A Comparative Analysis of Pain Control Methods after Ankle Fracture Surgery with a Peripheral Nerve Block: A Single-Center Randomized Controlled Prospective Study.

Background and Objectives: Patients experience severe pain after surgical correction of ankle fractures. Although their exact mechanism is unknown, dexamethasone and epinephrine increase the analgesic effect of anesthetics in peripheral nerve blocks. This study aimed to compare the postoperative pain control efficacy of peripheral nerve blocks with ropivacaine combined with dexamethasone/epinephrine and peripheral nerve blocks with only ropivacaine and added patient-controlled analgesia in patients with ankle fractures. Materials and Methods: This randomized, controlled prospective study included patients aged 18-70 years surgically treated for ankle fractures between December 2021 and September 2022. The patients were divided into group A (n = 30), wherein pain was controlled using patient-controlled analgesia after lower extremity peripheral nerve block, and group B (n = 30), wherein dexamethasone/epinephrine was combined with the anesthetic solution during peripheral nerve block. In both groups, ropivacaine was used as the anesthetic solution for peripheral nerve block, and this peripheral nerve block was performed just before ankle surgery for the purpose of anesthesia for surgery. Pain (visual analog scale), patient satisfaction, and side effects were assessed and compared between the two groups. Results: The patients' demographic data were similar between groups. Pain scores were significantly lower in group B than in group A postoperatively. Satisfaction scores were significantly higher in group B (p = 0.003). There were no anesthesia-related complications in either group. Conclusions: Dexamethasone and epinephrine as adjuvant anesthetic solutions can effectively control pain when performing surgery using peripheral nerve blocks for patients with ankle fractures.

Feasibility of 3D-Printed Locking Compression Plates with Polyether Ether Ketone (PEEK) in Tibial Comminuted Diaphyseal Fractures.

The applicability of a polyether ether ketone locking compression plate (PEEK LCP) fabricated using FDM (fused deposition modeling)-based 3D printing to treat actual patients was studied. Three different tests-bending, axial compression, and axial torsion-were conducted on tibial non-osteoporotic comminuted diaphyseal fracture samples fixed with the commercial titanium alloy LCP and 3D-printed PEEK LCP. Comparing the outcomes of these tests revealed that the commercial titanium alloy LCP underwent plastic deformation in the bending and axial torsion tests, though the LCP did not fail even when an external force greater than the maximum allowable load of the tibia fixture of the LCP was applied. Elastic deformation occurred in the 3D-printed PEEK LCP in the bending and axial torsion tests. However, deformation occurred even under a small external force, and its stiffness was 10% compared to commercial titanium alloy LCP. Thus, 3D-printed PEEK LCP can be applied to the fracture conditions in non-weight-bearing regions. The experimental results reveal detailed insights into the treatment of actual patients by considering the stiffness and high toughness of 3D-printed PEEK LCP.

Difference in Joint Stability Between Small Posterior Malleolar Fragments With Fixation and Those Without Fixation: A Biomechanical Cadaver Study.

The indication for the surgical treatment of ankle fractures that involve a posterior malleolar fragment remains controversial. This cadaver study assessed the biomechanical results of rotation stiffness of Haraguchi type 1 posterior malleolar fragments with or without cannulated screw fixation. Twelve anatomic lower-extremity specimens from 6 cadavers were tested. Six right legs were subjected to posterior malleolus osteotomy (Haraguchi type I) followed with (group A; n = 3) or without (group B; n = 3) fixation using a cannulated screw. Ankle joint stability was measured under both external rotation force and axial loading, and the passive resistive torque was measured in both groups. The mean torque value in group A was 0.1093 Nm/º, while that in group B was 0.0537 Nm/º. There was a significant intergroup difference (p = .004). In group B, the torque value was further increased in the latter rotation period (about 40-60 degrees). Group A proved more stable under experimental conditions than group B. Fixation in type I posterior malleolar fragments produced improved stability in ankle rotation, even for posterior malleolar fragments involving <25% of the articular surface, and has been considered an effective aid in treatment.

Extended Distal Chevron Osteotomy and Akin Osteotomy Using Bioabsorbable Materials for Treatment of Moderate to Severe Hallux Valgus.

The purpose of this study was to investigate the suitability of bioabsorbable materials for fixation of extended distal chevron osteotomy and Akin osteotomy for the treatment of moderate to severe hallux valgus. We performed a retrospective analysis of extended distal chevron osteotomy and Akin osteotomy for the treatment of moderate to severe hallux valgus (33 patients, 42 feet). Fixation of extended distal chevron osteotomy and Akin osteotomy was performed using poly-l-lactic acid pins and polylactic acid/polyglycolic acid copolymer sutures, respectively. The radiological outcomes were evaluated based on the preoperative and 3-year follow-up intermetatarsal angle, hallux valgus angle, and hallux interphalangeal angle. The clinical results were assessed according to 3-year follow-up Manchester-Oxford Foot Questionnaire scores, patient satisfaction, and postoperative complications. All radiological and clinical results were compared with those of a control group treated with metallic implants. The mean 3-year follow-up intermetatarsal angle, hallux valgus angle, and hallux interphalangeal angle were significantly corrected from the preoperative values (all p < .001). The mean 3-year follow-up Manchester-Oxford Foot Questionnaire scores score was significantly improved from the preoperative values (p < .001). Regarding patient satisfaction, 88.1% of the patients reported good to excellent results. A total of seven complications were reported. All radiological and clinical results were comparable with those of control group treated with metallic implant. Based on these results, we recommend using bioabsorbable materials as another reliable device for fixation of extended distal chevron osteotomy and Akin osteotomy even for the treatment of moderate to severe hallux valgus.

Clinical analyses of ultrasound-guided nerve block in lower-extremity surgery: A retrospective study.

PURPOSE: The purpose of this study is to examine the clinical effects and results of lower-extremity surgery under ultrasound-guided nerve block; time required for nerve block, anesthesia onset time, duration of anesthesia, duration of analgesia, tolerable tourniquet time, visual analog scale (VAS) satisfaction score, and anesthetic-related complications. METHODS: A total of 3312 cases (2597 patients) from January 2010 to April 2015 were analyzed retrospectively. A senior author performed ultrasound-guided nerve block of the lateral femoral cutaneous nerve (LFCN, 630 cases), femoral nerve (FN, 2503 cases), obturator nerve (ON, 366 cases), sciatic nerve (SN, 3271 cases), or posterior femoral cutaneous nerve (PFCN, 222 cases) depending on the type of surgery. Time required for nerve block, anesthesia onset time, duration of anesthesia, duration of analgesia, tolerable tourniquet time, VAS satisfaction score, and anesthetic-related complications were analyzed. RESULTS: The mean times required were 1.1 min for SN block, 2.5 min for FN/SN block (1762 cases), and 4.8 min for FN/SN/LFCN/ON block. The mean anesthesia onset time was 48 min. The mean durations of anesthesia were 4.5 h for FN dermatome and 5.6 h for SN dermatome. The mean duration of analgesia was 11.5 h. The mean tolerable tourniquet times after were 35, 51, and 84 min after SN block, FN/SN block, and FN/SN/LFCN/ON block, respectively. The mean VAS satisfaction score was 9.3. There were no anesthetic-related complications, such as infection, hematoma, paralysis, or nerve irritation. CONCLUSION: Selective block of the LFCN, FN, ON, SN, and PFCN based on the locations of lesions and type of surgery showed favorable clinical results with high efficacy. Ultrasound-guided nerve block may be a good option for anesthesia and analgesia in lower-extremity surgery.

The role and clinical relevance of the ligamentum teres: long-term outcomes after hip arthroscopic surgery of cam-type femoroacetabular impingement.

We aimed to compare clinical and radiologic outcomes in patients with cam-type femoroacetabular impingement (FAI), with and without a partial ligamentum teres (LT) tear, who underwent hip arthroscopy (HA) with ≥10 years of follow-up. Among the patients who underwent HA for a cam-type FAI diagnosis with a labral tear, 28 patients (28 hips) with a partial LT tear and 87 patients (99 hips) with an intact LT were assigned to Groups A and B, respectively. All patients underwent partial labral debridement and femoroplasty. Debridement and thermal shrinkage were performed for LT tears. The grade of chondral damage was measured intraoperatively. Clinical items were assessed preoperatively and at the last follow-up. Patients' satisfaction with the surgery and changes in postoperative sports ability in those who had previously been active in sports were assessed at the last follow-up. The Tönnis grade was assessed preoperatively and at the last follow-up for radiologic evaluation. Chondral damage to the acetabular and femoral head detected intraoperatively was significantly different between the groups (P = 0.005 and P < 0.001). At the last follow-up, Group A patients experienced more difficulty performing sports activities than Group B patients (P = 0.056), and significantly, more Group A patients had stopped exercising despite their active participation in sports preoperatively (P = 0.002). Regarding the Tönnis grade, significant differences were found only at the final follow-up (P = 0.020). Patients with partial LT tear showed a higher grade of chondral damage, experienced decreased exercise capacity and had significantly worsened Tönnis grades, suggesting hip osteoarthritis progression compared to those with an intact LT.

Perioperative axial loading computed tomography findings in varus ankle osteoarthritis: Effect of supramalleolar osteotomy on abnormal internal rotation of the talus.

BACKGROUND: We used axial loading computed tomography (AL CT) to evaluate preoperative and postoperative talocrural joints of patients who underwent supramalleolar osteotomy (SMO) to treat varus ankle osteoarthritis. METHODS: We performed retrospective analyses of 16 patients (18 feet) who underwent SMO including fibular osteotomy. Radiographic assessment was performed with weightbearing radiographs and AL CT. Clinical outcomes were assessed based on American Orthopedic Foot & Ankle Society (AOFAS) scale, visual analog scale (VAS) for pain, and Foot and Ankle Ability Measure (FAAM). RESULTS: The mean 2-year follow-up tibial-ankle surface angle, talar tilt angle, Takakura stage, and tibial-lateral surface angle were all significantly different relative to preoperative parameters (P<.05). The mean 6-month follow-up talus rotation ratio was significantly corrected compared to the preoperative value (P=.001). The mean 2-year follow-up AOFAS, VAS at gait, and FAAM scores were all significantly improved relative to preoperative measurements (P=.001). CONCLUSIONS: Abnormal internal rotation of the talus in mild to moderate varus ankle osteoarthritis found on AL CT was significantly corrected after SMO. LEVEL OF EVIDENCE: Therapeutic Level IV.

Flexible Intramedullary Nailing in High-Energy Tibial Fractures With Extensive Soft-Tissue Loss: A Case Report.

CASE REPORT: An 83-year-old woman presented with a high-energy tibial fracture. We treated her with temporary external fixation and delayed flexible intramedullary nailing because of extensive soft-tissue damage and interference from the hardware retained from a previous total knee arthroplasty. CONCLUSIONS: In our opinion, flexible intramedullary nailing is an effective procedure and provides good functional and radiological results in high-energy tibial fractures with extensive soft-tissue loss.

The utility of hip arthroscopy for patients with painful borderline hip dysplasia.

PURPOSE: We measured the width of the acetabular labra in, and the clinical outcomes of, patients with borderline hip dysplasia (HD) who underwent arthroscopy. METHODS: A total of 1436 patients who underwent hip arthroscopy to treat symptomatic, acetabular labral tears were enrolled. From this cohort, we extracted a borderline HD group (162 cases). Lateral labral widths were evaluated using preoperative magnetic resonance imaging scans. Clinical data including the modified Harris hip score (mHHS), non-arthritic hip score (NAHS), hip outcome score-activity of daily living (HOS-ADL) score, visual analog scale (VAS) pain score, and Tönnis grade were collected. In addition, patient satisfaction with arthroscopy outcomes was rated. All complications and reoperations were noted. RESULTS: The mean follow-up time was 87.4 months. The lateral labral width was 7.64 mm in those with normal hips and 7.73 mm in borderline HD patients, respectively (p = 0.870). The Tönnis grade progressed mildly from 0.46 to 0.76 (p = 0.227). At the last follow-up, clinical outcome scores (mHHS, NAHS, and HOS-ADL scores) and the VAS score were improved (p < 0.001). The mean patient satisfaction was scored at 8.2. The reoperation rate was higher in those who underwent labral debridement (25.6%) than labral repair (4.1%). CONCLUSIONS: The lateral labral width did not differ significantly between the borderline HD group and the nondysplastic control group. Arthroscopy relieved the symptoms of painful borderline HD and did not accelerate osteoarthritis. Therefore, if such patients do not respond to conservative treatment, hip arthroscopy can be considered for further treatment.

Midterm-clinical Outcomes after Hip Arthroscopy in Middle-aged Patients with Early Osteoarthritis.

PURPOSE: Although the number of hip arthroscopies is rapidly increasing in non-elderly patients, outcomes of this procedure in middle-aged patients are not well documented or clearly understood. The purpose of this study was to evaluate the clinical and radiological outcomes after hip arthroscopy in middle-aged patients with early osteoarthritis. MATERIALS AND METHODS: This retrospective study analyzed 189 patients with early osteoarthritis of various diagnoses aged 40 years or older who underwent hip arthroscopy between January 2010 and December 2015. Clinical (e.g., modified Harris hip score [mHHS], hip outcome score-activities of daily living [HOS-ADL], visual analogue scale [VAS] for pain, range of motion) and radiological (change of Tönnis grade) outcomes were assessed at a minimum of 3-year follow-up. RESULTS: The mean preoperative and final mHHS and HOS-ADL improved from 61.2 and 60.6 to 79.5 and 81.8, respectively, while the VAS pain score decreased from 6.3 to 3.2 (P<0.001). Although the mean range of internal rotation and flexion increased from 14.2 and 100.7° preoperatively to 30.4 and 110.6° at 1-year postoperatively, they decreased slightly to 27.4 and 105.4° at the final follow-up, respectively. Eight cases (4.2%) underwent revision arthroscopic surgery and three cases (1.6%) were converted to total hip arthroplasty. CONCLUSION: Patients with early-stage osteoarthritis of various diagnoses achieved improved clinical outcomes. Therefore, using hip arthroscopy in middle-aged patients with early osteoarthritis, it is possible to achieve good surgical options.

A comparative study of innovative percutaneous repair and open repair for acute Achilles tendon rupture: Innovative usage of intraoperative ultrasonography.

PURPOSE: There is no definitive consensus on the optimal treatment of Achilles tendon rupture. We comparatively analyzed the clinical outcomes of two types of repair surgeries in treating Achilles tendon rupture. METHODS: This retrospective study included 12 patients of Achilles tendon rupture (group A) treated with ultrasound-guided percutaneous repair and 18 patients (group B) treated with open repair. Clinical evaluation was performed using the Arner-Lindholm scale, American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, Achilles Tendon Total Rupture score (ATRS), visual analog scale, time to single heel raise, bilateral calf circumferences, recovery of athletic ability, and other complications. RESULTS: While the Arner-Lindholm scale, AOFAS ankle-hindfoot score, ATRS, time point when single heel raise was possible, differences in bilateral calf circumference, and recovery of athletic ability compared to pre-rupture level were not significantly different between the two groups (p = 0.999, 0.235, 0.357, 0.645, 0.497, and 0.881, respectively), overall and aesthetic satisfaction levels were higher in the group treated with percutaneous repair under ultrasonography guidance (p = 0.035 and 0.001, respectively). Overall, there were no cases involving sural nerve injury in either group. CONCLUSION: Innovative percutaneous repair provides not only similar clinical outcomes but also greater overall and aesthetic satisfaction levels of operative outcomes and minimal complications (i.e. sural nerve injury) compared to open repair surgeries. Therefore, percutaneous repair may be a useful technique in the treatment of Achilles tendon rupture.

Incidence and location of heterotopic ossification following hip arthroscopy.

BACKGROUND: We investigated the incidence and location of heterotopic ossification (HO) following hip arthroscopy. METHODS: This retrospective study enrolled 327 patients who underwent hip arthroscopy from January 2010 to December 2015. From this cohort, we extracted an HO group with simple radiographs or three-dimensional computed tomography (3D CT). Findings consistent with HO were classified according to the Brooker classification aided with 3D CT for the location of HO. The indication for revision arthroscopic excision of HO was painful, functional impairment of the hip. Patient clinical outcomes were assessed pre- and postoperatively, with modified Harris Hip Scores (mHHS), a visual analogue scale (VAS) for pain, and the Hip Outcome Score-Activity of Daily Living (HOS-ADL) and Sport Specific Subscales (HOS-SSS). RESULTS: In all, 14 (4.28%) of the 327 patients had confirmed HO radiographically. The mean follow-up was 39 months. In 13 patients, HO formed in the central area of the arthroscopic portals or capsulotomy. Ten patients had Brooker Grade 1 and four had Grade 2. At the last follow-up, 12 asymptomatic patients had significant (P < 0.001) improvements in all clinical outcome scores (mHHS, pain VAS, HOS-ADL, and HOS-SSS). Two patients developed symptoms sufficient to require revision hip arthroscopy for HO excision. After revision hip arthroscopy, both symptomatic patients had improved significantly in all clinical outcomes at the final follow-up. CONCLUSIONS: HO is a minor complication of hip arthroscopy, but sometimes induces severe pain and functional impairment. Usually, HO forms in the arthroscopic portal or capsulotomy area.

An Innovative Pain Control Method Using Peripheral Nerve Block and Patient-Controlled Analgesia With Ketorolac After Bone Surgery in the Ankle Area: A Prospective Study.

Although postoperative pain is inevitable after bone surgery, there is no general consensus regarding its ideal management. We hypothesized that the combination of ultrasound-guided peripheral nerve block (PNB) and patient-controlled analgesia (PCA) with ketorolac would be useful for pain control and reducing opioid usage. This prospective study aimed to evaluate the effectiveness of this method. This study included 95 patients aged >18 years who underwent bone surgery in the ankle area from June to December 2018. All operations were performed under anesthetic PNB, and additional PNB was given for pain control ∼11 hours after preoperative PNB. An additional PCA with ketorolac, started before rebound pain was experienced, was used for pain control in group A (49 patients) but not group B (46 patients). We used intramuscular injection with pethidine or ketorolac as rescue analgesics if pain persisted. A visual analogue scale (VAS) for pain was used to quantify pain at 6, 12, 18, 24, 36, 48, and 72 hours postoperatively. Patient satisfaction was assessed, along with side effects in both groups. VAS pain scores differed significantly between the groups at 24 hours after the operation (p = .013). All patients in group A were satisfied with the pain control method; however, 5 patients in group B were dissatisfied (p = .001), 3 owing to severe postoperative pain and 2 owing to postoperative nausea and vomiting. An average of 0.75 and 11.40 mg pethidine per patient was used in groups A and B, respectively, for 3 days. We concluded that the combined use of ultrasound-guided PNB and PCA with ketorolac can be an effective postoperative method of pain control that can reduce opioid usage.

Pathological Fracture of the Femoral Neck due to Tophaceous Gout: An Unusual Case of Gout.

A 48-year-old man visited the emergency room with right hip pain that started abruptly while walking out of the bathroom. Computed tomography showed an intraosseous mass in the femoral neck. The patient had a 15-year history of gout and had numerous bilateral tophi in his hands, feet, knees, and elbows. After operation, we diagnosed a pathological fracture due to intraosseous tophi. Patients with hip pain who have many subcutaneous tophi and long-standing gout should be diagnosed carefully. Peri-hip joint pain caused by gout is uncommon, however, if a patient complains of pain, a simple X-ray may be required. If intraosseous tophi are present, appropriate treatment (e.g., strict hyperuricemia control with or without prophylactic internal fixation), may be required before fracture occurs.

Arthroscopic Treatment for Femoroacetabular Impingement with Extraspinal Diffuse Idiopathic Skeletal Hyperostosis.

BACKGROUND: Patients with extraspinal diffuse idiopathic skeletal hyperostosis (DISH) involving the hip joint have symptoms like femoroacetabular impingement (FAI). To date, no reported study has determined the clinical outcomes of arthroscopic treatment in extraspinal DISH involving the hip joint. METHODS: A total of 421 hips with FAI that underwent arthroscopic treatment were reviewed retrospectively. We determined the extraspinal involvement of DISH with three-dimensional computed tomography (3D-CT) and simple radiography of the pelvis and hip joint. Clinical outcomes were evaluated at a minimum of 2 years postoperatively. The visual analog scale score (VAS), modified Harris hip score (MHHS), and hip outcome score-activity of daily living scale (HOS-ADL) were used, and hip range of motion (ROM) was evaluated pre- and postoperatively and at the time of the final follow-up. RESULTS: Among the 421 hips (372 patients) with FAI that underwent arthroscopic treatment, 17 hips (12 patients, 4.04%) had extraspinal DISH on the hip joints. The mean age of the patients was 51.5 years. The 3D-CT scans and simple radiographs showed extraspinal DISH on multiple points around the pelvis and hip joint. Nine of the 17 hips (seven of 12 patients) had spinal DISH. At the final follow-up, VAS, MHHS, and HOS-ADL improved significantly from 6.5, 65.3, and 66.6, respectively, to 1.2, 87.8, and 89.5, respectively, and hip flexion and internal rotation improved significantly from 97.7° and 7.9°, respectively, to 117.1° and 18.2°, respectively. CONCLUSIONS: This study has demonstrated that extraspinal DISH involving the hip joint could lead to FAI, and arthroscopic treatment could result in relief of symptoms, including pain and ROM limitation, in extraspinal DISH patients.

Screw Fixation of the Posterior Malleolus Fragment in Ankle Fracture.

BACKGROUND: This study aimed to evaluate the outcomes of ankle fractures with posterior malleolus fragments (PMFs) involving <25% of the articular surface treated with or without screw fixation. METHODS: Among patients with ankle fractures and PMFs who underwent surgery between March 2014 and February 2017, 62 with type 1 PMFs involving <25% of the articular surface were included. Of these 62 patients, 32 underwent screw fixation for PMFs and lateral and/or medial malleolar fracture fixation (group A) and 30 underwent internal fixation for malleolar fractures without screw fixation for PMFs (group B). Ankle joint alignment and fracture healing were measured using plain radiography and computed tomography (CT). Clinical outcomes were determined using the American Academy of Orthopaedic Surgeons Foot and Ankle Questionnaire, Short Form-36, and American Orthopaedic Foot & Ankle Society Scale. RESULTS: Nonunion was not noted in either group. However, we detected union with a step-off of 2 mm or more in 2 cases from group B. With regard to ankle joint alignment, 1 case in group A and 3 cases in group B showed mild asymmetry of the medial and lateral clear spaces on CT at 12 months. Clinical outcomes at 6 and 12 months after surgery were better in group A than in group B. CONCLUSION: Screw fixation of PMFs was effective for fracture healing and maintaining ankle alignment. Additionally, it improved short-term clinical outcomes, which we believe was due to stabilization of ankle fractures with PMFs involving <25% of the articular surface. LEVEL OF EVIDENCE: Level II, prospective comparative study.

Comparison of postoperative pain control methods after bony surgery in the foot and ankle.

BACKGROUND: We performed a prospective study to evaluate and compare the effectiveness of postoperative pain control methods after bone surgery in the foot and ankle. METHODS: Among the patients who underwent foot and ankle surgery from June 2014 to September 2015 with an ultrasound-guided nerve block, 84 patients who fully completed a postoperative pain survey were enrolled. An opioid patch (fentanyl patch, 25mg) was applied in group A (30 patients). Diluted anesthetic (0.2% ropivacaine, 30ml) was injected into the sciatic nerve once, about 12h after the preoperative nerve block, in group B (27 patients). Periodic intramuscular injection of an analgesic (ketorolac [Tarasyn], 30mg) was performed in group C (27 patients). The visual analogue scale (VAS) pain scores at 6, 12, 18, 24, and 48h after surgery were checked, and the complications of all methods were monitored. RESULTS: The mean VAS pain score was lower in group B, with a statistically significant difference (P<.05) between groups A, B, and C at 12 and 18h after surgery. Four patients in group A experienced nausea and vomiting; however, no other patients complained of any complications or adverse effects. CONCLUSION: The ultrasound-guided injection of a diluted anesthetic into the sciatic nerve seemed to be the most useful method for controlling pain in the acute phase after bone surgery in the foot and ankle. The injection of the diluted anesthetic once on the evening of the day of surgery resulted in less postoperative pain in the patients. LEVEL OF EVIDENCE: II.

Neuroprotective effects of systemic cerebral endothelial cell transplantation in a rat model of cerebral ischemia.

Human cerebral microvascular endothelial cell line (hCMEC)/D3 cells, which are from a stable clonal cell line of human immortalized cerebral endothelial cells, were intra-arterially transplanted through the common carotid artery in a rat model of photochemical-induced cerebral ischemia. Their therapeutic effects on infarct size, blood-brain barrier (BBB) breakdown, and outcome were examined. The hCMEC/D3 cells were genetically modified with the firefly luciferase gene for in vivo imaging post-transplantation. Transplanted hCMEC/D3 cells were identified in the infarcted brain by bioluminescence imaging at 1 day after transplantation. Compared with the control group, the hCMEC/D3-transplanted group showed reduced infarct size on day 3, reduced Evans blue dye leakage on day 1 indicating decreased BBB breakdown, and early recovery from Rotarod test neurological deficits. The hCMEC/D3-transplanted group also showed decreased levels of matrix metalloproteinase (MMP)-9, which were inversely correlated with TIMP-1 levels on post-transplantation days 1 and 3. The expression of tumor necrosis factor-α and interleukin-1ß were markedly diminished in the hCMEC/D3-transplanted group compared with controls. The systemically transplanted cells selectively migrated and integrated into the ischemically lesioned area, which accelerated neurological recovery. This new cerebral endothelial cell-based therapy may hold promise for clinical trials in patients with ischemic stroke.

The HIF-1 inhibitor YC-1 decreases reactive astrocyte formation in a rodent ischemia model.

Astrocytes become reactive after central nervous system injury, re-expressing glial fibrillary acidic protein (GFAP), vascular endothelial growth factor (VEGF), and nestin. Hypoxia-inducible transcription factor alpha (HIF-1α) is an important transcription factor for several genes including the VEGF and nestin genes, the expression of which generate reactive astrocytes and cause gliosis after cerebral ischemia. To evaluate the role of HIF-1α in reactive astrocyte formation, we applied the potent HIF-1α inhibitor YC-1 to a focal cerebral ischemia model and analyzed the expression of HIF-1α, VEGF, nestin, and GFAP. Quantitative real-time reverse transcription polymerase chain reaction and western blot analyses demonstrated that the expression of HIF-1α and its downstream genes (VEGF and nestin) were markedly attenuated in the YC-1-treated group versus the control group (HIF-1α, VEGF: p < 0.01; nestin: p < 0.05). GFAP expression was also effectively inhibited in the YC-1-treated group (p < 0.05). Immunohistochemical evaluations showed that GFAP-positive (GFAP+) cells in the YC-1-treated group were sparse in the peri-infarct area, while an immunofluorescence assay revealed that the number of VEGF+/GFAP+ and nestin+/GFAP+ reactive astrocytes were decreased in the YC-1-treated group (p < 0.05). These results demonstrate that HIF-1α suppression decreases the formation of reactive astrocytes and gliosis that occur following focal ischemia.