Effect of a monocyte chemoattractant protein-1 synthesis inhibitor on fibroblasts from patients with carpal tunnel syndrome.

BACKGROUND: Carpal Tunnel Syndrome (CTS) is an idiopathic fibrotic disorder. Fibrosis in the subsynovial connective tissues (SSCT) of CTS and many other fibrotic diseases is mediated by Transforming growth factor ß (TGF-ß). Recently monocyte chemoattractant protein-1 (MCP-1) a cytokine involved in cellular recruitment has been suggested to regulate TGF-ß activity. It is related to the onset of diseases which are caused by fibrosis, such as idiopathic pulmonary fibrosis, renal fibrosis, and systemic scleroderma. In this study, we evaluated the effect of the MCP-1 synthesis inhibitor, Bindarit, on primary cultures of fibroblasts from the SSCT of five CTS patients. METHODS: Fibroblasts were treated with Bindarit (10 µM, 50 µM, 100 µM, or 300 µM). Responses to inhibitors were evaluated by regulation of CTS fibrosis-associated genes, fibrosis gene array and Smad luciferase reporter assay. We also assessed the combination effect of Bindarit and SD208, a TGF-ß receptor type 1 inhibitor on TGF-ß signaling. RESULTS: Collagen type III A1 (Col3), connective tissue growth factor (CTGF), and SERPINE1 expression were significantly down-regulated by Bindarit (300 µM) compared to vehicle control. In the fibrosis array, expression of inhibin beta E chain precursor (INHBE), beta actin (ACTB), endothelin 1 (EDN1) and hypoxanthine phosphoribosyltransferase 1 (HPRT1) were significantly down-regulated, and integrin beta-3 (ITGB3) was significantly up-regulated by Bindarit (300 µM). Smad signal transduction activation was significantly down-regulated by Bindarit (300 µM) and/or SD208 (1 µM) with TGF-ß1 compared to vehicle control with TGF-ß1. CONCLUSIONS: These results suggest that Bindarit in combination with SD208 may be beneficial as medical therapy for the SSCT fibrosis associated with CTS.

Blocking fibrotic signaling in fibroblasts from patients with carpal tunnel syndrome.

Fibrosis of the subsynovial connective tissue (SSCT) in carpal tunnel syndrome (CTS) patients is increasingly recognized as an important aspect of CTS pathophysiology. In this study, we evaluated the effect of blocking profibrotic pathways in fibroblasts from the SSCT in CTS patients. Fibroblasts were stimulated with transforming growth factor ß1 (TGF-ß1), and then treated either with a specific fibrosis pathway inhibitor targeting TGF-ß receptor type 1 (TßRI), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), or vascular endothelial growth factor receptor (VEGFR). Fibrosis array and quantitative real-time polymerase chain reaction of fibrotic genes were evaluated. Array gene expression analysis revealed significant down-regulation of multiple fibrotic genes after treatment with TßRI, PDGFR, and VEGFR inhibitors. No array fibrotic genes were significantly down-regulated with EGFR inhibition. Further gene expression analysis of known CTS fibrosis markers collagen type I A2 (Col1), collagen type III A1 (Col3), connective tissue growth factor (CTGF), and SERPINE1 showed significantly down-regulation after TßRI inhibition. In contrast, VEGFR inhibition significantly down-regulated CTGF and SERPINE1, whereas, PDGFR and EGFR inhibition significantly down-regulated Col3. Taken together the inhibition of TßRI appears to be the primary mediator of fibrotic gene expression in fibroblasts from CTS patients. TGF-ß/Smad activity was further evaluated, and as expected inhibition of Smad activity was significantly down-regulated after inhibition of TßRI, but not with PDGFR, VEGFR, or EGFR inhibition. These results indicate that local therapies specifically targeting TGF-ß signaling alone or in combination offer the potential of a novel local antifibrosis therapy for patients with CTS.

Proteomics analysis of site- and stage-specific protein expression after peripheral nerve injury.

BACKGROUND: The peripheral nervous system has greater regenerative potential than the CNS. This fact suggests the existence of molecules that act as key factors in nerve regeneration during molecular changes in the peripheral nervous system. METHODS: The right sciatic nerve of female Sprague-Dawley rats was exposed and transected at the mid-thigh level. Animals were sacrificed at 5, 10 or 35 days after nerve transection. Proximal and distal nerve segments (1-cm in length) were dissected. We then sought to observe overall molecular changes after peripheral nerve injury using a proteomic approach. For an overview of the identified proteins, each protein was classified according to its biological and molecular functions. We identified a number of proteins showing site- and stage-specific patterns of expression. RESULTS: Both proximal and distal molecular changes at 5, 10 and 35 days after nerve transection were investigated, and a total of 2353 proteins were identified. Among the various expression patterns observed, aFGF and GAP-43 were found to increase in the proximal stump at 10 days after transection, and PN-1, RPL9 and prosaposin increased in the distal stump at 5 days after transection. Among these proteins, aFGF, GAP-43, PN-1 and prosaposin were found to be associated with nerve regeneration. CONCLUSION: We demonstrated that aFGF, GAP-43, PN-1 and prosaposin expression increased at specific stages and in specific sites, such as the proximal or distal stump, after nerve transection by comprehensive measurement using proteomics analysis. We believe that these specific expression patterns might play important roles during regeneration after nerve injury.

Time to functional recovery after arthroscopic surgery for tennis elbow.

BACKGROUND: This study evaluated recovery from chronic lateral epicondylitis after arthroscopic treatment. METHODS: Twenty-three consecutive patients (5 men, 18 women) with chronic lateral epicondylitis underwent arthroscopic surgery. Patients were a mean age of 49 years. Prospective outcome data were collected before the operation and at 1, 2, 3, 6, 12 and 24 months after surgery. Outcomes were assessed using a visual analog scale (VAS: 0-100), grip strength percentage (compared with the unaffected side), the Japanese Orthopaedic Association elbow score, and the Disability of the Arm, Shoulder and Hand questionnaire. RESULTS: A mean VAS score at rest of 26 preoperatively improved to 8 (P = .0026), 6, and 3 at 1, 2, and 3 months after surgery, respectively. A mean VAS score during activity improved from 68 preoperatively to 35 (P < .001), 23, and 19 at 1, 2, and 3 months after surgery, respectively. Both VAS scores gradually decreased up to 24 months after surgery. The mean grip strength improved from 66.1% preoperatively to 88.7% at 2 months after surgery (P < .001). The mean Japanese Orthopaedic Association elbow score improved from 38 points preoperatively to 61 points at 1 month after surgery (P < .001). The mean Disability of the Arm, Shoulder and Hand score improved from 32 points preoperatively to 15 points at 3 months after surgery (P < .001). CONCLUSION: Arthroscopic surgery for lateral epicondylitis provides significant improvement in pain and functional recovery up to 3 months after surgery. However, it takes more than 6 months for the VAS score during activity to fall below 10 points.

Efficacy of axillary nerve block in elbow arthroscopic surgery: a randomized trial.

BACKGROUND: The purpose of this study was to evaluate postoperative pain levels after arthroscopic elbow surgery under general anesthesia and to determine whether an axillary nerve block provides additional pain management benefits compared with a portal site injection of local anesthetic. METHODS: Thirty-six patients undergoing arthroscopic elbow surgery under general anesthesia were randomized to either a study group receiving axillary nerve block (Ax group) or a control group receiving portal site injections of local anesthetic (Lo group). During the first 48 hours after surgery, pain visual analog scale (VAS) scores (0-100), total amount of oral analgesics required, and patient satisfaction were assessed. RESULTS: Among all 36 patients, mean pain VAS scores at rest were 37, 18, and 9 for the first 12-hour period and at 24 and 48 hours after surgery, respectively. The mean pain VAS scores during physiotherapy were 47 and 33 at 24 and 48 hours postoperatively, respectively. No intergroup differences were observed between the Ax and Lo groups at any time point after surgery (P value range, .41 to .87). The mean number of loxoprofen tablets required during the 48-hour study period was 5.1 in the Ax group and 4.5 in the Lo group (P = .90). The Ax and Lo groups had mean overall patient satisfaction scores of 91 and 91, respectively (P = .98). CONCLUSIONS: Postoperative pain levels after arthroscopic elbow surgery could be well managed with oral analgesics and local anesthetic. An axillary nerve block was not found to provide any postoperative pain control benefits.

Nonunion of the ulnar styloid associated with distal radius malunion.

PURPOSE: Malunion is a complication of distal radius fractures and may be associated with a nonunion of the ulnar styloid. We tested the null hypothesis that there is no difference in outcome between patients without ulnar styloid fracture and those with the ulnar styloid nonunion after corrective radial osteotomy for distal radius malunion. METHODS: A total of 19 patients with dorsally angulated distal radius malunion who had simultaneous radial closing-wedge and ulnar shortening osteotomies were included. There were 16 women and 3 men with a mean age of 63 years. All patients were followed up for a minimum of 1 year. During surgery, the accompanying ulnar styloid nonunion was not internally fixed in any patient. Eight patients had no ulnar styloid fracture, and 11 had a nonunion of the ulnar styloid. Each group of patients was evaluated on the basis of objective radiographic measurements and functional outcomes as determined on the basis of clinical examination, including wrist motion, grip strength, pain-rating score, Mayo wrist score, and Disabilities of the Arm, Shoulder, and Hand score. RESULTS: There were no differences in the demographic and preoperative radiographic measurements between the nonfracture and nonunion groups. Postoperative radiographic measurements and functional outcomes improved significantly compared with the preoperative status in both groups. There were no significant differences in postoperative radiographic measurements, motion, strength, pain scores, Mayo scores, or Disabilities of the Arm, Shoulder, and Hand scores between the 2 groups. Four of the 11 ulnar styloid nonunions were healed within 1 to 12 months after corrective radial osteotomy. CONCLUSIONS: An accompanying ulnar styloid nonunion in patients with distal radius malunion has no apparent adverse effect on outcome or function after corrective radial osteotomy. An accompanying nonunion of the ulnar styloid can heal following corrective radial osteotomy.

Reconstruction of chronic thumb metacarpophalangeal joint radial collateral ligament injuries with a half-slip of the abductor pollicis brevis tendon.

PURPOSE: To evaluate a reconstructive method for chronic radial collateral ligament (RCL) injuries of the thumb metacarpophalangeal (MCP) joint using a combination of RCL advancement and the transfer of a half-slip of the abductor pollicis brevis tendon. METHODS: Eight patients (4 male and 4 female; mean age, 25 y) with chronic RCL injury of the thumb MCP joint were enrolled. All patients were referred to our institution because of continuing pain and instability on the radial side of the MCP joint when grasping or pinching objects. The mechanism of the injury was adduction stress to the thumb during sporting activities in 5 patients, a heavy object falling on the thumb in 1, and a fall in 2. The mean duration from RCL injury to surgery was 20 weeks. The average postoperative follow-up was 51 months. We evaluated postoperative outcomes including pain, range of motion of the thumb MCP joint, grip strength, key pinch strength, Disabilities of the Arm, Shoulder, and Hand score, and ability to return to preinjury work or sporting activities. RESULTS: No patients demonstrated continuing symptoms, and the MCP joint was stable after surgery. Postoperative grip and pinch strength (37 and 6.3 kg, respectively) were increased compared with preoperative values (34 and 3.9 kg, respectively). All patients returned fully to their preinjury work or sporting activities within 6 months after surgery. Although postoperative flexion was decreased by an average of 6°, no patients noted functional deficiency. CONCLUSIONS: We recommend the reconstructive method of RCL advancement and transfer of a half-slip of the abductor pollicis brevis tendon to alleviate pain and improve grip and pinch strength in chronic RCL injuries of the thumb MCP joint.

Diagnostic features of sciatica without lumbar nerve root compression.

STUDY DESIGN: Retrospective case series review of patients showing sciatica without radiographic evidence of nerve root compression. OBJECTIVE: To elucidate clinical features of sciatica caused by extralumbar spinal lesions. SUMMARY OF BACKGROUND DATA: Sciatica caused by extralumbar spinal lesions has been reported sporadically. Given the paucity of case series studies, however, the pathology and clinical features of such sciatica remain not fully understood. METHODS: Sixty-one patients who presented with persistent sciatica were examined with lumbar magnetic resonance (MR) imaging. Of these, the records of patients showing no detectable nerve root compression in MR images were reviewed with respect to demographics, neurologic status, further diagnostic procedures, treatments, and treatment outcomes. RESULTS: Of 61 patients, 10 (16.4%) showed sciatica and a lack of nerve root compression in the lumbar MR imaging. In demographics, there was female sex dominance (9 patients) and right side preference (9 patients). Eight patients exhibited sensory disturbance beyond a single dermatome. Piriformis syndrome was diagnosed in 3 patients and 5 patients were considered to have sacral plexus pathologies associated with gynecologic conditions such as ectopic endometriosis, ovarian cyst, and pregnancy. A review of the literature also supported the right side preference in sciatica associated with gynecologic conditions. CONCLUSIONS: Piriformis syndrome and gynecologic conditions account for most cases of extralumbar spinal sciatica. Female sex, right side involvement, and overlapping sensory disturbance are suggestive of extralumbar spinal sciatica associated with gynecologic conditions.

Comparative Analysis of Surgical Options for Medial Collateral Ligament Repair in Terrible Triad Injury of the Elbow.

The aim of our study is to evaluate the clinical and radiologic outcomes in patients with terrible triad injury, who underwent surgical treatment with or without the medial collateral ligament (MCL) repair. Fourteen patients who underwent surgery with a minimum of 12-month follow-up (mean, 17 months) were reviewed. Based on the systematic treatment protocol, radial head fracture, lateral collateral ligament, and coracoid fracture were treated. Subsequently, torn MCL was repaired in 7 patients, whereas in the remaining 7 patients, the MCL was not treated. Range of motion, elbow function, and radiographs regarding the arthrosis and heterotopic ossification were assessed. At final follow-up, no significant differences were found in elbow motion or function between the groups with and without MCL repair; except the pronation and supination which had superior range in repair group. In contrast, radiologic findings such as the arthrosis were seen more frequently in patients without MCL repair than those with repair. Our results indicate the effect of MCL repair on elbow motion and function might be small, whereas osteoarthritic changes occurred more frequently in elbows without MCL repair.

An individualized approach to surgical reconstruction for lateral polydactyly of the foot with an emphasis on collateral ligament reconstruction.

BACKGROUND: Most previous studies concerning the treatment of polydactyly of the foot have focused on surgical techniques for aesthetic improvement rather than functional alignment of the reconstructed toe. The purpose of this study was to present the authors' surgical procedures for preventing postoperative malalignment of the reconstructed toe and evaluate whether those procedures were useful for the treatment of polydactyly of the foot. METHODS: The study included 30 feet from 26 patients, four male and 22 female, with four bilateral cases. The average age of the patients at surgery was 20 months, and average duration of the postoperative follow-up was 32 months. The ligamentous stability of the toe joint was reconstructed using the collateral ligament/periosteal sleeve from the excised toe. The authors evaluated postoperative complications of the toe involving varus or valgus deformities, thickening of the reconstructed toe, pigmentation of the grafted skin, and scar formation. RESULTS: No cases revealed any varus or valgus deformities, pigmentation of the grafted skin, functional disturbance, or pain in the reconstructed toe after surgery. Regarding postoperative complications, the authors observed visible thickening in eight toes and scar formation in three toes, although the parents' evaluation in each case was "very satisfied" or "satisfied." CONCLUSION: The authors recommend reconstruction of the ligamentous stability of the toe joint using the collateral ligament/periosteal sleeve from the excised toe to prevent postoperative malalignment. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Metallothionein deficiency in the injured peripheral nerves of complex regional pain syndrome as revealed by proteomics.

Complex regional pain syndrome (CRPS) is characterized by persistent and severe pain after trauma or surgery; however, its molecular mechanisms in the peripheral nervous system are poorly understood. Using proteomics, we investigated whether injured peripheral nerves of CRPS patients have altered protein profiles compared with control nerves. We obtained nerve samples from 3 patients with CRPS-2 who underwent resection of part of an injured peripheral nerve. Sural nerves from fresh cadavers with no history of trauma or neuropathic pain served as controls. Proteomic analysis showed that the number and functional distribution of proteins expressed in CRPS and control nerves was similar. Interestingly, metallothionein was absent in the injured nerves of CRPS-2, although it was readily detected in control nerves. Western blotting further confirmed the absence of metallothionein in CRPS-2 nerves, and immunohistochemistry corroborated the deficiency of metallothionein expression in injured nerves from 5 of 5 CRPS patients and 2 of 2 patients with painful neuromas. In contrast, all control nerves, including 5 sural nerves from fresh cadavers and 41 nerves obtained from surgically resected tumors, expressed MT. Furthermore, expression of S100 as a marker for Schwann cells, and neurofilament M as a marker of axons was comparable in both CRPS-2 and controls. Metallothioneins are zinc-binding proteins that are probably involved in protection against injury and subsequent regeneration after CNS damage. Their absence from the injured peripheral nerves of patients with CRPS-2 suggests a potential pathogenic role in generating pain in the damaged peripheral nerves.