Jaco Bakker

Preclinical evaluation of [18F]PK-209, a new PET ligand for imaging the ion-channel site of NMDA receptors

INTRODUCTION The present study was designed to assess whether [(18)F]PK-209 (3-(2-chloro-5-(methylthio)phenyl)-1-(3-([(18)F]fluoromethoxy)phenyl)-1-methylguanidine) is a suitable ligand for imaging the ion-channel site of N-methyl-D-aspartate receptors (NMDArs) using positron emission tomography (PET). METHODS Dynamic PET scans were acquired from male rhesus monkeys over 120min, at baseline and after the acute administration of dizocilpine (MK-801, 0.3mg/kg; n=3/condition). Continuous and discrete arterial blood samples were manually obtained, to generate metabolite-corrected input functions. Parametric volume-of-distribution (VT) images were obtained using Logan analysis. The selectivity profile of PK-209 was assessed in vitro, on a broad screen of 79 targets. RESULTS PK-209 was at least 50-fold more selective for NMDArs over all other targets examined. At baseline, prolonged retention of radioactivity was observed in NMDAr-rich cortical regions relative to the cerebellum. Pretreatment with MK-801 reduced the VT of [(18)F]PK-209 compared with baseline in two of three subjects. The rate of radioligand metabolism was high, both at baseline and after MK-801 administration. CONCLUSIONS PK-209 targets the intrachannel site with high selectivity. Imaging of the NMDAr is feasible with [(18)F]PK-209, despite its fast metabolism. Further in vivo evaluation in humans is warranted.

Comparative virulence of in vitro-cultured primate- and pig-associated Helicobacter suis strains in a BALB/c mouse and a Mongolian gerbil model.

Helicobacter suis (H. suis) is the most prevalent gastric non‐H. pylori Helicobacter species in humans. This bacterium mainly colonizes the stomach of pigs, but it has also been detected in the stomach of nonhuman primates. The aim of this study was to obtain better insights into potential differences between pig‐ and primate‐associated H. suis strains in virulence and pathogenesis.

Single subcutaneous dosing of cefovecin in rhesus monkeys (Macaca mulatta): a pharmacokinetic study

Cefovecin is a third-generation cephalosporin approved for antibacterial treatment with a 14-day dosing interval in dogs and cats. This antibiotic may also be useful for zoo and wildlife veterinary medicine, because of its broad spectrum and long duration of activity. The aim of the study was to determine whether cefovecin is a suitable antibiotic to prevent skin wound infection in rhesus monkeys. Therefore, the pharmacokinetics (PK) of cefovecin after a single subcutaneous injection at 8 mg/kg bodyweight in four rhesus monkeys (Macaca mulatta) and sensitivity of bacterial isolates from fresh skin wounds were determined. After administration, blood, urine, and feces were collected, and concentrations of cefovecin were determined. Further, the minimum inhibitory concentrations (MIC) for bacteria isolated from fresh skin wounds of monkeys during a health control program were determined. The mean maximum plasma concentration (C(max) ) of cefovecin was 78 μg/mL and was achieved after 57 min. The mean apparent long elimination half-life (t½) was 6.6 h and excretion occurred mainly via urine. The MIC for the majority of the bacteria examined was >100 μg/mL. The PK of cefovecin in rhesus monkeys is substantially different than for dogs and cats. Cefovecin rapidly reached C(max) which however was lower than most of the MIC levels and with a very short t½. Therefore, cefovecin is not recommended for treating skin wounds in rhesus monkeys.

Evidence for a primate origin of zoonotic Helicobacter suis colonizing domesticated pigs

Helicobacter suis is the second most prevalent Helicobacter species in the stomach of humans suffering from gastric disease. This bacterium mainly inhabits the stomach of domesticated pigs, in which it causes gastric disease, but it appears to be absent in wild boars. Interestingly, it also colonizes the stomach of asymptomatic rhesus and cynomolgus monkeys. The origin of modern human-, pig- or non-human primate-associated H. suis strains in these respective host populations was hitherto unknown. Here we show that H. suis in pigs possibly originates from non-human primates. Our data suggest that a host jump from macaques to pigs happened between 100 000 and 15 000 years ago and that pig domestication has had a significant impact on the spread of H. suis in the pig population, from where this pathogen occasionally infects humans. Thus, in contrast to our expectations, H. suis appears to have evolved in its main host in a completely different way than its close relative Helicobacter pylori in humans.

ACUTE-PHASE RESPONSES IN HEALTHY AND DISEASED RHESUS MACAQUES (MACACA MULATTA)

Abstract: Five acute-phase reactants—serum amyloid A (SAA), C-reactive protein (CRP), haptoglobin, albumin, and iron—were measured using commercially available assays in 110 healthy rhesus macaques (Macaca mulatta), and reference intervals were established for future use in health monitoring of this species. Reference intervals established were as follows: SAA, 29.5–87.7 mg/L; CRP, 0–17.5 mg/L; haptoglobin, 354.3–2,414.7 mg/L; albumin, 36.1–53.0 g/L; and iron, 13.3–40.2 μmol/L. Furthermore, changes in the acute-phase reactants were studied in two additional groups of animals: eight rhesus macaques suffering from acute traumatic injuries and nine rhesus macaques experimentally infected with Mycobacterium tuberculosis reflecting a chronic active inflammation. In animals with inflammation, SAA and haptoglobin concentrations were moderately increased, while CRP increased more than 200-fold. In addition, marked decreases in albumin and iron concentrations were observed. These results show that SAA, CRP, and haptoglobin are positive acute-phase proteins, whereas albumin and iron are negative acute-phase reactants in rhesus macaques.

Evaluation of ultrasonic vocalizations in common marmosets (Callithrix jacchus) as a potential indicator of welfare

The vocal repertoire in common marmosets (Callithrix jacchus) has been assumed to consist not only of vocalizations audible to humans but also of ultrasonic vocalizations (USVs). The use of USVs to socially indicate distress has not been evaluated in this species, however. The authors analyzed the ultrasonic vocal repertoire of the common marmoset under normal housing conditions, under various experimental manipulations intended to elicit positive or negative emotional responses and during stressful experiences including blood draw and exposure to a perceived predator. Analysis of the recordings showed that marmosets produced vocalizations with ultrasonic components as part of their normal vocal repertoire, but these vocalizations all have audible components as well. Only 4 of the 13 types of vocalizations had ultrasonic components. These ultrasonic components were not reliably associated with responses to different experimental manipulations, suggesting that they are not used to indicate pain, discomfort or distress.

Numerical chromosome disorders in the common marmoset (Callithrix jacchus) – comparison between two captive colonies

Chromosomal analyses were performed for marmosets from two colonies – Deutsches Primatenzentrum (DPZ) and Biomedical Primate Research Centre (BPRC). Chlorine‐based disinfectants are used in DPZ; no chemical disinfection is applied in BPRC.

Ultrasonic Components of Vocalizations in Marmosets

Abstract Marmosets are social arboreal primates that developed various characteristic ways of communication. One of them is their vocalization that contains information about their social organization, environment, and the presence of food or predators. Interestingly, some of these calls reach up into the ultrasonic level. Understanding the vocalizations (including the ultrasonic components) that an animal emits under particular physical, environmental, or social conditions can be informative and serve as an index of the affective state of the animal. The purpose of this review is to provide a description of marmoset vocalizations in which ultrasonic frequencies are present and to explore the behavioral contexts associated with these species-specific vocalizations. Although marmosets produce ultrasonic frequencies, current data show that they do not produce vocalizations with frequencies exclusively in the ultrasonic range. As most of the vocal signals are relatively closely linked to specific social situations, it is possible to establish functional categories such as contact calls or mobbing calls. We will discuss the function and possible biological benefits of ultrasonic components of vocalizations in marmosets. This information is important for understanding the behaviors of these animals both in the wild and under laboratory conditions.

25-OH-vitamin D, parathyroid hormone, and calcium serum levels in captive common marmosets (Callithrix jacchus): Reference values and effect of age, sex, season, and closure of long bone epiphyses

To date, reference values for 25‐OH‐vitamin D, parathyroid hormone (PTH), and calcium in serum of common marmosets (Callithrix jacchus) based on a large sample size are not available.

Defining predictive factors for reproductive output in captive common marmosets (Callithrix jacchus)

Common marmosets (Callithrix jacchus) demonstrate variations in reproductive output, not only in terms of total reproductive output during a lifetime but also in litter size per parturition. The present study explores factors, such as parents’ litter size, parturition number, maternal body weight at conception and maternal age, which may account for this variation. A retrospective analysis of clinical records of a captive breeding colony was conducted over a 9‐year period yielding reproductive summaries of 26 dams and 22 sires producing a total of 115 litters. Dams born from litters of  ≤2 (N = 20) more often produced litters of ≤2, whereas dams born from litters of >2 (N = 6) more often produced litters of >2 (p < 0.05). The dams’ maternal body weight at the time of conception had also a significant effect on subsequent litter size. In addition, the chance of triplets was higher after the second parturition. Maternal age, interbirth interval, and season of birth had no effect on litter size. Factors relating to the sire had a negligible effect on the size of the litter. Multivariate statistical modeling revealed that the dams’ original litter size, maternal bodyweight at conception and parturition number are determining factors for the number of babies per litter. This study identified factors determining marmoset litter size, some of which (maternal litter size) are novel to this study and were not reported previously. Further exploration of the potential role of maternal litter size as a determinant of the litter sizes produced by marmoset breeders is warranted.