Temporal lobe epilepsy: where do the seizures really begin?

Defining precisely the site of seizure onset has important implications for our understanding of the pathophysiology of temporal lobe epilepsy, as well as for the surgical treatment of the disorder. Removal of the limbic areas of the medial temporal lobe has led to a high rate of seizure control, but the relatively large number of patients for whom seizure control is incomplete, as well as the low rate of surgical cure, suggests that the focus extends beyond the usual limits of surgical resection. Reevaluation of the extent of the pathology, as well as new data from animal models, suggests that the seizure focus extends, at least in some cases, beyond the hippocampus and amygdala, which are usually removed at the time of surgery. In this review, we examine current information about the pathology and physiology of mesial temporal lobe epilepsy syndrome, with special emphasis on the distribution of the changes and patterns of seizure onset. We then propose a hypothesis for the nature of the seizure focus in this disorder and discuss its clinical implications, with the ultimate goal of improving surgical outcomes and developing nonsurgical therapies that may improve seizure control.     

Herztumor als Manifestation eines Li-Fraumeni-Syndroms

Li-Fraumeni syndrome is a disease with autosominal dominant heredity, characterized by the appearance of multiple tumors in young patients, first described in 1969 by Frederick P. Li and Joseph F Fraumeni. The cause for the disease is generally a mutation in the p53 gene on chromosome 17. We report a 46-year-old female patient. In February 2008 she presented at our clinic with a cardiac tumor. CT imaging showed a tumor obstructing the right ventricular outflow tract (RVOT) and infiltrated the pulmonary artery. Intraoperatively, the tumor reached the bifurcation of the pulmonary artery with infiltration of the pericardium. To remove the tumor, the pulmonary artery had to be resected. The RVOT was reconstructed with a Contegra^© graft. Due to the medical history we performed a genetic analysis, which confirmed Li-Fraumeni syndrome. Histology showed a low differentiated pleomorphic sarcoma. After 9 months of follow-up the patient has fully recovered with no tumor recurrence of the heart.     

Three-Dimensional Imaging Reveals Ureteric and Mesenchymal Defects in Fgfr2-Mutant Kidneys

Current techniques to morphologically characterize the processes of nephrogenesis and ureteric branching during kidney development have many limitations. Here, we used in vivo three-dimensional analysis to study renal development in mice lacking fibroblast growth factor receptor 2 in the ureteric bud (Fgfr2^UB−/−) and in littermate controls. We found that Fgfr2^UB−/− mice have more severe defects in ureteric branching morphogenesis than previously reported, including significantly fewer branches and tips than control mice. Furthermore, these mice had decreased ureteric volume and surface area and longer ureteric segments than control mice. We also observed previously unrecognized abnormalities in nephrogenesis, including a gradual increase in volume and surface area during maturation from renal vesicles to mature nephrons, in the mutant mice. Finally, we quantified many events of normal renal development that are either difficult or impossible to measure without this three-dimensional technique. In summary, the three-dimensional approach is a powerful and quantitative means to characterize branching morphogenesis and nephrogenesis.Development of the permanent kidney (metanephros) occurs via reciprocal signaling between metanephric mesenchyme and the ureteric bud.^1,2 The mesenchyme stimulates outgrowth of the bud from the Wolffian duct. After the bud invades the mesenchyme, it undergoes mostly dichotomous branching at the ampullary tips. In turn, ureteric tips stimulate mesenchymal tissue to differentiate into nephrons, the functional units of the kidney. The ureteric epithelium ends as a complex three-dimensional (3D) structure draining thousands (rodent) to millions (humans) of nephrons in each kidney through single ureters.³ Insufficient or inefficient ureteric branching results in an underendowment of nephrons, predisposing to kidney disease.^4,5Characterizing ureteric branching in 3D kidneys has been challenging. It is largely undertaken in cultured kidney explants that flatten, allowing for visualization of branching by whole-mount immunofluorescent staining or transgenic green fluorescence protein (GFP) expression. Branching is quantitated by counting ureteric tips or branch points in whole-mount specimens. Recently, investigators have used confocal microscopy to quantify ureteric branch lengths in cultured kidney explants.⁶ Despite the elegant studies, these approaches are limited in that explants are removed from their physiologic environment and fail to grow in three dimensions. There is also significant variability due to operator skill, culture conditions (media, incubator conditions), and in precise ages of the explants.Recent reports have focused on ureteric branching in kidneys that developed in vivo. One study estimated branch lengths and tips in fluorescently labeled serial ultrathick murine cryosections.⁷ Despite the elegant study, the technique was limited by the need for special stains and potential sampling errors caused by the thick sections. Others have generated 3D images of fluorescently labeled ureteric trees using confocal microscopy without quantitating branching.^7,8 Finally, the EuReGene database contains elegant 3D images of kidneys that can be linked to segment specific gene expression (see http://www.euregene.org/atlas/pages/section_viewer.html?project=euregene_atlas&stack=fullResKidney_substack); however, there is not an ability to measure ureteric branching. Thus, there are no published data to quantitatively describe 3D ureteric branching morphogenesis.Concurrent with ureteric branching is nephron differentiation/maturation (nephrogenesis). Initially, nephrogenic mesenchyme condenses around ureteric tips and converts into epithelial vesicles (the most immature “nephrons”). Vesicles differentiate into comma- and then S-shaped bodies that join with the collecting ducts before maturing into functional nephrons (glomeruli and tubules).^9–12 Experimentally, assessment of nephron formation in real kidneys has mostly been qualitative. Quantitative assessment has only been achieved in vitro utilizing immunohistochemical staining in cultured kidney explants. Thus relative distribution, 3D structure, and size of developing nephrons (vesicles through mature nephrons) have not been determined to our knowledge.Given limitations of the aforementioned techniques, we developed a new 3D procedure to quantify branching morphogenesis and nephrogenesis of developing murine kidneys in vivo. We hypothesized that the technique would reveal new insights about renal defects in mice with deletion of fibroblast growth factor receptor 2 in the ureteric bud (Fgfr2^UB−/−),¹³ and reveal new data about renal development in controls.     

Cocaine-induced dopamine overflow within the nucleus accumbens measured by in vivo microdialysis: a meta-analysis

A meta-analysis was conducted on data obtained from published articles which used in vivo microdialysis to assess dose-response curves of cocaine on dopamine (DA) overflow within the nucleus accumbens (NAC). Different experimental and biological parameters such as route of administration (ip, sc, iv, local), rat and mouse strains, gender, age aspects, and regions cannulated (NAC core and shell) were considered. Data from 116 experiments involving 833 animals (out of 266 publications) fulfilled our selection criteria and were analyzed in relation to absolute basal DA levels, the maximum peak of DA overflow (peak [%] baseline) and the time when this peak (peak time) occurred. Our meta-analysis revealed that absolute basal DA levels lie at 2.39 nM (median of all experiments) and that cocaine-induced DA overflow in the NAC is significantly enhanced in a linear dose-response fashion within the applied dose range as the regression function increases following either iv or ip administration. Peak time was reached fastest in iv experiments and slowest following local application. Furthermore, it was shown in ip experiments that the higher the dose, the longer it took to reach the zenith. Results from the NAC shell region displayed greater DA overflow as compared with the NAC core. DA overflow properties following cocaine treatment in mice did not differ from that in rats. Thus, neither species differences nor other biological factors such as, age, gender, and rat/mouse strain have a pronounced impact on cocaine-induced DA overflow. Technical parameters of the microdialysis procedure such as calcium concentration of the perfusion medium and collected sample amount have also no significant effect in terms of DA overflow properties (peak [%] baseline and peak time) following cocaine treatment. In conclusion, these data may be deemed useful for textbook knowledge and a better comparability of data given by the generalization of already existing data as well as for investigators in maximizing the effect of cocaine-induced DA overflow. Finally, this study examplifies how meta- analyses may be applied to a wide range of data within the field of neurochemistry.     

Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls

Mood and anxiety disorders are considered stress-related diseases characterized by an impaired function of mineralocorticoid and glucocorticoid receptors (MR and GR, respectively), the major regulatory elements of the hypothalamus–pituitary–adrenocortical (HPA) axis. A number of so-called chaperone proteins moderate the function of these receptors. Genetic variations in one of these chaperones, FKBP5, were associated with antidepressant treatment response in depression and with a major risk-factor for the development of posttraumatic stress disorder. To further investigate the effect of FKPB5 polymorphisms on corticosteroid receptor-mediated HPA axis regulation we conducted the Trier Social Stress test, a standardized procedure to evaluate psychosocial stress response, in 64 healthy volunteers. We genotyped rs4713916, rs1360780 and rs3800737, the three single nucleotide polymorphisms (SNPs) in the FKBP5 region which had shown the strongest effect in previous studies. In addition, we evaluated the effects of the GR polymorphisms Bcl1 and N363S as well as the MR polymorphism I180V. Subjects homozygous for any of the FKBP5 variants displayed an incomplete normalization of the stress-elicited cortisol secretion. This was also observed following a second test additionally accompanied by an increased self-reported anxiety. Regarding GR and MR, only carriers of the Bcl1 variant displayed an altered cortisol response in the prognosticated direction. While Bcl1 was predominantly associated with anticipatory cortisol, homozygous carriers of the FKBP5 minor allele showed insufficient cortisol recovery and increased self-reported anxiety after psychosocial stress. This reaction pattern suggests that subjects carrying these variants are at risk of displaying chronically elevated cortisol levels after repeated stress constituting a risk factor for stress-related diseases.