Woven Endobridge (WEB) augmented by Y-stent in a shallow basilar tip aneurysm.

The Woven Endobridge (WEB) device can be an effective and simple treatment modality for wide-neck bifurcation intracranial aneurysms. We present a case of a shallow basilar tip aneurysm treated with the WEB device that required stabilization with Y-stent through radial access.

Spinal dural attachments to the vertebral column: An anatomic report and review of the literature.

BACKGROUND: The spinal dura is anchored within the vertebral canal by connective tissue in the epidural space as well as the spinal roots. Inadvertent disruption of these dural attachments may lead to durotomy and cerebrospinal fluid (CSF) leaks. We observed well-developed connective tissue ligaments connecting the lumbar dura to the spinal column and examined these tissues microscopically. METHODS: Intraoperative images were obtained during lumbar laminectomy procedures. They demonstrated connective tissue attachments, linking the lumbar dura to the spinal column in the dorsal midline and dorsolaterally. Tissue samples were obtained and examined microscopically. We then conducted a search of the literature to find references to dural attachments to the spinal column. RESULTS: Histological examination of the samples showed minimal cellular fibrous tissue. To date no references to these attachments have been made in neurosurgical literature. Previous studies, including live, cadaveric, and radiographic examinations, have demonstrated a dorsomedian fold of dura attached to the junction of the ligamentum flavum, and dorsolateral ligaments that divide the dorsal epidural space into an anterior and posterior compartment. CONCLUSIONS: Epidural fibrous connections or ligaments between the dura and the lumbar spinal column may be of clinical importance to the neurosurgeon. Care should be taken during lumbar procedures not to disrupt or tear these ligaments as this may cause dural tears and CSF leaks. Identifying these ligaments and cutting them sharply may prevent inadvertent durotomies.

Chordoma in the lateral medullary cistern in a patient with tuberous sclerosis: A case report and review of the literature.

BACKGROUND: Chordomas are rare intracranial tumors. There are several reported cases of these tumors arising in patients with tuberous sclerosis (TSC), a neurocutaneous disorder inherited in autosomal dominant fashion that predisposes patients to hamartomatous and neoplastic lesions. CASE DESCRIPTION: A 38-year-old man with the diagnosis of TSC presented with the complaint of dizziness and near syncope. Imaging revealed a mass in the lateral medullary cistern that was found at the time of surgery to be a chordoma. The patient underwent a left far lateral approach for removal of the tumor. Upon opening of the dura, the tumor could be seen under the arachnoid. The tumor was carefully debulked within the limits of safety. The patient did well postoperatively and was referred to the radiation oncology department at our institution for follow-up radiotherapy of the tumor bed. CONCLUSION: This study presents an unusual presentation and location for a chordoma and contributes to the growing literature associating chordomas with TSC.

The relationship between the zygomatic arch and the floor of the middle cranial fossa: a radiographic study.

OBJECTIVE: Access to the floor of the middle cranial fossa (MCF) is often required for approaches to cranial base lesions. This study measures the craniocaudal distance between the zygomatic arch (ZA) and the floor of the MCF from a random sample of high-resolution computed tomography scans of the cranial base. METHODS: Forty computed tomography scans were imported into an OsiriX station and reconstructed in multiple planes. The most caudal point of the MCF was determined in each computed tomography scan. The distances between that point and the root of the zygoma and the middle point of the ZA were calculated. The thickness of the temporalis muscle and the vertical height of the zygoma were also calculated. A 2-tailed, paired Student t test was used to compare right and left measurements with a 95% confidence interval and P value <.05 as statistically significant. RESULTS: The foramen ovale was consistently the lowest point of the MCF. The average root-to-floor measurement was 5.05 +/- 0.42 mm above the floor of the MCF and distance of the mid-zygoma to the floor was 1.94 +/- 0.61 mm above the floor of MCF. The average temporalis muscle thickness and vertical height of the ZA were 22.22 +/- 0.36 mm and 8.10 +/- 0.13 mm, respectively. The muscle-to-floor measurement (muscle thickness + mid-zygoma-to-floor measurement) was 24.16 +/- 0.74 mm. CONCLUSION: The routine use of a zygomatic osteotomy in approaches to the MCF does not provide very much increased exposure. However, in patients with exceptionally thick temporalis muscles or a high ZA, a zygomatic osteotomy may be helpful in providing exposure of the floor of the MCF.

Overexpression of dimethylarginine dimethylaminohydrolase protects against cerebral vascular effects of hyperhomocysteinemia.

RATIONALE: Hyperhomocysteinemia is a cardiovascular risk factor that is associated with elevation of the nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA). OBJECTIVE: Using mice transgenic for overexpression of the ADMA-hydrolyzing enzyme dimethylarginine dimethylaminohydrolase-1 (DDAH1), we tested the hypothesis that overexpression of DDAH1 protects from adverse structural and functional changes in cerebral arterioles in hyperhomocysteinemia. METHODS AND RESULTS: Hyperhomocysteinemia was induced in DDAH1 transgenic (DDAH1 Tg) mice and wild-type littermates using a high methionine/low folate (HM/LF) diet. Plasma total homocysteine was elevated approximately 3-fold in both wild-type and DDAH1 Tg mice fed the HM/LF diet compared with the control diet (P<0.001). Plasma ADMA was approximately 40% lower in DDAH1 Tg mice compared with wild-type mice (P<0.001) irrespective of diet. Compared with the control diet, the HM/LF diet diminished endothelium-dependent dilation to 10 micromol/L acetylcholine in cerebral arterioles of both wild-type (12 + or - 2 versus 29 + or - 3%; P<0.001) and DDAH1 Tg (14 + or - 3 versus 28 + or - 2%; P<0.001) mice. Responses to 10 micromol/L papaverine, a direct smooth muscle dilator, were impaired with the HM/LF diet in wild-type mice (30 + or - 3 versus 45 + or - 5%; P<0.05) but not DDAH1 Tg mice (45 + or - 7 versus 48 + or - 6%). DDAH1 Tg mice also were protected from hypertrophy of cerebral arterioles (P<0.05) but not from accelerated carotid artery thrombosis induced by the HM/LF diet. CONCLUSIONS: Overexpression of DDAH1 protects from hyperhomocysteinemia-induced alterations in cerebral arteriolar structure and vascular muscle function.

Overexpression of dimethylarginine dimethylaminohydrolase inhibits asymmetric dimethylarginine-induced endothelial dysfunction in the cerebral circulation.

BACKGROUND AND PURPOSE: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). An elevation of plasma ADMA levels is associated with cardiovascular disease. ADMA is hydrolyzed by dimethylarginine dimethylaminohydrolases (DDAHs). The goal of this study was to determine whether overexpression of human DDAH-1 in transgenic (DDAH-1-Tg) mice inhibits the vascular effects of ADMA. METHODS: Using nontransgenic (non-Tg) and DDAH-1-Tg mice, we compared responses of the carotid artery and aorta (in vitro) and of the cerebral arterioles (in vivo) in the absence or presence of ADMA. DDAH-1 expression and plasma levels of ADMA were also measured. RESULTS: Western blotting indicated that vascular expression of DDAH-1 was increased markedly in DDAH-1-Tg mice. Plasma levels of ADMA were reduced by approximately 50% in DDAH-1-Tg mice compared with non-Tg mice (0.19+/-0.02 vs 0.37+/-0.04 micromol/L, P<0.05). Contraction of the aorta to nitro-l-arginine methyl ester (an inhibitor of NOS), an index of basal production of NO, was increased in DDAH-1-Tg mice compared with controls (50+/-4% vs 34+/-4%, P<0.05). Relaxation of the carotid artery to acetylcholine (an endothelium-dependent agonist) was enhanced in DDAH-1-Tg animals compared with control mice (relaxation of 74+/-6% vs 59+/-5%, respectively, in response to 10 micromol/L acetylcholine, P<0.05). ADMA (100 micromol/L) impaired the vascular response to acetylcholine in both non-Tg and DDAH-1-Tg mice, but the relative difference between the 2 strains remained. Responses to the endothelium-independent NO donor nitroprusside were similar in all groups. In vivo, ADMA (10 micromol/L) reduced responses of the cerebral arterioles to acetylcholine by approximately 70% in non-Tg mice (P<0.05), and this inhibitory effect was largely absent in DDAH-1-Tg mice. CONCLUSIONS: These findings provide the first evidence that overexpression of DDAH-1 increases basal levels of vascular NO and protects against ADMA-induced endothelial dysfunction in the cerebral circulation.

Emerging concepts in the treatment of intracranial aneurysms: stents, coated coils, and liquid embolic agents.

Endovascular techniques for the treatment of intracranial aneurysms are rapidly evolving. Modifications of more traditional coils have been introduced. Such modifications include newer coils coated with various polymers to increase both coil thrombogenicity and degree of aneurysm packing. In addition, newer coil designs aimed at improving the conformability of the coil to the aneurysm have been used with promising preliminary results. The availability of a newer generation of stents specifically designed for intracranial navigation allows for more effective treatment of aneurysms with wide necks, which usually have been considered unsuitable for optimal endovascular treatment. Endovascular alternatives to coil embolization, such as liquid embolic materials, also have been explored for the treatment of intracranial aneurysms, with varying results. We summarize the rationale for use of these newer devices and early clinical experiences. Areas of current research and future directions of endovascular aneurysm treatment also are discussed.

Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis.

BACKGROUND: This study was designed to determine whether overexpression of the enzyme dimethylarginine dimethylaminohydrolase (DDAH) could enhance angiogenesis by reducing levels of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). METHODS AND RESULTS: In DDAH1 transgenic (TG) and wild-type mice (each n=42), the role of DDAH overexpression on angiogenesis was studied by use of the disk angiogenesis system and a murine model of hindlimb ischemia (each n=21). After surgery, animals were treated with either PBS or the NOS inhibitors ADMA or N(omega)-nitro-L-arginine methyl ester (L-NAME; each 250 micromol x kg(-1) x d(-1)) by use of osmotic minipumps (each n=7). L-NAME was chosen to study an inhibitor that is not degraded by DDAH. Neovascularization in the disk angiogenesis system was impaired by both NOS inhibitors; however, TG animals were resistant to the effects of ADMA on neovascularization. Similarly, TG mice were more resistant to the inhibitory effect of ADMA on angioadaptation (angiogenesis and arteriogenesis) after hindlimb ischemia, as assessed by fluorescent microsphere studies and postmortem microangiograms. Enhanced neovascularization and limb perfusion in TG mice were associated with reduced plasma and tissue ADMA levels and enhanced tissue NOS enzyme activity. CONCLUSIONS: We describe a novel mechanism by which DDAH regulates postnatal neovascularization. Therapeutic manipulation of DDAH expression or activity may represent a novel approach to restore tissue perfusion.

Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence.

BACKGROUND: NO is a major regulator of cardiovascular physiology that reduces vascular and cardiac contractility. Accumulating evidence indicates that endogenous inhibitors may regulate NOS. The NOS inhibitors asymmetric dimethylarginine (ADMA) and N-monomethylarginine are metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). This study was designed to determine if increased expression of DDAH could reduce tissue and plasma levels of the NOS inhibitors and thereby increase NO synthesis. METHODS AND RESULTS: We used gene transfer and transgenic approaches to overexpress human DDAH I in vitro and in vivo. The overexpression of DDAH in cultured endothelial cells in vitro induced a 2-fold increase in NOS activity and NO production. In the hDDAH-1 transgenic mice, we observed approximately 2-fold increases in tissue NOS activity and urinary nitrogen oxides, associated with a 2-fold reduction in plasma ADMA. The systolic blood pressure of transgenic mice was 13 mm Hg lower than that of wild-type controls (P<0.05). The systemic vascular resistance and cardiac contractility were decreased in response to the increase in NO production. CONCLUSIONS: DDAH I overexpression increases NOS activity in vitro and in vivo. The hDDAH-1 transgenic animal exhibits a reduced systolic blood pressure, systemic vascular resistance, and cardiac stroke volume. This study provides compelling evidence that the elaboration and metabolism of endogenous ADMA plays an important role in regulation of NOS activity.

Human mesenchymal stem cells transduced with recombinant bone morphogenetic protein-9 adenovirus promote osteogenesis in rodents.

The present study was undertaken to determine whether ex vivo bone morphogenetic protein-9 (BMP-9) gene therapy using human mesenchymal stem cells (hMSCs) can induce endochondral bone formation in athymic nude rats. An in vitro study was initially performed on hMSCs to evaluate morphological changes and osteoblastic differentiation induced by replication-defective adenovirus type 5 with the cytomegalovirus promoter and either the BMP-9 (Ad-BMP-9) or beta-galactosidase (Ad-beta-gal) gene. In vivo, athymic nude rats received an injection (10(6) hMSCs transduced with recombinant adenovirus at 50 PFU/cell) into the anterior thigh musculature: Ad-BMP-9 on the left and Ad-beta-gal (control) on the right. Computed tomography scans and histological analysis were obtained 7, 14, 28, 42, 56, and 84 days postinjection. In vitro, human mesenchymal stem cells treated with Ad-BMP-9 (50 PFU/cell) showed signs of differentiation, whereas hMSCs treated with 250 and 1250 PFU/cell showed cytotoxicity. In vivo, computed tomography and histological analysis clearly demonstrated ectopic bone at hMSC/Ad-BMP-9 treatment sites, whereas the hMSC/Ad-beta-gal treatment sites showed no evidence of osteogenesis. None of the animals showed clinical evidence of toxicity. Ex vivo gene therapy with hMSC/BMP-9 may be efficacious for promoting bone formation for a variety of bone pathologies and certainly warrants further investigations.

Ex vivo bone morphogenetic protein-9 gene therapy using human mesenchymal stem cells induces spinal fusion in rodents.

OBJECTIVE: Ex vivo gene therapy with the use of human mesenchymal stem cells (hMSCs) and bone morphogenetic protein (BMP) genes provides a local supply of precursor cells and a supraphysiological dose of osteoinductive molecules that may promote bone formation in patients with inadequate hMSC populations because of age, osteoporosis, metastatic bone disease, iatrogenic depletion, or other metabolic derangements. This study was undertaken to evaluate the efficacy of ex vivo gene therapy with the use of hMSCs and the BMP-9 gene to promote spinal fusion in the rat. METHODS: Sixteen athymic nude rats were treated with hMSCs transduced with recombinant, replication-defective Type 5 adenovirus containing the cytomegalovirus promoter and either the BMP-9 (Ad-BMP-9) or the beta-galactosidase (Ad-beta-gal) gene. Ad-beta-gal served as the control. Each animal received a percutaneous, paraspinal injection of 10(6) hMSCs transduced with 50 plaque-forming units/cell adenovirus in the lumbar region, with Ad-BMP-9 on the left and Ad-beta-gal on the right. At 8 weeks postinjection, computed tomographic scans of the lumbosacral spine were obtained, and the lumbosacral spine specimens were examined histologically. RESULTS: Both computed tomographic studies and histological analysis clearly demonstrated large volumes of ectopic bone at the Ad-BMP-9-transduced hMSC injection sites, resulting in successful spinal fusion and no evidence of nerve root compression or local or systemic toxicity. The contralateral regions that were treated with Ad-beta-gal-transduced hMSCs showed no evidence of osteogenesis. CONCLUSION: The results of this study suggest that hMSC and BMP-9 ex vivo gene therapy may be useful in inducing spinal fusion as well as other related procedures and certainly warrants further clinical development.

Ectopic osteogenesis using adenoviral bone morphogenetic protein (BMP)-4 and BMP-6 gene transfer.

Bone morphogenetic proteins (BMPs) delivered on scaffolds can induce ectopic bone formation after subcutaneous injection. Adenoviral vectors (Ad) carrying BMP2, BMP7, and BMP9 cDNAs have been shown to produce bone through endochondral ossification. The present study was performed to elucidate the histological events leading to ectopic ossification for two novel first-generation adenoviral constructs encoding BMPs, AdBMP4 and AdBMP6. In vitro, the viral constructs produced and secreted the mature BMP4 and BMP6 proteins. In vivo, the calf muscles of athymic nude rats were injected with AdBMP4, AdBMP6, AdBMP2, or AdlacZ. Rats were sacrificed 3, 6, 9, 16, 21, 60, and 90 days postinjection. Whereas AdBMP4 produced ectopic bone through mechanisms similar to endochondral ossification, AdBMP6 seemed to induce bone by way of mechanisms similar to both intramembranous and endochondral ossification pathways. At the relatively low vector dose used in this study, AdBMP2 caused an initial recruitment of primitive mesenchymal cells, without further development to bone. From computed tomographic analysis, AdBMP6 produced the most rapid tissue calcification. The ultimate density of ectopic bone formed by AdBMP4 and AdBMP6 was comparable. The current study demonstrates that AdBMP4 and AdBMP6 are more potent than the prototypical osteogenic adenoviral vector AdBMP2 and seem to induce ectopic bone by different mechanisms.

Nicotine accelerates angiogenesis and wound healing in genetically diabetic mice.

Recently, we have discovered an endogenous cholinergic pathway for angiogenesis mediated by endothelial nicotinic acetylcholine receptors (nAChRs). Since angiogenesis plays a major role in wound repair, we hypothesized that activation of nAChRs with nicotine would accelerate wound healing in a murine excisional wound model. In genetically diabetic and control mice full-thickness skin wounds (0.8 cm) were created on the dorsum and topically treated over 7 days with either vehicle (phosphate-buffered saline, PBS) or nicotine (10(-8) mol/L, 10(-9) mol/L; each, n = 5). Wound size was measured over 14 days followed by resection, histological analysis, and quantitation of vascularity. In diabetic animals an agonist (epibatidine, 10(-10) mol/L) or antagonist (hexamethonium, 10(-4) mol/L) of nAChRs as well as the positive control basic fibroblast growth factor (bFGF, 25 microg/kg) were also tested. To further study the role of endothelial nAChRs in angiogenesis, we used an ex vivo vascular explant model. In diabetic mice wound healing was markedly impaired. Nicotine significantly accelerated wound healing as assessed by closure rate and histological score. The effects of nicotine were equal to bFGF and were mimicked by epibatidine and blocked by hexamethonium. Histomorphometry revealed increased neovascularization in animals treated with nicotine. Furthermore, capillary-like sprouting from vascular explants was significantly enhanced by nicotine. In conclusion, agonist-induced stimulation of nAChRs accelerates wound healing in diabetic mice by promoting angiogenesis. We have discovered a cholinergic pathway for angiogenesis that is involved in wound healing, and which is a potential target for therapeutic angiogenesis.