How do glial-neuronal interactions fit into current neurotransmitter hypotheses of schizophrenia?

Evidence is accumulating that the exclusive dopamine hypothesis of schizophrenia has to be abandoned. Instead, a more integrative approach combines different neurotransmitter systems, in which glutamatergic, GABAergic and dopaminergic pathways interact. This paradigm shift coincides with the recognition that, while typical and modern atypical antipsychotic drugs have efficiently controlled the dramatic psychotic symptoms of schizophrenia, their impact on negative and cognitive symptoms is negligible. Indeed, cognitive decline is now believed to represent the core of schizophrenic morbidity and in this context, impairment of glutamate and more specifically NMDA function is of major importance. Given that astrocytes are important in controlling glutamate homeostasis, it is necessary to assign a significant role to glial-neuronal interactions in the pathophysiology of schizophrenia. Indeed, recent data from several animal and human studies corroborate this notion. This review outlines current neurotransmitter hypotheses and evidence for glial impairment in schizophrenia. Furthermore, findings from recent studies of (13)C nuclear magnetic resonance spectroscopy in experimental models of schizophrenia and NMDA hypofunction are presented and their implications for future research on glial-neuronal interactions discussed.     

Vertical and Horizontal Distributions of Zn,Cd, Pb,Cu, and Hg in Uncultivated Soil in the Vicinity of a Zinc Smelter at Odda,Norway

In the present work the extent and variation of Zn, Cd, Pb, Cu, and Hg loading in undisturbed surface soil (0–5 cm) and the vertical transport of the metals in soil profiles are studied in the vicinity of a zinc smelter in Norway. Three major controlling factors on the metal concentrations in soil have been assessed: 1) distance from the anthropogenic point source; 2) organic matter content (O.M.); and 3) the prevailing wind directions. Moreover metal distributions in proximal soil profiles in 1972 and 2003 are compared. Current concentrations of Zn, Cd, Pb, Cu, and Hg in surface soil reach 14000, 60, 980, 430, and 7.0 mg·kg ^{? 1} , respectively, near the smelter and decrease regularly with distance in the northerly direction according to the regression model (y = ax^{? b} ). The Zn concentrations are significantly different from the background range up to 30 km from the smelter, whereas the other metals approach background at only 10 km distance. Subsurface concentration peaks of Pb, Cu, and Hg are found at greater depth in soil profiles than peaks of Zn and Cd. Levels of Zn, Cd, and Pb in surface soil seem to have decreased from 1972 to 2003, whereas for Cu the levels appear not to be significantly different.     

Computer tomographic investigation of subcutaneous adipose tissue as an indicator of body composition

Background  

Modern computer tomography (CT) equipment can be used to acquire whole-body data from large animals such as pigs in minutes or less. In some circumstances, computer assisted analysis of the resulting image data can identify and measure anatomical features. The thickness of subcutaneous adipose tissue at a specific site measured by ultrasound, is used in the pig industry to assess adiposity and inform management decisions that have an impact on reproduction, food conversion performance and sow longevity. The measurement site, called "P2", is used throughout the industry. We propose that CT can be used to measure subcutaneous adipose tissue thickness and identify novel measurement sites that can be used as predictors of general adiposity.     

Double-strand break DNA repair genotype predictive of later mortality and cancer incidence in a cohort of non-smokers

We followed-up for mortality and cancer incidence 1088 healthy non-smokers from a population-based study, who were characterized for 22 variants in 16 genes involved in DNA repair pathways. Follow-up was 100% complete. The association between polymorphism and mortality or cancer incidence was analyzed using Cox Proportional Hazard regression models. Ninety-five subjects had died in a median follow-up time of 78 months (inter-quartile range 59-93 months). None of the genotypes was clearly associated with total mortality, except variants for two Double-Strand Break DNA repair genes, XRCC3 18067 C>T (rs#861539) and XRCC2 31479 G>A (rs#3218536). Adjusted hazard ratios were 2.25 (1.32-3.83) for the XRCC3 C/T genotype and 2.04 (1.00-4.13) for the T/T genotype (reference C/C), and 2.12 (1.14-3.97) for the XRCC2 G/A genotype (reference G/G). For total cancer mortality, the adjusted hazard ratios were 3.29 (1.23-7.82) for XRCC3 C/T, 2.84 (0.81-9.90) for XRCC3 T/T and 3.17 (1.21-8.30) for XRCC2 G/A. With combinations of three or more adverse alleles, the adjusted hazard ratio for all cause mortality was 17.29 (95% C.I. 8.13-36.74), and for all incident cancers the HR was 5.28 (95% C.I. 2.17-12.85). Observations from this prospective study suggest that polymorphisms of genes involved in the repair of DNA double-strand breaks significantly influence the risk of cancer and non-cancer disease, and can influence mortality.     

Repeated injection of MK801: An animal model of schizophrenia?

Glutamate-induced neurotoxicity plays an important role in neurological and psychiatric diseases. Thus, much attention has been given to the potential neuroprotective role of glutamate receptor antagonists, especially to those acting on the N-methyl-d-aspartate (NMDA) subtype. However, in addition to their neuroprotective potential, these compounds have also neurotoxic and psychotogenic properties. In the present study we used repeated injections of MK801 to examine if this non-competitive NMDA receptor antagonist could be used to produce schizophrenia-like alterations in behavior and brain metabolism in animals. Rats were given injections of MK801 (0.1 mg/kg) on six consecutive days, the last dose together with [1-(13)C]glucose and [1,2-(13)C]acetate, to probe neuronal and astrocytic metabolism, respectively. Analyses of extracts from parts of the frontal cortex plus cingulate and retrosplenial cortices and temporal lobes were performed using (13)C and (1)H magnetic resonance spectroscopy. Changes in glutamate and glutamine were restricted to the temporal lobe, in which amounts and labeling from [1-(13)C]glucose and [1,2-(13)C]acetate were increased compared to control. Locomotor activity was slightly higher in rats treated with MK801 compared to untreated animals. Metabolic changes did not resemble the alterations occurring in schizophrenia and those after repeated high dose (0.5 mg/kg) [Kondziella, D., Brenner, E., Eyjolfsson, E.M., Markinhuhta, K.R., Carlsson, M., Sonnewald, U., 2005. Glial-neuronal interactions are impaired in the schizophrenia model of repeated MK801 exposure. Neuropsychopharmacology, Epub ahead of print] but rather those caused by MK801 seen after a single high dose (0.5 mg/kg) [Brenner, E., Kondziella, D., Haberg, A., Sonnewald, U., 2005. Impaired glutamine metabolism in NMDA receptor hypofunction induced by MK801. J. Neurochem. 94, 1594-1603.].     

Population studies of Laminaria hyperborea from its northern range of distribution in Norway

Eight populations of Laminaria hyperborea from wave-exposed localities in Finnmark (70–71°N) were compared with two populations in Vega (65°N). Standing stock in shallow water (3–5 m) was within the same range in the two areas (6–16 kg fr. wt. m^–2). Both the highest and lowest value of standing stock were registered in Finnmark. Degree of wave-exposure was determined by the numbers of sectors exposed to open sea at each locality, with each sector given a relative wind force value. The most wave-exposed locality in Vega had a slightly higher annual biomass production as a function of plant age compared with the populations from Finnmark within a similar range of wave exposure. Of the two localities in Vega the most wave-exposed one had a higher annual biomass production per plant than the more sheltered one. The most wave-exposed locality examined was situated in Finnmark and exhibited the lowest annual biomass production per plant. Recruits (one-year-old plants) were found at all the localities except at one locality in Finnmark. The plants reached a higher age in Finnmark (13–18 years) than in Vega (8–9 years).     

Transfer of 85Sr and 134Cs from diet to reindeer foetuses and milk

Sr-85 and ¹³⁴Cs in aqueous solution of the chlorides were administered daily to four pregnant reindeer during the last part of gestation. Radionuclide concentrations were determined in calves sacrificed at birth, and secretion of the nuclides was measured in milk. Although the gastrointestinal absorption of ⁸⁵Sr was low, an apparently higher transfer of the absorbed fraction of ⁸⁵Sr than ¹³⁴Cs from the mother to the foetus led to similar accumulation of ⁸⁵Sr and ¹³⁴Cs in foetuses. At birth 1.4–1.6 and 1.5–2.5% of the total administered activities of ⁸⁵Sr and ¹³⁴Cs, respectively, were present in the calves‘ bodies. Transfer coefficients (F _m) for ⁸⁵Sr and ¹³⁴Cs from feed to milk were estimated at 0.0218±0.0026 and 0.185±0.025 day kg⁻¹, respectively, and the observed ratio (OR_milk-diet) for ⁸⁵Sr was 0.124±0.037. Transfer of radiostrontium to reindeer milk was in agreement with previously reported relationships between Ca intake and radiostrontium transfer in ruminants. These relationships suggest that the transfer of radiostrontium to foetuses and milk of free-ranging reindeer can be 3–4 times higher than observed in this experiment (due to lower Ca intake with natural forage), but the transfer to milk will not be as high as that of ionic ¹³⁴Cs. The concentrations of ⁸⁵Sr in milk suggested that the does mobilized skeletal stores of Ca and ⁸⁵Sr for milk production, although the diet appeared to satisfy the Ca requirements. In reindeer with radiostrontium intake during the whole year, radiostrontium concentrations in milk will therefore be higher than indicated by the F _m value observed in our study. No differences in half-times for ⁸⁵Sr and ¹³⁴Cs secretion in milk were detected. Both nuclides were secreted with short- and long-term half-times of 1–2 and 12–19 days, respectively. For ⁸⁵Sr, 80–90% of the activity was excreted with the short half-time, whereas the corresponding value for ¹³⁴Cs was 30–50%.     

First report of phytochelatins in a mushroom: induction of phytochelatins by metal exposure in Boletus edulis

Some species of macromycetes (mushrooms) consistently are found to contain high concentrations of toxic metals such as cadmium (Cd) and mercury (Hg), and consumption of wild-growing mushrooms is acknowledged as a significant source for Cd and Hg in humans. Yet little is known about the speciation of Cd and Hg in mushroom tissues. Here we present the first evidence of peptides of the phytochelatin family being responsible for binding a large fraction of Cd in caps of the macromycete Boletus edulis exposed to excess metals. Concentrations of Cd, Zn, Cu and Hg, as well as cytosolic Cd-binding capacity (CCBC), glutathione (GSH) and free proline (Pro) were quantified in fruiting bodies of B. edulis differentially exposed to a wide range of metals. Metal distribution among cytosolic compounds were investigated by size exclusion chromatography (SEC), followed by metal determinations with atomic absorption chromatography (AAS) and HR-ICP-MS. Cd-binding compounds in SEC elutates were investigated further by high performance liquid chromatography-mass spectrometry (HPLC-MS). CCBC was >90 times higher in the exposed group relative to the reference group (Mann-Whitney's P < 0.001), whereas concentrations of free Pro were almost identical for the two groups. For the whole study selection, CCBC correlated positively with metal exposure (Spearman's P < 0.001 for all four metals), suggesting dose-dependent induction of Cd-binding compounds by exposure to these metals, possibly as a defense mechanism. The presence of phytochelatins (PCs), a family of cystein-rich oligopeptides, was confirmed in Cd-containing SEC fractions by HPLC-MS. The appearance of more complex PCs was coupled to declining concentrations of GSH. To our knowledge this is the first report demonstrating the presence of PCs in a macromycete.     

Multiple miscarriages are associated with the risk of ovarian cancer: results from the European Prospective Investigation into Cancer and Nutrition

While the risk of ovarian cancer clearly reduces with each full-term pregnancy, the effect of incomplete pregnancies is unclear. We investigated whether incomplete pregnancies (miscarriages and induced abortions) are associated with risk of epithelial ovarian cancer. This observational study was carried out in female participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 274,442 women were followed from 1992 until 2010. The baseline questionnaire elicited information on miscarriages and induced abortions, reproductive history, and lifestyle-related factors. During a median follow-up of 11.5 years, 1,035 women were diagnosed with incident epithelial ovarian cancer. Despite the lack of an overall association (ever vs. never), risk of ovarian cancer was higher among women with multiple incomplete pregnancies (HR(≥4vs.0): 1.74, 95% CI: 1.20-2.70; number of cases in this category: n?=?23). This association was particularly evident for multiple miscarriages (HR(≥4vs.0): 1.99, 95% CI: 1.06-3.73; number of cases in this category: n?=?10), with no significant association for multiple induced abortions (HR(≥4vs.0): 1.46, 95% CI: 0.68-3.14; number of cases in this category: n?=?7). Our findings suggest that multiple miscarriages are associated with an increased risk of epithelial ovarian cancer, possibly through a shared cluster of etiological factors or a common underlying pathology. These findings should be interpreted with caution as this is the first study to show this association and given the small number of cases in the highest exposure categories.