Glial cell line-derived neurotrophic factor family receptors are abnormally expressed in aganglionic bowel of a subpopulation of patients with Hirschsprung's disease

Hirschsprung's disease (HSCR), a congenital disease, is characterized by the absence of ganglion cells in the ganglion plexuses of the caudal most gut. In the aganglionic colon, the plexus remnants are replaced by aggregates of glial cells and hypertrophied nerve fibers. Signaling of glial cell line-derived neurotrophic factor (GDNF)-GFRAs-receptor tyrosine kinase (RET) is crucial for the development and maintenance of ganglion cells. Mutations of genes such as GDNF and RET lead to the perturbation of this signaling pathway, which causes HSCR. To understand the role of GFRAs in ganglion cells and the pathogenesis of HSCR, we intended to determine the specific cell lineages in the enteric nervous system that normally express GFRAs but are affected in HSCR. We studied colon biopsy specimens from 13 patients with HSCR (aged 1 day to 38 months) and 6 age-matched patients without HSCR as normal controls. RT-PCR, in situ hybridization, and immunohistochemistry were performed to examine the expression and cellular distributions of GFRAs in resected bowel segments of normal infants and those with HSCR. In normal infants and normoganglionic colon of patients with HSCR, the expression of GFRA1 was restricted to the glial cells and neurones of the ganglion plexuses. GFRAs expression was found to be markedly reduced in the aganglionic colons of 3 infants with HSCR but was unaffected in the aganglionic colons of 10 other infants with HSCR. Residual GFRA expression was restricted to enteric glial cells in the plexus remnants of the aganglionic colons. Hypertrophied nerve fibers were not found to express GFRA1. We provide the first evidence that abnormal expression of GFRAs in the enteric nervous system may be involved in the pathogenesis of HSCR in a subpopulation of patients.     

Multidetector CT angiography of peripheral vascular disease: a prospective comparison with intraarterial digital subtraction angiography

OBJECTIVE: The purpose of this study was to determine the accuracy of CT angiography using a multidetector scanner in the evaluation of patients with peripheral vascular disease. SUBJECTS AND METHODS: Eighteen patients with peripheral vascular disease who were referred for elective digital subtraction angiography (DSA) also underwent CT angiography. We scanned patients from the level of the superior mesenteric artery to the pedal arteries in a single helical scan. CT angiograms were produced using maximum-intensity-projection reconstructions. Findings were graded according to six categories: 1, normal (0% stenosis); 2, mild (1-49% stenosis); 3, moderate (50-74% stenosis); 4, severe (75-99% stenosis); 5, occluded; and 6, nondiagnostic. CT angiography findings were compared with DSA findings for each arterial segment. RESULTS: We found agreement for the degree of stenosis in 77.7% of the arteries and discrepancy for 22.3% of the arteries when all categories were considered. Grouping the six categories according to the threshold for treatment (categories 1 and 2 as one group and categories 3, 4, and 5 as the second group) resulted in an agreement of 91.95%. Compared with DSA, CT angiography yielded a sensitivity of 90.9% and a specificity of 92.4%. CONCLUSION: Multidetector CT angiography is an accurate, noninvasive technique for the imaging of peripheral vascular disease.     

Vertebroplasty success in a case of aggressive hemangioma

Vertebral hemangioma is a vascular tumor most oftenly asymptomatic and of casual radiological discovery. More rarely, it can be aggressive, causing neurological complications and therefore requiring a convenient and sustained therapy where vertebroplasty is of essential importance. In this context, we report a case of an aggressive vertebral angioma of L4 which was responsible for lumbocruralgy. She underwent verterbroplasty and then had a very good outcome. In this way we deal with the the different technics of vertebroplasty, their advantages compared to other therapeutic medical, and or surgical methods, as well as their complications.     

Cell surface association of matrix metalloproteinase-9 (gelatinase B)

Matrix metalloproteinase (MMP)-9 (gelatinase B) belongs to the MMP family of zinc-dependent endopeptidases that has been associated with tumor cell invasion and metastasis and tumor-induced angiogenesis. As a secreted MMP, pro-MMP-9 is released into the extracellular environment by both tumor and stroma cells, where it fulfills its proteolytic functions degrading both extracellular matrix (ECM) and non-ECM proteins. A major dilemma in our understanding of MMP-9 function is how the released protease is targeted to the right location and how its activity is controlled at the pericellular space. It has been proposed that MMP-9 interact with cell surface components and that this type of interaction positively regulates enzymatic activation and activity. However, recent evidence shows that association of MMP-9 with the cell surface is mediated by a distinct array of surface proteins that serve to regulate multiple aspects of the enzyme function including localization, inhibition and internalization. How these distinct mechanisms regulate the overall MMP-9 activity at the pericellular space remains an important goal in our understanding of MMP-9 function at the cell surface. Furthermore, the study of surface-associated MMP-9 imposes new conceptual and methodological challenges with particular consideration to the unique structural and functional characteristics of this key enzyme.     

Reduced constitutive 8-oxoguanine-DNA glycosylase expression and impaired induction following oxidative DNA damage in the tuberin deficient Eker rat

The Tsc-2 tumor suppressor gene encodes the protein tuberin, a multi-functional protein with sequence homology to the GTPase activating protein (GAP) for Rap1. Mutations in the Tsc-2 gene are associated with the development of renal tumors. The Eker rat (Tsc-2(EK/+)) bears a mutation in one allele of the Tsc-2 gene, which predisposes these animals to renal cancer. Treatment of wild-type (Tsc-2(+/+)) and mutant (Tsc-2(EK/+)) Eker rats with 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ; 7.5 micro mol/kg. i.v.), a potent redox active and nephrotoxic metabolite of hydroquinone increases the incidence of renal tumors only in animals carrying the mutant Tsc-2(EK/+) allele. We now show that the constitutive expression of 8-oxoguanine-DNA glycosylase (OGG1) in Tsc-2(EK/+) rats is three-fold lower than in wild-type Tsc-2(+/+) rats. Moreover, treatment of wild-type and mutant Eker rats with TGHQ greatly increases 8-oxo-deoxyguanosine (8-oxo-dG) levels within the outer stripe of the outer medulla. Tsc-2(EK/+) rats, with lower constitutive renal OGG1 expression, experience substantially higher levels of 8-oxo-dG than do wild type Tsc-2(+/+) rats. Interestingly, whereas OGG1 expression was rapidly (4 h) induced in Tsc-2(+/+) rats following exposure to TGHQ, it was significantly reduced in Tsc-2(EK/+) rats. The combination of the higher constitutive expression of OGG1 in Tsc-2(+/+) rats, and its rapid induction in response to TGHQ treatment, coupled to the initial decrease in OGG1 expression in Tsc-2(EK/+) rats, results in Tsc-2(EK/+) OGG1 protein levels just 5% of those seen in Tsc-2(+/+) rats 8 h after treatment. Coincidentally, 8-oxo-dG levels in Tsc-2(+/+) rats 8 h after treatment with TGHQ are just 5% of those that occur in Tsc-2(EK/+) rats. The results indicate that the Tsc-2 gene influences constitutive OGG1 expression and the ability of OGG1 to respond to an oxidative stress, consistent with the proposal that Tsc-2 is an acute-phase response gene. In keeping with this view, acute TGHQ-induced cytotoxicity was greater in Tsc-2(EK/+) rats than in Tsc-2(+/+) rats. The mechanism(s) coupling tuberin expression to the regulation of OGG1 are not known and are under investigation.     

Acute disseminated encephalomyelitis cohort study: prognostic factors for relapse.

To date, there is no available epidemiological study about prognostic factors of acute disseminated encephalomyelitis (ADEM) in children, using a cohort of patients with homogenous inclusion criteria. We aimed to evaluate prognostic factors for relapse after ADEM in children. A total of 132 children from the French National KIDSEP Neuropediatric Cohort (mean age at onset: 6+/-3.3 years; mean follow-up: 5.4+/-3.3 years; lost to follow-up: 10%). ADEM diagnosis was considered in a previously healthy patient acutely presenting more than one neurological deficit, change in mental state and MRI alterations including white matter changes. We used multivariate survival analysis (Cox model) evaluating the prognostic value of baseline clinical, biological and MRI covariates, for the occurrence of a second attack. Twenty-four (18%) of included patients had a second attack. An increased risk of relapse was associated with optic neuritis (hazard ratio, 5.23; 95% CI, 2-13.65), familial history of central nervous system inflammatory demyelination (7.79; 1.54-39.5), Barkhof multiple sclerosis (MS) criteria on MRI (2.52; 1.04-6.12) and no neurological sequelae after first attack (3.79; 1.12-12.85). Clinical and MRI prognostic factors for relapse in ADEM may contribute to an early distinction between monophasic and relapsing disease, which may be related to MS.     

Prior Surface Integrity Assessment of Coated and Uncoated Carbide Inserts Using Atomic Force Microscopy

Coated carbide inserts are considered vital components in machining processes and advanced functional surface integrity of inserts and their coating are decisive factors for tool life. Atomic Force Microscopy (AFM) implementation has gained acceptance over a wide spectrum of research and science applications. When used in a proper systematic manner, the AFM features can be a valuable tool for assessment of tool surface integrity. The aim of this paper is to assess the integrity of coated and uncoated carbide inserts using AFM analytical parameters. Surface morphology of as-received coated and uncoated carbide inserts is examined, analyzed, and characterized through the determination of the appropriate scanning setting, the suitable data type imaging techniques and the most representative data analysis parameters using the MultiMode AFM microscope in contact mode. The results indicate that it is preferable to start with a wider scan size in order to get more accurate interpretation of surface topography. Results are found credible to support the idea that AFM can be used efficiently in detecting flaws and defects of coated and uncoated carbide inserts using specific features such as “Roughness” and “Section” parameters. A recommended strategy is provided for surface examination procedures of cutting inserts using various AFM controlling parameters.