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PubMed1994

Lateralization of temporal lobe epilepsy based on regional metabolic abnormalities in proton magnetic resonance spectroscopic images.

Magnetic resonance spectroscopic imaging (MRSI) is capable of determining the spatial distribution in vivo of cerebral metabolites, including N-acetylaspartate (NAA), a compound found only in neurons. We used this technique in 10 patients with temporal lobe epilepsy (TLE) to determine the location of maximal neuronal/axonal loss or damage and to evaluate the potential of MRSI for presurgical lateralization. Asymmetry of the relative resonance intensity of NAA to creatine was determined for mid and posterior regions of the temporal lobes defined anatomically and also for "metabolic lesions" defined as the regions of maximal abnormality on MRSI. MRSI revealed decreased relative signal intensity in at least one temporal lobe of all patients. Two patients had a widespread reduction in NAA in both temporal lobes. The region of maximal abnormality was usually in the posterior temporal lobe but sometimes in the mid temporal lobe. The side of lowest NAA was ipsilateral to the clinical electroencephalographic lateralization in all patients. Lateralization based on NAA to creatine correlated with the atrophy of amygdala and hippocampus in 8 patients who showed this on magnetic resonance imaging volumetric measurements. MRSI can demonstrate regional neuronal loss or damage that correlates with clinical electroencephalographic and structural lateralization in temporal lobe epilepsy. The ability to identify a region of maximal metabolic abnormality on spectroscopic images may confer greater sensitivity than that available from single voxel methods. The maximal metabolic abnormality may not be located in a voxel defined a priori, and based on anatomical considerations, without knowledge of the distribution of the metabolic abnormality.

Adult↗

PubMed1996

Normalization of contralateral metabolic function following temporal lobectomy demonstrated by 1H magnetic resonance spectroscopic imaging.

We studied 10 medically intractable temporal lobe epilepsy (TLE) patients prior to surgery using proton magnetic resonance spectroscopic imaging (MRSI) to localize seizure foci. We found significantly elevated creatine/N-acetylaspartate (Cr/NAA) unilaterally in 8 and bilaterally in 2 patients. Five patients have been studied again 1 year after surgery. In the 2 patients with bilateral temporal seizure onsets, MRSI showed normalization of Cr/NAA in the unoperated contralateral tissue following surgical elimination of seizures. This study suggests that metabolic recovery can occur in contralateral temporal areas following surgical treatment of partial epilepsy.

Adult↗

PubMed2005

Preferred conformations of peptides containing tert-leucine, a sterically demanding, lipophilic alpha-amino acid with a quaternary side-chain Cbeta atom.

Terminally protected homopeptides of tert-leucine, from the dimer to the hexamer, co-oligopeptides of tert-leucine in combination with alpha-aminoisobutyric acid or glycine residues up to the hexamer level, and simple dipeptides representing known scaffolds for catalysts in asymmetric organic reactions were prepared by solution methods and fully characterized. The results of conformation analysis, performed by use of FT-IR absorption, NMR, CD, and X-ray diffraction techniques, indicate that this hydrophobic alpha-amino acid with tetrasubstitution at the Cbeta atom is structurally versatile. We show that it prefers extended or semiextended conformations, but can also be accommodated in folded structures, provided that these are biased by the presence of helicogenic residues. The current large-scale production of Tle, combined with its conformational preferences unravelled in this work, should make this bulky, hydrophobic, Calpha-trisubstituted alpha-amino acid a regular building block of any strategy seeking to tailor peptides with improved catalytic and pharmacological properties.

Hydrophobic and Hydrophilic Interactions↗

PubMed2004

Coexpression of Cux-1 and Notch signaling pathway components during kidney development.

Cux-1 is the murine homologue of the Drosophila gene cut, which is required for cellular differentiation in several tissues, including the wing margin and Malpighian tubule. Mammalian cut proteins function as cell cycle-dependent transcriptional repressors in proliferating cells. Targets of Cux-1 repression include the cyclin kinase inhibitors p21 and p27. However, little is known about the regulation of Cux-1. In Drosophila, multiple genetic interactions between Cut and the Notch and Wingless signaling pathways occur during wing development. To begin to determine whether Cux-1 regulation by the Notch signaling pathway is conserved in mammals, we compared the expression patterns of Cux-1, the murine Notch receptors (Notch 1-4), and the murine ligands (Jagged 1, Jagged 2, and Delta 1) during murine embryogenesis and kidney development. In this report, we demonstrate that Cux-1 expression overlaps with that of Notch signaling pathway components in multiple tissues during embryonic development. In the developing kidney, Cux-1 expression overlaps with that of Notch pathway components in the condensing mesenchyme, in pretubular aggregates (comma and S-shaped bodies), and in the presumptive podocytes of capillary loop stage glomeruli. Furthermore, Cux-1 was significantly up-regulated in the rat kidney epithelial cell line RKE expressing a constitutively active Notch 1, and this finding was associated with a reduction of p27. Moreover, Cux-1 interacts with the Groucho homolog TLE-4, a corepressor recruited by Notch effector proteins. Taken together, these results suggest that Cux-1 may function in the context of the Notch signaling pathway in multiple tissues during mammalian embryogenesis.

Animals↗

PubMed2005

Mammalian Groucho homologs: redundancy or specificity?

The proteins termed TLE in humans, Grg in mice and Groucho in Drosophila constitute a family of transcriptional corepressors. In mammalians there are five different genes encoding an even larger number of proteins. Interactions between these TLE/Grg proteins and an array of transcription factors has been described. But is there any specificity? This review tries to make a case for a non-redundant function of individual TLE/Grg proteins. The specificity may be brought about by a tightly controlled temporo-spatial expression pattern, post-translational modifications, and subtle structural differences leading to distinct preferences for interacting transcription factors. A confirmation of this concept will ultimately need to come from genetic experiments.

Animals↗

PubMed2006

Transcriptional co-repressors of Runx2.

Runx2 is an essential transcription factor for skeletal mineralization because it stimulates osteoblast differentiation of mesenchymal stem cells, promotes chondrocyte hypertrophy, and contributes to endothelial cell migration and vascular invasion of developing bones. Runx2 is also expressed during mouse embryo development in nascent mammary gland epithelium. Recent evidence implicates deregulation of Runx2 as a contributing factor in breast cancer-induced osteolysis and invasion, as well as in ectopic vascular calcification. Like other Runt domain proteins, Runx2 is a context-dependent transcriptional activator and repressor of genes that regulate cellular proliferation and differentiation. Proteins that temporally and spatially associate with Runx2 dictate these opposing transcriptional activities. Recent studies have identified several co-repressor proteins that bind to Runx2 to regulate gene expression. These co-factors include histone deacetylases (HDACs), transducin-like enhancer of split (TLE) proteins, mSin3a, and yes-associated protein (YAP). These proteins do not bind DNA themselves and appear to act by preventing Runx2 from binding DNA, altering chromatin structure, and/or by possibly blocking co-activator complexes. The nuclear localization of several of these factors is regulated by extracellular signaling events. Understanding the mechanisms whereby co-repressor proteins affect Runx2 activity during normal cellular development and tumor progression will identify new therapeutic targets for skeletal disorders such as osteoporosis and for bone metastatic cancers.

Animals↗

PubMed2006

Alterations in intranuclear localization of Runx2 affect biological activity.

The transcription factor Runx2 controls osteoblast proliferation and differentiation. Runx2 organizes and assembles gene-regulatory complexes in nuclear microenvironments where target genes are activated or suppressed in a context-dependent manner. Intranuclear localization of Runx2 is mediated by the nuclear matrix-targeting signal (NMTS), an autonomous motif with a loop (L1)-turn-loop (L2) structure that forms predicted protein-protein interaction surfaces. Here we examined the functional consequences of introducing mutations in the L1 and L2 loops of the NMTS. These mutant proteins enter the nucleus, interact with the hetero-dimeric partner Cbfbeta, and bind to DNA in vitro and in vivo. In addition, these mutants retain interaction with the carboxy-terminus interacting co-regulatory proteins that include TLE, YAP, and Smads. However, two critical mutations in the L2 domain of the NMTS decrease association of Runx2 with the nuclear matrix. These subnuclear targeting defective (STD) mutants of Runx2 compromise target gene activation or repression. The biological significance of these findings is reflected by decreased osteogenic differentiation of mesenchymal progenitors, concomitant with major changes in gene expression profiles, upon expression of the STD Runx2 mutant. Our results demonstrate that fidelity of temporal and spatial localization of Runx2 within the nucleus is functionally linked with biological activity.

Amino Acids↗

PubMed2005

Nogo signaling and non-physical injury-induced nervous system pathology.

The Nogo gene products were described first as myelin-associated inhibitors that prevent neuronal regeneration upon injury. Recent findings have also implicated Nogo in several neuronal pathologies that are not induced by physical injury. Nogo-A may be an important determinant of autoimmune demyelinating diseases, as active immunization with Nogo-A fragments attenuates the symptoms of experimental autoimmune encephalomyelitis (EAE). Nogo-A levels are elevated markedly in hippocampal neurons of patients with temporal lobe epilepsy (TLE), in brain and muscle of patients with amyotrophic lateral sclerosis (ALS), and in schizophrenic patients. Concrete evidence for a direct role of Nogo-A in the latter neuropathies is not yet available, but such a role is logically in line with new findings associated with localization of Nogo-A and Nogo-Nogo-66 receptor (NgR)-mediated signaling. We speculate on possible linkages between the effect of aberrant elevation of Nogo levels and the signaling consequences that could lead to nervous system pathology.

Amyotrophic Lateral Sclerosis↗

PubMed2006

Reorganization of CA3 area of the mouse hippocampus after pilocarpine induced temporal lobe epilepsy with special reference to the CA3-septum pathway.

We showed that when CA3 pyramidal neurons in the caudal 80% of the dorsal hippocampus had almost disappeared completely, the efferent pathway of CA3 was rarely detectable. We used the mouse pilocarpine model of temporal lobe epilepsy (TLE), and injected iontophoretically the anterograde tracer phaseolus vulgaris leucoagglutinin (PHA-L) into gliotic CA3, medial septum and the nucleus of diagonal band of Broca, median raphe, and lateral supramammillary nuclei, or the retrograde tracer cholera toxin B subunit (CTB) into gliotic CA3 area of hippocampus. In the afferent pathway, the number of neurons projecting to CA3 from medial septum and the nucleus of diagonal band of Broca, median raphe, and lateral supramammillary nuclei increased significantly. In the hippocampus, where CA3 pyramidal neurons were partially lost, calbindin, calretinin, parvalbumin immunopositive back-projection neurons from CA1-CA3 area were observed. Sprouting of Schaffer collaterals with increased number of large boutons in both sides of CA1 area, particularly in the stratum pyramidale, was found. When CA3 pyramidal neurons in caudal 80% of the dorsal hippocampus have almost disappeared completely, surviving CA3 neurons in the rostral 20% of the dorsal hippocampus may play an important role in transmitting hyperactivity of granule cells to surviving CA1 neurons or to dorsal part of the lateral septum. We concluded that reorganization of CA3 area with its downstream or upstream nuclei may be involved in the occurrence of epilepsy.

Animals↗

PubMed2006

1H magnetic resonance spectroscopy at 3 T in cryptogenic and mesial temporal lobe epilepsy.

The objectives of this work were to compare concentrations of N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln), Glx (=Glu + Gln), myo-inositol (mI), total creatine (Cre) and other metabolites in the temporal lobes of patients with mesial temporal lobe epilepsy (mTLE), cryptogenic TLE (cTLE), who show no abnormalities in high-resolution MRI, and healthy controls using single voxel (1)H MRS at 3 T. Twelve patients with mTLE, nine with cTLE and 22 controls were investigated using a short echo time STEAM protocol. Voxels were positioned bilaterally in the medial and lateral temporal lobes. Spectra were processed with LCModel. Significantly lower mean NAA were detected in mTLE patients (P < 0.001) and a trend towards lower NAA in cTLE patients compared to controls (P = 0.053). Glx was not different between groups. Estimates of Glu showed a different metabolic pattern in mTLE with elevated Glu in lateral compared with medial voxels on the ipsilateral side to seizure onset (P = 0.019). MI concentrations were significantly lower in cTLE (P < 0.001) and in mTLE patients (P = 0.005) compared with healthy controls. MI/Cre was significantly reduced in cTLE patients only (P = 0.004). The results confirm low NAA in mTLE and to a lesser extent in cTLE patients. MI and mI/Cre were identified as potential metabolic indicators of the epileptogenic area in cTLE.

Adult↗

PubMed2006

Fluorescein-labeled stable neurotensin derivatives.

Neurotensin(8-13) analogs containing a glycine or 5-aminovaleroyl spacer were labeled with fluorescein through formation of an N-terminal thiourea function. The receptor binding was measured in HT-29 cell cultures and showed a substantial decrease in affinity, especially for the metabolically stabilized [MeArg(9), Tle(11)] analog. Using fluorescence microscopy, the internalization of the fluorescent neurotensin analogs into HT-29 cells was observed.

Fluorescein-5-isothiocyanate↗

PubMed1996

Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif.

Groucho is a protein implicated in Notch signaling and involved in segmentation and neural development in Drosophila. Groucho forms transcription complexes with the basic helix-loop-helix proteins encoded by the hairy/Enhancer of split ("hairy-like") gene family. These interactions are mediated by the carboxyl-terminal WRPW motif of Hairy-like proteins. We are interested in determining whether Groucho and its mammalian homologues, the TLE proteins, perform conserved functions. We show that TLE1 interacts with HES-1, a murine homologue of Drosophila Hairy-like proteins, both in the yeast two-hybrid assay and in an interaction assay based on glutathione S-transferase fusion proteins. These results show that Groucho/TLE proteins and Hairy-like/HES proteins are involved in similar interactions in Drosophila and mammals and further suggest that these proteins perform conserved cellular functions.

Amino Acid Sequence↗

PubMed1999

Hippocampal involvement in spatial and working memory: a structural MRI analysis of patients with unilateral mesial temporal lobe sclerosis.

Forty-seven patients with unilateral temporal lobe epilepsy (TLE) were investigated on the Nine-Box Maze. The task was designed to compare working memory and spatial mapping theories of the functions of the hippocampus and provide measures of spatial, object, working, and reference memory. The results extended our previous findings in a larger group of patients. Spatial memory deficits across both working and reference memory conditions were found in patients with a right epileptogenic focus. There was no evidence of an object working memory deficit, but a nonlateralized impairment in object reference memory was revealed, which is consistent with our previous findings. The pattern of results was confirmed in a subgroup of 33 patients with unilateral atrophy localized to the hippocampus and parahippocampal gyrus, as verified by volumetric analysis of magnetic resonance images. In addition spatial memory errors significantly correlated with volumetric measures of mesial temporal lobe structures and not with measures of the remaining temporal cortex. In contrast, object reference memory errors correlated with volumetric measures of the temporal cortex and not with mesial temporal lobe structures. These findings support a specialized role for the right hippocampal region in spatial memory.

Adult↗

PubMed2001

Single and Dual Pathologies of the Temporal Lobe: Effects on Cognitive Function in Children with Epilepsy.

The neuropathologies associated with temporal lobe epilepsy (TLE) are heterogeneous. The performance of 61 children with single pathology of hippocampal sclerosis (HS), temporal lobe tumor, or cortical dysplasia (CD) or dual pathology of HS + tumor or HS + CD was examined on measures of intelligence, language, memory, and executive function. Children with single pathologies performed significantly better than did children with HS + CD on all standardized measures of IQ. Children with tumors performed significantly better than children with dual pathology on receptive vocabulary. These results support prior research of an association between neuropathology and cognitive function in children with epilepsy and extend the findings to include additional neuropathologies and measures of cognitive functioning.

Journal Article↗

PubMed1987

Molecular cloning and DNA homology of plasmid-mediated beta-lactamase genes.

Molecular cloning of DNA fragments between 1.5 and 8 kb from BamHI, EcoRI, HindIII, SalI, or Sau3A digests permitted the isolation of structural genes coding for TEM-1, ROB-1, OXA-1, OXA-3, OXA-4, OXA-5, PSE-1, PSE-2, PSE-3, PSE-4, CARB-3, CARB-4, AER-1, and LCR-1 beta-lactamases. Ampicillin-resistant clones were selected and it was confirmed that they contained the respective beta-lactamase genes by isoelectric focusing. Detailed physical maps of 14 different recombinant plasmids were constructed using 8 restriction endonucleases. Plasmid deletions and lacZ fusions were used to localize the beta-lactamase structural genes. DNA probes were constructed for the TEM-1, ROB-1, OXA-1, and PSE-1 genes. Under conditions of high stringency, hybridization was observed between the genes for TEM-1 and TEM-2 or TLE-1, OXA-1 and OXA-4, and PSE-1 and PSE-4 or CARB-3, while the ROB-1 gene probe showed no cross-hybridization. Such bla gene probes should facilitate studies of beta-lactamase molecular epidemiology.

Cloning, Molecular↗

PubMed1998

[Ictal syncopes. Cardiac sympathetic innervation disorder as the etiology?].

We report 3 cases of an ictal sinus arrest. All patients suffered from temporal lobe epilepsy (TLE). Seizures were monitored with simultaneous video-eeg during preoperative epilepsy diagnosis. One patient with cortical dysplasia, who frequently suffered from long lasting syncopes, had a nearly completely missing cardiac sympathetic innervation in MIBG-SPECT (=Meta-Iodide-Benzyle-Guanidine-single-photon-emission tomography). Cardiac investigation including long-term ECG and echocardiography had shown normal findings. After epilepsy surgery the syncopal events in all patients disappeared. A dominant parasympathetic ictal stimulus following excitation of the reticular formation might cause the ictal bradycardia and sinus arrest. A missing sympathetic innervation, possibly occurring as fehlbildung together with cortical dysplasia, which makes autoregulation impossible, might then be the explanation for sudden cardiac ictal death.

Adult↗

PubMed2000

[Temporal lobe epilepsy: longitudinal clinical, neuropsychological and psychosocial follow-up of surgically and conservatively managed patients].

Little is known about the differential long-term outcome from surgical and nonsurgical therapy in patients with chronic epilepsy. In the present study, 161 surgically or nonsurgically treated patients with drug-resistant temporal lobe epilepsy (TLE) were re-evaluated according to a detailed clinical, neuropsychological, and psychosocial protocol with a mean follow-up interval of 58 months. Freedom from seizures was achieved in 64% of the surgical group; yet 23% of the nonsurgical patients became seizure-free as a result of modifications in drug therapy. Generally, socioeconomic development was poorer in nonsurgical than in surgical patients. Freedom from seizures, employment, and the absence of depression were significant determinants of better quality of life. As for neuropsychological outcome, verbal memory impairment was common after left-sided temporal resection; however, there was no evidence of a marked progression of cognitive impairment after the first postoperative year. In nonsurgical patients, too, cognitive capacities were surprisingly stable over time, although persisting seizures and good baseline performance predicted a poorer neuropsychological outcome.

Adult↗

PubMed2006

fMRI evaluation of hemispheric language dominance using various methods of laterality index calculation.

Several functional MR imaging studies evaluating the lateralisation of linguistic functions in patients who underwent Wada testing have been reported. There is extensive variance in the Laterality index (LI) calculation across the studies, and the optimal calculation method remains unclear. We attempted to calculate the LI in different ways in the same subjects, in order to find the LI calculation method with the highest correlation to the Wada test. Fifteen patients (10 females, 5 males) suffering from medically intractable temporal lobe epilepsy (TLE) (12 left, 3 right) were admitted for the study. The patients underwent a standardized bilateral intracarotid short-acting barbiturate test. Language testing included spontaneous speech, oral comprehension, reading, object and picture naming, and repetition. All the tasks were scored separately in order to increase the possibility of correlation between Wada and LI. A silent phonemic verbal fluency task (VFT) was used as a language paradigm for functional measurement. Regions of interest (ROIs), with a known association with language function (Broca's area, the lateral prefrontal cortex, etc.), were defined. First, the LIs were calculated from the ROIs using a previously reported method (simple suprathreshold count). Next, we used several new methods of LI calculation (t-weighting of voxels, methods independent of the choice of the statistical threshold, etc.) The most significant correlation with Wada was proven in the LIs that were evaluated from Broca's area (up to R = 0.94, P = 1 x 10(-7)). However, the new LI calculation methods used in the present study did not produce a statistically significant benefit in comparison to previously reported methods.

Adult↗