bluuebunny/crossref_metadata_2025 huggingface dataset:
Active and Total Transforming Growth Factor-β1 Are Differentially Regulated by Dopamine and Estradiol in the Pituitary
Authors: Recouvreux M. Victoria , Guida M. Clara , Rifkin Daniel B. , Becu-Villalobos Damasia , Díaz-Torga Graciela
Published: April 2011

Dopamine, acting through the dopamine type 2 receptor (Drd2), is the main inhibitor of pituitary prolactin (PRL) secretion and lactotroph proliferation. TGF-β1 is involved, at least in part, in mediating these actions. It was described that TGF-β1 synthesis in rat pituitary lactotrophs is up-regulated by dopamine and down-regulated by estradiol. TGF-β1 is secreted as a large latent complex. The local regulation of cytokine activation in the pituitary has not yet been explored. In this work, we studied pituitary active and total TGF-β1 content, as well as TGF-β1 mRNA, and the in vivo role of dopamine and estradiol on pituitary TGF-β1 levels. Adult female mice (wild type), and female mice with a null mutation in the Drd2 (Drd2−/−), were used. The loss of dopaminergic tone induced a decrease in TGF-β1 mRNA expression, in active and total cytokine content, and in TGF-β type II receptor expression. Dopamine regulation of pituitary TGF-β1 activation process was inferred by the inhibition of active cytokine by in vivo sulpiride treatment. Interestingly, in the absence of dopaminergic tone, estradiol induced a strong increase in active TGF-β1. PRL secretion correlated with active, but not total cytokine. TGF-β1 inhibitory action on lactotroph proliferation and PRL secretion was decreased in Drd2−/− pituitary cells, in correlation with decreased TGF-β type II receptor. The study of the TGF-β1 activation process and its regulation is essential to understand the cytokine activity. As an intermediary of dopamine inhibition of lactotroph function, TGF-β1 and local activators may be important targets in the treatment of dopamine agonist-resistant prolactinomas.
Odometry and insect navigation
Authors: Wolf Harald
Published: April 2011

Animals have needed to find their way about almost since a free-living life style evolved. Particularly, if an animal has a home – shelter or nesting site – true navigation becomes necessary to shuttle between this home and areas of other activities, such as feeding. As old as navigation is in the animal kingdom, as diverse are its mechanisms and implementations, depending on an organism's ecology and its endowment with sensors and actuators. The use of landmarks for piloting or the use of trail pheromones for route following have been examined in great detail and in a variety of animal species. The same is true for senses of direction – the compasses for navigation – and the construction of vectors for navigation from compass and distance cues. The measurement of distance itself – odometry – has received much less attention. The present review addresses some recent progress in the understanding of odometers in invertebrates, after outlining general principles of navigation to put odometry in its proper context. Finally, a number of refinements that increase navigation accuracy and safety are addressed.
Growth and the regulation of myotomal muscle mass in teleost fish
Authors: Johnston Ian A. , Bower Neil I. , Macqueen Daniel J.
Published: April 2011

Teleost muscle first arises in early embryonic life and its development is driven by molecules present in the egg yolk and modulated by environmental stimuli including temperature and oxygen. Several populations of myogenic precursor cells reside in the embryonic somite and external cell layer and contribute to muscle fibres in embryo, larval, juvenile and adult stages. Many signalling proteins and transcription factors essential for these events are known. In all cases, myogenesis involves myoblast proliferation, migration, fusion and terminal differentiation. Maturation of the embryonic muscle is associated with motor innervation and the development of a scaffold of connective tissue and complex myotomal architecture needed to generate swimming behaviour. Adult muscle is a heterogeneous tissue composed of several cell types that interact to affect growth patterns. The development of capillary and lymphatic circulations and extramuscular organs – notably the gastrointestinal, endocrine, neuroendocrine and immune systems – serves to increase information exchange between tissues and with the external environment, adding to the complexity of growth regulation. Teleosts often exhibit an indeterminate growth pattern, with body size and muscle mass increasing until mortality or senescence occurs. The dramatic increase in myotomal muscle mass between embryo and adult requires the continuous production of muscle fibres until 40–50% of the maximum body length is reached. Sarcomeric proteins can be mobilised as a source of amino acids for energy metabolism by other tissues and for gonad generation, requiring the dynamic regulation of muscle mass throughout the life cycle. The metabolic and contractile phenotypes of muscle fibres also show significant plasticity with respect to environmental conditions, migration and spawning. Many genes regulating muscle growth are found as multiple copies as a result of paralogue retention following whole-genome duplication events in teleost lineages. The extent to which indeterminate growth, ectothermy and paralogue preservation have resulted in modifications of the genetic pathways regulating muscle growth in teleosts compared to mammals largely remains unknown. This review describes the use of compensatory growth models, transgenesis and tissue culture to explore the mechanisms of muscle growth in teleosts and provides some perspectives on future research directions.
Ontogenetic changes in jaw-muscle architecture facilitate durophagy in the turtleSternotherus minor
Authors: Pfaller Joseph B. , Gignac Paul M. , Erickson Gregory M.
Published: April 2011

Differential scaling of musculoskeletal traits leads to differences in performance across ontogeny and ultimately determines patterns of resource use during development. Because musculoskeletal growth of the feeding system facilitates high bite-force generation necessary to overcome the physical constraints of consuming more durable prey, durophagous taxa are well suited for investigations of the scaling relationships between musculoskeletal growth, bite-force generation and dietary ontogeny. To elucidate which biomechanical factors are responsible for allometric changes in bite force and durophagy, we developed and experimentally tested a static model of bite-force generation throughout development in the durophagous turtle Sternotherus minor. Moreover, we quantified the fracture properties of snails found in the diet to evaluate the relationship between bite force and the forces required to process durable prey. We found that (1) the static bite-force model accurately predicts the ontogenetic scaling of bite forces, (2) bite-force positive allometry is accomplished by augmenting muscle size and muscle pennation, and (3) the rupture forces of snails found in the diet show a similar scaling pattern to bite force across ontogeny. These results indicate the importance of muscle pennation for generating high bite forces while maintaining muscle size and provide empirical evidence that the allometric patterns of musculoskeletal growth in S. minor are strongly linked to the structural properties of their primary prey.
Bottles as models: predicting the effects of varying swimming speed and morphology on size selectivity and filtering efficiency in fishes
Authors: Paig-Tran E. W. Misty , Bizzarro Joseph J. , Strother James A. , Summers Adam P.
Published: April 2011

We created physical models based on the morphology of ram suspension-feeding fishes to better understand the roles morphology and swimming speed play in particle retention, size selectivity and filtration efficiency during feeding events. We varied the buccal length, flow speed and architecture of the gills slits, including the number, size, orientation and pore size/permeability, in our models. Models were placed in a recirculating flow tank with slightly negatively buoyant plankton-like particles (∼20–2000 μm) collected at the simulated esophagus and gill rakers to locate the highest density of particle accumulation. Particles were captured through sieve filtration, direct interception and inertial impaction. Changing the number of gill slits resulted in a change in the filtration mechanism of particles from a bimodal filter, with very small (≤50 μm) and very large (>1000 μm) particles collected, to a filter that captured medium-sized particles (101–1000 μm). The number of particles collected on the gill rakers increased with flow speed and skewed the size distribution towards smaller particles (51–500 μm). Small pore sizes (105 and 200 μm mesh size) had the highest filtration efficiencies, presumably because sieve filtration played a significant role. We used our model to make predictions about the filtering capacity and efficiency of neonatal whale sharks. These results suggest that the filtration mechanics of suspension feeding are closely linked to an animal's swimming speed and the structural design of the buccal cavity and gill slits.
The contractile sponge epitheliumsensu lato– body contraction of the demospongeTethya wilhelmais mediated by the pinacoderm
Authors: Nickel Michael , Scheer Corina , Hammel Jörg U. , Herzen Julia , Beckmann Felix
Published: April 2011

Sponges constitute one of the two metazoan phyla that are able to contract their bodies despite a complete lack of muscle cells. Two competing hypotheses on the mechanisms behind this have been postulated to date: (1) mesohyl-mediated contraction originating from fusiform smooth muscle-like actinocytes (‘myocytes’) and (2) epidermal contraction originating in pinacocytes. No direct support exists for either hypothesis. The question of agonist–antagonist interaction in sponge contraction seems to have been completely neglected so far. In the present study we addressed this by studying sponge contraction kinetics. We also tested both hypotheses by carrying out volumetric studies of 3D synchrotron radiation-based x-ray microtomography data obtained from contracted and expanded specimens of Tethya wilhelma. Our results support the pinacoderm contraction hypothesis. Should mesohyl contraction be present, it is likely to be part of the antagonist system. We conclude that epithelial contraction plays a major role in sponges. Contractile epithelia sensu lato may be regarded as part of the ground pattern of the Metazoa.
How muscles define maximum running performance in lizards: an analysis using swing- and stance-phase muscles
Authors: Higham Timothy E. , Korchari Paul G. , McBrayer Lance D.
Published: April 2011

Maximum locomotor performance is crucial for capturing prey, escaping predators and many other behaviors. However, we know little about what defines maximum performance in vertebrates. Muscles drive the movement of the limbs during locomotion, and thus likely play a major role in defining locomotor capacity. For lizards, the iliofibularis, a swing-phase muscle, is often linked to ecology and/or performance. However, stance-phase muscles likely limit performance given that they propel the animal. Using a small semi-arboreal lizard (Sceloporus woodi), we compared how swing- and stance-phase muscles relate to maximum running speed and acceleration. We employed both a level and vertical trackway to elicit ecologically relevant locomotor performance. Six individuals were filmed at 250 frames s–1 in lateral view. Following performance trials, upper and lower hindlimbs were sectioned and assessed using histochemistry. Fast glycolytic, fast oxidative and slow oxidative fibers were detected and counted in the gastrocnemius (GA; stance phase) and iliofibularis (IF; swing phase) muscles. In addition, the mean fiber diameter for each fiber type in each muscle was determined, as was the fiber cross-sectional area. We found that properties of the GA, but not the IF, were positively correlated with performance. Interestingly, certain attributes of the GA were correlated with maximum vertical locomotion whereas others were correlated with maximum level locomotion. We conclude that stance phase, not swing phase, limits maximum performance in this species of lizard. In addition, we highlight the need to include properties of stance-phase muscles and a spectrum of ecologically relevant behaviors when attempting to correlate locomotor physiology with ecology and/or performance.
Social interactions influence dopamine and octopamine homeostasis in the brain of the ant Formica japonica
Authors: Wada-Katsumata Ayako , Yamaoka Ryohei , Aonuma Hitoshi
Published: April 2011

In ants, including Formica japonica, trophallaxis and grooming are typical social behaviors shared among nestmates. After depriving ants of either food or nestmates and then providing them with either food or nestmates, a behavioral change in type and frequency of social interactions was observed. We hypothesized that starvation and isolation affected levels of brain biogenic amines including dopamine (DA) and octopamine (OA) – neuromediators modifying various insect behaviors – and tested the relationship between brain biogenic amines and social behaviors of stressed ants. Ants starved for 7 days contained lower brain DA levels and they did not perform trophallaxis toward nestmates. Feeding starved ants sucrose solution re-established trophallaxis but not brain DA levels. The performance of trophallaxis induced recovery of brain DA content to the level of untreated ants. Ants that were isolated for 2 days displayed markedly increased OA levels, which following nestmate interactions, returned to levels similar to those of control (non-isolated) ants and ants isolated for 1 h. We conclude that: (1) starvation reduced brain DA level but had no significant effect on brain OA (trophallaxis recovered the brain DA levels), and (2) isolation increased brain OA level but had no effect on brain DA (trophallaxis and grooming events recovered the brain OA levels). We suggest that social interactions with nestmates influenced brain biogenic amine homeostasis in stressed F. japonica.
Activity of the claw retractor muscle in stick insects in wall and ceiling situations
Authors: Bußhardt Philipp , Gorb Stanislav N. , Wolf Harald
Published: April 2011

The activity of the middle part of the claw retractor muscle was examined in two species of stick insects (Carausius morosus and Cuniculina impigra). We performed electromyographic recordings while the animals were standing on a smooth or a rough surface of a platform in horizontal, vertical or inverted positions, as well as during rotations of the platform. We recorded tonic and phasic motor units. The tonic units were active all the time without significant differences in spike frequency, regardless of the position of the animals (although there was a tendency for higher discharge frequencies to occur during platform rotations). The phasic units were active almost exclusively during platform movement. In contrast to the tonic units, we detected significant differences in the activities of the phasic units; namely, higher spike frequencies during rotations compared with the stationary phases, especially for rotations into ‘more awkward’ positions. A comparison of the two species revealed no difference in muscle activity, despite differences in the animals' tarsal attachment structures. The same was true when comparing the muscle activity of the two species on both the smooth and the rough surfaces.
High background noise shapes selective auditory filters in a tropical cricket
Authors: Schmidt Arne K. D. , Riede Klaus , Römer Heiner
Published: April 2011

Because of call frequency overlap and masking interference, the airborne sound channel represents a limited resource for communication in a species-rich cricket community like the tropical rainforest. Here we studied the frequency tuning of an auditory neuron mediating phonotaxis in the rainforest cricket Paroecanthus podagrosus, suffering from strong competition, in comparison with the same homologous neuron in two species of European field crickets, where such competition does not exist. As predicted, the rainforest species exhibited a more selective tuning compared with the European counterparts. The filter reduced background nocturnal noise levels by 26 dB, compared with only 16 and 10 dB in the two European species. We also quantified the performance of the sensory filter under the different filter regimes by examining the representation of the species-specific amplitude modulation of the male calling song, when embedded in background noise. Again, the filter of the rainforest cricket performed significantly better in terms of representing this important signal parameter. The neuronal representation of the calling song pattern within receivers was maintained for a wide range of signal-to-noise ratios because of the more sharply tuned sensory system and selective attention mechanisms. Finally, the rainforest cricket also showed an almost perfect match between the filter for sensitivity and the peripheral filter for directional hearing, in contrast to its European counterparts. We discuss the consequences of these adaptations for intraspecific acoustic communication and reproductive isolation between species.
Repeatability of standard metabolic rate, active metabolic rate and aerobic scope in young brown trout during a period of moderate food availability
Authors: Norin Tommy , Malte Hans
Published: April 2011

Standard metabolic rate (SMR) and active metabolic rate (AMR) are two fundamental physiological parameters providing the floor and ceiling in aerobic energy metabolism. The total amount of energy available within these two parameters confines constitutes the absolute aerobic scope (AAS). Previous studies on fish have found SMR to closely correlate with dominance and position in the social hierarchy, and to be highly repeatable over time when fish were provided an ad libitum diet. In this study we tested the temporal repeatability of individual SMR, AMR and AAS, as well as repeatability of body mass, in young brown trout (Salmo trutta L.) fed a moderately restricted diet (0.5–0.7% fish mass day–1). Metabolism was estimated from measurements of oxygen consumption rate () and repeatability was evaluated four times across a 15-week period. Individual body mass was highly repeatable across the entire 15 week experimental period whereas residual body-mass-corrected SMR, AMR and AAS showed a gradual loss of repeatability over time. Individual residual SMR, AMR and AAS were significantly repeatable in the short term (5 weeks), gradually declined across the medium term (10 weeks) and completely disappeared in the long term (15 weeks). We suggest that this gradual decline in repeatability was due to the slightly restricted feeding regime. This is discussed in the context of phenotypic plasticity, natural selection and ecology.
Effects of fore–aft body mass distribution on acceleration in dogs
Authors: Walter Rebecca M. , Carrier David R.
Published: April 2011

The ability of a quadruped to apply propulsive ground reaction forces (GRF) during rapid acceleration may be limited by muscle power, foot traction or the ability to counteract the nose-up pitching moment due to acceleration. Because the biomechanics of acceleration change, both throughout the stride cycle and over subsequent strides as velocity increases, the factors limiting propulsive force production may also change. Depending on which factors are limiting during each step, alterations in fore–aft body mass distribution may either increase or decrease the maximum propulsive GRF produced. We analyzed the effects of experimental alterations in the fore–aft body mass distribution of dogs as they performed rapid accelerations. We measured the changes in trunk kinematics and GRF as dogs accelerated while carrying 10% body mass in saddlebags positioned just in front of the shoulder girdle or directly over the pelvic girdle. We found that dogs applied greater propulsive forces in the initial hindlimb push-off and first step by the lead forelimb in both weighted conditions. During these steps dogs appear to have been limited by foot traction. For the trailing forelimb, propulsive forces and impulses were reduced when dogs wore caudally placed weights and increased when dogs wore cranially placed weights. This is consistent with nose-up pitching or avoidance thereof having limited propulsive force production by the trailing forelimb. By the second stride, the hindlimbs appear to have been limited by muscle power in their ability to apply propulsive force. Adding weights decreased the propulsive force they applied most in the beginning of stance, when limb retractor muscles were active in supporting body weight. These results suggest that all three factors: foot traction, pitching of the body, and muscle power play roles in limiting quadrupedal acceleration. Digging in to the substrate with claws or hooves appears to be necessary for maximizing propulsion in the initial hindlimb push-off and first forelimb step. Shifting the center of mass forward, as occurred with the loss of the large and heavy tail in the evolution of mammals, is likely to increase the contribution of the forelimbs to acceleration. Hindlimb muscle power appears to play a greater role in limiting acceleration than does forelimb muscle power. As such, we might expect animals built for rapid acceleration to have an increased ratio of hindlimb to forelimb muscle mass.
Chronic social stress impairs thermal tolerance in the rainbow trout (Oncorhynchus mykiss)
Authors: LeBlanc Sacha , Middleton Stephen , Gilmour Kathleen M. , Currie Suzanne
Published: April 2011

When faced with limited resources, juvenile salmonid fish form dominance hierarchies that result in social stress for socially subordinate individuals. Social stress, in turn, can have consequences for the ability of the fish to respond to additional stressors such as pathogens or exposure to pollutants. In the present study, the possibility that social stress affects the ability of rainbow trout (Oncorhynchus mykiss) to tolerate acute increases in water temperature was investigated. To this end, we first evaluated physiological and cellular stress responses following a 1 h heat shock in juvenile fish in dominance hierarchies. We measured stress hormone (cortisol and catecholamines) concentrations and blood, brain and liver tissue levels of three heat shock proteins (HSPs), the stress inducible HSP70, the constitutive HSC70 and HSP90, in dominant and subordinate trout. No effects of social status on the hormonal response to the heat stress were detected, but the cellular heat shock response in the brain and liver of dominant and subordinate individuals was inhibited. We then assessed thermal tolerance in dominant and subordinate fish through critical thermal maximum temperature (CTmax) trials and measured HSPs following the heat shock. Subordinate fish were less thermally tolerant than their dominant counterparts. We conclude that social stress impacts the ability of fish to respond, on a cellular scale and in a tissue-specific manner, to increases in water temperature, with likely consequences for overall fitness.
Gender-Based Taxation and the Division of Family Chores
Authors: Alesina Alberto , Ichino Andrea , Karabarbounis Loukas
Published: April 2011

Gender-based taxation (GBT) satisfies Ramsey's rule because it taxes at a lower rate the more elastic labor supply of women. We study GBT in a model in which labor elasticities emerge endogenously from intrahousehold bargaining. We explore the cases of superior bargaining power for men, higher male wages, and higher female home productivity. In all cases, men commit to a career in the market, take less home duties than women, and have lower labor supply elasticity. When society resolves its distributional concerns efficiently with gender-specific lump sum transfers, GBT with higher marginal tax rates on (single and married) men is optimal. (JEL D13, H21, H24, J16, J22)
The End of Court-Ordered Desegregation
Authors: Lutz Byron
Published: April 2011

In response to three Supreme Court rulings in the early 1990s, numerous court-ordered desegregation plans have been terminated. Using a unique dataset and an event study research design, this paper explores the impact of these terminations. The results suggest that termination produces a moderate increase in racial segregation. Outside of the south, dismissal also increases the rate at which black students drop out of school and attend private school. In the south, in contrast, there is no change in the school attendance patterns of blacks. Finally, evidence is presented that whites re-enter dismissed districts in large numbers in the south. (JEL H75, I21, I28, J15, K10)
The Surprising Incidence of Tax Credits for the Toyota Prius
Authors: Sallee James M
Published: April 2011

This paper estimates the incidence of tax incentives for the Toyota Prius. Transaction microdata indicate that both federal and state incentives were fully captured by consumers. This is surprising because Toyota faced a binding production constraint, which suggests that they could have appropriated the gains. The paper proffers an explanation based on an intertemporal link in pricing that stems from search frictions, which has the unconventional implication that statutory burden influenced economic burden. The paper develops a bounding estimator to account for endogenous selection into preferential tax regimes that may be useful in other contexts. (JEL H22, H24, L11, L62)
Manipulation of Social Program Eligibility
Authors: Camacho Adriana , Conover Emily
Published: April 2011

We document how manipulation of a targeting system for social welfare programs evolves over time. First, there was strategic behavior of some local politicians in the timing of the household interviews around local elections. Then, there was corrupt behavior with the sudden emergence of a sharp discontinuity in the score density, exactly at the eligibility threshold, which coincided with the release of the score algorithm to local officials. The discontinuity at the threshold is larger where mayoral elections are more competitive. While cultural forces are surely relevant for corruption, our results also highlight the importance of information and incentives. (JEL D72, I32, I38, O15, O17).
Identifying the Aggregate Productivity Effects of Entry and Size Restrictions: An Empirical Analysis of License Reform in India
Authors: Chari A. V
Published: April 2011

Distortions in the allocation of resources between heterogeneous producers have the potential to generate large reductions in aggregate productivity, a point that has been stressed by recent studies. There is, however, little direct empirical evidence from actual policy experiments on the magnitude of these effects. This paper proposes a simple methodology that empirically identifies the separate effects of entry and size restrictions on aggregate productivity, and uses it to analyse the impact of a policy reform in India. (JEL L11, L24, O14, O47)
No Child Left Behind: Subsidized Child Care and Children's Long-Run Outcomes
Authors: Havnes Tarjei , Mogstad Magne
Published: April 2011

Many developed countries are currently considering a move toward subsidized, widely accessible child care or preschool. However, studies on how large-scale provision of child care affects child development are scarce, and focused on short-run outcomes. We analyze a large-scale expansion of subsidized child care in Norway, addressing the impact on children's long-run outcomes. Our precise and robust difference-in-differences estimates show that subsidized child care had strong positive effects on children's educational attainment and labor market participation, and also reduced welfare dependency. Subsample analyses indicate that girls and children with low-educated mothers benefit the most from child care. (JEL J13, J16)
Penetration of a fractured Bird's Nest filter strut into the liver parenchyma: report of two cases
Authors: Maleux Geert , Heye S , Verhamme P , Vaninbroukx J , Delcroix M
Published: April 2011

This report deals with two rare but similar cases of asymptomatic fracture of a Bird's Nest inferior vena cava (IVC) filter strut, penetrated into the liver parenchyma. Follow-up over 4 and 6 years, respectively, could not reveal any changes in the position of the fragmented strut in the liver parenchyma or any evidence of clinical symptoms owing to the migrated strut fragment.
Fully differentiable coarse-grained and all-atom knowledge-based potentials for RNA structure evaluation
Authors: Bernauer Julie , Huang Xuhui , Sim Adelene Y.L. , Levitt Michael
Published: April 2011

RNA molecules play integral roles in gene regulation, and understanding their structures gives us important insights into their biological functions. Despite recent developments in template-based and parameterized energy functions, the structure of RNA—in particular the nonhelical regions—is still difficult to predict. Knowledge-based potentials have proven efficient in protein structure prediction. In this work, we describe two differentiable knowledge-based potentials derived from a curated data set of RNA structures, with all-atom or coarse-grained representation, respectively. We focus on one aspect of the prediction problem: the identification of native-like RNA conformations from a set of near-native models. Using a variety of near-native RNA models generated from three independent methods, we show that our potential is able to distinguish the native structure and identify native-like conformations, even at the coarse-grained level. The all-atom version of our knowledge-based potential performs better and appears to be more effective at discriminating near-native RNA conformations than one of the most highly regarded parameterized potential. The fully differentiable form of our potentials will additionally likely be useful for structure refinement and/or molecular dynamics simulations.
Treatment of Alternaria Keratitis with Intrastromal and Topical Caspofungin in Combination with Intrastromal, Topical, and Oral Voriconazole
Authors: Neoh Chin Fen , Leung Lok , Vajpayee Rasik B , Stewart Kay , Kong David CM
Published: April 2011

Objective:

To report a case of refractory atypical Alternaria keratitis that was treated with intrastromal and topical caspofungin 0.5% in combination with topical, oral, and intrastromal voriconazole.

Case Summary:

A 67-year-old female with a history of bilateral intraocular lens exchange and left pseudophakic bullous keratopathy was referred to the emergency department of the Royal Victorian Eye and Ear Hospital, Melbourne, Australia. Visual acuity of her left eye was limited to counting fingers. A fine branching pattern was noted throughout the anterior stroma of her left corneal graft. The anterior chamber was deep and quiet. Hourly topical voriconazole 1% was initiated, with limited response. One week later, Alternaria spp. was cultured from the corneal scraping. Subsequently, topical caspofungin 0.5% was added, with concomitant use of topical, oral, and intrastromal voriconazole. Despite gradual symptomatic improvement, topical voriconazole was increased to 2% and intrastromal caspofungin was added. The patient was discharged after almost 5 weeks of treatment. Topical voriconazole 2% and topical caspofungin 0.5% were continued for an additional 3 weeks and 1 week, respectively, in the outpatient setting. The patient underwent left penetrating keratoplasty 3 weeks postdischarge. Visual acuity was stable at 20/150, with no reported adverse event 15 months postoperative.

Discussion:

Treatment for Alternaria keratitis remains challenging, as it is refractory to existing antifungal agents. To our knowledge, this is the first reported instance of the use of intrastromal caspofungin to treat Alternaria keratitis in a case in which clinical resolution was not fully achieved despite the use of topical caspofungin in addition to extensive use of topical, intrastromal, and oral voriconazole. This case highlights the importance of intensive pharmacologic management and therapeutic penetrating keratoplasty in preventing evisceration of the patient's eye, especially when Alternaria keratitis is involved.

Conclusions:

Intrastromal and topical caspofungin were employed in combination with voriconazole for the management of refractory Alternaria keratitis, with no observed adverse effects.
Generic Substitution of Levetiracetam Resulting in Increased Incidence of Breakthrough Seizures
Authors: Fitzgerald Christine L , Jacobson Mercedes P
Published: April 2011

Objective:

We report on 4 patients having an increased incidence of seizures when treatment was switched from brand name levetiracetam (Keppra) to generic levetiracetam formulations.

Case Summary:

Patients reported an increase in seizure activity to their neurologists after treatment was switched from Keppra to generic levetiracetam formulations. To confirm the timeline of increased seizure activity with use of the generic drug and report these adverse events to MedWatch, we made a telephone call to each patient's pharmacy to collect information on dispensing dates and the generic formulations' manufacturers. Subsequent to the increase in seizure frequency with generic levetiracetam, treatment in all 4 patients was switched back to Keppra. Seizure frequency in all patients returned to baseline when Keppra was reinstituted.

Discussion:

The Food and Drug Administration (FDA) considers generic medications to be therapeutically equivalent to their corresponding brand name formulation when the generic meets bioequivalence criteria. Considering the linear pharmacokinetic profile of levetiracetam, loss of seizure control or fluctuations of serum concentrations are unexpected if the patient remains on a consistent dose. However, there is growing evidence to support the concept that brand name antiepileptic drugs (AEDs) are not clinically equivalent to their generic counterparts. Because the FDA relies on voluntary reporting of adverse events from health-care professionals and consumers to their MedWatch program, underreporting makes it difficult to quantify the significance of brand to generic switches, and, equally important, generic to generic switches.

Conclusions:

Until the use of generic AEDs can be evaluated in a large randomized blinded controlled study, clinicians must be vigilant in their efforts to report to MedWatch adverse events resulting from the switch from an AED brand to generic formulation of an AED.
Caudal Granular Insular Cortex Is Sufficient and Necessary for the Long-Term Maintenance of Allodynic Behavior in the Rat Attributable to Mononeuropathy
Authors: Benison Alexander M. , Chumachenko Serhiy , Harrison Jacqueline A. , Maier Steven F. , Falci Scott P. , Watkins Linda R. , Barth Daniel S.
Published: April 2011

Mechanical allodynia, the perception of innocuous tactile stimulation as painful, is a severe symptom of chronic pain often produced by damage to peripheral nerves. Allodynia affects millions of people and remains highly resistant to classic analgesics and therapies. Neural mechanisms for the development and maintenance of allodynia have been investigated in the spinal cord, brainstem, thalamus, and forebrain, but manipulations of these regions rarely produce lasting effects. We found that long-term alleviation of allodynic manifestations is produced by discreetly lesioning a newly discovered somatosensory representation in caudal granular insular cortex (CGIC) in the rat, either before or after a chronic constriction injury of the sciatic nerve. However, CGIC lesions alone have no effect on normal mechanical stimulus thresholds. In addition, using electrophysiological techniques, we reveal a corticospinal loop that could be the anatomical source of the influence of CGIC on allodynia.
Peripheral Nervous System Progenitors Can Be Reprogrammed to Produce Myelinating Oligodendrocytes and Repair Brain Lesions
Authors: Binder Ellen , Rukavina Marion , Hassani Hessameh , Weber Marlen , Nakatani Hiroko , Reiff Tobias , Parras Carlos , Taylor Verdon , Rohrer Hermann
Published: April 2011

Neural crest stem cells (NCSCs) give rise to the neurons and glia of the peripheral nervous system (PNS). NCSC-like cells can be isolated from multiple peripheral organs and maintained in neurosphere culture. Combiningin vitroculture and transplantation, we show that expanded embryonic NCSC-like cells lose PNS traits and are reprogrammed to generate CNS cell types. When transplanted into the embryonic or adult mouse CNS, they differentiate predominantly into cells of the oligodendrocyte lineage without any signs of tumor formation. NCSC-derived oligodendrocytes generate CNS myelin and contribute to the repair of the myelin deficiency inshiverermice. These results demonstrate a reprogramming of PNS progenitors to CNS fates without genetic modification and imply that PNS cells could be a potential source for cell-based CNS therapy.
β3GnT2 Maintains Adenylyl Cyclase-3 Signaling and Axon Guidance Molecule Expression in the Olfactory Epithelium
Authors: Henion Timothy R. , Faden Ashley A. , Knott Thomas K. , Schwarting Gerald A.
Published: April 2011

In the olfactory epithelium (OE), odorant receptor stimulation generates cAMP signals that function in both odor detection and the regulation of axon guidance molecule expression. The enzyme that synthesizes cAMP, adenylyl cyclase 3 (AC3), is coexpressed in olfactory sensory neurons (OSNs) with poly-N-acetyllactosamine (PLN) oligosaccharides determined by the glycosyltransferase β3GnT2. The loss of either enzyme results in similar defects in olfactory bulb (OB) innervation and OSN survival, suggesting that glycosylation may be important for AC3 function. We show here that AC3 is extensively modified withN-linked PLN, which is essential for AC3 activity and localization. On Western blots, AC3 from the wild-type OE migrates diffusely as a heavily glycosylated 200 kDa band that interacts with the PLN-binding lectin LEA. AC3 from the β3GnT2−/−OE loses these PLN modifications, migrating instead as a 140 kDa glycoprotein. Furthermore, basal and forskolin-stimulated cAMP production is reduced 80–90% in the β3GnT2−/−OE. Although AC3 traffics normally to null OSN cilia, it is absent from axon projections that aberrantly target the OB. The cAMP-dependent guidance receptor neuropilin-1 is also lost from β3GnT2−/−OSNs and axons, while semaphorin-3A ligand expression is upregulated. In addition, kirrel2, a mosaically expressed adhesion molecule that functions in axon sorting, is absent from β3GnT2−/−OB projections. These results demonstrate that PLN glycans are essential in OSNs for proper AC3 localization and function. We propose that the loss of cAMP-dependent guidance cues is also a critical factor in the severe axon guidance defects observed in β3GnT2−/−mice.
β-Adrenergic Receptor Antagonism Prevents Anxiety-Like Behavior and Microglial Reactivity Induced by Repeated Social Defeat
Authors: Wohleb Eric S. , Hanke Mark L. , Corona Angela W. , Powell Nicole D. , Stiner La'Tonia M. , Bailey Michael T. , Nelson Randy J. , Godbout Jonathan P. , Sheridan John F.
Published: April 2011

Psychosocial stress is associated with altered immune function and development of psychological disorders including anxiety and depression. Here we show that repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior in a β-adrenergic receptor-dependent manner. Repeated social defeat also significantly increased the number of CD11b+/CD45high/Ly6Chighmacrophages that trafficked to the brain. In addition, several inflammatory markers were increased on the surface of microglia (CD14, CD86, and TLR4) and macrophages (CD14 and CD86) after social defeat. Repeated social defeat also increased the presence of deramified microglia in the medial amygdala, prefrontal cortex, and hippocampus. Moreover, mRNA analysis of microglia indicated that repeated social defeat increased levels of interleukin (IL)-1β and reduced levels of glucocorticoid responsive genes [glucocorticoid-induced leucine zipper (GILZ) and FK506 binding protein-51 (FKBP51)]. The stress-dependent changes in microglia and macrophages were prevented by propranolol, a β-adrenergic receptor antagonist. Microglia isolated from socially defeated mice and culturedex vivoproduced markedly higher levels of IL-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 after stimulation with lipopolysaccharide compared with microglia from control mice. Last, repeated social defeat increased c-Fos activation in IL-1 receptor type-1-deficient mice, but did not promote anxiety-like behavior or microglia activation in the absence of functional IL-1 receptor type-1. These findings indicate that repeated social defeat-induced anxiety-like behavior and enhanced reactivity of microglia was dependent on activation of β-adrenergic and IL-1 receptors.
The Diabetes Drug Liraglutide Prevents Degenerative Processes in a Mouse Model of Alzheimer's Disease
Authors: McClean Paula L. , Parthsarathy Vadivel , Faivre Emilie , Hölscher Christian
Published: April 2011

Type 2 diabetes is a risk factor for Alzheimer's disease, most likely linked to an impairment of insulin signaling in the brain. The incretin hormone glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting GLP-1 analogs, such as liraglutide, are on the market as diabetes therapeutics. GLP-1 has been shown to have neuroprotective propertiesin vitroandin vivo. Here we tested the effects of peripherally injected liraglutide in an Alzheimer mouse model, APPswe/PS1ΔE9(APP/PS1). Liraglutide was shown to cross the blood–brain barrier in an acute study. Liraglutide was injected for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old APP/PS1 and wild-type littermate controls. In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model. Overall β-amyloid plaque count in the cortex and dense-core plaque numbers were reduced by 40–50%, while levels of soluble amyloid oligomers were reduced by 25%. The inflammation response as measured by activated microglia numbers was halved in liraglutide-treated APP/PS1 mice. Numbers of young neurons in the dentate gyrus were increased in APP/PS1 mice with treatment. Liraglutide treatment had little effect on littermate control mice, whose behavior was comparable to wild-type saline controls; however, synaptic plasticity was enhanced in the drug group. Our results show that liraglutide prevents key neurodegenerative developments found in Alzheimer's disease, suggesting that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.
Dopamine Transport by the Serotonin Transporter: A Mechanistically Distinct Mode of Substrate Translocation
Authors: Larsen Mads Breum , Sonders Mark S. , Mortensen Ole Valente , Larson Gaynor A. , Zahniser Nancy R. , Amara Susan G.
Published: April 2011

The serotonin transporter (SERT) is the principal mechanism for terminating serotonin (5-HT) signals in the nervous system and is a site of action for a variety of psychoactive drugs including antidepressants, amphetamines, and cocaine. Here we show that human SERTs (hSERTs) and rat SERTs are capable of robust dopamine (DA) uptake through a process that differs mechanistically from 5-HT transport in several unanticipated ways. DA transport by hSERT has a higher maximum velocity than 5-HT transport, requires significantly higher Na+and Cl−concentrations to sustain transport, is inhibited noncompetitively by 5-HT, and is more sensitive to SERT inhibitors, including selective serotonin reuptake inhibitors. We use a thiol-reactive methane thiosulfonate (MTS) reagent to modify a conformationally sensitive cysteine residue to demonstrate that hSERT spends more time in an outward facing conformation when transporting DA than when transporting 5-HT. Cotransfection of an inactive or an MTS-sensitive SERT with wild-type SERT subunits reveals an absence of cooperative interactions between subunits during DA but not 5-HT transport. To establish the physiological relevance of this mechanism for DA clearance, we show usingin vivohigh-speed chronoamperometry that SERT has the capacity to clear extracellularly applied DA in the hippocampal CA3 region of anesthetized rats. Together, these observations suggest the possibility that SERT serves as a DA transporterin vivoand highlight the idea that there can be distinct modes of transport of alternative physiological substrates by SERT.
The Lipid Sulfatide Is a Novel Myelin-Associated Inhibitor of CNS Axon Outgrowth
Authors: Winzeler Alissa M. , Mandemakers Wim J. , Sun Matthew Z. , Stafford Melissa , Phillips Carolyn T. , Barres Ben A.
Published: April 2011

CNS myelin is strongly inhibitory to growing axons and is thought to be a major contributor to CNS axon regenerative failure. Although a number of proteins present in myelin, including Nogo, MAG, and oligodendrocyte-myelin glycoprotein (OMgp), have been identified as myelin-associated inhibitors, studies of mice lacking these genes suggest that additional inhibitors present in CNS myelin remain to be identified. Here we have investigated the hypothesis that myelin lipids contribute to CNS regenerative failure. We identified sulfatide, a major constituent of CNS myelin, as a novel myelin-associated inhibitor of neurite outgrowth. Sulfatide, but not galactocerebroside or ceramide, strongly inhibited the neurite outgrowth of retinal ganglion cells (RGCs) when used as a purified lipid substrate. The mechanism involved in sulfatide-mediated inhibition may share features with other known inhibitors, because the Rho inhibitor C3 transferase lessened these effects. Myelin in which sulfatide was lacking or blocked using specific antibodies was significantly less inhibitory to RGC neurite outgrowthin vitrothan was wild-type myelin, indicating that sulfatide is a major component of the inhibitory activity of CNS myelin. Mice unable to make sulfatide did not regenerate RGC axons more robustly after optic nerve crush than wild-type littermates under normal conditions but did exhibit a small but significant enhancement in the extent of zymosan-induced regeneration. These results demonstrate that specific lipids can powerfully inhibit axon growth, identify sulfatide as a novel myelin-associated axon growth inhibitor, and provide evidence that sulfatide inhibition contributes to axon regenerative failurein vivo.
Variability of Brain Signals Processed Locally Transforms into Higher Connectivity with Brain Development
Authors: Vakorin Vasily A. , Lippé Sarah , McIntosh Anthony R.
Published: April 2011

A number of studies have characterized the changes in variability of brain signals with brain maturation from the perspective of considering the human brain as a complex system. Specifically, it has been shown that complexity of brain signals increases in development. On one hand, such an increase in complexity can be attributed to more specialized and differentiated brain regions able to express a higher repertoire of mental microstates. On the other hand, it can be explained by increased integration between widely distributed neuronal populations and establishment of new connections. The goal of this study was to see which of these two mechanisms is dominant, accounting for the previously observed increase in signal complexity. Using information-theoretic tools based on scalp-recorded EEG measurements, we examined the trade-off between local and distributed variability of brain signals in infants and children separated into age groups of 1–2, 2–8, 9–24, and 24–66 months old. We found that developmental changes were characterized by a decrease in the amount of information processed locally, with a peak in alpha frequency range. This effect was accompanied by an increase in the variability of brain signals processed as a distributed network. Complementary analysis of phase locking revealed an age-related pattern of increased synchronization in the lower part of the spectrum, up to the alpha rhythms. At the same time, we observed the desynchronization effects associated with brain development in the higher beta to lower gamma range.