Epilepsy surgery in children: results and predictors of outcome on seizures

PURPOSE: To retrospectively analyze the results on seizures of surgery in children with drug-resistant focal epilepsy. To identify the factors predicting seizure control among several presurgical, surgical, and postsurgical variables. METHODS: One hundred thirteen patients (67 male, 46 female), younger than 16 years, operated on from 1996 to 2004 and followed-up for at least 2 years were identified. Individualized microsurgical resections, aimed at removal of the epileptogenic zone, were performed according to the results of tailored presurgical evaluations, which included stereo-electroencephalographic recording with intracerebral electrodes when needed. Risk of seizure recurrence was assessed for the considered variables by bivariate and multivariate analysis. RESULTS: Mean age at surgery was 8.8 years, mean duration of epilepsy was 5.7 years, and mean age at seizure onset was 3.1 years. One hundred eight patients (96%) had an abnormal magnetic resonance imaging. At postoperative follow-up (mean duration 55.1 month), 77 patients (68%) were in Engel's class I, with 68 patients (60%) being seizure free (Engel's classes Ia and Ic). At multivariate analysis, variables associated with a significantly lower risk of seizure recurrence were unifocal lesion at MRI and older age at seizure onset (presurgical variables), temporal unilobar resection and complete lesionectomy (surgical variables), diagnosis of glial-neuronal tumors (postsurgical variables). CONCLUSIONS: Surgery is a valuable option for children with drug-resistant focal epilepsies which may provide excellent results in a considerable amount of cases. Since results of surgery for epilepsy strongly depend on the presurgical identification of the Epileptogenic Zone, future work should be focused on refinement and implementation of diagnostic strategies.     

Coupling of minor motor events and epileptiform discharges with arousal fluctuations in NFLE

Purpose: We recently demonstrated that in nocturnal frontal lobe epilepsy (NFLE) highly stereotyped minor motor events (MMEs, in the form of short‐lasting stereotyped movements involving the limbs, the axial musculature, and/or the head), could occur in either the presence or absence of an epileptiform discharge (ED). In lack of a systematic analysis, both MMEs and EDs were frequently observed to occur in association with arousal fluctuations. Hereby, in the same group of refractory NFLE subjects, we report a methodical neurophysiolgical investigation set out to investigate whether, and how, the arousal mechanism, monitored through visual scoring of the cyclic alternating pattern, modulates the expression of MMEs and EDs. Methods: The relationship of MMEs, EDs and arousal fluctuation was assessed in subjects explored using implanted electrodes. Results: The occurrence of both EDs and MMEs was associated with higher level of arousal (p < 0.0001). Multivariate logistic regression analysis shows a significant effect of interaction of EDs and MMEs during CAP sleep (p < 0.001). Conclusions: Both MMEs and EDs are associated with arousal. We suggest that recurrence of EDs in itself can induce an increase in arousal level, which in turn, through a gate effect, facilitate the occurrence of MMEs. Thus, MMEs wouldn't be a direct effect of EDs, but rather originate from an indirect effect related to loss of cortical inhibition, which is secondary to arousal. In this perspective MMEs may be regarded as the result of aspecific dishinibition, triggered by internal epileptiform stimuli, of innate motor patterns generated by central pattern generators (CPGs). The CPG system might represent, through arousal facilitation, the substrate of the heterogeneous expression of MMEs in NFLE.     

Autologous in vivo adipose tissue engineering in hyaluronan-based gels--a pilot study

BACKGROUND: There is a major clinical need for strategies for adequately reconstructing the soft tissue defects found after deep burns, tumor resection, or trauma. A promising solution is adipose tissue engineering with preadipocytes, stem-cell derived precursors of the adipose tissue, implanted within biomaterials. This pilot study evaluated hyaluronan gels mixed with autologous undifferentiated preadipocytes in a pig model for their potency to generate new fat. MATERIALS AND METHODS: Preadipocytes were isolated from intra-abdominal pig fat by collagenase digestion, plated on fibronectin-coated culture dishes in Dulbecco's modified Eagle medium/Ham's F12 (Biochrom, Berlin, Germany) combined with 10% pig serum, expanded, and mixed with hyaluronan gel. Two types of gels with varying degrees of amidation of the carboxyl groups were tested (HYADD3, HYADD4). Cell-loaded gels and unseeded controls were injected subcutaneously into the ears of three pigs, explanted at 6 wk, and analyzed histologically. RESULTS: Both cell-loaded specimens were detected macroscopically. They demonstrated a slight volume effect with limited stability after 6 wk. Unloaded HYADD3 and HYADD4 controls could not be identified at the time of explantation. Histology of HYADD3 revealed islets of mature adipocytes and vessels embedded in fat tissue surrounded by gel. In contrast, no fat formation was found in HYADD4 gels when implanted in the ear. CONCLUSIONS: Histological findings demonstrate that HYADD3 is a promising gel for generating adipose tissue. Even though HYADD3 might be a potential material for the reconstruction of small tissue defects, the question remains as to whether the adipose tissue within the gel is attributable to preadipocyte maturation or ingrowth from neighboring tissue.     

Shockwave lithotripsy and protective role of inosine: early and late evaluation in an experimental model

PURPOSE: Extracorporeal shockwave lithotripsy (SWL) is one of the most common treatments for urinary stones. Despite technological improvements, it may cause side effects varying from minor reversible microscopic damage to severe large renal hematomas. The aim of our experimental study is to assess the efficacy of inosine in avoidance of acute renal damage after SWL. MATERIALS AND METHODS: We used 25 Wistar rats that had previously had left nephrectomy. The rats were divided into three groups: group A consisted of 10 rats undergoing renal SWL; group B consisted of 10 rats that received adjunctive treatment with IP injection of inosine 40 minutes before SWL; and group C consisted of 5 rats that served as controls. N-acetylglucosaminidase (NAG) and lactate dehydrogenase (LDH) concentrations were evaluated 24 hours before and 24 hours after SWL. All the rats were subsequently sacrificed (4 rats in group A and 4 in group B at 48 hours post-SWL, and the remaining rats were sacrificed 30 days post-SWL). Renal tissue was submitted to histologic and electron microscopic examination to assess early and late alterations. RESULTS: NAG and LDH values were significantly increased after SWL in group A (P<0.001), while no significant NAG and LDH differences were detected in group B (P<0.16). Early histologic examination revealed a considerable amount of cellular degeneration in group A with ultrastructural vacuolization and disruption of lysosomal membranes; the tubular features and cellular structures appeared to be well preserved in group B. No late histologic alterations were evident in any of the specimens. CONCLUSIONS: Inosine is helpful and protective in the prevention of early microscopic damage to renal parenchyma due to SWL.     

Discovery of diaryl imidazolidin-2-one derivatives, a novel class of muscarinic M3 selective antagonists (Part 1)

Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki = 4.8 nM and for M2 receptor Ki = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.     

Sedation of neurologically impaired children undergoing MRI: a sequential approach

BACKGROUND: The purpose of this retrospective study was to determine the efficacy of a sequential approach meant to rescue failed chloral hydrate sedation and to obtain a low rate of adverse events along with predictable timings in neurologically impaired children undergoing magnetic resonance imaging. METHODS: We retrospectively evaluated 1104 chloral hydrate sedations performed between 2002 and 2004 on 862 children weighing <26 kg. If the desired sedation score (3 on the Skeie Scale) was not reached within 30 min after oral administration of chloral hydrate, sedation was considered as potentially failed, and supplementation with sevoflurane, i.m. or i.v. ketamine, and i.v. pentobarbital and midazolam was started. RESULTS: Twenty-seven sessions failed because of excessive movement. Mean induction time was significantly higher for patients who received supplementation (52.2 min vs 39.1 min), while no differences in recovery and total sedation times were found. Supplementation significantly increased the incidence of respiratory obstruction (4.6% vs 2.4%), although the incidence of other adverse events was unaffected. CONCLUSIONS: Administering up to 1.5 g of chloral hydrate without supplementation was associated with a failure rate of approximately 20%, but the proposed sequential approach enabled us to rescue the majority of failed sedations while maintaining an acceptably low incidence of adverse events.     

Effect of human skin-derived stem cells on vessel architecture, tumor growth, and tumor invasion in brain tumor animal models

Glioblastomas represent an important cause of cancer-related mortality with poor survival. Despite many advances, the mean survival time has not significantly improved in the last decades. New experimental approaches have shown tumor regression after the grafting of neural stem cells and human mesenchymal stem cells into experimental intracranial gliomas of adult rodents. However, the cell source seems to be an important limitation for autologous transplantation in glioblastoma. In the present study, we evaluated the tumor targeting and antitumor activity of human skin-derived stem cells (hSDSCs) in human brain tumor models. The hSDSCs exhibit tumor targeting characteristics in vivo when injected into the controlateral hemisphere or into the tail vein of mice. When implanted directly into glioblastomas, hSDSCs distributed themselves extensively throughout the tumor mass, reduced tumor vessel density, and decreased angiogenic sprouts. In addition, transplanted hSDSCs differentiate into pericyte cell and release high amounts of human transforming growth factor-beta1 with low expression of vascular endothelial growth factor, which may contribute to the decreased tumor cell invasion and number of tumor vessels. In long-term experiments, the hSDSCs were also able to significantly inhibit tumor growth and to prolong animal survival. Similar behavior was seen when hSDSCs were implanted into two different tumor models, the chicken embryo experimental glioma model and the transgenic Tyrp1-Tag mice. Taken together, these data validate the use of hSDSCs for targeting human brain tumors. They may represent therapeutically effective cells for the treatment of intracranial tumors after autologous transplantation.     

Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression

Tumor initiation and progression provide a multitude of occasions for the generation of DNA damage and the consequent activation of the DNA damage response (DDR) pathway. DDR signaling involves the engagement of key factors such as ATM, CHK2, 53BP1 and the phosphorylation of histone H2AX (gamma-H2AX). The systematic study of DDR in human tumors and normal tissues by high-throughput tissue microarrays revealed that ATM and gamma-H2AX were engaged in cancer but the extent of their activation was strongly affected by the organ and cell type involved, whereas 53BP1 loss was the most consistent feature among the tumor studied. Unexpectedly, we also observed activated DDR markers in morphologically normal tissues, also in association with inflammation. Analysis of the dynamic engagement of DDR along the different stages of lung tumorigenesis showed that 53BP1 loss occurs early at the transition from normal to dysplastic change whereas the activated forms of ATM and CHK2, but not gamma-H2AX, initially accumulate in pre-invasive lesions and are then lost during tumor progression. In individual lung tumors, the activation of ATM, CHK2 and the presence of 53BP1 were consistently correlated, whereas gamma-H2AX did not correlate with activated ATM. Finally, the study of associations between critical clinicopathological parameters and activated DDR factors highlighted a statistically meaningful correlation between reduced local tumor extension and the phosphorylation of ATM, CHK2 and the presence of 53BP1, whereas no significant correlations with parameters such as survival or relapse of early-stage lung carcinomas were found.