Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT1B Inhibitor

AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5-hydroxytryptamine (5-HT_1B) receptor, was explored as a potential treatment for depression. To support clinical trials, repeat dose toxicity studies in rats and dogs were conducted. Here we report toxicity findings in dogs after dosing from 1 to 3 months. In the 1-month study, there were minimal neuronal vacuolation in the brain, a marked increase in liver enzymes accompanied by hepatocellular degeneration/necrosis and phospholipidosis (PLD), and PLD/cholecystitis in the gallbladder of animals dosed at 47 mg/kg/day. In the 3-month study, neurotoxicity resulted in euthanasia of one animal dosed at 30 mg/kg/day after 86 days. Extensive pathologic changes were seen in all animals in retina epithelium (inclusion bodies), brain (neuronal vacuolation, degeneration, or necrosis and nerve fiber degeneration), spinal ganglia (vacuolation, degeneration, or necrosis), as well as sciatic and optic nerves (degeneration). Pigment-laden macrophages were observed in the lung, kidney, liver, gallbladder, bone marrow, gastrointestinal tract, and lymphoid tissues. Also seen were vitrel and retinal hemorrhage in the eyes. A brain concentration and pathology study showed that the concentration of AZD3783 in the brain was approximately 4 times higher than in the plasma after 4 weeks of dosing, however, they were similar in all regions examined, and did not correlate with areas with pathologic findings. Our findings with AZD3783 in dogs have not been reported previously with other CNS compounds that effect through serotonergic pharmacology.     

Compensatory Growth of Pond-reared Hybrid Striped Bass, Morone chrysops × Morone saxatilis, Fingerlings

Compensatory growth (CG) or “catch‐up growth” is a period of super‐accelerated growth following a period of suboptimal conditions (i.e., lack of prey availability or overwintering). Little is known about the CG response in pond‐raised fish and whether hybrid striped bass (HSB), Morone chrysops × Morone saxatilis, might exhibit the rapid growth states or improvements in other production characteristics that may accompany the response. To evaluate the potential for CG in HSB culture, a 16‐wk growth trial in twelve 0.1‐ha earthen ponds was conducted. Approximately 2850 fish (mean weight ± SD = 3.2 g ± 1.1) were stocked into ponds and subjected to one of four cyclic feeding regimens. Treatment regimens included a control (0 wk, fed twice daily to apparent satiation) and cycles of 1, 2, or 4 wk of feed deprivation, followed by 1, 2, or 4 wk of feeding to apparent satiation. Fish in the 4‐wk feeding regimen were offered feed twice during the feed‐deprivation period (once every other week). Growth, specific growth rate (SGR), hepatosomatic index (HSI), intraperitoneal fat ratio, and condition factor (CF) were measured every other week, while overall growth, feed efficiency (FE) (FE = [weight gain/feed fed] × 100), and survival were calculated at the trial termination. The effect of these feeding regimens on water quality was examined by monitoring pH, turbidity, total ammonia nitrogen, nitrite–nitrogen, nitrate–nitrogen, soluble reactive phosphorus, and chlorophyll a weekly; total nitrogen and phosphorous biweekly; and dissolved oxygen and temperature twice daily. Cyclic feeding elicited CG; fish subjected to the 2‐wk regimen had a significantly higher SGR than 0‐wk controls during all but the final refeeding period. FE was higher for all fish in the cyclic regimens, although only FE for fish in the 2‐wk regimen was statistically greater (40%) than the controls. HSI was the most responsive measure and significantly decreased in the 2‐ and 4‐wk treatments during feed‐deprivation period and overcompensated during the refeeding period. CF also varied with feeding cycle and proved to be an effective nonlethal measure of predicting a CG response. No statistical differences in water quality parameters were observed. These data suggest that CG can be effectively induced in pond‐raised HSB and that the increase in FE warrants further research for practical application. Future pond studies with fingerling HSB fish should be conducted with emphasis on feed‐deprivation periods of 2 wk and refeeding periods of at least twice that of the feed‐deprivation period.     

How does the landscape context of occurrence data influence models of invasion risk? A comparison of independent datasets in Massachusetts,USA

The spatial distribution of non-native, invasive plants on the landscape is strongly influenced by human action. People introduce non-native species to new landscapes and regions (propagule pressure) as well as increase ecosystem invasibility through disturbance of native ecosystems. However, the relative importance of different landscape drivers of invasion may vary with landscape context (i.e., the types and amounts of surrounding land cover and land use). If so, data collected in one context may not be appropriate for predicting invasion risk across a broader landscape. To test whether independent occurrence datasets suggest similar landscape drivers of invasion, we compared landscape models based on data compiled by the Invasive Plant Atlas of New England (IPANE), which are contributed opportunistically by trained citizen scientists, to models based on Forest Stewardship plans (FSPs), which are located in privately owned and relatively undisturbed forests. We evaluated 16 landscape variables related to propagule pressure and/or disturbance for significant predictors of invasive plant presence based on presence/absence and count regression models. Presence and richness of invasive plants within FSPs was most influenced by proportion of open land and proximity to residential areas, which are both sources of propagules in forest interiors. In contrast, IPANE invasive plant presence and richness for the same area was influenced by distance to roads and streams. These results suggest that landscape drivers of invasion vary considerably depending on landscape context, and the choice of occurrence dataset will strongly influence model results.     

Remedies for pseudoreplication

Pseudoreplication is the failure of a statistical analysis to properly incorporate the true structure of randomness present in the data. It has been well documented and studied in the ecological literature but has received little attention in the fisheries literature. Avoiding pseudoreplication in analyses of fisheries data can be difficult due to the complexity of the statistical procedures required. However, recent developments in statistical methodology are decreasing the extent to which pseudoreplication has to be tolerated. Seven examples are given here, beginning with simple design-based remedies and progressing to more challenging examples including the model-based remedies of mixed-effects modelling, generalized linear mixed models, state-space models, and geostatistics.     

Machine learning highlights the importance of primary and secondary production in determining habitat for marine fish and macroinvertebrates

1. Species distribution models for marine organisms are increasingly used for a range of applications, including spatial planning, conservation, and fisheries management. These models have been constructed using a variety of mathematical forms and drawing on both physical and biological independent variables; however, what might be called first-generation models have mainly followed the form of linear models, or smoothing splines, informed by data collected in the context of fish surveys.
2. The performance of different classes of variables were tested in a series of species occurrence models built with machine learning methods, specifically evaluating the potential contribution of lower trophic level data. Random forest models were fitted based on the classification of the absence/presence for fish and macroinvertebrates surveyed on the US Northeast Continental Shelf.
3. The potential variables included physical, primary production, secondary production, and terrain variables. For accepted model fits, six variable importance measures were computed, which collectively showed that physical and secondary production variables make the greatest contribution across all models. In contrast, terrain variables made the least contribution to these models.
4. Multivariable analyses that account for all performance measures reinforce the role of water depth and temperature in defining species presence and absence; however, chlorophyll concentration and some specific zooplankton taxa, such as Metridia lucens and Paracalanus parvus, also make important contributions with strong seasonal variations.
5. Our results suggest that lower trophic level variables, if available, are valuable in the creation of species distribution models for marine organisms.

     

Connectivity,habitat, and flow regime influence fish assemblage structure: Implications for environmental water management in a perennial river of the wet–dry tropics of northern Australia

1. Environmental water management seeks to balance competing demands between the water needed to sustain human populations and their economic activities and that required to sustain functioning freshwater ecosystems and the species they support. It must be predicated on an understanding of the environmental, hydrological, and biological factors that determine the distribution and abundance of aquatic species.
2. The Daly River of the wet–dry tropics of northern Australia consists of a perennially flowing main stem and large tributaries, as well as many small to large naturally intermittent tributaries, and associated off‐channel wetlands. Increased groundwater abstraction to support irrigated agriculture during the dry season threatens to reduce dry‐season flows that maintain perenniality and persistence of freshwater fishes.
3. Fish assemblages were surveyed at 55 locations during the dry season over a 2‐year period with the goal of establishing the key landscape‐scale and local‐scale (i.e. habitat) drivers of fish species distribution.
4. Longitudinal (upstream/downstream) and lateral (river/floodplain) gradients in assemblage structure were observed with the latter dependent on the position in the river landscape. Underlying these gradients, stream flow intermittency influenced assemblage composition, species richness, and body size distributions. Natural constraints to dispersal were identified and their influence on assemblage structure was also dependent on position within the catchment.
5. Eight distinct assemblage types were identified, defined by differences in the abundance of species within five groups differing in functional traits describing body size, spawning requirements, and dispersal capacity. These functional groups largely comprised species widely distributed in northern Australia.
6. The results of the study are discussed with reference to the environmental flow needs of the Daly River and other rivers of northern Australia. The findings may also be applied to environmental flow management in savannah rivers elsewhere.

     

Contrasting intraspecific dietary shifts in two terapontid assemblages from Australia’s wet‐dry tropics

Abstract – This study assessed the size‐related patterns of dietary resource use in terapontid assemblages from two north Australian wet‐dry tropical river systems exhibiting contrasting long‐term flow regimes. Substantially higher size‐related dietary divergence in the form of additional trophic guilds and lower levels of dietary overlap were evident among terapontids from the comparatively stable Daly River system, particularly during the dry season. Relatively restricted expression of size‐related dietary shifts in conjunction with higher levels of dietary overlap and no significant seasonal effects on dietary overlap were features of assemblage interaction in the highly variable Burdekin River. Results highlight size‐related dietary shifts as a complex aspect of terapontid trophic habits, and one that can exhibit considerable spatial dynamism.     

Multifactorial resistance to transpermethrin in field-collected strains of the tobacco budworm Heliothis virescens F.

The penetration, degradation and excretion of [³H]transpermethrin were examined in susceptible and field-collected pyrethroid-resistant strains of the tobacco budworm Heliothis virescens. No consistent differences in labelled materials excreted or recovered in cuticle rinses were found between the resistant (R) and susceptible (S) larvae. Considerably lower levels of the parent compound were present internally in R compared with S larvae after 24h (P <0.01), clearly identifying a metabolic resistance mechanism in Meloland and Westmorland larvae. Moderate levels of absorbed permethrin accompanied by an absence of poisoning symptoms were observed in certain individuals of both R strains, suggesting a second resistance mechanism. Neurobioassays of R larvae showed a consistently lower sensitivity of the neuromuscular system to pyrethroids when compared with the S larvae, thus confirming the indication from metabolic studies of the additional (site-insensitive) mechanism. Toxicity values suggest a cross-resistance to other pyrethroids.     

Effects of stage of lactation, month, age, origin and heart girth on lameness in dairy cattle

Lameness in herds during one year was commonest in the first month of lactation (15 per cent of all cases). Leg lesions were particularly common at this time (24 per cent of all cases of leg lesions) but white line abscess and sole ulcer were more common a month later. Foul-in-the-foot was one of the two most common lesions at all stages of pregnancy and lactation, and white line abscess the most common (20 per cent of all lesions) in late lactation. Both sole ulcer and underrun heel had lower incidence in the second half of the year than the first. White line abscess was particularly common in March and November although there were significant interactions between month and veterinary practice; foul-in-the-foot was most common in October. Susceptibility to lameness increased with age; 10-year-old cows were over four times more likely to develop lameness than three-year-old cows. This was due particularly to increased incidence with age of white line abscess and sole ulcer and, to a lesser extent, underrun heel. In contrast, foul-in-the-foot and leg lesions showed little change with age. Whereas these lesions accounted for 68 per cent of the total in cows up to two years old, they accounted for only 15 per cent of all lesions in cows over 10 years old. White line abscess was slightly commoner in cows with large heart girths.