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.     

Morphological characterization and notes on the life cycle of a newly discovered variant of Loma salmonae (Putz, Hoffman & Dunbar) from a natural infection of chinook salmon, Oncorhynchus tshawytscha (Walbaum)

Two variants of Loma salmonae occur in net-pen reared chinook salmon, Oncorhynchus tshawytscha. The typical variant (OA) has a host specificity for salmonids of the genus Oncorhynchus whereas the atypical variant (SV) has a host specificity for brook trout, Salvelinus fontinalis, and in this study, the ultrastructure of the two are compared. In fish at 8 weeks post-exposure xenomas of the SV variant have a very high proportion of mature spores compared with other developmental stages, while in xenomas of the OA variant there are fewer spores and many other developmental stages. Spores of the SV variant had up to 20 turns of their polar tube whereas those of the OA variant only had 17. Furthermore, the spores of the SV variant were significantly larger than those of the OA variant. The sporophorous vesicle for both variants appears to form around a sporogonial plasmodia, which results in many spores developing within the vesicle.     

Impact of vegetation management on macroinvertebrates in chalk streams

Dense growths of macrophytes are a characteristic feature of chalk streams which may cause problems both to farmers and anglers. Weed is frequently cut to reduce flooding of surrounding land and provide open water for anglers. The objective of this study was to examine short-term responses of macroinvertebrate faunal assemblages in main flow and marginal samples to both weed-cutting and the application of herbicide and to compare these with untreated controls. No statistically significant effect could be demonstrated on such faunal parameters as biotic score, richness and abundance and a multivariate analysis of all available data showed that the weed-cut and herbicide treated sites could not be distinguished from the control sites III and V on the basis of their fauna. It is suggested that for conservation purposes small-scale management with ‘recovery strips’ separating the treated reaches can achieve the desired objectives of avoiding flooding and providing open water for anglers with minimal effects on the river biota.     

Ammonia distribution and excretion in fish

This paper reviews the literature concerning ammonia production, storage and excretion in fish. Ammonia is the end product of protein catabolism and is stored in the body of fish in high concentrations relative to basal excretion rates. Ammonia, if allowed to accumulate, is toxic and is converted to less toxic compounds or excreted. Like other weak acids and bases, ammonia is distributed between tissue compartments in relation to transmembrane pH gradients. NH₃ is generally equilibrated between compartments but NH₄ ⁺ is distributed according to pH. Ammonia is eliminated from the blood upon passage through the gills. The mechanisms of branchial ammonia excretion vary between different species of fish and different environments, and primarily involves NH₃ passive diffusion and NH₄ ⁺/Na⁺ exchange. Water chemistry near the gill surface may also be important to ammonia excretion, but a more accurate measurement of the NH₃ gradient across the gill epithelium is required before a more detailed analysis of NH₃ and NH₄ ⁺ excretion can be made.     

促性腺激素诱发大西洋鲑卵黄发生期卵巢滤泡释放性类固醇激素的离体研究

提要应用大麻哈鱼(Oncovhynchus keta)促性腺激素(GTH)诱发大西洋鲑(Salmosalar)卵黄发生期的离体卵巢滤泡(直径为3．4毫米)产生性类固醇激素的研究表明，不论用0．1或1微克／毫升GTH刺激，经培育10天后，未出现卵母细胞卵核消失的现象，卵核偏位也不明显。对培养液中17α，20β-双羟孕酮(17α20βP)的积累浓度测定结果，仅1微克／毫升GTH组含少量的17α20βP；0．1微克／毫升GTH组，培养液中雌二醇的积累浓度明显高于对照组和1微克／毫升GTH组，并为后者的两倍。除雌二醇外，孕酮，17α-羟孕酮，17α20βP，雄烯二酮和睾酮的产生，都呈现对GTH剂量的依赖关系，1微克／毫升GTH组的产生量明显高于0．1微克／毫升GTH组和对照组。离体研究的结果表明，处于卵黄发生期的卵巢滤泡对低剂量(0．1微克／毫升)和高剂量(1微克／毫升)GTH的反应不同。低浓度的GTH，引起性类固醇激素生物合成的途径沿着形成雌二醇的方向进行，雄激素被芳香化成雌激素，雌二醇再而刺激肝脏合成卵黄物质的前体，从而促进卵黄发生。高浓度的GTH，有抑制雌二醇合成的作用，而是促使卵母细胞向着最终成熟的方向发展，使性类固醇生物合成的途径转向形成大量雄激素和孕激素，特别是17α20βP。这与已充分生长和卵黄积累完成的卵巢滤泡离体试验的结果一致，与活体观察以上各种性类固醇激素的变化一致。     

Mode of inheritance and stability of resistance to Bacillus thuringiensis var kurstaki in a diamondback moth (Plutella xylostella) population from Malaysia

Genetic inheritance of resistance to Bacillus thuringiensis var kurstaki (BTK) was examined in a diamondback moth (Plutella xylostella) population collected from the Melaka region of Malaysia. A BTK‐selected sub‐population (BTK‐SEL) which was more than 100‐fold resistant to BTK compared with a susceptible (ROTH) population of P xylostella was used with standard reciprocal crosses and back‐crosses between ROTH and BTK‐SEL. Logit regression analysis of F ₁ reciprocal crosses indicated that BTK resistance was inherited as an incompletely recessive autosomal trait and controlled by a single locus. In contrast, other studies have shown that resistance to Cry1Ac is inherited as an incompletely dominant autosomal trait in a Cry1Ac‐selected sub‐population of the same Melaka population. The frequency of the allele responsible for resistance decreased without exposure to insecticide in the laboratory. © 2000 Society of Chemical Industry     

Effects of area and isolation of woodland patches on herbaceous plant species richness across Great Britain

Richness of Ancient Woodland Indicator plant species was analysed in 308 woodland patches that were surveyed during the Countryside Survey of Great Britain carried out in 1998. The Countryside Survey recorded vegetation plots and landscape structure in 569 stratified 1 km sample squares and developed a remotely-sensed land cover map of the UK. Using these datasets, we tested the hypothesis that Ancient Woodland Indicator species richness in woodland fragments was limited by patch area, shape and spatial isolation and that woodland patches located in the lowland region of Great Britain would respond differently than those in the upland region. The variation in Ancient Woodland Indicator species richness in the British lowlands (n = 218) was mainly explained by patch area and two measures of connectivity, the length of hedgerows and lines of trees in the 1 km square and the area of woodland within 500 m of the vegetation plot. By contrast, variation in Ancient Woodland Indicator species richness in the British uplands (n = 90) was related to Ellenberg scores of the vegetation communities sampled – a surrogate for habitat quality – and no significant effect of spatial structure was detected. It therefore appears that the degree of fragmentation of woodland in the British lowlands limits the distribution of Ancient Woodland Indicator species, while in the uplands, failed colonisation is a matter of habitat quality rather than a result of landscape structure.This revised version was published online in May 2005 with corrections to the Cover Date.     

Uterine, cervical and vaginal microflora of the normal bitch throughout the reproductive cycle

Samples for microbiological culture were collected from the uterus of bitches using transcervical uterine cannulation (31 samples, 23 bitches) and from the uterus, cervix and vagina post mortem (19 bitches) at all stages of the reproductive cycle. Samples were cultured for aerobic and anaerobic bacteria and for aerobic mycoplasmas. Bacteria were always found in the uterus during prooestrus and oestrus (12 positive in 12 cultures) and rarely at other stages of the reproductive cycle: during anoestrus (one in 14) and other stages (none in 24). When microorganisms were detected at three sites post mortem, those found in the cervix and vagina were always of the same species as those found in the uterus. In six out of 13 instances, microorganisms were found in the cervix or vagina when none were found in the uterus. The mean number of isolates, number of bacteria seen in uterine cytology and bacterial growth were greater (P < 0–005) during oestrus and pro-oestrus than at other stages. Bacteria isolated from the uterus, in order of frequency, were Escherichia coli, Haemophilus species, α-haemo-lytic streptococci, Corynebacterium species, Streptococcus canis, Alcaligenes faecalis, Bac-teroides species, Pasteurella species and Proteus mirabilis. No mycoplasmas were cultured from the samples. This study indicates that the uterus of the normal bitch has a uterine microflora during pro-oestrus and oestrus that is similar to that of the vagina and cervix.