Differential glutamate dehydrogenase (GDH) activity profile in patients with temporal lobe epilepsy

PURPOSE: Pathophysiologic mechanisms underlying temporal lobe epilepsy (TLE) are still poorly understood. One major hypothesis links alterations in energy metabolism to glutamate excitotoxicity associated with seizures in TLE. The purpose of this study was to determine whether changes in the activities of enzymes critical in energy and neurotransmitter metabolism contributed to the alterations in metabolic status leading to the excitotoxic effects of glutamate. METHODS: Activities of four key enzymes involved in energy metabolism and glutamate cycling in the brain [aspartate aminotransferase (AAT), citrate synthase (CS), glutamate dehydrogenase (GDH), and lactate dehydrogenase (LDH)] were measured in anterolateral temporal neocortical and hippocampal tissues obtained from three different groups of medically intractable epilepsy patients having either mesial, paradoxical, or mass lesion-associated temporal lobe epilepsy (MTLE, PTLE, MaTLE), respectively. RESULTS: We found that GDH activity was significantly decreased in the temporal cortex mainly in the MTLE group. A similar trend was recognized in the hippocampus of the MTLE. In all three patient groups, GDH activity was considerably lower, and AAT and LDH activities were higher in cortex of MTLE as compared with the corresponding activities in hippocampus (p<0.05). In the MTLE cortex and hippocampus, GDH activities were negatively correlated with the duration since the first intractable seizure. CONCLUSIONS: Our results support the hypothesis suggesting major alteration in GDH activity mainly in the MTLE group. It is proposed that significant alterations in the enzyme activities may be contributing to decreased metabolism of glutamate, leading to its accumulation.     

Different inflammatory responses induced by three LDL‐lowering apheresis columns

Low‐density lipoprotein (LDL) apheresis is well‐established in selected patients with uncontrolled LDL levels. As such treatment affects biomarkers important in atherosclerosis and acute coronary syndromes, we systematically compared the inflammatory response induced by three LDL apheresis columns. Three patients with heterozygous familial hypercholesterolemia participated in a cross‐over study with six consecutive treatments with three different LDL apheresis columns: DL‐75 (whole blood adsorption), LA‐15 (plasma adsorption), and EC‐50W (plasma filtration). Biochemical parameters and inflammatory biomarkers, including complement activation products and 27 cytokines, chemokines, and growth factors were measured before and after treatment. Complement was activated through the alternative pathway. The final end product sC5b‐9 increased significantly (P < 0.01) and equally with all devices, whereas the anaphylatoxins C3a and C5a were lower by use of the adsorption columns. Hs‐CRP was reduced by 77% (DL‐75), 72% (LA‐15), and 43% (EC‐50W). The cytokines were consistently either increased (IL‐1ra, IP‐10, MCP‐1), decreased (IFN‐γ, TNF‐α, RANTES, PDGF, VEGF), or hardly changed (including IL‐6, IL8, MIP‐1αβ) during treatment. The changes were in general less pronounced with the adsorption columns. All columns reduced LDL significantly and to the same extent. In conclusion, three LDL‐apheresis devices with equal cholesterol‐lowering effect differed significantly with respect to the inflammatory response. J. Clin. Apheresis, 2009. © 2009 Wiley‐Liss, Inc.     

Reproductive factors and risk of meningioma and glioma

Female sex hormones have previously been suggested as possible risk factors for brain tumors, but published studies have reported conflicting results. We conducted a population-based case-control study of glioma (n=626) and meningioma (n=906) cases and randomly selected controls stratified on age and geographic region (n=1,774) in Denmark, Finland, Norway, Sweden, and the United Kingdom. Unconditional logistic regression was used to estimate odds ratios (OR) for glioma and meningioma in relation to reproductive factors. A decreased glioma risk was associated with ever-pregnancy compared with never-pregnancy [OR, 0.8; 95% confidence interval (95% CI), 0.6-1.0]. Meningioma risk among women ages <50 years was increased in relation to number of pregnancies leading to a live birth (OR, 1.8; 95% CI: 1.1-2.8 for giving birth to 3 children compared with nulliparous women; P(trend) among parous women=0.01). This relation was not found for older women. Breast-feeding among parous women increased the glioma risk (OR, 2.2; 95% CI, 1.3-3.9 for breast-feeding 36 months or more compared with breast-feeding 3 months or less). Menopausal status and age at menopause were not associated with meningioma or glioma risk. Our findings imply that reproductive hormones may influence the occurrence of meningioma and glioma.     

Use of mobile phones in Norway and risk of intracranial tumours.

To test the hypothesis that exposure to radio-frequency electromagnetic fields from mobile phones increases the incidence of gliomas, meningiomas and acoustic neuromas in adults. The incident cases were of patients aged 19-69 years who were diagnosed during 2001-2002 in Southern Norway. Population controls were selected and frequency-matched for age, sex, and residential area. Detailed information about mobile phone use was collected from 289 glioma (response rate 77%), 207 meningioma patients (71%), and 45 acoustic neuroma patients (68%) and from 358 (69%) controls. For regular mobile phone use, defined as use on average at least once a week or more for at least 6 months, the odds ratio was 0.6 (95% confidence interval 0.4-0.9) for gliomas, 0.8 (95% confidence interval 0.5-1.1) for meningiomas and 0.5 (95% confidence interval 0.2-1.0) for acoustic neuromas. Similar results were found with mobile phone use for 6 years or more for gliomas and acoustic neuromas. An exception was meningiomas, where the odds ratio was 1.2 (95% confidence interval 0.6-2.2). Furthermore, no increasing trend was observed for gliomas or acoustic neuromas by increasing duration of regular use, the time since first regular use or cumulative use of mobile phones. The results from the present study indicate that use of mobile phones is not associated with an increased risk of gliomas, meningiomas or acoustic neuromas.     

Cleavage of tensin during cytoskeleton disruption in YTX-induced apoptosis.

Yessotoxin (YTX) is a marine algal toxin previously shown to induce apoptosis in L6 and BC3H1 myoblast cell lines. Disassembly of the F-actin cytoskeleton and cleavage of tensin, a cytoskeletal protein localised at the focal adhesion contacts, appear during this apoptotic process. Tensin binds to actin filaments at the focal adhesion contacts and it links the actin cytoskeleton to the extracellular matrix (ECM). This binding occurs via integrin receptors and it makes tensin a potential link between the actin cytoskeleton and signal transduction. This study evaluates disruption in the F-actin cytoskeleton and change of tensin in myoblast cell lines exposed to 100 nM YTX up to 72 h. YTX treatment cleaves tensin and makes it translocate to the cell centre. Tensin has normally a role in the maintenance of cell shape and YTX-treatment may therefore alter the shape of the cells. YTX exposure also induces formation of lamellas associated with pseudopodia. Alternative linkages and cytoskeletal proteins anchoring the actin filaments to focal contacts remain to be identified.     

Cancer risk after renal transplantation in the nordic countries, 1964–1986

The theory that cancer may arise under conditions of reduced immune capacity is supported by observations of humans with immune deficiencies such as occur following organ transplants. However, no study on humans has been done in which the reference population was the same as that in which the cancer cases arose and in which there was a sufficiently long period of follow-up. Information on 5,692 Nordic recipients of renal transplants in 1964–1982 was linked with the national cancer registries (1964-1986) and population registries. Person-years at risk were calculated from the date of first transplantation until death or the end of the study period and were multiplied by the appropriate age- and calender-specific incidence rates to obtain the expected numbers of cancers. Standardized incidence ratios (SIR) were calculated after stratification by a number of recorded variables. Altogether, 32,392 person-years were accrued, and 471 cancers occurred, yielding overall SIR of 4.6 (95% CI, 4.0 to 5.2) for males and 4.5 (95% CI, 4.0 to 5.2) for females. Significant overall 2- to 5-fold excess risks in both sexes were seen for cancers of the colon, larynx, lung and bladder, and in men also for cancers of the prostate and testis. Notably high risks, 10-fold to 30-fold above expectation, were associated with cancers of the lip, skin (non-melanoma), kidney and endocrine glands, also with non-Hodgkin's lymphoma, and in women also with cancers of the cervix and vulva-vagina. Among a number of donor and recipient variables studied, including tissue types and compatibility (ABO, HLA, DR), age below 45 years at the time of transplantation was the most important determinant for increased risk at most sites. Kidney transplantation increases the risk of cancer in the short and in the long term, consistent with the theory that an impaired immune system allows carcinogenic factors to act. The tumor risk is small in comparison with the benefits of transplants, but patients should be followed up for signs of cancer. © 1995 Wiley-Liss. Inc.     

Incidence of breast cancer in Norwegian female radio and telegraph operators

Exposure to electromagnetic fields may cause breast cancer in women if it increases susceptibility to sex-hormone-related cancer by diminishing the pineal gland's production of melatonin. We have studied breast cancer incidence in female radio and telegraph operators with potential exposure to light at night, radio frequency (405 kHz-25 MHz), and, to some extent, extremely low frequency fields (50 Hz). We linked the Norwegian Telecom cohort of female radio and telegraph operators working at sea to the Cancer Registry of Norway to study incident cases of breast cancer. The cohort consisted of 2,619 women who were certified to work as radio and telegraph operators between 1920 and 1980. Cancer incidence was analyzed on the basis of the standardized incidence ratio (SIR), with the Norwegian female population as the comparison group. The incidence of all cancers was close to unity (SIR=1.2). An excess risk was seen for breast cancer (SIR=1.5). Analysis of a nested case-control study within the cohort showed an association between breast cancer in women aged 50 + years and shift work. In a model with adjustment for age, calendar year, and year of first birth, the rate ratio for breast cancer associated with being a radio and telegraph operator-in comparison with all Norwegian women born 1935 or later-analyzed with Poisson regression, was 1.5 after adjustment for fertility factors. These results support a possible association between work as a radio and telegraph operator and breast cancer. Future epidemiologic studies on breast cancer in women aged 50 and over, should address possible disturbances of chronobiological parameters by environmental factors.Mssrs Tynes, Andersen, and Haldorsen are with the Cancer Registry of Norway, Oslo, Norway. Authors are also affiliated with the Radiation Protection Authority, Østerås (Ms Hannevik, Mr Tynes), and the University of Oslo, Physics Department, Oslo, Norway (Dr Vistnes). Address correspondence to Mr Tynes, Norwegian Radiation Protection Authority, Pilestredet 46, N-0167 Oslo, Norway.     

Cytokine release in healthy donors and patients with chronic granulomatous disease upon stimulation with Aspergillus fumigatus

The release of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-10 upon stimulation with non-viable conidia and hyphal fragments from Aspergillus fumigatus was investigated in an ex vivo whole-blood model. In healthy volunteers, high numbers of conidia (between 10(6) and 3 x 10(8)/ml) induced a moderate release of TNF-alpha and IL-6. Hyphal fragments (2.5 x 10(5)/ml) were more potent in stimulating the release of these pro-inflammatory cytokines. Although some IL-10 release was observed upon stimulation with either conidia or hyphal fragments, it was not significantly different from that in unstimulated controls. In comparison, in whole blood obtained from 4 patients with chronic granulomatous disease (CGD), a high release of pro-inflammatory cytokines together with a significantly higher IL-10 release than in the healthy controls was seen after stimulation with A. fumigatus. In conclusion, A. fumigatus can trigger the release of pro-inflammatory cytokines in a human whole-blood system, which is likely to be central to the activation of antifungal defence mechanisms. In contrast, A. fumigatus stimulates a higher release of anti-inflammatory cytokines in CGD patients, which may suggest that a dysregulation between pro- and anti-inflammatory cytokines contributes to the increased susceptibility to invasive aspergillosis in this patient group.     

Chromosomal abnormalities and microsatellite instability in sporadic endometrial cancer

Defective DNA mismatch repair and nonfunctional mechanisms controlling the proper progression of the cell cycle have been proposed as being responsible for the genomic instability and accumulation of karyotypic alterations in endometrial cancer (EC). To assess whether numerical chromosomal anomalies (aneuploidy) and microsatellite instability (MSI) might be representative of distinctive tumour behaviour, paraffin-embedded tissue samples from 86 patients with sporadic EC were evaluated by both fluorescence in situ hybridisation (FISH) and microsatellite analysis, using free nuclei and genomic DNAs (respectively). Approximately one-third of the tumours analysed (24/74; 32%) exhibited MSI, whereas 38/86 (44%) of the EC samples displayed aneuploidy. The majority of the unstable cases (15/24; 63%) were from advanced-stage patients. Conversely, 23 (61%) out of the 38 tumours with aneuploidy were from early-stage patients. No apparent correlation was found between MSI and aneuploidy, whereas the immunohistochemical (IHC) analysis revealed that inactivation of the MLH1 mismatch repair gene may be involved in the majority of the MSI+ sporadic ECs. No genetic or cytogenetic alteration analysed here seems to add any significant predictive value to the stage of disease.