Restricted driving for people with epilepsy.
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Automobile Driving↗
Biomedical subjects
J Engel
Publications and source records attributed to J Engel.
A new crystal structure, Ca2+ dependence and mutational analysis reveal molecular details of E-cadherin homoassociation.
Electron microscopy of ECADCOMP, a recombinant E-cadherin ectodomain pentamerized by the assembly domain of cartilage oligomeric matrix protein, has been used to analyze the role of cis-dimerization and trans-interaction in the homophilic association of this cell adhesion molecule. The Ca2+ dependency of both interactions was investigated. Low Ca2+ concentrations (50 microM) stabilized the rod-like structure of E-cadherin. At medium Ca2+ concentration (500 microM), two adjacent ectodomains in a pentamer formed cis-dimers. At high Ca2+ concentration (>1 mM), two cis-dimers from different pentamers formed a trans-interaction. The X-ray structure of an N-terminal domain pair of E-cadherin revealed two molecules per asymmetric unit in an intertwisted X-shaped arrangement with closest contacts in the Ca2+-binding region between domains 1 and 2. Contrary to previous data, Trp2 was docked in the hydrophobic cavity of its own molecule, and was therefore not involved in cis-dimerization of two molecules. This was supported further by W2A and A80I (a residue involved in the hydrophobic cavity surrounding Trp2) mutations in ECADCOMP which both led to abrogation of the trans- but not the cis-interaction. Structural and biochemical data suggest a link between Ca2+ binding in the millimolar range and Trp2 docking, both events being essential for the trans-association.
Base Sequence↗
Prevalence rates of otitis media with effusion from 0 to 2 years of age: healthy-born versus high-risk-born infants.
In a prospective-longitudinal study, prevalence rates of otitis media with effusion (OME) were analysed in 150 healthy-born and 100 high-risk-born infants, aged 0-2 years. In order to determine OME, otoscopy and tympanometry were performed at 3-monthly intervals beginning at term date. The Maastricht Otitis Media with Effusion Study (MOMES) algorithm was used to standardize the diagnosis. The distribution of relevant background characteristics was similar in both groups except for gestational age and birth weight, which were significantly lower (P < 0.001) in the high-risk-born group. The ratio of unilateral:bilateral OME was 2:3. Prevalence rates of OME were strongly associated with age (P < 0.001). During the first months of life, OME prevalence rates increased rapidly in both groups, but did not differ significantly. However, from the age of 6 months on, OME prevalence rates of the high-risk group became significantly higher compared with the normal group (P < 0.05). The peak prevalence of OME (59% in the high-risk group versus 49% in the normal group) was observed around the age of 10 months. Although gradually decreasing prevalence rates were noted in both groups with aging, the differences between high-risk and normal infants remained, at least up to 24 months. In conclusion, OME is a very prevalent, age-dependent disorder during infancy, especially in high-risk infants. Peak prevalence of OME was found in the second half of the first year of life.
Age Factors↗
Contributions of the ionization states of acidic residues to the stability of the coiled coil domain of matrilin-1.
The pKa values of eight glutamic acid residues in the homotrimeric coiled coil domain of chicken matrilin-1 have been determined from 2D H(CA)CO NMR spectra recorded as a function of the solution pH. The pKa values span a range between 4.0 and 4.7, close to or above those for glutamic acid residues in unstructured polypeptides. These results suggest only small favorable contributions to the stability of the coiled coil from the ionization of its acidic residues.
Animals↗
The timing of surgical intervention for mesial temporal lobe epilepsy: a plan for a randomized clinical trial.
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Epilepsy, Temporal Lobe↗
High-frequency oscillations in human brain.
Ripples are 100-200 Hz short-duration oscillatory field potentials that have recently been recorded in rat hippocampus and entorhinal cortex. They reflect fast IPSPs on the soma of pyramidal cells, which occur during synchronous afferent excitation of principal cells and interneuron networks. We now describe two similar types of high-frequency field oscillations recorded from the entorhinal cortex and hippocampus of patients with mesial temporal lobe epilepsy. The first type appears be the human equivalent of normal ripples in the rat. The second, which we have termed fast ripples (FR), are in the frequency range of 250-500 Hz. FR are found in the epileptogenic region and may reflect pathological hypersynchronous population spikes of bursting pyramidal cells.
Action Potentials↗
Small conductance potassium channels cause an activity-dependent spike frequency adaptation and make the transfer function of neurons logarithmic.
We made a computational model of a single neuron to study the effect of the small conductance (SK) Ca2+-dependent K+ channel on spike frequency adaptation. The model neuron comprised a Na+ conductance, a Ca2+ conductance, and two Ca2+-independent K+ conductances, as well as a small and a large (BK) Ca2+-activated K+ conductance, a Ca2+ pump, and mechanisms for Ca2+ buffering and diffusion. Sustained current injection that simulated synaptic input resulted in a train of action potentials (APs) which in the absence of the SK conductance showed very little adaptation with time. The transfer function of the neuron was nearly linear, i.e., both asymptotic spike rate as well as the intracellular free Ca2+ concentration ([Ca2+]i) were approximately linear functions of the input current. Adding an SK conductance with a steep nonlinear dependence on [Ca2+]i (. Pflügers Arch. 422:223-232; Köhler, Hirschberg, Bond, Kinzie, Marrion, Maylie, and Adelman. 1996. Science. 273:1709-1714) caused a marked time-dependent spike frequency adaptation and changed the transfer function of the neuron from linear to logarithmic. Moreover, the input range the neuron responded to with regular spiking increased by a factor of 2.2. These results can be explained by a shunt of the cell resistance caused by the activation of the SK conductance. It might turn out that the logarithmic relationships between the stimuli of some modalities (e.g., sound or light) and the perception of the stimulus intensity (Fechner's law) have a cellular basis in the involvement of SK conductances in the processing of these stimuli.
Action Potentials↗
Interstitial deletion of 8(q13q22) in diffuse large B-cell gastric lymphoma.
An interstitial deletion in the long arm of chromosome 8 as the sole structural anomaly was detected in a primary gastric diffuse large B-cell lymphoma, high-grade mucosa-associated lymphoid tissue (MALT) type, from a 74-year-old man. Low-grade MALT lymphoma was not seen in the sections submitted for examination. Helicobactor pylori organisms were found in a biopsy performed prior to resection of the tumor. The karyotype was described as 45, X,-Y,del(8)(q13q22). No rearrangement between chromosome 8 and others was detected with fluorescence in situ hybridization using a whole chromosome 8 painting probe. Fluorescence in situ hybridization with the C-MYC gene showed its normal location at 8q24 on both chromosomes 8 without rearrangement. Amplification of C-MYC was not detected in interphase cells. Deletion of 8q may represent a unique genomic alteration in this particular subtype of primary gastric lymphoma.
Aged↗
Homophilic adhesion by cadherins.
Cadherins mediate cell-cell adhesion through homophilic interactions. High-resolution structures have greatly enhanced our understanding of this phenomenon over the past few years. Nonetheless, some of the original concepts about cadherin interactions need revision, with the new structural and additional mutagenesis data currently available. Furthermore, in vivo studies on cadherins have provided supplementary information.
Amino Acid Substitution↗
Oral treatment of visceral leishmaniasis with miltefosine.
In a pilot trial, 28 days of oral treatment with 100-200 mg miltefosine (hexadecylphosphocholine) per day cured 14 of 15 patients with Indian visceral leishmaniasis (VL). To extend the testing of this regimen, 45 additional subjects with VL, of whom 17 had failed previous antimony therapy, were treated with 100 (N = 17), 150 (N = 18) or 200 (N = 10) mg/day. Enrollment at 200 mg/day was stopped after three subjects in this treatment arm developed reversible but serious (grade-3) adverse reactions. The overall clinical and parasitological responses to miltefosine were rapid, with 40 [89%; 95% confidence interval (CI) = 76%-96%] and 44 (98%; CI = 88%-100%) of the patients apparently cured on days 14 and 28, respectively. The one 'treatment failure' recorded on day 28 (and at 6 months) was a subject lost to follow-up. Those apparently cured by day 28 included six patients (one on 100 mg, two on 150 mg and three on 200 mg/day) removed from treatment on days 7-17 because of grade-3 diarrhoea (two cases), vomiting (two cases), diarrhoea and hepatotoxicity (one case) or nephrotoxicity (one case). Transient, mild-moderate vomiting and/or diarrhoea were common during weeks 1-2 and about 25% of the patients also developed primarily mild, self-limited increases in concentrations of aspartate aminotransferase and creatinine and/or blood urea nitrogen. At a 6-month follow-up, all 44 patients apparently cured at day 28 were considered complete responders (definitive cures), including the six treated for only 7-17 days. These results indicate that 100 mg miltefosine/day for 28 days is a promising oral-treatment regimen for VL cases, including those with antimony-unresponsive infections.
Administration, Oral↗
Rewarding community-based preceptors.
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Community-Institutional Relations↗
Changes in blood lymphocyte populations after multiple trauma: association with posttraumatic complications.
OBJECTIVE: To study the frequency of several lymphocyte subsets, circulating cytokines, and prostaglandin plasma values at their time course over a period of 14 days in severely injured trauma patients in relation to the development of sepsis and multiple organ failure (MOF). DESIGN: Prospective study. SETTING: An operative intensive care unit (ICU) of a university hospital. PATIENTS: Sixty-eight consecutive severely injured trauma patients. INTERVENTIONS: Patients were separated into patients without sepsis and MOF (group 1, n = 51), and patients who developed sepsis and MOF (group 2, n = 17) during their stay in the ICU. Therapy was adjusted to the standards of modern intensive care management by physicians who were not involved in the study. MEASUREMENTS AND MAIN RESULTS: In arterial blood samples, the profile of lymphocyte subset frequencies was performed by flow cytometry and, together with interleukin (IL)-1, IL-10, tumor necrosis factor (TNF)-alpha soluble TNF-alpha receptor 1 (sTNF-alpha r1 [p55]), and prostaglandin E2 (PGE2alpha)-alpha, serially measured after arrival in the ICU (baseline value) and during the next 14 days. Mean plasma IL-1 (29.3 +/- 5.8 [SD] pg/mL), TNF-alpha (138.5 +/- 22.4 pg/mL), and soluble TNF-alpha r1 (6.1 +/- 0.3 ng/mL) values were significantly higher in group 2 patients before clinical evidence of sepsis and MOF. With the onset of severe infections in group 2 patients, IL-1, TNF-alpha, and sTNF-alpha r1 values decreased, while immunosuppressive IL-10 (191.7 +/- 29.1 pg/mL) and PGE2alpha (87.7 +/- 20.4 pg/mL) values further increased and remained elevated during the time course. Analysis of lymphocyte subsets revealed a fall in total lymphocyte levels, in CD4+ T lymphocytes, and natural killer (NK) cells, but no change in CD8+ T lymphocyte subset. Despite a marked change in the T helper (CD4+) to T suppressor (CD8+) ratio (from 1:1.72 to 1:1.10), patients without MOF (group 1) had no significant difference in any of the markers tested compared with baseline values. In addition to the inverse CD4+/CD8+ T cell ratio (from 1:1.75 to 1:0.91) and increased activated T cells, each of these markers was significantly elevated and peaked before the onset of MOF in group 2 patients. CONCLUSIONS: A severely depressed cellular immune response associated with increased suppressive mediators might be closely related to the development of severe sepsis and MOF in trauma patients. Therefore, an in-depth understanding of the deficits in host defense following multiple trauma will provide the basis for therapeutic interventions.
Adult↗
Electrophysiologic analysis of a chronic seizure model after unilateral hippocampal KA injection.
PURPOSE: Unilateral intrahippocampal injections of kainic acid (KA) in rats produce spontaneous recurrent limbic seizures and morphologic changes in hippocampus that resemble hippocampal sclerosis in patients with medically refractory mesial temporal lobe epilepsy (MTLE), that form of temporal lobe epilepsy (TLE) associated with hippocampal sclerosis. Interictal in vivo electrophysiologic studies have revealed high-frequency (250-500 Hz) oscillations, termed fast ripples (FRs). These oscillations may uniquely occur in or adjacent to the site of hippocampal KA injection, in areas that generate spontaneous seizures. Similar field potentials also have been demonstrated in the epileptogenic region of patients with TLE. We have now characterized ictal electrographic patterns in this rat model for comparison with those in human TLE and begun to evaluate the role of FRs in the transition to ictus in the KA-treated rat. METHODS: Rats received unilateral intrahippocampal injections of KA and, after the development of spontaneous seizures, were implanted with multiple fixed and moveable microelectrodes for single unit, field potential, and EEG recording. They were then monitored by using video-EEG telemetry for several weeks to capture and evaluate electrographic and behavioral seizure types. Results were correlated with Timm's stain demonstration of mossy fiber sprouting. RESULTS: Low-voltage fast (LVF) and hypersynchronous electrographic ictal-onset patterns were seen in the KA-treated rat that resembled similar ictal-onset patterns in patients with TLE. Hypersynchronous, but not LVF, ictal discharges were associated with recurrent FRs. As in the human, hypersynchronous ictal onsets originated predominantly in hippocampus, whereas LVF ictal onsets more often involved extrahippocampal structures. LVF ictal onsets occurred during wakefulness or paradoxical sleep and were usually associated with motor behavior, whereas hypersynchronous ictal onsets occurred during slow-wave sleep or periods of immobility and were not associated with motor behavior unless there was transition to another ictal electrographic pattern. Mossy fiber sprouting did not correlate with the frequency of ictal EEG discharges exhibited by each rat but was greater in those rats that demonstrated frequent behavioral seizures. CONCLUSIONS: The electrographic features of spontaneous seizures in the KA-treated rat resemble those of patients with medically refractory TLE with respect to EEG pattern and localization. Our data suggest that hypersynchronous ictal onsets represent epileptogenic disturbances in hippocampal circuits, whereas LVF ictal onsets may involve extrahippocampal areas having more direct connections to the motor system. Hypersynchronous seizures may involve the same neuronal mechanisms that generate interictal FRs.
Animals↗
Hippocampal and entorhinal cortex high-frequency oscillations (100--500 Hz) in human epileptic brain and in kainic acid--treated rats with chronic seizures.
PURPOSE: Properties of oscillations with frequencies >100 Hz were studied in kainic acid (KA)-treated rats and compared with those recorded in normal and kindled rats as well as in patients with epilepsy to determine differences associated with epilepsy. METHODS: Prolonged in vivo wideband recordings of electrical activity were made in hippocampus and entorhinal cortex (EC) of (a) normal rats, (b) kindled rats, (c) rats having chronic recurrent spontaneous seizures after intrahippocampal KA injections, and (d) patients with epilepsy undergoing depth electrode evaluation in preparation for surgical treatment. RESULTS: Intermittent oscillatory activity ranging from 100 to 200 Hz in frequency and 50-150 ms in duration was recorded in CA1 and EC of all three animal groups, and in epileptic human hippocampus and EC. This activity had the same characteristics in all groups, resembled previously observed "ripples" described by Buzsáki et al., and appeared to represent field potentials of inhibitory postsynaptic potentials (IPSPs) on principal cells. Unexpectedly, higher frequency intermittent oscillatory activity ranging from 200 to 500 Hz and 10-100 ms in duration was encountered only in KA-treated rats and patients with epilepsy. These oscillations, termed fast ripples (FRs), were found only adjacent to the epileptogenic lesion in hippocampus, EC, and dentate gyrus, and appeared to represent field potential population spikes. Their local origin was indicated by correspondence with the negative phase of burst discharges of putative pyramidal cells. CONCLUSIONS: The persistence of normal-appearing ripples in epileptic brain support the view that inhibitory processes are preserved. FRs appear to be field potentials reflecting hyper-synchronous bursting of excitatory neurons and provide an opportunity to study the role of this pathophysiologic phenomenon in epilepsy and seizure initiation. Furthermore, if FR activity is unique to brain areas capable of generating spontaneous seizures, its identification could be a powerful functional indicator of the epileptic region in patients evaluated for surgical treatment.
Action Potentials↗
Personality disorders among medically refractory epileptic patients.
DSM-III-R personality disorders were assessed in 52 medically refractory epileptic patients. Twenty-one percent of patients met threshold criteria for an Axis II disorder. Dependent and avoidant personality disorders were the most common diagnoses. Epileptic aura was positively correlated with the presence of personality disorders. These results support previous studies that have demonstrated an increased rate of dependency and social isolation in epileptic patients. This increase may be related to disrupted psychosocial functioning as a consequence of having epilepsy, to disrupted neuronal function in central nervous system structures as a consequence of repeated epileptiform discharge or to some combination of the two.
Adult↗
Cerebral microdialysis combined with single-neuron and electroencephalographic recording in neurosurgical patients. Technical note.
Monitoring physiological changes in the brain parenchyma has important applications in the care of neurosurgical patients. A technique is described for measuring extracellular neurochemicals by cerebral microdialysis with simultaneous recording of electroencephalographic (EEG) and single-unit (neuron) activity in selected targets in the human brain. Forty-two patients with medically intractable epilepsy underwent stereotactically guided implantation of a total of 423 intracranial depth electrodes to delineate potentially resectable seizure foci. The electrodes had platinum alloy contacts for EEG recordings and four to nine 40-microm microwires for recording single-unit neuron activity. Eighty-six electrodes also included microdialysis probes introduced via the electrode lumens. During monitoring on the neurosurgical ward, electrophysiological recording and cerebral microdialysis sampling were performed during seizures, cognitive tasks, and sleep-waking cycles. The technique described here could be used in developing novel approaches for evaluation and treatment in a variety of neurological conditions such as head injury, subarachnoid hemorrhage, epilepsy, and movement disorders.
Adolescent↗
[Evaluation of guidelines in oncology].
Several activities regarding guidelines have been developed in Germany within a short time. It is desirable especially in the field of oncology that procedures are stated as proven effective, proven ineffective, and possibly effective by using procedures of evidence based medicine. However, the low impact of guidelines on the medical practice has to be taken into account. The kind of errors of known deviations should decrease the expectations. This altogether should motivate for a closer look what really happens in the daily routine. It should also reflect the hospital's and physician's outcome and might provide hints to medical standards. Improving the still insufficient documentation, which may describe quality of care, can provide important features. This has to be remembered when undertaking activities regarding guidelines.
Evaluation Studies as Topic↗
A phase I single-dose trial of gadolinium texaphyrin (Gd-Tex), a tumor selective radiation sensitizer detectable by magnetic resonance imaging.
Gadolinium Texaphyrin (Gd-Tex) is a radiation sensitizer with a novel mechanism of action that sensitizes both oxic and hypoxic cells, localizes selectively in tumors, and is detectable by magnetic resonance imaging (MRI). This Phase I single-dose trial of Gd-Tex administered concurrently with radiation therapy was carried out to determine the maximally tolerated dose (MTD), dose-limiting toxicities, pharmacokinetics, and biolocalization of Gd-Tex as determined by MRI. Adults with incurable cancers of any histology requiring radiation therapy were eligible. A single i.v. dose of Gd-Tex was followed at least 2 h later by radiation therapy. The Gd-Tex dose was escalated in cohorts of 3 to 5 patients. Thirty-eight patients (median age, 58 years; range, 35-77 years) with incurable cancers of the lung (26), cervix (3), or other solid tumors (9) received a total of 41 single administrations of Gd-Tex. The Gd-Tex dose was escalated from 0.6 to 29.6 mg/kg. Irradiated sites included the thorax, brain, pelvis, bone, soft tissue, and sites of nodal metastases. The MTD was 22.3 mg/kg, determined by reversible acute tubular necrosis as the dose-limiting toxicities. Gd-Tex selectively accumulated in primary and metastatic tumors as demonstrated by MRI. No increase in radiation toxicity to normal tissues was seen. The median half-life of Gd-Tex after single-dose administration is 7.4 h. This study demonstrates that Gd-Tex is well tolerated in doses below the MTD, and that there is selective biolocalization in tumors. The maximum recommended dose for single administrations is 16.7 mg/kg.
Adult↗