Components of the choline oxidation pathway modify the association between the apolipoprotein ε4 gene variant and cognitive decline in patients with dementia.

BACKGROUND: Metabolites involved in one-carbon metabolism (OCM) may predict cognitive prognosis in dementia. The link between OCM, apolipoprotein E (APOE), and DNA methylation creates a biologically plausible mechanism of interaction. AIM: To assess OCM metabolites as predictors of 5-year cognitive prognosis in patients with mild dementia, and in subgroups defined by the APOEε4 allele variant. METHODS: We followed one-hundred and fifty-two patients with mild dementia (86 with Alzheimer's disease, 66 with Lewy body dementia, including 90 with at least one APOEε4 allele) for 5 years with annual Mini-Mental State Examinations (MMSE). Total homocysteine, methionine, choline, betaine, dimethylglycine, sarcosine, folate, cobalamin and pyridoxal 5'-phoshate were measured in serum at baseline. We used linear mixed models to assess metabolite-MMSE associations, including 3-way interactions between metabolites, time, and APOEε4. False-discovery rate adjusted p-values (Q-values) are reported. RESULTS: Metabolite concentrations were not different in patients with dementia according to the presence of APOEε4. Overall, serum concentration of total homocysteine was inversely associated with MMSE performance, while betaine was positively associated with MMSE (Q < 0.05), but neither was associated with MMSE decline. Serum concentrations of betaine, dimethylglycine and sarcosine, however, were associated with slower MMSE decline in patients with APOEε4, but with faster MMSE decline in patients without the allele (all 3-way interactions: Q < 0.05). CONCLUSION: Components of the choline oxidation pathway are associated with a better cognitive prognosis in APOEε4 carriers and a worse cognitive prognosis in non-carriers. Further research investigating targeted metabolic interventions according to APOE allele status is warranted.

The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia.

BACKGROUND: The apolipoprotein E ε4 gene variant (APOEε4) confers considerable risk for dementia and affects neuroinflammation, brain metabolism, and synaptic function. The kynurenine pathway (KP) gives rise to neuroactive metabolites, which have inflammatory, redox, and excitotoxic effects in the brain. AIM: To assess whether the presence of at least one APOEε4 allele modifies the association between kynurenines and the cognitive prognosis. METHODS: A total of 152 patients with sera for metabolite measurements and APOE genotype were included from the Dementia Study of Western Norway. The participants had mild Alzheimer disease and Lewy body dementia. Apolipoprotein E ε4 gene variant allele status was classified as one or more ε4 versus any other. Mini-Mental State Examination (MMSE) was measured at baseline and for 5 consecutive years. Mann-Whitney U tests and linear mixed-effects models were used for statistical analysis. RESULTS: There were no significant differences in serum concentrations of tryptophan and kynurenine according to the presence or absence of APOEε4. High serum concentrations of kynurenic acid, quinolinic acid, and picolinic acid, and a higher kynurenine-to-tryptophan ratio, were all associated with more cognitive decline in patients without APOEε4 compared to those with the APOEε4 allele (P-value of the interactions < .05). CONCLUSIONS: Kynurenic acid, quinolinic acid, picolinic acid, and the kynurenine-to-tryptophan ratio were associated with a significant increase in cognitive decline when the APOEε4 variant was absent, whereas there was a relatively less decline when the APOEε4 variant was present.

Impact of deep-water fish farms on benthic macrofauna communities under different hydrodynamic conditions.

In this study the environmental impacts of two fish farms located over deep water (180-190 m) were compared. MC-Farm was located at a site with slightly higher water currents (mean current speed 3-5 cms(-1)) than LC-farm (<2 cms(-1)). Macrofauna composition, bioirrigation and benthic fluxes (CO2 and NH4(+)) were quantified at different stages of the production cycle, revealing very different impact of the two farms. Macrofauna abundance and bioirrigation were stimulated compared to a non-impacted reference site at MC-farm, while macrofauna diversity was only moderately reduced. In contrast, macrofauna communities and related parameters were severely impoverished at LC-Farm. This study suggests that deep-water fish farms should not be sited in low current areas (<2 cms(-1)), since this will hamper waste dispersal and aggravate environmental impacts. On the other hand, fish farming at slightly more dynamic sites can lead to stimulated benthic macrofauna communities and only moderate environmental impacts.

Distribution and persistence of the anti sea-lice drug teflubenzuron in wild fauna and sediments around a salmon farm, following a standard treatment.

The salmon louse (Lepeoptheirus salmonis) is a challenge in the farming of Atlantic salmon (Salmo salar). To treat an infestation, different insecticides are used like the orally administered chitin synthetase inhibitor teflubenzuron. The concentrations and distribution of teflubenzuron were measured in water, organic particles, marine sediment and biota caught in the vicinity of a fish farm following a standard medication. Low concentrations were found in water samples whereas the organic waste from the farm, collected by sediment traps had concentrations higher than the medicated feed. Most of the organic waste was distributed to the bottom close to the farm but organic particles containing teflubenzuron were collected 1100 m from the farm. The sediment under the farm consisted of 5 to 10% organic material and therefore the concentration of teflubenzuron was much lower than in the organic waste. Teflubenzuron was persistent in the sediment with a stipulated halflife of 170 days. Sediment consuming polychaetes had high but decreasing concentrations of teflubenzuron throughout the experimental period, reflecting the decrease of teflubenzuron in the sediment. During medication most wild fauna contained teflubenzuron residues and where polychaetes and saith had highest concentrations. Eight months later only polychaetes and some crustaceans contained drug residues. What dosages that induce mortality in various crustaceans following short or long-term exposure is not known but the results indicate that the concentrations in defined individuals of king crab, shrimp, squat lobster and Norway lobster were high enough shortly after medication to induce mortality if moulting was imminent. Considering food safety, saith and the brown meat of crustaceans contained at first sampling concentrations of teflubenzuron higher than the MRL-value set for Atlantic salmon. The concentrations were, however, moderate and the amount of saith fillet or brown meat of crustaceans to be consumed in order to exceed ADI is relatively large.

Biogeochemical malfunctioning in sediments beneath a deep-water fish farm.

We investigated the environmental impact of a deep water fish farm (190 m). Despite deep water and low water currents, sediments underneath the farm were heavily enriched with organic matter, resulting in stimulated biogeochemical cycling. During the first 7 months of the production cycle benthic fluxes were stimulated >29 times for CO(2) and O(2) and >2000 times for NH(4)(+), when compared to the reference site. During the final 11 months, however, benthic fluxes decreased despite increasing sedimentation. Investigations of microbial mineralization revealed that the sediment metabolic capacity was exceeded, which resulted in inhibited microbial mineralization due to negative feed-backs from accumulation of various solutes in pore water. Conclusions are that (1) deep water sediments at 8 °C can metabolize fish farm waste corresponding to 407 and 29 mmol m(-2) d(-1) POC and TN, respectively, and (2) siting fish farms at deep water sites is not a universal solution for reducing benthic impacts.

Pharmacokinetics of florfenicol in cod Gadus morhua and in vitro antibacterial activity against Vibrio anguillarum.

The pharmacokinetic profile of the antibacterial agent florfenicol was studied in plasma after intravenous (i.v.) injection and in plasma, muscle and liver following oral (p.o.) administration to cod Gadus morhua, held in seawater at 8 degrees C and weighing 100 to 200 g. Following i.v. injection, the plasma drug concentration-time profile showed 2 distinct phases. The plasma distribution half-life (t1/2alpha) was estimated to be 1.6 h, the elimination half-life (t1/2beta) to be 43 h, the total body clearance (ClT) to be 0.015 1 kg(-1) h(-1) and mean residence time (MRT) to be 74 h. The volume of distribution at steady state, Vd(ss), was calculated to be 1.1 l kg(-1). Following p.o. administration, the bioavailability was estimated to be 91%, the peak plasma concentrations (Cmax) to be 10.8 microg ml(-1) and the time to peak plasma concentrations (Tmax) to be 7 h. Corresponding Cmax and Tmax values were 13.0 microg g(-1) and 9 h, respectively, in muscle and 12.1 microg g(-1) and 9 h, respectively, in liver. The in vitro minimum inhibitory concentration (MIC) values of florfenicol against 3 Vibrio anguillarum strains isolated from diseased cod (A-21, HI-610, HI-618) were 0.5 microg ml(-1) for all 3 strains.

The stability and persistence of diflubenzuron in marine sediments studied under laboratory conditions and the dispersion to the sediment under a fish farm following medication.

A high performance liquid chromatographic (HPLC) method was developed to determine the concentration of diflubenzuron, a delousing agent used in fish farming, in marine mud and shell sand. The recovery of diflubenzuron from mud was 100.8+/-1.1% and 105.5+/-4.3% for shell sand. The limit of quantitation was found to be 0.1 microg g(-1). The stability of diflubenzuron was studied under laboratory conditions in marine sediments at different temperatures (4 and 14 degrees C). No degradation of diflubenzuron occurred in the organic rich mud sediment or in the shell sand sediment during the experimental period of 204 days. Increasing the temperature from 4 to 14 degrees C had no effect on the stability. Furthermore, diflubenzuron showed to be persistent in both mud and shell sand sediment since no detectable diffusion from the sediment to the water phase occurred during the experimental period of 204 days. Increasing the water current in the tanks had no effect on the persistence. Under field conditions, the concentrations of diflubenzuron found in the organic material from sediment traps placed 2 m from the bottom under the cage in a fish farm during medication were high and ranged from 71 to 259 microg g(-1). The concentrations of diflubenzuron in the sediment under the fish farm were, however, low, with a maximum concentration of 5.4 microg g(-1). The dispersion of diflubenzuron to the sediment was limited to less than 20 m from the edge of the cage in every direction. Fifteen months following the medication, only traces (< 0.1 microg g(-1)) of diflubenzuron were detected in the sediment under the fish farm. Possible explanations for this decrease are resuspension and redistribution of sediment and/or oxic degradation of the drug.