Increased number of neural progenitors in human temporal lobe epilepsy

An increased neurogenesis is reported in animal models of mesial temporal lobe epilepsy (MTLE) but the fate of newborn cells is unknown. Here, we attempted to demonstrate neurogenesis in adult epileptic tissue obtained after hippocampectomy. MTLE hippocampi showed increased expression of division markers and of Musashi-1, a marker of neural progenitors, compared to control hippocampi. Large quantities of Musashi-1+ cells were obvious in the subgranular layer and the subventricular zone, both known neurogenic areas, and in the fissura hippocampi. Musashi-1 was expressed by small cells that were mainly vimentin+ or nestin+, rarely Dcx+ or PSA-NCAM+ and negative for markers of mature neurons or astrocytes. Some of them are present in the granular layer, the hilus, and CA1 area resembling the ectopic positions described in rodents. These findings demonstrate that neural progenitors proliferate in chronic epilepsy and suggest that the fissura hippocampi behaves like another neurogenic area.     

GABA receptor 1 polymorphism (G1465A) and temporal lobe epilepsy

PURPOSE: To reevaluate the genetic contribution of the polymorphism G1465A of the gene coding for gamma-aminobutyric acid (GABA)(B) receptor 1 subunit [GABA(B)(1)] in a sample of French patients with temporal lobe epilepsy (TLE) and to perform an exploratory analysis in other phenotypic subgroups. METHODS: The 134 patients were genotyped for the polymorphism G1465A. This sample was divided in two groups. The first one had patients with nonlesional TLE, and the second one, with lesional TLE. Then these two groups were compared with a sample of 145 healthy individuals. RESULTS: The genotype and allele distributions for the polymorphism G1465A showed no difference between patients and controls. CONCLUSIONS: The association between the variant G1465A and the sample of patients could not be replicated, so these results exclude a major effect of this polymorphism in the susceptibility to nonlesional TLE. Larger samples should be tested to determine whether the G1465A in exon 7 of the GABA(B)(1) receptor gene is a susceptibility factor for nonlesional TLE.     

Concerns About Infectious Hepatitis and Delacorte's Welfare Island Fountain

In 1969, philanthropist George T. Delacorte donated a spectacular water fountain to New York City on the southern tip of Welfare Island. Architects designed the fountain's jet geyser to pump a plume of water from the East River more than 400 feet into the air. Public health experts feared that the water from the heavily polluted East River could be a possible source for the spread of infectious hepatitis. Water droplets could be airborne by the prevailing winds to land on the densely populated east side of Manhattan. Upon the insistence of the New York City Department of Health, the fountain's water intake source was chlorinated. This action was initiated before the discovery of the hepatitis A virus (HAV) in 1973. A miscellany of continuing problems plagued the fountain for about two decades, causing the donor to label the fountain "Delacorte's Folly." Eventually, Delacorte gave up. In the late 1980s, the fountain ceased spouting and was finally dismantled.     

Cooling gel improves pulsed KTP laser treatment of facial telangiectasia

BACKGROUND AND OBJECTIVE: Pulsed KTP lasers effectively treat facial telangiectasia without purpura production. Transient side effects following treatment include erythema, edema, and vesiculation leading to crust formation. The aim of this study was to investigate the utility of an aqueous gel in reducing side effects associated with pulsed KTP laser treatment of facial telangiectasia. STUDY DESIGN/MATERIALS AND METHODS: Nineteen patients with extensive facial telangiectasias were treated with a pulsed KTP laser (Versapulse, Coherent, Palo Alto, CA). The laser was used with the water cooled handpiece chilled to 4C, a 4 mm spot size, a 10-millisecond pulse duration and a fluence of 9.5 J/cm2. One side of the face was treated with the laser using the cooling handpiece alone. The other side was treated using the cooling handpiece applied to a 2-mm film of aqueous gel spread over the treatment area. RESULTS: Treatment side effects, including pain, erythema, edema, vesiculation, and crusting were scored following treatment with and without the aqueous gel. Use of the aqueous gel in conjunction with the cooling handpiece decreased the incidence and severity of pain, erythema, edema, and crusting following pulsed KTP laser treatment of facial telangiectasia. Most patients demonstrated 50-75% clearance of their telangiectasias 1 month after one treatment session, and use of the gel did not alter the treatment efficacy. CONCLUSIONS: The application of an aqueous gel during pulsed KTP laser treatment of facial telangiectasia improves treatment associated side effects without affecting vessel clearance.     

Memory deficits induced byγ-l-glutamyl-l-aspartate andd-2-amino-5-phosphonovalerate in a Y-maze avoidance task: relationship to NMDA receptor antagonism

Post-training administration (ICV) of-l-glutamyl-l-aspartate (-lGLA) ord-2-amino-5-phosphonovalerate (d-AP5), a competitive NMDA antagonist, decreased retention of the temporal component but not the spatial discrimination component of a Y-maze active avoidance task. Inverted U-shaped dose-response curves were obtained for the ability of-lGLA andd-AP5 to decrease retention, with maximum effects occurring at doses of 2–20 nmol/mouse for-lGLA and 0.02 nmol/mouse ford-AP5.-lGLA andd-AP5 impaired the traction reflex only at doses (80 and 2 nmol/mouse, respectively) higher than those producing retention deficits. Convulsions induced by ICV administration of 1 nmol NMDA were antagonized by-lGLA andd-AP5 with ED₅₀ values of 46 (32–66) and 0.2 (0.16–0.25) nmol/mouse, respectively. The dose-effect curve of NMDA for producing convulsions was shifted to the right in a parallel manner and to the same extent by 80 nmol-lGLA and by 0.3 nmold-AP5. Taken together, these results are consistent with previous studies suggesting that the behavioral effects of-lGLA might be related to its NMDA receptor antagonist properties. The selectivity of the memory deficits induced by-lGLA andd-AP5 is in agreement with recent reports suggesting a role for NMDA receptors in the mechanisms underlying posttraining organization of memory traces.     

Comparative genomic hybridization detects specific cytogenetic abnormalities in pediatric ependymomas and choroid plexus papillomas

Pathogenesis and genetic abnormalities of ependymomas are not well known and differential diagnosis with choroid plexus tumors may be difficult when these tumors are located in the ventricles. We analyzed 16 samples of primary pediatric ependymomas and seven choroid plexus tumors for significant gains or losses of genomic DNA, using comparative genomic hybridization (CGH). Four ependymoma samples were obtained after surgery for relapse, including one patient whose tumor was analyzed at diagnosis and at first and second relapses. Three out of 16 ependymomas and none of the choroid plexus tumors appeared normal by CGH. In the remaining ependymomas, the number of regions with genomic imbalance was limited. The most frequent copy number abnormality in ependymomas was 22q loss. In one patient from whom multiple samples could be analyzed during tumor progression, no abnormality was present at diagnosis; gain of chromosome 9 and loss of 6q were observed at first relapse and, at second relapse, additional genomic imbalances were loss of 3p, 10q, and chromosome 15. In choroid plexus tumors, recurrent abnormalities were gains of chromosome 7 and region 12q. The recurrent chromosomal abnormalities were clearly different between ependymomas and choroid plexus papillomas (CPP). Recurrent loss of 22q suggests that this region harbors tumor suppressor genes important in the pathogenesis of ependymomas; however, other pathogenic pathways may exist involving 6q and chromosome 10 losses or gain of 1q and chromosome 9. CPP can be distinguished from ependymoma on the basis of CGH abnormalities.     

In vitro and in vivo characterization of TC‐1827, a novel brain α4β2 nicotinic receptor agonist with pro‐cognitive activity

Nicotine activates specific receptors that are cation‐permeable ionic channels located in the central and autonomous nervous systems, as well as at the neuromuscular junction. Administration of nicotine to animals and humans has been shown to enhance cognitive processes. However, side effects linked to the activation of peripheral nicotinic receptors limit the usefulness of nicotine for the treatment of cognitive disorders such as Alzheimer's disease (AD) or mild cognitive impairments (MCI). The synthesis and properties of TC‐1827, a novel metanicotine derivative that activates brain α₄β₂ nicotinic receptors is described. TC‐1827 has high affinity for nicotine‐labeled receptors in the cortex (K_i=34 nM), full‐agonist intrinsic activity in α₄β₂‐mediated neurotransmitter release studies in synaptosomes, and has no functional activity at nicotinic receptors in ganglionic or muscular cell lines. The compound enhances long‐term potentiation in hippocampal slices, a form of synaptic plasticity thought to be involved in information storage at the cellular level. In vivo studies demonstrate that TC‐1827 dose‐dependently occupies thalamic nicotinic receptors labeled with [³H]‐cytisine, increases cortical extracellular acetylcholine levels following oral administration, and enhances cognitive performance in rat and mice behavioral procedures of learning and memory. Pharmacokinetic studies in mice, rats, and monkeys indicated that TC‐1827 has good oral absorption with a first pass effect resulting in bioavailabilities of 13–65% across dose/species. Cardiovascular safety studies indicate good cardiovascular tolerability for this compound. The present data demonstrate that TC‐1827 is a selective and potent activator of brain α₄β₂ nicotinic receptors and is a prototypical member of a new class of compounds with potential utility in the symptomatic treatment of cognitive disorders including AD and MCI. Drug Dev. Res. 62:26–40, 2004. © 2004 Wiley‐Liss, Inc.     

β-Thalassemia: evolving treatment options beyond transfusion and iron chelation

Open in a separate window     

And justice for all? Aboriginal victims of sexual violence

Concern for the recognition, support, and rights of victims within the criminal justice system has grown in recent years, leading to legislative and procedural changes in the administration of justice that have improved the experiences of victims. What is not clear is whether all victims have benefited from changes in the system regardless of race and social class. This study investigates the experiences Aboriginal people who are victims of sexual violence have with the Canadian criminal justice system. The authors seek to explore perspectives about their encounters with the judicial system from the point of first contact with the police through involvement with the court and community service providers, utilizing grounded theory qualitative methodology. They conclude that race is a key determinant in the manner in which a victim will be perceived by the people in the justice system and the manner in which the victim will approach the judicial process.     

Potent therapeutic activity of irinotecan (CPT-11) and its schedule dependency in medulloblastoma xenografts in nude mice

The anti-tumor activity of irinotecan (CPT-11), a DNA-topoisomerase I inhibitor, was evaluated in 5 advanced stage subcutaneous medulloblastoma xenografts in nude mice, using different schedules of administration. With a 5-day schedule, the highest i.v. dose tested (40 mg kg⁻¹ day⁻¹) induced complete regressions in all xenografts but 1, and delays in tumor growth always exceeded 30 days. Two xenografts, IGRM11 and IGRM33, were highly sensitive, and animals survived tumor-free beyond 120 days after treatment. CPT-11 clearly retained its anti-tumor activity at a lower dosage (27 mg kg⁻¹ day⁻¹). CPT-11 was significantly more active than cyclophosphamide, thiotepa and etoposide against the 3 xenografts evaluated. To study the schedule dependency of its anti-tumor activity, CPT-11 was given i.v. at the same total doses over the same period (33 days) using either a protracted or a sequential schedule in IGRM34-bearing mice. With a dose of 10 mg kg⁻¹ day⁻¹ given on days 0–4, days 7–11, days 21–25 and days 28–32 (total dose, 200 mg kg⁻¹), 3 of 6 animals were tumor free on day 378. The same total dose given with a sequential schedule, i.e., 20 mg kg⁻¹ day⁻¹ on days 0–4 and days 28–32, failed to induce complete regression. The plasma pharmacokinetics of CPT-11 and SN-38 were studied in IGRM34-bearing animals after a single i.v. dose of 10 and 40 mg kg⁻¹. The plasma clearance rate of CPT-11 was dose dependent. The ratio between the SN-38 and CPT-11 area under the curve in plasma was 0.4–0.65, i.e., significantly higher than that observed in humans at the maximum tolerated dose (0.01–0.05). Conversely, this ratio was 10-fold lower in tumor than in plasma. Clinical development of irinotecan is warranted in pediatric malignancies. Int. J. Cancer 73:156–163, 1997. © 1997 Wiley-Liss, Inc.