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Ocular drug delivery in hydrogel forming film form has several benefits over conventional dosage forms. An ophthalmic anti-inflammation study was undertaken using topically applied aspirin in a hydrogel film formulation. A hydroxypropyl methylcellulose (HPMC) matrix film formulation was prepared by the solvent casting and evaporation technique by taking triethanolamine (TEA) as a plasticizer. Ex vivo corneal permeation as well as anti-inflammatory potential of aspirin was studied on carrageenan induced rabbit eye model. Moisture uptake was found to be in the range of 17.1 and 19.1 % for all the film formulations. The film with the higher HPMC content exhibited both increased moisture uptake and amount of swelling. Among the formulations, the swelling order was found to increase with increasing amount of HPMC in the film. Presence of the hydrogel matrix forming polymer sustained the drug release and corneal permeation for more than 6 h and controlled the process by the diffusion mechanism. The signs of carrageenan induced acute inflammation was inhibited completely within just 2 h of placing the film in the rabbit eye whilst the positive control continued showing redness and increased tear secretion. Aspirin ocular film formulation could be utilized for ocular anti-inflammation for an extended period of time with better patient compliance.

Moderate exercise may reduce the risk of upper respiratory tract infections, but intense training can increase that risk. Though the average cold does not appear to hinder athletic performance, short-term symptomatic treatment consisting of topical decongestants and/or nasal ipratropium bromide may be useful for active patients. Vitamin C and zinc lozenges may reduce the duration of cold symptoms. Antibiotics are appropriate for treating such complications as acute bacterial sinusitis, otitis media, or pneumonia but are ineffective against viral infection. Some drugs are banned by sports organizations, and others, such as first-generation antihistamines, may impair performance. [ABSTRACT FROM AUTHOR]

Abstract Background Secreted Frizzled related proteins (SFRPs) are extracellular regulators of Wnt signaling. These proteins contain an N-terminal cysteine rich domain (CRD) highly similar to the CRDs of the Frizzled family of seven-transmembrane proteins that act as Wnt receptors. SFRPs can bind to Wnts and prevent their interaction with the Frizzled receptor. Recently it has been reported that a splice variant of human Frizzled-4 (FZD4S) lacking the transmembrane and the cytoplasmic domains of Frizzled-4 can activate rather than inhibit Wnt-8 activity in Xenopus embryos. This indicates that secreted CRD containing proteins such as Frizzled ecto-domains and SFRPs may not always act as Wnt inhibitors. It is not known how FZD4S can activate Wnt/β-catenin signaling and what biological role this molecule plays in vivo. Results Here we report that the Xenopus frizzled-4 is alternatively spliced to give rise to a putative secreted protein that lacks the seven-transmembrane and the cytoplasmic domains. We performed functional experiments in Xenopus embryos to investigate how this novel splicing variant, Xfz4S, can modulate the Wnt/β-catenin pathway. We show that Xfz4S as well as the extracellular domain of Xfz8 (ECD8) can act as both activators and inhibitors of Wnt/β-catenin signaling dependent on the Wnt ligand presented. The positive regulation of Wnt/β-catenin signaling by the extracellular domains of Frizzled receptors is mediated by the members of low density lipoprotein receptor-related protein (LRP-5/6) that act as Wnt coreceptors. Conclusion This work provides evidence that the secreted extracellular domains of Frizzled receptors may act as both inhibitors and activators of Wnt signaling dependent on the Wnt ligand presented.

II-V semiconductor nanocrystals such as Cd 3 P 2 and Zn 3 P 2 have enormous potential as materials in next-generation optoelectronic devices requiring active optical properties across the visible and infrared range. To date, this potential has been unfulfilled due to their inherent instability with respect to air and moisture. Core-shell system Cd 3 P 2 /Zn 3 P 2 is synthesized and studied from structural (morphology, crystallinity, shell diameter), chemical (composition of core, shell, and ligand sphere), and optical perspectives (absorbance, emission-steady state and time resolved, quantum yield, and air stability). The improvements achieved by coating with Zn 3 P 2 are likely due to its identical crystal structure to Cd 3 P 2 (tetragonal), highlighting the key role crystallographic concerns play in creating cutting edge core-shell NCs.

Particles stabilize fluid interfaces. In particular, oil/water Pickering emulsions undergo limited coalescence, yielding droplets of smaller size as the amount of particles is increased. Herein, we studied the effect of hydrophobic nanoparticles (<10 nm, alkyl-coated) on submicronic droplets (ca 100 nm) formed in an Ouzo system. We investigated thoroughly the water/tetrahydrofuran (THF)/butylated hydroxytoluene (BHT) reference diagram, in the absence and in the presence of nanoparticles, using the Nanoparticle Tracking Analysis (NTA) technique. This allowed us to characterize the size distributions in a much finer way than what is usually obtained using conventional Dynamic Light Scattering (DLS). Both a Surfactant-Free Microemulsion (SFME, thermodynamically stable) and an Ouzo (metastable spontaneous emulsion) domains were identified and the transition from one to the other could be characterized by specific features of the droplet size distributions. We found that the presence of the nanoparticles limits coalescence in the metastable domain. We also show that the alkyl-coated nanoparticles are irreversibly attached to the liquid-liquid interface., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Motor-skill learning is associated with cerebellar synaptogenesis and astrocytic hypertrophy, but most of these assessments of cerebellar ultrastructure have been completed after one month of training. After one month of training, the motor-skills necessary to complete these tasks have been acquired for weeks. This experiment aimed to characterize cerebellar ultrastructure during the acquisition phase of motor-skill learning, at a point when performance is still improving. Male and female rats trained for four days on the acrobatic motor learning task, which involved traversing challenging obstacles such as narrow beams and ladders. Concurrently, rats in the motor control condition walked a flat alleyway requiring no skilled movements. After training was complete, all rats were euthanized, and tissue was prepared for electron microscopy. Unbiased stereology techniques were used to assess synaptic and astrocytic plasticity. Results indicated that during the initial days of training, female rats made fewer errors and had shorter latencies on the acrobatic course compared to male rats. However, there were no sex differences in cerebellar ultrastructure. Male and female rats that completed four days of acrobatic training displayed an increase in the density of parallel fiber-Purkinje cell synapses per Purkinje cell and an increase in astrocytic volume, relative to rats in the motor control group., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Exercise is beneficial to brain health, and historically, the advantageous effects of exercise on the brain have been attributed to neuronal plasticity. However, it has also become clear that the brain vascular system also exhibits plasticity in response to exercise. This plasticity occurs in areas involved in movement, such as the motor cortex. This experiment aimed to further characterize the effects of exercise on structural vascular plasticity in the male rat motor cortex, by specifically identifying whether features of angiogenesis, the growth of new capillaries, or changes in vessel diameter were present. Male rats in the exercise group engaged in a 5-week bout of voluntary wheel running, while a second group of rats remained sedentary. After the exercise regimen, vascular corrosion casts, resin replicas of the brain vasculature, were made for all animals and imaged using a scanning electron microscope. Results indicate sprouting angiogenesis was the primary form of structural vascular plasticity detected in the motor cortex under these aerobic exercise parameters. Additionally, exercised rats displayed a slight increase in capillary diameter and expanded endothelial cell nuclei diameters in this region.

The quest of exploring alternative materials for the replacement of toxic cadmium- and lead-based quantum dots (QDs) is necessary for envisaging a sustainable future but remains highly challenging. Tackling this issue, we present the synthesis of Zn3P2 nanocrystals (NCs) of unprecedented quality. New, reactive zinc precursors yield highly crystalline, colloidally stable particles, exhibiting oxide-free surfaces, size tunability and outstanding optical properties relative to previous reports of zinc phosphide QDs.

Vascular pathologies represent the leading causes of mortality worldwide. The nervous system has evolved mechanisms to compensate for the cerebral hypoxia caused by many of these conditions. Vessel dilation and growth of new vessels are two prominent responses to hypoxia, both of which play a critical role in maintaining cerebral homeostasis. One way to facilitate cerebrovascular plasticity, and develop neuroprotection against vascular pathologies, is through aerobic exercise. The present study explored the long-term consequences of aerobic exercise on vascular structure and function in the motor cortex. Rats were assigned to a sedentary condition or were provided access to running wheels for 26 weeks. Rats were then anesthetized, and angiograms were captured using spectral domain optical coherence tomography (SD-OCT) to explore cerebrovascular reactivity in response to altered oxygen and carbon dioxide status. Following this procedure, all rats were euthanized, and unbiased stereological quantification of blood vessel density was collected from sections of the primary motor cortex infused with India ink. Results demonstrated that chronic exercise increased capillary and arteriole surface area densities and enhanced arteriole reactivity in response to hypercapnia-hypoxia, as displayed by increased vasodilation within the motor cortex of exercised animals., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The addition of zinc complexes to the syntheses of indium phosphide nanocrystals (InP NCs) has become commonplace, due to their ability to alter and significantly improve observed optical properties. In this paper, the role of zinc complexes on the synthesis and observed properties of InP is carefully examined. Produced InP and InP:Zn 2+ NCs are thoroughly characterized from both structural (core and surface) and optical perspectives over a wide range of Zn 2+ compositions (0%-43% atomic content). We find no differences in the physical (NC size and polydispersity) and structural properties (crystallographic phase) of InP and InP:Zn 2+ NCs. Optically, significant changes are observed when zinc is added to InP syntheses, including blueshifted absorption edges and maxima, increased quantum yields, and the near elimination of surface state emission. These improved optical properties result from surface passivation by zinc carboxylate moieties. Changes to the optical properties begin at zinc concentrations as low as 5%, demonstrating the high sensitivity of InP optical properties to exogenous species.

Research has implicated the deep cerebellar nuclei in autism. This study questioned whether fastigial nuclei abnormalities account for some of the irregular social behaviors seen in autism. Bilateral cannulation surgery was performed on 13 rats. An ABABAB reversal design was implemented. All animals received a microinfusion of saline during the baseline (A) phases. The experimental animal was placed in an open field with an unfamiliar confederate animal, and social interactions between the two animals were measured for 10 min. Seven animals received microinfusions of bupivacaine during the treatment phases (B), which temporarily inactivated the fastigial nuclei. Six control animals received saline again, and social interaction was retested. This sequence was executed 3 times over 6 days to achieve an ABABAB reversal design. Because the cerebellum is involved in motor behavior, the animals' locomotion was analyzed to ensure results were not because of locomotor deficits. A gait analysis and distance traveled in the open field were used to measure locomotion. No differences were found in locomotor behavior. Results of the social interaction analyses indicate animals with inactivated fastigial nuclei engage in less intense social interactions and engage in more behaviors to prevent social interaction. Knowledge that the fastigial nuclei mediate social interaction can further the understanding of pathology in the autistic brain and lead to breakthrough treatments. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Background: Exercise induces plasticity in the hippocampus, which includes increases in neurogenesis, the proliferation of new neurons, and angiogenesis, the sprouting of new capillaries from preexisting blood vessels. Following exercise, astrocytes also undergo morphological changes that parallel the events occurring in the neurovascular system. Interestingly, there have also been reports of apoptosis in the hippocampus following aerobic exercise. This experiment aimed to identify which population of hippocampal cells undergoes apoptosis after an acute bout of exercise., Methods: Cleaved caspase-3, a terminal protein in the apoptotic cascade, was initially used to identify apoptotic cells in the hippocampus after rats completed an acute bout of exercise. Next, the proportion of immature neurons, adult neurons, astrocytes, or radial glia-like cells expressing cleaved caspase-3 was quantified. TUNEL staining was completed as a second measure of apoptosis., Results: Following exercise, cleaved caspase-3 expression was increased in the CA1 and DG regions of the hippocampus. Cleaved caspase-3 was not highly expressed in neuronal populations, and expression was not increased in these cells postexercise. Instead, cleaved caspase-3 was predominantly expressed in astrocytes. Following exercise, there was an increased number of cleaved caspase-3 positive astrocytes in DG and CA1, and cleaved caspase-3 positive radial glia-like cells located in the subgranular zone. To determine whether cleaved caspase-3 expression in these glial cells was associated with apoptosis, a TUNEL assay was completed. TUNEL staining was negligible in all groups and did not mirror the pattern of caspase-3 labeling., Conclusions: Cleaved caspase-3 expression was detected largely in non-neuronal cell populations, and the pattern of cleaved caspase-3 expression did not match that of TUNEL. This suggests that after exercise, cleaved caspase-3 expression may serve a nonapoptotic role in these hippocampal astrocytes and radial glia-like cells. It will be important to identify the function of exercise-induced cleaved caspase-3 expression in the future experiments., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Aerobic exercise benefits the body and brain. In the brain, benefits include neuroprotection and improved cognition. These exercise-induced changes are attributed in part to angiogenesis: the growth of new capillaries from preexisting vessels. One critical factor involved in the regulation of angiogenesis is VEGF and its receptors Flk-1 and Flt-1. Although exercise is generally found to be beneficial, there are wide variations in exercise regimens across experiments. This study standardized some of these variations. Rats were assigned to a voluntary or a forced wheel running exercise condition. Within each condition, animals ran for either a long (1000m) or short distance (500m) for up to 24h. Additionally, one voluntary group had unrestricted access to the wheels for the full 24h. Exercising animals were then compared to inactive controls, based on unbiased stereological quantification of Flk-1 and Flt-1 immunohistochemical labeling in the hippocampus and cerebellum. Findings indicated that voluntary exercise, but not forced exercise, could significantly increase Flk-1 and Flt-1 expression in the hippocampus. Interestingly, Flk-1 expression was elevated in astrocytes and Flt-1 in vessels. In the cerebellum long distance forced exercise resulted in the least Flk-1 expression compared to other conditions, and Flt-1 expression in exercising animals either did not change or was suppressed relative to inactive controls., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We report a tunable library of N,N,N'-trisubstituted selenourea precursors and their reaction with lead oleate at 60-150 °C to form carboxylate-terminated PbSe nanocrystals in quantitative yields. Single exponential conversion kinetics can be tailored over 4 orders of magnitude by adjusting the selenourea structure. The wide range of conversion reactivity allows the extent of nucleation ([nanocrystal] = 4.6-56.7 μM) and the size following complete precursor conversion (d = 1.7-6.6 nm) to be controlled. Narrow size distributions (σ = 0.5-2%) are obtained whose spectral line widths are dominated (73-83%) by the intrinsic single particle spectral broadening, as observed using spectral hole burning measurements. The intrinsic broadening decreases with increasing size (fwhm = 320-65 meV, d = 1.6-4.4 nm) that derives from exciton fine structure and exciton-phonon coupling rather than broadening caused by the size distribution.

Anatomical tracing studies in primates have revealed neural tracts from the cerebellar dentate nuclei to prefrontal cortex, implicating a cerebellar role in nonmotor processes. Experiments in rats examining the functional role of this cerebellothalamocortical pathway have demonstrated the development of visuospatial and motivational deficits following lesions of the dentate nuclei, in the absence of motor impairment. These behavioral deficits possibly occur due to structural modifications of the cerebral cortex secondary to loss of cerebellar input. The current study characterized morphological alterations in prefrontal cortex important for visuospatial and motivational processes following bilateral cerebellar dentate nuclei lesions. Rats received either bilateral electrolytic cerebellar dentate nuclei lesions or sham surgery followed by a 30-day recovery. Randomly selected Golgi-impregnated neurons in prefrontal cortex were examined for analysis. Measures of branch length and spine density revealed no differences between lesioned and sham rats in either apical or basilar arbors; however, the proportion of immature to mature spines significantly decreased in lesioned rats as compared to sham controls, with reductions of 33% in the basilar arbor and 28% in the apical arbor. Although expected pruning of branches and spines did not occur, the results are consistent with the hypothesis that cerebellar lesions influence prefrontal morphology and support the possibility that functional deficits following cerebellar dentate nuclei lesions are related to prefrontal morphological alteration., (© 2013 Published by Elsevier B.V.)

Capillary growth and expansion (angiogenesis) is a prerequisite for many forms of neural and behavioral plasticity. It is commonly observed in both brain and muscle of aerobically exercising animals. As such, several histological methods have been used to quantify capillary density, including perfusion with India ink, various Nissl stains, and immunohistochemistry. In this chapter, we will describe these histological procedures and describe the stereological analysis used to quantify vessel growth in response to aerobic exercise.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Aerobic exercise promotes rapid and profound alterations in the brain. Depending upon the pattern and duration of exercise, these changes in the brain may extend beyond traditional motor areas to regions and structures normally linked to learning, cognition, and emotion. Exercise-induced alterations may include changes in blood flow, hormone and growth factor release, receptor expression, angiogenesis, apoptosis, neurogenesis, and synaptogenesis. Together, we believe that these changes underlie elevations of mood and prompt the heightened behavioral plasticity commonly observed following adoption of a chronic exercise regimen. In the following paper, we will explore both the psychological and psychobiological literatures relating to exercise effects on brain in both human and non-human animals and will attempt to link plastic changes in these neural structures to modifications in learned behavior and emotional expression. In addition, we will explore the therapeutic potential of exercise given recent reports that aerobic exercise may serve as a neuroprotectant and can also slow cognitive decline during normal and pathological aging.

Effort-based decision making occurs when subjects are given a choice between a reward available at a high response cost and a reward available at a low response cost and is altered in individuals with disorders such as autism or particular patterns of brain injury. The current study explored the relationship between effort-based decision making and reinforcement characteristics in the T maze. This was done using both normal animals and animals with bilateral inactivation of the cerebellar dentate nuclei. Rats chose between alternatives in which one arm contained high-density reinforcement (HR) and the other arm contained low-density reinforcement (LR). During training, the HR arm was obstructed and the point at which the animal no longer worked for reinforcement (breaking point) was determined. The cerebellar dentate nuclei were then transiently inactivated and once again breaking points were assessed. The results indicated that inactivation of the dentate nucleus disrupted effort-based decision making. Additionally, altering both the palatability and the magnitude of the reinforcement were assessed in an attempt to reestablish the original preinactivation breaking point. It was hypothesized that an increase in the strength or magnitude of the reinforcement would promote an increase in the breaking point of the animal even when the cerebellum was inactivated. The results indicated that with both strategies animals effectively reestablished original breaking points. The results of this study will inform the current literature regarding the modification of behavior after brain injury and further the understanding of the behavioral deficits associated with cerebellar dysfunction.

In its strictest application, the term "reinforcement learning" refers to a computational approach to learning in which an agent (often a machine) interacts with a mutable environment to maximize reward through trial and error. The approach borrows essentials from several fields, most notably Computer Science, Behavioral Neuroscience, and Psychology. At the most basic level, a neural system capable of mediating reinforcement learning must be able to acquire sensory information about the external environment and internal milieu (either directly or through connectivities with other brain regions), must be able to select a behavior to be executed, and must be capable of providing evaluative feedback about the success of that behavior. Given that Psychology informs us that reinforcers, both positive and negative, are stimuli or consequences that increase the probability that the immediately antecedent behavior will be repeated and that reinforcer strength or viability is modulated by the organism's past experience with the reinforcer, its affect, and even the state of its muscles (e.g., eyes open or closed); it is the case that any neural system that supports reinforcement learning must also be sensitive to these same considerations. Once learning is established, such a neural system must finally be able to maintain continued response expression and prevent response drift. In this report, we examine both historical and recent evidence that the cerebellum satisfies all of these requirements. While we report evidence from a variety of learning paradigms, the majority of our discussion will focus on classical conditioning of the rabbit eye blink response as an ideal model system for the study of reinforcement and reinforcement learning.

Long-term aerobic exercise improves cognition in both human and nonhuman animals and induces plastic changes in the central nervous system (CNS), including neurogenesis and angiogenesis. However, the early and immediate effects of exercise on the CNS have not been adequately explored. There is some evidence to suggest that exercise is initially challenging to the nervous system and that the plastic changes commonly associated with chronic exercise may result as adaptations to this challenge. The current experiment assessed levels of apoptosis, angiogenesis, and neurogenesis during the first week of an exercise regimen in the adult rat. The results indicate that exercise rapidly induces these processes in the hippocampus and cerebellum. The temporal pattern of these events suggests that voluntary exercise in the adult rat rapidly and transiently induces apoptosis, followed by angiogenesis. Neurogenesis is an immediate and independent consequence of exercise in the hippocampus that may require the additional metabolic support supplied by angiogenesis. This is the first report of CNS neuronal apoptosis as a consequence of exercise in the adult rat and suggests that this process is a potential mediator of rapid exercise-induced plasticity., ((PsycINFO Database Record (c) 2011 APA, all rights reserved).)

Recently identified pathways from the dentate nuclei of the cerebellum to the rostral cerebral cortex via the thalamus suggest a cerebellar role in frontal and prefrontal non-motor functioning. Disturbance of cerebellar morphology and connectivity, particularly involving these cerebellothalamocortical (CTC) projections, has been implicated in motivational and cognitive deficits. The current study explored the effects of CTC disruption on motivation in male Long Evans rats. The results of two experiments demonstrate that electrolytic lesions of the cerebellar dentate nuclei lower breaking points on an operant conditioning progressive ratio schedule and decrease open field exploration compared to sham controls. Changes occurred in the absence of motor impairment, assessed via lever pressing frequency and rotarod performance. Similar elevated plus maze performances between lesioned and sham animals indicated that anxiety did not influence task performance. Our results demonstrate hedonic and purposive motivational reduction and suggest a CTC role in global motivational processes. These implications are discussed in terms of psychiatric disorders such as schizophrenia and autism, in which cerebellar damage and motivational deficits often present concomitantly., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The GacS/GacA two-component signal transduction system regulates virulence, biofilm formation and symbiosis in Vibrio species. The present study investigated this regulatory pathway in Vibrio vulnificus, a human pathogen that causes life-threatening disease associated with the consumption of raw oysters and wound infections. Small non-coding RNAs (csrB1, csrB2, csrB3 and csrC) commonly regulated by the GacS/GacA pathway were decreased (P<0.0003) in a V. vulnificus CMCP6 ΔgacA : : aph mutant compared with the wild-type parent, and expression was restored by complementation of the gacA deletion mutation in trans. Of the 20 genes examined by RT-PCR, significant reductions in the transcript levels of the mutant in comparison with the wild-type strain were observed only for genes related to motility (flaA), stationary phase (rpoS) and protease (vvpE) (P=0.04, 0.01 and 0.002, respectively). Swimming motility, flagellation and opaque colony morphology indicative of capsular polysaccharide (CPS) were unchanged in the mutant, while cytotoxicity, protease activity, CPS phase variation and the ability to acquire iron were decreased compared with the wild-type (P<0.01). The role of gacA in virulence of V. vulnificus was also demonstrated by significant impairment in the ability of the mutant strain to cause either skin (P<0.0005) or systemic infections (P<0.02) in subcutaneously inoculated, non-iron-treated mice. However, the virulence of the mutant was equivalent to that of the wild-type in iron-treated mice, demonstrating that the GacA pathway in V. vulnificus regulates the virulence of this organism in an iron-dependent manner.

Aerobic exercise has been well established to promote enhanced learning and memory in both human and non-human animals. Exercise regimens enhance blood perfusion, neo-vascularization, and neurogenesis in nervous system structures associated with learning and memory. The impact of specific plastic changes to learning and memory performance in exercising animals are not well understood. The current experiment was designed to investigate the contributions of angiogenesis and neurogenesis to learning and memory performance by pharmacologically blocking each process in separate groups of exercising animals prior to visual spatial memory assessment. Results from our experiment indicate that angiogenesis is an important component of learning as animals receiving an angiogenesis inhibitor exhibit retarded Morris water maze (MWM) acquisition. Interestingly, our results also revealed that neurogenesis inhibition improves learning and memory performance in the MWM. Animals that received the neurogenesis inhibitor displayed the best overall MWM performance. These results point to the importance of vascular plasticity in learning and memory function and provide empirical evidence to support the use of manipulations that enhance vascular plasticity to improve cognitive function and protect against natural cognitive decline., (Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

The present study was conducted in an effort to evaluate whether chromosomal substitution can repair impaired exploration learning and memory. It has previously been observed that Dahl salt-sensitive (SS) rodents exhibit impaired cognitive function along with abnormal physiological responses to muscle stimulation. Introgression of Brown Norway chromosome (13(BN)) has been found to restore normal physiological processes in SS animals. However, the effect of chromosomal substitution on cognitive performance has not been explored. It was hypothesized that 13(BN) also rescues cognitive impairments in these animals. Visual spatial learning and cognitive flexibility were evaluated using the Morris water maze (MWM) and the T-maze. This manipulation is effective in rescuing impaired task acquisition, but not perseveration observed in the SS animal. These animals may represent a natural animal model in which to isolate genetic information responsible for learning and memory function.

Conjugated Linoleic Acid (CLA) is fatty acid found endogenously in food sources that prevents new tumor development and reduces the growth of existing tumors in laboratory animals. CLA exerts its anti-carcinogenic effect by reducing VEGF and bFGF serum levels and by blocking flk-1 receptors, thereby inhibiting vascular growth critical to tumor growth and survival. Although the ability of CLA to inhibit angiogenesis in the peripheral nervous system is well characterized, it remains unknown whether CLA also affects vascular morphology in the central nervous system. Therefore, in the present study, exercising and sedentary animals received either standard rat chow or a specially formulated diet consisting of 0.5% CLA for 24 days. The brains were then examined to determine the extent of vascular growth in the cerebellum, a region known to exhibit robust exercise-induced angiogenesis. Our results indicate that CLA administration significantly reduces angiogenesis in the cerebellum. This study is the first to demonstrate the anti-angiogenic effect of CLA in the brain, and suggests that CLA be explored as a therapeutic treatment for cancer and tumors in the brain.

Exercise promotes multiple changes in hippocampal morphology and should, as a result, alter behavioral function. The present experiment investigated the effect of exercise on learning using contextual and auditory Pavlovian fear conditioning. Rats remained inactive or voluntarily exercised (VX) for 30 days, after which they received auditory-cued fear conditioning. Twenty-four hours later, rats were tested for learning of the contextual and auditory conditional responses. No differences in freezing behavior to the discrete auditory cue were observed during the training or testing sessions. However, VX rats did freeze significantly more compared to controls when tested in the training context 24 hr after exposure to shock. The enhancement of contextual fear conditioning provides further evidence that exercise alters hippocampal function and learning., (Copyright 2004 APA.)

Following bilateral lesions targeting lateral deep cerebellar nuclei, rats were subjected to a bridge test as a measure of visuomotor coordination and were trained on the Morris water maze (MWM) as a measure of visuospatial processing. Lesioned rats were significantly impaired in visuospatial processing, but not visuomotor coordination, relative to sham rats. In a 2nd experiment, rats were pretrained on a delayed spatial alternation task (T maze) before MWM training. Pretraining reversed the visuospatial deficit caused by the lesions as compared with nonpretrained rats. Results suggest that lateral deep cerebellar nuclei contribute to visuospatial processing with a negligible contribution to visuomotor skills and that visuospatial deficits resulting from lateral nuclei damage can be reversed with pretraining on aspatial working memory task.

Acetaminophen administration is gaining popularity as a postsurgical analgesic in many rodent labs despite reports that animals may consume suboptimal doses as a result of taste neophobia. The present study evaluated the presence, duration, and extent of acetaminophen neophobia in adult male and female rats (Long Evans) with the intent of developing a protocol for administration of this analgesic in the rodent surgery lab. After a 7-day baseline period in which average water consumption, food consumption, and body weight were established for 32 rats (20 females and 12 males), cherry-flavored acetaminophen was administered (6 mg/ml) in the animals' water bottles for an additional 7 days. Fluid consumption, food consumption, and weight were monitored during this period of drug exposure. Male rats displayed a transient period (1 day) of reduced fluid consumption followed by elevated fluid consumption on subsequent days. Female animals displayed normal to elevated fluid consumption on all days of drug exposure. Both male and female animals, however, decreased their food intake after drug exposure and subsequently lost weight. Recommendations for the oral administration of acetaminophen as a postsurgical analgesic are discussed.

Plastic changes in motor cortex capillary structure and function were examined in three separate experiments in adult rats following prolonged exercise. The first two experiments employed T-two-star (T(2)*)-weighted and flow-alternating inversion recovery (FAIR) functional magnetic resonance imaging to assess chronic changes in blood volume and flow as a result of exercise. The third experiment used an antibody against the CD61 integrin expressed on developing capillaries to determine if motor cortex capillaries undergo structural modifications. In experiment 1, T(2)*-weighted images of forelimb regions of motor cortex were obtained following 30 days of either repetitive activity on a running wheel or relative inactivity. The proton signal intensity was markedly reduced in the motor cortex of exercised animals compared with that of controls. This reduction was not attributable to alterations of vascular iron levels. These results are therefore most consistent with increased capillary perfusion or blood volume of forelimb regions of motor cortex. FAIR images acquired during experiment 2 under normocapnic and hypercapnic conditions indicated that resting cerebral blood flow was not altered under normal conditions but was elevated in response to high levels of CO(2), suggesting that prolonged exercise increases the size of a capillary reserve. Finally, the immunohistological data indicated that exercise induces robust growth of capillaries (angiogenesis) within 30 days from the onset of the exercise regimen. Analysis of other regions failed to find any changes in perfusion or capillary structure suggesting that this motor activity-induced plasticity may be specific to motor cortex.These data indicate that capillary growth occurs in motor areas of the cerebral cortex as a robust adaptation to prolonged motor activity. In addition to capillary growth, the vascular system also experiences heightened flow under conditions of activation. These changes are chronic and observable even in the anesthetized animal and are measurable using noninvasive techniques.

While limited research is available, evidence indicates that physical and mental activity influence the aging process. Human data show that executive functions of the type associated with frontal lobe and hippocampal regions of the brain may be selectively maintained or enhanced in humans with higher levels of fitness. Similarly enhanced performance is observed in aged animals exposed to elevated physical and mental demand and it appears that the vascular component of the brain response may be driven by physical activity whereas the neuronal component may reflect learning. Recent results have implicated neurogenesis, at least in the hippocampus, as a component of the brain response to exercise, with learning enhancing survival of these neurons. Non-neuronal tissues also respond to experience in the mature brain, indicating that the brain reflects both its recent and its longer history of experience. Preliminary measures of brain function hold promise of increased interaction between human and animal researchers and a better understanding of the substrates of experience effects on behavioral performance in aging., (Copyright 2002 Elsevier Science Inc.)

Fragile-X syndrome is a common form of mental retardation resulting from the inability to produce the fragile-X mental retardation protein. The specific function of this protein is unknown; however, it has been proposed to play a role in developmental synaptic plasticity. Examination of human brain autopsy material has shown that fragile-X patients exhibit abnormalities in dendritic spine structure and number, suggesting a failure of normal developmental dendritic spine maturation and pruning in this syndrome. Similar results using a knockout mouse model have previously been described; however, it was noted in retrospect that the mice used in that study may have carried a mutation for retinal degeneration, which may have affected cell morphology in the visual cortex of those animals. In this study, dendritic spines on layer V pyramidal cells of visual cortices, taken from fragile-X knockout and wild-type control mice without the retinal degeneration mutation and stained using the Golgi-Cox method, were investigated for comparison with the human condition. Quantitative analyses of the lengths, morphologies, and numbers of dendritic spines, as well as amount of dendritic arbor and dendritic branching complexity, were conducted. The fragile-X mice exhibited significantly more long dendritic spines and significantly fewer short dendritic spines than control mice. Similarly, fragile-X mice exhibited significantly more dendritic spines with an immature-like morphology and significantly fewer with a more mature type morphology. However, unlike the human condition, fragile-X mice did not exhibit statistically significant dendritic spine density differences from controls. Fragile-X mice also did not demonstrate any significant differences from controls in dendritic tree complexity or dendritic arbor. Long dendritic spines with immature morphologies are characteristic of early development or a lack of sensory experience. These results are similar to those found in the human condition and further support a role for the fragile-X mental retardation protein specifically in normal dendritic spine developmental processes. They also support the validity of these mice as a model of fragile-X syndrome., (Copyright 2002 Wiley-Liss, Inc.)

Protein phosphatase 5 is a recently discovered Ser/Thr phosphatase that is structurally related to calcineurin and protein phosphatases 1 and 2. Northern blot and in situ hybridization studies have shown that protein phosphatase 5 mRNA is present at high levels in brain and is localized to discrete regions. In the present study, we used immunocytochemistry and immunoblot analyses to examine the regional and subcellular distribution of this enzyme in brain. Our work demonstrates that protein phosphatase 5 is widely expressed throughout brain, but is not uniformly distributed. The most intense staining occurred in neurons of the cerebellum, cerebral cortex, and the supraoptic nucleus of the hypothalamus. Other areas also contained immunoreactive cell bodies, including the globus pallidus, hippocampus, thalamus, lateral preoptic area of the hypothalamus, substantia nigra and other brainstem nuclei. Staining in these cells was observed primarily in perikarya and proximal processes.

Fragile-X syndrome is a common form of mental retardation resulting from the inability to produce the fragile-X mental retardation protein. Qualitative examination of human brain autopsy material has shown that fragile-X patients exhibit abnormal dendritic spine lengths and shapes on parieto-occipital neocortical pyramidal cells. Similar quantitative results have been obtained in fragile-X knockout mice, that have been engineered to lack the fragile-X mental retardation protein. Dendritic spines on layer V pyramidal cells of human temporal and visual cortices stained using the Golgi-Kopsch method were investigated. Quantitative analysis of dendritic spine length, morphology, and number was carried out on patients with fragile-X syndrome and normal age-matched controls. Fragile-X patients exhibited significantly more long dendritic spines and fewer short dendritic spines than did control subjects in both temporal and visual cortical areas. Similarly, fragile-X patients exhibited significantly more dendritic spines with an immature morphology and fewer with a more mature type morphology in both cortical areas. In addition, fragile-X patients had a higher density of dendritic spines than did controls on distal segments of apical and basilar dendrites in both cortical areas. Long dendritic spines with immature morphologies and elevated spine numbers are characteristic of early development or a lack of sensory experience. The fact that these characteristics are found in fragile-X patients throughout multiple cortical areas may suggest a global failure of normal dendritic spine maturation and or pruning during development that persists throughout adulthood., (Copyright 2001 Wiley-Liss, Inc.)

The Fragile-X mental retardation protein, the protein absent in Fragile-X syndrome, is synthesized near synapses upon neurotransmitter activation. Humans and mice lacking this protein exhibit abnormal dendritic spine lengths and numbers. Here we investigated Fragile-X protein levels in animals exposed to behavioral paradigms that induce neuronal morphological change. Fragile-X protein immunoreactivity was examined in visual cortices of rats reared in a complex environment for 10 or 20 days, motor cortices of rats trained on motor-skill tasks for 3 or 7 days, and either visual or motor cortices of inactive controls. Rats exposed to a complex environment for 20 days or trained for 7 days on motor-skill tasks exhibited increased Fragile-X protein immunoreactivity in visual or motor cortices, respectively. These results provide the first evidence for a behaviorally induced alteration of Fragile-X protein expression and are compatible with previous findings suggesting synaptic regulation of its expression. These results also strengthen the association of Fragile-X mental retardation protein expression with the alteration of synaptic structure.

Unlabelled: The purpose of this review is to present the evidence-based pharmacotherapeutic properties of vitamin E and provide clinical recommendations for use in the arena of atherosclerosis., Methods: A literature search was conducted from 1966 through March 1999. All usable papers were retrieved, with large, randomized, double-blinded, clinical trials and epidemiological trials receiving emphasis., Results: Vitamin E, a lipid soluble vitamin, is a potent antioxidant. Several epidemiological studies have demonstrated positive relationships between vitamin E intake and the prevention of atherosclerotic heart disease; however, only one, large randomized clinical trial (The CHAOS Trial) has been conducted using more than 400 IU per day of vitamin E. Positive outcomes included a 77-percent reduction in nonfatal myocardial infarction (MI), but no corresponding reduction in mortality. Several large clinical trials are ongoing, investigating vitamin E for the prevention of atherosclerosis. Much less work has been undertaken studying vitamin E for prevention of cerebro- and peripheral vascular disease, but there appears to be promise in these areas as well., Conclusions: On the basis of the literature search, the authors recommend 400 IU or more per day of vitamin E to patients at high risk or already diagnosed with coronary artery disease. Vitamin E supplementation may also be beneficial in the prevention of cerebro- and peripheral vascular diseases.

It has been demonstrated previously that pairing of tone CS and intracerebellar stimulation of lobule HVI white matter as the US produces conditioning that is robust and in many ways similar to that obtained with an airpuff US. The first study in this report addressed the effect of interpositus lesions on conditioned performance in rabbits trained with white matter stimulation as the US. It was found that interpositus lesions effectively eliminated the CR irrespective of the behavioral response measured. In addition, it was shown that the interpositus lesions also abolished the UR, providing strong evidence that the effects of the electrical stimulation were confined to the cerebellum and did not require the activation of brainstem structures. The second experiment examined performance on US-alone trials of varying durations. Response initiation within 100 ms of the US onset, regardless of US duration, indicated that reflex generation could not be due to rebound excitation of the interpositus following termination of Purkinje cell inhibition of that structure but instead likely reflects orthodromic activation of interpositus neurons via climbing fiber and/or mossy fiber collaterals. The impact of US preexposure on associative conditioning in this paradigm was also determined. Animals which received only 108 US-alone trials were massively impaired during subsequent training compared to rabbits that received fewer than 12 US-alone trials., (Copyright 1999 Academic Press.)

The effects of complex motor task learning on subsequent motor performance of adult rats exposed to alcohol on postnatal days 4 through 9 were studied. Male and female Long-Evans rats were assigned to one of three treatments: (1) alcohol exposure (AE) via artificial rearing to 4.5.g kg-1 day-1 of ethanol in a binge-like manner (two consecutive feedings), (2) gastrostomy control (GC) fed isocaloric milk formula via artificial rearing, and (3) suckling control (SC), where pups remained with lactating dams. After completion of the treatments, the pups were fostered back to lactating dams, and after weaning they were raised in standard cages (two-three animals per cage) until they were 6 months old. Rats from each of the postnatal treatments then spent 20 days in one of three conditions: (1) inactive condition (IC), (2) motor control condition (MC) (running on a flat oval track), or (3) rehabilitation condition (RC) (learning to traverse a set of 10 elevated obstacles). After that all the animals were tested on three tasks, sensitive to balance and coordination deficits (parallel bars, rope climbing and traversing a rotating rod). On parallel bars, both male and female rats demonstrated the same pattern of outcomes: AE-IC rats made significantly more mistakes (slips and falls) than IC rats from both control groups. After 20 days of training in the RC condition, there were no differences between AE and both SC and GC animals in their ability to perform on the parallel bars test. On rope climbing, female animals showed a similar pattern of abilities: AE-IC rats were the worst group; exercising did not significantly improve the AE rats' ability to climb, whereas the RC groups (SC, GC and AE) all performed near asymptote and there were no significant differences among three neonatal treatment groups. There was a substantial effect of the male rats' heavier body weight on climbing ability, and this may have prevented the deficits in AE rats behavior from being detected. Nevertheless, male animals from all three postnatal treatments (SC, GC and AE) were significantly better on this task after RC. Female and male rats from all three postnatal groups demonstrated significantly better performance on the rotarod task after 20 days of 'rehabilitation'. These results suggest that complex motor skill learning improves some of the motor performance deficits produced by postnatal exposure to alcohol and can potentially serve as a model for rehabilitative intervention., (Copyright 1998 Elsevier Science B.V. All rights reserved.)

Complex motor skill learning, but not mere motor activity, leads to an increase in synapse number within the cerebellar cortex. The present experiment used quantitative electron microscopy to determine which synapse types were altered in number. Adult female rats were allocated to either an acrobatic condition (AC), a voluntary exercise condition (VX), or an inactive condition (IC). AC animals were trained to traverse an elevated obstacle course requiring substantial motor coordination to complete. VX animals were housed with unlimited access to running wheels and IC animals received no motor training but were handled briefly each day. Results showed the AC animals to have significantly more parallel fiber to Purkinje cell synapses than both the VX and IC animals. No other synapse type was significantly altered. Thus, the learning-dependent increase in synapse number observed within the cerebellar cortex is accomplished primarily through the addition of parallel fiber synapses., (Copyright 1998 Academic Press.)

Background: Headaches are a common entity in the ambulatory population. Physicians involved in sports medicine must be able to accurately diagnose headaches in athletes and whether they are exacerbated by exertion. Many medications have proven or theoretical negative effects on athletic performance. Thus, we should consider all aspects of medical management and determine which therapy is least intrusive to the athlete's performance. We planned this review because of the small number of papers available on the effects of various medications on athletic performance., Methods: We used MEDLINE to search from 1992 to current citations, using the medical subject headings of headache, prophylaxis, treatment, review, athletes, and exercise, alone or in combination., Results: Fifty-two articles were identified and deemed appropriate for inclusion in this review., Conclusions: Acute therapy for tension headaches in the athletic population is best done with nonsteroidal anti-inflammatory drugs. Prophylaxis of chronic, recurrent tension headaches is best accomplished by night-time tricyclic antidepressants (especially nortriptyline) or selective serotonin reuptake inhibitors. Acute therapy for athletes with migraines is best managed with sumatriptan or DHE 45 and prophylaxis can be accomplished with verapamil, antidepressants, or valproate. Exertional, cluster, and structural/infectious headaches are also discussed briefly.

Objective: To study the effects of over-the-counter dosages of the pure alpha 1-agonists pseudoephedrine (PSE) and phenylpropanolamine (PPA) on selected parameters of exercise performance, and to establish a range of corresponding drug levels in the urine of the athletes who use these drugs., Design: Placebo-controlled, randomized, double-blinded, multiple-dose trial., Setting: The National Institute of Fitness and Sport, the Department of Family Medicine, Indiana University, and the Sports Medicine Lab, Department of Pathology, Indiana University, Indianapolis, Indiana., Participants: A convenience sample of 20 male cyclists, aged 18-35, from the local cycling community. Inclusion criteria required cycling at least 50 miles a week, no chronic medical problems, and not taking any medications. Subjects were recruited by local ads and word of mouth., Intervention: Patients were randomized to one of two groups of 10 subjects. Each subject in both groups performed three separate bicycle ergometer tests after ingestion of varying dosages of alpha 1-agonists. One group performed tests after receiving placebo, 0.33 mg/kg PPA, and 0.66 mg/kg PPA, whereas the other group received placebo, 1 mg/kg PSE, and 2 mg/kg PSE. A minimum 1-week washout period was required between tests. Urine for drug testing was collected 1 h before, immediately afterward, and the next morning after testing. Drug testing was performed by gas GC/MCD at a facility approved by the International Olympic Committee., Main Outcome Measures: Maximum oxygen uptake (VO2max), time to exhaustion, urine drug levels of PSE and PPA, peak blood pressures (BPs), peak pulse, and Borg scale (rating of perceived exertion or RPE)., Main Results: In the PPA group, the 0.33-mg/kg dose resulted in insignificant changes in peak systolic BP (+5.4 mm Hg, p = 0.260), peak diastolic BP (-1.6 mm Hg, p = 0.622), peak pulse (-2.2 beats/min, p = 0.12), peak Borg (RPE = -0.10 (p = 0.823), time to exhaustion (-16.9 s, p = 0.287), and VO2max (+0.50 ml/kg/min, p = 0.71). No significant change was noted in any study variable at the 0.66-mg/kg PPA dose, and some effects were dissimilar to the lower PPA dose effects. Peak systolic BP increased 2.8 mm Hg (p = 0.617), diastolic BP decreased 1.6 mm Hg (p = 0.634), peak pulse increased 1.4 beats/min (p = 0.504), peak Borg RPE decreased 0.80 (p = 0.210), time to exhaustion decreased 2.6 s (p = 0.861), and VO2max decreased 2.92 ml/kg/min (p = 0.14). In the 1-mg/kg PSE group, there was a significant increase in peak systolic BP (+10.6 mm Hg, p = 0.029). No significant changes occurred in peak diastolic BP (+2.4 mm Hg, p = 0.333), peak pulse (+2.2 beats/min, p = 0.306), peak RPE (+0.2, p = 0.62), time to exhaustion (+21.4 s, p = 0.289), and VO2max (+2.29 ml/kg/min, p = 0.31). In the 2-mg/kg PSE dose trial, there were insignificant changes in peak systolic BP of +2.4 mm Hg (p = 0.559), +3.8 mm Hg in peak diastolic BP (p = 0.106), +1.6 beats/min in peak pulse (p = 0.586), -0.1 in peak Borg RPE scales (p = 0.76), -10.4 s in time to exhaustion (p = 0.41), and +1.79 ml/kg/min in VO2max (p = 0.43). Urine drug levels in those subjects receiving 1 mg/kg PSE ranged from 7-55 micrograms/ml before performance and 30-128 micrograms/ ml after performance to 7-35 micrograms/ml the next morning. Levels in those receiving 2 mg/kg ranged from 5-160 micrograms/ml before performance and 44-200 micrograms/ml after performance to 8-44 micrograms/ ml the next day. In the PPA 0.33-mg/kg dose trials, the levels ranged 1-36 micrograms/ml before performance and 9-50 micrograms/ml after performance to < 1-14 micrograms/ml the next morning. In the PPA 0.66-mg/kg dose trials, the levels were 4-52 micrograms/ml before performance, 8-80 micrograms/ml after performance, and 6-74 micrograms/ml the next day., Conclusions: We found no significant differences between trials in maximum oxygen uptake (VO2max), peak or progression of Borg Scale (RPE), maximum systolic and diastolic BPs, peak pulse, or t

Folic acid, a water-soluble vitamin, has been used since the 1940s to treat some cases of macrocytic anemia without neurologic disease. Folate deficiency is best diagnosed with red blood cell folate levels along with macrocytosis and/or megaloblastic anemia. In addition to reversing overt deficiency, the vitamin may reduce the incidence of neural tube defects by 45% in women who receive 400 micrograms per day. It is recommended that all women of childbearing age take 400 micrograms of folate per day. Elevations in homocysteine levels, a metabolite intimately associated with folate, are also being found with increasing regularity in those with cardiovascular diseases. Homocysteine levels are reduced by folic acid administration. Therefore, there is some biologic plausibility, but not currently direct proof, for the assumption that folate supplements may prevent heart disease, stroke, and peripheral arterial disease. Controlled trials should take place before widespread food supplementation with folate is carried out on a large scale because of the possibility of outbreaks of permanent B12-related neurologic damage in those with undiagnosed pernicious anemia. However, if a patient has a premature cardiovascular event and has minimal risk factors, ordering a test to determine homocysteine level may be advisable, and if elevated, treating with folic acid supplement as long as B12 deficiency does not coexist.

Recent work has shown that motor learning, but not mere motor activity, changes the morphology of Purkinje cells, the major projection neurons of the cerebellar cortex. In the present study we examined how motor skill learning affects the dendritic morphology of the stellate local circuit neurons. Adult female rats were either trained to complete a complex motor learning task or forced to traverse a flat, obstacle-free runway. Golgi impregnated stellate cells were then traced via camera lucida and their dendritic arborizations examined with a concentric ring analysis. Results showed the motor learning animals to have significantly greater stellate cell dendritic arborizations than the activity controls. Thus these local circuit neurons exhibit morphological plasticity.

Iron deficiency anemia is a common problem encountered in primary care practice. Once the diagnosis is confirmed and the possible causes are identified, replacement of iron stores is indicated. Most patients respond favorably to oral iron preparations. However, therapy with intravenous iron dextran (InFeD) may be warranted in some cases. Side effects, which are usually mild, occur in 25% of patients. Test doses of undiluted iron dextran occasionally elicit anaphylactic reactions. However, affected patients still may be successfully treated intravenously with the use of prophylactic antihistamines, corticosteroids, and histamine2 blockers. Treatment of iron deficiency anemia almost always brings symptomatic improvement.

Stimulating electrodes were implanted in rabbit cerebellum, providing an electrical conditioned stimulus (CS) activating cortical parallel fibers and thence Purkinje and other cells, and an electrical unconditioned stimulus (US) activating underlying white matter and eliciting unconditioned responses. Paired CS-US presentations led to the development of conditioned responses, which showed extinction following CS-alone trials and reacquisition with significant savings on reinstatement of paired trials. Increased local excitability as a result of paired training (but not following unpaired stimulus presentations) was observed in cerebellar cortex, as manifested in substantial decreases in CS threshold for response elicitation in all subjects. This preparation offers a model for the study of plastic neuronal interactions within cerebellar networks critically involved in associative learning.