DAIR in treating chronic PJI after total knee arthroplasty using continuous local antibiotic perfusion therapy: a case series study.

BACKGROUND: Antimicrobial agents are administered via intramedullary antibiotic perfusion (iMAP)/intrasoft tissue antibiotic perfusion (iSAP) to infected lesions to control osteoarticular and soft tissue infections. Continuous local antibiotic perfusion (CLAP) has been reported to be useful. This study aimed to investigate the outcomes of DAIR combined with CLAP for chronic PJI after total knee arthroplasty performed at our hospital. SUBJECTS AND METHODS: Six patients (male; one case, female; five cases, mean age 79.5 years (70-94)) underwent CLAP for chronic PJI after TKA at our hospital between July 2020 and June 2022. They were followable for at least one year after surgery. Seven months (17-219), with a mean follow-up of 24.3 months (12-36). In addition to direct debridement and insert exchange, systemic antimicrobial treatment, and CLAP with gentamicin were performed using NPWT. We investigated the organisms causing the inflammation, the duration of iMAP/iSAP implantation, the maximum daily dose of GM, the maximum GM blood concentration, and the presence or absence of GM-induced adverse events. RESULT: Two of six patients had a recurrence of infection at five weeks and five months after initial CLAP and required repeat CLAP treatment, but all patients could preserve their components. The organisms responsible for the flare-ups were MSSA in three cases: ESBL-producing E. coli, mixed MSSA and streptococcal infection, Klebsiella pneumonia in one case each, and unknown pathogens in one case. CLAP therapy for all patients was administered eight times in 6 cases: iMAP, mean: 10.0 days (5-16); iSAP, mean: 19.3 days (15-28); GM dose, mean: 162.5 mg/day (80-240); and GM blood concentration, mean: 1.4 µg/mL (0.2-5.0). Adverse events included one case of reversible acute kidney injury during CLAP in a patient with recurrent infection. DAIR with CLAP for chronic post-TKA infection can be a useful treatment option to preserve components and allow the infection to subside, provided the implant is not markedly loosened.

Delayed cortical bone healing due to impaired nuclear Nrf2 translocation in COPD mice.

The effect of the pathogenesis of chronic obstructive pulmonary disease (COPD) on bone fracture healing is unknown. Oxidative stress has been implicated in the systemic complications of COPD, and decreased activity of Nrf2 signaling, a central component of the in vivo antioxidant mechanism, has been reported. We investigated the process of cortical bone repair in a mouse model of elastase-induced emphysema by creating a drill hole and focusing on Nrf2 and found that the amount of new bone in the drill hole was reduced and bone formation capacity was decreased in the model mice. Furthermore, nuclear Nrf2 expression in osteoblasts was reduced in model mice. Sulforaphane, an Nrf2 activator, improved delayed cortical bone healing in model mice. This study indicates that bone healing is delayed in COPD mice and that impaired nuclear translocation of Nrf2 is involved in delayed cortical bone healing, suggesting that Nrf2 may be a novel target for bone fracture treatment in COPD patients.

Comparison of gender differences in health-related quality of life between patients with hand disease and those with other musculoskeletal disorders of the knee and lumbar spine.

BACKGROUND: Musculoskeletal diseases are a major public health concern among older adults. There has been an increase in the number of studies on pain between men and women, such as knee and lumbar pain. However, there is a dearth of research on pain between men and women in hand disease. This study compared health-related quality of life (HRQOL) between patients with musculoskeletal disorders of the hand and those with disorders of the knee and the lumbar spine. METHODS: From 2014 to 2018, 5595 adult patients completed a questionnaire on HRQOL. Among these patients, we identified patients with hand disease (n = 1038), knee disease (n = 680), and lumbar spine disease (n = 2021) resulting in a total sample of 3739 patients (1749 men and 1992 women). Patients' responses to the EuroQol (EQ-5D), the Short Form 12-item Survey (SF-12), and three visual analogue scales (VAS), as different measures of the HRQOL, were evaluated. RESULTS: It was found that the EQ-5D index was lowest in the lumbar spine patients, followed by knee and hand patients. The VAS scores were negatively affected in all groups. The EQ-5D index was significantly lower in women than in men only in the hand disease group. Multivariate analysis revealed that for the EQ-5D index, age, gender, and VAS scores for job and activities of daily living were explanatory factors in the hand disease group. Gender was not a significant predictor in the other groups. CONCLUSIONS: This study demonstrated that pain negatively affected HRQOL, and gender differences in HRQOL were found only in patients with hand disease. Gender differences in HRQOL in patients with hand disease warrant appropriate clinical attention.

Oxidative stress causes muscle structural alterations via p38 MAPK signaling in COPD mouse model.

INTRODUCTION: Sarcopenia is a complication of Chronic Obstructive Pulmonary Disease (COPD) that negatively affects physical activity and quality of life. However, the underlying mechanism by which COPD affects skeletal muscles remains to be elucidated. Therefore, we investigated the association between oxidative stress and structural alterations in muscles in elastase-induced emphysema mouse models. MATERIALS AND METHODS: Twelve-week-old male C57BL/6J mice were treated with either intratracheal porcine pancreatic elastase (PPE) dissolved in saline, or saline alone. The mice were euthanized 12 weeks after treatment, and the lungs and limb muscles were used for protein analysis of oxidative stress, p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway and muscle atrophy signaling pathway related with oxidative stress. Furthermore, C57BL/6J mice treated with PPE or saline were analyzed for the effects of oral administration of astaxanthin or p38 inhibitor. RESULTS: The weight of the soleus muscle, proportion of type I muscle fibers, and cross-sectional areas of muscle fibers in the PPE group were lower than those in the control group. Oxidative stress marker levels in the PPE group were elevated in skeletal muscles. The p38 MAPK signaling pathway was activated in the soleus muscles, leading to the activation of the ubiquitin-proteasome system and autophagy. Astaxanthin and p38 inhibitors attenuated alterations in muscle structure through the deactivation of the p38 MAPK signaling pathway. CONCLUSIONS: This study provides first evidence in COPD mouse model that oxidative stress trigger a series of muscle structural changes. Our findings suggest a novel target for sarcopenia in COPD.

Potential of Continuous Local Antibiotic Perfusion Therapy for Fracture-Related Infections.

INTRODUCTION: Fracture-related infections (FRIs) are challenging for orthopedic surgeons, as conventional surgical treatment and systemic antimicrobial therapy cannot completely control local infections. Continuous local antibiotic perfusion (CLAP) is a novel and innovative therapy for bone and soft-tissue infections, and is expected to eradicate biofilms by maintaining a sustained high concentration of antimicrobial agents at the infected site. If CLAP therapy can eradicate infection even in cases with implants while preserving the implants, it would be an ideal and effective treatment for local refractory infections. This study aimed to evaluate the usefulness of novel CLAP therapy for FRIs. METHODS: Nine patients treated with CLAP therapy were retrospectively analyzed. The mean age was 65.9 (43-82) years, and the mean follow-up period was 14.9 (6-45) months. In all cases, the infected sites were related to the lower extremities (tibia, n = 6; fibula, n = 1; hip joint, n = 1; foot, n = 1). All patients underwent similar procedures for this therapy combined with negative-pressure wound therapy after thorough irrigation and debridement of infected tissues. RESULTS: The pathogens identified were Staphylococcus aureus (methicillin-resistant S. aureus, n = 5; methicillin-susceptible S. aureus, n = 1), Pseudomonas aeruginosa (n = 3), Enterococcus faecalis (n = 2), Corynebacterium (n = 1), and Enterobacter (n = 1); pathogens were not detected in one case. The mean duration of CLAP was 17.0 (7-35) days. In all cases, implants were preserved until bone union was achieved. Five cases relapsed; however, infection was finally suppressed in all cases by repeating this method. No side effects were observed. CONCLUSION: This novel case series presents treatment outcomes using CLAP therapy for FRIs. This method has the potential to control the infection without removing the implants, because of the sustained high concentration of antimicrobial agents at the infected site, and could be a valuable treatment option for refractory FRIs with implants, in which bone union has not been achieved.

Development of a novel knee contracture mouse model by immobilization using external fixation.

AIMS: Several studies have used animal models to examine knee joint contracture; however, few reports detail the construction process of a knee joint contracture model in a mouse. The use of mouse models is beneficial, as genetically modified mice can be used to investigate the pathogenesis of joint contracture. Compared to others, mouse models are associated with a lower cost to evaluate therapeutic effects. Here, we describe a novel knee contracture mouse model by immobilization using external fixation. METHODS: The knee joints of mice were immobilized by external fixation using a splint and tape. The passive extension range of motion (ROM), histological and immunohistochemical changes, and expression levels of fibrosis-related genes at 2 and 4 weeks were compared between the immobilized (Im group) and non-immobilized (Non-Im group) groups. RESULTS: The extension ROM at 4 weeks was significantly lower in the Im group than in the Non-Im group (p < 0.01). At 2 and 4 weeks, the thickness and area of the joint capsule were significantly greater in the Im group than in the Non-Im group (p < 0.01 in all cases). At 2 weeks, the mRNA expression levels of the fibrosis-related genes, except for the transforming growth factor-ß1, and the protein levels of cellular communication network factor 2 and vimentin in the joint capsule were significantly higher in the Im group (p < 0.01 in all cases). CONCLUSION: This mouse model may serve as a useful tool to investigate the etiology of joint contracture and establish new treatment methods.

Molecular and Clinical Elucidation of the Mechanism of Action of Steroids in Idiopathic Carpal Tunnel Syndrome.

BACKGROUND: Carpal tunnel steroid injection is a nonoperative intervention for the treatment for idiopathic carpal tunnel syndrome (CTS). The antifibrotic, anti-inflammatory, and antiedematous properties of steroids account for their therapeutic effects in the context of CTS; however, their relative contribution has not been clarified. METHODS: Fibroblasts from subsynovial connective tissues (SSCT) were intraoperatively collected from patients with idiopathic CTS and were incubated with or without the steroid triamcinolone acetonide (TA) for 1, 3, and 7 days; the expression of fibrosis-related genes and inflammatory cytokines was evaluated using quantitative reverse transcription-polymerase chain reaction. A clinical prospective study was conducted with patients who received carpal tunnel TA injections. We performed clinical and electrophysiological evaluations before and 1, 3, and 5 months after TA injection; and we compared the median nerve, flexor tendon, and SSCT areas and the median nerve flattening ratio before and 1 month after TA injection using 3-T magnetic resonance imaging (MRI). RESULTS: TA induced downregulation of the fibrosis-related genes Col1A1 (collagen type I alpha 1 chain), Col1A2, and Col3A1 but not the inflammation-related genes. The nerve flattening ratio did not change after TA injection according to the MRI-based observation of the median nerve, flexor tendon, and SSCT areas. CONCLUSIONS: The therapeutic effects of injected TA are apparently mediated by its antifibrotic rather than its anti-inflammatory and antiedematous properties. TA probably alters the properties but not the morphology of SSCT. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Long-term outcomes of metacarpal fractures surgically treated using bioabsorbable plates: a retrospective study.

BACKGROUND: Implants made from bioabsorbable unsintered hydroxyapatite and poly-L-lactate composites (u-HA/PLLA) are widely used in the oral, maxillofacial, and orthopedic fields. This study assess the long-term (> 5 years) outcomes of patients with metacarpal fractures who were surgically treated using bioabsorbable plates and screws (Super-Fixsorb MX40 mesh; Teijin Medical Technology, Osaka, Japan). METHODS: A retrospective analysis of six patients with eight metacarpal fractures treated with bioabsorbable plates was done. All patients were followed for more than 5 years post-surgery. The clinical outcomes were evaluated using Q-DASH scores and the grip strength (GS): opposite side ratio. The resorption status of implants was assessed on plain computed tomography (CT) scans at final follow-up appointments. RESULTS: The mean age of the patients at the time of surgery was 29.5 years (16-54), and the median follow-up period was 81.8 months (68-101). All fractures united without displacement after an average of 3.5 months, and there were no implant specific complications associated with the use of absorbable plates. The mean grip strength ratio was 85.1% (56.8-104.5). The mean Q-DASH scores of 11.36 points (0-34.09) was good in all but two patients. We also observed that it took more than 8 years for the plates to be absorbed completely. CONCLUSIONS: This study demonstrates that the process of bioabsorption in metacarpal fractures might be completed in about 8 years, and the absorption speeds were different inside and outside of the bone. The bioabsorbable plates are more cost-effective than metallic implants. The potential for bioabsorbable plates to be used in various clinical procedures is promising.

Performance of two bone substitutes of novel cotton-like ß-TCP/PDLGA and granular ß-TCP on bone regeneration in the femoral bone defect of the Beagle dogs.

This study aimed to clarify whether novel cotton-like composite made of ß-tricalcium phosphate (ß-TCP) and poly(Dl-lactide-co-glycolide) (PDLGA) has a different effect on in vivo bone regeneration after bone defect than that of granular ß-TCP. Five male Beagle dogs served as subjects. Cortical and medullary bone defect as non-through holes were made at the diaphysis of the bilateral femurs. One side was implanted with ß-TCP/PDLGA (ß-TCP/PDLGA group) and the other side was implanted with granular ß-TCP (ß-TCP group). At 4 weeks after implantation, we found no significant differences in the percentages of newly formed bone area and fibrous tissue area in the bone defect between the two groups. The ß-TCP/PDLGA group showed more uniform filling on the surface and earlier disappearance of the material in the medullary region, and there were fewer inflammatory cells and osteoclasts in the bone defect in the ß-TCP/PDLGA group. In conclusion, ß-TCP/PDLGA performs better at filling the bone defect uniformly and disappears earlier at the cortical and medullary regions while causing less inflammation and bone resorption. Although bone formation activity of the ß-TCP/PDLGA group in the cortical region was lower, the newly formed bone volume in bone defect of the ß-TCP/PDLGA group was equal to that of the ß-TCP group.

Four-corner fusion method using a bioabsorbable plate for scapholunate advanced collapse and scaphoid nonunion advanced collapse wrists: a case series study.

BACKGROUND: Scaphoid excision and four-corner arthrodesis is an acceptable salvage procedure for the treatment of scapholunate advanced collapse (SLAC) and scaphoid nonunion advanced collapse (SNAC) wrists, since first popularized in the 1980s. We investigated the potential application of novel bioabsorbable plates and screws made of un-sintered hydroxyapatite/poly-L-lactide composite for the treatment of metacarpal fractures. We used this material for the fixation of four-corner fusions for SLAC or SNAC wrists commencing from April 2009. The purpose of this study was to clarify the controversy in the literature regarding the use of these plates. METHODS: The surgical procedures and clinical outcomes of four-corner fusions using a bioabsorbable (poly-L-lactic acid and hydroxyapatite) plate were reported. Ten patients (mean age, 59.2 years) with SLAC or SNAC wrists underwent fusions between April 2009 and June 2016. The primary diseases were scapholunate ligament injury, Preiser disease, and scaphoid pseudarthrosis. The mean postoperative follow-up period was 45.9 months (range, 12-86). RESULTS: In all patients, bone union was achieved without dislocation or pain. The mean wrist flexion and extension arc improved from 78.5 degrees before surgery to 90.5 degrees after surgery. Mean grip strength improved from 51 to 69% after surgery, and the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score improved from 53.5 to 14.3. No complications such as infection, avascular swelling, or tendon adhesion were observed. This implant requires no removal of internal fixation devices, produces stable outcomes, and is an effective fusion technique. CONCLUSIONS: We summarized the outcomes of four-corner arthrodesis using bioabsorbable plates. Satisfactory clinical results were shown, with no obvious complications. This novel plate also serves as a good alternative for patients who are allergic to metals. Furthermore, bioabsorbable plates are advantageous as they do not require removal.

Transient receptor potential vanilloid 1 and 4 double knockout leads to increased bone mass in mice.

Calcium balance is important in bone homeostasis. The transient receptor potential vanilloid (TRPV) channel is a nonselective cation channel permeable to calcium and is activated by various physiological and pharmacological stimuli. TRPV1 and TRPV4, in particular, have important roles in intracellular Ca2+ signaling and extracellular calcium homeostasis in bone cells. TRPV1 and TRPV4 separately mediate osteoclast and osteoblast differentiation, and deficiency in any of these channels leads to increased bone mass. However, it remains unknown whether bone mass increases in the absence of both TRPV1 and TRPV4. In this study, we used TRPV1 and TRPV4 double knockout (DKO) mice to evaluate their bone mass in vivo, and osteoclast and osteoblast differentiation in vitro. Our results showed that DKO mice and wild type (WT) mice had no significant difference in body weight and femur length. However, the results of dual-energy X-ray absorption, microcomputed tomography, and bone histomorphometry clearly showed that DKO mice had higher bone mass than WT mice. Furthermore, DKO mice had less multinucleated osteoclasts and had lower bone resorption. In addition, the results of cell culture using flushed bone marrow from mouse femurs and tibias showed that osteoclast differentiation was suppressed, whereas osteoblast differentiation was promoted in DKO mice. In conclusion, our results suggest that the increase in bone mass in DKO mice was induced not only by the suppression of osteoclast differentiation and activity but also by the augmentation of osteoblast differentiation and activity. Our findings reveal that both the single deficiency of TRPVs and the concurrent deficiency of TRPVs result in an increase in bone mass. Furthermore, our data showed that DKO mice and single KO mice had varying approaches to osteoclast and osteoblast differentiation in vitro, and therefore, it is important to conduct further studies on TRPVs regarding the increase in bone mass to explore not only individual but also a combination of TRPVs.

Disruption of the aldehyde dehydrogenase 2 gene increases the bone anabolic response to intermittent PTH treatment in an ovariectomized mouse model.

Aldehyde dehydrogenase 2 (ALDH2) is the enzyme that oxidizes the acetaldehyde produced by alcohol metabolism. This variant not only affects the response to alcohol but is also associated with several diseases, such as esophageal cancer, myocardial infarction, and particularly osteoporosis. In our previous study, we reported that compared to wild-type (WT) mice, Aldh2 knockout (KO) mice naturally have a strong bone formation ability, and high expression of parathyroid hormone receptor (PTHR1) in osteocytes. The effect of the Aldh2 gene on bone metabolism in response to intermittent PTH treatment is unknown. The purpose of this study was to clarify the effect of the Aldh2 gene on the bone anabolic response to intermittent PTH treatment in ovariectomized mice. Female KO and WT mice were ovariectomized at 8 weeks of age. At 14 weeks of age, the KO and WT mice were divided into vehicle-treated (Veh) and PTH-treated (PTH) groups (i.e., the WT-Veh, WT-PTH, KO-Veh and KO-PTH groups). PTH (1-34) and vehicle were subcutaneously administered to each group at a dose of 40 µg/kg body weight (BW) five times per week for 4 weeks. Micro-CT showed that the bone volume (BV), trabecular number (Tb.N), connectivity density (Conn.D), and cortical thickness (Ct.Th) values in the KO-PTH mice were significantly higher than those in the KO-Veh mice. Histomorphometric analysis showed that the BV, Tb.N, and mineral apposition rate (MAR) values in the KO-PTH group were significantly higher than those in the KO-Veh group. The mRNA expression level of PTHR1 in the KO-PTH group was significantly increased and that of p21 in the KO-PTH group was significantly decreased compared with the levels in the KO-Veh group. The expression of PTHR in osteocytes from the KO-PTH group was also significantly increased compared with that in osteocytes from the KO-Veh group. Furthermore, cell cultures revealed that the ALP+CFU-f/total CFU-f percentage was significantly higher in the KO-PTH group than in the KO-Veh group. We concluded that in ovariectomized Aldh2 KO mice, the bone anabolic response to intermittent PTH treatment was significantly enhanced compared to that in WT mice, which may be mediated by the high expression level of PTHR1.

Effect of estradiol on fibroblasts from postmenopausal idiopathic carpal tunnel syndrome patients.

Fibrosis of the subsynovial connective tissue (SSCT) is a characteristic finding in patients with idiopathic carpal tunnel syndrome (CTS). Idiopathic CTS frequently occurs in postmenopausal women; therefore, female steroid hormones, especially estrogens, may be involved in its development. In this study, we evaluated the effect of the estradiol on the expression of genes and proteins related to fibrosis of SSCT fibroblasts from patients with idiopathic CTS. This study included 10 postmenopausal women (mean age 76 years). Fibroblasts derived from SSCT were treated with estradiol (10-4 -10-12 M), and the expression levels of TGF-ß-responsive genes were evaluated. The relationships between the expression of untreated estrogen receptor α (ERα) and ERß and changes in gene expression due to estradiol treatment were examined by quantitative real-time polymerase chain reaction. The effects of 10-4 M estradiol on collagen type I (Col1) and collagen type III (Col3) protein expression levels were also evaluated by fluorescent staining. The relationships between ERα/ß and Col1/3 expression were evaluated by immunohistochemical staining. The reduction in Col1A1 mRNA expression due to estradiol treatment was positively correlated with ERα expression (r = 0.903, p < 0.01). At the protein level, expression of Col1 and Col3 were down-regulated. These results indicated that ERα-mediated signaling may be involved in the regulation of Col1A1, and its regulatory effect may be dependent on the ERα expression level. The accurate evaluation of ERα expression level in the SSCT of individual patients with idiopathic CTS might guide the effective use of new estrogen replacement therapy.

Cortical bone loss due to skeletal unloading in aldehyde dehydrogenase 2 gene knockout mice is associated with decreased PTH receptor expression in osteocytes.

Aldehyde dehydrogenase 2 (ALDH2) is the enzyme that degrades and detoxifies the acetaldehyde produced by alcohol metabolism. In our previous study, we found that compared with wild-type mice (WT), climbing exercises did not increase trabecular bone mass in Aldh2 knockout mice (KO). The purpose of this study was to clarify the effect of the Aldh2 gene on cortical bone structure and on the dynamics of skeletal unloading. Eight-week-old male KO and WT were divided into ground control (GC) or tail suspension (TS) groups for one week (i.e., the KOGC, KOTS, WTGC and WTTS groups). We measured the bone mineral density (BMD) of the femur using dual-energy X-ray absorptiometry. We assessed the femoral morphometry using peripheral quantitative computed tomography (pQCT) and evaluated the femoral cortex histomorphometry, and cortical mRNA using quantitative RT-PCR and cortical bone immunohistostaining. No significant differences were found between the femoral BMD of WTGC and that of WTTS, but the BMD in KOTS was significantly lower than that of KOGC. The pQCT results revealed that the cortical BMD of the femoral diaphysis in KOTS was significantly lower than that of KOGC. Furthermore, the cortical bone area and cortical thickness were significantly lower in KOTS than in the other three groups. Cortical histomorphometric analysis revealed that the endosteal and periosteal bone formation parameters were significantly lower in KOTS than in KOGC. Bone formation signals such as parathyroid hormone receptor (PTHR) were significantly decreased in KOTS compared with the levels in KOGC. Cortical bone immunohistostaining revealed a significantly decreased expression of PTHR in the osteocytes of KOTS compared with the expression level in KOGC. Thus, we concluded that when the Aldh2 gene is disrupted, skeletal unloading suppresses bone formation to decrease cortical bone mass, which may be mediated by a decreased expression of PTH receptors in osteocytes.