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.     

Evaluation of ground grain versus pre- and post-pellet whole grain additions to poultry diets via a response surface design

1. The objective of this study was to compare the effects of pre- and post-pellet whole grain wheat additions to diets on growth performance, gizzard and pancreas development, nutrient utilisation and starch and protein (N) digestibility coefficients in broiler chickens via an equilateral triangle response surface design.

2. The three apical treatments of the equilateral triangle comprised (1A) a standard diet containing 600 g/kg ground wheat, (2B) the same diet containing 600 g/kg pre-pellet whole wheat and (3C) the same diet containing 300 g/kg ground wheat and 300 g/kg post-pellet whole wheat. Seven blends of the three apical diets were located within the triangle to complete the design and a total of 360 male Ross 308 chicks were offered the ten experimental diets from 7 to 28 d post-hatch. Model prediction and response surface plots were generated with R 3.0.3 software.

3. The most efficient FCR of 1.466 was observed in birds offered an almost equal mixture of the pre- and post-pellet whole grain apical dietary treatments, which corresponded to 172 g/kg ground grain, 256 g/kg pre-pellet whole grain, 172 g/kg post-pellet whole grain in a diet containing 600 g/kg wheat.

4. The most efficient energy utilisation (ME:GE ratio of 0.766) was observed in birds offered a blend of the ground grain and pre-pellet whole grain apical dietary treatments which corresponded to a mixture of 384 g/kg pre-pellet whole grain and 216 g/kg ground grain.

5. Pre-pellet whole grain feeding generated the most pronounced responses in increased relative gizzard contents, reduced gizzard pH and increased relative pancreas weights. Consideration is given to the likely differences between pre- and post-pellet whole grain feeding.     

CNS mastitis: nothing to worry about?

In this paper, we analyzed a very large field data set on intramammary infections (IMI) and the associated somatic cell count (SCC) in dairy cows. The objective of the study was to analyze the impact of coagulase-negative staphylococci (CNS) IMI on cow SCC, both mean and variability, and on the potential of these infections to have a major impact on the bulk milk SCC (BMSCC). Data and milk samples for bacterial culture were collected by Quality Milk Production Services (QMPS) between 1992 and March of 2007. The QMPS program services dairy farms in New York State and other states in the Northeastern USA and operates in conjunction with Cornell University. Only records from cows where SCC and milk production data were available, and where only one organism was isolated from bacterial cultures of milk samples (or where culture was negative) were used for this analysis. A total of 352,614 records from 4200 whole herd mastitis screening sampling qualified for this study. Within herds an average of 15% (S.D. 12%) of cows sampled were infected with CNS, ranging between 0 and 100%. Average within herd prevalence of cows with a CNS IMI and an SCC over 200,000 cells/ml was 2% (S.D. 4%) with a minimum of 0% and a maximum of 50%. Results of linear mixed models showed three distinct populations of IMI statuses: negative cultures with the lowest SCC; CNS and Corynebacterium bovis with a moderate increase in SCC, and Streptococcus agalactiae, Streptococcus spp. and Staphylococcus aureus showing an important increase in SCC. Surprisingly, milk production was slightly but significantly higher in CNS infected cows compared to culture-negative cows, whereas it was strongly reduced in cows with a major pathogen IMI. The percentage contribution of CNS infections to the BMSCC was 17.9% in herds with a BMSCC less than 200,000 cells/ml. This value decreased to 11.9 and 7.9% in herds with bulk milk SCC between 200,000 and 400,000 and over 400,000 cells/ml, respectively. We concluded that very few herds with milk quality problems would have an important increase in BMSCC that could be mostly attributed to CNS infections. On the other hand, in herds with low BMSCC, CNS infections may be an important contributor to the total number of somatic cells in the bulk milk.     

Ultrasonographic Examination of the Scrotal Content in the Rabbit

This study was performed to describe a practical technique for ultrasound examination of the scrotal content of the rabbit. The scrotal content of normal rabbits and those with induced lesions (i.e. needle biopsy of the testis and epididymal ligation) were viewed using a portable scanner connected to a 5 or 7.5 MHz real time, B-mode linear array transducer. The effect of frequency (5 and 7.5 MHz), pad material placed under the testicle (rubber, plastic and carton) and the presence of a water sack between the probe and organ were examined to optimize the technique. The best image quality was obtained using a 5-MHz probe when the testicle was fixed on a rubber pad and covered by a water sack. Testicular parenchyma was imaged as homogeneous and moderately echoic. Caput and cauda epididymis were identified as homogeneous and less echoic compared with the testis parenchyma. Variations in the testicular echotexture that occur secondarily to epididymal ligation and testis biopsy could be screened readily. In conclusion, real-time ultrasonography, performed as described in this study, may provide a valuable tool to screen scrotal contents and to identify certain pathological conditions that affect fertility in the rabbit.     

Reactions of goldfish (Carassius auratus) to three suture patterns following full thickness skin incisions

Three different suture patterns (simple interrupted, interrupted horizontal mattress, subcuticular) were placed in a full thickness incision (skin and body wall) of 18 goldfish (Carassius auratus). After 14 days all fish were euthanized using benzocaine solution. The tissue reactions were evaluated by gross visual inspection and histopathological examination. The superficial inflammatory reactions were graded on a scale from 0 (no inflammation) to 3 (severe inflammation). The inflammatory response in histological examination was graded on a scale from 0 (no inflammatory response or normal skin tissue) to 5 (severe inflammatory response and necrosis). The interrupted horizontal mattress induced a moderately severe to severe inflammatory response and necrosis (grades 4–5) but the subcuticular suture induced a very mild to mild inflammatory response (grades 0–1). The simple interrupted suture induced a moderate to moderately severe inflammatory response (grades 2–4). In conclusion, results showed that a subcuticular suture is the most appropriate to use in the closure of a full thickness body wall incision.     

Effects of percutaneous liver biopsy in alpacas and llamas

OBJECTIVE: To determine changes in results of selected serum biochemical tests after a single percutaneous liver biopsy and changes in results of hematologic and selected serum biochemical tests after multiple percutaneous liver biopsies in alpacas and llamas. ANIMALS: 5 llamas and 10 alpacas. PROCEDURE: A single percutaneous liver biopsy was performed in 5 llamas and 6 alpacas. Blood samples were collected before and 1, 2, and 3 days after liver biopsy, and submitted for serum biochemical analysis. In the other 4 alpacas, liver biopsy was performed on day 0 and then weekly for 4 weeks. Blood samples were collected at the time of each biopsy, and CBC and serum biochemical analyses were performed. Attitude and appetite of all animals were evaluated daily. RESULTS: None of the animals developed clinically apparent adverse effects. A mild decrease in sorbitol dehydrogenase activity was detected in animals that underwent a single liver biopsy, and mild decreases in plasma protein and albumin concentrations were detected in animals that underwent multiple biopsies. Other significant changes were not detected. CONCLUSIONS: Results of this study suggest that liver biopsy is safe in healthy llamas and alpacas and that, if necessary, multiple weekly liver biopsies can be performed safely in healthy alpacas.     

Trichinella antigens: a review

This paper presents a review of the Trichinella antigens within the context of species variation. As with other parasites, Trichinella antigens can be classified according to their localisation as surface, excretory/secretory (ES) and somatic components. Surface antigens are mainly constituents of the outer cuticle although secretions from inner parts of the body wall as well as from the oesophagus can temporarily accumulate in the surface. ES antigens come mainly from the excretory granules of the stichosome, whereas somatic constitutive antigens come from the internal parts of the worms. ES products are considered very important from an immunological point of view as they are easily targeted by the immune system, whereas parasite death is required for exposure of somatic products. Some of the antigenic components have been characterised chemically. Phosphorylcholine is an important hapten that modulates the immune responses in Trichinella infections. Glycoproteins are the major components of surface and excretory/secretory products. A 43-kDa glycoprotein has been regarded as a good candidate for diagnosis and vaccination purposes. Recently some glycans have received special attention either as relevant epitopes or as parasite evasion strategies.     

Ultrastructural identification of small granule prolactin (PRL) cells in goat adenohypophysis by the colloidal-gold method

We describe ultrastructural characteristics of PRL cells with small secretory granules, immunostained with ovine antiserum, in adult Murciano-Granadina milking goats during anoestrus, the last third of gestation and lactation. This cell subtype is considered to comprise a stable population that decreases numerically during gestation and lactation, and that may change during these stages to show large granules.     

Detection of a corpus luteum in apparently anoestrous cows by manual palpation, transrectal ultrasonography and plasma progesterone concentration

AIMS: To determine the level of agreement between transrectal ultrasonography, manual palpation and measurement of progesterone in the detection of corpora lutea in post-partum cows. To evaluate the reproductive performance of cows not detected in oestrus prior to mating, but detected with a corpus luteum at the start of mating. METHODS: Cows from seven herds which were not detected in oestrus were examined between 5 and 7 days before the herd's planned start of mating. Ovaries were examined by palpation and ultrasonography in 160 cows and plasma progesterone concentrations were also measured in 103 cows. Insemination dates and pregnancy data were recorded in 159 cows not detected in oestrus but having a corpus luteum and 1405 cycling herd mates. RESULTS: The level of agreement between ultrasonography and measurement of progesterone (kappa = 0.74) was higher than with manual palpation (kappa = 0.67) although it was significant for both techniques (p <0.001). Cows which were not detected in oestrus, but detected with a corpus luteum had a longer interval to first service (12 v. 10 days, p <0.05) and conception (19 v. 15 days, p = 0.01) than cycling herd mates and had a higher empty rate (9.7% v. 3.8%, p <0.001). CONCLUSIONS: These data indicate that ultrasonography may provide a better diagnostic tool for examining cows not detected in oestrus than manual palpation or measurement of progesterone concentration. Cows not detected in oestrus but having a corpus luteum were shown to have significantly poorer reproductive performance than cycling herd mates.     

Productive,Physiological and Biochemical Changes in Imported and Locally Born Friesian and Holstein Lactating Cows under Hot Summer Conditions of Egypt

Twenty each of healthy lactating Friesian and Holstein cows were studied. They were of similar age and body weight, nonpregnant in their third lactation and 80–100 days post partum. The investigation was carried out for 8 weeks on two farms at the same time during the hot summer season in Egypt. The first farm was in Demietta (North east of the Nile Delta, 31° 40 N) on 20 Friesian cows and the second was in Fakous (East of the Nile Delta, 30° 40 N) on 20 Holstein cows. On each of the two farms, 10 cows were newly imported and 10 were born in Egypt.The average daily milk yield and total milk production in the third lactation of the newly imported cows were significantly higher than those of the locally born cows for both Friesians and Holsteins. At the same time, the T₄, T₃, urea-N, haematological values and AST enzyme activity in the newly imported cows were significantly lower than those in the locally born ones in both breeds, while the locally born cows showed significantly lower values for rectal temperature and respiration rate, as well as for AST and Alk-P enzyme activities, than the newly imported cows of either breed.Holstein cows surpassed the Friesians in milk production, as well as thyroid hormone secretion and cholesterol, haemoglobin, packed cell volume and erythrocyte count values. The opposite was found for serum total protein, urea-N and creatinine concentrations, leukocyte count and AST, ALT and Alk-P enzyme activities.