Predictive values of spinal cord diffusion magnetic resonance imaging to characterize outcomes after contusion injury.

OBJECTIVES: To explore filtered diffusion-weighted imaging (fDWI), in comparison with conventional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI), as a predictor for long-term locomotor and urodynamic (UD) outcomes in Yucatan minipig model of spinal cord injury (SCI). Additionally, electrical conductivity of neural tissue using D-waves above and below the injury was measured to assess correlations between fDWI and D-waves data. METHODS: Eleven minipigs with contusion SCI at T8-T10 level underwent MRI at 3T 4 h. post-SCI. Parameters extracted from region of interest analysis included Daxial from fDWI at injury site, fractional anisotropy and radial diffusivity from DTI above the injury site along with measures of edema length and cord width at injury site from T2 -weighted images. Locomotor recovery was assessed pre- and weekly post-SCI through porcine thoracic injury behavior scale (PTIBS) and UD were performed pre- and at 12 weeks of SCI. D-waves latency and amplitude differences were recorded before and immediately after SCI. RESULTS: Two groups of pigs were found based on the PTIBS at week 12 (p < 0.0001) post-SCI and were labeled "poor" and "good" recovery. D-waves amplitude decreased below injury and increased above injury. UD outcomes pre/post SCI changed significantly. Conventional MRI metrics from T2 -weighted images were significantly correlated with diffusion MRI metrics. Daxial at injury epicenter was diminished by over 50% shortly after SCI, and it differentiated between good and poor locomotor recovery and UD outcomes. INTERPRETATION: Similar to small animal studies, fDWI from acute imaging after SCI is a promising predictor for functional outcomes in large animals.

SmartPill™ Administration to Assess Gastrointestinal Function after Spinal Cord Injury in a Porcine Model-A Preliminary Study.

Gastrointestinal (GI) complications, including motility disorders, metabolic deficiencies, and changes in gut microbiota following spinal cord injury (SCI), are associated with poor outcomes. After SCI, the autonomic nervous system becomes unbalanced below the level of injury and can lead to severe GI dysfunction. The SmartPill™ is a non-invasive capsule that, when ingested, transmits pH, temperature, and pressure readings that can be used to assess effects in GI function post-injury. Our minipig model allows us to assess these post-injury changes to optimize interventions and ultimately improve GI function. The aim of this study was to compare pre-injury to post-injury transit times, pH, and pressures in sections of GI tract by utilizing the SmartPill™ in three pigs after SCI at 2 and 6 weeks. Tributyrin was administered to two pigs to assess the influences on their gut microenvironment. We observed prolonged GET (Gastric Emptying Time) and CTT (Colon Transit Time), decreases in contraction frequencies (Con freq) in the antrum of the stomach, colon, and decreases in duodenal pressures post-injury. We noted increases in Sum amp generated at 2 weeks post-injury in the colon, with corresponding decreases in Con freq. We found transient changes in pH in the colon and small intestine at 2 weeks post-injury, with minimal effect on stomach pH post-injury. Prolonged GETs and CTTs can influence the absorptive profile in the gut and contribute to pathology development. This is the first pilot study to administer the SmartPill™ in minipigs in the context of SCI. Further investigations will elucidate these trends and characterize post-SCI GI function.

Porcine spinal cord injury model for translational research across multiple functional systems.

Animal models are necessary to identify pathological changes and help assess therapeutic outcomes following spinal cord injury (SCI). Small animal models offer value in research in terms of their easily managed size, minimal maintenance requirements, lower cost, well-characterized genomes, and ability to power research studies. However, despite these benefits, small animal models have neurologic and anatomical differences that may influence translation of results to humans and thus limiting the success of their use in preclinical studies as a direct pipeline to clinical studies. Large animal models, offer an attractive intermediary translation model that may be more successful in translating to the clinic for SCI research. This is largely due to their greater neurologic and anatomical similarities to humans. The physical characteristics of pig spinal cord, gut microbiome, metabolism, proportions of white to grey matter, bowel anatomy and function, and urinary system are strikingly similar and provide great insight into human SCI conditions. In this review, we address the variety of existing porcine injury models and their translational relevance, benefits, and drawbacks in modeling human systems and functions for neurophysiology, cardiovascular, gastrointestinal and urodynamic functions.

Evaluation of topical oclacitinib and nail trimming as a treatment for murine ulcerative dermatitis in laboratory mice.

Murine ulcerative dermatitis (UD) is a common, multifactorial skin disease of C57BL/6 and C57BL/6-background strains of mice. Many treatment options have been previously reported but have been variably successful and may interfere with specific research studies. Janus kinase (JAK) inhibitors, such as oclacitinib, have been used to treat allergic dermatitis in humans, dogs, and other species. Additionally, topical oclacitinib was shown to improve an induced model of dermatitis in mice. We hypothesized that topical application of oclacitinib in conjunction with hind limb nail trimming would improve UD lesion scores more than our institutional standard treatment regime using meloxicam, topical antibiotic ointment, and nail trimming or nail trimming alone. To test this, mice with naturally occurring UD were recruited to the study and assigned to one of three treatment groups (n = 14/group): nail trim only; nail trim plus meloxicam and topical triple antibiotic ointment; or nail trim plus topical oclacitinib. UD was assessed on days 1, 7, and 14 for all treatment groups, and scored based on a previously published scoring system that quantitatively scored UD lesions based on pruritus, character of the lesion, size of lesion, and location of lesion. Here we found that mean UD scores decreased from day 1 to day 7 and from day 1 to day 14 for all treatment groups. However, there was no significant difference in mean UD score between the treatment groups at any timepoint. These data show that topical oclacitinib and nail trimming together improved UD lesion scores comparably to our institutional standard treatment and nail trimming alone. However, further studies may be warranted to investigate other potential applications of oclacitinib to treat UD.

Characterization of Lower Urinary Tract Dysfunction after Thoracic Spinal Cord Injury in Yucatan Minipigs.

There is an increasing need to develop approaches that will not only improve the clinical management of neurogenic lower urinary tract dysfunction (NLUTD) after spinal cord injury (SCI), but also advance therapeutic interventions aimed at recovering bladder function. Although pre-clinical research frequently employs rodent SCI models, large animals such as the pig may play an important translational role in facilitating the development of devices or treatments. Therefore, the objective of this study was to develop a urodynamics protocol to characterize NLUTD in a porcine model of SCI. An iterative process to develop the protocol to perform urodynamics in female Yucatan minipigs began with a group of spinally intact, anesthetized pigs. Subsequently, urodynamic studies were performed in a group of awake, lightly restrained pigs, before and after a contusion-compression SCI at the T2 or T9-T11 spinal cord level. Bladder tissue was obtained for histological analysis at the end of the study. All anesthetized pigs had bladders that were acontractile, which resulted in overflow incontinence once capacity was reached. Uninjured, conscious pigs demonstrated appropriate relaxation and contraction of the external urethral sphincter during the voiding phase. SCI pigs demonstrated neurogenic detrusor overactivity and a significantly elevated post-void residual volume. Relative to the control, SCI bladders were heavier and thicker. The developed urodynamics protocol allows for repetitive evaluation of lower urinary tract function in pigs at different time points post-SCI. This technique manifests the potential for using the pig as an intermediary, large animal model for translational studies in NLUTD.

Treadmill-Based Gait Kinematics in the Yucatan Mini Pig.

Yucatan miniature pigs (YMPs) are similar to humans in spinal cord size as well as physiological and neuroanatomical features, making them a useful model for human spinal cord injury. However, little is known regarding pig gait kinematics, especially on a treadmill. In this study, 12 healthy YMPs were assessed during bipedal and/or quadrupedal stepping on a treadmill at six speeds (1.0, 1.5, 2.0, 2.5, 3.0, and 3.5 km/h). Kinematic parameters, including limb coordination and proximal and distal limb angles, were measured. Findings indicate that YMPs use a lateral sequence footfall pattern across all speeds. Stride and stance durations decreased with increasing speed whereas swing duration showed no significant change. Across all speeds assessed, no significant differences were noted between hindlimb stepping parameters for bipedal or quadrupedal gait with the exception of distal limb angular kinematics. Specifically, significant differences were observed between locomotor tasks during maximum flexion (quadrupedal > bipedal), total excursion (bipedal > quadrupedal), and the phase relationship between the timing of maximum extension between the right and left hindlimbs (bipedal > quadrupedal). Speed also impacted maximum flexion and right-left phase relationships given that significant differences were found between the fastest speed (3.5 km/h) relative to each of the other speeds. This study establishes a methodology for bipedal and quadrupedal treadmill-based kinematic testing in healthy YMPs. The treadmill approach used was effective in recruiting primarily the spinal circuitry responsible for the basic stepping patterns as has been shown in cats. We recommend 2.5 km/h (0.7 m/sec) as a target walking gait for pre-clinical studies using YMPs, which is similar to that used in cats.

Development of a goat model for evaluation of withaferin A: Cervical implants for the treatment of cervical intraepithelial neoplasia.

Cervical cancer is caused by human papillomavirus (HPV). The disease develops over many years through a series of precancerous lesions. Cervical cancer can be prevented by HPV-vaccination, screening and treatment of precancer before development of cervical cancer. The treatment of high-grade cervical dysplasia (CIN 2+) has traditionally been by cervical conization. Surgical procedures are associated with increased risk of undesirable side effects including bleeding, infection, scarring (stenosis), infertility and complications in later pregnancies. An inexpensive, non-invasive method of delivering therapeutics locally will be favorable to treat precancerous cervical lesions without damaging healthy tissue. The feasibility and safety of a sustained, continuous drug-releasing cervical polymeric implant for use in clinical trials was studied using a large animal model. The goat (Capra hircus), non-pregnant adult female Boer goats, was chosen due to similarities in cervical dimensions to the human. Estrus was induced with progesterone CIDR® vaginal implants for 14days followed by the administration of chorionic gonadotropins 48h prior to removal of the progesterone implants to relax the cervix to allow for the placement of the cervical implant. Cervical implants, containing 2% and 4% withaferin A (WFA), with 8 coats of blank polymer, provided sustained release for a long duration and were used for the animal study. The 'mushroom'-shaped cervical polymeric implant, originally designed for women required redesigning to be accommodated within the goat cervix. The cervical implants were well tolerated by the animals with no obvious evidence of discomfort, systemic or local inflammation or toxicity. In addition, we developed a new method to analyze tissue WFA levels by solvent extractions and LS/MS-MS. WFA was found to be localized to the target and adjacent tissues with 12-16ng WFA/g tissue, with essentially no detectable WFA in distant tissues. This study suggests that the goat is a good large animal model for the future development and evaluation of therapeutic efficacy of continuous local drug delivery by cervical polymeric implants to treat precancerous cervical lesions.

Feasibility study of particulate extracellular matrix (P-ECM) and left ventricular assist device (HVAD) therapy in chronic ischemic heart failure bovine model.

Myocardial recovery with left ventricular assist device (LVAD) support is uncommon and unpredictable. We tested the hypothesis that injectable particulate extracellular matrix (P-ECM) with LVAD support promotes cell proliferation and improves cardiac function. LVAD, P-ECM, and P-ECM + LVAD therapies were investigated in chronic ischemic heart failure (IHF) calves induced using coronary embolization. Particulate extracellular matrix emulsion (CorMatrix, Roswell, GA) was injected intramyocardially using a 7 needle pneumatic delivery tool. Left ventricular assist devices (HVAD, HeartWare) were implanted in a left ventricle (LV) apex to proximal descending aorta configuration. Cell proliferation was identified using BrdU (5 mg/kg) injections over the last 45 treatment days. Echocardiography was performed weekly. End-organ regional blood flow (RBF) was quantified at study endpoints using fluorescently labeled microspheres. Before treatment, IHF calves had an ejection fraction (EF) of 33 ± 2% and left ventricular end-diastolic volume of 214 ± 18 ml with cardiac cachexia (0.69 ± 0.06 kg/day). Healthy weight gain was restored in all groups (0.89 ± 0.03 kg/day). EF increased with P-ECM + HVAD from 36 ± 5% to 75 ± 2%, HVAD 38 ± 4% to 58 ± 5%, and P-ECM 27 ± 1% to 66 ± 6%. P-ECM + HVAD demonstrated the largest increase in cell proliferation and end-organ RBF. This study demonstrates the feasibility of combined LVAD support with P-ECM injection to stimulate new cell proliferation and improve cardiac function, which warrants further investigation.

Early feasibility testing and engineering development of the transapical approach for the HeartWare MVAD ventricular assist system.

Implantation of ventricular assist devices (VADs) for the treatment of end-stage heart failure (HF) falls decidedly short of clinical demand, which exceeds 100,000 HF patients per year. Ventricular assist device implantation often requires major surgical intervention with associated risk of adverse events and long recovery periods. To address these limitations, HeartWare, Inc. has developed a platform of miniature ventricular devices with progressively reduced surgical invasiveness and innovative patient peripherals. One surgical implant concept is a transapical version of the miniaturized left ventricular assist device (MVAD). The HeartWare MVAD Pump is a small, continuous-flow, full-support device that has a displacement volume of 22 ml. A new cannula configuration has been developed for transapical implantation, where the outflow cannula is positioned across the aortic valve. The two primary objectives for this feasibility study were to evaluate anatomic fit and surgical approach and efficacy of the transapical MVAD configuration. Anatomic fit and surgical approach were demonstrated using human cadavers (n = 4). Efficacy was demonstrated in acute (n = 2) and chronic (n = 1) bovine model experiments and assessed by improvements in hemodynamics, biocompatibility, flow dynamics, and histopathology. Potential advantages of the MVAD Pump include flow support in the same direction as the native ventricle, elimination of cardiopulmonary bypass, and minimally invasive implantation.

Large animal models for left ventricular assist device research and development.

In vivo preclinical testing of left ventricular assist devices (LVADs) warrants a large animal model that faithfully simulates human etiology. Although LVAD recipients are in end-stage heart failure (HF), healthy, young animals have served as the experimental platform for most LVAD research and development (R&D) to demonstrate device safety, reliability, and biocompatibility. The rapidly growing HF epidemic, donor heart shortage, and clinical acceptance of LVAD for bridge-to-transplant therapy (BTT) has led to the expanded role of LVAD for destination therapy and bridge-to-recovery therapy. New paradigms for the clinical care of these emerging patient populations are needed. Clinically relevant, robust, and reproducible large animal models of HF are required to demonstrate efficacy, investigate physiologic responses, elucidate genetic, molecular, and cellular mechanism(s), and develop LVAD control strategies. The animal model must be comparable in size, anatomical structure, and phenotype; the technique used to initiate HF must reflect the clinical portrait, should be technically and financially feasible, result in predictable, stable, and irreversible HF, and demonstrate bidirectionality of the remodeling cascade. In this review, large animal species commonly used in cardiac research, techniques used to create chronic HF, and the combined applicability to preclinical LVAD R&D studies are presented.

Bovine model of chronic ischemic cardiomyopathy: implications for ventricular assist device research.

Ventricular assist devices (VADs) have emerged as a successful treatment option for advanced heart failure. The objective of this study was to develop a clinically relevant model of chronic ischemic cardiomyopathy to investigate functional, histological, and molecular changes during mechanical circulatory support. In calves (n = 17, 94 ± 7 kg), 90 µm microspheres were injected percutaneously into the left coronary artery. Serial echocardiography was performed weekly to evaluate cardiac function. Sixty days after coronary microembolization, a terminal study was performed via thoracotomy to measure hemodynamics. Regional myocardial and end-organ blood flows were quantified with 15-µm fluorescent-labeled microspheres. Myocardial fibrosis, myocyte size, and myocardial apoptosis were quantified with histological stains. Eleven animals survived coronary microembolization and exhibited clinical and statistically significant echocardiographic and hemodynamic signs of severe systolic dysfunction. Statistically significant decreases in regional myocardial blood flow and increases in myocardial fibrosis, myocyte size, total myocardial apoptosis, and cardiac myocyte-specific apoptosis were observed. End-organ hypoperfusion was observed. Coronary microembolization induced stable and reproducible chronic left ventricular failure in calves. The anatomical size and physiology of the bovine heart and thorax are appropriate to study novel interventions for the clinical management of heart failure. This model is an appropriate physiological substrate in which to test VAD and adjunctive biological therapies.

Benefits of aggressive medical management in a bovine model of chronic ischemic heart failure.

A major limitation in the development of mechanical circulatory support (MCS) devices has been the lack of a clinically relevant, stable, and reproducible large animal chronic heart failure (HF) model. High mortality rates have been reported with large animal chronic HF models. In this study, methods of medical management to improve survival rate (SR) were investigated. Chronic ischemic HF (IHF) was induced in Jersey calves using a microembolization technique via fluoroscopy-guided injection of 90 µm microspheres into the coronary vasculature. Animals were divided into 1) Control--multiple embolization procedures with conservative therapy (n = 9); 2) treatment group 1 (TG1)--single embolization procedure with moderately aggressive therapy (n = 8); and 3) TG2--single embolization procedure with aggressive medical management (n = 20). The groups were not randomized with data analyzed retrospectively. Mean SR, body condition score, body weight, hemodynamic, echocardiography, and histopathology indices were recorded up to 60 days postembolization. SR improved from 56% (Control) to 75% (TG1) and 90% (TG2) using an aggressive medical management regimen of analgesia, diuretics, beta-blockade, antiarrhythmics, vasodilators, and inotropes. These findings support the hypothesis that a single coronary microembolization procedure and aggressive medical therapy produces a clinically relevant chronic IHF model with a significantly higher SR than conservative medical therapy.

Molecular imaging reveals a progressive pulmonary inflammation in lower airways in ferrets infected with 2009 H1N1 pandemic influenza virus.

Molecular imaging has gained attention as a possible approach for the study of the progression of inflammation and disease dynamics. Herein we used [(18)F]-2-deoxy-2-fluoro-D-glucose ([(18)F]-FDG) as a radiotracer for PET imaging coupled with CT (FDG-PET/CT) to gain insight into the spatiotemporal progression of the inflammatory response of ferrets infected with a clinical isolate of a pandemic influenza virus, H1N1 (H1N1pdm). The thoracic regions of mock- and H1N1pdm-infected ferrets were imaged prior to infection and at 1, 2, 3 and 6 days post-infection (DPI). On 1 DPI, FDG-PET/CT imaging revealed areas of consolidation in the right caudal lobe which corresponded with elevated [(18)F]-FDG uptake (maximum standardized uptake values (SUVMax), 4.7-7.0). By days 2 and 3, consolidation (CT) and inflammation ([(18)F]-FDG) appeared in the left caudal lobe. By 6 DPI, CT images showed extensive areas of patchy ground-glass opacities (GGO) and consolidations with the largest lesions having high SUVMax (6.0-7.6). Viral shedding and replication were detected in most nasal, throat and rectal swabs and nasal turbinates and lungs on 1, 2 and 3 DPI, but not on day 7, respectively. In conclusion, molecular imaging of infected ferrets revealed a progressive consolidation on CT with corresponding [(18)F]-FDG uptake. Strong positive correlations were measured between SUVMax and bronchiolitis-related pathologic scoring (Spearman's ρ = 0.75). Importantly, the extensive areas of patchy GGO and consolidation seen on CT in the ferret model at 6 DPI are similar to that reported for human H1N1pdm infections. In summary, these first molecular imaging studies of lower respiratory infection with H1N1pdm show that FDG-PET can give insight into the spatiotemporal progression of the inflammation in real-time.

Ferret thoracic anatomy by 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (18F-FDG PET/CT) imaging.

The domestic ferret (Mustela putorius furo) has been a long-standing animal model used in the evaluation and treatment of human diseases. Molecular imaging techniques such as 2-deoxy-2-((18)F)fluoro-D-glucose ((18)F-FDG) positron emission tomography (PET) would be an invaluable method of tracking disease in vivo, but this technique has not been reported in the literature. Thus, the aim of this study was to establish baseline imaging characteristics of PET/computed tomography (CT) with (18)F-FDG in the ferret model. Twelve healthy female ferrets were anesthetized and underwent combined PET/CT scanning. After the images were fused, volumes of interest (VOIs) were generated in the liver, heart, thymus, and bilateral lung fields. For each VOI, standardized uptake values (SUVs) were calculated. Additional comparisons were made between radiotracer uptake periods (60, 90, and >90 minutes), intravenous and intraperitoneal injections of (18)F-FDG, and respiratory gated and ungated acquisitions. Pulmonary structures and the surrounding thoracic and upper abdominal anatomy were readily identified on the CT scans of all ferrets and were successfully fused with PET. VOIs were created in various tissues with the following SUV calculations: heart (maximum standardized uptake value [SUV(Max)] 8.60, mean standardized uptake value [SUV(Mean)] 5.42), thymus (SUV(Max) 3.86, SUV(Mean) 2.59), liver (SUV(Max) 1.37, SUV(Mean) 0.99), right lung (SUV(Max) 0.92, SUV(Mean) 0.56), and left lung (SUV(Max) 0.88, SUV(Mean) 0.51). Sixty- to 90-minute uptake periods were sufficient to separate tissues based on background SUV activity. No gross differences in image quality were seen between intraperitoneal and intravenous injections of (18)F-FDG. Respiratory gating also did not have a significant impact on image quality of lung parenchyma. The authors concluded that (18)F-FDG PET and CT imaging can be performed successfully in normal healthy ferrets with the parameters identified in this study. They obtained similar imaging features and uptake measurements with and without respiratory gating as well as with intraperitoneal and intravenous (18)F-FDG injections. (18)F-FDG PET and CT can be a valuable resource for the in vivo tracking of disease progression in future studies that employ the ferret model.

Irreversible electroporation of the pancreas: definitive local therapy without systemic effects.

BACKGROUND: The use of thermal tumor ablative techniques in the pancreas is limited due to the risk of pancreatitis and damage to major vascular structures. Irreversible electroporation (IRE) is a non-thermal ablation technique that could allow ablation in the pancreas while preserving vital surrounding blood vessels. The aim of this study was to assess the safety and ablation volume of IRE in porcine pancreatic tissue. METHODS: IRE of swine pancreases was performed using an open technique and ultrasound guidance and the animals were followed for 72 hr, 7 days, and 14 days post-IRE. RESULTS: All pigs underwent IRE, with one pig was unsuccessful after three attempts using at 3,000 V due to inability to achieve a stable current. All animals recovered well and revealed only mild adhesions, no ascites, and no pancreatic necrosis. All animals had transient increases in amylase and lipase that normalized on post-IRE day 3. Pathologic analysis revealed that ablation defects (median size 3 cm × 2.8 cm) were seen in electroporated areas with significant destruction of the pancreatic tissue with patent vascular structures. CONCLUSIONS: This animal model demonstrates that IRE of the pancreas performed at an optimal voltage is well tolerated, with rapid resolution of pancreatic inflammation and preservation of vascular structures.

Transapical miniaturized ventricular assist device: design and initial testing.

BACKGROUND: Left ventricular assist devices are increasingly used to treat patients with advanced and otherwise refractory heart failure as bridge to transplant or destination therapy. We evaluated a new miniaturized left ventricular assist device that requires minimal surgery for implantation, potentially allowing implantation in earlier stage heart failure. METHODS: HeartWare (Miami Lakes, Fla) developed transapical miniaturized ventricular assist device. Acute (n = 4), 1-week (n = 2), and 30-day (n = 4) bovine model experiments evaluated hemodynamic efficacy and biocompatibility of the device, which was implanted through small left thoracotomy with single insertion at apex of left ventricle without cardiopulmonary bypass. The device outflow cannula was positioned across the aortic valve. The international normalized ratio was maintained between 2.0 and 2.5 with warfarin. Hemodynamic, echocardiographic, fluoroscopic, hematologic, and blood chemistry measurements were evaluated. RESULTS: The device was successfully implanted through the left ventricular apex in all 10 animals. The device was operated at 15,000 ± 1000 rpm (power consumption, 3.5-6.0 W). The device maintained normal end-organ perfusion with no significant hemolysis (0-30 mg/dL). There were no pump failures or device-related complications. At autopsy, no abnormalities were seen in endocardium, aortic valve leaflets, or aortic root. There was no evidence of thromboembolism or abnormalities in any peripheral end organs. CONCLUSIONS: We successfully demonstrated feasibility of a novel intraventricular assist device that can be completely implanted through left ventricular apex. This transapical surgical approach eliminates needs for sternotomy, device pocket, cardiopulmonary bypass, ventricular coring, and construction of an outflow graft anastomosis.

A novel subcutaneous counterpulsation device: acute hemodynamic efficacy during pharmacologically induced hypertension, hypotension, and heart failure.

The miniaturization of mechanical assist devices and less invasive implantation techniques may lead to earlier intervention in patients with heart failure. As such, we evaluated the effectiveness of a novel, minimally invasive, implantable counterpulsation device (CPD) in augmenting cardiac function during impaired hemodynamics. We compared the efficacy of a 32-mL stroke volume CPD with a standard 40-mL intra-aortic balloon pump (IABP) over a range of clinically relevant pathophysiological conditions. Male calves were instrumented via thoracotomy, the CPD was anastomosed to the left carotid artery, and the IABP was positioned in the descending aorta. Hemodynamic conditions of hypertension, hypotension, and heart failure were pharmacologically simulated and data were recorded during CPD and IABP support (off, 1:2, 1:1 modes) for each condition. In all three pathophysiological conditions, the CPD and IABP produced similar and statistically significant (P < 0.05) increases in coronary artery blood flow normalized to the left ventricular (LV) workload. During hypotension and heart failure conditions, however, the CPD produced significantly greater reductions in LV workload and myocardial oxygen consumption as compared with the IABP. A novel 32-mL CPD connected to a peripheral artery produced equivalent or greater hemodynamic benefits than a standard 40-mL IABP during pharmacologically induced hypertension, hypotension, and heart failure conditions.

Creating a long-term diabetic rabbit model.

This study was to create a long-term rabbit model of diabetes mellitus for medical studies of up to one year or longer and to evaluate the effects of chronic hyperglycemia on damage of major organs. A single dose of alloxan monohydrate (100 mg/kg) was given intravenously to 20 young New Zealand White rabbits. Another 12 age-matched normal rabbits were used as controls. Hyperglycemia developed within 48 hours after treatment with alloxan. Insulin was given daily after diabetes developed. All animals gained some body weight, but the gain was much less than the age-matched nondiabetic rabbits. Hyperlipidemia, higher blood urea nitrogen and creatinine were found in the diabetic animals. Histologically, the pancreas showed marked beta cell damage. The kidneys showed significantly thickened afferent glomerular arterioles with narrowed lumens along with glomerular atrophy. Lipid accumulation in the cytoplasm of hepatocytes appeared as vacuoles. Full-thickness skin wound healing was delayed. In summary, with careful management, alloxan-induced diabetic rabbits can be maintained for one year or longer in reasonably good health for diabetic studies.