Animal Model

An epidemiological study of Attention Deficit / Hyperactivity Disorder (ADHD) suggests that the prevalence may be two to three times higher than the figure of 3 ± 5% often cited. In addition, the data suggest that both underdiagnosis and overdiagnosis occur frequently. Rodent animal models of ADHD, like the Spontaneously Hypertensive Rat (SHR) and other rat models such as those with chemical and radiationinduced brain lesions and cerebellar stunting, and the Coloboma mouse model exhibit clear similarities with several aspects of the human disorder and should prove useful in studying specific traits. Operant behavioral tasks that model learning, short -term memory and simple discriminations are sensitive to ADHD and methylphenidate has been shown to normalize ADHD performance in a short -term memory task. Recent findings challenge not only the current postulate that response inhibition is a unique deficit in ADHD, but also the concepts of ADHD and its treatment, which presume intact perceptual abilities. Time perception deficits may account, in part, for the excessive variability in motor response times on speeded reaction time tasks, motor control problems and motor clumsiness associated with ADHD. The Multimodality Treatment Study of ADHD (MTA) provided data suggesting that pharmacological interventions that included systematic and frequent follow -up with parents and teachers, with or without psychosocial interventions, are superior to psychosocial interventions or standard community care alone. Additionally, the MTA was one of the first studies to demonstrate benefits of multimodal and pharmacological interventions lasting longer than 1 year. Imaging studies have demonstrated differences in brain areas in children with ADHD: anterior corpus callosum, right anterior white matter, and cerebellar volumes are all decreased in children with ADHD and there is less brain asymmetry in ADHD subjects. Additionally, functional imaging studies, coupled with pharmacological manipulations, suggest decreased blood flow and energy utilization in prefrontal cortex and striatum, and the dysregulation of catecholamine systems in persons with ADHD. D (M.G. Paule).

Our aim was to study histopathological changes in lung tissue at the light microscopic and ultrastructural level during recovery from immunosuppression and Pneumocystis carinii pneumonia. Male Wistar rats were immunosuppressed by per oral dexamethasone for 12 weeks to induce P. carinii pneumonia, after which dexamethasone was stopped. Recovery was monitored 1, 2 and 4 weeks after cessation of the immunosuppression. In immunosuppressed animals, CD4+ and CD8+ lymphocytes were both decreased in situ. CD8+ lymphocytes increased above control level at week one. Like CD8+ cells, the ED1+ macrophages increased rapidly in situ. This was accompanied by a progressively increasing migration (more transient for lymphocytes) of macrophages into bronchoalveolar fluid, associated with morphological signs of activation and phagocytosis and proliferation of type II pneumocytes. Bronchoalveolar lavage (BAL) fluid tumour necrosis factor-alpha (TNF-alpha) increased from subnormal levels to a 4 week pea...

Recent experimental evidence indicates that progesterone (PROG) protects against various models of brain injury, including ischemic stroke. Most human studies of pharmacologic treatments for acute cerebral stroke have failed despite initial success in animal models. To simulate better the typical human stroke without reperfusion, the present study was conducted to examine the efficacy of PROG on infarct volume and functional outcome in a permanent model of stroke, using direct cauterization of the middle cerebral artery (MCA). Twenty-four male adult Sprague-Dawley rats underwent pMCAO by electro-coagulation and sham operation. After induction of permanent MCA occlusion (pMCAO), the rats received an initial intraperitoneal injection of PROG (8 mg/kg) or vehicle at 1h post-occlusion followed by subcutaneous injections at 6, 24 and 48 h. Functional deficits were tested on the rotarod and grip strength meter at 24, 48 and 72 h after pMCAO. The rats were killed 72 h after surgery and isolated brain was sectioned into coronal slices and stained with 2, 3, 5triphenyltetrazolium chloride (TTC). PROG-treated rats showed a substantial reduction (54.05%) in the volume of the infarct (% contralateral hemisphere) compared to vehicle controls. In addition there was a significant improvement in ability to remain on an accelerating rotarod and increased grip strength observed in the pMCAO rats treated with PROG compared to vehicle. Taken together, these data indicate that PROG is beneficial in one of the best-characterized models of stroke, and may warrant further testing in future clinical trials for human stroke.

Objective. This investigation aims to determine (1) whether shockwave treatment helps fracture healing and (2) whether the effect of shockwave treatment on fracture healing is dose dependent. Design. Shockwave was applied over tibial osteotomy in an animal model to assess its effect on the healing of the fracture. Methodology. Bilateral tibial diaphyseal transverse osteotomy was conducted on 42 rabbits, dividing into experimental and control group, immobilized using an external skeletal fixator, with one leg tested with shockwave therapy and the contralateral leg acting as the control without therapy. Serial radiography and measurement of bone mineral density via dual-energy X-ray absorptiometry were performed to assess the fracture healing. The experimental animals had two or three sessions of shockwave therapy (5000 impulses, 0.32 mJ/mm 2 , Orthopedice) over the osteotomy sites on day 7, 21 and 35; while the control group did not receive any treatment. The animals were sacrificed on day 42 or 56. Then, bilateral tibias were harvested and sent for mechanical tests as well as the histological examination. The pertinent statistic methods were applied to analyze the results. Background. Shockwave therapy has become a useful alternative approach in treating various orthopedic conditions, but the mechanism which it works remains unclear. Thus far, shockwave therapy has been found effective in treating long bone pseudoarthrosis, but whether it can benefit fresh fracture healing continues to be debated. Results. Higher union rates occurred during the early but not the late stages in the experimental group, while mechanical strength was higher in the experimental group than in the control group. No significant dose-dependent response occurred between the second and third applications of shockwave treatment. No significant difference in mechanical strength occurred between the experimental groups at 4 weeks and the control group at 6 weeks, or between the experimental groups at 6 and 8 weeks. Furthermore, no significant correlation occurred between the absolute values of maximum torque and bone mineral density. Conclusion. Based on this investigation, shockwave treatment has a positive effect on early fracture healing while its long term effects require further investigation. Relevance Shockwave therapy can be a useful alternative adjunct modality in the treatment of fresh long bone fracture.

BACKGROUND Recent studies have focused on mechanical thrombectomy as a means to reduce the time required for revascularization and increase the revascularization rate in acute stroke. To date no systematic evaluation has been made of the different mechanical devices in this novel and fast-developing field of endovascular interventions. To facilitate such evaluations, we developed a specific in vivo model for mechanical thrombectomy that allows visualization of dislocation or fragmentation of the thrombus during angiographic manipulation. METHODS Angiography and embolization with a preformed thrombus was performed in 8 swine. The thrombus was generated by mixing 25 IU bovine thrombin and 10 mL autologous blood. For visualization during angiography, 1 g barium sulfate was added. RESULTS The preformed thrombus exhibited mechanical stability, reproducibility, and high radiographic absorption, providing excellent visibility during angiography. The setting allowed selective embolization o...

The animal models are pivotal for understanding the characteristics of acute renal failure (ARF) and development of effective therapy for its optimal management. Since the etiology for induction of renal failure is multifold, therefore, a large number of animal models have been developed to mimic the clinical conditions of renal failure. Glycerol-induced renal failure closely mimics the rhabdomyolysis; ischemia-reperfusion-induced ARF simulate the hemodynamic changes-induced changes in renal functioning; drug-induced such as gentamicin, cisplatin, NSAID, ifosfamide-induced ARF mimics the renal failure due to clinical administration of respective drugs; uranium, potassium dichromate-induced ARF mimics the occupational hazard; S-(1,2-dichlorovinyl)-Lcysteine-induced ARF simulate contaminated water-induced renal dysfunction; sepsis-induced ARF mimics the infection-induced renal failure and radiocontrast-induced ARF mimics renal failure in patients during use of radiocontrast media at the time of cardiac catheterization. Since each animal model has been created with specific methodology, therefore, it is essential to describe the model in detail and consequently interpret the results in the context of a specific model.

three strains of mutant rats with congenital conjugated The workshop covered three major areas: Unconjuhyperbilirubinemia. (2) The roles of the classical and gated bilirubin (UCB) chemistry and physical chemistry; newer molecular biological approaches to identification UCB transport and intracellular trafficking; and evaluaof these transporters were contrasted, and their limitation and therapy of neonatal and congenital hyperbilitions were discussed. (3) The relative roles of the multirubinemias. Findings of studies in the chemistry and ple carriers in UCB transport under different conditions physical chemistry area were as follows. (1) Nuclear and substrate concentrations were discussed. (4) Cytomagnetic resonance (NMR) studies of highly enriched solic UCB-binding proteins (e.g., ligandin) were shown 13 COOH mesobilirubin in water-dimethyl sulfoxide systo promote transcellular movement of UCB by solubiliztems indicated that the pK a values of the carboxyl ing and transporting the pigment in the aqueous phase groups are 4.2 and 4.9, respectively. This finding differs while limiting binding of UCB to the relatively immobile from some reports that suggest that the two pK a values membranes of cell organelles. (5) Mechanisms were prein aqueous systems are near or above pH 7.0. (2) Consented for translocation of UDP-glucuronic acid (UDtrasting views of the hydrophobic interactions of UCB PGA) into the lumenal location of UDPGA transferase with bile salts were presented: one suggested that multiin the endoplasmic reticulum, as well as the enhanceple bile salt monomers bind to one UCB molecule; the ment of this process by N-acetyl-glucosamine. Studies other suggested that UCB binds to the nonpolar surface in the neonatal and congenital jaundice area were as of helical bile salt micelles. (3) Structures were proposed follows. (1) Criteria were reviewed for initiating treatfor the varied calcium and copper bilirubinate salts ment of neonatal jaundice, emphasizing the primacy of formed at various pH values and cation/UCB ratios. (4) serum bilirubin levels, gestational age, and hemolysis Studies of binding of UCB to human serum albumin as risk factors for kernicterus. (2) New methods were (HSA) showed marked diminution of UCB-binding affinpresented for frequent, automated monitoring of serum ity as albumin and chloride concentrations increased. bilirubin levels and breath CO levels as an index of rates (5) A unique UCB derivative, bilirubin-C10-sulfonic acid, of formation of UCB from heme. (3) The current status was identified as the major bile pigment in bullfrog bile. and limitations of new approaches to treatment of se-(6) New methods were presented for removal of impurivere unconjugated hyperbilirubinemia were discussed: ties from preparations of bile salts and UCB. Findings hepatocyte transplantation and gene therapy, still in the of studies in the transport area were as follows. (1) Four stage of development in animal models, have provided putative basolateral and two putative canalicular hepaonly partial and temporary relief of hyperbilirubinemia; tocytic transporters of UCB and related organic anions extracorporeal liver assist devices have had some sucwere described. Special emphasis was given to the adencess in initial human studies; and inhibition of heme osine triphosphate (ATP)-dependent canalicular multioxygenase (HO) with metalloporphyrins, especially tin specific organic anion transporter that is defective in mesoporphyrin, which markedly decreases bilirubin production for prolonged periods, is a new alternative Abbreviations: UCB, unconjugated bilirubin; NMR, nuclear magnetic resonance; NOE, to phototherapy. (4) The ontogeny of the two HO isonuclear Overhauser enhancement; DMSO, dimethyl sulfoxide; TC, taurocholate; CMC, criti-zymes was contrasted in the liver, spleen, kidney, and cal micellar concentration; CD, circular dichroism; Bf, concentration of unbound UCB; Kf,

REEK, S., ET AL.: Inducibility of Sustained Ventricular Tachycardia in a Closed-Chest Ovine Model of Myocardial Infarction. Tbe two goals of this study were (1) to develop a closed-chest animal model of monomorphic ventricular tachycardia; and (2) to investigate the effect of dual site pacing on inducibility of ventricular tachycardia. In the first part ofthe study, 10 of 14 sheep underwent successful induction of myocardial infarction by temporary balloon occlusion of the left anterior descending coronary artery. After a foUow-up period of 21-43 days, sustained monomorphic ventricular tachycardia could be induced during programnwd electrical stimulation usinga "clinical" stimulation protocol in dofthe lOsheep. The number of ventricular tachycardia episodes per animal varied between 5 and 70. Ventricular fibrillation was never induced during programmed electrical stimulation. Ventricular tachycardia episodes lasted from 30 seconds up to 15 minutes and were terminated by antitachycardia pacing or DC cardioversion. In the second part ofthe study, the effect of dual site stimulation on ventricular tachycardia inducibility was investigated. High current stimuli from an area within the infarcted zone were given with the Si programmed stimulation protocol. This dual site stimulation showed no effect on ventricular tachycardia induction during programmed electrical stimulation. This animal model shows a high induction rate of sustained monomorphic ventricular tachycardia in the chronic phase of myocardial infarction. The high incidence of ventricular tachycardia inducibility provides a reliable tool to study new techniques for the prevention of ventricular tachyarrhythmias.

D-002 is a natural mixture of high molecular weight alcohols isolated and purified from beeswax, which contains triacontanol among its main components. This study was undertaken to investigate the anti-inflammatory effects of D-002 administered by the oral route in two animal models commonly used in the pharmacological screening of anti-inflammatory drugs. D-002 administered orally to rats (100 and 200 mg/kg) produced a mild but significant reduction of exudate volume in carrageenan-induced pleuritic inflammation that was accompanied by a marked and significant decrease of leukotriene B 4 (LTB4) levels in the exudate. D-002 (25, 50 and 200 mg/kg) also significantly diminished the granuloma weight in the cotton pellet granuloma in rats. In both cases, D-002 was less effective than indomethacin, which was used as an established anti-inflammatory reference drug. On the other hand, D-002 administered from 25-1000 mg/kg did not induce erosions or gastromucosal lesions in rats, which differs from results usually obtained with non steroidal anti-inflammatory drugs. These results indicate that D-002 is a mild antiinflammatory agent without any ulcerogenic effect associated. The results suggest that these effects are probably not mediated through an inhibition of cyclooxygenase, but a reduction in LTB4 levels induced by D-002 could explain these results.

The substituted amphetamines 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') and methamphetamine (METH, 'ice', 'speed') are increasingly popular drugs amongst party-drug users. Studies with humans have investigated the acute and possible long-term adverse effects of these drugs, yet outcomes of such studies are often ambiguous due to a variety of confounding factors. Studies employing animal models have value in determining the acute and long-term effects of MDMA and METH on brain and behaviour. Self-administration studies show that intravenous METH is a particularly potent reinforcer in rats and other species. In contrast, MDMA appears to have powerful effects in enhancing social behaviour in laboratory animals. Brief exposure to MDMA or METH may produce long-term reductions in dopamine, serotonin and noradrenaline in the brain and alterations in the density of various receptor and transporter proteins. However it is still unclear, particularly in the case of MDMA, whether this reflects a 'neurotoxic' effect of the drug. Lasting alterations in social behaviour, anxiety, depressive symptoms and memory have been demonstrated in laboratory rats given MDMA or METH and this matches long-term changes reported in some human studies. Recent laboratory studies suggest that MDMA/METH combinations may produce greater adverse neurochemical and behavioural effects than either drug alone. This is of some concern given recent evidence that party drug users may be frequently exposed to this combination of drugs. [Clemens KJ, McGregor IS, Hunt GE, Cornish JL. MDMA, methamphetamine and their combination: possible lessons for party drug users from recent preclinical research. Drug Alcohol Rev 2007;26:9 -15]

Aims/hypothesis We evaluated the insulinotropic and antihyperglycaemic actions of glucokinase activators (GKAs), especially through acute and subchronic studies in rodent diabetes models with (2R)-2-(4-cyclopropanesulphonylphenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a novel and potent GKA. Materials and methods The action of PSN-GK1 on or in the following were investigated: (1) on human liver glucokinase, insulin secretion from MIN6 cells and 2-deoxy-d-[3H]glucose (2-DG) uptake into rat hepatocytes; and (2) in Zucker diabetic fatty rats and in non-diabetic C57Bl/6, diabetic db/db and ob/ob mice. Results At 5 mmol/l glucose, PSN-GK1 activated glucokinase (4.3-fold, median effective concentration [EC50] 130 nmol/l), increased MIN6 insulin secretion (26-fold, EC50 267 nmol/l) and 2-DG hepatocytic uptake (threefold, EC50 1 μmol/l); at higher glucose concentrations, EC50s and fold-effectiveness were both lower. In C57Bl/6 mice, PSN-GK1 reduced blood glucose at 1 and 10 mg/kg (by mouth), but insulin was increased significantly at only the higher dose. In hyperinsulinaemic 10-mmol/l glucose clamps, PSN-GK1 increased 2-DG incorporation into liver glycogen sixfold, directly demonstrating liver effects. PSN-GK1 improved glycaemic profiles in db/db mice and Zucker diabetic fatty rats, diabetic animal models in which GKA efficacy has not previously been described, without causing hypoglycaemia. In ob/ob mice, it dose-dependently reduced excursions in OGTTs. Moreover, after subchronic administration, no tachyphylaxis was evident and glycaemia was improved without alterations to lipid levels, liver weight, glycogen content or body weight. Conclusions/interpretation PSN-GK1 was potently antihyperglycaemic through its effects on insulin release and hepatic glucose metabolism. It is one of the most potent GKAs described in the literature and is active in diabetic animal models where GKAs have not been reported to show efficacy to date. Ongoing human trials are investigating the potential of this novel therapeutic approach.

The L5 spinal nerve ligation model of neuropathic pain in rats has been proposed as a model for sympathetically maintained pain (SMP) based on the effects of surgical or chemical sympathectomy on nerve injury induced behavior. In an attempt to confirm that the lesion produces an animal model of SMP, surgical sympathectomies were independently conducted in two different laboratories (Johns Hopkins and University Kiel) using male Sprague-Dawley (n = 30) or Wistar rats (n = 14). The L5 spinal nerve was ligated or cut and ligated. Using von Frey hairs, paw withdrawal threshold and incidence of paw withdrawal were tested concurrently before and after the sympathectomy. The sympathectomy was either verified by (a) glyoxylic acid staining of peripheral blood vessels of the hindpaw or (b) skin temperature measurements of the hindpaws. To blind the experimenter, surgeries and behavioral tests were performed by two different investigators and a sham sympathectomy was performed at Johns Hopkins. Decreased paw withdrawal thresholds and increased frequencies of paw withdrawal on the lesioned side were observed after the L5 lesion. Thus, the L5 spinal nerve ligation resulted in behavioral signs of allodynia and hyperalgesia to mechanical stimuli. Lumbar surgical sympathectomy 1-3 weeks after the lesion or prior to lesion with bilateral removal of the sympathetic ganglia L2-L4, however, did not reverse or prevent the behavioral changes induced by the nerve injury. The lack of effect of the sympathectomies was independent of the testing paradigm used. Experiments in Wistar and Sprague-Dawley rats yielded the same results. Potential reasons for the discrepancies between the present study and earlier reports are discussed. These results indicate that an L5 spinal nerve injury rat model is not a reliable model for SMP. © 1999 International Association for the Study of Pain. Published by Elsevier Science B.V.

Troxacitabine (Troxatyl; BCH-4556; (-)-2'-deoxy-3'-oxacytidine), a deoxycytidine analogue with an unusual dioxolane structure and nonnatural L-configuration, has potent antitumor activity in animal models and is in clinical trials against human malignancies. The current work ...

An algorithm is described to estimate variance components for a univariate animal model using REML. Sparse matrix techniques are employed to calculate those elements of the inverse of the coefficient matrix required for the first derivatives of the likelihood. Residuals and fitted ...

We present techniques for automatically creating and animating models obtained from human whole body scanned data. A layered model is developed in which the underlying skeleton, simplified surface and mapping of the surface to the skeletal structure are generated without manual intervention. External body landmarks such as those employed in anthropometric surveys are used to obtain the skeleton, these landmarks are then reused to help map the model surface consistently to the skeleton. The main contribution of this work is to show how automatically or even manually extracted surface landmarks greatly simplify the task of skeleton generation and surface bone mapping, the later uses surface connectivity to grow surface regions as opposed to conventional volume searches. The techniques are illustrated by animation from motion capture data in which a vertex blending technique is used to create continuous and smooth deformation.

An understanding of how drugs are transferred between mother and fetus during the gestational period is an important medical issue of relevance to both therapeutic drugs and drugs of abuse. Though there are several in vitro and in vivo methods to examine this issue, all have limitations. Furthermore, ethical and safety considerations generally preclude such studies in pregnant humans. PET and appropriately labeled compounds have the ability to provide information on both maternal-fetal drug pharmacokinetics and pharmacodynamics. We present here a nonhuman primate animal model and the methodology for combining PET and MRI to identify fetal organs and to measure maternal and fetal isotope distribution using (18)F-FDG and a whole-body imaging protocol to demonstrate proof-of-principle.

Lactoferrin (LF) is a multifunctional immunoregulatory protein that has been associated with host defense at mucosal surfaces through its antibacterial properties. The antibacterial and anti-inflammatory properties of LF were further explored with an animal model of experimental urinary tract infection. Bovine LF (bLF), human LF (hLF), and synthetic peptide sequences based on the antibacterial region of hLF (amino acid residues 16 to 40 [HLD1] and 18 to 40 [HLD2]) were given orally to female mice 30 min after the instillation of 10 8 Escherichia coli bacteria into the urinary bladder. The control groups received phosphate-buffered saline or water. C3H/Tif mice were treated with hLF or bLF, and C3H/HeN mice were treated with bLF only. The numbers of bacteria in the kidneys and bladder of C3H/Tif and C3H/HeN mice were significantly reduced 24 h later by the LF treatments compared to the findings for the control group. The hLF-treated group showed the strongest reduction compared with ...

The available mathematical models describing tumor growth and the effect of anticancer treatments on tumors in animals are of limited use within the drug industry. A simple and effective model would allow applying quantitative thinking to the preclinical development of oncology drugs. In this article, a minimal pharmacokinetic-pharmacodynamic model is presented, based on a system of ordinary differential equations that link the dosing regimen of a compound to the tumor growth in animal models. The growth of tumors in nontreated animals is described by an exponential growth followed by a linear growth. In treated animals, the tumor growth rate is decreased by a factor proportional to both drug concentration and number of proliferating tumor cells. A transit compartmental system is used to model the process of cell death, which occurs at later times. The parameters of the pharmacodynamic model are related to the growth characteristics of the tumor, to the drug potency, and to the kinetics of the tumor cell death. Therefore, such parameters can be used for ranking compounds based on their potency and for evaluating potential differences in the tumor cell death process. The model was extensively tested on discovery candidates and known anticancer drugs. It fitted well the experimental data, providing reliable parameter estimates. On the basis of the parameters estimated in a first experiment, the model successfully predicted the response of tumors exposed to drugs given at different dose levels and/or schedules. It is, thus, possible to use the model prospectively, optimizing the design of new experiments.

Major depressive disorder is a severe psychiatric condition which forms a substantial burden to patients and society. Despite continuous efforts to unravel its etiology and pathophysiology, many questions remain. The majority of neurobiological research and classical pharmacotherapy regimens have approached this illness as the consequence of a failing monoaminergic neurotransmitter system. In the last decades, involvement of adult hippocampal neurogenesis in the pathogenesis and treatment of depressive disorder has gained an enormous interest. Numerous neurobiological systems and circuits thus appear to underlie this complex multi-factorial disease. One of them is the cholinergic system, which plays a major role in the regulation of various CNS functions, such as arousal, attention, cognition and memory. Cognitive impairments are often observed in depression, next to low mood, anhedonia and other clinical symptoms. Cholinergic dysfunctions may account for the development of cognitive symptoms during the course of depression. Changes in hippocampal neurogenesis, often associated with chronic stress in animal models, may be in part mediated by cholinergic dysfunction, which in turn could underlie the cognitive disturbances observed in depression. Here, we discuss the involvement of the cholinergic system in depressive disorder, with particular focus on its role in associated cognitive impairment. Since such deficits are often modified by cholinergic drugs, application of these neuropharmacological findings may provide a new therapeutic niche while yielding valuable insight into the pathophysiology of this complex illness.

Meriones unguiculatus commonly known as gerbils are widely used as animal models for a variety of parasitic infections such as Brugia malayi, Entamoeba histolytica, Giardia duodenalis, Toxoplasma gondi, Helicobacter pylori, Strongyloides stercoralis and Echinococcus multilocularis. Groups of BALB/c mice, gerbils and XID mice were studied for antibody responses to T-independent antigens. Gerbils were found to be signi®cantly de®cient in eliciting antibodies to both dextran and phosphorylcholine (PC) in comparison to BALB/c mice. The antibody response of gerbils to T-independent antigens was found to be similar to the response observed in Bruton's tyrosine kinase (Btk) de®cient XID mice, which are known to be poor responders to T-independent antigens. Similar to XID mice, normal gerbil sera were found to be de®cient in naturally occurring antibodies to single stranded DNA (SS-DNA), lipopolysaccharide (LPS) and phospholipids. This raises the possibility of a de®ciency of CD5 1 B-lymphocytes (also known as B-1 cells) in gerbils, since de®ciency of this sub-population of Blymphocytes has been attributed to the absence of such naturally occurring antibodies in XID mice. These results indicate the need to study immunogenicity of parasite T-independent antigens and their relationship to protective immunity in parasitic infections in gerbils.

Embolism is responsible for half of cerebral infarctions, yet few animal models were developed due to the unpredictability of the embolus-induced infarcts. We manufactured artificial embolic particles by blending chitin and poly(D,L-Lactide-co-glycolide) (chitin/PLGA) for their good biocompatibility and rapid hydration expansion property. We subdivided the chitin/PLGA microparticles into 10 size groups (from 38e45 mm to 255e350 mm) and injected them through the external carotid artery toward the bifurcation of the common carotid artery in the rat. Reduced blood flow of the ipsilateral hemisphere was evident immediately after the injection of particles. The spherical appearance of the particle was critical in occluding the cerebral vessels. Particle 212e250mm produced the greatest diffuse infarction in the ipsilateral hemisphere, including the cortex, hippocampus, basal ganglion, thalamus, midbrain and cerebellum. Particle 75-90mm induced single or sparse isolated infarcts mainly located in the subcortical region, resembling lacunar stroke observed in humans. Particle 38e45mm frequently crossed to the contralateral hemisphere and induced diffuse infarctions in both hemispheres. The cortex infarct volumes were positively correlated to neurologic score and seizure incidence. In conclusion, we have established embolic stroke animal models, including a novel model that mainly expresses lacunar infarction, by intravenous injection of chitin/PLGA microparticles.

Increasing evidence suggests that the detrimental effects of glucocorticoid (GC) hypersecretion occur by activation of the hypothalamic-pituitary-adrenal (HPA) axis in several human pathologies, including obesity, Alzheimer's disease, AIDS dementia, and depression. The different patterns of response by the HPA axis during chronic activation are an important consideration in selecting an animal model to assess HPA axis function in a particular disorder. This article will discuss how chronic HPA axis activation and GC hypersecretion affect hippocampal function and contribute to the development of obesity. In the brain, the hippocampus has the highest concentration of GC receptors. Chronic stress or corticosterone treatment induces neuropathological alterations, such as dendritic atrophy in hippocampal neurons, which are paralleled by cognitive deficits. Excitatory amino acid (EAA) neurotransmission has been implicated in chronic HPA axis activation. EAAs play a major role in neuroendocrine regulation. Hippocampal dendritic atrophy may involve alterations in EAA transporter function, and decreased EAA transporter function may also contribute to chronic HPA axis activation. Understanding the molecular mechanisms of HPA axis activation will likely advance the development of therapeutic interventions for conditions in which GC levels are chronically elevated. R. (1990) Glucocortioicds inhibit glucose transport in cultured hippocampal neurons and glia. Neuroendocrinol-0gy 52, 57-62.

Background: 1E10 monoclonal antibody is a murine anti-idiotypic antibody that mimics N-glycolyl-GM3 gangliosides. This antibody has been tested as an anti-idiotypic cancer vaccine, adjuvated in Al(OH) 3 , in several clinical trials for melanoma, breast, and lung cancer. During early clinical development this mAb was obtained in vivo from mice ascites fluid. Currently, the production process of 1E10 is being transferred from the in vivo to a bioreactor-based method.

1. Genetic parameters of slaughter and carcase traits were estimated for 5-week-old Japanese quail reared under the one-to-one sire and dam pedigree recorded system. Data were analysed using restricted maximum likelihood (REML) with relationship matrix. Records of 1244 animals from 119 sires and 156 dams were analysed.2. An individual animal model was used which had the animals’ genetic effect as the only random factor. Heritability and standard errors of slaughter, cold carcase, breast, leg, wing, others, liver weights and dressing percentage were 0·40 ± 0·07, 0·55 ± 0·07, 0·58 ± 0·07, 0·54 ± 0·07, 0·49 ± 0·07, 0·42 ± 0·06, 0·13 ± 0·04 and 0·21 ± 0·05 respectively. Moderate to high heritability for most of the studied traits suggested that selection to increase or decrease these traits will be successful.3. The strongest genetic correlation was found between slaughter, carcase and breast weights (0·97–0·87). These high genetic correlations provide an opportunity to select for breast weight on the basis of 5-week weight.4. It can be concluded that carcase weight and 5-week weight of quail can be included in a selection index to increase the weights of valuable carcass parts.

Introduction Controversy exists as to whether Matrix coils are an improvement over bare platinum coils in preventing aneurysm recanalization in endosaccularly coiled large aneurysms. We investigated Matrix coils in a dog model of a wide-necked large bifurcation aneurysm. Methods Six experimental aneurysms were created in dogs and these aneurysms were endosaccularly coiled with 100% Matrix coils. Angiographic and histopathological data were analyzed at 2 weeks and at 3 months.

Compounds with dioxin-like toxicity are suspected to adversely affect human reproduction even at current background exposures. Endometriosis, a gynecological disorder often associated with infertility, has been hypothesized to be linked to dioxins and similar chemicals, a hypothesis supported by the outcome of experimental studies on animal models. Endometriosis severity and incidence in Belgium is one of the highest of the world: in this country, the general population exposure to dioxin-like compounds has been, on average, higher than in most industrialized countries. Here we show the results of a pilot case-control study carried out on 22 Italian and 18 Belgian women of reproductive age, with and without endometriosis. No significant differences were found in dioxin-like compound body burdens between cases and controls on a country basis, whereas the body burdens of the Italian women resulted to be significantly lower than that of the Belgian. In particular, total TEQs in Italian and Belgian women without endometriosis were respectively 18 and 45 pg WHO-TE/g lb.

A reproducible large animal model of fulminant hepatic failure was developed in the anesthetized dog by the administration of the amino sugar D-galactosamine. Galactosamine in 5% dextrose in water (DsW), was given as an intravenous bolus to 10 young male dogs weighing 27 to 30 kg. Three dogs that received an equal volume of D5W alone served as controls. Galactosamine at 0.5 g/ kg (n = 5) produced significant biochemical evidence of liver injury with 100% survival at 48 hours. Galactosamine 1.0 g/kg (n = 5) yielded in 100% 48-hour mortality resulting from fulminant liver failure characterized by a progressive increase in liver enzymes, total bilirubin, ammonia, and lactate and associated coagulopathy, hypoglycemia, coma, and increased intracranial pressure. Necropsy showed liver pallor, ascites, and brain swelling. Liver histology showed significant hepatocellular necrosis. This clinically relevant large animal model will enable the quantitative evaluation of new technologies, such as the bioartificial liver, for the support of hepatic failure in humans. 21:796-804.) Abbreviations: FHF, fulminant hepatic failure; IV, intravenous. From the Departments of 1Surgery, 2Medicine, and 4Chemical Engineering and Materials Sciences, University of Minnesota, Minneapolis; and 3Cellex Biosciences, Coon Rapids, MN.

We investigated the effect of thiamine (B1) treatment on bladder dysfunction in streptozotocin (STZ)induced diabetic rats. A total of 40 rats were randomly divided into four groups: a control group, a group given thiamine only, a diabetic group and a diabetic group given thiamine therapy. Diabetes was induced in the rats by 65 mg/kg STZ via an intraperitoneal injection. Thiamine was given 50 mg/kg/day. Diabetic cystopathy was confirmed on cystometry 8 weeks later in diabetic groups. Rats' body and bladder weights were measured. Contractile response to carbachol and potassium chloride (KCl) of detrusor strips in all groups was studied in vitro. The body weights were significantly decreased (p<0.01), the bladder weights were significantly increased (p<0.01), and the cystometric bladder capacity and the residual urine volumes were significantly increased (p<0.001, p<0.01 respectively) in STZ-induced diabetic groups compared to the control group and the group given thiamine only. Contractile responses increased in the diabetic group in high carbachol and KCl concentrations (p<0.01, p<0.01, respectively). On the other hand, there were no differences in the other groups. These data suggest that highdose thiamine (B 1) treatment may be beneficial in delaying the progression of diabetic cystopathy in this experimental animal model.

A key application for microsystems in life-science are active microimplants for restoring and substituting lost or impaired biological functions in humans. The development of functional microdevices that ®t in the human eye and that take over lost biological functions to restore vision is a challenge that several international research are engaged in. This paper describes the joint multi-team efforts of German scientists to develop a microelectromechnical implant to stimulate retinal structures for regaining lost visional functions. Different types of active eye implants have been developed for stimulation in the epiretinal and subretinal space. Microelectrode arrays for electrical stimulation have been integrated into¯exible and rigid substrates. Innovative microtechniques have been developed for obtaining biocompatible¯exible microstructures, interconnects, and hybrid assemblies to ®t in the eye ball. Biocompatibility of material and devices was investigated in all design phases utilizing in vitro cell and tissue culture test. Devices at various stages of development have been evaluated in acute and chronic animal models. Passive stimulator electrode arrays (without electronic components) remained in animals for more than 6 months after implantation. Furthermore, animal experiments have shown that active devices equipped with silicon chips could be inserted and housed into the eye. Fully functional chronic devices are presently tested in animals. Experiments on humans are planned in the near future.

Activation of nuclear factor kappa B (NF-jB) in synovial cells is seen in RA and OA patients. Caffeic acid phenethyl ester (CAPE) is a specific and potent inhibitor of NF-jB. We aimed to determine the in vivo effects of intra-articular injections of CAPE on cartilage in an ...

Since the discovery that the therapeutic efficacy of antipsychotic drugs was significantly correlated to their ability to block dopamine D 2 receptors, abnormal dopamine transmission in the forebrain has been postulated to underlie psychosis in schizophrenia. In the past 15 years, an impressive amount of clinical and basic research aimed at the study of schizophrenia has indicated that prefrontal and temporal cortical abnormalities may be more important in the etiology of many of the symptoms of schizophrenia, including psychosis. However, the cortical systems that appear to have structural and/or metabolic abnormalities in schizophrenia patients potently regulate forebrain dopamine transmission through a number of mechanisms. In turn, dopamine modulates excitatory transmission mediated by frontal and temporal cortical projections to the basal ganglia and other regions. The present review summarizes the multiple interactions between forebrain DA systems and frontal and temporal corticostriatal transmission. It then examines the role of these interactions in normal behaviors and the psychopa

During cardiogenesis, the epicardium grows from the proepicardial organ to form the outermost layer of the early heart. Part of the epicardium undergoes epithelial-mesenchymal transformation, and migrates into the myocardium. These epicardium-derived cells differentiate into interstitial fibroblasts, coronary smooth muscle cells, and perivascular fibroblasts. Moreover, epicardium-derived cells are important regulators of formation of the compact myocardium, the coronary vasculature, and the Pur-kinje fiber network, thus being essential for proper cardiac development. The fibrous structures of the heart such as the fibrous heart skeleton and the semilunar and atrioventricular valves also depend on a contribution of these cells during development. We hypothesise that the essential properties of epicardium-derived cells can be recapitulated in adult diseased myocardium. These cells can therefore be considered as a novel source of adult stem cells useful in clinical cardiac regeneration therapy.

Obesity and its associated metabolic pathologies are the most common and detrimental diseases, affecting over 50% of the adult population. Our knowledge about the protective effects of melatonin against high-fat diet (HFD)-induced obesity is still marginal. In this investigation, we hypothesized that melatonin can minimize the metabolic pathologies and morphological changes associated with obesity in animals receiving an HFD. To examine these effects, and to test our hypothesis, an animal model formed of male Boscat white rabbits was established. The animals were divided into three groups: (i) a control group fed regular diet; (ii) an obesity group fed an HFD for 12 weeks; and (iii) a treated group fed HFD for 12 weeks and then treated with melatonin for 4 weeks. The animals were killed and their serum and tissues were evaluated for: (i) lipid profile (cholesterol, triglycerides and low-density lipoprotein) and glucose; (ii) antioxidant enzyme (serum glutathione peroxidase, GSH-PX); and (iii) fatty changes (liver, kidney and blood vessels). Compared with the control group, intake of HFD (obesity group) was associated with: (i) a statistically significant increase in blood pressure, heart rate, sympathetic nerve activity, body weight, food consumption, serum lipids, blood glucose levels and atherogenic index; (ii) decreased level of GSH-PX and high-density lipoprotein (HDL); and (iii) fatty changes in the liver and kidney as well as atheromatous changes in the blood vessels. Compared with the obesity group, intake of melatonin (treated group) was associated with: (i) a statistically significant decrease in blood pressure, heart rate, sympathetic nerve activity, body weight, food consumption, serum lipids, blood glucose levels and atherogenic index; (ii) increased level of GSH-PX and HDL; and (iii) disappearance of fatty changes in the liver and kidney as well as atheromatous changes in the blood vessels. The administration of melatonin reduced the metabolic pathologies associated with the intake of HFD, suggesting a protective role. Although the underlying mechanisms are unclear, they may include its antioxidant and receptormediated effects. The clinical ramifications of these effects await further investigations.

Approximately 2 million people in the United States suffer from Alzheimer's disease (AD), which is the most common cause of chronic dementia among the aging population. During the last 7 yr, excellent opportunities to screen drugs against AD have been provided by animal models of the disease. Because even in the fastest model, AD pathology does not start before the end of the second month, it has been necessary to wait at least until that age to inject drugs into the animal to assess whether they prevent, reduce, or revert synaptic impairment, plaque formation, and increase of β-amyloid (Aβ) levels, the main features of the disease. A solution to the problems mentioned above is achieved by the present fast, efficient, and reproducible cultured cell system from animal models of AD or Aβ-associated diseases, for the screening and testing of compounds for the treatment and therapy of AD or Aβ-associated diseases.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the third of four papers. It examines inclusion and exclusion criteria that can influence the design and analysis of clinical trials in SCI, together with confounding variables and ethical considerations. Inclusion and exclusion criteria for clinical trials should consider several factors. Among these are (1) the enrollment of subjects at appropriate stages after SCI, where there is supporting data from animal models or previous human studies; (2) the severity, level, type, or size of the cord injury, which can influence spontaneous recovery rate and likelihood that an experimental treatment will clinically benefit the subject; and (3) the confounding effects of various independent variables such as pre-existing or concomitant medical conditions, other medications, surgical interventions, and rehabilitation regimens. An issue of substantial importance in the design of clinical trials for SCI is the inclusion of blinded assessments and sham surgery controls: every effort should be made to address these major issues prospectively and carefully, if clear and objective information is to be gained from a clinical trial. The highest ethical standards must be respected in the performance of clinical trials, including the adequacy and clarity of informed consent.

Recent evidence suggests that a variety of environmental factors, including dietary and gastrointestinal agents, may contribute to autism spectrum disorders (ASD). Here we administered propionic acid (PPA), a short chain fatty acid that is used as a food preservative and also is a metabolic end-product of enteric bacteria in the gut, to adolescent (41 ± 4 days) male rats in a study of restricted/repetitive behavior, social behavior, and cognition. The goal was to further evaluate the effects of PPA in young rodents. PPA (4 l of 0.26 M solution) was administered intracerebroventricularly prior to each behavioral test. Rats treated with PPA displayed restricted behavioral interest to a specific object among a group of objects, impaired social behavior, and impaired reversal in a T-maze task compared to controls given phosphate buffered saline. Immunohistochemical analysis of brain tissue from PPA rats revealed reactive astrogliosis and activated microglia, indicating an innate neuroinflammatory response. These findings are consistent with our earlier findings of ASD-relevant behavioral and brain events in adult rats given PPA, and support further study of effects of PPA in young rodents by establishing similar effects in adolescent animals.

Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.

MRL/MpJ-Fas lpr (MRL/lpr) mice are an accepted animal model to study human systemic lupus erythematosus. We tested if a commonly used analgesic (buprenorphine hydrochloride) would reduce pain and distress in these mice without impacting the progression of autoimmune disease. Female MRL/lpr mice were randomly separated into four groups. Experimental groups received cyclophosphamide (25 mg/kg i.p. weekly), buprenorphine (0.09 mg/kg/mouse/day via drinking water), or cyclophosphamide + buprenorphine from 11 to 21 weeks of age. Controls received no treatments. Mice were monitored daily by a licensed veterinarian (blinded observer) and assigned a score weekly on parameters associated with pain and distress as well as progression of disease. Proteinuria was measured weekly, and serum anti-dsDNA antibody levels were determined at 11, 15, and 18 weeks of age. At 21 weeks of age, the animals were euthanized and the kidneys and spleens were removed for evaluation. Regardless of the parameter observed, buprenorphine did not significantly decrease distress when compared to the controls. Buprenorphine did not alter the progression of autoimmune disease, based on characteristics of splenic architecture and splenocyte cell profiles, development of lymphadenopathy, or kidney histology as compared to controls. This study indicates that buprenorphine at this dose and route of administration was ineffective in reducing distress associated with disease progression in the MRL/lpr strain. More studies are needed to determine if, at a different dose or route, buprenorphine would be useful as adjunctive therapy in reducing distress in MRL/lpr mice.

This study compared the effects of ad libitum (AL) overfeeding and moderate or marked dietary restriction (DR) on the pathogenesis of aged-related pituitary gland changes in Sprague-Dawley (SD) rats. SD rats were fed Purina Certified Rodent Diet AL (group 1), DR at 72-79% of AL (group 2), DR at 68-72% of AL (group 3) or DR at 47-48% of AL (group 4) for 106 weeks. Interim necropsies were performed at 13, 26, and 53 weeks, after a 7-day 5-bromo-2-deoxyuridine (BrdU)-filled minipump implantation. Body weights, organ weights and insulin-like growth factor 1 (IGF-1) serum levels were measured at interim and final necropsies. Serum levels of prolactin (PRL), progesterone, estradiol, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured at 53 and/or 106 weeks. In addition to the routine histopathologic examination, determination of 7 stereologic parameters after pituitary immunohistochemistry of PRL, growth hormone (GH) and BrdU was done in both sexes at 13, 26, and 53 weeks. Body and pituitary weights were proportional to the food intake. In AL-fed rats, hyperplastic and neoplastic changes developed early and progressed with age, affecting almost all animals by 106 weeks. These changes were associated with high PRL serum levels. Pituitary adenomas were the most common cause of death in both sexes. In DR rats, a delayed onset and a decreased incidence of pituitary tumors were observed in association with decreased serum IGF-1, PRL, estradiol, and LH levels. The results of the stereological analysis demonstrated that, compared to AL-fed rats, pituitary glands from DR rats contained lower PRL and GH secreting cell volumes, and a lower epithelial cell BrdU labeling index, which correlated with a lower incidence of pituitary tumors at study termination. Moderate and marked degrees of DR delayed the onset of pituitary tumors in a temporaland dose-related manner. In contrast to marked DR, which dramatically reduced the incidence of hyperplastic and neoplastic pituitary gland changes, moderate DR delayed the onset but did not prevent the development of pituitary tumors.

Background/purpose: Persistent inflammatory response secondary to congenital or acquired biliary choleastasis plays an important role in the pathophysiology of hepatic tissue damage. The polyunsaturated fatty acids (PUFA) have been shown to suppress the inflammatory reactions in vivo and in vitro. PUFA has been shown also to protect againts various types of experimental liver damage in animal models and isolated hepatocytes.

An investigation examined the efncacy of antibiotics in a novel feline model of pancreatic infection in acute pancreatitis. Acute pancreatitis was induced in cats using an established technique. In control animals (no pancreatitis) and cats with pancreatitis, Escherichia coli (lo4 in Omlml) was placed in the pancreatic duct. Reoperation was performed after 24 h in six controls and six cats with pancreatitis. E. coli was cultured from the pancreas in five control animals and five cats with 103: 1902-8.

Animals often spend a signifi cant portion of their lives engaged in interactions with conspecifi cs (Allee 1927 ), and engage in helping, aggression, competition, mating and cooperation, to name but a few possible exchanges. As a result, many behaviours, if not the majority, have a social facet, and even those behaviours How and when social behaviour evolves has long been a focus of study within evolutionary biology, yielding the entire subfi eld of sociobiology and behavioural ecology. Although social behaviours may be explored in the same way as any other type of phenotype, the genetics underlying social behaviours diff er from traits that do not vary depending on the social environment in which they are expressed. Social behaviour is best described as an interacting phenotype : a phenotype that depends at least in part on interactions with social partners for its expression. Models of indirect genetic eff ects provide a quantitative genetic framework for understanding the sources of variation underlying interacting phenotypes. Th ey also suggest a genetic mechanism for inheriting traits that are expressed among rather than within individual animals, and identify selection arising from the interactions (termed social selection ).

Over the past few years, substantial progress has been made in the field of stem cell regeneration of the intervertebral disc. Autogenic mesenchymal stem cells in animal models can arrest intervertebral disc degeneration or even partially regenerate it and the effect is suggested to be dependent on the severity of degeneration. Mesenchymal stem cells (MSCs) are able to escape alloantigen recognition which is an advantage for allogenic transplantation. A number of injectable scaffolds have been described and various methods to pre-modulate MSCs’ activity have been tested. In future, work will need to address the use of mesenchymal stem cells in large animal models and the fate of the implanted mesenchymal stem cells, particularly in the long term, in animals. This review examines the state-of-the-art in the field of stem cell regeneration of the intervertebral disc, and critically discusses, with scientific support, the issues involved, before stem cells could be used in human subjects.

We advocate the use of point sets to represent shapes. We provide a definition of a smooth manifold surface from a set of points close to the original surface. The definition is based on local maps from differential geometry, which are approximated by the method of moving least squares (MLS). The computation of points on the surface is local, which results in an out-of-core technique that can handle any point set. We show that the approximation error is bounded and present tools to increase or decrease the density of the points, thus allowing an adjustment of the spacing among the points to control the error. To display the point set surface, we introduce a novel point rendering technique. The idea is to evaluate the local maps according to the image resolution. This results in high quality shading effects and smooth silhouettes at interactive frame rates.

The zebrafish (Danio rerio) embryo has emerged as an important model of vertebrate development. As such, this model system is finding utility in the investigation of toxic agents that inhibit, or otherwise interfere with, developmental processes (i.e. developmental toxins), including compounds that have potential relevance to both human and environmental health, as well as biomedicine. Recently, this system has been applied increasingly to the study of microbial toxins, and more specifically, as an aquatic animal model, has been employed to investigate toxins from marine and freshwater microalgae, including those classified among the so-called "harmful algal blooms" (HABs). We have developed this system for identification and characterization of toxins from cyanobacteria (i.e. "blue-green algae") isolated from the Florida Everglades and other freshwater sources in South and Central Florida. Here we review the use of this system as it has been applied generally to the investigation of toxins from marine and freshwater microalgae, and illustrate this utility as we have applied it to the detection, bioassay-guided fractionation and subsequent characterization of developmental toxins from freshwater cyanobacteria.

Cocaine-and amphetamine-regulated transcript (CART) is expressed in the hypothalamus, and putative peptides encoded by CART potently inhibit feeding when administered centrally. CART is strongly down-regulated in the lateral hypothalamic area and the arcuate nucleus in animal models of obesity with disrupted leptin signaling. Here we have used in situ hybridization and immunohistochemistry to study CART expression in mice homozygous for the anorexia (anx) mutation which are characterized by a much reduced food intake and premature death. anx /anx mice had significantly decreased levels of CART mRNA label and peptide-immunoreactive cell bodies and fibers in the arcuate nucleus and a lower number of detectable CART-expressing cells in the dorsomedial hypothalamic nucleus / lateral hypothalamic area. Moreover, serum leptin levels were significantly lower in anx /anx mice compared to normal littermates, most likely due to the prominent depletion of body fat in these animals. The decrease in the anorexigenic agents leptin and CART, may reflect a compensatory down-regulation in response to the energy-deprived state of anx /anx mice. Alternatively, the reduced arcuate CART expression may be a consequence of a molecular defect in the arcuate nucleus of these animals.