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.     

Influence of the Cumulus and Gonadotropins on the Metabolic Profile of Porcine Cumulus–Oocyte Complexes During In Vitro Maturation

The aim of this work was to examine the influence of the cumulus and gonadotropins on the metabolic profile of porcine cumulus oocyte complexes (COCs) during in vitro maturation. Immature COCs were assigned to morphological classes A₁ (with a dense cumulus), A₂ (with a translucent cumulus), B₁ (with the corona radiata), B₂ (with only some remaining cumulus cells) and matured with or without gonadotropins. Glycolysis and ammonia production were higher in the A class COCs; gonadotropins increased both, especially in the A₁ COCs (p < 0.05). The A class COCs had the highest initial protein contents and at the end of in vitro maturation. Furthermore, hormonal stimulation induced a similar increase in protein contents of both A classes (p < 0.05). The neutral lipid content and reactive oxygen species (ROS) levels were similar in the immature oocytes of the COCs of all classes. A reduction was seen in both these variables when maturation proceeded either in the presence or absence of gonadotropins. The cumulus type surrounding the oocyte is related to the metabolism of carbohydrates and amino acids by the COC during in vitro maturation under gonadotropic stimulation. Oocyte lipolytic activity and ROS production appear to be independent of the surrounding cumulus and the presence of gonadotropins.     

High pressure processing treatment prevents embryonation of eggs of Trichuris vulpis and Ascaris suum and induces delay in development of eggs

High hydrostatic pressure processing (HPP) is an effective non-thermal treatment used to inactivate pathogens from a variety of food and food products. It has been extensively examined using prokaryotic organisms and protozoan's but has had limited study on metazoans. Treatment using HPP has been shown to be effective in inactivating nematode larvae in food and preventing embryonation of Ascaris suum eggs. We conducted experiments using eggs of the canine whipworm Trichuris vulpis collected from naturally infected dogs and A. suum eggs from naturally infected pigs. We observed a delay in development of eggs of T. vulpis in a preliminary experiment and conducted 2 experiments to test the hypothesis that appropriate HPP levels can induce a delay in embryonation of nematode eggs. In experiment 1, nonembryonated T. vulpis eggs in tap water were packaged in sealable bags and exposed to 138-600 megapascals (MPa; 1 MPa=10 atm=147 psi) for 60s in a commercial HPP unit. In a second experiment, nonembryonated eggs of A. suum were exposed to 138-600 MPa and treated for 60s in the same commercial HPP unit. Embyronation of T. vulpis eggs was delayed by 4 and 5 days for eggs treated with 207 and 241 MPa but eventually eggs developed and the numbers of embryonated eggs was similar to controls on day 55. Embryonation of T. vulpis eggs treated with 345 or 350 MPa was delayed by 9 days and never reached more than 5% of eggs embryonated. On day 55 post treatment, 95% of control nontreated T. vulpis eggs were embryonated, 100-65% of eggs treated with 138-276 MPa were embryonated, a maximum of 5% of eggs treated with 345-350 MPa were embryonated, and 0% of eggs treated with ≥ 400 MPa were embryonated. T. vulpis eggs treated with ≥ 400 MPa did not undergo cell division. Embryrnation of A. suum eggs was delayed by 4, 10, and 16 days for eggs treated with 207, 241, and 250MPa, respectively, compared to nontreated control eggs. A. suum eggs treated with 207 MPa eventually embryonated to similar % embryonation values as controls and 138 MPa treated eggs but eggs treated with 241 or 250 MPa were always <5% embryonated. A. suum eggs treated with ≥ 300 MPa did not undergo cell division. On the final day of examination at day 56 after treatment, the % of embryonated eggs was 92% nontreated controls, 94% treated with 138 MPa, 84% treated with 207 MPa, 2% treated with 241 or 250 MPa, and 0% treated with 276, 200, 345, 400, or 414 MPa, respectively.     

Dual Sarcocystis neurona and Toxoplasma gondii infection in a Northern sea otter from Washington state, USA

Dual Sarcocystis neurona and Toxoplasma gondii infection was observed in a Northern sea otter from Washington, USA. The animal was found stranded, convulsed, and died shortly thereafter. Encephalitis caused by both S. neurona and T. gondii was demonstrated in histological sections of brain. Immunohistochemical examination of sections with S. neurona specific antisera demonstrated developmental stages that divided by endopolygeny and produced numerous merozoites. PCR of brain tissue from the sea otter using primer pairs JNB33/JNB54 resulted in amplification of a 1100 bp product. This PCR product was cut in to 884 and 216 bp products by Dra I but was not cut by Hinf I indicating that it was S. neurona [J. Parasitol. 85 (1999) 221]. No PCR product was detected in the brain of a sea otter which had no lesions of encephalitis. Examination of brain sections using T. gondii specific antisera demonstrated tachyzoites and tissue cysts of T. gondii. The lesions induced by T. gondii suggested that the sea otter was suffering from reactivated toxoplasmosis. T. gondii was isolated in mice inoculated with brain tissue. A cat that was fed infected mouse brain tissue excreted T. gondii oocysts which were infective for mice. This is apparently the first report of dual S. neurona and T. gondii in a marine mammal.     

Nonsurgical repair of an umbilical hernia in two Asian elephant calves (Elephas maximus)

Umbilical hernias were diagnosed in two captive-born, female Asian elephant (Elephas maximus) calves several weeks after birth. Daily manual reduction of the hernias for 5 wk in the first case and for 5 mo in the second resulted in complete closure of the defects. Nonsurgical repair of uncomplicated, fully reducible umbilical hernias in Asian elephants can be an alternative to surgery.     

Experimental infection by capillary tube feeding of Rhipicephalus sanguineus with Bartonella vinsonii subspecies berkhoffii

It has been speculated that ticks may serve as vectors of Bartonella species. Circumstantial, clinical, epidemiological and serological evidence suggest that B. vinsonii subspecies berkhoffii (B. v. berkhoffii) might be transmitted by Rhipicephalus sanguineus. The purpose of the present study was to determine whether adult R. sanguineus ticks can be infected with a B. v. berkhoffii genotype II isolate via capillary tube feeding and whether the infection can then be transmitted from adult females to their eggs via trans-ovarial transmission. Furthermore, tick fecal material was also collected and screened as a possible source of infectious inoculum for canine infections. B. v. berkhoffii DNA was detected in 50% (7 of 14) of females that did not oviposit and in 14.3% (2 of 14) of female ticks that laid eggs, but not detected in egg clutches (100 eggs/female). DNA was also detected in tick feces collected on days 2 through 6 post-capillary tube feeding, however, dogs (n=3) did not become bacteremic or seroconvert when inoculated with tick fecal material. Therefore, trans-ovarial transmission of B. v. berkhoffii by R. sanguineus is unlikely, but further studies are needed to determine if tick fecal material can serve as a source of infection to canines.     

The space requirement of potatoes in pallet boxes and the weight loss of such potatoes during storage

Summary Over a period of 3 years potatoes in pallet based boxes, having a nominal capacity of 1016 and 508 kg, were weighed as they were placed in and removed from a ventilated store. A total of 136 boxes were weighed and a value of 1.4 m³/ton can be used for estimating the capacity of such boxes. Average weight loss/day of potatoes in the stores was between 0.03 and 0.05%. The weight loss from the individual boxes varied from 2.4 to 14.6% over a storage period of 95 to 262 days.

---

Zusammenfasung Es ist wichtig, den Raumbedarf von in Kisten gelagerten Kartoffeln zu bestimmen, weil dieser Faktor einen Einfluss auf die Konstruktion eines Kartoffellagers, sowohl in Bezug auf das Gewicht der eingelagerten Kartoffeln als auch auf die n?tige W?rnmeabführung, ausüben kann. Auf zwei Betrieben wurde eine dreij?hrige Untersuchung durchgeführt, wobei die Kartoffeln in auf Paletten gestellten Kisten eingelagert waren. Die Kartoffellagerr?ume wurden mit Klimaanlagen ausgerüstet, und die Temperatur wurde zwischen 7 und 10°C gehalten. Zwei Kistengr?ssen mit einem Rauminhalt von 1016 und 508 kg wurden benutzt. Die Kisten einschliesslich Inhalt wurden bei der Ein- und Auslagerung gewogen. Der Raumbedarf der Kartoffeln war 1,4 m³/ 1000 kg für die beiden Kistengr?ssen (Tabelle 1). Der Gewichtsverlust der Kartoffeln in den Lagern belief sich auf 0,02–0.05% pro Tag. Gem?ss der Einlagerungsperiode von 95–262 Tagen lag der gesamte Verlust in den Kisten im Bereich von 2,4–14,6% (Tabelle 2). Im Herbst 1968 war das Wetter so nass, dass ein überm?ssiger Anteil an Erde mit den Kartoffeln in die Kisten gefüllt wurde. Bei den gr?sseren Kisten betrug das Nettogewicht der Kartoffeln nur 305–464 kg, d.h. unter ungünstigen Erntebedingungen k?nnte bis zur H?lfte des Inhalts eines Kartoffellagers aus Erde bestehen.

---

Résumé Il est important de déterminer l'espace occupé par les pommes de terre stockées en caisses-palettes, cette donnée pouvant influencer la construction des entrepots sant du point de vue poids de pommes de terre stockées que de la quantité de chaleur à évacuer. Pendant trois années, des études ont été poursuivies dans deux fermes dans lesquelles des pommes de terre étaient stockées en caisses-palettes placées dans des entrep?ts aérés où la température contr?lée variait de 7 à 10 C. Deux types de caisses furent utilisées dont la capacité normale était de 1016 kg et 508 kg. On a pesé les caisses avec leur contenu à l'entrée et à la sortie de l'entrep?t. L'exigence en espace était de 1,4m³ pour 1000 kg de pommes de terre pour les deux types de caisses (Tableau 1). La perte de poids pour les deux types de caisses était de 0,03–0,05% par jour tandis que celle-ci pour période de stockage de 95 à 262 jours variait de 2,4 à 14,6% (Tableau 2). En automne 1968, les conditions atmosphériques étaient tellement humides qu'une quantité exagérée de terre remplissait les caisses avec les pommes de terre. Dans le cas des caisses les plus grosses le poids net des pommes de terre était seulement de 305–464 kg; ainsi dans des conditions défavorables de récolte, une quantité allant jusqu'à la moitié du contenu d'une caisse peut être constituée de terre.

     

PrP genotype and lamb birth weight in a scrapie-free environment: Is there an association?

The National Scrapie Plan (NSP) for Great Britain includes selective breeding programmes. These aim to reduce the frequencies of the ovine prion protein (PrP) genotypes at high risk of developing clinical disease (principally those containing the VRQ allele) within the national flock, and select for the low-risk ARR-containing genotypes. The aim of this work was to use available data from embryo transfer programmes in guaranteed scrapie-free environments to investigate whether there was a difference in lamb birth weight associated with the lamb's PrP genotype, which might affect survival. The first analysis utilised data from 355 Cheviot lambs born between 2001 and 2004. The analysis was then repeated using a larger data set of 737 Cheviot, Dorset and Suffolk lambs born between 1999 and 2003. The most important determinants of mean lamb birth weight were litter size, sex and recipient ewe breed, plus lamb breed in the three breed analysis. In both analyses the effects of all these variables are consistent and of the same order of magnitude. In the first analysis there was evidence for an apparent increase in mean lamb birth weight for the ARR-containing genotypes of 0.3 kg (95% C.I. 0.1–0.5 kg). Whereas, in the second data set there was evidence for a decrease in mean lamb birth weight for the VRQ-containing genotypes of − 0.6 kg (95% C.I. − 0.8 to − 0.4 kg). This had been masked in the first analysis by the categorisation of these genotypes with the ARQ/ARQ genotype. Within these flocks, in a scrapie-free environment, neither finding provides support for concerns that selection for low risk ARR-containing genotypes would be detrimental to lamb birth weight, which is considered to be the most important determinant of lamb survival. Extension of this work into field flocks, where scrapie-status cannot be easily assured, will require the collection of sufficient data to adjust for known direct effects as well as any additional potential confounding effects.