Inhibition of the multidrug transporter P-glycoprotein improves seizure control in phenytoin-treated chronic epileptic rats

PURPOSE: Overexpression of multidrug transporters such as P-glycoprotein (P-gp) may play a significant role in pharmacoresistance, by preventing antiepileptic drugs (AEDs) from reaching their targets in the brain. Until now, many studies have described increased P-gp expression in epileptic tissue or have shown that several AEDs act as substrates for P-gp. However, definitive proof showing the functional involvement of P-gp in pharmacoresistance is still lacking. Here we tested whether P-gp contributes to pharmacoresistance to phenytoin (PHT) by using a specific P-gp inhibitor in a model of spontaneous seizures in rats. METHODS: The effects of PHT on spontaneous seizure activity were investigated in the electrical post-status epilepticus rat model for temporal lobe epilepsy, before and after administration of tariquidar (TQD), a selective inhibitor of P-gp. RESULTS: A 7-day treatment with therapeutic doses of PHT suppressed spontaneous seizure activity in rats, but only partially. However, an almost complete control of seizures by PHT (93 +/- 7%) was obtained in all rats when PHT was coadministered with TQD. This specific P-gp inhibitor was effective in improving the anticonvulsive action of PHT during the first 3-4 days of the treatment. Western blot analysis confirmed P-gp upregulation in epileptic brains (140-200% of control levels), along with approximately 20% reduced PHT brain levels. Inhibition of P-gp by TQD significantly increased PHT brain levels in chronic epileptic rats. CONCLUSIONS: These findings show that TQD significantly improves the anticonvulsive action of PHT, thus establishing a proof-of-concept that the administration of AEDs in combination with P-gp inhibitors may be a promising therapeutic strategy in pharmacoresistant patients.     

Lappensimulator für lokale Defektdeckungen

The Hannover Medical School (Germany) developed the"Flap Lab I" flap simulator, a practical improvement to surgeon training. It provides realistic conditions for understanding and following the principles for planning and performing local flaps for coverage of skin defects. The Flap Lab I has proved to be a very good training model in several training courses. This article introduces among others the Z-flap, reverse Z-flap (so-called hanging man), and Limberg flap.     

SLEEP AND TRAUMA: AN OVERVIEW

Sleep disturbance is common after traumatic events of various types, such as combat, physical trauma, and sexual abuse, and closely intertwined with Posttraumatic Stress Disorder (PTSD), a common outcome of severe and prolonged trauma. This paper reviews the current literature on the significance and characteristics of sleep disturbance occurring in the context of trauma, examines the relationship between sleep disturbance and PTSD, identifies gaps in knowledge relative to the role of sleep disturbance in trauma and PTSD, and discusses the implications of this body of knowledge for clinical practice.     

Prospective screening for subtelomeric rearrangements in children with mental retardation of unknown aetiology: the Amsterdam experience

Objective: The frequency of subtelomeric rearrangements in patients with unexplained mental retardation (MR) is uncertain, as most studies have been retrospective and case retrieval may have been biased towards cases more likely to have a chromosome anomaly. To ascertain the frequency of cytogenetic anomalies, including subtelomeric rearrangements, we prospectively screened a consecutive cohort of cases with unexplained MR in an academic tertiary centre.

Methods: Inclusion criteria were: age <18 years at referral, IQ<85, no aetiological diagnosis after complete examination, which included karyotyping with high resolution banding (HRB).

Results: In 266 karyotyped children, anomalies were detected in 20 (7.5%, seven numerical, 13 structural); 39 cases were analysed by FISH for specific interstitial microdeletions, and anomalies were found in nine (23%). FISH analyses for subtelomeric microdeletions were performed in 184 children (44% moderate-profound MR, 51% familial MR), and one rearrangement (0.5%) was identified in a non-familial MR female with mild MR (de novo deletion 12q24.33-qter). The number of probable polymorphisms was considerable: 2qter (n=7), Xpter (n=3), and Ypter (n=1). A significantly higher total number of malformations and minor anomalies was present in the cytogenetic anomaly group compared to the group without cytogenetic anomalies.

Conclusions: The total frequency of cytogenetic anomalies in this prospective study was high (1:10), but the frequency of subtelomeric rearrangements was low. The most likely explanations are the high quality of HRB cytogenetic studies and the lack of clinical selection bias. Conventional cytogenetic analyses, combined with targeted microdeletion testing, remain the single most effective way of additional investigation in mentally retarded children, also in a tertiary centre.

     

Fulminant B viral hepatitis: role of delta agent

The prevalence of delta-markers among 71 patients with fulminant B viral hepatitis was found to be 33.8%. The majority of the patients with delta-markers showed serologic evidence of simultaneous acute delta-infection and B viral infection. Only 5 of the 24 patients with serologic markers of acute delta-infection in this fulminant group were presumably infected chronically with hepatitis B virus as shown by the absence of immunoglobulin M antibody to hepatitis B core antigen. A study of serologic markers of acute delta-infection among 118 patients with nonfulminant acute B viral hepatitis, in contrast, revealed only 4.2% incidence. This significant difference in the prevalence of simultaneous acute B and delta viral infections between the fulminant and the nonfulminant acute hepatitis groups indicates a higher morbidity rate associated with simultaneous infection. When the fulminant group was divided into acute B viral infection without delta-markers (subgroup 1), simultaneous acute B and delta-infections (subgroup 2), and chronic asymptomatic B with acute delta-infections (subgroup 3), for comparison of survival data, the mortality rate was not significantly different in the first two groups when the patients were age matched.