Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex.

There is increasing evidence that polymorphisms of the adenosine 5' triphosphate membrane transporters ABCB1 (P-glycoprotein, MDR1) may affect expression and function, whereas less information is available about the impact of ABCC2 (multidrug resistance-associated protein (MRP2)) single-nucleotide polymorphisms . Particularly, their role in human kidney for drug elimination and in the etiology of renal cell carcinoma is poorly understood. ABCB1 and ABCC2 mRNA and protein expression levels were determined by real-time polymerase chain reaction or immunohistochemistry in kidney cancer and adjacent unaffected cortex tissue of 82 nephrectomized renal cell cancer (RCC) patients (63 clear-cell RCC (CCRCC), 19 non-CCRCC). The DNA of all patients was genotyped for ABCB1 -2352G>A, -692T>C, 2677G>T/A (Ala893Ser/Thr), and 3435C>T, and ABCC2 -24C>T, 1249G>A (Val417Ile) and 3972C>T. ABCB1 and ABCC2 were less expressed in CCRCC than in normal cortex on mRNA as well as on protein level. Although the overall genotype frequency distribution did not differ between the patients and a matched control group, ABCB1 2677T/A and 3435T genotypes were associated with higher (P=0.02 and P=0.04) and ABCC2 -24 T with lower mRNA levels in normal tissues (0.03). The expression of ABCB1 and ABCC2 was not related to genetic variants in RCC tissue. In a reporter gene assay in HepG2 cells, the ABCC2 -24T construct showed an 18.7% reduced activity (P=0.003). In conclusion, ABCB1 and ABCC2 genotypes modulate the expression in the unaffected renal cortex of RCC patients, possibly contributing to inter-individual differences in drug and xenobiotics elimination. Their role in RCC cancer susceptibility or chemotherapy resistance needs further elucidation.

Expression of multidrug transporters in dysembryoplastic neuroepithelial tumors causing intractable epilepsy.

OBJECTIVE: Dysembryoplastic neuroepithelial tumors (DNT) are relatively benign brain lesions that often cause medically intractable epilepsy. There is mounting evidence that multidrug transporters such as P-glycoprotein (P-gp) or multidrug resistance-associated proteins (MRP) play an important role in the development of resistance to antiepileptic drugs (AED). MATERIAL AND METHODS: In the present study, we examined the expression of several multidrug transporters in 14 cases of DNT. The peritumoral brain tissue as well as 9 cases of arteriovenous malformations (AVM) served as controls. P-gp, MRP2, MRP5 and breast cancer resistance protein (BCRP) expression was evaluated qualitatively and quantitatively using immunohistochemistry. RESULTS: All transporters were overexpressed quantitatively in DNT, but each revealed a different labeling pattern. P-gp and BCRP were predominantly located in the endothelium of brain vessels. MRP5 was detected primarily in endothelial cells, but notably also in neurons. The expression of P-gp, MRP2 and MRP5 was low in AVM, whereas BCRP demonstrated strong staining. Examination of MDR1 gene polymorphisms revealed no correlation with P-gp expression whereas the MRP2 exon 10 G1249A polymorphism was associated with different MRP2 labelling. CONCLUSIONS: Our results show that multidrug transporters are overexpressed in DNT. This finding supports the view that several of these transport proteins may play an important role in the mechanisms of drug resistance in epileptic brain tissue.

Cerebral beta-amyloid deposition is augmented by the -491AA promoter polymorphism in non-demented elderly individuals bearing the apolipoprotein E epsilon4 allele.

The apolipoprotein E epsilon4 allele (APOE, gene; apoE, protein) is widely accepted as a risk factor for Alzheimer's disease (AD). Our previous studies found that APOEepsilon4 promotes AD pathogenesis by fostering the early deposition of the amyloidogenic peptide Abeta in the aging brain. Recent reports suggest that polymorphisms in the upstream promoter region of APOE differentially affect the production of apoE and also may have an important influence on the probability of developing AD. In this study, we asked whether APOE promoter -491 (A/T) variants interact with APOE polymorphisms to modulate the degree of beta-amyloid- and tau-related pathology in the medial temporal lobe of the non-demented elderly. Our results confirm that APOEepsilon4 is associated with increased formation of senile plaques, cerebrovascular amyloid, and neurofibrillary tangles in the medial temporal lobe. We also found that homozygosity for A at position -491 of the APOE promoter (-491AA) correlates with increased Abeta17-24 and Abeta42 deposition in APOEepsilon4-positive cases, but not in cases lacking the epsilon4 allele. In comparison, Abeta burden is significantly less in epsilon4 carriers with the -491AT and -491TT promoter allelotypes. There was no effect of -491 polymorphisms on Abeta40 deposition (which is relatively sparse in the non-demented elderly), on the number of activated microglia, or on the amount of neurofibrillary tangles. We conclude that the amyloidogenic effects of apoE4 are exacerbated by polymorphisms in the APOE promoter that enhance apoE production.

Activated microglia do not mediate the early deposition of Abeta in carriers of the apolipoprotein Eepsilon4 allele.

Activated microglia are a prominent component of the senile plaques in end-stage Alzheimer's disease, but whether microglia contribute to the initiation of the lesions remains unknown. In a previous postmortem study of non-demented elderly cases, we found that amyloidogenesis is advanced by at least 10 years in carriers of the apoEepsilon4 allele. To determine whether microglia are involved in the initial stages of beta-amyloid pathogenesis and whether apoE genotype influences microglial activation, we quantified HLA-DR-immunoreactive microglia in the medial temporal lobe of 229 non-demented humans of various APOE genotypes who had died between 50 and 91 years of age. Our results show that the number of HLA-DR-immunoreactive microglia increases with advancing age in both the gray matter and the white matter. In contrast to amyloid plaques and neurofibrillary tangles, there is no significant correlation between apoE genotype and density of microglia, although apoEepsilon4 homozygotes tended to have more microglia than did other apoE groups. In sections double-immunostained for Abeta and activated microglia, activated microglia were associated with dense-cored plaques but not with diffuse plaques, suggesting that microglial activation is a relatively late event in the genesis of beta-amyloid. Activation of microglia thus appears not to be the initial impetus for Abeta-deposition in the elderly.

The effect of rifampin treatment on intestinal expression of human MRP transporters.

The importance of the ATP-dependent transporter P-glycoprotein, which is expressed in the brush border membrane of enterocytes and in other tissues with excretory function, for overall drug disposition is well recognized. For example, induction of intestinal P-glycoprotein by rifampin appears to be the underlying mechanism of decreased plasma concentrations of P-glycoprotein substrates such as digoxin with concomitant rifampin therapy. The contribution of transporter proteins other than P-glycoprotein to drug interactions in humans has not been elucidated. Therefore, we tested in this study the hypothesis whether the conjugate export pump MRP2 (cMOAT), which is another member of the ABC transporter family, is inducible by rifampin in humans. Duodenal biopsies were obtained from 16 healthy subjects before and after nine days of oral treatment with 600 mg rifampin/day. MRP2 mRNA and protein were determined by reverse transcription-polymerase chain reaction and immunohistochemistry. Rifampin induced duodenal MRP2 mRNA in 14 out of 16 individuals. Moreover, MRP2 protein, which was expressed in the apical membrane of enterocytes, was significantly induced by rifampin in 10 out of 16 subjects. In summary, rifampin induces MRP2 mRNA and protein in human duodenum. Increased elimination of MRP2 substrates (eg, drug conjugates) into the lumen of the gastrointestinal tract during treatment with rifampin could be a new mechanism of drug interactions.

Apolipoprotein E4 promotes the early deposition of Abeta42 and then Abeta40 in the elderly.

The apolipoprotein Eepsilon4 allele (ApoEepsilon4) is associated with a selective increase in deposition of the 40-amino acid form of the beta-amyloid peptide (Abeta40) in endstage Alzheimer's disease. To determine how apoE genotype affects the early events in beta-amyloid pathogenesis, we analyzed the medial temporal lobes of 244 elderly persons who were not clinically demented using antibodies selective for the C termini of Abeta40 and Abeta42. We found that: (1) the number of both Abeta42- and Abeta40-positive senile plaques increase with age; (2) Abeta42 appears at younger ages, and in more amyloid deposits, than does Abeta40 in all ApoE groups; (3) when compared at similar ages, older persons with ApoEepsilon4 are more likely to have Abeta42- and Abeta40-immunoreactive deposits than are persons without ApoEepsilon4; (4) Abeta40-containing plaques arise at least a decade later than do Abeta42 plaques, and are seldom found in the medial temporal lobe of older persons lacking ApoEepsilon4; and (5) in the absence of overt Alzheimer's disease, cerebral amyloid angiopathy is rare in the elderly, but in our sample was significantly augmented in ApoEepsilon4 homozygotes. We conclude that ApoEepsilon4 hastens the onset of Abeta42 deposition in the senescent brain, which in turn fosters the earlier evolution of fibrillar, Abeta40-positive plaques, thereby increasing the risk of Alzheimer's disease.

Fatal subarachnoid hemorrhage after endoscopic third ventriculostomy. Case report.

In recent years, endoscopic third ventriculostomy has become a well-established procedure for the treatment of various forms of noncommunicating hydrocephalus. Endoscopic third ventriculostomy is considered to be an easy and safe procedure. Complications have rarely been reported in the literature. The authors present a case in which the patient suffered a fatal subarachnoid hemorrhage (SAH) after endoscopic third ventriculostomy. This 63-year-old man presented with confusion and drowsiness and was admitted in to the hospital in poor general condition. Computerized tomography scanning revealed an obstructive hydrocephalus caused by a tumor located in the cerebellopontine angle. An endoscopic third ventriculostomy was performed with the aid of a Fogarty balloon catheter. Some hours postoperatively, the patient became comatose. Computerized tomography scanning revealed a severe perimesencephalic-peripontine SAH and progressive hydrocephalus. Despite emergency external ventricular drainage, the patient died a few hours later. Although endoscopic third ventriculostomy is considered to be a simple and safe procedure, one should be aware that severe and sometimes fatal complications may occur. To avoid vascular injury, perforation of the floor of the third ventricle should be performed in the midline, halfway between the infundibular recess and the mammillary bodies, just behind the dorsum sellae.

Fatal subarachnoid hemorrhage after endoscopic third ventriculostomy. Case report.

In recent years, endoscopic third ventriculostomy has become a well-established procedure for the treatment of various forms of noncommunicating hydrocephalus. Endoscopic third ventriculostomy is considered to be an easy and safe procedure. Complications have rarely been reported in the literature. The authors present a case in which the patient suffered a fatal subarachnoid hemorrhage (SAH) after endoscopic third ventriculostomy. This 63-year-old man presented with confusion and drowsiness and was admitted in to the hospital in poor general condition. Computerized tomography scanning revealed an obstructive hydrocephalus caused by a tumor located in the cerebellopontine angle. An endoscopic third ventriculostomy was performed with the aid of a Fogarty balloon catheter. Some hours postoperatively, the patient became comatose. Computerized tomography scanning revealed a severe perimesencephalic-peripontine SAH and progressive hydrocephalus. Despite emergency external ventricular drainage, the patient died a few hours later. Although endoscopic third ventriculostomy is considered to be a simple and safe procedure, one should be aware that severe and sometimes fatal complications may occur. To avoid vascular injury, perforation of the floor of the third ventricle should be performed in the midline, halfway between the infundibular recess and the mamillary bodies, just behind the dorsum sellae.

Apolipoprotein E4 promotes incipient Alzheimer pathology in the elderly.

To evaluate the influence of the apolipoprotein E (ApoE) epsilon4 allele on the age at which Alzheimer-like lesions appear in the brain, we analyzed the degree of cerebral beta-amyloidosis and neurofibrillary tangle formation in the hippocampal formation and adjacent cortical areas 28, 27, and 36 of persons who had died between the ages of 50 and 93 years and who had shown no signs of clinical dementia. The occurrence of the three common polymorphisms of the ApoE gene in this sample of 147 routine autopsy cases from eastern Germany was comparable to previously reported values in European and North American populations: ApoEepsilon2/2, 0.7%; ApoEepsilon2/3, 14.3%; ApoEepsilon2/4, 4.1%; ApoEepsilon3/3, 56.5%; ApoEepsilon3/4, 22.4%; and ApoEepsilon4/4, 2.0%. Nondemented persons carrying the ApoEepsilon4 allele were significantly more likely to have senile plaques, diffuse amyloid deposits, cerebrovascular amyloid, and neurofibrillary tangles than were those lacking E4. Comparing the two largest ApoE subgroups, ApoEepsilon3/3 and ApoEepsilon3/4, the relative increase in the occurrence of beta-amyloid in the epsilon3/4 group was evident by the mid-60s, with the relative increase in neurofibrillary tangles in this group emerging slightly earlier. The ApoEepsilon2 allele appears to delay the appearance of the lesions somewhat. We conclude that ApoEepsilon4 promotes the early appearance of beta-amyloid and neurofibrillary tangles in the elderly and that the increased frequency of these lesions is related to the higher risk of Alzheimer disease in persons bearing the ApoEepsilon4 allele.

Endoscopic treatment of an unusual multicystic lesion of the brainstem: case report.

We report a 32-year-old woman who presented with headache, mild hemiparesis and clumsiness of the right hand. CT and MRI revealed a multicystic formation of the brainstem involving the thalamus and midbrain. We inspected the formation endoscopically and fenestrated some of the cysts. In one of the cysts we found an anomalous vascular nidus. Postoperative MRI revealed reduction of the fenestrated cysts. The patient is doing well 13 months after endoscopy and has no neurological deficit.

Location of nucleolar organizer regions (AgNORs) in the nuclei of astrocytic tumors.

Seventy-nine astrocytic tumors classified according to the WHO classification and stained with a modified AgNOR staining technique were analyzed with the help of an automatic image analyzing system. With increasing malignancy there is an increase of AgNORs per cell. Furthermore, AgNORs move from a more central to a more peripheral position within the nucleus, thus leading to a significant increase of the AgNOR count at the periphery of the nucleus. An inverse relation was found at the center. With regard to AgNORs, there are little differences between anaplastic astrocytomas and small cell glioblastomas. The most striking differences were seen between differentiated (grade 2) and anaplastic (grade 3) astrocytomas.

Nucleolar organizer regions (AgNORs) in astrocytic tumors.

79 astrocytic tumors classified according to the WHO classification and stained with a modified AgNOR staining technique were analysed with the help of an automatic image analysing system. The number and area of AgNORs were determined. The mean AgNOR number per nucleus was 1.28 in pilocytic, 1.98 in differentiated, 2.84 in anaplastic astrocytomas, 3.33 in small cell glioblastomas and 4.24 in multiforme glioblastomas. The area of all AgNORs per cell ranged from 0.95 microns2 (pilocytic astrocytomas), 1.53 microns2 (differentiated astrocytomas), 2.73 microns2 (anaplastic astrocytomas), 3.1 microns2 (small cell glioblastomas) to 4.12 microns2 (multiforme glioblastomas). With regard to AgNORs there are little differences between anaplastic astrocytomas and small cell glioblastomas.

Melorheostosis--a very rare entity in neurosurgery.

Melorheostosis is of minor importance in neurosurgery. A case of this disease is reported, which required neurosurgical activity and the literature is reviewed.