bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Hyperinhibition Hypothesis in Epileptogenesis: An Assessment of the Evidence
Authors: Dudek F. Edward 
Published: February 2006

Hippocampal Granule Cell Activity and c-fos Expression During Spontaneous Seizures in Awake, Chronically Epileptic, Pilocarpine-treated Rats: Implications for Hippocampal Epileptogenesis Harvey BD, Sloviter RS J Comp Neurol 2005;488(4):442–463 The process of postinjury hippocampal epileptogenesis may involve gradually developing dentate granule cell hyperexcitability caused by neuron loss and synaptic reorganization. We tested this hypothesis by repeatedly assessing granule cell excitability after pilocarpine-induced status epilepticus (SE) and monitoring granule cell behavior during 235 spontaneous seizures in awake, chronically implanted rats. During the first week post-SE, granule cells exhibited diminished paired-pulse suppression and decreased seizure discharge thresholds in response to afferent stimulation. Spontaneous seizures often began during the first week after SE, recruited granule cell discharges that followed behavioral seizure onsets, and evoked c-fos expression in all hippocampal neurons. Paired-pulse suppression and epileptiform discharge thresholds increased gradually after SE, eventually becoming abnormally elevated. In the chronic epileptic state, interictal granule cell hyperinhibition extended to the ictal state; granule cells did not discharge synchronously before any of 191 chronic seizures. Instead, granule cells generated only low-frequency voltage fluctuations (presumed “field excitatory postsynaptic potentials”) during 89% of chronic seizures. Granule cell epileptiform discharges were recruited during 11% of spontaneous seizures, but these occurred only at the end of each behavioral seizure. Hippocampal c-fos after chronic seizures was expressed primarily by inhibitory interneurons. Thus, granule cells became progressively less excitable, rather than hyperexcitable, as mossy fiber sprouting progressed and did not initiate the spontaneous behavioral seizures. These findings raise doubts about dentate granule cells as a source of spontaneous seizures in rats subjected to prolonged SE and suggest that dentate gyrus neuron loss and mossy fiber sprouting are not primary epileptogenic mechanisms in this animal model.
Dancing the Delta Shuffle: Neurosteroids Regulate GABAA Receptor Expression
Authors: Lagrange Andre 
Published: February 2006

Ovarian Cycle-linked Changes in GABA(A) Receptors Mediating Tonic Inhibition Alter Seizure Susceptibility and Anxiety Maguire JL, Stell BM, Rafizadeh M, Mody I Nat Neurosci 2005;8(6):797–804 Disturbances of neuronal excitability changes during the ovarian cycle may elevate seizure frequency in women with catamenial epilepsy and enhance anxiety in premenstrual dysphoric disorder (PMDD). The mechanisms underlying these changes are unknown, but they could result from the effects of fluctuations in progesterone-derived neurosteroids on the brain. Neurosteroids and some anxiolytics share an important site of action: tonic inhibition mediated by δ subunit–containing GABAA receptors ( δGABAA Rs). Here we demonstrate periodic alterations in specific GABAA R subunits during the estrous cycle in mice, causing cyclic changes of tonic inhibition in hippocampal neurons. In late diestrus (high-progesterone phase), enhanced expression of δGABAA Rs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling of δGABAA Rs by antisense RNA treatment or gene knockout prevents the lowering of excitability during diestrus. Our findings are consistent with possible deficiencies in regulatory mechanisms controlling normal cycling of δGABAA Rs in individuals with catamenial epilepsy or PMDD. Short-term Steroid Treatment Increases δ GABAA Receptor Subunit Expression in Rat CA1 Hippocampus: Pharmacological and Behavioral Effects Shen H, Gong QH, Yuan M, Smith SS Neuropharmacology 2005;49(5):573–586 In this study, 48-h administration of 3 α-OH-5 β-pregnan-20-one (3 α,5 β-THP) or 17 β-estradiol (E2)+progesterone (P) to female rats increased expression of the δ subunit of the GABAA receptor in CA1 hippocampus. Coexpression of α4 and δ subunits was suggested by an increased response of isolated pyramidal cells to the GABA agonist 4,5,6,7-tetrahydroisoxazolo[5,4- c]pyridin-3-ol (THIP), following 48-h steroid treatment, and nearly complete blockade by 300 μM lanthanum (La3+). Because α4 βδ GABAA receptors are extrasynaptic, we also recorded pharmacologically isolated GABAergic holding current from CA1 hippocampal pyramidal cells in the slice. The La3+-sensitive THIP current, representative of current gated by α4 βδ GABAA receptor, was measurable only following 48-h steroid treatment. In contrast, the bicuculline-sensitive current was not altered by steroid treatment, assessed with or without 200 nM gabazine to block synaptic current. However, 48-h steroid treatment resulted in a tonic current insensitive to the benzodiazepine agonists lorazepam (10 μM) and zolpidem (100 nM). These results suggest that 48-h steroid treatment increases expression of α4 βδ GABAA receptors, which replace the ambient receptor population. Increased anxiolytic effects of THIP were also observed following 48-h steroid treatment. The findings from the present study may be relevant for alterations in mood and benzodiazepine sensitivity reported across the menstrual cycle.
Endocannabinoids: A Critical Regulator of Activity in the Developing Brain
Authors: Douglas A. Coulter 
Published: February 2006

Altering Cannabinoid Signaling During Development Disrupts Neuronal Activity Bernard C, Milh M, Morozov YM, Ben-Ari Y, Freund TF, Gozlan H Proc Natl Acad Sci USA 2005;102(26):9388–9393 In adult cortical tissue, recruitment of GABAergic inhibition prevents the progression of synchronous population discharges to epileptic activity. However, at early developmental stages, GABA is excitatory and thus unable to fulfill this role. Here, we report that retrograde signaling involving endocannabinoids is responsible for the homeostatic control of synaptic transmission and the resulting network patterns in the immature hippocampus. Blockade of cannabinoid type 1 (CB1) receptor led to epileptic discharges, whereas overactivation of CB1 reduced network activity in vivo. Endocannabinoid signaling thus is able to keep population discharge patterns within a narrow physiological time window, balancing between epilepsy on one side and sparse activity on the other, which may result in impaired developmental plasticity. Disturbing this delicate balance during pregnancy in either direction, for example, with marijuana as a CB1 agonist or with an antagonist marketed as an antiobesity drug, can have profound consequences for brain maturation even in human embryos.
Is Breast Milk the Best for Babies of Mothers on Levetiracetam?
Authors: Pennell Page B. 
Published: February 2006

Levetiracetam Concentrations in Serum and in Breast Milk at Birth and During Lactation Johannessen SI, Helde G, Brodtkorb E Epilepsia 2005;46(5):775–777 Purpose To study the pharmacokinetics of levetiracetam (LEV) at birth, during lactation, and in the nursed infant. Methods Eight consecutive breast-feeding women with epilepsy treated with LEV twice daily and their infants were studied. Results The mean umbilical cord serum/maternal serum ratio was 1.14 (range, 0.97–1.45) ( n = 4). The mean milk-maternal serum concentration ratio was 1.00 (range, 0.761.33) at 3–5 days after delivery ( n = 7). At sampling 2 weeks to 10 months after delivery ( n = 5), it was similar (range, 0.85–1.38). At 3–5 days after delivery, the infants had very low LEV serum concentrations (<10–15 μM), a finding that persisted during continued breast-feeding. No malformations were detected, and in none of the infants did signs of adverse effects develop. Conclusions Our data indicate an extensive transfer of LEV from mother to fetus and into breast milk. However, breast-fed infants had very low LEV serum concentrations, suggesting a rapid elimination of LEV.
Impact of Epilepsy Surgery on Developing Minds: How do we Weigh the Consequences?
Authors: Garcia Paul A. 
Published: February 2006

Cognitive Function in Preschool Children after Epilepsy Surgery: Rationale for Early Intervention Freitag H, Tuxhorn I Epilepsia 2005;46(4):561–567 Purpose The detrimental effect of frequent early seizures on the cognitive potential of children is a significant clinical issue. Epilepsy surgery in childhood offers a good prognosis for seizure control and improved developmental outcome. We studied the postoperative outcome and the developmental velocity after surgery and analyzed risk factors for developmental delay in 50 consecutive preschool children treated surgically for severe epilepsy at ages 3 to 7 years. Methods Pre- and postoperative developmental quotients (DQs) were analyzed with analysis of variance; step-wise linear regressions were performed on preoperative DQs and on a difference score between post- and preoperative DQs to determine risk factors for preoperative development and factors influencing postoperative development. Results Of the 50 patients, 70% were retarded, with IQ <70; 16% were of average intelligence, with IQ ranging from 85 to 115. Age at seizure onset and extent of lesion were predictive variables for preoperative cognitive development. Six to 12 months after surgery (early postoperative phase), 66% were seizure free (Engel outcome class I), 26% had substantial to worthwhile seizure reduction (classes II and III), and 8% were unchanged (class IV). Forty-one (82%) children showed stable velocity of development; three children showed gains of 15 IQ points; three had developmental decline (loss of 10 IQ points), which was transient in two children; and three children moved from not assessable to assessable. At last follow-up (6 months to 10 years after surgery), 11 children showed IQ/DQ gains of 15 IQ points. Gains in IQ were observed only in seizure-free children and were stable over time. Shorter duration of epilepsy was significantly associated with a postoperative increase in DQ. Conclusions (a) Substantial global mental delay is common in young children treated for epilepsy with surgery; (b) in most patients, postoperative development proceeded at a stable velocity; (c) catch-up development may occur but only in seizure-free patients; (d) substantial cognitive losses were noted in only one child; and (e) early seizure control stabilized developmental velocity in this patient cohort.
In the End, New Antiepileptics May be Less Expensive than Older Antiepileptics for Geriatric Patients
Authors: Kanner Andres M. 
Published: February 2006

New Onset Geriatric Epilepsy: A Randomized Study of Gabapentine, Lamotrigine, and Carbamazepine Rowan AJ, Ramsay RE, Collins JF, Pryor F, Boardman KD, Uthman BM, Spitz M, Frederick T, Towne A, Carter GS, Marks W, Felicetta J, Tomyanovich ML; VA Cooperative Study 428 Group Neurology 2005;64:1868–1873 Objective To determine the relative tolerability and efficacy of two newer antiepileptic drugs, lamotrigine (LTG) and gabapentin (GBP), as compared with carbamazepine (CBZ) in older patients with epilepsy. Methods This was an 18-center, randomized, double-blind, double dummy, parallel study of 593 elderly subjects with newly diagnosed seizures. Patients were randomly assigned to one of three treatment groups: GBP 1,500 mg/day, LTG 150 mg/day, CBZ 600 mg/day. The primary outcome measure was retention in trial for 12 months. Results Mean age was 72 years. The most common etiology was cerebral infarction. Patients had multiple medical conditions and took an average of seven comedications. Mean plasma levels at 6 weeks were as follows: GBP 8.67 ± 4.83 μg/mL, LTG 2.87 ± 1.60 μg/mL, CBZ 6.79 ± 2.92 μg/mL. They remained stable throughout the trial. Early terminations: LTG 44.2%, GBP 51%, CBZ 64.5% ( p = 0.0002). Significant paired comparisons: LTG vs CBZ: p < 0.0001; GBP vs CBZ: p = 0.008. Terminations for adverse events: LTG 12.1%, GBP 21.6%, CBZ 31% ( p = 0.001). Significant paired comparisons: LTG vs CBZ: p < 0.0001; LTG vs GBP: p = 0.015. There were no significant differences in seizure-free rate at 12 months. Conclusions The main limiting factor in patient retention was adverse drug reactions. Patients taking LTG or GBP did better than those taking CBZ. Seizure control was similar among groups. LTG and GBP should be considered as initial therapy for older patients with newly diagnosed seizures.
What Does Flumazenil PET Add to an Evaluation for Temporal Lobectomy?
Authors: Theodore William H. 
Published: February 2006

Periventricular White Matter Flumazenil Binding and Postoperative Outcome in Hippocampal Sclerosis Hammers A, Koepp MJ, Brooks DJ, Duncan JS Epilepsia 2005;46(6):944–948 Purpose In patients with hippocampal sclerosis (HS), anterior temporal lobe resection offers the possibility of a long-lasting suppression of seizures in two-thirds of patients. White matter (WM) [11C]flumazenil volume of distribution (FMZ-Vd) reflects the number of neuronal cell bodies in WM. Our objective was to correlate WM FMZ-Vd in patients with unilateral HS and postsurgical outcome. Methods We performed [11C]flumazenil positron emission tomography ([11C]FMZ-PET) in 15 patients with refractory mesial temporal lobe epilepsy (mTLE) and a quantitative MRI diagnosis of unilateral HS subsequently histologically verified in all cases. Median follow-up was 7 years (range, 6–9 years). Metabolite-corrected arterial plasma input functions and spectral analysis were used to generate parametric images of [11C]FMZ-Vd. Statistical parametric mapping (SPM99) with explicit masking was used to investigate the entire brain volume including WM. Results Eight patients had Engel class IA outcome (completely seizure-free since surgery), and seven were not seizure-free. Comparison of seizure-free patients with those who continued to have seizures after surgery revealed areas of increased FMZ binding around the posterior horns of the ipsilateral (z = 3.7) and contralateral (z = 2.7) ventricles in those with suboptimal outcomes. Conclusions Preoperative [11C]FMZ-PET can detect periventricular increases of WMFMZ binding, implying heterotopic neurons in WM, in patients with mTLE. The presence of such increases correlates with a poorer outcome.
Pathogenesis of bone metastasis: a review
Authors: Raubenheimer E. J. , Noffke C. E. E. 
Published: February 2006

Background: Metastasic deposits from malignancies frequently lodge in the skeleton, including the jawbones.Method: A review of the literature was performed in order to provide a coherent overview on the pathogenesis of bone metastasis.Results: Bone metastasis follows complex molecular interactions that enable tumor cells to detach from the primary site, invade the extracellular matrix, intravasate, extravasate, and proliferate within bone. They induce local bone changes that could manifest radiologically as either osteolytic or radiodense. In addition to the direct bone changes, malignancies can elaborate mediators that are released in circulation, leading to generalized osteopenia.Conclusions: The spread of malignant neoplasms to bone is not a random process but rather a cascade of specific molecular events orchestrated through complex interactions between neoplastic cells and their environment.
Expression of Bcl‐2 but not Bax has a prognostic significance in tongue carcinoma
Authors: de Vicente Juan Carlos , Olay Sonsoles , Lequerica‐Fernandez Paloma , Sánchez‐Mayoral Jacobo , Junquera Luis Manuel , Fresno Manuel Florentino 
Published: February 2006

Background:  Among the molecular mechanisms involved in carcinogenesis, defects in the regulation of programmed cell death (apoptosis) make important contributions to the pathogenesis and progression of cancer. Apoptosis regulatory genes include the antiapoptotic bcl‐2 gene and the proapoptotic bax gene. The aim of this study was to determine the spectrum of Bax and Bcl‐2 expression, and to correlate these findings with clinicopathologic variables and prognosis.Methods:  In this study we have evaluated the immunohistochemical expression of Bcl‐2 and Bax proteins in a series of 35 squamous cell carcinomas of the tongue.Results:  Immunoreactivity for Bax was detected in 37.1% and for Bcl‐2 in 8.6% of cells, and for both proteins the staining was cytoplasmic and granular. Bcl‐2 and Bax expression was mainly seen in peripheral cells of epithelial tumor islands with decreasing immunoreactivity toward the center of the neoplastic nests. Bax immunoexpression was significantly correlated with histologic grading (P = 0.05), but not with the remaining clinicopathologic variables. Bcl‐2 immunoreactivity was significantly correlated with N‐stage (P = 0.01) and survival. Patients with Bcl‐2‐negative tumors [mean survival: 73.97 months; 95% confidence interval (CI): 59–88] vs. Bcl‐2‐positive ones (mean survival: 17.67 months; 95% CI: 6–29) had a longer survival (P = 0.01; odds ratio = 6.9).Conclusions:  Bcl‐2 is associated with aggressive disease, neck lymph node metastasis, and poor prognosis. Whereas Bax is related with histologic grade.
Glandular odontogenic cyst in China: report of 12 cases and immunohistochemical study
Authors: Shen Jing , Fan Mingwen , Chen Xinming , Wang Shuozhi , Wang Li , Li Yuan 
Published: February 2006

Objective:  The purpose of this study was to present 12 additional cases of glandular odontogenic cyst (GOC) in the Department of Oral Pathology, School of Stomatology, Wuhan University, People's Republic of China, and to investigate their immunohistochemical cytokeratins (CKs) expression in the epithelial components.Methods:  A total of 12 GOCs were reviewed clinically and radiographically, and immunohistologic CKs AE1, 7, 8/18, 10/13, 14, 16, 19 and 20 were performed by using a standard biotin‐streptavidin immunoperoxidase technique on paraffin sections.Results:  The present series showed that eight occurred in males and four in females. The mean age was 37.6 years with a peak incidence occurring in the third decades (six of 12). Mandibles were more affected than maxillas (7:5), especially anterior mandible (four of seven). Radiographically, ratio multilocular to unilocular radiolucencies was 5:7 usually with well‐defined borders. Histologically, cystic spaces were lined by non‐keratinized stratified epithelia containing focal plaque‐like or whirlpool‐like thickenings; surface epithelial layer‐containing eosinophilic cuboidal cells; mucous cells; and mucin pools of microcystic areas in the epithelium. Immunohistochemistry showed that epithelium of GOCs stained for CKs AE1, 7, 8/18, 10/13, 14 and 19 with slight changes in their patterns, and no reaction to CKs 16 and 20.Conclusions:  Most clinical and histologic features in this study were analogous to those reported west population, although with slight difference between them. Histologically, the morphology of the epithelium strongly suggested an odontogenic origin, and CKs expression of GOC was similar to that of odontogenic epithelium, suggesting histochemically that GOC might be derived from odontogenic epithelium.
Osteonecrosis of the jaws in patients treated with bisphosphonates – histomorphologic analysis in comparison with infected osteoradionecrosis
Authors: Hansen Torsten , Kunkel Martin , Weber Achim , James Kirkpatrick C. 
Published: February 2006

Background:  Patients treated with bisphosphonates because of bone metastases have been shown to develop osteonecrosis of the jaws. In the present study, we examined the histologic findings of these cases. As similarities between this disorder and infected osteoradionecrosis (IORN) are described, both lesions were compared.Methods:  We investigated eight patients with bisphosphonate treatment and osteonecrosis (four female, four male; median age: 65.6 years; cancer: multiple myeloma in five patients, breast cancer in three patients; mandibular involvement in five patients, maxillar involvement in three cases), and 10 patients suffering from IORN (all male; median age: 61.3 years; cancer: squamous cell carcinoma in nine patients, adenoid cystic carcinoma in one patient; mandibular involvement in all cases). Multicentric and bilateral involvement was common in the bisphosphonate group. Histologically, the bone revealed diffuse and patchy areas of necrosis in the bisphosphonate group, while in IORN osteonecrosis was larger and not diffusely distributed.Results:  In all cases, we found Actinomyces attached to the necrotic bone tissue. In five of eight bisphosphonates cases, and in six of 10 IORN cases, numerous osteoclasts could be detected close to vital bone exhibiting signs of bone resorption. Pseudoepitheliomatous hyperplasia (PH) was revealed in five of eight bisphosphonate patients, and in seven of 10 IORN patients.Conclusion:  We conclude that Actinomyces is involved in the chronic, non‐healing inflammatory processes as a characteristic feature of both diseases. Together with the associated presence of increased osteoclast numbers, we suggest that both factors may be involved in osteolytic mechanisms.
Expression of TNF‐α in oral lichen planus treated with fluocinolone acetonide 0.1%
Authors: Thongprasom Kobkan , Dhanuthai Kittipong , Sarideechaigul Wilairat , Chaiyarit Ponlatham , Chaimusig Mantharop 
Published: February 2006

Background:  Oral lichen planus (OLP) is a common chronic inflammatory disease involving T cells‐mediated immunity. Tumor necrosis factor (TNF)‐α has been reported to be involved in the disease process. The purpose of this study was to investigate the effect of fluocinolone acetonide in orabase (FAO) 0.1% on the expression of TNF‐α in patients with OLP.Methods:  Eighteen Thai patients with atrophic or erosive OLP were recruited. Biopsy specimens were taken before and 1 month after treatment with FAO 0.1% and sent for histopathologic examination where they were immunohistochemically stained with antibody to TNF‐α. Twenty normal mucosa specimens were identically processed. Oral squamous cell carcinoma tissue was used as a positive control for TNF‐α expression, whereas OLP sections without primary antibody were served as negative control.Results:  Sixteen of 18 cases (88.89%) of OLP exhibited positive staining for TNF‐α. Most of the TNF‐α was observed in the mononuclear cells. Ten cases (55.56%) of OLP demonstrated TNF‐α expression in keratinocytes. The number of mononuclear cells positive for TNF‐α before the treatment with FAO 0.1% in orabase was statistically higher than that after the treatment (P = 0.000) and in the normal mucosa (P = 0.000). Moreover, the number of mononuclear cells after treatment with FAO 0.1% in orabase was statistically lower than before the treatment (P = 0.000).Conclusion:  Our study exhibited that TNF‐α may be associated with the immunopathogenesis of OLP in Thai patients and FAO 0.1% had an effect on the reduction of TNF‐α expression.