Vigabatrin in low doses selectively suppresses the clonic component of audiogenically kindled seizures in rats

PURPOSE: The effect of systemic administration of the gamma-aminobutyric acid (GABA)-transaminase inhibitor vigabatrin (VGB) on different components of convulsions was tested in the model of audiogenically kindled seizures, which consist of brainstem (running, tonus) and forebrain (clonus) elements. METHODS: Audiogenically susceptible rats of Krushinsky-Molodkina (KM), Wistar, and WAG/Rij strains received repeated sound stimulation (60 dB, 10-80 kHz) until kindled audiogenic seizures were reliably elicited. Kindled audiogenic seizures consisted of running, tonic, and generalized clonic phases in KM rats (severe audiogenic seizures) and of running and Racine stage 5 facial/forelimb clonus in Wistar and WAG/Rij rats (moderate seizures). Vehicle, 100, or 200 mg/kg of VGB was intraperitoneally injected 2, 4 and 24 h before the induction of kindled audiogenic seizures. RESULTS: At both doses, VGB did not change the seizure latency and the duration of running and tonic convulsions, but suppressed clonic ones in all rat strains. In KM rats, the mean duration of posttonic clonus was significantly reduced at 24 h after 100 mg/kg and from 4 h after 200 mg/kg. In Wistar and WAG/Rij rats, the mean duration of facial/forelimb clonus was reduced from 4 and 2 h after 100- and 200-mg/kg administration, respectively; 24 h after the high-dose injection, clonus was completely blocked in all rats of both strains. No difference in efficacy of VGB between Wistar and WAG/Rij rats was observed. CONCLUSIONS: VGB more effectively suppresses clonic convulsions than running and tonic ones in audiogenically kindled rats. It is supposed that this selective anticonvulsive effect of VGB results from different sensitivities of forebrain and brainstem epileptic networks to the presumed GABA enhancement.     

MR imaging correlates of survival in patients with high-grade gliomas

BACKGROUND AND PURPOSE: For patients with malignant gliomas, clinical data-including age, perioperative Karnofsky Performance Status (KPS), and tumor resection-and tumor imaging features-including necrosis and edema-have been found to correlate with survival. The purpose of this study was to assess the validity of these results and determine whether other imaging features are useful in predicting survival. METHODS: We analyzed the relationship between 15 imaging variables obtained from contrast-enhanced MR imaging scans and survival in patients with grade III (n = 43) and grade IV (n = 110) glioblastoma multiforme (GBM) gliomas. Image analysis was performed by 2 neuroradiologists who were blinded to clinical data. The Kaplan-Meier method was used to estimate survival probabilities. Univariable Cox models were used to assess the impact of imaging features on survival. A recursive partitioning analysis also was performed. RESULTS: As expected, age and KPS scores had significant prognostic value for both tumor grades. The extent of resection was not a statistically meaningful predictor of survival. For GBM, univariable analysis revealed the following imaging features to be significant, (hazard ratios in parentheses): noncontrast-enhancing tumor (nCET, 0.55), edema (1.62), satellites (1.74), and multifocality (4.34). For grade III tumors, the Cox hazard ratio for necrosis was 4.43 (P = .014) and correlated with a poor outcome and survival rates comparable to GBM patients. Lack of nCET, multifocality, and satellite lesions also were correlated with shortened survival. CONCLUSION: Of 15 tumor imaging features in GBM patients, only nCET, edema, and multifocality/satellites are statistically significant prognostic indicators. The survival advantage of nCET is a novel finding.     

Validation of a screening test of language and learning disorders for 6-year old children (ERTLA6)--a prospective study

Medical practitioners are, like the other health, education and childhood professionals, important actors of the language and learning disorders' screening. Six years old--the age at which children start the elementary school--is a key age for this screening. At the request of practitioners, a multidisciplinary staff had developed a screening tool: ERTLA6 (Epreuves de repérage des troubles du langage et des apprentissages de l'enfant de 6 ans). The objective was to validate the capacity of ERTLA6 to predict the school performance. A sample of 187 children was randomly constituted among the whole population of last year nursery school children in an area of France (the Académie de Nancy-Metz). Those children, aged from 5 to 6, were screened with ERTLA6 by the school practitioner during a medical visit (score from 0 [the best] to 18 [the worse]). The School outcomes (considered as judgment criteria) were assessed 2 or 3 years later, after two years of elementary school. 148 children had completed their follow-up (the others: 27 moving house, 6 absents the day of evaluation, 2 missing data). Mean age was 5; 10 years. With a threshold > or = 7, ERTLA6 sensibility and specificity were respectively 79% [63-94] and 87% [81-93]; the positive predictive value was 58% [42-74], the negative predictive value was 95% [90-99]. The percentage of well classified children was 84% [69-99]. To our knowledge, ERTLA6 is the first validated tool in France for screening language and learning disorders which can be used by practitioners for the prediction of school outcomes.     

Resistance of human periodontal ligament fibroblasts to the cytolethal distending toxin of Actinobacillus actinomycetemcomitans

BACKGROUND: The cytolethal distending toxin (CDT) of Actinobacillus actinomycetemcomitans is a typical member of this Gram-negative bacterium holotoxin family that targets a wide spectrum of eukarytotic cells, typically causing cell cycle arrest at either the G(1) or G(2)/M phase of the cell cycle. In view of the possible role of the CDT as a prominent A. actinomycetemcomitans virulence factor in periodontal diseases, we have examined the effects of the toxin on primary cultures of human periodontal ligament fibroblasts (HPLF). METHODS: HPLF and an immortalized human gingival epithelial cell line, GMSM-K, were exposed to recombinant A. actinomycetemcomitans CDT. Effects of the toxin on cell proliferation and cell cycle were assessed by a cell viability assay and flow cytometry, respectively. Double-strand DNA damage was detected by pulsed field gel electrophoresis. Binding of the toxin and its individual subunits to HPLF was examined by immunofluorescence microscopy. RESULTS: Viability of HPLF was not reduced following prolonged exposure to the CDT. There was no indication of cell cycle arrest or double-strand DNA damage. GMSM-K cells exhibited morphological alterations and a rapid decrease in cell viability within 6 and 12 hours, respectively, following exposure to the toxin for 5 minutes. These effects were dependent on toxin dose and age of the cultures and occurred more rapidly compared to CDT-treated HeLa cells. CDT-treated GMSM-K cells displayed cell cycle arrest at the S phase of growth and double-strand DNA damage was observed by 6 hours post-intoxication. Holotoxin and the CdtA subunit were detected on the surface of both HPLF and epithelial cells. CONCLUSIONS: These results demonstrate that HPLF are resistant to the cytotoxic effects of the A. actinomycetemcomitans CDT. The mechanism of resistance is not known but may be related to the inability of the toxin to cause DNA damage. The difference in sensitivities of HPLF and oral epithelial cells to the CDT has important implications for the role of this putative microbial virulence factor in periodontal pathogenesis.     

A truncation in the RYR1 gene associated with central core lesions in skeletal muscle fibres

A novel single-nucleotide deletion in exon 100 of the RYR1 gene, corresponding to deletion of nucleotide 14,510 in the human RyR1 mRNA (c14510delA), was identified in a man with malignant hyperthermia and in his two daughters who were normal for malignant hyperthermia. This deletion results in a RyR1 protein lacking the last 202 amino acid residues. All three subjects heterozygotic for the mutated allele presented with a prevalence of type 1 fibres with central cores, although none experienced clinical signs of myopathy. Expression of the truncated protein resulted in non-functional RYR1 calcium release channels. Expression of wild-type and RyR1(R4836fsX4838) proteins resulted in heterozygotic release channels with overall functional properties similar to those of wild-type RyR1 channels. Nevertheless, small differences in sensitivity to calcium and caffeine were observed in heterotetrameric channels, which also presented an altered assembly/stability in sucrose-gradient centrifugation analysis. Altogether, these data suggest that altered RYR1 tetramer assembly/stability coupled with subtle chronic changes in Ca2+ homoeostasis over the long term may contribute to the development of core lesions and incomplete malignant hyperthermia susceptibility penetrance in individuals carrying this novel RYR1 mutation.     

Establishing mild, moderate, and severe scores for cancer-related symptoms: how consistent and clinically meaningful are interference-based severity cut-points?

Methods are presented to separate 16 frequently occurring cancer symptoms measured on 10-point symptom severity rating scales into mild, moderate, and severe categories that are clinically interpretable and significant for use in oncology practice settings. At their initial intervention contact, 588 solid tumor cancer patients undergoing chemotherapy reported severity on a standard 11-point rating scale for 16 symptoms. All reporting a one or higher were asked to rate on an 11-point scale how much the symptom interfered with enjoyment of life, relationship with others, general daily activities, and emotions. Factor analysis revealed that these items tapped into the same dimension, and the items were summed to form an interference scale. Cut-points for mild, moderate, and severe categories of symptom severity were defined by comparing the differences in interference scores corresponding to each successive increases in severity for each symptom. The cut-points differed among symptoms. Pain, fatigue, weakness, cough, difficulty remembering, and depression had lower cut-points for each category compared to other symptoms. Cut-points for each symptom were not related to site or stage of cancer, age, or gender but were associated with a global depression measure. Cut-points were related to limitations in physical function, suggesting differences in the quality of patients' lives. The resulting cut-points summarize severity ratings into clinically significant and useful categories that clinicians can use to assess symptoms in their practices.