Human Leukocyte Antigens and Biomarkers in Type 1 Diabetes Mellitus Induced by Immune-Checkpoint Inhibitors

Background@#Type 1 diabetes mellitus induced by immune-checkpoint inhibitors (ICI-T1DM) is a rare critical entity. However, the etiology of ICI-T1DM remains unclear. @*Methods@#In order to elucidate risk factors for ICI-T1DM, we evaluated the clinical course and immunological status of patients with ICI-T1DM who had been diagnosed during 2016 to 2021. @*Results@#Seven of 871 (0.8%, six men and one woman) patients developed ICI-T1DM. We revealed that the allele frequencies of human leukocyte antigen (HLA)-DPA1*02:02 and DPB1*05:01 were significantly higher in the patients with ICI-T1DM In comparison to the controls who received ICI (11/14 vs. 10/26, P=0.022; 11/14 vs. 7/26, P=0.0027, respectively). HLA-DRB1*04:05, which has been found to be a T1DM susceptibility allele in Asians, was also observed as a high-risk allele for ICI-T1DM. The significance of the HLA-DPB1*05:01 and DRB1*04:05 alleles was confirmed by an analysis of four additional patients. The absolute/relative neutrophil count, neutrophils-lymphocyte ratio, and neutrophil-eosinophil ratio increased, and the absolute lymphocyte count and absolute/relative eosinophil count decreased at the onset as compared with 6 weeks before. In two patients, alterations in cytokines and chemokines were found at the onset. @*Conclusion@#Novel high-risk HLA alleles and haplotypes were identified in ICI-T1DM, and peripheral blood factors may be utilized as biomarkers.

Hooks at the Upper Instrumented Vertebra Can Adjust Postoperative Shoulder Balance in Patients with Adolescent Idiopathic Scoliosis: 5 Years or More of Follow-up

STUDY DESIGN: A retrospective cohort study. PURPOSE: This study aims to investigate postoperative shoulder imbalance (PSI) ≥5 years postoperatively in patients who underwent posterior spinal fusion using hooks at the upper instrumented vertebra (UIV) for Lenke type 1 adolescent idiopathic scoliosis (AIS). OVERVIEW OF LITERATURE: Studies have reported PSI due to excessive correction of the main thoracic curve. METHODS: We examined 56 patients with AIS who underwent a posterior spinal fusion with hooks at the UIV from 2004 to 2010. Of these, we enrolled 14 patients who underwent surgery, at least, 5 years ago. X-rays and Scoliosis Research Society-22 (SRS-22) questionnaire were administered. To evaluate the shoulder balance, T1 vertebral tilt angle (T1 tilt), clavicle angle, and radiographic shoulder height (RSH) were measured. PSI was considered as the absolute value of the postoperative RSH being ≥20 mm. Based on radiographs obtained immediately postoperatively, we divided patients into two groups as follows: the balanced group (absolute value of RSH <20 mm) and imbalanced group (absolute value of RSH ≥20 mm). RESULTS: The frequency of PSI was 28.6% immediately postoperatively, 0% 2 years postoperatively, and 7.1% at the last follow-up. In the balanced group, PSI did not occur even at 2 years postoperatively or at the last follow-up. In the imbalanced group, PSI was improved in all patients 2 years postoperatively and all patients, except one patient, at the last follow-up. No significant differences were noted in the frequency of distal adding-on at 2 years postoperatively or the last follow-up between the balanced group and the imbalanced group. We observed moderate negative correlations between the absolute value of T1 tilt and the SRS-22 pain and satisfaction at the last follow-up. CONCLUSIONS: Hooks at the UIV could adjust the shoulder balance to avoid long-term PSI in patients with AIS.

Perioperative Evaluation of Respiratory Muscle Strength after Scoliosis Correction in Patients with Duchenne Muscular Dystrophy

STUDY DESIGN: Retrospective cohort study. PURPOSE: To investigate the effect of spinal correction on respiratory muscle strength in patients with Duchenne muscular dystrophy (DMD). OVERVIEW OF LITERATURE: Several studies have reported that scoliosis correction in patients with DMD does not improve pulmonary function. In these studies, pulmonary function was evaluated using the traditional spirometric values of percent vital capacity (%VC) and percent forced vital capacity (%FVC). However, traditional spirometry may not be suitable for patients with DMD because the results can be influenced by patient fatigue or level of understanding. Therefore, we evaluated respiratory function focusing on respiratory muscle strength using maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and sniff nasal inspiratory pressure (SNIP), in addition to %VC and %FVC. METHODS: We retrospectively reviewed 16 patients with DMD who underwent spinal correction surgery between 2006 and 2011 at Kitasato University Hospital. All patients were males, and the mean age was 13.5 years. Respiratory muscle strength was evaluated using MIP, MEP, and SNIP. Measurements were obtained preoperatively and at 1 and 6 months postoperatively, and %VC and %FVC were obtained preoperatively and within 6 months postoperatively. RESULTS: The mean preoperative and postoperative %VC values were 54.0% and 51.7%, whereas the mean %FVC values were 53.9% and 53.2%, respectively. The mean MIP, MEP, and SNIP values obtained preoperatively and at 1 and 6 months postoperatively were as follows: MIP, 40.5, 42.7 and 47.2 cm H₂O; MEP, 26.0, 28.0, and 29.0 cm H₂O; and SNIP, 33.4, 33.0, and 33.0 cm H₂O; respectively. The mean MIP and MEP values significantly improved postoperatively. There were no significant differences in SNIP, %VC, or %FVC preand postoperatively. CONCLUSIONS: By focusing on respiratory muscle strength, our results suggest that scoliosis correction in patients with DMD might have a favorable effect on respiratory function.

Change of Lumbar Ligamentum Flavum after Indirect Decompression Using Anterior Lumbar Interbody Fusion

STUDY DESIGN: Retrospective case series. PURPOSE: The purpose of this study was to examine changes in the ligamentum flavum thickness and remodeling of the spinal canal after anterior fusion during a 10-year follow-up. OVERVIEW OF LITERATURE: Extreme lateral interbody fusion provides minimally invasive treatment of the lumbar spine; this anterior fusion without direct posterior decompression, so-called indirect decompression, can achieve pain relief. Anterior fusion may restore disc height, stretch the flexure of the ligamentum flavum, and increase the spinal canal diameter. However, changes in the ligamentum flavum thickness and remodeling of the spinal canal after anterior fusion during a long follow-up have not yet been reported. METHODS: We evaluated 10 patients with L4 spondylolisthesis who underwent stand-alone anterior interbody fusion using the iliac crest bone. Magnetic resonance imaging was performed 10 years after surgery. The cross-sectional area (CSA) of the dural sac and the ligamentum flavum at L1–2 to L5–S1 was calculated using a Picture Archiving and Communication System. RESULTS: Spinal fusion with correction loss (average, 4.75 mm anterior slip) was achieved in all patients 10 years postsurgery. The average CSAs of the dural sac and the ligamentum flavum at L1–2 to L5–S1 were 150 mm² and 78 mm², respectively. The average CSA of the ligamentum flavum at L4–5 (30 mm²) (fusion level) was significantly less than that at L1–2 to L3–4 or L5–S1. Although patients had an average anterior slip of 4.75 mm, the average CSA of the dural sac at L4–5 was significantly larger than at the other levels. CONCLUSIONS: Spinal stability induced a lumbar ligamentum flavum change and a sustained remodeling of the spinal canal, which may explain the long-term pain relief after indirect decompression fusion surgery.

Efficacy of Anti-NaV1.7 Antibody on the Sensory Nervous System in a Rat Model of Lumbar Intervertebral Disc Injury

PURPOSE: The pathophysiology of discogenic low back pain is not fully understood. Tetrodotoxin-sensitive voltage-gated sodium (NaV) channels are associated with primary sensory nerve transmission, and the NaV1.7 channel has emerged as an analgesic target. Previously, we found increased NaV1.7 expression in dorsal root ganglion (DRG) neurons innervating injured discs. This study aimed to examine the effect of blocking NaV1.7 on sensory nerves after disc injury. MATERIALS AND METHODS: Rat DRG neurons innervating the L5/6 disc were labeled with Fluoro-Gold (FG) neurotracer. Twenty-four rats underwent intervertebral disc puncture (puncture group) and 12 rats underwent sham surgery (non-puncture group). The injury group was divided into a saline infusion group (puncture+saline group) and a NaV1.7 inhibition group, injected with anti-NaV1.7 antibody (puncture+anti-NaV1.7 group); n=12 per group. Seven and 14 days post-surgery, L1 to L6 DRGs were harvested and immunostained for calcitonin gene-related peptide (CGRP) (an inflammatory pain marker), and the proportion of CGRP-immunoreactive (IR) DRG neurons of all FG-positive neurons was evaluated. RESULTS: The ratio of CGRP-IR DRG neurons to total FG-labeled neurons in the puncture+saline group significantly increased at 7 and 14 days, compared with the non-puncture group, respectively (p<0.05). Application of anti-NaV1.7 into the disc significantly decreased the ratio of CGRP-IR DRG neurons to total FG-labeled neurons after disc puncture at 7 and 14 days (40% and 37%, respectively; p<0.05). CONCLUSION: NaV1.7 antibody suppressed CGRP expression in disc DRG neurons. Anti-NaV1.7 antibody is a potential therapeutic target for pain control in patients with lumbar disc degeneration.

Do Physical Symptoms Predict the Outcome of Surgical Fusion in Patients with Discogenic Low Back Pain?

STUDY DESIGN: Retrospective case series. PURPOSE: To determine whether symptoms predict surgical outcomes for patients with discogenic low back pain (DLBP). OVERVIEW OF LITERATURE: Specific diagnosis of DLBP remains difficult. Worsening of pain on flexion is a reported symptom of DLBP. This study sought to determine whether symptoms predict surgical outcomes for patients with DLBP. METHODS: We investigated 127 patients with low back pain (LBP) and no dominant radicular pain. Magnetic resonance imaging was used to select patients with disc degeneration at only one level. If pain was provoked during discography, we performed fusion surgery (87 patients). Visual analogue scale score and responses to a questionnaire regarding symptoms including worsening of pain on flexion or extension were assessed. Symptom sites before surgery were categorized into LBP alone, or LBP plus referred inguinal or leg pain. We followed 77 patients (average 3.0 years) and compared symptoms before surgery with surgical outcome. RESULTS: Sixty-three patients with a good outcome showed postsurgical pain relief (≥60% pain relief) and 14 patients with a poor outcome did not (<60% pain relief). In patients with good outcomes, worsening of LBP was evident in 65% of cases on flexion and in 35% on extension. However, these findings were not significantly different from those in patients with poor outcomes. The percentage of patients with LBP alone was significantly lower and the percentage of patients with LBP plus referred inguinal or leg pain was significantly higher in the group with good surgical outcome compared with patients in the group with poor surgical outcome (p<0.05). CONCLUSIONS: Worsening of pain on extension may be a symptom of DLBP. Surgical outcomes were superior in patients with both LBP and either referred inguinal or leg pain compared with those having LBP alone.

Classification of Chronic Back Muscle Degeneration after Spinal Surgery and Its Relationship with Low Back Pain

STUDY DESIGN: Retrospective case series. PURPOSE: To classify back muscle degeneration using magnetic resonance imaging (MRI) and investigate its relationship with back pain after surgery. OVERVIEW OF LITERATURE: Back muscle injury and degeneration often occurs after posterior lumbar surgery, and the degeneration may be a cause of back pain. However, the relationship between back muscle degeneration and back pain remains controversial. METHODS: A total of 84 patients (average age, 65.1 years; 38 men, 46 women) with lumbar spinal stenosis underwent posterior decompression surgery alone. MRI (1.5 tesla) was evaluated before and more than a year after surgery in all patients. Muscle on MRI was classified into three categories: low intensity in T1-weighted imaging, high intensity in T2-weighted imaging (type 1), high intensity in both T1- and T2-weighted images (type 2), and low intensity in both T1- and T2-weighted imaging (type 3). The prevalence of the types and their relationship with back pain (determined on a visual analog scale) were evaluated. RESULTS: MRI revealed muscle degeneration in all patients after surgery (type 1, 6%; type 2, 82%; and type 3, 12%). Type 2 was significantly more frequent compared with types 1 and 3 (p0.05). CONCLUSIONS: Various pathologies of back muscle degeneration after posterior lumbar surgery were revealed. Type 2 (fatty) change was most frequent, and other patients had type 3 (scar) or type 1 (inflammation or water-like) changes. According to the Modic classification of bone marrow changes, Modic type 1 change is associated with inflammation and back pain. However, no particular type of back muscle degeneration was correlated with back pain after surgery.

Do Physical Symptoms Predict the Outcome of Surgical Fusion in Patients with Discogenic Low Back Pain?

STUDY DESIGN: Retrospective case series. PURPOSE: To determine whether symptoms predict surgical outcomes for patients with discogenic low back pain (DLBP). OVERVIEW OF LITERATURE: Specific diagnosis of DLBP remains difficult. Worsening of pain on flexion is a reported symptom of DLBP. This study sought to determine whether symptoms predict surgical outcomes for patients with DLBP. METHODS: We investigated 127 patients with low back pain (LBP) and no dominant radicular pain. Magnetic resonance imaging was used to select patients with disc degeneration at only one level. If pain was provoked during discography, we performed fusion surgery (87 patients). Visual analogue scale score and responses to a questionnaire regarding symptoms including worsening of pain on flexion or extension were assessed. Symptom sites before surgery were categorized into LBP alone, or LBP plus referred inguinal or leg pain. We followed 77 patients (average 3.0 years) and compared symptoms before surgery with surgical outcome. RESULTS: Sixty-three patients with a good outcome showed postsurgical pain relief (≥60% pain relief) and 14 patients with a poor outcome did not (<60% pain relief). In patients with good outcomes, worsening of LBP was evident in 65% of cases on flexion and in 35% on extension. However, these findings were not significantly different from those in patients with poor outcomes. The percentage of patients with LBP alone was significantly lower and the percentage of patients with LBP plus referred inguinal or leg pain was significantly higher in the group with good surgical outcome compared with patients in the group with poor surgical outcome (p<0.05). CONCLUSIONS: Worsening of pain on extension may be a symptom of DLBP. Surgical outcomes were superior in patients with both LBP and either referred inguinal or leg pain compared with those having LBP alone.

Classification of Chronic Back Muscle Degeneration after Spinal Surgery and Its Relationship with Low Back Pain

STUDY DESIGN: Retrospective case series. PURPOSE: To classify back muscle degeneration using magnetic resonance imaging (MRI) and investigate its relationship with back pain after surgery. OVERVIEW OF LITERATURE: Back muscle injury and degeneration often occurs after posterior lumbar surgery, and the degeneration may be a cause of back pain. However, the relationship between back muscle degeneration and back pain remains controversial. METHODS: A total of 84 patients (average age, 65.1 years; 38 men, 46 women) with lumbar spinal stenosis underwent posterior decompression surgery alone. MRI (1.5 tesla) was evaluated before and more than a year after surgery in all patients. Muscle on MRI was classified into three categories: low intensity in T1-weighted imaging, high intensity in T2-weighted imaging (type 1), high intensity in both T1- and T2-weighted images (type 2), and low intensity in both T1- and T2-weighted imaging (type 3). The prevalence of the types and their relationship with back pain (determined on a visual analog scale) were evaluated. RESULTS: MRI revealed muscle degeneration in all patients after surgery (type 1, 6%; type 2, 82%; and type 3, 12%). Type 2 was significantly more frequent compared with types 1 and 3 (p0.05). CONCLUSIONS: Various pathologies of back muscle degeneration after posterior lumbar surgery were revealed. Type 2 (fatty) change was most frequent, and other patients had type 3 (scar) or type 1 (inflammation or water-like) changes. According to the Modic classification of bone marrow changes, Modic type 1 change is associated with inflammation and back pain. However, no particular type of back muscle degeneration was correlated with back pain after surgery.

Modified Open-Door Laminoplasty Using a Ceramic Spacer and Suture Fixation for Cervical Myelopathy

PURPOSE: To introduce a new simple technique using suture anchors and ceramic spacers to stabilize the elevated laminae in open-door cervical laminoplasty. Although ceramic spacers were placed in the opened laminae and fixed with nylon threads in this series, it was occasionally difficult to fix the nylon threads to the lateral mass. MATERIALS AND METHODS: Study 1: A preliminary study was conducted using a suture anchor system. Sixteen consecutive patients who underwent surgery for cervical myelopathy were prospectively examined. Study 2: The second study was performed prospectively to evaluate the feasibility of this new technique based on the result of the preliminary study. Clinical outcomes were examined in 45 consecutive patients [cervical spondylotic myelopathy (CSM)] and 43 consecutive patients (OPLL). The Japanese Orthopedic Association scoring system (JOA score), axial neck pain, and radiological findings were analyzed. RESULTS: 1) In one case, re-operation was necessary due to dislodgement of the ceramic spacer following rupture of the thread. 2) In all patients, postoperative CT scans showed that the anchors were securely inserted into the bone. In the CSM group, the average JOA score improved from 9.5 points preoperatively to 13.3 at follow-up (recovery 51%). In the OPLL group, the average JOA score improved from 10.1 (5-14) points preoperatively to 14.4 (11-16) at follow-up (recovery 62%). There were no serious complications. CONCLUSION: The use of the suture anchor system made it unnecessary to create a hole in the lateral mass and enabled reliable and faster fixation of the HA spacers in open-door laminoplasty.

Mini-Open Anterior Retroperitoneal Lumbar Interbody Fusion: Oblique Lateral Interbody Fusion for Degenerated Lumbar Spinal Kyphoscoliosis

STUDY DESIGN: Prospective case series. PURPOSE: To examine the clinical efficacy of mini-open anterior retroperitoneal lumbar interbody fusion: oblique lateral interbody fusion (OLIF) for degenerated lumbar spinal kyphoscoliosis. OVERVIEW OF LITERATURE: The existing surgical procedures for the treatment of spinal kyphotic deformity, including Smith-Petersen osteotomy, pedicle subtraction osteotomy, and vertebral column resection procedures, are invasive in nature. Extreme lateral interbody fusion to provide less invasive treatment of the deformity has been reported, but complications including spinal nerve and psoas muscle injury have been noted. In the current study, we examined the clinical efficacy and complications of OLIF for degenerated lumbar spinal kyphoscoliosis. METHODS: Twelve patients with degenerated lumbar spinal kyphoscoliosis were examined. All patients underwent OLIF surgery (using a cage and bone graft from the iliac crest) with open pedicle screws or percutaneous pedicle screws, without real-time monitoring by electromyography. Visual analog scale score and Oswestry disability index were evaluated before and 12 months after surgery, and fusion rate at OLIF cage, correction of the deformity, total blood loss, and surgical complications were also evaluated. RESULTS: Pain scores significantly improved after surgery (p<0.05). Fusion rate was found to be 90%, balance parameters also improved after surgery (p<0.05), and average total blood loss was less than 350 mL. There was no spinal nerve, major vessel, peritoneal, or urinary injury, or breakage of instrumentation. CONCLUSIONS: OLIF surgery for degenerated lumbar spinal kyphoscoliosis is less invasive than other procedures and good surgical results were produced without major complications.

More than 6 Months of Teriparatide Treatment Was More Effective for Bone Union than Shorter Treatment Following Lumbar Posterolateral Fusion Surgery

STUDY DESIGN: Retrospective case series. PURPOSE: To examine the most effective duration of teriparatide use for spinal fusion in women with postmenopausal osteoporosis. OVERVIEW OF LITERATURE: We reported that daily subcutaneous injection of teriparatide (parathyroid hormone) significantly improved bone union after instrumented lumbar posterolateral fusion (PLF) in women with postmenopausal osteoporosis when compared with oral administration of bisphosphonate. However, the most effective duration of teriparatide use for spinal fusion has not been explored. METHODS: Forty-five women with osteoporosis diagnosed with degenerative spondylolisthesis from one of the three treatment groups were evaluated based on: short-duration treatment (average, 5.5 months; n=15; daily subcutaneous injection of 20 microg teriparatide), long-duration treatment (average, 13.0 months; n=15; daily subcutaneous injection of 20 microg teriparatide), and bisphosphonate treatment (average, 13.0 months; n=15; weekly oral administration of 17.5 mg risedronate). All patients underwent PLF with a local bone graft. Fusion rate and duration of bone union were evaluated 1.5 years after surgery. RESULTS: Bone union rate and average duration for bone union were 92% and 7.5 months in the long-duration treatment group, 80% and 8.5 months in the short-duration treatment group, and 70% and 10.0 months in the bisphosphonate treatment group, respectively. Results of bone union rate and average duration for bone union in the teriparatide treatment groups were significantly superior to those in the bisphosphonate treatment group (p<0.05); whereas, significantly superior results were observed in long-duration treatment group when compared with short-duration treatment group (p<0.05). CONCLUSIONS: Daily injection of teriparatide for bone union was more effective than oral administration of bisphosphonate. Furthermore, a longer period of teriparatide treatment for bone union was more effective than a shorter period of same treatment.

Efficacy of Direct Injection of Etanercept into Knee Joints for Pain in Moderate and Severe Knee Osteoarthritis

PURPOSE: Osteoarthritic (OA) pain is largely considered to be inflammatory pain. However, during the last stage of knee OA, sensory nerve fibers in the knee are shown to be significantly damaged when the subchondral bone junction is destroyed, and this can induce neuropathic pain. Several authors have reported that tumor necrosis factor-alpha (TNFalpha) in a knee joint plays a crucial role in pain modulation. The purpose of the current study was to evaluate the efficacy of etanercept, a TNFalpha inhibitor, for pain in knee OA. MATERIALS AND METHODS: Thirty-nine patients with knee OA and a 2-4 Kellgren-Lawrence grading were evaluated in this prospective study. Patients were divided into two groups; hyaluronic acid (HA) and etanercept injection. All patients received a single injection into the knee. Pain scores were evaluated before and 4 weeks after injection using a visual analogue scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and they were compared between the groups. RESULTS: Before injection, VAS and WOMAC scores were not significantly different between the groups (p>0.05). Significant pain relief was found in the etanercept group at 1 and 2 weeks by VAS, and at 4 weeks by WOMAC score, compared with the HA group (p<0.05). No adverse events were observed in either group. CONCLUSION: Direct injection of etanercept into OA knee joints was an effective treatment for pain in moderate and severe OA patients. Furthermore, this finding suggests that TNFalpha is one factor that induces OA pain.

Mini-Open Anterior Retroperitoneal Lumbar Interbody Fusion: Oblique Lateral Interbody Fusion for Lumbar Spinal Degeneration Disease

PURPOSE: Surgery for lumbar spinal degeneration disease is widely performed. While posterior decompression and fusion are popular, anterior lumbar interbody fusion (ALIF) is also used for treatment. Extreme lateral interbody fusion (XLIF) is commonly used for noninvasive ALIF; however, several complications, such as spinal nerve and psoas muscle injury, have been reported. In the current study, we examined the clinical efficacy and complications of oblique lateral interbody fusion (OLIF) for lumbar spinal degeneration disease. MATERIALS AND METHODS: Thirty-five patients with degenerated spondylolisthesis, discogenic pain, and kyphoscoliosis were examined. All patients underwent OLIF surgery (using a cage and bone graft from the iliac crest) with or without posterior decompression, without real-time electromyography monitoring. Posterior screws were used in all patients. Visual analog scale (VAS) score and Oswestry Disability Index (ODI) were evaluated before and 6 months after surgery. Surgical complications were also evaluated. RESULTS: Pain scores significantly improved after surgery, compared to those before surgery (p<0.05). There was no patient who underwent revision surgery. There was no spinal nerve, major vessel, peritoneal, or urinary injury. Few patients showed symptoms from psoas invasion. CONCLUSION: OLIF surgery produced good surgical results without any major complication.

Transient Receptor Potential Vanilloid 1-Immunoreactive Innervation Increases in Fractured Rat Femur

PURPOSE: Pain from vertebral or femoral neck fractures is a particularly important problem in clinical orthopaedics. Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel, and there are recent reports on an association between bone pain and TRPV1. However, an increase in TRPV1 activity has not been reported following femoral fracture. MATERIALS AND METHODS: We applied a neurotracer [Fluoro-gold (FG)] onto femur to detect dorsal root ganglia (DRGs) innervating the cortex of the femur in 30 Sprague Dawley rats. Seven days after application, a closed mid-diaphyseal fracture of the femur was performed. FG labeled TRPV1-immunoreactive (ir) DRGs innervating the femur were examined in nonfractured controls, and 3 days, 1 week, 2 weeks, and 4 weeks after fracture. We evaluated bone healing of the femur and compared the ratio of TRPV1-ir DRG neurons innervating the femur at the time points. RESULTS: Four weeks after fracture, complete bone union was observed. There was no significant difference in the ratio of FG labeled DRG neurons to total DRG neurons at each time point. The percentages of TRPV1-ir neurons in DRGs innervating the femur at 3 days and 1 week after fracture were significantly higher than those in control, 2 weeks, and 4 weeks after fracture (p<0.05). CONCLUSION: Fracture induced an increase of TRPV1-ir neurons in DRGs innervating the fractured femur within 3 days, and decreased during bone healing over 4 weeks. These findings show that TRPV1 may play a role in sensory sensation of bone fracture pain.

Progressive Change in Joint Degeneration in Patients with Knee or Hip Osteoarthritis Treated with Fentanyl in a Randomized Trial

PURPOSE: Opioids improve pain from knee and hip osteoarthritis (OA) and decrease the functional impairment of patients. However, there is a possibility that opioids induce analgesia and suppress the physiological pain of OA in patients, thereby inducing the progression of OA changes in these patients. The purpose of the current study was to investigate the possibility of progressive changes in OA among patients using opioids. MATERIALS AND METHODS: Two hundred knee or hip OA patients were evaluated in the current prospective, randomized, active-controlled study. Patients were randomized 1:1:1 into three parallel treatment groups: loxoprofen, tramadol/acetaminophen, and transdermal fentanyl groups. Medication was administered for 12 weeks. Pain scores and progressive OA changes on X-ray films were evaluated. RESULTS: Overall, pain relief was obtained by all three groups. Most patients did not show progressive OA changes; however, 3 patients in the transdermal fentanyl group showed progressive OA changes during the 12 weeks of treatment. These 3 patients used significantly higher doses than others in the transdermal fentanyl group. Additionally, the average pain score for these 3 patients was significantly lower than the average pain score for the other patients in the transdermal fentanyl group. CONCLUSION: Fentanyl may induce progressive changes in knee or hip OA during a relatively short period, compared with oral Non-Steroidal Anti-Inflammatory Drugs or tramadol.

Injection of Bupivacaine into Disc Space to Detect Painful Nonunion after Anterior Lumbar Interbody Fusion (ALIF) Surgery in Patients with Discogenic Low Back Pain

PURPOSE: Bupivacaine is commonly used for the treatment of back pain and the diagnosis of its origin. Nonunion is sometimes observed after spinal fusion surgery; however, whether the nonunion causes pain is controversial. In the current study, we aimed to detect painful nonunion by injecting bupivacaine into the disc space of patients with nonunion after anterior lumbar interbody fusion (ALIF) surgery for discogenic low back pain. MATERIALS AND METHODS: From 52 patients with low back pain, we selected 42 who showed disc degeneration at only one level (L4-L5 or L5-S1) on magnetic resonance imaging and were diagnosed by pain provocation on discography and pain relief by discoblock (the injection of bupivacaine). They underwent ALIF surgery. If the patients showed low back pain and nonunion 2 years after surgery, we injected bupivacaine into the nonunion disc space. Patients showing pain relief after injection of bupivacaine underwent additional posterior fixation using pedicle screws. These patients were followed up 2 years after the revision surgery. RESULTS: Of the 42 patient subjects, 7 showed nonunion. Four of them did not show low back pain; whereas 3 showed moderate or severe low back pain. These 3 patients showed pain reduction after injection of bupivacaine into their nonunion disc space and underwent additional posterior fixation. They showed bony union and pain relief 2 years after the revision surgery. CONCLUSION: Injection of bupivacaine into the nonunion disc space after ALIF surgery for discogenic low back pain is useful for diagnosis of the origin of pain.

Up-Regulation of Pain Behavior and Glial Activity in the Spinal Cord after Compression and Application of Nucleus Pulposus onto the Sciatic Nerve in Rats

STUDY DESIGN: Experimental animal study. PURPOSE: To evaluate pain-related behavior and changes in glial activity in the spinal dorsal horn after combined sciatic nerve compression and nucleus pulposus (NP) application in rats. OVERVIEW OF LITERATURE: Mechanical compression and inflammation caused by prostaglandins and cytokines at disc herniation sites induce pain. Structural changes and pain-associated cytokines in the dorsal root ganglia and spinal dorsal horn contribute to prolonged pain. Glial cells in the spinal dorsal horn may also function in pain transmission. METHODS: The sciatic nerve was compressed with NP for 2 seconds using forceps in the NP+nerve compression group; the sham-operated group received neither compression nor NP; and the control group received no operation. Mechanical hyperalgesia was measured for 3 weeks using von Frey filaments. Glial activity in the spinal dorsal horn was examined 7 days and 14 days postsurgery using anti-glial fibrillary acidic protein and anti-Ionized calcium binding adaptor molecule-1 antibodies to detect astrocytes and microglia, respectively. RESULTS: Mechanical hyperalgesia was detected throughout the 14-day observation in the NP+nerve compression group, but not in control or sham-operated groups (p<0.05). Both astrocytes and microglia were significantly increased in the spinal dorsal horn of the NP+nerve compression group compared to control and sham groups on days 7 and 14 (p<0.05). CONCLUSIONS: Nerve compression with NP application produces pain-related behavior, and up-regulates astrocytes and microglia in the spinal dorsal horn, suggesting that these glia may be related to pain transmission.

Evaluation of Behavior and Expression of Receptor Activator of Nuclear Factor-Kappa B Ligand in Dorsal Root Ganglia after Sciatic Nerve Compression and Application of Nucleus Pulposus in Rats

STUDY DESIGN: Experimental animal study. PURPOSE: To evaluate pain-related behavior and changes in nuclear factor-kappa B (NF-kB), receptor activator of NF-kB (RANK), and ligand (RANKL) in dorsal root ganglia (DRG) after combined sciatic nerve compression and nucleus pulposus (NP) application in rats. OVERVIEW OF LITERATURE: The pathological mechanisms underlying pain from lumbar-disc herniation have not been fully elucidated. RANKL are transcriptional regulators of inflammatory cytokines. Our aim was to evaluate pain-related behavior and RANKL expression in DRG after sciatic-nerve compression and application of NP in rats. METHODS: Mechanical hyperalgesia and RANKL expression were assessed in three groups of rats: NP+sciatic nerve compression (2 seconds), sham-operated, and controls (n=20 each). Mechanical hyperalgesia was measured every other day for 3 weeks using von Frey filaments. RANKL expression in L5 DRGs was examined at five and ten days after surgery using immunohistochemistry. RESULTS: Mechanical hyperalgesia was observed over the 12-day observation period in the NP+nerve compression group, but not in the control and sham-operated animal groups (p<0.05). RANKL immunoreactivity was seen in the nuclei of L5 DRG neurons, and its expression was significantly upregulated in NP+nerve compression rats compared with control and sham-operated rats (p<0.01). CONCLUSIONS: The exposure of sciatic nerves to mechanical compression and NP produces pain-related behavior and up-regulation of RANKL in DRG neurons. RANKL may play an important role in mediating pain after sciatic nerve injury with exposure to NP.

Increase of TRPV1-Immunoreactivity in Dorsal Root Ganglia Neurons Innervating the Femur in a Rat Model of Osteoporosis

PURPOSE: Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel, which can be activated by capsaicin and other noxious stimuli. Recently, an association between bone pain and TRPV1 has been reported. However, the influence of osteoporosis on TRPV1 in the sensory system innervating the femur has not been reported. MATERIALS AND METHODS: TRPV1-immunoreactive (ir) in dorsal root ganglia (DRG) neurons labeled with neurotracer [Fluoro-Gold (FG)] innervating the femurs of Sprague Dawley rats were examined in control, sham, and ovariectomized (OVX) rats. We evaluated osteoporosis in the femurs and compared the proportion of TRPV1-ir DRG neurons innervating femur between the 3 groups of rats. RESULTS: OVX rats showed osteoporotic cancellous bone in the femur. FG labeled neurons were distributed from L1 to L6 DRG, but there was no significant difference in the proportion of labeled neurons between the 3 groups (p>0.05). The proportions of FG labeled TRPV1-ir DRG neurons were 1.7%, 1.7%, and 2.8% of DRG neurons innervating the femur, in control, sham-operated, and OVX rats, respectively. The proportion of TRPV1-ir neurons in DRG innervating the femur in OVX rats was significantly higher than that in control and sham-operated rats (p<0.05). CONCLUSION: Under physiological conditions, DRG neurons innervating femurs in rats contain TRPV1. Osteoporosis increases the numbers of TRPV1-ir neurons in DRG innervating osteoporotic femurs in rats. These findings suggest that TRPV1 may have a role in sensory perception of osteoporotic femurs.