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The heart has a high‐metabolic rate, and its "around‐the‐clock" vital role to sustain life sets it apart in a regenerative setting from other organs and appendages. The landscape of vertebrate species known to perform intrinsic heart regeneration is strongly biased toward ectotherms—for example, fish, salamanders, and embryonic/neonatal ectothermic mammals. It is hypothesized that intrinsic heart regeneration is exclusively limited to the low‐metabolic hearts of ectotherms. The biomedical field of regenerative medicine seeks to devise biologically inspired regenerative therapies to diseased human hearts. Falsification of the ectothermy dependency for heart regeneration hypothesis may be a crucial prerequisite to meaningfully seek inspiration in established ectothermic regenerative animal models. Otherwise, engineering approaches to construct artificial heart components may constitute a more viable path toward regenerative therapies. A more strict definition of regenerative phenomena is generated and several testable sub‐hypotheses and experimental avenues are put forward to elucidate the link between heart regeneration and metabolism. Also see the video abstract here https://youtu.be/fZcanaOT5z8. [ABSTRACT FROM AUTHOR]

The conversion of endogenous alpha-synuclein (asyn) to pathological asyn-enriched aggregates is a hallmark of Parkinson's disease (PD). These inclusions can be detected in the central and enteric nervous system (ENS). Moreover, gastrointestinal symptoms can appear up to 20 years before the diagnosis of PD. The dual-hit hypothesis posits that pathological asyn aggregation starts in the ENS, and retrogradely spreads to the brain. In this study, we tested this hypothesis by directly injecting preformed asyn fibrils into the duodenum wall of wild-type rats and transgenic rats with excess levels of human asyn. We provide a meticulous characterization of the bacterial artificial chromosome (BAC) transgenic rat model with respect to initial propagation of pathological asyn along the parasympathetic and sympathetic pathways to the brainstem, by performing immunohistochemistry at early time points post-injection. Induced pathology was observed in all key structures along the sympathetic and parasympathetic pathways (ENS, autonomic ganglia, intermediolateral nucleus of the spinal cord (IML), heart, dorsal motor nucleus of the vagus, and locus coeruleus (LC)) and persisted for at least 4 months post-injection. In contrast, asyn propagation was not detected in wild-type rats, nor in vehicle-injected BAC rats. The presence of pathology in the IML, LC, and heart indicate trans-synaptic spread of the pathology. Additionally, the observed asyn inclusions in the stomach and heart may indicate secondary anterograde propagation after initial retrograde spreading. In summary, trans-synaptic propagation of asyn in the BAC rat model is fully compatible with the "body-first hypothesis" of PD etiopathogenesis. To our knowledge, this is the first animal model evidence of asyn propagation to the heart, and the first indication of bidirectional asyn propagation via the vagus nerve, i.e., duodenum-to-brainstem-to-stomach. The BAC rat model could be very valuable for detailed mechanistic studies of the dual-hit hypothesis, and for studies of disease modifying therapies targeting early pathology in the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Abstract: The Göttingen minipig is being used increasingly in biomedical research. The anatomical structure of the porcine peripheral nervous system has been extensively characterized, but no equivalent to the dermatome map, which is so valuable in human neurophysiological research, has been created. We characterized the medullar segmental skin and muscle innervations of the minipig hind body, using neurophysiological methodology. Six adult minipigs underwent unilateral laminectomy from L2 to S3, exposing the nerve roots. The skin of the hind part of the body was divided into 36 predefined fields, based on anatomical landmarks for consistent reproducibility. We recorded the evoked potential in each exposed nerve root L2‐S3 for cutaneous stimulation of each skin field, mapping the sensory innervation of the entire hind body. We subsequently recorded the motor response in seven predefined muscles during sequential stimulation of the L2‐S3 nerve roots. We obtained a clear sensory evoked potential in the nerve roots during stimulation of the skin fields, allowing us to map the sensory innervation of the minipig hind body. Neurophysiological data from skin stimulation and muscle recordings enabled us to map the sensory innervation of the Göttingen minipig hind body and provide information about muscular innervation. The skin fields were sensory innervated by more than one root. The muscles each had one dominant root with minor contribution from neighboring roots. This is consistent with experimental data from human studies. [ABSTRACT FROM AUTHOR]

The melting of marine terminating glaciers in Northeast Greenland is a visible sign that our climate is changing. This melt has been partly attributed to changes in oceanic heat fluxes, particularly warming of Atlantic Water (AW). Yet our understanding of the interaction between glaciers and the ocean is limited by the length of instrumental records. Here, we present a multi-proxy study (benthic foraminifera assemblages, CT scans, grain size, XRF, and stable isotope data) on core DA17-NG-ST08-092G, located 90 km east of the Northeast Greenland Ice Stream (NEGIS). Whilst the exact timing of deglaciation is uncertain, it is certain to have occurred at least as early as 12.5 ka cal BP, and likely before 13.4 ka cal BP. The inflow of AW may have played a role in the seemingly early deglaciation on the Northeast Greenland continental shelf. Following deglaciation, the site was overlain by an ice shelf, with AW and Polar Water (PW) flowing beneath until 11.2 ka cal BP. The NEGIS briefly retreated westwards between 11.2 and 10.8 ka cal BP before our site returned to glacier-proximal conditions dominated by colder subsurface water and persistent AW flowing beneath (10.8–9.6 ka cal BP). Between 9.6 and 7.9 ka cal BP the NEGIS retreated westwards; there was a continued presence of AW and PW at the site. A drastic shift in ocean circulation occurred at 7.9 ka cal BP, with a decline in AW flow and dominance of PW flowing beneath perennial sea ice. During the Late Holocene, there was return of AW and likely breakup of perennial sea ice. • Multi-proxy reconstruction on the Northeast Greenland continental shelf. • Deglaciation occurred before 12.5 ka cal BP, possibly even before 13.4 ka cal BP. • Atlantic water inflow likely played a key role in deglaciation in this region. • Drastic decline in Atlantic water inflow occurred at 7.9 ka cal BP. [ABSTRACT FROM AUTHOR]

The aim was to establish combined H 2 15 O PET/MRI during ex vivo normothermic machine perfusion (NMP) of isolated porcine kidneys. We examined whether changes in renal arterial blood flow (RABF) are accompanied by changes of a similar magnitude in renal blood perfusion (RBP) as well as the relation between RBP and renal parenchymal oxygenation (RPO)., Methods: Pig kidneys (n = 7) were connected to a NMP circuit. PET/MRI was performed at two different pump flow levels: a blood-oxygenation-level-dependent (BOLD) MRI sequence performed simultaneously with a H 2 15 O PET sequence for determination of RBP., Results: RBP was measured using H 2 15 O PET in all kidneys (flow 1: 0.42-0.76 mL/min/g, flow 2: 0.7-1.6 mL/min/g). We found a linear correlation between changes in delivered blood flow from the perfusion pump and changes in the measured RBP using PET imaging (r 2 = 0.87)., Conclusion: Our study demonstrated the feasibility of combined H 2 15 O PET/MRI during NMP of isolated porcine kidneys with tissue oxygenation being stable over time. The introduction of H215O PET/MRI in nephrological research could be highly relevant for future pre-transplant kidney evaluation and as a tool for studying renal physiology in healthy and diseased kidneys.

Previous research has established that some models of robotic lawn mowers are potentially harmful to hedgehogs. As the market for robotic lawn mowers is expanding rapidly and the populations of European hedgehogs ( Erinaceus europaeus ) are in decline, it is important to investigate this risk further to understand the potential threat which some robotic lawn mowers may pose to hedgehogs. We tested 19 models of robotic lawn mowers in collision with hedgehog cadavers to measure their effect on hedgehogs. Our results showed that some models of robotic lawn mowers may injure hedgehogs, whereas others are not harmful to them. Apart from one single incidence, all robotic lawn mowers had to physically touch the hedgehog carcasses to detect them. Larger hedgehog cadavers were less likely to be "injured", with height being the most influential measure of size. The firmness of the tested hedgehog cadavers (frozen or thawed) did not influence the outcome of the collision tests. Neither the position of the hedgehog cadavers nor the selected technical features of the lawn mowers affected the probability of injury. Based on the results, we designed a standardised safety test to measure the effect of a specific model of robotic lawn mower on hedgehogs.

The populations of European hedgehog ( Erinaceus europaeus ) are in decline, and it is essential that research identifies and mitigates the factors causing this. Hedgehogs are increasingly sharing habitats with humans, being exposed to a range of dangers in our backyards. Previous research has documented that some models of robotic lawn mowers can cause harm to hedgehogs. This study explored the personality and behaviour of 50 live hedgehogs when facing an approaching, disarmed robotic lawn mower. By combining a novel arena and novel object test, we found that 27 hedgehogs could be categorised as "shy" and 23 as "bold", independently of sex and age. The encounter tests with a robotic lawn mower showed that the hedgehogs positioned themselves in seven different ways. Personality did not affect their reactions. Adult hedgehogs tended to react in a shyer manner, and the hedgehogs, generally, acted less boldly during their second encounter with the robotic lawn mower. Additionally, our results show that bold individuals reacted in a more unpredictable way, being more behaviourally unstable compared to the shy individuals. This knowledge will be applied in the design of a standardised hedgehog safety test, eventually serving to produce and approve hedgehog-friendly robotic lawn mowers.

The bulk of biomedical positron emission tomography (PET)-scanning experiments are performed on mammals (ie, rodents, pigs, and dogs), and the technique is only infrequently applied to answer research questions in ectothermic vertebrates such as fish, amphibians, and reptiles. Nevertheless, many unique and interesting physiological characteristics in these ectothermic vertebrates could be addressed in detail through PET. The low metabolic rate of ectothermic animals, however, may compromise the validity of physiological and biochemical parameters derived from the images created by PET and other scanning modalities. Here, we review some of the considerations that should be taken into account when PET scanning fish, amphibians, and reptiles. We present specific results from our own experiments, many of which remain previously unpublished, and we draw on examples from the literature. We conclude that knowledge on the natural history and physiology of the species studied and an understanding of the limitations of the PET scanning techniques are necessary to avoid the design of faulty experiments and erroneous conclusions., Competing Interests: Declaration of Competing Interest The authors declare no known competing financial interests or personal relationships that influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Recently, a unique mechanism for protecting the airway during lunge feeding was discovered in rorqual whales (Balaenopteridae). This mechanism is based on an oral plug structure in the soft palate with similarities in musculo-fatty composition to the nasal plugs protecting the respiratory tract of rorquals from water entry and barotrauma during diving. As a follow-up, we present here a developmental series on fetal, prenatal, juvenile and adult specimens across five species of rorquals, showing differential maturation of the nasal and oral respiratory protection plugs. Nasal plugs are fully formed to serve an immediate crucial function at birth. By contrast, the soft palate remains muscular until the onset of solid food intake, where a musculo-fatty oral plug is developed., (© 2022 The Authors.)

To increase the efficiency and geographic expansion of nature conservation, large grazers have recently been used, either in the form of wild hoof-bearing animals or as domesticated ruminants including cattle. Using physical fencing limits migrating wildlife, while virtual fences encourage the animals to stay in the desired area without physical restrictions on wild animals. However, virtual fences raise ethical questions regarding the electric impulses emitted by the collar and stress in the fenced animals. Here, we tested if keeping twelve Angus cows ( Bos Taurus ) in a virtual fencing (Nofence©) compromised their welfare. For this purpose, we collected manure samples from five cows every second day prior to and after the transition from traditional to virtual fencing over a period of 18 days. Cortisol concentrations were 20.6 ± 5.23 ng/g w / w (mean ± SD), ranging from 12 to 42 ng/g w / w across individuals and concentrations did not change over the study period. We, therefore, conclude that there is no evidence suggesting that the cows were stressed from the use for virtual fencing, thus making virtual fencing a reasonable alternative to traditional electric physical fencing of cows.

Necropsy on an adult male pilot whale stranded in Denmark in an area with heavy boat traffic revealed internal lesions in the head and neck region, while the exterior did not show any visible lesions. We found multiple fractured bones, muscle trauma and extensive hemorrhage including a fractured occipital bone with several fragments and bone pieces deeply embedded into the cerebrum of the brain. The brain was literally smashed while the third and partially fourth cervical vertebrae were almost pulverized surrounded by large amounts of blood and muscle contusion. The whale was likely killed due to a ship collision, and this particular case substantiates the value of always performing full necropsies including incisions in head and neck regions on all stranded whales-especially in areas with heavy boat traffic. This case demonstrates the importance of veterinarians performing full necropsies of whales to rule out other causes of death. Otherwise, ship collisions may be an overlooked issue having implications for population health.

In modern nature conservation and rewilding there is a need for controlling the movements of large grazers in extensively managed areas. The inflexibility of physical fencing can be a limitation in nature management, and the physical boundaries created by physical fencing can have detrimental effects on wildlife. Virtual fencing systems provide boundaries without physical structures. These systems utilise collars with GPS technology to track animals and deliver auditory or electric cues to encourage the animals to stay within the predefined boundaries. This study aims to assess the use of virtual fencing (Nofence©) to keep twelve Angus cows (Bos taurus) within a virtual enclosure without compromising their welfare. As such, the study examines inter-individual differences between the cows as well as their herd behaviour, when reacting and learning to respond appropriately to virtual fencing. Moreover, the activity of the cows was used as an indicator of welfare. The virtual fencing was successful in keeping the herd within the designated area. Moreover, the cattle learned to avoid the virtual border and respond to auditory cues, where the cows received significantly more auditory warning and electric impulses per week throughout the first 14 days than the remaining 125 days (p < 0.001). The cows were found to express both inter-individual differences (p < 0.001) and herd behaviour. The cattle did not express any significant changes in their activity upon receiving an electrical impulse from the collar. Thus, indicating that there were little to no acute welfare implications associated with the use of virtual fencing in this study. This study clearly supports the potential for virtual fencing as a viable alternative to physical electric fencing. However, it also shows that both individual differences in personality and herd structure should be considered when selecting individuals for virtual fencing.

Neuronal aggregates of misfolded alpha-synuclein protein are found in the brain and periphery of patients with Parkinson's disease. Braak and colleagues have hypothesized that the initial formation of misfolded alpha-synuclein may start in the gut, and then spread to the brain via peripheral autonomic nerves hereby affecting several organs, including the heart and intestine. Age is considered the greatest risk factor for Parkinson's disease, but the effect of age on the formation of pathology and its propagation has not been studied in detail. We aimed to investigate whether propagation of alpha-synuclein pathology from the gut to the brain is more efficient in old versus young wild-type rats, upon gastrointestinal injection of aggregated alpha-synuclein. Our results demonstrate a robust age-dependent gut-to-brain and brain-to-gut spread of alpha-synuclein pathology along the sympathetic and parasympathetic nerves, resulting in age-dependent dysfunction of the heart and stomach, as observed in patients with Parkinson's disease. Moreover, alpha-synuclein pathology is more densely packed and resistant to enzymatic digestion in old rats, indicating an age-dependent maturation of alpha-synuclein aggregates. Our study is the first to provide a detailed investigation of alpha-synuclein pathology in several organs within one animal model, including the brain, skin, heart, intestine, spinal cord and autonomic ganglia. Taken together, our findings suggest that age is a crucial factor for alpha-synuclein aggregation and complete propagation to heart, stomach and skin, similar to patients. Given that age is the greatest risk factor for human Parkinson's disease, it seems likely that older experimental animals will yield the most relevant and reliable findings. These results have important implications for future research to optimize diagnostics and therapeutics in Parkinson's disease and other age-associated synucleinopathies. Increased emphasis should be placed on using aged animals in preclinical studies and to elucidate the nature of age-dependent interactions., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: Loss of neuronal synapse function is associated with a number of brain disorders. The [ 11 C]UCB-J positron emission tomography (PET) tracer allows for in vivo examination of synaptic density, as it binds to synaptic vesicle glycoprotein 2A (SV2A) expressed in presynaptic terminals. Here, we characterise [ 11 C]UCB-J imaging in Göttingen minipigs., Procedures: Using PET imaging, we examined tracer specificity and compared kinetic models. We explored the use of a standard blood curve and centrum semiovale white matter as a reference region. We compared in vivo [ 11 C]UCB-J PET imaging to in vitro autoradiography, Western blotting and real-time quantitative polymerase chain reaction., Results: The uptake kinetics of [ 11 C]UCB-J could be described using a 1-tissue compartment model and blocking of SV2A availability with levetiracetam showed dose-dependent specific binding. Population-based blood curves resulted in reliable [ 11 C]UCB-J binding estimates, while it was not possible to use centrum semiovale white matter as a non-specific reference region. Brain [ 11 C]UCB-J PET signals correlated well with [ 3 H]UCB-J autoradiography and SV2A protein levels., Conclusions: [ 11 C]UCB-J PET is a valid in vivo marker of synaptic density in the minipig brain, with binding values close to those reported for humans. Minipig models of disease could be valuable for investigating the efficacy of putative neuroprotective agents for preserving synaptic function in future non-invasive, longitudinal studies.

Background: No PET radioligand has yet demonstrated the capacity to map glutamate N-methyl-d-aspartate receptor ion channel (NMDAR-IC) function. [ 18 F]GE-179 binds to the phencyclidine (PCP) site in open NMDAR-ICs and potentially provides a use-dependent PET biomarker of these ion channels., Objective: To show [ 18 F]GE-179 PET can detect increased NMDAR-IC activation during electrical deep brain stimulation (DBS) of pig hippocampus., Methods: Six minipigs had an electrode implanted into their right hippocampus. They then had a baseline [ 18 F]GE-179 PET scan with DBS turned off followed by a second scan with DBS turned on. Brain [ 18 F]GE-179 uptake at baseline and then during DBS was measured with PET. Cerebral blood flow (CBF) was measured with [ 15 O]H 2 O PET at baseline and during DBS and parametric CBF images were generated to evaluate DBS induced CBF changes. Functional effects of injecting the PCP blocker MK-801 were also evaluated. Electrode positions were later histologically verified., Results: DBS induced a 47.75% global increase in brain [ 18 F]GE-179 uptake (p = 0.048) compared to baseline. Global CBF was unchanged by hippocampal DBS. [ 18 F]GE-179 PET detected a 5% higher uptake in the implanted compared with the non-implanted temporo-parietal cortex at baseline (p = 0.012) and during stimulation (p = 0.022). Administration of MK-801 before DBS failed to block [ 18 F]GE-179 uptake during stimulation., Conclusion: PET detected an increase in global brain [ 18 F]GE-179 uptake during unilateral hippocampal DBS while CBF remained unchanged. These findings support that [ 18 F]GE-179 PET provides a use-dependent marker of abnormal NMDAR-IC activation., Competing Interests: Declaration of competing interest GE Healthcare supported the study by supplying the precursor for [(18)F]GE-179. DJB is a consultant for Biogen and has been a consultant for GE Healthcare, Plexxikon, and GenePod. These funders had no role in the study design, data analyses, data interpretation or writing of the article., (Copyright © 2020. Published by Elsevier Inc.)

Osteomyelitis (OM) is an important cause of morbidity and sometimes mortality in children and adults. Long-term complications can be reduced when treatment is initiated in an early phase. The diagnostic gold standard is microbial examination of a biopsy and current non-invasive imaging methods are not always optimal. [ 111 In]-leukocyte scintigraphy is recommended for peripheral OM, but is time-consuming and not recommended in children. [ 18 F]FDG PET/CT is recommended for vertebral OM in adults, but has the disadvantage of false positive findings and a relatively high radiation exposure; the latter is a problem in children. [ 99m Tc]-based tracers are consequently preferred in children. We, therefore, aimed to find a [ 99m Tc]-marked tracer with high specificity and sensitivity for early detection of OM. Suppurating inflammatory lesions like OM caused by Staphylococcus aureus ( S. aureus ) will attract large numbers of neutrophils and macrophages. A preliminary study has shown that [ 99 m Tc]-labelled IL8 may be a possible candidate for imaging of peripheral OM. We investigated [ 99m Tc]IL8 scintigraphy in a juvenile pig model of peripheral OM and compared it with [ 18 F]FDG PET/CT. The pigs were experimentally inoculated with S. aureus to induce OM and scanned one week later. We also examined leukocyte count, serum CRP and IL8, as well as performed histopathological and microbiological investigations. [ 99m Tc]IL8 was easily and relatively quickly prepared and was shown to be suitable for visualization of OM lesions in peripheral bones detecting 70% compared to a 100% sensitivity of [ 18 F]FDG PET/CT. [ 99m Tc]IL8 is a promising candidate for detection of OM in peripheral bones in children., Competing Interests: None., (AJNMMI Copyright © 2020.)

Aims: Left ventricular filling pressure (preload) can be assessed by pulmonary capillary wedge pressure (PCWP) during pulmonary arterial catheterization (PAC). An emerging method [pulse indexed contour cardiac output (PICCO)] can estimate preload by global end-diastolic volume (GEDV) and congestion as extravascular lung water (EVLW) content. However, no reliable quantitative non-invasive methods are available. Hence, in a porcine model of pulmonary congestion, we evaluated EVLW and GEDV by positron emission tomography (PET). The method was applied in 35 heart failure (HF) patients and 9 healthy volunteers., Methods and Results: Eight pigs were studied. Pulmonary congestion was induced by a combination of beta-blockers, angiotensin-2 agonist and saline infusion. PAC, PICCO, computerized tomography, and 15O-H2O-PET were performed. EVLW increased from 521 ± 76 to 973 ± 325 mL (P < 0.001) and GEDV from 1068 ± 170 to 1254 ± 85 mL (P < 0.001). 15O-H2O-PET measures of EVLW increased from 566 ± 151 to 797 ± 231 mL (P < 0.001) and GEDV from 364 ± 60 to 524 ± 92 mL (P < 0.001). Both EVLW and GEDV measured with PICCO and 15O-H2O-PET correlated (r2 = 0.40, P < 0.001; r2 = 0.40, P < 0.001, respectively). EVLW correlated with Hounsfield units (HU; PICCO: r2 = 0.36, P < 0.001, PET: r2 = 0.46, P < 0.001) and GEDV with PCWP (PICCO: r2 = 0.20, P = 0.01, PET: r2 = 0.29, P = 0.002). In human subjects, measurements were indexed (I) for body surface area. Neither EVLWI nor HU differed between chronic stable HF patients and healthy volunteers (P = 0.11, P = 0.29) whereas GEDVI was increased in HF patients (336 ± 66 mL/m2 vs. 276 ± 44 mL/m2, P = 0.01)., Conclusion: The present study demonstrates that 15O-H2O-PET can assess pulmonary congestion and preload quantitatively. Hence, prognostic information from 15O-H2O-PET examinations should be evaluated in clinical trials., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Electroconvulsive therapy is an effective therapy of depression. We hypothesized that the beneficial effects are mediated partly by decreased serotonin receptor availability in the cortex., Aims: We used positron emission tomography with the serotonin 5HT 2A receptor radioligand [ 11 C]MDL100,907 to determine serotonin receptor availability in response to electroconvulsive stimulation (ECS)., Methods: Seven Göttingen minipigs were deeply anaesthetized and imaged at baseline before the onset of ECS, and at 1-2 and 8-10 days after the end of a clinical course of ECS, consisting of 10 sessions over 3.5 weeks, and post-ECS values were compared to baseline. One additional minipig was anaesthetized over 10 sessions without ECS, as a control. We analysed images with the Ichise model for binding in cortex and hippocampus, followed by whole-brain analysis by statistical non-parametric mapping., Results: We found significantly increased binding potential of [ 11 C]MDL100,907 in the cortex and hippocampus 1-2 days after ECS, consistent with increased serotonin receptor availability compared to baseline. By 8-10 days after the final ECS, the average tracer binding had returned towards baseline. However, we also found significantly decreased tracer binding in the subcortical regions of olfactory bulb, pons, thalamus and striatum., Conclusions: With ECS, minipigs, unlike primates but like rodents, have higher availability at cortical and hippocampal 5HT 2A receptors. Decreased tracer binding is consistent with reduced serotonin receptor availability as a differential effect of ECS on 5HT 2A receptors in subcortical regions of minipig brain.

Background: While metformin is the first-line pharmacological treatment of diabetes mellitus type 2, this drug is not considered safe to use in pregnant women because of its unknown consequences for the fetus. In this study, we aimed to investigate the biodistribution of metformin in the pregnant chinchilla, a species exhibiting placental characteristics comparable with the pregnant woman. Furthermore, we aimed to investigate the expression of metformin transporters in humans and chinchillas, respectively, in order to evaluate the pregnant chinchilla as a novel animal model for the use of metformin in pregnancy., Methods: Three chinchillas in the last part of gestation were injected with [ 11 C]-metformin and scanned by PET/CT for 70 minutes to visualize the distribution. To investigate the difference in expression of placenta transporters between humans and chinchillas, PCR was performed on samples from five chinchilla placentae and seven human placentae., Results: Dynamic PET with [ 11 C]-metformin showed that the metformin distribution in chinchillas was similar to that in nonpregnant humans, with signal from kidneys, liver, bladder, and submandibular glands. Conversely, no radioactive signal was observed from the fetuses, and no metformin was accumulated in the chinchilla fetus when measuring the SUV. PCR of placental mRNA showed that the human placentae expressed OCT3, whereas the chinchilla placentae expressed OCT1., Conclusion: Since metformin did not pass the placenta barrier in the pregnant chinchilla, as it is known to do in humans, we do not suggest the chinchilla as a future animal model of metformin in pregnancies.

In recent decades, our knowledge of bile salts has undergone a vast development, and bile salts are now known not only for their detergent properties that aid in the absorption of dietary lipids but also for their interaction with specific nuclear and membrane receptors. In particular, it has been realized that the response of the farnesoid X receptor (FXR) to bile acids provides a signal bridge between the liver and small intestine, controlling the intracellular levels, biosynthesis, and enterohepatic circulation of bile acids. Therefore, FXR and bile acid signaling has become an attractive target for treatment of, for example, cholestatic liver diseases, diabetes, and colorectal cancer. Previously, interest in the structure and chemistry of bile salts has focused on their cellular toxicity and involvement in digestion. However, insight into the extensive variation in the structure of bile salts in vertebrates and the concurrent evolution of the FXR has become increasingly important as their role as signal molecules has become clearer. In this review, we therefore focus on common structural features of bile salts as well as evolutionary aspects of bile salts and the FXR in vertebrates. Ultimately, a better understanding of the evolution of bile salts and the FXR may expand our knowledge of their function in health and disease, including their function outside the gastrointestinal tract, and aid in the development of new strategies for treatment.

Purpose: Quantification of hepatic tracer kinetics by PET requires measurement of tracer input from the hepatic artery (HA) and portal vein (PV). We wished to develop a method for estimating dual tracer input without the necessity to sample PV blood., Methods: Pigs weighing 40 kg were given bolus doses of C(15)O (CO), 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG), [(11)C]-methylglucose (MG), 2-[(18)F]fluoro-2-deoxy-D-galactose (FDGal) or H(2)(15)O(H(2)O). Tracer concentration 3-min time courses were measured in the femoral artery and PV by blood sampling. Blood flow was measured in the HA and PV using flow-meters. A model for transfer of tracer through the splanchnic circulation was used to estimate values of a tracer-specific model parameter β. Tracer-specific mean values of β were used to estimate tracer concentration time courses in the PV from the measured arterial concentration. A model-derived dual-input was calculated using the mean HA flow fraction (0.25) and validated by comparison of the use of the measured dual-input and a kinetic model with a fixed "true" K(1)(true), i.e. clearance of tracer from blood to liver cells., Results: The rank order of the means of β was CO < FDG ≈ MG < FDGal < H(2)O, reflecting their different splanchnic mean transit times. Estimated K(1)(est) was not significantly different from "true" K(1)(true)., Conclusion: The hepatic dual tracer input, which is of great importance for the assessment of processes such as transfer across the plasma-hepatocyte membrane or hepatic blood perfusion, can be well approximated in pigs without the necessity to sample PV blood and measure hepatic blood flow; only arterial blood sampling is needed.

We earlier reported an anomalous 50% decrease in [(11)C]N-methylspiperone ([(11)C]NMSP) binding to dopamine D(2)-like receptors in living pig striatum after challenge with 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), suggesting either (1) a species peculiarity in the vulnerability of butyrophenone binding to competition from dopamine or (2) a novel consequence of synergistic actions of serotonin and dopamine at dopamine receptors. To distinguish these possibilities, we used microPET to test the vulnerability of [(11)C]NMSP binding in striatum of rats with unilateral telencephalic serotonin lesions, later verified by [(125)I]RTI-55 autoradiography. Baseline [(11)C]NMSP microPET recordings were followed by either saline or MDMA-HCl (4 mg/kg) injections (i.v.), and a second [(11)C]NMSP recording, culminating with injection of [(3)H]raclopride for autoradiography ex vivo. Neither MDMA-challenge nor serotonin lesion had any detectable effect on [(11)C]NMSP binding. In contrast, MDMA challenge increased receptor occupancy by [(3)H]raclopride ex vivo (relative to the B(max) in vitro) from 8% to 12%, and doubled the free ligand concentration in cerebral cortex, apparently by blocking hepatic CYP2D6. Assuming a single binding-site model, the increased [(3)H]raclopride binding indicated doubling of the apparent equilibrium dissociation constant in vivo (K(app) (d)), revealing a 2-fold increase in competition from endogenous dopamine at [(3)H]raclopride binding sites. The results favor hypothesis (1) that the remarkable vulnerability of [(11)C]NMSP binding in pig striatum to MDMA challenge does not generalize to the rodent.

Since 2000 the annual use of laboratory animals in Denmark has remained constant at approx. 350,000 animals. Two thirds, i.e. approx. 220,000 of these, were used for medical research. The majority (48-69%) were used for research in neurological and psychiatric diseases, while 7-13% were used for cancer research, and 2-3% for cardiovascular research. The use of rabbits has declined since 2000, while the use of pigs is increasing.