Injective hydrogel loaded with liposomes-encapsulated MY-1 promotes wound healing and increases tensile strength by accelerating fibroblast migration via the PI3K/AKT-Rac1 signaling pathway.

Failed skin wound healing, through delayed wound healing or wound dehiscence, is a global public health issue that imposes significant burdens on individuals and society. Although the application of growth factor is an effective method to improve the pace and quality of wound healing, the clinically approved factors are limited. Parathyroid hormone (PTH) demonstrates promising results in wound healing by promoting collagen deposition and cell migration, but its application is limited by potentially inhibitory effects when administered continuously and locally. Through partially replacing and repeating the amino acid domains of PTH(1-34), we previously designed a novel PTH analog, PTH(3-34)(29-34) or MY-1, and found that it avoided the inhibitory effects of PTH while retaining its positive functions. To evaluate its role in wound healing, MY-1 was encapsulated in liposomes and incorporated into the methacryloyl gelatin (GelMA) hydrogel, through which an injectable nanocomposite hydrogel (GelMA-MY@Lipo, or GML) was developed. In vitro studies revealed that the GML had similar properties in terms of the appearance, microstructure, functional groups, swelling, and degradation capacities as the GelMA hydrogel. In vitro drug release testing showed a relatively more sustainable release of MY-1, which was still detectable in vivo 9 days post-application. When the GML was topically applied to the wound areas of rat models, wound closure as well as tensile strength were improved. Further studies showed that the effects of GML on wound repair and tensile strength were closely related to the promotion of fibroblast migration to the wound area through the controlled release of MY-1. Mechanically, MY-1 enhanced fibroblast migration by activating PI3K/AKT signaling and its downstream molecule, Rac1, by which it increased fibroblast aggregation in the early stage and resulting in denser collagen deposition at a later time. Overall, these findings demonstrated that the nanocomposite hydrogel system promoted skin wound healing and increased tensile strength, thus offering new potential in the treatment of wound healing.

Intra-arterial microguidewire electrocoagulation to treat intracranial vascular diseases.

OBJECTIVE: To investigate the therapeutic effect of intra-arterial microguidewire electrocoagulation on intracranial vascular diseases. METHODS: Data from 10 patients with cerebral aneurysms between May 2018 and September 2022 were analysed. Patients were treated with endovascular coil embolisation and microguidewire electrocoagulation. XperCT scans were conducted to identify new intracranial haemorrhage, infarction and hydrocephalus. Follow-up examinations were conducted 1, 3, 6 and 12 months after discharge. RESULTS: After the patients received electrocoagulation for different durations, Raymond Grade 1 embolisation was achieved in all 10 patients. No complications, such as haemorrhage, infarction or hydrocephalus, were found during or after surgery. Ten patients were followed up for 6-12 months, and none had any symptoms or new neurological dysfunction 1 month after their operation. Among them, nine were followed up for 12 months, and digital subtraction angiography showed no recurrence of aneurysms or occlusion of parent arteries. CONCLUSION: Intra-arterial microguidewire electrocoagulation can be used as a supplementary treatment for cerebral aneurysms. In cases of incomplete lesion embolisation and cases where tamponade treatment cannot continue, immediate thrombosis may occur. Thus, intra-arterial microguidewire electrocoagulation can help achieve patients' treatment goals.

Human Parathyroid Hormone Analog (3-34/29-34) promotes wound re-epithelialization through inducing keratinocyte migration and epithelial-mesenchymal transition via PTHR1-PI3K/AKT activation.

BACKGROUND: Re-epithelialization is important in the process of wound healing. Various methods have been identified to expedite the process, but their clinical application remains limited. While parathyroid hormone (PTH) has shown promising results in wound healing due to its role in promoting collagen deposition and cell migration, application is limited by its potentially inhibitive effects when being continuously and locally administrated. Herein, we developed a novel PTH analog, Human parathyroid hormone (hPTH) (3-34/29-34) (henceforth MY-1), by partially replacing and repeating the amino acid sequences of hPTH (1-34), and evaluated its effect on skin wound re-epithelialization. METHODS: CCK-8, colony formation unit assay, and Ki67 immunofluorescent staining were performed to evaluate the effect of MY-1 on HaCaT cell proliferation. Then, wound scratch assay, Transwell assay and lamellipodia staining were carried out to evaluate the effect of MY-1 on cell migration. Moreover, the epithelial-mesenchymal transition (EMT) markers were measured using qPCR and western blot analysis. For in-vivo drug delivery, gelatin methacryloyl (GelMA) hydrogel was employed to load the MY-1, with the physicochemical characteristics evaluated prior to its application in wound models. Then, MY-1's role in wound healing was determined via acute skin wound models. Finally, the mechanism that MY-1 activated was also detected on HaCaT cells and in-vivo wound models. RESULTS: In-vitro, MY-1 accelerated the migration and EMT of HaCaT cells, while having little effect on cell proliferation. GelMA and MY-1-incorporated GelMA hydrogels showed similar physicochemical characteristics and were used in the in-vivo studies, where the results revealed that MY-1 led to a stronger re-epithelialization by inducing basal keratinocyte migration and EMT. Further studies on in-vivo wound models and in-vitro HaCaT cells revealed that MY-1 regulated cell migration and EMT through activating PI3K/AKT signaling. The parathyroid hormone type 1 receptor (PTHR1), the main receptor of PTH, was found to be the upstream of PI3K/AKT signaling, through interfering PTHR1 expression with a small interference RNA following detection of the PI3K/AKT activation. CONCLUSION: Collectively, our study demonstrated that MY-1 accelerates skin wound re-epithelialization by inducing keratinocyte migration and EMT via PTHR1-PI3K/AKT axis activation. Video Abstract.

Is removal of the internal fixation after successful intervertebral fusion necessary? A case-control study based on patient-reported quality of life.

BACKGROUND: Intervertebral fusion and internal fixation are often applied to patients with lumbar spinal disease. Whether to remove the internal fixation after successful fusion remains uncertain, but such a question needs to be explored in light of concerns regarding patients' quality of life and health insurance. We sought to probe if the removal of internal fixation after successful lumbar intervertebral fusion affects patients' quality of life. METHODS: This was a real-world retrospective case-control study. Data of 102 patients who had undergone posterior lumbar fusion with cage and internal fixation to treat lumbar degenerative diseases were extracted from a single center from 2012 to 2020. Fifty-one patients had undergone internal fixation removal surgery, and 51 controls who retained internal fixations were matched according to demographic and medical characteristics. The quality of life of patients based on the Medical Outcomes Study Short Form 36 (SF-36) scale and their self-assessment were surveyed. RESULTS: There was no statistical difference in the overall score of the SF-36 questionnaire between the two groups, but the general health (GH) subscore was lower in the case group than in the control group (P = 0.0284). Among those patients who underwent internal fixation removal, the quality of life was improved after instrument removal as indicated by an increased overall score (P = 0.0040), physical functioning (PF) (P = 0.0045), and bodily pain (BP) (P = 0.0008). Among patients with pre-surgery discomfort, instrument removal generated better outcomes in 25% and poor outcomes in 4.2%. Among patients without pre-surgery discomfort, instrument removal generated better outcomes in 7.4% and poor outcomes in 11.1%. CONCLUSION: Among patients who achieved successful posterior lumbar internal fixation, whether or not to remove the fixation instruments should be evaluated carefully. In patients experiencing discomfort, instrument removal could improve their quality of life, but the benefits and risks should be comprehensively explained to these patients. Instrument removal should not be routinely performed due to its limited or even negative effect in patients who do not report discomfort before surgery.

Analysis of the Clinical Efficacy of Laparoscopy and Hysteroscopy in the Treatment of Tubal-Factor Infertility.

Objective: This study aims to investigate the clinical efficacy of laparoscopy and hysteroscopy in the treatment of tubal-factor infertility (TFI) to provide a basis for predicting postoperative pregnancy rates. Methods: The clinical data of 336 patients who underwent laparoscopy and hysteroscopy for TFI between February 2018 and December 2018 in the Department of Reproductive Gynecology at the First People's Hospital of Yunnan were retrospectively analyzed. After implementing the inclusion and exclusion criteria, 278 patients were included in the study. The patients were grouped according to pelvic adhesions, hydrosalpinx, twisted fallopian tubes, and fimbriae structure. The impact of the extent of fallopian tube diseases on postoperative pregnancy outcomes was analyzed. Results: Of the 278 patients, 129 got pregnant (pregnancy rate = 46.4%). Pelvic adhesions, hydrosalpinx, twisted/folded fallopian tubes, and damage to the fimbriae of the fallopian tubes were found to affect the natural pregnancy rate after surgery, and it decreased significantly with the aggravation of the disease (P < 0.001). Of the 129 patients who had natural pregnancies, 29 had ectopic pregnancies (ectopic pregnancy rate = 22.48%). Twisted/folded fallopian tubes and damage to the fimbriae structure significantly increased the incidence of postoperative ectopic pregnancy (P < 0.001). Conclusion: Laparoscopy and hysteroscopy are effective treatments for TFI. Pelvic adhesions, twisted/folded fallopian tubes, hydrosalpinx, and damage to the fimbriae of the fallopian tubes can affect postoperative pregnancy outcomes and lead to failure of a natural pregnancy after the operation. The incidence of ectopic pregnancy increases with the degree of fallopian tube twisting/folding and the degree of damage to the fimbriae of the fallopian tubes.

Posterior unilateral exposure and stability reconstruction with pedicle and lamina screw fixation for the cervical dumbbell tumorectomy: a case report and biomechanical study.

PURPOSE: Cervical dumbbell tumor is usually removed via a posterior approach and may require the spinal fixation sometimes. However, the present surgical methods involved either more trauma or a higher risk of instability of the cervical spine. A new technique of unilateral exposure and stability reconstruction with pedicle and lamina screws fixation for posterior cervical dumbbell tumorectomy was described and compared with conventional techniques. METHODS: Posterior unilateral exposure, hemi-laminectomy and facetectomy were performed in one patient with the cervical dumbbell tumor between C3 and C4. The stability was reconstructed by the unilateral pedicle and lamina screws fixation (UPLS), and a strip of shaped allograft bone was also implanted between the superior and inferior lateral mass. Biomechanical stability test of this new technique was investigated using seven fresh-frozen human cervical spine specimens (C4-C7) and compared with unilateral pedicle screw (UPS) and bilateral pedicle screw fixation (BPS) techniques. A continuous pure moment of ± 2.0 Nm was applied to the specimen in flexion, extension, lateral bending and axial rotation. RESULTS: The cervical dumbbell tumor was removed completely, and bone fusion with continuous bone trabecula was maintained in the patient on the final follow-up examination at 18 months postoperatively. Biomechanical stability tests revealed that the range of motion of the UPLS fixation plus graft bone implant was the same as the BPS fixation in flexion (1.8°vs. 1.5°, p = 0.58) and extension (2.3°vs. 2.2°, p = 0.73), but significantly bigger in lateral bending (3.9° vs. 1.0°, p < 0.001) and axial rotation (6.8° vs. 3.8°, p = 0.002), which were significantly smaller than the UPS fixation in all directions (all p < 0.001). CONCLUSIONS: For the treatment of cervical dumbbell tumor, posterior unilateral exposure and stability reconstruction with pedicle and lamina screws fixation following hemi-laminectomy and facetectomy appear to be a more stable and lesser trauma technique. LEVEL OF EVIDENCE: Diagnostic: individual cross-sectional studies with consistently applied reference standard and blinding.

Should adjacent asymptomatic lumbar disc herniation be simultaneously rectified? A retrospective cohort study of 371 cases that received an open fusion or endoscopic discectomy only on symptomatic segments.

BACKGROUND CONTEXT: In the treatment of multiple disc herniations, the decision of whether to include the presumed asymptomatic lumbar disc herniation (asLDH) at adjacent segments remains uncertain. On the one hand, the untouched asLDH might soon become symptomatic and require treatment. On the other hand, additional surgery involving more segments will introduce greater risk, complications, and cost. PURPOSE: To investigate the prognosis of untreated asLDH after open fusion or percutaneous endoscopic lumbar discectomy (PELD) on symptomatic lumbar disc herniation (LDHs) in patients. STUDY DESIGN: This is a retrospective cohort study. PATIENT SAMPLE: A total of 371 patients with multiple disc herniations who underwent open discectomy and fusion or PELD only for symptomatic levels from January 2012 to July 2018 were included. OUTCOME MEASURES: The primary outcome of interest was the development of symptomatic LDH at the previous asLDH of both groups that required reoperation. A second analysis was performed to compare the reoperation rate due to deterioration of asLDH among different severity grades of herniation. Reoperation rates of the original surgery at the symptomatic segment in both fusion and PELD groups were also reviewed. METHODS: The patients were divided into two groups based on the surgical procedure, with 264 patients undergoing fusion surgery and 107 patients undergoing PELD. Clinical and imaging follow-ups were performed at routine intervals for more than 3 years. The reoperation rates due to deterioration of previously asLDH and failure of original surgery were investigated and compared between the two groups, as well as among the different severity grades of herniation. RESULTS: The follow-up times were 48.2±24.2 and 41.1±17.5 months for the fusion and the PELD groups, respectively. The overall reoperation rate at the previous adjacent asLDH was 6.7% (25/317). According to the severity of the asLDH, a higher grade of asymptomatic herniation yielded a significantly higher rate of reoperation rate in both groups. If the nerve root was displaced by disc material prominently (nG2), the reoperation rate of asLDHs was 42.9% (3/7) in the fusion group and 20% (3/15) in the PELD group. Twenty out of 264 patients (7.6%) in the fusion group and 5 out of 107 patients (4.7%) in the PELD group required reoperation due to deterioration of asLDH. Reoperation rates due to failure of the original surgery were 7.6% (20/264) in the fusion group and 8.4% (9/107) in the PELD group. CONCLUSIONS: With multilevel LDHs, if the asLDH is left untreated, the reoperation rate is closely related to the degree of herniation. When confronting an asLDH graded as G2, a high possibility of reoperation should be clearly discussed with the patient, regardless of open fusion or PELD techniques. Considering that fusion and minimally invasive nonfusion techniques did not yield significantly different overall reoperation rates, ongoing degeneration seemed to have a greater contribution in terms of the deterioration of asLDH.

Postoperative comparison of laparoscopic radical resection and open abdominal radical hysterectomy for cervical cancer patient.

PURPOSE: There are limited data regarding postoperative complications and autoimmune reactions caused by surgery in early-stage cervical cancer patients who underwent laparoscopic radical resection (LRR). This study aimed to investigate the therapeutic effect of LRR of cervical cancer patients and its effect on cytokines. METHODS: 168 patients with cervical cancer were enrolled. The patients were divided into open group and laparoscopic group according to the random number table method, with 84 cases in each group. The surgical-related indexes and the incidence of complications of the two groups were observed, and the IFN-γ, TNF, and IL-1/2/4/6/8/10/12 levels in peripheral blood were compared before and after surgery in both groups. RESULTS: The operation time of the patients in the laparoscopic group was significantly shorter than that in the open group (119.56 ± 45.26 vs. 206.36 ± 54.39, P < 0.01). The intraoperative blood loss in the laparoscopic group was significantly less than that in the open group (155.29 ± 57.58 vs. 529.58 ± 162.4, P < 0.01). The postoperative visual analog scale (VAS) score was also significantly lower than that in the open group (3.65 ± 0.88 vs. 6.32 ± 1.12, P < 0.01). There was no significant difference in the incidence of complications between the two groups. The degree of inflammatory cytokines changes caused by LRR was less than that of open radical surgery (P < 0.001). CONCLUSIONS: LRR surgery has less stress on patients with early cervical cancer than open surgery within 5 days after surgery, which has certain reference value for early cervical cancer treatment.

Nomograms predicting survival for all four subtypes of breast cancer: a SEER-based population study.

BACKGROUND: The prognosis of female breast cancer (BC) patients is determined by many clinicopathological factors. In this study, we aimed to identify prognostic factors for BC and develop reliable nomograms to predict the 1-, 3-, and 5-year overall survival (OS) and breast cancer-specific survival (BCSS). METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to screen 227,989 eligible patients as the study cohort. The whole cohort was randomly divided into a training cohort (n=113,996) and a testing cohort (n=113,993). The log-rank test and Cox proportional hazards analysis were applied to select variables and build nomogram models based on the training cohort. Internal and external validation were performed to evaluate the performance of the models by calculating the C-index and generating calibration plots in the training cohort and testing cohort. RESULTS: The following factors were included in both the OS and BCSS nomograms: subtypes of BC, metastasis (bone, liver, lung, and brain), age at diagnosis, race, tumor size, grade, number of positive lymph nodes, and marital status. The calibration plots presented excellent consistency between the actual and nomogram-predicted survival probabilities in both the training cohort and testing cohort. The C-index values of the nomograms were 0.796 and 0.793 for OS and 0.856 and 0.853 for BCSS in the training and testing cohorts, respectively. CONCLUSIONS: The established nomograms provide a visualization of the risk of each prognostic factor and can assist clinicians in predicting the 1-, 3-, and 5-year OS and BCSS for all 4 subtypes of BC.

Resources utilisation and economic burden of percutaneous vertebroplasty or percutaneous kyphoplasty for treatment of osteoporotic vertebral compression fractures in China: a retrospective claim database study.

BACKGROUND: Osteoporotic vertebral compression fractures (OVCF) is a common and often debilitating complication of osteoporosis, leading to significant morbidity and increased mortality. Percutaneous vertebroplasty (PVP) and Percutaneous kyphoplasty (PKP) are recommendable surgical treatments for OVCF. OBJECTIVE: To evaluate PVP/PKP utilisation and their related direct medical costs for OVCF treatment in China from the payer perspective. METHODS: A population-based medical claims database of a metropolitan city in China was analysed from the payer perspective, which included all inpatient claims from 01/01/2015 to 31/12/2017. All vertebral fractures patients that met the eligibility criteria (aged ≥50 years old, having vertebral fracture diagnosis, without unrelated diseases diagnoses such as tumour and scoliosis, received PVP/PKP) were deemed as OVCF patients. Baseline characteristics, surgery rate, length of stay in hospital, time to re-surgery, and costs (including costs per hospitalisation and annual costs) were described. Survival analysis function was used to estimate the re-surgery rate. RESULTS: Of the 50,686 patients with OVCF identified, 14,527 (28.66%) received a total number of 15,599 records of PVP/PKP surgeries from 2015 to 2017. Mean age was 75 at the first surgery captured in the database analysis period; females accounted for 79.54% of all cases. The median length of surgery stay was 9 days. Cumulative re-surgery rates were 1.22% in 30 days, 2.58% in 90 days, 3.61% in 183 days, 5.42% in 1 year, and 7.95% in 2 years. There was no significant difference in re-surgery rate between PVP and PKP (p = 0.3897). The median time to the re-surgery was 139 days. Mean costs per PVP/PKP-related hospitalisation were 35,906 CNY/5122 USD (34,195 CNY/4878USD for PVP, 44,414 CNY/6336 USD for PKP, p < 0.01). The overall costs of hospitalisation averaged 186.61 million CNY (26.62 million USD) per year in this metropolitan city. CONCLUSION: From 2015 to 2017, nearly one-third of OVCF inpatients received PVP/PKP and the re-surgery rate was 7.95%. PVP/PKP procedures for OVCF place a high economic burden for both the healthcare system and patients. Early detection and treatment of patients with osteoporosis are critical in China.

A preliminary study of a novel robotic system for pedicle screw fixation: A randomised controlled trial.

BACKGROUND AND OBJECTIVE: Existing orthopaedic robotic systems are almost restricted to provide guidance for trajectory direction. In the present study, a novel spinal robotic system with automatic drilling power was introduced. The aim of this study is to evaluate the feasibility and safety in pedicle screw â€‹insertion of posterior lumbar interbody fusion assisted by this novel robotic system. METHODS AND MATERIALS: A randomised controlled trial was conducted for 17 participants who were required posterior lumbar interbody fusion process. Seven (3 M/4 F) were randomly assigned to the robot-assisted group (RA group), and the other ten (4 M/6 F) were assigned to the conventional technique group (FH group). A novel robotic system was used in the RA group. All measurements were based on postoperative computed tomography (CT) data. Accuracy of screw insertion was determined using the Gertzbein and Robbins Scale. Precision was measured by the entry point deviation distance and the trajectory rotation. Other variables included operation time, radiation time, length of stay, and screw-related complications. RESULT: A total of 82 pedicle screws were placed in the 17 participants. In the RA group, 90.6% of screws placed were Grade A, and 9.4% were Grade B. In the FH group, 78.0% of screws were Grade A, 20.0% were Grade B, and 2.0% were Grade C. No statistical difference was found in the operation time, radiation time per case, and length of stay between both groups. The radiation time per screw is significantly lower in the RA group. No screw-related complications or revision occurred in the present study. CONCLUSION: The outcome of screw accuracy of this robotic system was comparable with that of experienced surgeons, and no screw-related complication was found in the RA group during hospitalisation. In addition, radiation time per screw in the robotic group was significantly lower than that in the conventional group, which shows the potential to reduce radiation exposure of pedicle screw fixation assisted by this robotic system. TRANSLATIONAL POTENTIAL: Our study shows that pedicle screw fixation assisted by "Orthbot" system is accurate and safe. It is concluded that this novel robotic system offers a new option for internal implantation in spine surgery.

Analysis of pregnancy outcome after anastomosis of oviduct and its influencing factors.

BACKGROUND: This study aims to investigate the influencing factors of pregnancy after laparoscopic oviduct anastomosis. METHODS: The data of 156 cases of laparoscopic oviduct anastomosis in our hospital were analyzed. RESULTS: The pregnancy rate decreased with age (P < 0.005). The pregnancy rate after six years of anastomosis was higher in those with ligation (P < 0.005). The postoperative pregnancy rate significantly increased in subjects with oviduct lengths of > 7 cm (P < 0.01). The pregnancy rate of isthmus end-to-end anastomosis was higher (P < 0.005). The pregnancy rate after bilateral tubal recanalization was higher than that after unilateral tubal recanalization (P < 0.005). The pregnancy rate after laparoscopic tubal ligation and laparoscopic anastomosis was higher than that of open tubal ligation and laparoscopic anastomosis (P < 0.005). CONCLUSION: The pregnancy rate after laparoscopic oviduct anastomosis is higher in subjects below 35 years old, with a ligation duration of < 6 years, and a length of oviduct of > 7 cm, and those who underwent isthmus anastomosis and laparoscopic oviduct ligation and recanalization.

[Prolonged continuous infusion of teriparatide promotes bone metabolism in normal but not in castrated mice].

OBJECTIVE: To investigate the effects of continuous pumping of teriparatide (TPTD) on bone metabolism in ovariectomized and normal mice and provide experimental evidence for the selection of animal models for studying the effects of TPTD and its related peptides on osteoclasts. METHODS: Twenty-four female C57BL mice (6-weeks old) were subjected to ovariectomy (OVX) or sham operation followed 7 days later by continuous pumping of TPTD or the solvent vehicle (VEH) via a micropump (SHAM-VEH, SHAM-TPTD, OVX-VEH, and OVX-TPTD groups; n=6). Two weeks later, the tibial and femoral bones were harvested for micro-CT scanning to measure the parameters of the tibia and the femoral cortical bone. Histopathological examinations of the tibial tissue were conducted using HE staining and TRAP staining and the number of osteoclasts and the growth plate thickness were determined. The serum Ca2 + levels of the mice were measured. The primary osteoblasts from the cranial bone were treated with estradiol (E2) and TPTD for 48 h, and the expressions of ß-catenin and RANKL protein in the cells were analyzed. RESULTS: The trabecular bone mass of OVX mice was significantly lower than that of sham-operated mice (P < 0.05). Continuous TPTD pumping significantly reduced tibial cancellous bone mass and femoral cortical bone area in the sham-operated mice, while in the castrated mice, TPTD pumping increased the cancellous bone mass without changing the cortical bone area. TRAP staining showed that cancellous osteoblasts in the tibia increased significantly in the castrated mice as compared with the sham-operated mice, and TPTD pumping significantly increased the number of cancellous osteoblasts in the sham-operated mice (P < 0.05). In the primary cultured osteoblasts, treatment with both E2 and TPTD obviously lowered the expression of ß-catenin and increased the expression of RANKL as compared with TPTD treatment alone. CONCLUSIONS: Continuous pumping of TPTD promotes bone resorption in normal mice but does not produce obvious bone resorption effect in the ovariectomized mice, suggesting that castrated mice are not suitable models for studying the effect of TPTD and the related peptides on the osteoclasts.

[Delayed decompression for cauda equina syndrome secondary to lumbar disc herniation: long-term follow-up results].

OBJECTIVE: To assess the impact of delayed decompression on long-term neurological and bladder function recovery in patients with cauda equina syndrome (CES) secondary to lumbar disc herniation (LDH). METHODS: The clinical data of 35 patients receiving delayed decompression surgery for CES secondary to LDH were reviewed. The bladder empty function, bowel control, sexual ability and neurological functions of the lower limbs were evaluated after the operation, and the urodynamic changes were assessed in 6 patients with urodynamic data before and after the operation. RESULTS: Surgical decompression was performed at 4.1∓3.9 weeks in 12 patients with complete CES and at 5.5∓7.6 weeks in 23 patients with incomplete CES after the onset of symptoms. The patients were followed up for a mean of 43.0∓28.9 months (3-110 months). In the 23 patients with incomplete CES, 19 obtained full recovery, 4 had slight sensory alterations in the saddle area or the lower limbs. In the 12 patients with complete CES, 2 had full recovery, 4 reported slight sensory alterations in the saddle area or the lower limbs (including 2 with occasional constipation); 6 still had sense deficit in the saddle area and difficulties in bladder or bowl emptying, but they all reported significant improvements compared to the condition before operation. Urodynamic analysis in the 6 patients with pre- and postoperative urodynamic data showed increased abdominal pressure when voiding with significantly reduced residual urine in all the 6 patients; 4 patients with abnormal first desire volume before operation reported recovery after the operation. CONCLUSION: Patients with LDH-induced CES who missed the chance of early decompression can still expect favorable functional recovery in the long term. The improvement of bladder function following decompression is probably a result of recovery of bladder sensation and the compensation by increased intra-abdominal pressure. The key strategy to promote bladder function recovery in these patients is to promote the detrusor recovery.

Parathyroid Hormone Activates Phospholipase C (PLC)-Independent Protein Kinase C Signaling Pathway via Protein Kinase A (PKA)-Dependent Mechanism: A New Defined Signaling Route Would Induce Alternative Consideration to Previous Conceptions.

BACKGROUND Parathyroid hormone (PTH) is an effective anti-osteoporosis agent, after binding to its receptor PTHR1, several signaling pathways, including cAMP/protein kinase A (PKA) and phospholipase C (PLC)/protein kinase C (PKC), are initiated through G proteins; with the cAMP/PKA pathway as the major pathway. Earlier studies have reported that PTHR1 might also activate PKC via a PLC-independent mechanism, but this pathway remains unclear. MATERIAL AND METHODS In HEK293 cells, cAMP accumulation was measured with ELISA and PKC was measured with fluorescence resonance energy transfer (FRET) analysis using CKAR plasmid. In MC3T3-E1 cells, real-time PCR was performed to examine gene expressions. Then assays for cell apoptosis, cell differentiation, alkaline phosphatase activity, and mineralization were performed. RESULTS The FRET analysis found that PTH(1-34), [G1,R19]PTH(1-34) (GR(1-34), and [G1,R19]PTH(1-28) (GR(1-28) were all activated by PKC. The PKC activation ability of GR(1-28) was blocked by cAMP inhibitor (Rp-cAMP) and rescued with the addition of active PKA-α and PKA-ß. The PKC activation ability of GR(1-34) was partially inhibited by Rp-cAMP. In MC3T3-E1 cells, gene expressions of ALP, CITED1, NR4a2, and OSX that was regulated by GR(1-28) were significantly changed by the pan-PKC inhibitor Go6983. After pretreatment with Rp-cAMP, the gene expressions of ALP, CITED1, and OPG were differentially regulated by GR(1-28) or GR(1-34), and the difference was blunted by Go6983. PTH(1-34), GR(1-28), and GR(1-34) significantly decreased early apoptosis and augmented osteoblastic differentiation in accordance with the activities of PKA and PKC. CONCLUSIONS PLC-independent PKC activation induced by PTH could be divided into two potential mechanisms: one was PKA-dependent and associated with PTH(1-28); the other was PKA-independent and associated with PTH(29-34). We also found that PTH could activate PLC-independent PKC via PKA-dependent mechanisms.

Photothermal ablation of bone metastasis of breast cancer using PEGylated multi-walled carbon nanotubes.

This study investigates therapeutic efficacy of photothermal therapy (PTT) in an orthotropic xenograft model of bone metastasis of breast cancer. The near-infrared (NIR) irradiation on Multi-Walled Carbon Nanotubes (MWNTs) resulted in a rapid heat generation which increased with the MWNTs concentration up to 100 µg/ml. MWNTs alone exhibited no toxicity, but inclusion of MWNTs dramatically decreased cell viability when combined with laser irradiation. Thermographic observation revealed that treatment with 10 µg MWNTs followed by NIR laser irradiation resulted in a rapid increase in temperature up to 73.4±11.98 °C in an intraosseous model of bone metastasis of breast cancer. In addition, MWNTs plus NIR laser irradiation caused a remarkably greater suppression of tumor growth compared with treatment with either MWNTs injection or NIR irradiation alone, significantly reducing the amount of tumor-induced bone destruction. All these demonstrate the efficacy of PTT with MWNTs for bone metastasis of breast cancer.

[Effect of parathyroid hormone (1-34) on bone metastasis of lung cancer cells in mice].

OBJECTIVE: To investigate the effect of parathyroid hormone (1-34) (PTH) on tumor growth in a mouse model of lung cancer with bone metastasis. METHODS: Mouse models of proximal tibial bone metastasis of lung cancer were established in 30 female BALB%c mice. The mouse models were randomly divided into 3 groups and received injections with 40 mg%kg PTH (1-34), equal amount of solvent (blank control), or cyclophosphamide (positive control). Body weight of the mice was measured every 2 days and the right hind limb tumor growth was observed. The mice were sacrificed after 28 days for X-ray and CT examinations to observe the tumor shape, size, tibial bone density, and tumor volume. HE staining and immunohistochemistry were performed to observe the tumor morphology and pathological type, and serum concentration of serum alkaline phosphatase (ALP) was detected. RESULTS: The body weight change curves did not show significant difference between PTH (1-34) group and the blank control group (P>0.05). In both PTH (1-34) group and the blank control group, X-ray and micro-CT revealed significant bone defects, and in cyclophosphamide group the bone cortex was basically intact with only mild bone destruction. The tumor volume was similar between PTH (1-34) group and the blank control group (P>0.05), but significantly smaller in cyclophosphamide group (P<0.05). The bone density in PTH (1-34) group was significantly greater than that in the blank control group, but lower than that in cyclophosphamide group (P<0.05). Pathological examination revealed mainly osteolytic lesions mixed with bone destruction, which was severer in PTH (1-34) group and blank control group with obvious tumor cell filling of the defects; immunohistochemistry identified the tumors as adenomas. ALP activity was higher in PTH (1-34) group than in the other two group and differed significantly between the 3 groups (P<0.05). CONCLUSION: Intermittent small-dose injections of parathyroid hormone PTH (1-34) does not promote bone metastatic tumor growth in mice and increases the bone quantity around the metastatic lesions.

Nuclear translocation of CBP/p300-interacting protein CITED1 induced by parathyroid hormone requires serine phosphorylation at position 79 in its 63-84 domain.

The transcriptional cofactor CITED1 inhibits osteoblastic differentiation and blunts the stimulation of osteoblastic differentiation by parathyroid hormone (PTH). In the MC3T3-E1 osteoblastic cell line, we found that CITED1 was located predominantly in the cytoplasm and that hPTH(1-34) increased translocation of CITED1 from the cytoplasm to the nucleus. This response to hPTH(1-34) was not observed when all 9 serine residues within the 63-84 domain of CITED1 were mutated to alanines (CITED1 9S>A) or when a single serine to alanine mutation was made at position 79 (CITED1 S(79)>A). CITED1 containing mutations of these 9 serines to glutamic acid (9S>E) retained the same nuclear translocation response to hPTH(1-34) as the wild type CITED1. ALP activity and formation of mineralized nodules were inhibited in cells transfected with pcDNA3-CFP-CITED1 or with pcDNA3-CFP-CITED1 9S>E with or without hPTH(1-34) treatment (all P<0.05); these changes were not observed using CITED1 9S>A. Cells exposed to intermittent treatment with hPTH(1-34) expressed more ALP2, Runx2 and osteocalcin than vehicle-treated cells. These effects of hPTH(1-34) were inhibited in cells transfected with pcDNA3-CFP-CITED1 or pcDNA3-CFP-CITED1 9S>E, but were slightly enhanced by the alanine mutants. PKC activator (TPA) increased nuclear translocation of CITED1, whereas a PKC inhibitor (Go6983) blunted the effect of hPTH(1-34) on the nuclear translocation of wildtype CITED1 but not of CITED1 S(79)>E. The data indicated that serine phosphorylation at position 79 in the 63-84 domain is associated with PKC activation, and is required for both CITED1 nuclear translocation induced by PTH and the negative effects of CITED1 on osteoblastic differentiation and mineralization.

[Bone metastasis of lung cancer in a mouse model with normal immune function].

OBJECTIVE: To establish a model bearing human lung cancer xenograft with bone metastasis in mice with normal immune function. METHODS: Forty female C57BL/6J mice were randomly allocated into 4 equal groups, including a control group and 3 immunosuppression groups treated with low, moderate, and high doses of dexamethasone (50, 100, and 150 mg, respectively). Four days after immune suppression, the mice were subjected to percutaneous injection of1.0×10(9) L(-1) A549 cells into the tibial plateau, and the bone defects were assessed radiographically 28 days after modeling. HE staining and immunohistochemical staining were used to examine the tumor tissues and bone tissue damages. RESULTS: In each of the 4 groups one mouse died during tumor cell injection. Only 1 mouse showed tumor formation in low-dose immunosuppression group, as compared to 7 and 4 in moderate- and high-dose immunosuppression groups. X-ray and microCT scan showed significant tibial bone destruction in moderate- and high-dose groups. The moderate- and high-dose groups showed similar ALP activities but both were significantly higher than those in the other two groups (P<0.05). CONCLUSION: Immunosuppression with a moderate dose of dexamethasone results in longer survival time of the human lung cancer xenograft-bearing model mice as well as a higher tumor formation rate.

Interleukin-18-induced inflammatory responses in synoviocytes and chondrocytes from osteoarthritic patients.

The major pathological changes of osteoarthritis (OA) include cartilage degeneration and synovial inflammation. Previous studies confirmed that interleukin-1 (IL-1) stimulates the secretion of multiple inflammatory factors in synoviocytes and chondrocytes. IL-18 is a member of the IL-1 superfamily. In this study, the pro-inflammatory effects of IL-18 on synoviocytes and chondrocytes in patients with OA were investigated. Knee synovial membrane and cartilage samples were obtained from OA patients, then primary cells were cultured. Synoviocytes and primary chondrocytes at different generations (primary, secondary and tertiary), were stimulated with IL-18, then inflammatory marker levels, including tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2), were measured using reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay. IL-1 receptor antagonist (IL-1Ra) was applied to interfere with the IL-18 stimulation of chondrocytes, and then the COX-2 expression in chondrocytes and the PGE2 levels in the medium were measured. The expression of IL-18 receptor α (IL-18Rα) and IL-18 receptor ß (IL-18Rß) in synoviocytes and chondrocytes was assessed, using RT-PCR. Our results showed that IL-18 stimulated the COX-2 and TNF-α expressions in primary synoviocytes, while increasing PGE2 and TNF-α levels in the supernatant (P<0.05) of the culture medium in primary synoviocytes. IL-18 also induced high PGE2 level production in second-generation synoviocytes (P<0.05). Moreover, IL-18 upregulated COX-2 and TNF-α mRNA in chondrocytes, while promoting PGE2 and TNF-α (P<0.05) secretions in a dose-dependent manner. The induced effects were not attenuated by the addition of IL-1Ra (P<0.05). IL-18Rα was expressed in the chondrocytes and synoviocytes of 4/8 patients, while IL-18Rß was expressed in the chondrocytes of 4/8 patients and in the synoviocytes of 2/8 patients. We conclude that IL-18 induces inflammatory responses in synoviocytes and chondrocytes and that this effect was correlated with, although not entirely dependent on, IL-1ß.