Histopathological Confirmation of Axonal Sprouting in Regenerative Peripheral Nerve Interface.

Symptomatic neuroma represents a debilitating complication after major limb amputation. The regenerative peripheral nerve interface (RPNI) has emerged as a reproducible and practical surgery aimed at mitigating the formation of painful neuroma. Although previous animal studies revealed axonal sprouting, elongation, and synaptogenesis of proximal nerve stump within the muscle graft in RPNI, there is a lack of reports confirming these physiological reactions at the histopathological level in human samples. This report presents a case of below-knee amputation with RPNI due to foot gangrene resulting from polyarteritis nodosa. Subsequently, an above-knee amputation was necessitated due to the exacerbation of polyarteritis nodosa, providing the opportunity for histopathological examination of the RPNI site. The examination revealed sprouting, elongation, and existence of neuromuscular junction of the tibial nerve within the grafted muscle. To the best of our knowledge, this is the first report demonstrating axonal sprouting, elongation, and possibility of synaptogenesis of the nerve stump within the grafted muscle in a human sample.

Baricitinib ameliorates inflammatory and neuropathic pain in collagen antibody-induced arthritis mice by modulating the IL-6/JAK/STAT3 pathway and CSF-1 expression in dorsal root ganglion neurons.

BACKGROUND: Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at reducing pain than other similar drugs. Here, we aimed to elucidate the molecular mechanisms underlying the pain relief conferred by baricitinib, using a mouse model of arthritis. METHODS: We treated collagen antibody-induced arthritis (CAIA) model mice with baricitinib, celecoxib, or vehicle, and evaluated the severity of arthritis, histological findings of the spinal cord, and pain-related behaviours. We also conducted RNA sequencing (RNA-seq) to identify alterations in gene expression in the dorsal root ganglion (DRG) following baricitinib treatment. Finally, we conducted in vitro experiments to investigate the direct effects of baricitinib on neuronal cells. RESULTS: Both baricitinib and celecoxib significantly decreased CAIA and improved arthritis-dependent grip-strength deficit, while only baricitinib notably suppressed residual tactile allodynia as determined by the von Frey test. CAIA induction of inflammatory cytokines in ankle synovium, including interleukin (IL)-1ß and IL-6, was suppressed by treatment with either baricitinib or celecoxib. In contrast, RNA-seq analysis of the DRG revealed that baricitinib, but not celecoxib, restored gene expression alterations induced by CAIA to the control condition. Among many pathways changed by CAIA and baricitinib treatment, the interferon-alpha/gamma, JAK-signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways were considerably decreased in the baricitinib group compared with the celecoxib group. Notably, only baricitinib decreased the expression of colony-stimulating factor 1 (CSF-1), a potent cytokine that causes neuropathic pain through activation of the microglia-astrocyte axis in the spinal cord. Accordingly, baricitinib prevented increases in microglia and astrocytes caused by CAIA. Baricitinib also suppressed JAK/STAT3 pathway activity and Csf1 expression in cultured neuronal cells. CONCLUSIONS: Our findings demonstrate the effects baricitinib has on the DRG in relation to ameliorating both inflammatory and neuropathic pain.

Relationship between medial partite hallux sesamoid and hallux valgus in the general population.

BACKGROUND: An association between the medial partite hallux sesamoid (MPHS) and hallux valgus (HV) has been suggested; however, a causal relationship has not been confirmed. This study aimed to determine their causal relationship using a cross-sectional radiographic survey of a large-scale population cohort covering a wide age group. PATIENTS AND METHODS: The fifth survey of the Research on Osteoarthritis/Osteoporosis against Disability study involved 1997 participants aged 21-95 years who had undergone anteroposterior radiography of bilateral feet. The presence of MPHS, its morphology, and radiographic parameters related to the HV were assessed using radiographs. Changes in the prevalence of MPHS with age were assessed using trend tests. The relationship between the MPHS and HV was assessed based on sex and age. RESULTS: MPHS was found in 508 out of 3994 feet (12.7 %), with a significant difference in prevalence between men and women (10.0 % vs. 13.7 %, p < 0.001). Trend analysis demonstrated a significant decrease in MPHS occurrence with age in both sexes. HV angle was significantly higher in feet with MPHS than in those without (Men: 17.8 ± 7.0° vs. 14.0 ± 5.9°, p < 0.0001; Women: 19.6 ± 7.7° vs. 17.7 ± 7.9°, p < 0.0001). The prevalence of HV angle ≥ 20° was also significantly higher in feet with MPHS than in those without (Men: 33.3 % vs. 14.6 %, p < 0.0001; Women: 46.5 % vs. 34.6 %, p < 0.0001). This association between MPHS and HV was noticeable in younger adults and became less prominent with age. CONCLUSIONS: MPHS is associated with HV. The weakening of this relationship and the decreased prevalence of MPHS with age suggest that MPHS is not caused by HV, but is one of the causes of HV, especially in younger adults.

Associated correction of forefoot alignment with hindfoot fusion for pes planovalgus deformity.

BACKGROUND: The present study aimed to investigate changes in hallux alignment after corrective surgery for adult-acquired flatfoot deformity (AAFD). PATIENTS AND METHODS: The present study retrospectively investigated the changes of hallux alignment in 37 feet (33 patients) which were treated with double or triple arthrodesis of the hindfoot for AAFD between 2015 and 2021 and could be followed up to one year postoperatively. RESULTS: Hallux valgus (HV) angle significantly decreased by a mean 4.1° among the whole 37 subjects and by a mean 6.6° among the 24 subjects who had a preoperative HV angle of 15° or more. Those who had HV correction (HV angle correction ≥ 5°) demonstrated more near-normal postoperative alignment of the medial longitudinal arch and hindfoot than those without HV correction. CONCLUSIONS: Hindfoot fusion for AAFD could improve preoperative HV deformity to some degree. HV correction was associated with proper realignment of the midfoot and hindfoot. LEVEL OF EVIDENCE: Level IV; retrospective case series.

Upregulation of Mineralocorticoid Receptor Contributes to Development of Salt-Sensitive Hypertension after Ischemia-Reperfusion Injury in Rats.

The ischemia-reperfusion injury (IRI) of rat kidneys is used as a model of acute kidney injury. Salt-sensitive hypertension occurs in rats after IRI, and the distal nephrons play important roles in the development of this condition. We investigated the role of the mineralocorticoid receptor (MR) in the progression of IRI-induced salt-sensitive hypertension in rats. Fourteen days after right-side nephrectomy, IRI was induced by clamping the left renal artery, with sham surgery performed as a control. IRI rats were provided with normal water or water with 1.0% NaCl (IRI/NaCl), or they were implanted with an osmotic mini-pump to infuse vehicle or aldosterone (IRI/Aldo). Esaxerenone, a non-steroidal MR blocker (MRB), was administered to IRI/NaCl and IRI/Aldo rats for 6 weeks. MR expression increased by day 7 post-IRI. Blood pressure and urinary protein excretion increased in IRI/NaCl and IRI/Aldo rats over the 6-week period, but these effects were negated by MRB administration. The MRB attenuated the expression of the gamma-epithelial sodium channel (ENaC) and renal damage. The ENaC inhibitor, amiloride, ameliorated hypertension and renal damage in IRI/NaCl and IRI/Aldo rats. Our findings thus showed that MR upregulation may play a pivotal role in ENaC-mediated sodium uptake in rats after IRI, resulting in the development of salt-sensitive hypertension in response to salt overload or the activation of the renin-angiotensin-aldosterone system.

Effect of gait protocols and postoperative shoes on off-loading of forefoot in preoperative patients for forefoot disorders.

OBJECTIVES: The purpose of this study was to clarify the effect of gait protocols and postoperative shoes on forefoot load in preoperative patients for forefoot disorders and compare footwear comfort between different types of postoperative shoes. METHODS: Fourteen subjects scheduled to undergo forefoot surgeries were recruited. The maximum force under the forefoot region was measured during 10 m straight walking in two gait patterns with six different shoe types. Visual analogue scale (VAS) scores for footwear comfort, subjective lower thigh pain, and electrical activities of lower thigh muscles were also evaluated. RESULTS: The body weight-normalized maximum force under the forefoot region significantly decreased in step-to gait compared to normal gait regardless of the shoe types used. Under the same gait condition, no significant difference was observed in the forefoot off-loading effect between the different shoe types used. Significantly worse VAS scores, significantly higher tibialis anterior muscle activities, and complaints of lower thigh pain were demonstrated in the gait with the reverse camber shoe. CONCLUSIONS: Gait protocol of step-to gait had more forefoot off-loading effect than postoperative shoes. The forefoot off-loading effect did not differ among the postoperative shoes, suggesting that postoperative shoes can be selected with an emphasis on footwear comfort.

Clinical Outcomes After First Metatarsophalangeal Joint Arthrodesis by Flat Cut Joint Preparation With Individual Adjustment for Sagittal Alignment.

Sagittal misalignment is a major cause of patient dissatisfaction and re-operation after first metatarsophalangeal (MTP) joint arthrodesis. The stereotypical application of the fixed angle would be undesirable, especially in cases of flat or cavus foot. We retrospectively reviewed 31 cases (27 patients) in which first MTP joint arthrodesis was performed using the flat cut joint preparation technique with reference to the plantar clearance beneath the pulp of the toe while simulating weightbearing by pushing a board against the sole. The most common underlying cause of surgery was rheumatoid arthritis (22 cases [71%]). Clinical outcomes were evaluated by the Japanese of Surgery of the Foot (JSSF) hallux scale and the self-administered foot evaluation questionnaire (SAFE-Q). Twenty-three cases were also examined by pedobarography to evaluate postoperative walking plantar pressure. At the most recent follow-up of a mean 19.6 months, the toe-to-floor distance of the hallux in static standing posture was a mean of 2.5 mm (range, 0-10 mm). All but 1 foot (97%) achieved bone union. There were no complications or revisions due to misalignment of the fused MTP joint. JSSF hallux scales improved significantly from 47 preoperatively to 82 postoperatively. All subscale scores except general health and well-being in the SAFE-Q improved significantly at final follow-up versus preoperative period. Plantar pressure under the hallux was correlated with the toe-to-floor distance but not radiographic parameter. In conclusion, first MTP joint arthrodesis achieved good clinical outcomes when using toe-to-floor distance and Kirschner wire template for flat cut joint preparation.

Comparison between suture and staple fixations as internal fixation techniques for Akin osteotomy.

BACKGROUND: Suture and staple fixations are commonly used methods for Akin osteotomy; however, there has been a paucity of studies comparing these methods without bias. PATIENTS AND METHODS: We retrospectively compared the outcomes of 58 Akin osteotomies performed by a single surgeon using suture fixation and 39 Akin osteotomies performed by the same surgeon using staple fixation during the same period. RESULTS: Bone union at the osteotomy site was achieved in all cases with no cases of complications related to the materials used. Occurrence of breakage of the lateral cortex of the proximal phalanx showed no significant difference between the suture and staple groups. The lateral cortex breakage produced greater instability at the osteotomy site with the staple fixation compared to the suture fixation. CONCLUSIONS: Comparison of suture and staple fixations of Akin osteotomy demonstrated the superiority of suture fixation against staple fixation in terms of stability and cost-efficiency.

Symptomatic Medial Bone Excrescence in the Distal Phalanx of the Hallux after the First Metatarsophalangeal Joint Arthrodesis: A Case Report and Radiographic Reviews.

Medial bone excrescence at the base of the distal phalanx of the hallux is a common manifestation which is rarely painful. In this case report, we described the first case of the excrescence becoming symptomatic one year after a metatarsophalangeal (MTP) joint arthrodesis of the great toe in a 74-year-old female. The medial bony excrescence which was obscure preoperatively became obvious postoperatively in the anteroposterior foot radiographs. The patient was successfully treated by an excision of the excrescence. In order to clarify the pathology of the excrescence, we reviewed the radiographs with respect to the excrescence before and after hallux surgeries including 97 metatarsal osteotomies and 33 MTP joint arthrodesis. The width of the excrescence measured in the anteroposterior foot radiographs displayed substantial increment one month after the hallux surgeries (osteotomy group: 0.9 ± 0.7 vs. 1.5 ± 0.7 mm, p < 0.01; arthrodesis group: 1.3 ± 0.8 vs. 1.8 ± 1.0 mm, p < 0.01). However, there was no significant difference in the width of the excrescence between one month after surgery and at the most recent follow-up of around 20 months in average after the surgery (osteotomy group: 1.5 ± 0.7 vs. 1.4 ± 0.7 mm, p = 0.62; arthrodesis group: 1.8 ± 1.0 vs. 1.8 ± 0.7 mm, p = 0.37). The present case and our radiographic review suggested that the postoperative medial bony excrescence was not the result of change of position of the preexisting excrescence. The correction of pronation deformity through hallux surgeries could emphasize the medial bony excrescence and cause symptomatic irritation upon shoe contact.

Outcomes of Scarf and Akin Osteotomy with Intra-Articular Stepwise Lateral Soft Tissue Release for Correcting Hallux Valgus Deformity in Rheumatoid Arthritis.

BACKGROUND: The effectiveness of scarf and Akin osteotomy with intra-articular lateral soft tissue release for the correction of hallux valgus (HV) in patients with rheumatoid arthritis (RA) has not been elucidated. METHODS: A total of 36 feet in 28 patients with RA who had scarf and Akin osteotomy with intra-articular stepwise lateral soft tissue release between 2015 and 2020 at a single institute were investigated retrospectively, with a mean follow-up period of 32.0 ± 16.9 months. Radiographic evaluations including the HV angle, intermetatarsal angle, and sesamoid position were performed preoperatively and postoperatively. Clinical outcomes were assessed using the Japanese Society of Surgery of the Foot (JSSF) hallux scale and self-administered foot evaluation questionnaire (SAFE-Q). RESULTS: The procedure resulted in significant HV correction, with a recurrence rate of 13.9%. The JSSF scale and all five SAFE-Q subscale scores significantly improved (p < 0.05), with no major complications. More than 90% of cases achieved adequate lateral soft tissue release without sacrificing the adductor tendon of the hallux. CONCLUSIONS: Intra-articular stepwise lateral soft tissue release in combination with scarf and Akin osteotomy provided satisfactory radiographic and patient-reported outcomes for the correction of HV in patients with RA with minimum lateral soft tissue release.

Systemic inflammatory responses after orthopedic surgery in patients with rheumatoid arthritis treated with tofacitinib.

OBJECTIVE: To investigate the acute phase response to surgical stress in patients with rheumatoid arthritis (RA) treated with tofacitinib, a Janus kinase (JAK) inhibitor. METHODS: A retrospective matched pair analysis of 34 patients treated with tofacitinib and 34 patients treated with conventional disease-modifying anti-rheumatic drugs (csDMARDs) was performed. Patients were matched for age, sex, and type of surgery; body temperature, C-reactive protein (CRP) level, and white blood cell (WBC) count, neutrophil count, and lymphocyte count were compared between the tofacitinib and csDMARDs groups within 2 weeks after orthopedic surgery. Postoperative complications within 90 days were also assessed. RESULTS: No surgical site infection or delayed wound healing was observed in the tofacitinib group; whereas, one case of superficial infection was noted in the csDMARDs group. A similar postoperative increase in body temperature and CRP level was observed in both the groups. Postoperatively, the tofacitinib group showed an increase in WBC and neutrophils counts and a decrease in lymphocyte count, unlike the csDMARDs group. In contrast to two patients (2.6%) in the csDMARDs group, seven patients (20.6%) in the tofacitinib group had lymphocyte counts below 500 cells/µL within 2 weeks postoperatively. CONCLUSION: Tofacitinib did not suppress postoperative increase in body temperature and CRP level. Because of the postoperative decrease in lymphocyte count in patients treated with tofacitinib, the timing for resuming tofacitinib treatment after surgery should be carefully considered. Key Points • This study is the first to report the complications and systemic inflammatory responses after orthopedic surgery in patients treated with tofacitinib in comparison with matched pairs treated with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) • While tofacitinib does not suppress postoperative increase in body temperature and CRP level, the postoperative decrease in lymphocyte count in patients treated with tofacitinib is significant compared with patients treated with csDMARDs • Attention should be paid to a reduced lymphocyte count when to resume tofacitinib after surgery.

Juvenile Dysplasia Epiphysealis Hemimelica with Multiple Ankle Free Body.

Dysplasia epiphysealis hemimelica (DEH), also known as Trevor's disease, is a rare overgrowth of cartilage that commonly arises in the epiphyseal bone of children. We report a rare case of DEH originating from a talus accompanied by multiple intra-articular free bodies in a 7-year-old patient with ankle instability. After the primary surgery for free body removal and microfracture technique for the cartilage defects in the ankle joint, the free body recurred. Secondary surgery of arthroscopic free body removal with lateral ankle ligament repair succeeded in treating the patient, without further recurrence of the free body.

Surgical Treatment of Pathological Tibial Shaft Fracture in Adult Patient With Gnathodiaphyseal Dysplasia: A Case Report.

CASE: Gnathodiaphyseal dysplasia is a generalized skeletal syndrome characterized by frequent bone fractures in childhood, sclerosis and bowing of tubular bones, and cemento-osseous lesions of the jawbones. We present the case of a 53-year-old man with gnathodiaphyseal dysplasia who presented with pathological fracture of the tibial shaft. Internal fixation with the Ender nail was successfully performed with 2 years of follow-up. CONCLUSION: This is the first report describing the treatment of fracture in an adult patient with gnathodiaphyseal dysplasia. Internal fixation with the Ender nail was effective for the tubular bone with deformity. Callus formation was observed without delay.

Highly Sensitive Determination of Amino Acids by LC-MS under Neutral Conditions.

Peptide drug leads possess unusual structural features that allow them to exert their unique biological activities and ideal physicochemical properties. In particular, these peptides often have D-amino acids, and therefore the absolute configurations of the component amino acids have to be elucidated during the structural determination of newly isolated peptide drug leads. Recently, we developed the highly sensitive labeling reagents D/L-FDVDA and D/L-FDLDA for the structural determination of the component amino acids in peptides. In an LC-MS-based structural study of peptides, these reagents enabled us to detect infinitesimal amounts of amino acids derived from mild degradative analysis of the samples. Herein, we firstly report the improved LC-MS protocols for the highly sensitive analyses of amino acids. Second, two new labeling reagents were synthesized and their detection sensitivities evaluated. These studies increase our understanding of the structural basis of these highly sensitive labeling reagents, and should provide opportunities for future on-demand structural modifications of the reagents to enhance their hydrophobicity, stability, and affinity for applications to specialized HPLC columns.

Longicatenamides A-D, Two Diastereomeric Pairs of Cyclic Hexapeptides Produced by Combined-culture of Streptomyces sp. KUSC_F05 and Tsukamurella pulmonis TP-B0596.

Longicatenamides A-D, two diastereomeric pairs of new cyclic hexapeptides, were isolated from the combined-culture of Streptomyces sp. KUSC_F05 and Tsukamurella pulmonis TP-B0596. Their planar structures were determined by spectroscopic analysis including extensive 2D NMR and MS analysis. The absolute configurations of their component amino acids were determined by the use of highly sensitive reagents we recently developed; the highly sensitive-advanced Marfey's method (HS-advanced Marfey's method), which led us to reduce the sample loss and prevent incorrect structural determination. Particularly, the Cß-stereochemistry of hyGlu in longicatenamides A and C was assigned without any use of Cß-Marfey's methods. Longicatenamide A exhibited weak but preferential antimicrobial activity against Bacillus subtilis.

Joint-Preserving Surgery for Hyperextension Deformity of the Hallux Interphalangeal Joint in a Patient with Rheumatoid Arthritis.

Interphalangeal hyperextension is one of the major hallux deformities in patients with rheumatoid arthritis; however, there is yet no established surgical method for this deformity. We here present the case of a 69-year-old female patient with rheumatoid arthritis who developed hallux interphalangeal hyperextension and painful callosity on the plantar hallux accompanied by limited dorsiflexion at the metatarsophalangeal joint. Lateral weight-bearing radiograph of the foot revealed misalignment of the medial column and hallux, including a collapsed medial arch, elevated first metatarsal, plantar flexion and deviation of the proximal phalanx, and hyperextension of the distal phalanx. The foot was successfully treated and became symptom-free with opening wedge osteotomy of the medial cuneiform, plantar and proximal translation of the metatarsal head, and tenotomy of the extensor hallucis longus. This case suggests that reconstruction of the sagittal alignment of the medial column and hallux through a combination of osteotomy and soft tissue intervention could be an optional treatment for interphalangeal hyperextension.

Excision Arthroplasty With Interpositional Achilles Tendon Autograft: A Novel Approach to Talonavicular Joint Osteoarthritis Associated With Ankle Arthrodesis.

Talonavicular joint arthritis is a great concern after ankle fusion. Although arthrodesis is the gold standard treatment for this complication, it could initiate a vicious cycle of further adjacent joint arthritis. An alternative that may delay or eliminate the need for arthrodesis is excision arthroplasty; however, there are only a few reports on its application on a talonavicular joint. We report 3 cases of excision arthroplasty with interpositional Achilles tendon autograft for the treatment of end-stage talonavicular osteoarthritis in low-demand elderly patients. In 1 patient, excision arthroplasty was performed after tibiotalocalcaneal arthrodesis, and in 2 patients, it was performed after tibiotalar arthrodesis, in which the subtalar joints were also damaged and fused simultaneously on performance of the interpositional arthroplasty of the talonavicular joint. In all cases, pain relief and functional activities of daily living improvement were achieved with this procedure. At a minimum follow-up of 1 year, no patient reported adjacent joint symptoms or flatfoot progression. These cases show that interpositional arthroplasty with Achilles tendon autograft is an effective treatment for end-stage talonavicular arthritis in patients with fused ankle and subtalar joints. This procedure was helpful in relieving pain and improving activities of daily living function in low-demand elderly patients with the preservation of movement of the talonavicular joint. Autograft was considered to be superior to other grafts with respect to availability, graft rejection, or allergy development. Fused subtalar joint resolved the concerning issues, such as flatfoot progression and muscular weakness of ankle plantar flexion, associated with this procedure.

Factors affecting bone union after distal shortening oblique osteotomy of the lesser metatarsals.

Objectives: There have been few reports on factors affecting bone union after metatarsal osteotomies. The purpose of this study was to clarify the factors affecting bone union after distal shortening oblique osteotomy of the lesser metatarsals.Methods: Patients who underwent distal shortening oblique osteotomy of the lesser metatarsals were retrospectively investigated. Failure to achieve bone union at 6 months after surgery was defined as delayed union. Background characteristics and radiographic measurements were compared between patients with and those without delayed union, and factors affecting bone union were assessed using multivariate analysis.Results: Among 204 toes in 58 patients evaluated in this study, delayed union occurred in 28%. In multivariate analysis, corticosteroid use (odds ratio (OR), 3.68; 95% confidence interval (CI), 1.65-8.16; p< .01), larger preoperative overlap between the metatarsal and the proximal phalanx (OR, 1.11 (per 1 mm increase); 95% CI, 1.02-1.21; p= .02), and larger gap at the osteotomy site (OR, 3.02 (per 1 mm increase); 95% CI, 1.76-5.16; p< .01) were identified as independent risk factors of delayed union.Conclusion: The identified risk factors of delayed union after distal shortening metatarsal osteotomies were corticosteroid use, preoperative overlap between the metatarsal and the proximal phalanx, and a gap at the osteotomy site.