HS Cases Research Articles

Major vault protein, a marker of drug resistance, is upregulated in refractory epilepsy.

The molecular basis of drug resistance in epilepsy is being explored. Two proteins associated with drug resistance in cancer, P-glycoprotein and multidrug resistance-associated protein 1, are upregulated in human epileptogenic pathologies. Other proteins associated with resistance in cancer include major vault protein (MVP) and breast cancer resistance protein (BCRP). We hypothesized that these proteins would also be upregulated in human epileptogenic pathologies. Hippocampal sclerosis (HS), focal cortical dysplasia (FCD), and dysembryoplastic neuroepithelial tumor (DNT) were studied by using immunohistochemistry for MVP and BCRP. Nonepileptogenic control and histologically normal brain adjacent to epileptogenic tissue were used for comparison. MVP and BCRP were expressed ubiquitously in brain capillary endothelium. Ectopic upregulation of MVP was seen in hilar neurons in HS, dysplastic neurons in FCD, and lesional neurons in DNT. Only in HS cases were rare extralesional neurons immunoreactive. Glial upregulation was not seen. There was no qualitative upregulation of BCRP. These results show that more than one resistance protein may be upregulated in a given epileptogenic pathology and may contribute to drug resistance. Determination of the types, amounts, and distribution of such proteins will be necessary for rational treatment for drug resistance in epilepsy.

Hepatosplenic T-Gammadelta Lymphoma in a Patient with Crohn's Disease Treated with Azathioprine

Hepatosplenic γ δ T-cell lymphoma (HS γ δ TCL) is an uncommon type of peripheral T-cell lymphoma, which has been associated in some cases with immunosuppression, mainly after solid organ transplants. We describe a case of HS γ δ TCL with a leukaemic course in a patient with Crohn's disease who had received azathioprine during the previous 55 years. Sinusoidal infiltration by atypical lymphocytes was observed in the liver, spleen and bone marrow and the typical cytogenetic abnormalities (isochromosome 7 and trisomy 8) were found. The patient did not respond to intensive chemotherapy. This case shows the importance of ruling out HS γ δ TCL in patients with hepatosplenomegaly, B-symptoms and any immunosuppressive condition.

The Role of Drug-resistance Proteins in Medically Refractory Epilepsy.

Drug Resistance in Epilepsy: Expression of Drug-resistance Proteins in Common Causes of Refractory Epilepsy Sisodiya SM, Lin WR, Harding BN, Squier MV, Thom M. Brain 2002;125(Pt 1):22–31 Epilepsy is resistant to drug treatment in about one third of cases, but the mechanisms underlying this drug resistance are not understood. In cancer, drug resistance has been studied extensively. Among the various resistance mechanisms, overexpression of drug-resistance proteins, such as multidrug resistance gene-1 P-glycoprotein (MDR1) and multidrug resistance–associated protein 1 (MRP1), has been shown to correlate with cellular resistance to anticancer drugs. Previous studies in human epilepsy have shown that MDR1 and MRP1 also may be overexpressed in brain tissue from patients with refractory epilepsy; expression has been shown in glia and neurons, which do not normally express these proteins. We examined expression of MDR1 and MRP1 in refractory epilepsy from three common causes, dysembryoplastic neuroepithelial tumors (DNTs; eight cases), focal cortical dysplasia (FCD; 14 cases), and hippocampal sclerosis (HS; eight cases). Expression was studied immunohistochemically in lesional tissue from therapeutic resections and compared with expression in histologically normal adjacent tissue. With the most sensitive antibodies, in all eight DNT cases, reactive astrocytes within tumor nodules expressed MDR1 and MRP1. In five of eight HS cases, reactive astrocytes within the gliotic hippocampus expressed MDR1 and MRP1. Of 14 cases of FCD, MDR1 and MRP1 expression was noted in reactive astrocytes in all cases. In five FCD cases, MRP1 expression also was noted in dysplastic neurons. In FCD and DNTs, accentuation of reactivity was noted around lesional vessels. Immunoreactivity was always more frequent and intense in lesional reactive astrocytes than in glial fibrillary acidic protein–positive reactive astrocytes in adjacent histologically normal tissue. MDR1 is able to transport some antiepileptic drugs (AEDs), and MRP1 also may do so. The overexpression of these drug-resistance proteins in tissue from patients with refractory epilepsy suggests one possible mechanism for drug resistance in patients with these pathologies. We propose that overexpressed resistance proteins reduce the interstitial concentration of AEDs in the vicinity of the epileptogenic pathology and thereby render the epilepsy caused by these pathologies resistant to treatment with AEDs. P-Glycoprotein and Multidrug Resistance–associated Protein Are Involved in the Regulation of Extracellular Levels of the Major Antiepileptic Drug Carbamazepine in the Brain Potschka H, Fedrowitz M, Loscher W. Neuroreport 2001;12:3557–3560 Despite considerable advances in the pharmacotherapy of epilepsy, about 30% of epilepsy patients are refractory to antiepileptic drugs (AEDs). In most cases, a patient who is resistant to one major AED also is refractory to other AEDs, although these drugs act by different mechanisms. The mechanisms that lead to drug resistance in epilepsy are not known. Recently, overexpression of multidrug transporters, such as P-glycoprotein (PGP) and multidrug resistance–associated protein (MRP), has been reported in surgically resected epileptogenic human brain tissue and suggested to contribute to the drug resistance of epilepsy. However, it is not known to what extent multidrug transporters such as PGP or MRP are involved in transport of AEDs. In the present study, we used in vivo microdialysis in rats to study whether the concentration of carbamazepine in the extracellular fluid of the cerebral cortex can be enhanced by inhibition of PGP or MRP, using the PGP inhibitor verapamil and the MRP inhibitor probenecid. Local perfusion with verapamil or probenecid via the microdialysis probe increased the extracellular concentration of carbamazepine. The data indicate that both PGP and MRP participate in the regulation of extracellular brain concentrations of the major AED carbamazepine.

Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy.

Epilepsy is resistant to drug treatment in about one-third of cases, but the mechanisms underlying this drug resistance are not understood. In cancer, drug resistance has been studied extensively. Amongst the various resistance mechanisms, overexpression of drug resistance proteins, such as multi-drug resistance gene-1 P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1), has been shown to correlate with cellular resistance to anticancer drugs. Previous studies in human epilepsy have shown that MDR1 and MRP1 may also be overexpressed in brain tissue from patients with refractory epilepsy; expression has been shown in glia and neurones, which do not normally express these proteins. We examined expression of MDR1 and MRP1 in refractory epilepsy from three common causes, dysembryoplastic neuroepithelial tumours (DNTs; eight cases), focal cortical dysplasia (FCD; 14 cases) and hippocampal sclerosis (HS; eight cases). Expression was studied immunohistochemically in lesional tissue from therapeutic resections and compared with expression in histologically normal adjacent tissue. With the most sensitive antibodies, in all eight DNT cases, reactive astrocytes within tumour nodules expressed MDR1 and MRP1. In five of eight HS cases, reactive astrocytes within the gliotic hippocampus expressed MDR1 and MRP1. Of 14 cases of FCD, MDR1 and MRP1 expression was noted in reactive astrocytes in all cases. In five FCD cases, MRP1 expression was also noted in dysplastic neurones. In FCD and DNTs, accentuation of reactivity was noted around lesional vessels. Immunoreactivity was always more frequent and intense in lesional reactive astrocytes than in glial fibrillary acidic protein-positive reactive astrocytes in adjacent histologically normal tissue. MDR1 is able to transport some antiepileptic drugs (AEDs), and MRP1 may also do so. The overexpression of these drug resistance proteins in tissue from patients with refractory epilepsy suggests one possible mechanism for drug resistance in patients with these pathologies. We propose that overexpressed resistance proteins lower the interstitial concentration of AEDs in the vicinity of the epileptogenic pathology and thereby render the epilepsy caused by these pathologies resistant to treatment with AEDs.

Altered Hippocampal Kainate-Receptor mRNA Levels in Temporal Lobe Epilepsy Patients

This study determined whether hippocampal kainate (KA) receptor mRNA levels were increased or decreased in temporal lobe epilepsy patients compared with nonseizure autopsies. Hippocampal sclerosis (HS;n= 17), nonsclerosis (non-HS;n= 11), and autopsy hippocampi (n= 9) were studied for KA1–2 and GluR5–7 mRNA levels using semiquantitativein situhybridization techniques, along with neuron densities. Compared with autopsy hippocampi, HS and non-HS cases showed decreased GluR5 and GluR6 hybridization densities per CA2 and/or CA3 pyramid. Furthermore, HS patients demonstrated increased KA2 and GluR5 hybridization densities per granule cell compared with autopsy hippocampi. These findings indicate that chronic temporal lobe seizures were associated with differential changes in hippocampal KA1–2 and GluR5–7 hybridization densities that vary by subfield and pathology group. In temporal lobe epilepsy patients, these results support the hypothesis that pyramidal cell GluR5 and GluR6 mRNA levels are decreased as a consequence of seizures, and in HS patients granule cell KA2 and GluR5 mRNA levels are increased in association with aberrant fascia dentata mossy fiber sprouting and/or hippocampal neuronal loss.

Erythrocyte membrane skeleton abnormalities in hereditary spherocytosis.

Erythrocyte ghosts from eight individuals with hereditary spherocytosis have been compared with respect to their protein compositions as judged by SDS gel electrophoresis, their ease of spectrin extractability, and their freeze-etch electron microscopic appearance after incubation in condition designed to promote aggregation of the intramembrane particles. Four of these HS cases were unrelated, while the other four represented two generations from a single family, including a pair of identical twins, one of whom had not undergone splenectomy when this investigation was initiated. Of the four unrelated cases, one showed no departures from normal under the conditions of this investigation, whereas the other three exhibited features which suggested a membrane skeleton lesion. In one of these there was a reduced proportion of spectrin tetramers relative to dimers in 4 degrees C extracts, while the two remaining cases exhibited abnormal intramembrane particle aggregation. The four related cases had almost identical variations from normal. Spectrin was not extractable from their ghost membranes during a mild extraction incubation which removed spectrin from normal control ghosts. However, the intramembrane particle aggregation subsequently induced in these ghosts was of a degree unobtainable in normal ghosts without such spectrin extraction. In addition the ghosts from one twin, the only one of these patients who had not undergone splenectomy at the start of this investigation, showed a reduced amount of band 4.2. However, when this patient's blood was re-tested after splenectomy, this protein was found to be at normal levels. Our results support the view that hereditary spherocytosis is not a single disease, but is rather a term used to describe a variety of different molecular lesions of the erythrocyte membrane skeleton with similar clinical manifestations.

Wave induced random oscillations of pipelines during laying

A study is presented of wave induced random vibrations of pipelines suspended in the J-configuration. The analysis is based on the use of Morison's equation for the hydrodynamic forces and a linearized spectral analysis of response in the first five normal modes of oscillation. Three pipelines are studied for an operational sea state of HS = 4.57 m and a survival case of HS = 12 m. Extensive results are given for the expected peak deflections and stresses. Under operational conditions the expected peak stresses were found to be well below the maximum allowable stress for both the pipeline and the concrete coating, but in the survival case the peak stresses were found to be unacceptably high.