were retrospectively analyzed. There were 56 males and 22 females. Their ages ranged from 28 to 65 years (median 41 years). There were 27 patients with skin involvement. After preoperative imaging assessment, 17 patients whose common carotid arteries or internal carotid arteries were difficult to separate routinely attained the carotid balloon occlusion test which confirmed that 15 cases of cerebral arterial circle open to compensation, however, two cases of poor compensation. Surgical procedures included expanded neck mass resection (21 cases), unilateral radical neck dissection (49 cases) and bilateral radical neck dissection (8 cases). Of them 5 patients were with unilateral internal carotid artery resection. Neck defects were repaired with pectoralis major muscle flaps (15 cases), free anterolateral femoral skin flaps (9 cases) and trapezius muscle flaps (3 cases). Of the 78 patients, 13 with microscopic positive diseases and 2 with residual diseases in internal carotid artery walls underwent postoperative radiotherapy, with the doses of 45 to 50 Gy. RESULTS: All patients were closely followed-up more than 5 years. Three- and five-year survival rates were 46.2% and 28.3% respectively. Neck defects were successfully repaired with skin flaps immediately after resecting diseases in 27 cases, only one patient with delayed healing. Of 51 patients without skin flap repair, neck wounds healed successfully in 45 patients and with delayed healing in 6 patients. Pathological positive rates of lymph nodes located in the level I, II, III, IV and V were 10.5%, 61.4%, 10.5%, 1.8% and 28.1% respectively. CONCLUSIONS: Preoperative balloon occlusion test is required to assess the function of Willis' ring before determining ligation or resection of internal carotid artery. Residual or recurrent diseases commonly exist in level II, VA and III, which should be included in neck dissection. Pectoralis major muscle flap and free anterolateral femoral skin flap are recommended for the repair of neck defect.

[Management of thyroid goiters invading mediastinum and thoracic cavity].

OBJECTIVE: To investigate the diagnosis and treatments of thyroid goiters invading mediastinum and thoracic cavity. METHODS: Seventy-eight cases of thyroid goiters invading mediastinum and thoracic cavity and undergoing surgery from 1995 to 2005 were reviewed. There were 22 males and 56 females and their age ranged from 45 years to 78 years with a median age of 59 years. According to the classification of intrathoracic thyroid goiters, there were 50 cases in Class I, 20 cases in Class II and 8 cases in Class III. In these patients, 38 cases suffered from dyspnea at degree I and 20 cases at degree II. Of the patients, 71 underwent thyroidectomy through neck approach and 7 underwent thyroidectomy by a combined approach of neck incision plus sternotomy or lateral thoracotomy. Tracheal defects in 4 cases and esophageal defects in 3 cases were repaired. Postoperative residual diseases were found in tracheoesophageal wall (5 cases) and mediastinum (6 cases). Eleven patients received postoperative radiotherapy and 18 underwent (131)I treatment. No case died of operation and no case with wound infection. RESULTS: The time of follow-up was 60 - 180 months with a median of 110 months. Three patients lost follow-up. Dyspnea in 58 cases were improved after operation. Three of 49 patients with nodular goiters died from cardiocerebrovascular diseases. Of 29 patients with thyroid papillary carcinoma, 2 died from lung metastasis and 3 died from neck relapse. Five-year survival rate was 75.0% in the patients with thyroid cancer. CONCLUSIONS: Most of thyroid goiters invading mediastinum and thoracic cavity can be completely resected via neck approach, but a combined approach of neck incision plus sternotomy or lateral thoracotomy may be used in some cases with malignant goiters to dissect the diseases completely. Postoperative external beam radiotherapy are required for the residual diseases. (131)I may be considered in high-risk differentiated thyroid carcinoma cases.

[Free anterolateral thigh flap for repairing the defects of oral cavity and maxillofacial].

OBJECTIVE: To investigate the outcomes following the tumor resection of oral cavity and maxillofacial and reconstruction with free anterolateral thigh flaps (ALT). METHODS: Thirty one patients underwent ALT reconstruction following the tumor resection from Dec. 2004 to Dec. 2005. Among them, 17 cases were squamous cell carcinoma (SCC) of tongue, 6 cases of buccal SCC and 8 other malignant. The size of the ALT flaps ranged from 4 to 8 cm in width and 6 to 23 cm in length. Tracheotomy were performed for 4 cases intraoperatively. RESULTS: The overall successful rate was 96.8%. Thirty cases survival no cancer, 1 case died of recurrent and no-controlled of lymph-node in 8 months after operation. Postoperative vessel thrombosis occurred in 3 flaps between 12 hours to 4 days after operation. Two of them were saved. The necrosis area of the third flap was 25%. CONCLUSIONS: The ALT was benefit to repair the defects of oral cavity and maxillofacial, and the donor place was more easily hidden and didn't not influence the outlook and function; the important normal functional framing such as teeth and bone should be preserved; the pedicle of vessel could't be twisted during the procedure of reconstruction to avoid vein oppressed; the size of flap should be suitable to defects in order to avoid flaps being crowd and blood clot; tracheotomy was safe while repairing the defect of hard and soft palate. Reconstructive surgical procedures;