Wogonin, a Bioactive Ingredient from Huangqi Guizhi Formula, Alleviates Discogenic Low Back Pain via Suppressing the Overexpressed NGF in Intervertebral Discs.

Purpose: To investigate whether wogonin, a key bioactive ingredient of Huangqi Guizhi formula (HQGZ formula; a Traditional Chinese Medicine herbal formula) according to network pharmacology analysis, has analgesic effects on discogenic low back pain (LBP) via regulating the nerve growth factor (NGF) in intervertebral discs (IVDs). Methods: The lumbar IVDs of rats were punctured to discogenic LBP, and the therapeutic effect of orally administrated HQGZ for discogenic LBP was investigated by measuring mechanical and cold allodynia and histological analysis. A network pharmacology analysis was conducted to search for bioactive ingredients from the HQGZ formula, and wogonin was suggested to be the most possible bioactive ingredient for LBP treatment. Subsequently, the analgesic effect of wogonin was investigated in the LBP model, and the gene expression of propain peptides in the bilateral dorsal root ganglia was analyzed using RT-PCR. Finally, immunohistochemical staining was performed for NGF expression of NGF in the IVDs to determine whether wogonin treatment would ameliorate NGF-induced LBP. Results: Oral administration of HQGZ for two weeks significantly ameliorated puncture-induced IVD degeneration (IDD) and LBP. In addition, the network pharmacology analysis revealed that wogonin, quercetin, and kaempferol were the potential candidate components of HQGZ for LBP treatment. Furthermore, we proved that wogonin had significant analgesic effects in the LBP model. Finally, wogonin was demonstrated to suppress the upregulated NGF in the IVD and ameliorate NGF-induced LBP in rats. Conclusions: The HQGZ formula has significant analgesic effects for LBP. In addition, the bioactive ingredient of wogonin was extracted from HQGZ and ameliorated LBP by suppressing the overexpressed NGF in degenerated IVDs. Therefore, wogonin has potential to be alternative treatment for LBP in clinical.

No Benefit to Platelet-rich Plasma Over Placebo Injections in Terms of Pain or Function in Patients with Hemophilic Knee Arthritis: A Randomized Trial.

BACKGROUND: Hemophilic knee arthritis is one of the most common presenting symptoms of hemophilia, and its management continues to be challenging to practitioners. Preliminary research has suggested that platelet-rich plasma (PRP) may have short-term efficacy in the treatment of hemophilic knee arthritis, but evidence for this treatment is limited. QUESTIONS/PURPOSES: What is the effectiveness of PRP compared with placebo in (1) reducing pain and improving knee joint function (as measured by WOMAC, VAS, and Hemophilia Joint Health Score [HJHS]) and (2) improving quality of life (as measured by SF-36 scores) in patients with hemophilic knee arthritis through 24 months of follow-up? METHODS: This was a prospective, parallel-group, double-blinded, single-center, placebo-controlled randomized clinical trial that included participants from a tertiary care center starting January 1, 2019, with follow-up completed on November 30, 2021. Participants were older than 18 years and had hemophilic knee arthritis confirmed by MRI, and they were randomly allocated to interventions in a 1:1 ratio. The investigators were not informed of the randomization sequence generated by the computer. Patient groups were comparable with respect to age, gender, BMI, hemophilia type, and disease severity at baseline. Physicians delivered three sessions (one per week) of a standard intraarticular injection of PRP (n = 95) or placebo (n = 95). The rate of successful blinding was balanced across the groups, which was assessed by asking participants which injection they thought they had received. The primary outcome was the WOMAC score (range 0 to 96; higher scores indicate more pain and worse function; minimum clinically important difference, 6.4 points) over 24 months. Among the 190 patients assigned to PRP or saline injections (mean age 31 ± 7 years), 100% (190) of patients were men). There was no between-group difference in the proportion of patients who completed the trial; 97% (92 of 95) of patients in the PRP group and 94% (89 of 95) of patients in the placebo group completed the trial. The most common adverse events were injection site discomfort 8% (8 of 95) in the PRP group and 4% (4 of 95) in the placebo group. An intention-to-treat analysis was planned, but there was no crossover between groups. All patients were included in the analyses. With 95 patients in each group, the study was powered a priori at 90% to detect a difference in WOMAC score of 6.4 points, which was considered a clinically important difference. RESULTS: There were no clinically important differences in the mean WOMAC, VAS pain, HJHS, SF-36, and MRI scores between groups at any timepoint. Intraarticular PRP did not ameliorate function, symptoms, and quality of life in patients with hemophilic knee arthritis. At 24 months of follow-up, the mean difference between the PRP and placebo groups in the WOMAC score was -1 (95% CI -5 to 2; p = 0.42). The mean difference in the VAS pain score was -0.3 (95% CI -0.8 to 0.2; p = 0.19), in the HJHS was -0.6 (95% CI -1.4 to 0.1; p = 0.10), in the SF-36 physical component summary was 0 (95% CI -2 to 3; p = 0.87), and in the SF-36 mental component summary was -1 (95% CI -3 to 2; p = 0.64). The mean differences in the MRI scores of soft tissue and osteochondral subscore were 0.1 (95% CI -0.3 to 0.5; p = 0.59) and -0.3 (95% CI -0.7 to 0.1; p = 0.19), respectively. CONCLUSION: Among patients with hemophilic knee arthritis, three intraarticular PRP injections, compared with placebo injections, did not improve hemophilic knee symptoms, function, and quality of life over 24 months. The results of this study do not support the use of PRP injections in patients who have hemophilic knee arthritis. LEVEL OF EVIDENCE: Level I, therapeutic study.

Intra-articular injections of platelet-rich plasma decrease pain and improve functional outcomes than sham saline in patients with knee osteoarthritis.

PURPOSE: To compare the long-term clinical efficacy provided by intra-articular injections of either Pure Platelet-rich Plasma (P-PRP) or sham saline to treat knee osteoarthritis (KOA). METHODS: This prospective, parallel-group, double-blind, multi-center, sham-controlled randomized clinical trial recruited participants with KOA from orthopedic departments at nine public hospitals (five tertiary medical centers, four secondary medical units) starting January 1, 2014, with follow-up completed on February 28, 2021. Participants were randomly allocated to interventions in a 1:1 ratio. Data were analyzed from March 1, 2021, to July 15, 2021. Three sessions (1 every week) of P-PRP or sham saline injected by physicians. The primary outcome was the Western Ontario and McMaster Universities Arthritis Index (WOMAC) at 3, 6, 12, 24, 60 months of follow-up. Secondary outcomes included the International Knee Documentation Committee (IKDC) subjective score, visual analogue scale (VAS) score, intra-articular biochemical marker concentrations, cartilage volume, and adverse events. Laboratory of each hospital analyzed the content and quality of P-PRP. RESULTS: 610 participants (59% women) with KOA who received three sessions of P-PRP (n = 308, mean age 53.91 years) or sham saline (n = 302, mean age 54.51 years) injections completed the trial. The mean platelet concentration in PRP is 4.3-fold (95% confidence interval 3.6-4.5) greater than that of whole blood. Both groups showed significant improvements in IKDC, WOMAC, and VAS scores at 1 month of follow-up. However, only the P-PRP group showed a sustained improvement in clinical outcome measurements at month 24 (P < 0.001). There were statistically significant differences between the P-PRP and sham saline groups in all clinical outcome measurements at each follow-up time point (P < 0.001). The benefit of P-PRP was clinically better in terms of WOMAC-pain, WOMAC-physical function and WOMAC-total at 6, 12, 24, and 60 months of follow-up. No clinically significant differences between treatments were documented in terms of WOMAC-stiffness at any follow-up. A clinically significant difference favoring P-PRP group against saline in terms of IKDC and VAS scores was documented at 6, 12, 24 and 60 months of follow-up. At 6 months after injection, TNF-α and IL-1ß levels in synovial fluid were lower in the P-PRP group (P < 0.001). Tibiofemoral cartilage volume decreased by a mean value of 1171 mm3 in the P-PRP group and 2311 mm3 in the saline group over 60 months and the difference between the group was statistically significant (intergroup difference, 1140 mm3, 95% CI - 79 to 1320 mm3; P < 0.001). CONCLUSIONS: In this randomized clinical trial of patients with KOA, P-PRP was superior to sham saline in treating KOA. P-PRP was effective for achieving at least 24 months of symptom relief and slowing the progress of KOA, with both P-PRP and saline being comparable in safety profiles.

Nanoscaled Bionic Periosteum Orchestrating the Osteogenic Microenvironment for Sequential Bone Regeneration.

Periosteum orchestrates bone repair. Previously developed artificial periosteum was mainly focusing on materials modification to simply enhance bone formation, but few were attempting to make the artificial periosteum fit different bone repair stages. Here, we constructed a functionalized periosteum, which was composed of an electrospun scaffold grafted with leptin receptor antibody (LepR-a) and BMP2-loaded hollow MnO2 (h-MnO2) nanoparticles through a polydopamine (PDA)-assisted technique. The bionic periosteum showed suitable mechanical properties and favorable biocompatibility. It effectively recruited skeletal stem cells (SSCs) through antigen-antibody interactions, as in in vitro cell adhesion tests, we observed that more SSCs attached to the LepR-a-grafted periosteum compared to the control group. In vivo, the LepR-a-grafted periosteum covered on the cranial defect in Prx1-Cre/ERT2, -EGFP mice recruited more Prx1-EGFP cells to the fracture site compared to control groups at post-surgery day 3, 7, and 14. Co-staining with Sp7 indicated that most of the recruited Prx1-EGFP cells underwent osteogenic lineage commitment. Sustained BMP2 release from h-MnO2 promoted osteogenesis by accelerating the osteogenic differentiation of recruited SSCs, as demonstrated by alkaline phosphatase (ALP) and alizarin red staining (ARS) in vitro and microcomputed tomography (micro-CT) in vivo. Interestingly, we also observed the growth of osteogenic coupled capillaries (CD31hiEmcnhi) in the bone repair site, which might be induced by increased platelet-derived growth factor-BB (PDGF-BB) in the regenerative microenvironment subsequent to SSCs' differentiation. Taken together, the findings from this study indicate that the multifunctionalized periosteum efficiently recruited and motivated the SSCs in vivo and orchestrated the osteogenic microenvironment for bone repair in a sequence manner. Thus, the construction of the bionic periosteum to couple with natural bone regeneration stages has been demonstrated to be effective in facilitating bone healing.

Achillon versus modified minimally invasive repair treatment in acute Achilles tendon rupture.

PURPOSE: To date, the best treatment of acute Achilles tendon rupture (AATR) is still inconclusive. Achillon seems to be a promising approach with satisfactory function and low complication rate. We hypothesize a modified minimally invasive repair (MMIR), which provides direct visualization of proximal tendon stump without specialized equipment that could provide comparable results. This trial is aimed to evaluate the functional and surgical outcomes of MMIR comparing with Achillon. METHODS: From February 2013 to February 2017, 114 patients with AATR were enrolled in this trial, underwent an alternative operation (Achillon or MMIR), and accelerated rehabilitation protocol. Forty-four patients took the Achillon and the other 70 patients took the MMIR at their subjective choice. One hundred eleven full follow-up data were obtained including Achilles tendon total rupture score (ATRS), time back to work, rerupture rate, overall complication rate, and operation time. RESULTS: There was no significant difference between groups in demographic characters. There was no statistical difference between both groups regarding to time return to work and ATRS at 3rd, 6th, 12th, and 24th month, respectively. Five reruptures and two Achilles tendons tethering to skins were found in the Achillon group, and two reruptures and one sural nerve injury in the MMIR group. No wound infection and dehiscence occurred. Overall complication rate in the Achillon group is higher (16.3% vs. 4.4%, p = 0.044). The operation time of Achillon is less than MMIR (34.84 vs. 39.71, p < 0.001). CONCLUSION: Both techniques combining with accelerated rehabilitation showed to be reliable and effective. MMIR is safer and more economical, and Achillon is faster.

Combination of NF-kB targeted siRNA and methotrexate in a hybrid nanocarrier towards the effective treatment in rheumatoid arthritis.

BACKGROUND: The transcription factor NF-kB plays an important role in the pathogenesis of rheumatoid arthritis (RA). Effective treatment of RA is hindered due to the lack of specificity of small molecules in the inflamed joints. In this study, we aimed to develop a unique hybrid-nanoparticles system comprised of calcium phosphate/liposome to deliver NF-kB-targeted siRNA and methotrexate (MTX) to diseased site. RESULTS: We have successfully demonstrated that the combination of siRNA and MTX in a calcium phosphate/liposome-based hybrid nanocarrier could effectively treat the RA. We have showed that folate receptor-targeted nanocarrier system significantly suppression the arthritis progression in mice model. Substantial accumulation of F-siRML was observed in LPS-activated macrophages. These kind of activated macrophages are generally present in the RA and osteoarthritis and folate-targeted nanoparticle enables the effective accumulation of therapeutics in the diseased site. The combinational nanoparticles effectively blocked the NF-kB signaling pathways and reduced the expression of pro-inflammatory cytokines. Furthermore, siRML and F-siRML did not show any decrease in the lymphocyte count indicating that it can avoid the adverse effect of MTX. CONCLUSION: Therefore, siRML and F-siRML provides unique benefits of excellent therapeutic efficacy with excellent safety profile in the arthritic mice and could be an promising approach in the treatment of rheumatoid arthritis.

Melatonin Inhibits Reactive Oxygen Species-Driven Proliferation, Epithelial-Mesenchymal Transition, and Vasculogenic Mimicry in Oral Cancer.

Globally, oral cancer is the most common type of head and neck cancers. Melatonin elicits inhibitory effects on oral cancer; however, the biological function of melatonin and underlying mechanisms remain largely unknown. In this study, we found that melatonin impaired the proliferation and apoptosis resistance of oral cancer cells by inactivating ROS-dependent Akt signaling, involving in downregulation of cyclin D1, PCNA, and Bcl-2 and upregulation of Bax. Melatonin inhibited the migration and invasion of oral cancer cells by repressing ROS-activated Akt signaling, implicating with the reduction of Snail and Vimentin and the enhancement of E-cadherin. Moreover, melatonin hampered vasculogenic mimicry of oral cancer cells through blockage of ROS-activated extracellular-regulated protein kinases (ERKs) and Akt pathways involving the hypoxia-inducible factor 1α. Consistently, melatonin retarded tumorigenesis of oral cancer in vivo. Overall, these findings indicated that melatonin exerts antisurvival, antimotility, and antiangiogenesis effects on oral cancer partly by suppressing ROS-reliant Akt or ERK signaling.

Long-term mortality after parathyroidectomy among chronic kidney disease patients with secondary hyperparathyroidism: a systematic review and meta-analysis.

Parathyroidectomy (PTx) and medical treatments are both recommended for reducing serum intact parathyroid hormone (iPTH) and curing secondary hyperparathyroidism (sHPT) in patients with chronic kidney disease (CKD), but their therapeutic effects on long-term mortality are not well-known. Thus, we aim to assess such therapeutic effect of PTx. Electronic literatures published on Pubmed, Embase, and Cochrane Central Register of Controlled Trials in any language until 27 November 2015 were systematically searched. All literatures that compared outcomes (survival rate or mortality rate) between PTx-treated and medically-treated CKD patients with sHPT were included. Finally, 13 cohort studies involving 22053 patients were included. Data were extracted from all included literatures in a standard form. The outcomes of all-cause and cardiovascular mortalities were assessed using DerSimonian and Laird's random effects model. We find PTx-treated versus medically-treated patients had a 28% reduction in all-cause mortality and a 37% reduction in cardiovascular mortality. Thus, PTx versus medical treatments might reduce the risks of all-cause and cardiovascular mortalities in CKD patients with sHPT. Further studies with prospective and large-sample clinical trials are needed to find out the real effect of PTx and to assess whether mortality rates differ among patterns of PTx.

[Radiographic analysis of the osseous fixation zone for the iliac crest external fixation with Schanz screws].

OBJECTIVE: To radiographically analyze the osseous fixation zone for the iliac crest external fixation with Schanz screws and in order to guide their placement. METHODS: Nine adults with 2.0-mm-slice continuous pelvic axial CT scans were selected as research subjects. Each CT scan data was imported into MIMICS 10.0. The osseous fixation zone the upper portion of the anterior column of the acetabulum which is located between the anterior superior iliac spine and the gluteal medius pillar and between the iliac crest and the acetabulum-for the iliac crest external fixation with Schanz screws was reconstructed into true sagittal and true coronal planes by using the software. Then the measurements were taken on the reconstructed planes with measuring tools. Finally, the measured data was analyzed. RESULTS: The palpable iliac crest segment, which was of 49.6 mm width and located 16.5 mm posterior to the anterior superior iliac spine could be used to locate the start points of the Schanz screws. Under the above-mentioned iliac crest segment, the osseous zone was deep, got ample bony materials and could intraosseously contain Schanz screws with 5.0 mm diameter. The screws could be safely inserted to a minimal depth of 71.7 mm towards the acetabular dome and to a maximal depth of 143.5 mm posterior to the acetabulum. CONCLUSION: The study can guide the effective insertion of the iliac crest Schanz screws. By setting a suitable start point in the above-mentioned iliac crest region and angling correctly relative to the acetabulum,the Schanz screw can be inserted into the relative strong cancellous bone above or posterior to the acetabulum with a considerable depth, to getting more bone engagement.

[Radiographic anatomical analysis of the pelvic Teepee view].

OBJECTIVES: To research radiographic anatomy of the main structure of the pelvic Teepee view, including its azimuth direction and view anatomy structure. METHODS: From June 2013 to June 2014 adult pelvic CT examination results were filtered, excluding skeletal deformities and pelvic osseous destruction caused by tumors, trauma, etc. The data of 2.0 mm contiguous CT scan of 9 adults' intact pelves was,selected and input into Mimics 10.01 involving 7 males and 2 females with an average age of (41.2±10.3) years old. Utilizing the software, the 3D CT reconstructions of the pelves were completed. Setting the transparency being high,the pelvic 3D reconstructions were manipulated from the pelvic anteroposterior view to the combined obturator oblique outlet view and fine-tuned till the regular Teepee-or teardrop-shaped appearance emerges. Cutting tools of the software were at the moment applied to separate the "Teepee" from the main pelvis for each reconstruction. Then the "Teepee" and the rest (main) part of the pelvis were displayed in different color to facilitate the analysis on the Teepee, iliac-oblique, and anteroposterior views. RESULTS: The "Teepee" started from the posterolateral aspect of the anterior inferior iliac spine and finished at the cortex between the posterior superior iliac spine and the posterior inferior iliac spine in a direction of being from caudal-anterior-lateral to cranial-posterior-medial. The radiographic anatomical composition of the "Teepee" contained one tip, one base,and two aspects. With the inner and outer iliac tables being the inner and outer aspects of the "Teepee", the tip is consequently formed by their intersection. The base is imaged from the cortex of the greater sciatic notch. The medial-inferior-posterior portion of the "Teepee" contains a small part of sacroiliac joint and its corresponding side of bone of the sacrum. CONCLUSIONS: The "Teepee" is a zone of ample osseous structures of the pelvis, aside from a small medial-inferior-posterior portion, the main zone of which can be accepted as a safe osseous zone for the anchor of implants stabilizing certain pelvic and acetabular fracture patterns. The Teepee view can be utilized as guidance for the safe percutaneous insertion of such implants.

[Influence of the included angle between anterior aspects of S2 and S1 vertebral bodies on pelvic inlet imaging in mid-line sagittal plane].

OBJECTIVE: To analyze the influence of included angle between the anterior aspects of S2 and S vertebral bodies on pelvic inlet imaging in the pelvic midline sagittal plane. METHODS: Totally 58 axial pelvic CT scans were chosen as study objects including 43 males and 15 females,with an average age of 40.7 years old (ranged,18 to 68 years old). The angles between the anterior aspects of S2 and S1, vertebral bodies and the horizontal plane on midline sagittal CT reconstruction were measured to simulate the optimal S2 and S1 inlet angles. The included angle between the anterior aspects of S2 and S1 vertebral bodies was calculated by subtrocting the S1,inlet angle from the S2 inlet angle defined as a base number. Then, the impact of the calculated included angles on the pelvic inlet imaging was analyzed. Results:The S2 inlet angles averaged (30.5±6.5) degrees; the S inlet angles averaged (25.7±5.9) degrees. The difference between them was significant (t=3.35, P=0.001). Ten patients had zero angle between the anterior aspects of S2 and S1 vertebral bodies; 14 patients had negative angle, averaged-(8.9±8.1) degrees; 34 patients had positive angle,averaged (11.8+6.4) degrees. CONCLUSION: The difference of included angle between the anterior aspects of S2 and S1 vertebral bodies leads to the difference between S1 inlet view and S2 inlet view in most cases, complicating the pelvic inlet imaging,and affecting the reliability of the application of pelvic inlet view. Utilizing the angles measured on the preoperative midlihe sagittal CT reconstruction to obatin the patient-customized S1 and S2 inlet views could accurately guide the S1 and S2 iliosacral screw insertion.

[Classification of upper sacral segment based on continuous axial pelvic computed tomography scan].

OBJECTIVES: To introduce a classification system of upper sacral segment and its significance based on the continuous pelvic axial computed tomography scan. METHODS: The whole pelvis 2.0 mm thick axial scan images of 127 cases were observed, the sacroiliac screw channel of S1 were measured, according to the size of the transverse screw channel the upper sacral segment were classified. Such as transverse screw channel existed and in at least 4 layer scan images its width was > 7.3 mm, it was defined as sacral segment of the normal type. Such as transverse screw channel existed and its maximum width was 7.3 mm or less on scanning level, it was defined as a transitional. Such as transverse channel did not exist, or its width on all scanning level was 0 mm or less, it was defined as dysplastic. Various cases,percentage, and the average of the transverse screw channel were calculated. RESULTS: There were 58 normal (45.7%),42 transitional (33.1%), and 27 dysplastic (21.2%) upper sacral segments with an averaged width of the tansverse screw channel of 13.9 mm, 5.2 mm, and 0.9 mm, respectively. Each specimen could be defined as one of the three types of upper sacral segment without exceptions. CONCLUSION: It is possible to insert a transverse iliosacral screw into a normal upper sacral segment when indicated because of the capacious transverse screw channel. The transverse iliosacral screw placement into the transitional and dysplastic upper sacral segments was contraindicated because of the limited or none transverse screw channel. The transitional upper sacral segment was superior to the dysplastic segment due to its starting point location restriction on the true lateral sacral view.