Stereotactic radiosurgery using the Leksell Gamma Knife: current trends and future directives.

Stereotactic radiosurgery is the extremely precise administration of a radiation dosage in three-dimensional space to treat an increasingly broad spectrum of intracranial and skull-base lesions. 455 patients with various indications were treated using the 201 Source Co-60 Leksell Model "B" Gamma Knife(r) at Louisiana State University Health Sciences Center in Shreveport, Louisiana. 273 (60.2%) patients received radiosurgery as the first line of treatment for their disease. The mean Karnofsky Performance Score (KPS) of the patients was 70. Cerebral metastases were the main indications for radiosurgery at our center accounting for 27% of the patients, while meningioma, AVM, trigeminal neuralgia, movement disorders, and primary CNS malignant tumors were the other indications. Our institutional experience and results indicate that low incidence of complications coupled with a high tumor control rate makes Gamma Knife stereotactic radiosurgery a viable option for patients who must undergo neurosurgery. As the Gamma Knife continues to prove itself as a first-line treatment of many complex brain disorders, new indications for this technology will continue to emerge, further broadening the scope of patient care.

Gamma knife irradiation increases cerebral endothelial expression of intercellular adhesion molecule 1 and E-selectin.

OBJECTIVE: Alterations in multiple functions of the microvasculature occur in response to gamma irradiation and are thought to contribute to radiation-induced end organ damage by inducing inflammatory responses, particularly leukocyte infiltration into the affected area. Endothelial cell adhesion molecules (ECAMs) mediate leukocyte adhesion and migration. Here, we validate a method to study the effect of Leksell gamma knife stereotactic radiosurgery on the expression of ECAMs on human cerebral endothelium at 0, 24, 48, and 72 hours after irradiation. METHODS: A human brain endothelial cell line (IHEC) was cultured on 12-mm coverslips and subjected to 50 Gy of collimated gamma irradiation with the Leksell gamma knife (Elekta Instruments, Inc., Atlanta, GA). Lactate dehydrogenase release was measured at 24, 48, and 72 hours after irradiation and caspase-3 at 24, 48, 72, 96, and 120 hours. ECAM expression was measured at postirradiation intervals of 0, 24, 48, and 72 hours by cell enzyme-linked immunoabsorbent assay. We used a cell irradiator composed of two chambers. The upper chamber holds the coverslips firmly in place while they are immersed in media. The lower chamber is connected to a peristaltic pump, which pumps water into the chamber and maintains the media in the upper chamber at 37 degrees C through convection. RESULTS: None of the ECAMs tested was significantly elevated compared with the control basally. Twenty-four hours after irradiation, intercellular adhesion molecule 1 was significantly elevated on brain endothelial cells but there was no significant elevation of E-selectin. Vascular cell adhesion molecule 1 was increased slightly but not significantly and decreased at 48 hours. At 72 hours, E-selectin expression was significantly increased; intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were not altered relative to sham controls. CONCLUSION: Increased ECAM expression and lactate dehydrogenase release support the idea that the cerebral microvasculature undergoes an inflammatory response after Leksell gamma knife stereotactic radiosurgery.

Ischemic preconditioning prevents postischemic arteriolar, capillary, and postcapillary venular dysfunction: signaling pathways mediating the adaptive metamorphosis to a protected phenotype in preconditioned endothelium.

Prolonged ischemia followed by reperfusion (I/R) results in impaired endothelial cell function in all segments of the microvasculature. Moreover, endothelial dysfunction plays a major role in the genesis of the reperfusion component of total tissue injury in I/R. Thus, preservation of endothelial function is an important therapeutic goal for ameliorating injury in tissues subjected to I/R. An accumulating body of evidence indicates that both microvascular endothelium and parenchymal cells can be rendered resistant to the pathological effects of I/R by antecedent exposure to brief periods of ischemia, a phenomenon referred to as ischemic preconditioning (IPC). Although the mechanisms underlying the microvascular effects of preconditioning have been far less extensively studied, work conducted to date indicates that there are fundamental differences in the signaling pathways that underlie the adaptive transformation to a protected or defensive phenotype in the endothelium compared to those that contribute to the development of a preconditioned state in parenchymal cells. Thus, the purposes of this review are to summarize our current understanding of the mechanisms whereby IPC induces the adaptive transformation to a protected or defensive phenotype in parenchymal cells and to compare and contrast this with the signaling pathways that invoke a preconditioned state in arteriolar, capillary, and venular endothelium. In addition, we highlight understudied areas with regard to microvascular protection afforded by antecedent ischemia in the hopes that this will stimulate investigation of the underlying mechanisms. Understanding these signaling pathways may provide a mechanistic rationale for the development of novel treatment interventions that target both the microcirculatory and parenchymal sequelae to I/R, thereby maximizing the therapeutic potential of the protected phenotypes produced by pharmacological preconditioning.

The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin reduces disease activity and inflammation in dextran-sulfate induced colitis.

The dextran sulfate (DSS) model of colitis causes intestinal injury sharing many characteristics with inflammatory bowel disease, e.g., leukocyte infiltration, loss of gut epithelial barrier, and cachexia. These symptoms are partly mediated by entrapped leukocytes binding to multiple endothelial adhesion molecules (MAdCAM-1, VCAM-1, ICAM-1, and E-selectin). Pravastatin, an 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, has anti-inflammatory potency in certain inflammation models; therefore, in this study, we measured the effects of pravastatin in DSS-induced colitis. The administration of pravastatin (1 mg/kg) relieved DSS-induced cachexia, hematochezia, and intestinal epithelial permeability, with no effect on serum cholesterol. Histopathologically, pravastatin prevented leukocyte infiltration and gut injury. Pravastatin also blocked the mucosal expression of MAdCAM-1. DSS treatment promoted mucosal endothelial nitric-oxide synthase (eNOS) mRNA degradation, an effect that was blocked by pravastatin. Importantly, the protective effects of pravastatin in DSS-induced colitis were not found in eNOS-deficient mice. Our results demonstrate that HMG-CoA reductase inhibitors preserve intestinal integrity in colitis, most likely via increased eNOS expression and activity, independent of cholesterol metabolism.