Cell-specific expression of ENACα gene by FOXA1 in the glucocorticoid receptor pathway.

INTRODUCTION: The glucocorticoid receptor (GR) is one of the most widely studied ligand-dependent nuclear receptors. The combination of transcriptional regulatory factors required for the expression of individual genes targeted by GR varies across cell types; however, the mechanisms underlying this cell type-specific regulation of gene expression are not yet clear. METHODS: Here, we investigated genes regulated by GR in two different cell lines, A549 and ARPE-19, and examined how gene expression varied according to the effect of pioneer factors using RNA-seq and RT-qPCR. RESULTS: Our RNA-seq results identified 19 and 63 genes regulated by GR that are ARPE-19-specific and A549-specific, respectively, suggesting that GR induces the expression of different sets of genes in a cell type-specific manner. RT-qPCR confirmed that the epithelial sodium channel (ENACα) gene is an ARPE-19 cell-specific GR target gene, whereas the FK506 binding protein 5 (FKBP5) gene was A549 cell-specific. There was a significant decrease in ENACα expression in FOXA1-deficient ARPE-19 cells, suggesting that FOXA1 might function as a pioneer factor enabling the selective expression of ENACα in ARPE-19 cells but not in A549 cells. CONCLUSION: These findings indicate that ENACα expression in ARPE-19 cells is regulated by FOXA1 and provide insights into the molecular mechanisms of cell type-specific expression of GR-regulated genes.

Association of Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms with Osteoporotic Vertebral Compression Fractures (OVCFs) in Postmenopausal Women.

Osteoporosis and osteoporotic fractures are strongly associated with mortality and morbidity, both in developing and developed countries. Menopause accelerates bone loss due to estrogen deficiency and age-related linear bone loss. We investigated plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms in postmenopausal women with osteoporotic vertebral compression fractures (OVCFs). In this case-control study, 355 postmenopausal women were genotyped for the presence of PAI-1 gene polymorphisms -844A > G, -675 4G > 5G, 43G > A, 9785A > G, and 11053T > G. Genetic polymorphisms of PAI-1 were analyzed by the polymerization chain reaction restriction fragment length polymorphism assay, and their association with disease status and folate and homocysteine levels was determined in 158 OVCF patients and 197 control subjects. The PAI-1 -675 5G5G (adjusted odds ratio (AOR), 3.302; p = 0.017) and 43GA + AA (AOR, 2.087; p = 0.042) genotype frequencies showed significant association with the increased prevalence of OVCFs in postmenopausal women. In addition, we performed gene-environment interaction studies and demonstrated an association between PAI-1 gene polymorphisms and OVCF prevalence. Our novel finding is the identification of several PAI-1 genetic variants that increase susceptibility to OVCF. Our findings suggest that polymorphisms in PAI-1 may contribute to OVCF, and that they can be developed as biomarkers for evaluating OVCF risk.

Riluzole blocks perioperative ischemia-reperfusion injury and enhances postdecompression outcomes in cervical spondylotic myelopathy.

Although surgical decompression is considered the gold standard treatment for cervical spondylotic myelopathy (CSM), a proportion of cases show postoperative decline or continue to exhibit substantial neurological dysfunction. To investigate this further, we first examined data from the prospective multicenter AOSpine North America CSM study, finding that 9.3% of patients exhibited postoperative functional decline (ΔmJOA, ≤-1) and that 44% of patients were left with substantial neurological impairment 6 months postoperatively. Notably, 4% of patients experienced perioperative neurological complications within 20 days after surgery in otherwise uneventful surgeries. To shed light on the mechanisms underlying this phenomenon and to test a combination therapeutic strategy for CSM, we performed surgical decompression in a rat model of CSM, randomizing some animals to also receive the U.S. Food and Drug Administration-approved drug riluzole. Spinal cord blood flow measurements increased after decompression surgery in rats. CSM rats showed a transient postoperative neurological decline akin to that seen in some CSM patients, suggesting that ischemia-reperfusion injury may occur after decompression surgery. Riluzole treatment attenuated oxidative DNA damage in the spinal cord and postoperative decline after decompression surgery. Mechanistic in vitro studies also demonstrated that riluzole preserved mitochondrial function and reduced oxidative damage in neurons. Rats receiving combined decompression surgery and riluzole treatment displayed long-term improvements in forelimb function associated with preservation of cervical motor neurons and corticospinal tracts compared to rats treated with decompression surgery alone.

Bone loss of the superior adjacent vertebral body immediately posterior to the anterior flange of Bryan cervical disc.

BACKGROUND: No previous reports have mentioned bone loss of the superior adjacent vertebra immediately posterior to the anterior flange of Bryan cervical disc (Medtronic Sofamor Danek, Memphis, TN, USA), which plays a central role to prevent posterior migration of the device. The purpose of this study is to describe a new potential complication, bone loss immediately posterior to the anterior total disc replacement (TDR) flange on the superior adjacent vertebra following the Bryan cervical TDR and to discuss the possible mechanism. METHODS: The authors retrospectively reviewed 37 patients undergoing cervical TDR with the Bryan cervical disc. The clinical and radiological outcome data were collected at 1, 3, 6, 12, 24, and 36 months postoperatively, and at last follow-up, which ranged from 42 to 113 moths (average, 60.1 months). Clinical evaluation included the visual analog scale and neck disability index, and the radiographic evaluation included measurements of the functional spinal unit range of motion on flexion and extension and identification of radiographic changes such as bone loss. RESULTS: The Bryan TDR showed good mid-term clinical and radiological outcomes. Interestingly, however, bone loss was noted immediately posterior to the TDR flange on superior adjacent vertebra in 3 total patients; at 3 months (n = 2) and 6 months (n = 1). Although the bone loss was increased up to 6 months, this did not progress and no degradation of clinical and radiological outcomes occurred at last follow-up. CONCLUSIONS: Bone loss immediately posterior to the anterior TDR flange on the superior adjacent vertebra can occur in the early postoperative period due to possibly stress shielding effect. However, it did not result in clinical changes or increased rates of graft failure at last follow-up. A long-term follow-up study is mandatory to evaluate the long-term effects of the bone loss.

Effect of vertebroplasty with bone filler device and comparison with balloon kyphoplasty.

PURPOSE: To evaluate the effect of vertebroplasty with a bone filler device compared with balloon kyphoplasty. METHODS: A total of 222 patients underwent operations from January 2008 to October 2012. One-level fractures numbered 169 (86.7%) cases and two-level fractures numbered 26 (13.3%). A total of 221 vertebral levels were analyzed consequently. Vertebral height, compression ratio, and segmental Cobb's angle were measured in preoperative and postoperative lateral X-rays. RESULTS: The compression ratio was the most influential parameter among three variables. Adjusted postoperative compression ratio was not significantly different between two operation groups. Bone cement leakage rates did not differ (p < 0.05). Bone cement distribution was spongy type in the majority of the vertebroplasty with bone filler device (94.5%), but only in 42.0% of the kyphoplasty. High bone densitometry readings and long period from diagnosis to operation were significant risk factors for bone cement leakage. CONCLUSIONS: Vertebroplasty with a bone filler device could achieve equivalent compression reduction and bone cement leakage rate, as well as greater sponge-type bone cement distribution, which were advantages over balloon kyphoplasty.

Very high resolution ultrasound imaging for real-time quantitative visualization of vascular disruption after spinal cord injury.

Spinal cord injury (SCI) is characterized by vascular disruption with intramedullary hemorrhage, alterations in blood-spinal cord barrier integrity, and perilesional ischemia. A safe and easily applied imaging technique to quantify evolving intraspinal vascular changes after SCI is lacking. We evaluated the utility of very high resolution ultrasound (VHRUS) imaging to assess SCI-induced vascular disruption in a clinically relevant rodent model. The spinal cords of Wistar rats were lesioned at the 11th thoracic vertebra (Th11) by a 35 g 1-minute clip compression. Three-dimensional quantification of intraspinal hemorrhage using VHRUS (at an acute 90-min and subacute 24-h time point post-SCI) was compared with lesional hemoglobin and extravasated Evans blue dye measured spectrophotometrically. The anatomy of hemorrhage was comparatively assessed using VHRUS and histology. Time-lapse videos demonstrated the evolution of parenchymal hemorrhage. VHRUS accurately depicted the structural (gray and white matter) and vascular anatomy of the spinal cord (after laminectomy) and was safely repeated in the same animal. After SCI, a hyperechoic signal extended from the lesion epicenter. Significant correlations were found between VHRUS signal and hemorrhage in the acute (r=0.88, p<0.0001) and subacute (r=0.85, p<0.0001) phases and extravasated Evans blue (a measure of vascular disruption) in the subacute phase (r=0.94, p<0.0001). Time-lapse videos demonstrated that the expanding parenchymal hemorrhage is preceded by new perilesional hemorrhagic foci. VHRUS enables real-time quantitative live anatomical imaging of acute and subacute vascular disruption after SCI in rats. This technique has important scientific and clinical translational applications.

Anti-inflammatory effects of α-galactosylceramide analogs in activated microglia: involvement of the p38 MAPK signaling pathway.

Microglial activation plays a pivotal role in the development and progression of neurodegenerative diseases. Thus, anti-inflammatory agents that control microglial activation can serve as potential therapeutic agents for neurodegenerative diseases. Here, we designed and synthesized α-galactosylceramide (α-GalCer) analogs to exert anti-inflammatory effects in activated microglia. We performed biological evaluations of 25 α-GalCer analogs and observed an interesting preliminary structure-activity relationship in their inhibitory influence on NO release and TNF-α production in LPS-stimulated BV2 microglial cells. After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis. We confirmed that 4d and 4e regulate the expression of iNOS, COX-2, IL-1ß, and IL-6 at the mRNA level and the expression of TNF-α at the post-transcriptional level. In addition, both 4d and 4e inhibited LPS-induced DNA binding activities of NF-κB and AP-1 and phosphorylation of p38 MAPK without affecting other MAP kinases. When we examined the anti-inflammatory effect of a p38 MAPK-specific inhibitor, SB203580, on microglial activation, we observed an identical inhibitory pattern as that of 4d and 4e, not only on NO and TNF-α production but also on the DNA binding activities of NF-κB and AP-1. Taken together, these results suggest that p38 MAPK plays an important role in the anti-inflammatory effects of 4d and 4e via the modulation of NF-κB and AP-1 activities.

Spinal subarachnoid hematoma as a complication of an intramuscular stimulation : case report and a review of literatures.

Intramuscular stimulation (IMS) is widely used to treat myofascial pain syndrome. IMS is a safe procedure but several complications have been described. To our knowledge, spinal subarachnoid hematoma has never been reported as a complication of an IMS. The authors have experienced a case of spinal subarachnoid hematoma occurring after an IMS, which was tentatively diagnosed as intracranial subarachnoid hemorrhage because of severe headache. Patient was successfully treated with surgery. Here, we report our case with a review of literature.

Changes in simple visual matching task performance and physiological signals in intellectually and developmentally disabled people due to administration of highly concentrated oxygen.

BACKGROUND: This study attempted to identify the effect of administration of highly concentrated oxygen on simple visual matching task performance, blood oxygen saturation [SpO2 (%)], and heart rate [HR (bpm)] of intellectually and developmentally disabled people. METHODS: Nineteen intellectually and developmentally disabled people (mean age 30.6 ± 5.7 years) participated in an experiment consisting of a simple visual matching task performed under 21% and 92% oxygen. SpO2 and HR were measured under both oxygen conditions. RESULTS: When 92% oxygen was supplied, the response time decreased, SpO2 increased, and HR decreased compared to the vales obtained using 21% oxygen. The response time decreased for subjects with a high SpO2 and HR during the simple visual matching task phase. CONCLUSION: This result supports the hypothesis that administration of highly concentrated oxygen can positively affect the cognitive performance of intellectually and developmentally disabled people.

Subacute course of common iliac arterial laceration in lumbar disc surgery.

Vascular injuries in lumbar disc surgery are serious complications which may be overlooked due to a broad range of clinical manifestations. It is important to be aware of the perioperative implications of this rare occurrence to lower mortality risk. A 20-yr-old man with a right L4-5 lumbar disc protrusion was operated on routinely under a surgical microscope. A bloody surgical field was noted temporarily during a discectomy along with a decreased blood pressure. After fluid resuscitation with an ephedrine injection, the bleeding soon stopped spontaneously and his vital signs were stabilized. Fifty hours after the operation, the patient showed signs of hypovolemic hypotension with abdominal distension. The right femoral artery pulsation was absent on palpation. An enhanced CT angiography revealed a retroperitoneal hematoma and obstruction of the left common iliac artery. An urgent laparotomy was done to repair the injured vessel by excision and interposition of a graft. The patient had an uneventful recovery.The subacute course of deterioration might have been due to intermittent blood leakage from the lacerated common iliac artery, which was sealed spontaneously. It is very important to pay close attention to post-surgical clinical manifestations to avoid a potentially fatal outcome in lumbar disc surgery.

Correlation between cognitive ability measured by response time of 1-back task and changes of SpO2 by supplying three different levels of oxygen in the elderly.

AIM: This study investigated the correlation between response time of the 1-back task and changes of blood oxygen saturation (SpO2 ) by supplying three different levels of oxygen (21%, 1 L/min; 93%, 1 L/min; 93%, 5 L/min) in the elderly. METHODS: A total of 17 older adults (mean age 72.9 ± 4.7 years) participated in the experiment. A 1-back task was used as a cognitive task. The experiment consisted of three phases, which included the adaptation phase (3 min) after oxygen administration, the control phase (2 min) that maintained a stable condition before the task, and the task phase (2 min) where the 1-back task was carried out. SpO2 was measured during each phase. RESULTS: As concentration level and supply of oxygen increased, SpO2 increased and response time of the 1-back task decreased. CONCLUSION: Highly concentrated oxygen administration can increase SpO2 in the elderly and an increase in cognitive performance, such as a decrease in response time, can be observed.

A nonthiazolidinedione peroxisome proliferator-activated receptor α/γ dual agonist CG301360 alleviates insulin resistance and lipid dysregulation in db/db mice.

Activation of peroxisome proliferator-activated receptors (PPARs) have been implicated in the treatment of metabolic disorders with different mechanisms; PPARα agonists promote fatty acid oxidation and reduce hyperlipidemia, whereas PPARγ agonists regulate lipid redistribution from visceral fat to subcutaneous fat and enhance insulin sensitivity. To achieve combined benefits from activated PPARs on lipid metabolism and insulin sensitivity, a number of PPARα/γ dual agonists have been developed. However, several adverse effects such as weight gain and organ failure of PPARα/γ dual agonists have been reported. By use of virtual ligand screening, we identified and characterized a novel PPARα/γ dual agonist, (R)-1-(4-(2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy)benzyl)piperidine-2-carboxylic acid (CG301360), exhibiting the improvement in insulin sensitivity and lipid metabolism. CG301360 selectively stimulated transcriptional activities of PPARα and PPARγ and induced expression of their target genes in a PPARα- and PPARγ-dependent manner. In cultured cells, CG301360 enhanced fatty acid oxidation and glucose uptake and it reduced pro-inflammatory gene expression. In db/db mice, CG301360 also restored insulin sensitivity and lipid homeostasis. Collectively, these data suggest that CG301360 would be a novel PPARα/γ agonist, which might be a potential lead compound to develop against insulin resistance and hyperlipidemia.

Anti-obesity agents: a focused review on the structural classification of therapeutic entities.

In addition to its enormous impacts on an individual's quality of life, obesity is a daunting health problem in the world today and the increasing rate of obesity is now causing a severe burden on health care systems. Fortunately, the normalization or reduction of increased body fat reverses the obesity-associated morbidities, such as hypertension, glucose intolerance, dyslipidemia, and fatty liver diseases. However, the modification of lifestyle in a case of established clinical obesity is very difficult to achieve. Recent breakthroughs in relation to the molecular mechanism regulating body weight and energy metabolism give us hopes for the development of anti-obesity drugs. Even with the high social demand for an effective treatment for obesity and extensive researches, both in academia and the pharmaceutical industry, only two weight-loss drugs, sibutramine and orlistat, have been approved by the FDA for long-term treatment. In addition, the current bottleneck in drug discovery shows that a more detailed understanding of the pathogenesis of obesity is an essential element for the development of efficacious treatment. In this review article, we focus on the structural origin of chemical entities for anti-obesity treatment along with the rationale for drug discovery, rather than categorizing the clinical efficacy or pharmacological target of obesity. For the clarification of the structural origin, we formed a collection with 4 major groups, including natural products, natural product mimetics, synthetic small molecules, and peptides/hormones. This analysis might provide strategic plans for medicinal chemists, biologists, and physicians to begin an optimistic era with a new class of pharmaceutical adjuncts for obesity therapy.

Therapeutic endovascular treatments for traumatic vertebral artery injuries.

OBJECTIVE: Traumatic vertebral artery injuries pose difficulty in early diagnosis and management because of concomitant neurologic dysfunction and limitations in direct surgical access. The purpose of this report is to review endovascular therapy in patients with traumatic vertebral artery injuries for preservation of the parent artery, and to determine the safety and efficacy of such endovascular therapy. METHODS: Six patients with traumatic vertebral artery lesions were treated using therapeutic endovascular methods. Endovascular therapy was accomplished by stent insertion or coil embolization or both. RESULTS: Except one patient who underwent coil embolization of a transected vertebral artery, all dissections and pseudoaneurysms were successfully treated by stent placement or stent-assisted coiling with preservation of parent arteries. No additional surgical procedures for vascular lesions were required. There were no delayed neurologic or vascular complications and no lesions recurred during the follow-up period (mean, 36.7 months). CONCLUSION: The author's experience demonstrates that endovascular therapy using stents and coils is both feasible and safe in the treatment of traumatic vertebral artery injuries. Endovascular therapy selectively eliminated the vascular abnormality while maintaining the normal patency of the cerebral arteries. Long-term follow-up review of these repairs will be necessary to provide a full evaluation of the safety and efficacy of these devices.

Posttraumatic infarction in the territory supplied by the lateral lenticulostriate artery after minor head injury.

BACKGROUND: Occlusion of the intracranial arteries due to blunt head traumas has been less frequently observed in patients with minor head injuries. CASE REPORT: A 4-year-old boy presented with speech disturbance 2 h after minor head injury. An initial computed tomography (CT) scan showed a questionable finding of a focal punctate high density in the left basal ganglia. Hemiparesis developed on the right limbs 8 h post-injury, and a subsequent CT scan revealed a discrete low-density change around the focal high density. Diffusion-weighted images revealed a clearly demarcated high-signal intensity lesion in similar area on T2-weighted and fluid-attenuated inversion recovery sequences images, compatible with infarcted tissues on the territory supplied by the lateral lenticulostriate artery. His hemiparesis improved gradually, and by post-trauma day 10 he was able to walk briefly without assistance. He was discharged on foot at post-trauma day 14. DISCUSSION AND CONCLUSION: Children with minor head trauma who have normal findings on initial CT scan may rarely have basal ganglionic infarction resulting from arterial spasm or thromboembolism of the perforating arteries. Hospital admission and careful observation should be considered for patients with minor head injury and persistent neurologic deficits despite normal CT findings. Magnetic resonance study is valuable for the evaluation of posttraumatic infarction, differentiating from hemorrhagic diffuse axonal injuries.

Endovascular thrombolysis and stenting of a middle cerebral artery occlusion beyond 6 hours post-attack: special reference to the usefulness of diffusion-perfusion MRI.

Intra-arterial thrombolysis and percutaneous angioplasty is feasible in patients with acute middle cerebral artery (MCA) occlusion limited to 6 hours post-ictus, but there are some limitations such as reocclusion or hemorrhagic complications. In this report, we describe a stent placement in the treatment of a refractory artherothrombotic MCA occlusion beyond 6 hours of symptom onset. A 57-year-old man presented with a progressive left-sided weakness and verbal disturbance resulting from an acute thrombotic occlusion of the right MCA superimposed on severe proximal atheromatous stenosis. Diffusion-perfusion magnetic resonance imaging (MRI) demonstrated the significant diffusion-perfusion mismatch. After chemical and mechanical thrombolysis of the clot, balloon angioplasty of the underlying MCA stenosis was performed 2 days post-attack, without significant angiographic improvement. Percutaneous endovascular deployment of a stent (Driver 2.5 x 12 mm, MTI, Irvine, CA) was subsequently performed, with excellent angiographic results. Follow-up diffusion-perfusion MRI showed improved perfusion in the hypoperfused area. The patient's National Institutes of Health Stroke Scale (NIHSS) score was increased from 12 to 3. Clot thrombolysis and subsequent stenting in patients with refractory proximal MCA occlusion is feasible and allows for a significant reduction in the amount of thrombolytic drug required. In selective patients with acute MCA occlusion, the therapeutic window for recanalization procedures can be safely and effectively extended beyond the 'traditional 6 hours'. Diffusion-perfusion MRI in acute MCA occlusion is important for indication of therapy.

Treatment of intra- and extracranial arterial dissections using stents and embolization.

PURPOSE: To evaluate the safety and efficacy of stent placement for extracranial and intracranial arterial dissections. METHODS: Eighteen patients underwent endovascular treatment of carotid and vertebral dissections using intraluminal stent placement. Five patients with arterial dissection were treated, 2 using one insertion of a single stent and 3 using placement of two stents. Patients with a dissecting aneurysm were treated as follows: 7 patients with insertion of one stent, 4 with placement of two stents, and 2 by stent-assisted Guglielmi detachable coil embolization. In the 18 patients in whom stenting was attempted, the overall success in reaching the target lesion was 94.4%. Of the 17 patients treated with stents, stent release and positioning were considered optimal in 16 (94%) and suboptimal in one (6%). In patients who underwent a successful procedure, all parent arteries were preserved. There were no instances of postprocedural ischemic attacks, new neurologic deficits, or new minor or major strokes prior to patient discharge. In follow up, all patients were assessed, using the modified Rankin scale, as functionally improved or of stable clinical status. The reduction in dissection-induced stenosis or pseudoaneurysm, the patency rate obtained at follow-up, and the lack of strokes (ischemic or hemorrhagic) suggest that stent placement offers a viable alternative to complex surgical bypass or reconstructive procedures. The long-term efficacy and durability of stent placement for arterial dissection remain to be determined in a larger series.

Isolated pineal region metastasis of small cell lung cancer.

The pineal region is an unusual site for brain metastasis and most metastatic pineal lesions are asymptomatic. Rarely the symptoms of metastatic involvement of the pineal gland precede those of the primary tumor or other metastatic sites. An 83 year-old man presented with gait disturbance and limitation of upward gaze. Brain MRI showed homogeneous enhancement of a solitary mass in the pineal region with obstructive hydrocephalus. A stereotactic biopsy was performed, and small cell carcinoma was diagnosed. A systemic investigation for the primary lesion subsequently revealed small cell carcinoma of the lung. The patient was referred for radiotherapy and chemotherapy. Although rare, metastatic tumor should be considered in the differential diagnosis of pineal region tumors, particularly in elderly patients.

Therapeutic endovascular treatments for traumatic carotid artery injuries.

OBJECTIVE: The diagnosis and management of traumatic carotid vessel injuries continue to be controversial, with direct surgical repair with parent artery preservation still presenting difficulties. The purpose of this report is to review the endovascular therapy of patients with traumatic carotid vessel injuries for preservation of the parent artery, and to determine the safety and efficacy of endovascular therapy. METHODS: Ten patients with traumatic carotid lesions were treated using therapeutic endovascular methods. Endovascular therapy was accomplished by implanting balloons, porous or polytetrafluoroethylene-covered stents, and/or embolic materials including coils or glue. RESULTS: All fistulas and pseudoaneurysms were successfully embolized with no periprocedural complications including vessel disruption/rupture, distal embolization, or new neurologic deficits. The parent arteries of all patients except one were preserved. The reason for the parent artery sacrifice was a thrombus formation due to coil migration into the parent artery. No additional surgical procedures for vascular lesions were required. There were no delayed neurologic or vascular complications, and no lesions recurred during the follow-up periods (mean 20.3 months). CONCLUSION: The goal of endovascular therapy is the selective elimination of the vascular pathology with the normal patency of the cerebral arteries. The authors' experience demonstrates that endovascular therapy using stents, balloons, and coils is both feasible and safe for treatment of traumatic carotid injuries. Of these endovascular methods, the stent can be used to exclude the aneurysm or fistula from the circulation and preserve the parent artery in selective cases. Long-term follow-up review of these repairs will be necessary to provide a full evaluation of the safety and efficacy of these devices.

Therapeutic effects of Holmium-166 chitosan complex in rat brain tumor model.

This study examined the effectiveness of Holmium-166 (Ho-166) chitosan complex therapy for a malignant glioma. Cultured C6 glioma cells (100,000 in 5 microl) were injected into the caudate/putamen of 200-250 gram Wistar rats. Five days later, a Ho-166 chitosan complex was injected into the same site of the glioma injection. Four injection doses were administered: the control group received PBS 10 microl, group 1 received an injection of 100 microCi (10 microl), group 2 received an injection of 50 microCi (5 microl), and group 3 received an injection of 10 microCi (1 microl). The average tumor volume for each group was 1.385 mm3 for the control group, 0.036 mm3 for group 1, 0.104 mm3 for group 2, and 0.111 mm3 for group 3. Compared with the control group, the size of the tumors in groups 1, 2 and 3 was reduced by an average of 97.4%, 92.5% and 91.9%, respectively. The Kaplan-Meier survival curve of group 2 was the longest, followed by groups 3, group 1 and the control. The mean survival was 22.8, 59, 60, and 44.6 days for the control group and groups 3, 2 and 1, respectively. H-E staining revealed that group 2 yielded the best results in the destruction of the malignant glioma. TUNEL staining and immunohistochemical studies indicated apoptotic features. The Ho-166 chitosan complex proved to be effective in destroying the malignant glioma.