Small-animal PET/CT for monitoring the development and response to chemotherapy of thymic lymphoma in Trp53-/- mice

Transgenic mouse models of human cancers represent one of the most promising approaches to elucidate clinically relevant mechanisms of action and provide insights into the treatment efficacy of new antitumor drugs. The use of Trp53 transgenic mice (Trp53 knockout [Trp53(-/-)] mice) for these kinds of studies is, so far, restricted by limitations in detecting developing tumors and the lack of noninvasive tools for monitoring tumor growth, progression, and treatment response.

Controversies in the use of hydroxyethyl starch solutions in small animal emergency and critical care

OBJECTIVES: To (1) review the development and medical applications of hydroxyethyl starch (HES) solutions with particular emphasis on its physiochemical properties; (2) critically appraise the available evidence in human and veterinary medicine, and (3) evaluate the potential risks and benefits associated with their use in critically ill small animals. DATA SOURCES: Human and veterinary original research articles, scientific reviews, and textbook sources from 1950 to the present. HUMAN DATA SYNTHESIS: HES solutions have been used extensively in people for over 30 years and ever since its introduction there has been a great deal of debate over its safety and efficacy. Recently, results of seminal trials and meta-analyses showing increased risks related to kidney dysfunction and mortality in septic and critically ill patients, have led to the restriction of HES use in these patient populations by European regulatory authorities. Although the initial ban on the use of HES in Europe has been eased, proof regarding the benefits and safety profile of HES in trauma and surgical patient populations has been requested by these same European regulatory authorities. VETERINARY DATA SYNTHESIS: The veterinary literature is limited mostly to experimental studies and clinical investigations with small populations of patients with short-term end points and there is insufficient evidence to generate recommendations. CONCLUSIONS: Currently, there are no consensus recommendations regarding the use of HES in veterinary medicine. Veterinarians and institutions affected by the HES restrictions have had to critically reassess the risks and benefits related to HES usage based on the available information and sometimes adapt their procedures and policies based on their reassessment. Meanwhile, large, prospective, randomized veterinary studies evaluating HES use are needed to achieve relevant levels of evidence to enable formulation of specific veterinary guidelines.

Pre-clinical in vivo models for the screening of bone biomaterials for oral/craniofacial indications: focus on small-animal models.

Preclinical in vivo experimental studies are performed for evaluating proof-of-principle concepts, safety and possible unwanted reactions of candidate bone biomaterials before proceeding to clinical testing. Specifically, models involving small animals have been developed for screening bone biomaterials for their potential to enhance bone formation. No single model can completely recreate the anatomic, physiologic, biomechanic and functional environment of the human mouth and jaws. Relevant aspects regarding physiology, anatomy, dimensions and handling are discussed in this paper to elucidate the advantages and disadvantages of small-animal models. Model selection should be based not on the 'expertise' or capacities of the team, but rather on a scientifically solid rationale, and the animal model selected should reflect the question for which an answer is sought. The rationale for using heterotopic or orthotopic testing sites, and intraosseous, periosseous or extraskeletal defect models, is discussed. The paper also discusses the relevance of critical size defect modeling, with focus on calvarial defects in rodents. In addition, the rabbit sinus model and the capsule model in the rat mandible are presented and discussed in detail. All animal experiments should be designed with care and include sample-size and study-power calculations, thus allowing generation of meaningful data. Moreover, animal experiments are subject to ethical approval by the relevant authority. All procedures and the postoperative handling and care, including postoperative analgesics, should follow best practice.

Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation.

AIMS In this work, we provide novel insight into the morphology of dissecting abdominal aortic aneurysms in angiotensin II-infused mice. We demonstrate why they exhibit a large variation in shape and, unlike their human counterparts, are located suprarenally rather than infrarenally. METHODS AND RESULTS We combined synchrotron-based, ultra-high resolution ex vivo imaging (phase contrast X-Ray tomographic microscopy) with in vivo imaging (high-frequency ultrasound and contrast-enhanced micro-CT) and image-guided histology. In all mice, we observed a tear in the tunica media of the abdominal aorta near the ostium of the celiac artery. Independently we found that, unlike the gradual luminal expansion typical for human aneurysms, the outer diameter increase of angiotensin II-induced dissecting aneurysms in mice was related to one or several intramural haematomas. These were caused by ruptures of the tunica media near the ostium of small suprarenal side branches, which had never been detected by the established small animal imaging techniques. The tear near the celiac artery led to apparent luminal dilatation, while the intramural haematoma led to a dissection of the tunica adventitia on the left suprarenal side of the aorta. The number of ruptured branches was higher in those aneurysms that extended into the thoracic aorta, which explained the observed variability in aneurysm shape. CONCLUSION Our results are the first to describe apparent luminal dilatation, suprarenal branch ruptures, and intramural haematoma formation in dissecting abdominal aortic aneurysms in mice. Moreover, we validate and demonstrate the vast potential of phase contrast X-ray tomographic microscopy in cardiovascular small animal applications.

Pros and cons of low-field magnetic resonance imaging in veterinary practice

Low-field (LF) (0.2-0.4T) magnetic resonance (MR) imaging predominates in veterinary practice. Advantages of LF MR include reduced costs, better patient access, and greater safety. High quality examinations can be achieved using appropriate protocols and investing more scanning time than with high-field (HF) systems. The main disadvantage of LF MR is the reduced signal to noise ratio compared with HF systems. LF MR protocols for small animal brain and spine imaging are described.

Future prospects for SPECT imaging using the radiolanthanide terbium-155 — production and preclinical evaluation in tumor-bearing mice

We assessed the suitability of the radiolanthanide 155 Tb (t1/2 = 5.32 days, Eγ = 87 keV (32%), 105 keV (25%)) in combination with variable tumor targeted biomolecules using preclinical SPECT imaging. Methods 155Tb was produced at ISOLDE (CERN, Geneva, Switzerland) by high-energy (~ 1.4 GeV) proton irradiation of a tantalum target followed by ionization and on-line mass separation. 155 Tb was separated from isobar and pseudo-isobar impurities by cation exchange chromatography. Four tumor targeting molecules – a somatostatin analog (DOTATATE), a minigastrin analog (MD), a folate derivative (cm09) and an anti-L1-CAM antibody (chCE7) – were radiolabeled with 155 Tb. Imaging studies were performed in nude mice bearing AR42J, cholecystokinin-2 receptor expressing A431, KB, IGROV-1 and SKOV-3ip tumor xenografts using a dedicated small-animal SPECT/CT scanner. Results The total yield of the two-step separation process of 155 Tb was 86%. 155 Tb was obtained in a physiological l-lactate solution suitable for direct labeling processes. The 155 Tb-labeled tumor targeted biomolecules were obtained at a reasonable specific activity and high purity (> 95%). 155 Tb gave high quality, high resolution tomographic images. SPECT/CT experiments allowed excellent visualization of AR42J and CCK-2 receptor-expressing A431 tumors xenografts in mice after injection of 155 Tb-DOTATATE and 155 Tb-MD, respectively. The relatively long physical half-life of 155 Tb matched in particular the biological half-lives of 155 Tb-cm09 and 155 Tb-DTPA-chCE7 allowing SPECT imaging of KB tumors, IGROV-1 and SKOV-3ip tumors even several days after administration. Conclusions The radiolanthanide 155 Tb may be of particular interest for low-dose SPECT prior to therapy with a therapeutic match such as the β--emitting radiolanthanides 177Lu, 161 Tb, 166Ho, and the pseudo-radiolanthanide 90Y.

Dissecting abdominal aortic aneurysm in Angiotensin II-infused mice: the importance of imaging

INTRODUCTION Since the initial publication in 2000, Angiotensin II-infused mice have become one of the most popular models to study abdominal aortic aneurysm in a pre-clinical setting. We recently used phase contrast X-ray based computed tomography to demonstrate that these animals develop an apparent luminal dilatation and an intramural hematoma, both related to mural ruptures in the tunica media in the vicinity of suprarenal side branches. AIMS The aim of this narrative review was to provide an extensive overview of small animal applicable techniques that have provided relevant insight into the pathogenesis and morphology of dissecting AAA in mice, and to relate findings from these techniques to each other and to our recent PCXTM-based results. Combining insights from recent and consolidated publications we aimed to enhance our understanding of dissecting AAA morphology and anatomy. RESULTS AND CONCLUSION We analyzed in vivo and ex vivo images of aortas obtained from macroscopic anatomy, histology, high-frequency ultrasound, contrast-enhanced micro-CT, micro-MRI and PCXTM. We demonstrate how in almost all publications the aorta has been subdivided into a part in which an intact lumen lies adjacent to a remodeled wall/hematoma, and a part in which elastic lamellae are ruptured and the lumen appears to be dilated. We show how the novel paradigm fits within the existing one, and how 3D images can explain and connect previously published 2D structures. We conclude that PCXTM-based findings are in line with previous results, and all evidence points towards the fact that dissecting AAAs in Angiotensin II-infused mice are actually caused by ruptures of the tunica media in the immediate vicinity of small side branches.

A 20-channel receive-only mouse array coil for a 3 T clinical MRI system

A 20-channel phased-array coil for MRI of mice has been designed, constructed, and validated with bench measurements and high-resolution accelerated imaging. The technical challenges of designing a small, high density array have been overcome using individual small-diameter coil elements arranged on a cylinder in a hexagonal overlapping design with adjacent low impedance preamplifiers to further decouple the array elements. Signal-to-noise ratio (SNR) and noise amplification in accelerated imaging were simulated and quantitatively evaluated in phantoms and in vivo mouse images. Comparison between the 20-channel mouse array and a length-matched quadrature driven small animal birdcage coil showed an SNR increase at the periphery and in the center of the phantom of 3- and 1.3-fold, respectively. Comparison with a shorter but SNR-optimized birdcage coil (aspect ratio 1:1 and only half mouse coverage) showed an SNR gain of twofold at the edge of the phantom and similar SNR in the center. G-factor measurements indicate that the coil is well suited to acquire highly accelerated images.

The low-energy β− and electron emitter 161Tb as an alternative to 177Lu for targeted radionuclide therapy

The low-energy β− emitter 161Tb is very similar to 177Lu with respect to half-life, beta energy and chemical properties. However, 161Tb also emits a significant amount of conversion and Auger electrons. Greater therapeutic effect can therefore be expected in comparison to 177Lu. It also emits low-energy photons that are useful for gamma camera imaging. The 160Gd(n,γ)161Gd→161Tb production route was used to produce 161Tb by neutron irradiation of massive 160Gd targets (up to 40 mg) in nuclear reactors. A semiautomated procedure based on cation exchange chromatography was developed and applied to isolate no carrier added (n.c.a.) 161Tb from the bulk of the 160Gd target and from its stable decay product 161Dy. 161Tb was used for radiolabeling DOTA-Tyr3-octreotate; the radiolabeling profile was compared to the commercially available n.c.a. 177Lu. A 161Tb Derenzo phantom was imaged using a small-animal single-photon emission computed tomography camera. Up to 15 GBq of 161Tb was produced by long-term irradiation of Gd targets. Using a cation exchange resin, we obtained 80%–90% of the available 161Tb with high specific activity, radionuclide and chemical purity and in quantities sufficient for therapeutic applications. The 161Tb obtained was of the quality required to prepare 161Tb–DOTA-Tyr3-octreotate. We were able to produce 161Tb in n.c.a. form by irradiating highly enriched 160Gd targets; it can be obtained in the quantity and quality required for the preparation of 161Tb-labeled therapeutic agents.

Necrotising encephalitis in a French bulldog

A 20-month-old, female French bulldog was presented with a three-month history of generalised seizures and progressive ataxia with occasional falling over on either side. Neurological examination revealed signs, suggesting a multifocal intracranial lesion. Magnetic resonance imaging of the brain revealed two connected lesions on the left side of the caudal brainstem and a further lesion in the cerebrum. The dog was euthanased, and histopathological examination revealed lesions which closely resembled those of necrotising encephalitis in Yorkshire terriers. This is the first case describing this type of necrotising encephalitis in a French bulldog.

Empty sella syndrome, hyperadrenocorticism and megaoesophagus in a dachshund

A five-year-old, entire, male dachshund was presented with a five day history of hypersalivation and regurgitation as well as polyuria and polydipsia for several months. Chest radiographs demonstrated megaoesophagus and aspiration pneumonia. Furthermore, hyperadrenocorticism was demonstrated by means of elevations in levels of serum alkaline phosphatase and cholesterol, decreased urinary specific gravity, increased response to adrenocorticotropic hormone stimulation, insufficient suppression of the post-dexamethasone plasma cortisol levels, an increased endogenous adrenocorticotropic hormone concentration and bilaterally enlarged adrenal glands on abdominal ultrasound. The dog became severely dyspnoeic and was euthanased after magnetic resonance imaging was performed. The magnetic resonance imaging and necropsy revealed the sellar region mainly filled with fluid, with only small tissue remnants, a condition defined as empty sella syndrome in human medicine. To the author's knowledge, this is the first dog described with empty sella syndrome and only the second dog described with hyperadrenocorticism secondary to ectopic adrenocorticotropic hormone production. However, the association between empty sella syndrome and hyperadrenocorticism may be no more than incidental.

Cerebellar cortical degeneration with selective granule cell loss in Bavarian mountain dogs

Three Bavarian mountain dogs aged between 18 and 20 months, not related to each other, were presented with chronic signs of cerebellar dysfunction. On sagittal T2-weighted magnetic resonance imaging brain images, the tentative diagnosis of cerebellar hypoplasia was established based on an enlarged cerebrospinal fluid space around the cerebellum and an increased cerebrospinal fluid signal between the folia. Post-mortem examination was performed in one dog and did show an overall reduction of cerebellar size. On histopathologic examination, a selective loss of cerebellar granule cells with sparing of Purkinje cells was evident. Therefore, the Bavarian mountain dog is a breed where cerebellar cortical degeneration caused by the rather exceptional selective granule cell loss can be seen as cause of chronic, slowly progressive cerebellar dysfunction starting at an age of several months.

Small intestinal intussusception in five dogs with acute renal failure and suspected leptospirosis (L. australis)

OBJECTIVES This case series describes 5 dogs with small intestinal intussusception and acute kidney injury due to infection with Leptospira interrogans serovar Australis. CASE SERIES SUMMARY Small intestinal intussusception was observed in 4 dogs diagnosed with acute kidney injury due to leptospirosis presented between 1997 and 2005. Intussusception was diagnosed at initial presentation or later during hospitalization. An additional dog fulfilling our inclusion criteria was presented to a small animal specialty clinic nearby and was included. Upon admission, all dogs were severely azotemic and thrombocytopenic. All 5 dogs showed the strongest microscopic agglutination test serology reaction to L. interrogans serovar Australis. Two dogs survived with no apparent residual renal damage, 1 survived with subsequent mild chronic kidney disease, and 2 dogs were euthanized at the owners' request due to a guarded prognosis. NEW OR UNIQUE INFORMATION PROVIDED Intussusception can occur or may be seen in dogs with leptospirosis due to L. interrogans serovar Australis and patients should be monitored closely for this potential complication. As all 5 dogs described in this case series showed the highest titer for L. interrogans serovar Australis, these precautions may be especially applied in geographic areas where this particular serovar is seen.

In Vivo Evaluation of the Phenox CRC Mechanical Thrombectomy Device in a Swine Model of Acute Vessel Occlusion

Mechanical thrombectomy in ischemic stroke is of increasing interest as it is a promising strategy for fast and efficient recanalization. Several thrombectomy devices have been introduced to the armentarium of mechanical thrombectomy. Currently, new devices are under development and are continuously added to the neurointerventional tool box. Each device advocated so far has a different design and mechanical properties in terms of thrombus-device interaction. Therefore, a systematic evaluation under standardized conditions in vivo of these new devices is needed. The purpose of this study was to evaluate the efficiency, thrombus-device interaction, and potential complications of the novel Phenox CRC for distal mechanical thrombectomy in vivo. The device was evaluated in an established animal model in the swine. Recanalization rate, thromboembolic events, vasospasm, and complications were assessed. Radiopaque thrombi (2 cm length) were used for the visualization of thrombus-device interaction during retrieval. The Phenox CRC (4 mm diameter) was assessed in 15 vessel occlusions. For every occlusion a maximum of 3 retrieval attempts were performed. Complete recanalization (TICI 3/TIMI 3) was achieved in 86.7% of vessel occlusions. In 66.7% (10/15), the first retrieval attempt was successful, and in 20% (3/15), the second attempt led to complete recanalization of the parent artery. In 2 cases (13.3%) thrombus retrieval was not successful (TICI 0/TIMI 0). In 1 case (6.7%) a minor embolic event occurred in a small side branch. No distal thromboembolic event was observed during the study. Thrombus-device interaction illustrated the entrapment of the thrombus by the microfilaments and the proximal cage of the device. No significant thrombus compression was observed. No vessel perforation, dissection, or fracture of the device occurred. In this small animal study, the Phenox CRC was a safe and effective device for mechanical thrombectomy. The unique design with a combination of microfilaments and proximal cage reduces thrombus compression with a consequently high recanalization and low complication rate.