Patient deprivation and perceived scan burden negatively impact the quality of whole-body MRI.

AIM: To evaluate the association between the image quality of cancer staging whole-body magnetic resonance imaging (WB-MRI) and patient demographics, distress, and perceived scan burden. MATERIALS AND METHODS: A sample of patients recruited prospectively to multicentre trials comparing WB-MRI with standard scans for staging lung and colorectal cancer were invited to complete two questionnaires. The baseline questionnaire, administered at recruitment, collated data on demographics, distress and co-morbidity. The follow-up questionnaire, completed after staging investigations, measured perceived WB-MRI scan burden (scored 1 low to 7 high). WB-MRI anatomical coverage, and technical quality was graded by a radiographic technician and grading combined to categorise the scan as "optimal", "sub-optimal" or "degraded". A radiologist categorised 30 scans to test interobserver agreement. Data were analysed using the chi-square, Fisher's exact, t-tests, and multinomial regression. RESULTS: One hundred and fourteen patients were included in the study (53 lung, 61 colorectal; average age 65.3 years, SD=11.8; 66 men [57.9%]). Overall, 45.6% (n=52), scans were classified as "optimal" quality, 39.5% (n=45) "sub-optimal", and 14.9% (n=17) as "degraded". In adjusted analyses, greater deprivation level and higher patient-reported scan burden were both associated with a higher likelihood of having a sub-optimal versus an optimal scan (odds ratio [OR]: 4.465, 95% confidence interval [CI]: 1.454 to 13.709, p=0.009; OR: 1.987, CI: 1.153 to 3.425, p=0.013, respectively). None of the variables predicted the likelihood of having a degraded scan. CONCLUSIONS: Deprivation and patients' perceived experience of the WB-MRI are related to image quality. Tailored protocols and individualised patient management before and during WB-MRI may improve image quality.

Quantitative Analysis of Conebeam CT for Delineating Stents in Stent-Assisted Coil Embolization.

BACKGROUND AND PURPOSE: Innovative techniques and device-related advances have improved the outcomes of neuroendovascular treatment. 3D imaging has previously used 2 × 2 binning, but 1 × 1 binning has recently been made available. The aim of this study was to evaluate the quantitative ability of conebeam CT for stent delineation and to investigate its effectiveness in the clinical environment. MATERIALS AND METHODS: Four acquisition groups of 3D MIP images acquired using conebeam CT with varying conditions (acquisition time, 10 or 20 seconds and binning, 1 × 1 or 2 × 2) were compared. Two methods of analysis were performed, a phantom study and an analysis of 28 randomly selected patients. The phantom study assessed the contrast-to-noise ratio and full width at half maximum values in conebeam CT images of intracranial stent struts. In the clinical subjects, we assessed contrast-to-noise ratio, full width at half maximum, and dose-area product. RESULTS: In the phantom study, the contrast-to-noise ratio was not considerably different between 10- and 20-second acquisition times at equivalent binning settings. Additionally, the contrast-to-noise ratio at equivalent acquisition times did not differ considerably by binning setting. For the full width at half maximum results, equivalent acquisition times differed significantly by binning setting. In the clinical analyses, the 10-second/1 × 1 group (versus 20 second/2 × 2) showed a higher contrast-to-noise ratio (P < .05) and a dose-area product reduced by approximately 70% (P < .05), but the difference in full width at half maximum was not significant (P = .20). CONCLUSIONS: For stent-assisted coil embolization, quantitative assessment of conebeam CT showed that 10 second/1 × 1 was equivalent to 20 second/2 × 2 for imaging deployed intracranial stents. Furthermore, the 10-second/1 × 1 settings resulted in a much smaller DAP.

Patient-controlled bolus femoral nerve block after knee arthroplasty: quadriceps recovery, analgesia, local anesthetic consumption.

BACKGROUND: Continuous femoral nerve block (cFNB) induces quadriceps muscle weakness, but patient-controlled femoral nerve block (PCFNB) can provide analgesia with lower consumption of local anesthetics compared to cFNB. We hypothesized that cFNB followed by PCFNB leads to accelerated recovery of quadriceps weakness after total knee arthroplasty compared to cFNB alone. Secondary outcomes were local anesthetic consumption, pain, and mobilization. METHODS: Fifty-six subjects received post-operative cFNB for 24 h and then randomized to receive either cFNB (basal infusion of 6 ml/h using a dummy bolus button; n = 27) or PCFNB (bolus infusion of 3 ml with a lockout time of 30 min and no basal infusion; n = 29) using 0.08% levobupivacaine for the subsequent 24 h in a double-blind manner (registration: UMIN000010105). Quadriceps strength was assessed using a hand-held dynamometer. The percentage change from baseline was compared between groups. RESULTS: Quadriceps strength at 48 h was 47.3 ± 18.3% in the cFNB group and 49.7 ± 15.7% in the PCFNB group (95% confidence interval -7.0-11.9%, P = 0.61). Local anesthetic consumption during the post-operative period was significantly lower in the PCFNB group compared to the cFNB group (102 ± 10.8 ml vs.146 ± 4.6 ml; P < 0.001). No significant differences were found in any of the other outcomes, including pain scores at rest and during knee rehabilitation. CONCLUSION: Continuous femoral nerve block followed by PCFNB does not improve quadriceps strength recovery time compared to cFNB alone after total knee arthroplasty, but similar analgesic effects were demonstrated with reduced levobupivacaine consumption.

Shear Stiffness of 4 Common Intracranial Tumors Measured Using MR Elastography: Comparison with Intraoperative Consistency Grading.

BACKGROUND AND PURPOSE: The stiffness of intracranial tumors affects the outcome of tumor removal. We evaluated the stiffness of 4 common intracranial tumors by using MR elastography and tested whether MR elastography had the potential to discriminate firm tumors preoperatively. MATERIALS AND METHODS: Thirty-four patients with meningiomas, pituitary adenomas, vestibular schwannomas, and gliomas scheduled for resection were recruited for MR elastography. On the elastogram, the mean and the maximum shear stiffnesses were measured by placing an ROI on the tumor. Blinded to the MR elastography findings, surgeons conducted qualitative intraoperative assessment of tumor consistency by using a 5-point scale. Histopathologic diagnosis was confirmed by using the resected specimens. The mean and maximum shear stiffnesses were compared with histopathologic subtypes, and the intraoperative tumor consistency was graded by the surgeons. RESULTS: The mean and maximum shear stiffnesses were the following: 1.9 ± 0.8 kPa and 3.4 ± 1.5 kPa for meningiomas, 1.2 ± 0.3 kPa and 1.8 ± 0.5 kPa for pituitary adenomas, 2.0 ± 0.4 kPa and 2.7 ± 0.8 kPa for vestibular schwannomas, and 1.5 ± 0.2 kPa and 2.7 ± 0.8 kPa for gliomas. The mean and maximum shear stiffnesses for meningiomas were higher than those of pituitary adenomas (P < .05). The mean and maximum shear stiffnesses were significantly correlated with the surgeon's qualitative assessment of tumor consistency (P < .05). The maximum shear stiffness for 5 firm tumors was higher than that of nonfirm tumors (P < .05). CONCLUSIONS: MR elastography could evaluate intracranial tumors on the basis of their physical property of shear stiffness. MR elastography may be useful in discriminating firm tumors preoperatively.

Endovascular Treatment of Unruptured Paraclinoid Aneurysms: Single-Center Experience with 400 Cases and Literature Review.

BACKGROUND AND PURPOSE: Paraclinoid aneurysms have been increasingly treated endovascularly. The natural history of these aneurysms has gradually been elucidated. The purpose of this study was to assess the safety and efficacy of endovascular treatment for these aneurysms. MATERIALS AND METHODS: We performed a retrospective review of 377 patients with 400 paraclinoid aneurysms treated between January 2006 and December 2012. Their clinical records, endovascular reports, and radiologic and clinical outcomes were analyzed. Because aneurysms ≥7 mm are at higher risk of rupture, we classified aneurysms as small (<7 mm) or large (≥7 mm). RESULTS: Overall, 115 of the 400 aneurysms (28.8%) were large (≥7 mm). Thromboembolic complications were found significantly more often with large aneurysms than with small ones (7.4% vs 1.0%, P = .001). Hemorrhagic complications were found only with small aneurysms (0.7%). The 6-month morbidity rates were similar for small (1.0%) and large (0.8%) aneurysms. Immediate angiographic outcomes were similar (P = .37), whereas recurrences and retreatment occurred more frequently with large aneurysms (P = .001 and P = .007, respectively). Multivariate analysis showed that aneurysm size was the only independent predictor for recurrence (P = .005). Most recurrences (81%) were detected by scheduled angiography at 6 months. CONCLUSIONS: Aneurysm size influenced the type of complication (thromboembolic or hemorrhagic) and the recurrence rate. Given the approximately 1% annual rupture rate for aneurysms ≥7 mm, analysis of our data supports the rationale of using prophylactic endovascular treatment for unruptured paraclinoid aneurysms ≥7 mm.

Low-dose CT screening using hybrid iterative reconstruction: confidence ratings of diagnoses of simulated lesions other than lung cancer.

OBJECTIVE: To evaluate the confidence ratings of diagnoses of simulated lesions other than lung cancer on low-dose screening CT with hybrid iterative reconstruction (IR). METHODS: Simulated lesions (emphysema, mediastinal masses and interstitial pneumonia) in a chest phantom were scanned by a 320-row area detector CT. The scans were performed by 64-row and 160-row helical scans at various dose levels and were reconstructed by filtered back projection (FBP) and IR. Emphysema, honeycombing and reticular opacity were visually scored on a four-point scale by six thoracic radiologists. The ground-glass opacity as a percentage of total lung volume (%GGO), CT value and contrast-to-noise ratio (CNR) of mediastinal masses were calculated. These scores and values were compared between FBP and IR. Wilcoxon's signed-rank test was used (p < 0.05). Interobserver agreements were evaluated by κ statistics. RESULTS: There were no significant differences in visual assessment. Interobserver agreement was almost perfect. CT values were almost equivalent between FBP and IR, whereas CNR with IR was significantly higher than that with FBP. %GGO significantly increased at low-dose levels with FBP; however, IR suppressed the elevation. CONCLUSION: The confidence ratings of diagnoses of simulated lesions other than lung cancer on low-dose CT screening were not degraded with hybrid IR compared with FBP. ADVANCES IN KNOWLEDGE: Hybrid IR did not degrade the confidence ratings of diagnoses on visual assessment and differential diagnoses based on CT value of mediastinal masses, and it showed the advantage of higher GGO conspicuity at low-dose level. Radiologists can analyse images of hybrid IR alone on low-dose CT screening for lung cancer.

The Piccolo Intronic Single Nucleotide Polymorphism rs13438494 Regulates Dopamine and Serotonin Uptake and Shows Associations with Dependence-Like Behavior in Genomic Association Study.

Piccolo (PCLO) inhibits methamphetamine-induced neuropharmacological effects via modulation of dopamine (DA) uptake and regulation of the transport of synaptic vesicles in neuronal cells. Clinical studies have recently suggested that the single nucleotide polymorphism (SNP) rs13438494 in the intron 24 of the PCLO gene is associated with psychiatric disorder, in the meta-analysis of GWAS. Therefore, in this study, we attempted to evaluate the possible role of the PCLO SNP in the mechanisms of uptake of monoamines. To characterize rs13438494 in the PCLO gene, we constructed plasmids carrying either the C or A allele of the SNP and transiently transfected them into SH-SY5Y cells to analyze genetic effects on the splicing of PCLO mRNA. The C and A allele constructs produced different composition of the transcripts, indicating that the intronic SNP does affect the splicing pattern. We also transfected DA and serotonin (5-hydroxytryptamine; 5- HT) transporters into cells and analyzed their uptakes to elucidate the association to psychiatric disorders. In the cells transfected with the C allele, both the DA and 5-HT uptake were enhanced compared to the A allele. We also conducted a clinical study, in order to clarify the genetic associations. PCLO rs13438494 exhibits a relationship with the symptoms of drug dependence or related parameters, such as the age of first exposure to methamphetamine, eating disorders, tobacco dependence and fentanyl requirement. Our findings suggest that rs13438494 is associated with drug abuse and contributes to the pathogenesis of psychiatric disorders via modulation of neurotransmitter turnover.

Arterial spin-labeled perfusion imaging reflects vascular density in nonfunctioning pituitary macroadenomas.

BACKGROUND AND PURPOSE: Angiogenesis is very important in clinical features of pituitary adenomas. We investigated the relationship between the blood flow of nonfunctioning pituitary macroadenomas measured by arterial spin-labeled perfusion imaging and the microvessel attenuation of the tissue. MATERIALS AND METHODS: Conventional MR imaging with contrast-enhanced T1WI and arterial spin-labeled perfusion imaging were performed before surgery in 11 consecutive patients with nonfunctioning pituitary macroadenomas. ROIs were drawn on the tumors, and the degrees of enhancement were calculated by dividing the signal intensity on the contrast-enhanced T1WI by that on the nonenhanced TIWI. As an index of tumor perfusion, a quantitative analysis was performed by using normalized tumor blood flow values calculated by dividing the mean value of the tumor region of interest by the mean region of interest values in the 2 cerebellar hemispheres. The relative microvessel attenuation was determined as the total microvessel wall area divided by the entire tissue area on CD-31-stained specimens. The degree of enhancement and the normalized tumor blood flow values were compared with relative microvessel attenuation. Additionally, intra- and postoperative tumor hemorrhages were visually graded. RESULTS: The degree of enhancement was not correlated with relative microvessel attenuation. Statistically significant correlations were observed between normalized tumor blood flow values and relative microvessel attenuation (P < .05). At surgery, 3 cases were visually determined to be hypervascular tumors, and 1 of these cases had symptomatic postoperative hemorrhage. A statistically significant difference in normalized tumor blood flow values was observed visually between the intraoperative hypovascular and hypervascular groups (P < .05). CONCLUSIONS: Arterial spin-labeled perfusion imaging reflects the vascular density of nonfunctioning pituitary macroadenomas, which may be useful in the preoperative prediction of intra- and postoperative tumor hemorrhage.

CXCR1 deficiency does not alter liver regeneration after partial hepatectomy in mice.

Previous studies have shown that CXC chemokines containing Glu-Leu-Arg (ELR) in their amino-terminus stimulate hepatocyte proliferation and liver regeneration after partial hepatectomy. These ELR+CXC chemokines bind to two receptors, CXCR1 and CXCR2. Previous work has shown that CXCR2 is involved in the proliferative effects of CXC chemokines. However, the function of CXCR1 during the regenerative response has not been studied. The aim of the current study was to investigate the role of CXCR1 in liver regeneration after partial hepatectomy. C57BL/6 (wild type) or CXCR1-/- mice were subjected to 70% partial hepatectomy or sham surgery and sacrificed on day 2 and 4 after operation. There were no significant differences in liver-to-body weight ratio or hepatocyte proliferation. The data suggest that CXCR1 does not mediate the proliferative effects of ELR+ CXC chemokines during liver regeneration after partial hepatectomy.

A notable case report of May-Hegglin anomaly with immune complex-related nephropathy: a genetic and histological analysis.

May-Hegglin anomaly (MHA) is a rare autosomal dominant disease characterized by macrothrombocytopenia and leukocyte inclusions with microfilaments in the ribosomes. Mutations in the MYH9 gene, encoding non-muscle myosin heavy chain IIA (NMMHC-IIA) have been identified in patients with MHA and other MYH9-related diseases. Two young males (an older and younger brother) presented with macrothrombocytopenia and leukocyte inclusion bodies. Electron microscopy (EM) revealed parallel filaments in leukocyte inclusion bodies characteristic of MHA. Immunofluorescence microscopy (IF) showed NMMHC-IIA antibodies in 1 - 2 leukocyte inclusion bodies. These findings were consistent with MHA and they were identified to express the MYH9 mutation, D1424H. The older brother underwent a renal biopsy because of persistent proteinuria. Histology revealed mesangial proliferative glomerulonephritis with granular deposits of IgG and C1q. EM showed that the dense deposits were located in subendothelial cells, mesangial cells and Bowman's capsule. Immunocytochemistry revealed that NMMHC-IIA antibodies were localized in podocyte and endothelial cells in the glomerulus. Moreover, the expression of nephrin and podocin, slit diagram protein, was normal. An inflammatory mechanism may occur separately from MYH9-related disease. This report presents a case of MHA with immune complex-related nephropathy.

Measurement of a number of indices of hand and movement angles in pianists with overuse disorders.

Abduction angles of the thumb and little finger, hand span, length of thumb, middle finger and little finger were measured using radiographs of the right hand with the thumb and the little finger abducted, in a comparative study of 220 pianists with overuse disorder and 62 unaffected pianists. Overuse disorders included tenosynovitis, lateral and medial epicondylitis, forearm flexor muscle pain, distal tendinitis of the wrist extensors and flexors and intrinsic muscle pain. Hand span or other hand size parameters showed significant differences, while abduction angles showed no difference. The patients' group had smaller hand size than the controls when analyzed for tenosynovitis, epicondylitis and muscle pain. From these results we hypothesize that pianists with small hands tend to hyper-abduct and hyper-extend the thumb to attain greater hand span. Their little finger is also stiffer and the hypothenar muscle and the wrist flexors need greater strength to resist the reaction force in each piano key.

Metabotropic glutamate receptor subtype-1 is essential for in vivo growth of melanoma.

Ectopic expression of metabotropic glutamate receptor subtype 1 (mGluR1) in mouse melanocytes induces melanoma formation. Although requirement of mGluR1 for development of melanoma in the initial stage has been demonstrated, its role in melanoma growth in vivo remains unclear. In this study, we developed novel transgenic mice that conditionally express mGluR1 in melanocytes, using a tetracycline regulatory system. Pigmented lesions on the ears and tails of the transgenic mice began to appear 29 weeks after activation of the mGluR1 transgene, and the transgenic mice produced melanomas at a frequency of 100% 52 weeks after transgene activation. Subsequent inactivation of the mGluR1 transgene in melanoma-bearing mice inhibited melanoma growth with reduction of immunoreactivity to phosphorylated ERK1/2, whereas mice with persistent expression of mGluR1 developed larger melanoma burdens. mGluR1 expression is thus required not only for melanoma development but also for melanoma growth in vivo. These findings suggest that growth of melanoma can be inhibited in vivo by eliminating only one of the multiple genetic anomalies involved in tumorigenesis.

Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that maintains the glomerular and peritubular capillary (PTC) network in the kidney. The soluble form of the VEGF receptor-1 (soluble fms-like tyrosine kinase 1 (sFlt-1)) is known to regulate VEGF activity by binding VEGF in the circulation. We hypothesized that VEGF may be beneficial for maintaining glomerular filtration barrier and vascular network in rats with progressive glomerulonephritis (GN). For blockade of VEGF activity in vivo, rats were transfected twice with plasmid DNA encoding the murine sFlt-1 gene into femoral muscle 3 days before and 2 weeks after the induction of antiglomerular basement membrane antibody-induced GN. Inhibition of VEGF with sFlt-1 resulted in massive urinary protein excretion, concomitantly with downregulated expression of nephrin in nephritic rats. Further, blockade of VEGF induced mild proteinuria in normal rats. Administration of sFlt-1 affected neither the infiltration of macrophages nor crescentic formation. In contrast, treatment of sFlt-1 accelerated the progression of glomerulosclerosis and interstitial fibrosis accompanied with renal dysfunction and PTC loss at day 56. VEGF may play a role in maintaining the podocyte function as well as renal vasculature, thereby protecting glomeruli and interstitium from progressive renal insults.

Fructooligosaccharide consumption improves the decreased dentin formation and mandibular defects following gastrectomy in rats.

OBJECTIVE: We examined the effects of fructooligosaccharides (FOS) consumption on gastrectomy-evoked osteopenia and disorders of dentin formation in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats (n = 28, 35-day old) were equally divided into two groups; sham-operated and gastrectomized, and sham-operation or total gastrectomy was performed. Four weeks after each surgery, the rats were divided into two sub-groups (n = 7 each); with or without 7.5% FOS-feeding for 6 weeks. Backscattered electron images of the mandibular sections were taken to calculate trabecular bone area, cortical bone area and total scan area. Thereafter, the dentin formation rate in maxilla were calculated using a fluorescent microscope. RESULTS: Trabecular bone area and cortical bone area in GX rats were markedly decreased. FOS-feeding significantly counteracted this reduction, but not to the level seen in sham-operated rats. Total scan area in gastrectomized groups was significantly decreased. The dentin formation rate was not statistically different among the groups, except the gastrectomized group. CONCLUSION: These results suggest that FOS consumption partially restored osteopenia and almost completely restored the reduction in dentin formation following gastrectomy in rats.

Enzyme replacement therapy in Japanese Fabry disease patients: the results of a phase 2 bridging study.

Fabry Disease (alpha-galactosidase A deficiency) is an X-linked hereditary disorder leading to the pathological accumulation of globotriaosylceramide (GL-3) in lysosomes, particularly in the vascular endothelium of the kidney, heart and brain. We report the results of an open-label phase 2 study that was undertaken to evaluate whether ethnic differences exist that would affect agalsidase beta (Fabrazyme) treatment of Fabry patients in the Japanese population, relative to safety and efficacy. The study design mirrored the design of the completed phase 3 clinical trial that led to approval of the product agalsidase beta. The 13 Japanese, male Fabry patients enrolled in the study received the enzyme replacement therapy over a period of 20 weeks as biweekly infusions. All selected efficacy end points showed improvements that were comparable with findings from the phase 3 study. These improvements included reductions of GL-3 accumulation in both kidney and skin capillary endothelial cells to (near) normal levels (92% of patients). Kidney and plasma GL-3 levels decreased by 51.9% and 100%, respectively, by ELISA. Renal function remained normal. Fabry-associated pain, and quality of life, showed improvement over baseline in multiple categories. Related adverse events were mild or moderate in intensity and mostly infusion-associated (fever and rigors). As expected, IgG antibody formation was observed in 85% of the patients, but had no effect on treatment response. These results suggest that treatment with agalsidase beta is safe and effective in Japanese patients with Fabry disease. With regard to safety and efficacy, no differences were observed as compared to the caucasian population.

Discrepancy between lesion distributions on methionine PET and MR images in patients with glioblastoma multiforme: insight from a PET and MR fusion image study.

OBJECTIVE: To examine (11)C-methyl methionine (MET) accumulation on positron emission tomographic (PET) imaging of glioblastoma multiforme to determine the distribution of metabolic abnormality compared with magnetic resonance imaging (MRI). METHODS: Contemporaneous MRI was superimposed on corresponding MET-PET images in 10 patients with newly diagnosed glioblastoma multiforme before treatment. Differences between the extended area of MET accumulation on PET imaging (MET area), the gadolinium (Gd) enhanced area on T1 weighted images (Gd area), and the abnormal high signal intensity area on T2 weighted images (T2-high area) were assessed. RESULTS: The MET area was larger than the Gd area and included the entire Gd area. The discrepancy in volume between the MET and Gd areas became greater with increasing tumour diameter. On average, 58.6% of the MET area was located within the Gd area, 90.1% within 10 mm outside the Gd area, 98.1% within 20 mm, and 99.8% within 30 mm. A newly developed Gd area had emerged in five of the 10 cases up to the time of study. In three of the five cases this was in the MET area even after complete surgical resection of the Gd area on the initial MRI; in the remaining two it originated in the residual Gd area after surgery. In all cases, the T2-high area was larger than the MET area. The MET area extended partly beyond the T2-high area in nine cases, and was completely within it in one. CONCLUSIONS: Glioblastoma multiforme cells may extend over the Gd area and more widely with increasing tumour size on Gd-MRI. The T2-high area includes the greater part of the tumour but not its entire area. The methods reported may be useful in planning surgical resection, biopsy, or radiosurgery.

Considerations in the surgical treatment of superior-wall type aneurysm at the proximal (M1) segment of the middle cerebral artery.

OBJECTIVE: To present our experience and analyze the risks of neck clipping for superior-wall type aneurysms of the proximal segment of the middle cerebral artery (M1-Sup aneurysm). METHODS: Of 14 patients with M1-Sup aneurysms, 4 suffered postoperative infarctions in the territory of the lenticulostriate arteries (LSA) or fronto-orbital arteries. We re-examined our intraoperative findings and clinical records in an effort to identify possible causes. RESULTS: The patency of the LSA was confirmed at the end of surgery in all 14 cases. We posit that temporary occlusion of the LSA by a permanent clip resulted in delayed obstruction of the LSA in 3 patients. Other possibilities we considered were relatively long temporary occlusion of the M1, slipping of the clips and twisting of the clip blades after release of the brain retractors. CONCLUSION: M1-Sup aneurysms are some of the most complicated aneurysms; they carry the risk of perforator injury during neck clipping. Surgical considerations to avoid perforator injury are discussed.

Molecular mechanisms of TNF-alpha-induced ceramide formation in human glioma cells: P53-mediated oxidant stress-dependent and -independent pathways.

The present study was designed to examine the roles of p53, reactive oxygen species (ROS), and ceramide, and to determine their mutual relationships during tumor necrosis factor (TNF)-alpha-induced apoptosis of human glioma cells. In cells possessing wild-type p53, TNF-alpha stimulated ceramide formation via the activation of both neutral and acid sphingomyelinases (SMases), accompanied by superoxide anion (O2-*) production, and induced mitochondrial depolarization and cytochrome c release, whereas p53-deficient cells were partially resistant to TNF-alpha and lacked O2-* generation and neutral SMase activation. Restoration of functional p53 sensitized glioma cells expressing mutant p53 to TNF-alpha by accumulation of O2-*. z-IETD-fmk (benzyloxycarbonyl-Ile-Glu-Thr-Asp fluoromethyl ketone), but not z-DEVD-fmk (benzyloxycarbonyl-Asp-Glu-Val-Asp fluoromethyl ketone), blocked TNF-alpha-induced ceramide formation through both SMases as well as O2-* generation. Caspase-8 was processed by TNF-alpha regardless of p53 status of cells or the presence of antioxidants. Two separate signaling cascades, p53-mediated ROS-dependent and -independent pathways, both of which are initiated by caspase-8 activation, thus contribute to ceramide formation in TNF-alpha-induced apoptosis of human glioma cells.

p53-Independent ceramide formation in human glioma cells during gamma-radiation-induced apoptosis.

Although the p53 tumor-suppressor gene product plays a critical role in apoptotic cell death induced by DNA-damaging chemotherapeutic agents, human glioma cells with functional p53 were more resistant to gamma-radiation than those with mutant p53. U-87 MG cells with wild-type p53 were resistant to gamma-radiation. U87-W E6 cells that lost functional p53, by the expression of type 16 human papillomavirus E6 oncoprotein, became susceptible to radiation-induced apoptosis. The formation of ceramide by acid sphingomyelinase (A-SMase), but not by neutral sphingomyelinase, was associated with p53-independent apoptosis. SR33557 (2-isopropyl-1-(4-[3-N-methyl-N-(3,4-dimethoxybphenethyl)amino]propyloxy)benzene-sulfonyl) indolizine, an inhibitor of A-SMase, suppressed radiation-induced apoptotic cell death. In contrast, radiation-induced A-SMase activation was blocked in glioma cells with endogenous functional p53. The expression of acid ceramidase was induced by gamma-radiation, and was more evident in cells with functional p53. N-oleoylethanolamine, which is known to inhibit ceramidase activity, unexpectedly downregulated acid ceramidase and accelerated radiation-induced apoptosis in U87-W E6 cells. Moreover, cells with functional p53 could be sensitized to gamma-radiation by N-oleoylethanolamine, which suppressed radiation-induced acid ceramidase expression and then enhanced ceramide formation. Sensitization to gamma-radiation was also observed in U87-MG cells depleted of functional p53 by retroviral expression of small interfering RNA. These results indicate that ceramide may function as a mediator of p53-independent apoptosis in human glioma cells in response to gamma-radiation, and suggest that p53-dependent expression of acid ceramidase and blockage of A-SMase activation play pivotal roles in protection from gamma-radiation of cells with endogenous functional p53.