bluuebunny/crossref_metadata_2025 huggingface dataset:
Dabigatran Etexilate: A Novel Oral Thrombin Inhibitor for Thromboembolic Disease
Authors: Bovio Jessica A , Smith Steven M , Gums John G
Published: May 2011

Objective:

To evaluate the efficacy and safety of dabigatran etexilate, approved by the Food and Drug Administration (FDA) in October 2010 for the prevention of cardioembolic stroke in patients with atrial fibrillation; potential off-label use is treatment and prevention of venous thromboembolic disorders.

Data Sources:

Literature was accessed through MEDLINE (1977-April 2011) and International Pharmaceutical Abstracts (1977-April 2011) using the terms dabigatran, dabigatran etexilate, BIBR 1048, direct thrombin inhibitor, anticoagulant, and thromboembolism. In addition, US government Web sites, including clinicaltrials.gov and fda.gov, were reviewed for pertinent information. Lastly, reference citations from publications identified in the initial search were reviewed.

Study Selection and Data Extraction:

All English-language articles identified from the data sources were evaluated. For the evaluation of clinical efficacy and safety, only Phase 2 and 3 studies are included in this review.

Data Synthesis:

In 6 published Phase 3 trials to date, dabigatran has exhibited a similar efficacy and safety profile to that of comparator drugs, including dose-adjusted warfarin and enoxaparin, at various dosages. In the largest of these trials, RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), dabigatran was at least as effective as dose-adjusted warfarin in reducing stroke or systemic embolism. Overall bleeding risks were similar; however, dabigatran may be associated with a lower incidence of intracranial bleeding and hemorrhagic stroke but a higher incidence of gastrointestinal bleeding. Although dabigatran is not approved for venous thromboembolism (VTE) prevention or treatment, results of the RE-MODEL and RENOVATE trials suggest similar efficacy to once-daily dosing of enoxaparin 40 mg but inferior efficacy to the FDA-approved twice-daily dosing of enoxaparin 30 mg in the RE-MOBILIZE trial.

Conclusions:

Dabigatran is an effective and safe alternative to oral vitamin K antagonists for stroke prevention in patients with nonvalvular atrial fibrillation, with fewer drug interactions and monitoring requirements. Additionally, dabigatran may be a viable alternative to enoxaparin in VTE prevention and warfarin in VTE treatment, although current trial data are limited.
Extended-Infusion Eptifibatide to Prevent Stent Thrombosis in a Patient Undergoing Orthopedic Surgery
Authors: Lizza Bryan D , Kauflin Matthew J
Published: May 2011

Objective:

To report the use of extended-infusion eptifibatide in a patient who had undergone placement of a drug-eluting stent and required repeat intervention of a hip fracture following mechanical failure.

Case Summary:

An 82-year-old female with an extensive history of coronary disease who had undergone placement of a drug-eluting stent was admitted following continued problems with her surgically repaired right hip. Radiographic imaging of the area revealed mechanical failure of the surgically repaired hip, requiring intervention. Clopidogrel and aspirin therapy was discontinued and intravenous eptifibatide 1 μg/kg/min was initiated prior to surgery; the drugs were then discontinued 4 hours before the procedure. During this admission, the patient received a total of 155 hours of eptifibatide to prevent acute coronary stent thrombosis white awaiting surgical intervention. Postoperatively, the patient experienced anemia and severe thrombocytopenia and required 11 units of packed red blood cells, but displayed no signs of stent thrombosis.

Discussion:

Use of eptifibatide in this patient minimized the potential risk for stent thrombosis by reducing the interruption in antiplatelet therapy from 5 days, as is recommended for use with clopidogrel, to 4 hours. While this patient required several transfusions and experienced severe thrombocytopenia postoperatively, she recovered and had no cardiac-related problems. It is unclear whether the use of eptifibatide contributed to these complications, given the chronology of events.

Conclusions:

Extended-infusion eptifibatide appears to be an option for prevention of stent thrombosis in patients who require an interruption in antiplatelet therapy and are scheduled to undergo major orthopedic procedures. Careful consideration should be given regarding the risks and benefits of extended infusions of eptifibatide, as the potential for significant hemorrhage is a concern. Further research is warranted in this area.
Current Treatment Strategies for Clozapine-Induced Sialorrhea
Authors: Bird Angela M , Smith Tawny L , Walton Amy E
Published: May 2011

Objective:

To provide an understanding of the underlying pathophysiology and current treatment options for clozapine-induced sialorrhea.

Data Sources:

Literature was retrieved through MEDLINE (1977-February 2011) using the key search terms clozapine, sialorrhea, hypersalivation, drooling, and treatment. In addition, reference citations from identified publications were reviewed.

Study Selection and Data Extraction:

All articles published in English identified from the data source were evaluated and included in the review.

Data Synthesis:

Sialorrhea is a common and disabling adverse effect of clozapine use. Current treatment options include topical and oral antimuscarinic medications and α-adrenergic agents. New areas of investigation include glycopyrrolate, botulinum toxin, and substitute benzamide derivatives. Thirteen clinical trials (2 retrospective, 5 open-label, 6 double-blind) and 13 case reports were reviewed. Overall, there are weak data on use of antimuscarinic agents, consisting mostly of small open-label or retrospective studies. Glycopyrrolate, however, demonstrated significant reduction of hypersalivation in a randomized controlled trial. Medications with activity at α-adrenergic receptors have shown positive results in case reports, retrospective evaluations, and an open-label trial, but have not been investigated in a double-blind, controlled fashion. Botulinum toxin also significantly improved sialorrhea in both a case report and double-blind study, although the trial included hypersalivation from other etiologies in addition to clozapine. Substitute benzamide derivatives have demonstrated significant improvements in randomized controlled trials; however, they are not available in the US. Overall, few treatment strategies have been evaluated in controlled settings, warranting further randomized controlled trials to identify more effective treatment options.

Conclusions:

Current pharmacologic treatment options for clozapine-induced sialorrhea are limited in number and efficacy. Although few randomized controlled trials have been conducted, this review identifies potential treatment alternatives for this common and sometimes severe adverse effect.
Pancreatic Enzyme Products: Digesting the Changes
Authors: Giuliano Christopher A , Dehoorne-Smith Michelle L , Kale-Pradhan Pramodini B
Published: May 2011

Objective:

To review the pharmacology, dosage regimens, efficacy, and safety of currently marketed pancreatic enzyme products (PEPs).

Data Sources:

Studies were identified by PubMed (1966-January 2011), clintcaltrials.gov, fda.gov, and International Pharmaceutical Abstracts. Search terms included pancreatic enzyme, lipase, Creon, Zenpep, Pancreaze, and exocrine pancreatic insufficiency (EPI).

Study Selection and Data Extraction:

All human studies evaluating the efficacy of currently approved or potential PEPs were reviewed.

Data Synthesis:

PEPs are composed of porcine lipase, amylase, and protease and are used in patients with EPI secondary to cystic fibrosis, chronic pancreatitis, and pancreatectomy. In 1938, PEPs were exempted from the Food, Drug, and Cosmetic Act of 1938 and never underwent a formal Food and Drug Administration (FDA) review process. In response to reports of treatment failures during product interchange, the FDA conducted a review of available PEP products. This review found a large variability of response between the unapproved PEP products, which resulted in the FDA requiring approval of all PEP products by April 2010. The 3 delayed-release, enteric-coated PEPs currently approved by the FDA (Creon, Zenpep, and Pancreaze) have demonstrated efficacy and safety in EPI secondary to cystic fibrosis. Creon has also demonstrated safety and efficacy in EPI secondary to chronic pancreatitis and pancreatectomy. Cost difference between the 3 products is minimal. Treatment-related adverse events in clinical studies for all PEPs were less than or similar to those with placebo.

Conclusions:

At this time, Creon is an appropriate first-line agent, as it has been approved for chronic pancreatitis, pancreatectomy, and cystic fibrosis.
National Export-Promotion Programs as Drivers of Organizational Resources and Capabilities: Effects on Strategy, Competitive Advantage, and Performance
Authors: Leonidou Leonidas C. , Palihawadana Dayananda , Theodosiou Marios
Published: May 2011

The authors present the results of a study that empirically tests a model connecting national export-promotion programs with export performance through the intervening role of export-related organizational resources and capabilities, export marketing strategy, and export competitive advantage. The study reveals that the adoption of specific national export-promotion programs positively strengthens the firm's export-related resources and capabilities, which in turn are instrumental in developing a sound export marketing strategy. By realizing this strategy, the firm enjoys competitive advantages related to costs, products, or services, which in turn help it achieve superior export performance in both market and financial dimensions. In addition, the firm's export market performance has a positive impact on export financial performance. This study also shows that the effect of national export-promotion programs on export-related resources and capabilities is stronger among smaller firms and, for some programs, among firms with less export experience.
A Cross-Cultural Examination of Corporate Social Responsibility Marketing Communications in Mexico and the United States: Strategies for Global Brands
Authors: Becker-Olsen Karen L. , Taylor Charles R. , Hill Ronald Paul , Yalcinkaya Goksel
Published: May 2011

This study examines the impact of marketing-oriented corporate social responsibility (CSR) communications on perceptions of the firm and its brands among consumers in two diverse cultures, economies, and political landscapes. The authors’ main hypotheses are based on global brand positioning theory, which posits that consumer perceptions are enhanced if the brand is viewed as global. In general, the results support the notion that multinational firms emphasizing global CSR efforts engender more positive perceptions across multiple dimensions. Yet regarding tactical issues, the results also show the importance of some specific needs according to local tastes and experiences. The authors provide implications for marketing theory and practice as well as future research directions.
A Cross-Cultural Perspective of Marketing Departments’ Influence Tactics
Authors: Engelen Andreas , Brettel Malte
Published: May 2011

Recent marketing literature has shown that an influential marketing department is a driver of an organizationwide market orientation and, in some studies, of firm performance. Recognizing the importance of a strong marketing department, this study develops a theoretical model of the levers of marketing departments’ influence and examines the degree to which the effects of the levers are subject to national cultural variations. The authors empirically validate the theoretical model using 740 firms from six Western and Asian countries. The findings reveal both culturally dependent and independent effects. For example, although a great degree of innovativeness in the marketing department has a positive impact on the department's influence across cultures, a high level of accountability and integration with other departments shows cultural dependencies. Global marketing managers learn whether they should advise their local marketing department to use standardized influence tactics or make necessary adaptations to local circumstances.
Gains and Losses from the Misperception of Brand Origin: The Role of Brand Strength and Country-of-Origin Image
Authors: Balabanis George , Diamantopoulos Adamantios
Published: May 2011

Mounting empirical evidence shows that consumers often associate brands with the wrong country of origin (COO) or are unable to classify a brand to any COO. In this study, the authors investigate the consequences of brand origin misclassification and nonclassification on consumers’ brand image evaluations and associated purchase intentions. Drawing from categorization theory, the authors test hypotheses regarding the impact of brand strength and COO image on misclassification gains and losses on a sample of U.K. consumers. The results show that both misclassification and non-classification have mostly adverse consequences on both brand evaluations and purchase intentions. The findings further show that strong brands are not immune to misclassification and stress the importance of ensuring that consumers are aware of a brand's true COO.
Xylan deposition onto eucalypt pulp fibers during oxygen delignification
Authors: dos Santos Muguet Marcelo Coelho , Pedrazzi Cristiane , Colodette Jorge Luiz
Published: May 2011

A novel alternative was investigated for elevating the xylan content of eucalyptus pulp through xylan deposition in the course of the oxygen delignification stage. The pH in the range of 10–13 was the only variable evaluated, while the other variables were kept constant in a range similar to industrial practice. Xylans were obtained from unbleached and bleached eucalyptus pulps by cold caustic extraction (CCE), giving rise to brown xylan liquor (BXL) and white xylan liquor (WXL), respectively. The liquors were added to a commercial brown pulp during oxygen delignification. The xylan-enriched pulps were subsequently bleached to 90% ISO with the D(EP)D sequence, beaten in a PFI mill and evaluated for their physical and mechanical properties. Xylan deposition occurred at variable degrees depending upon the pH. Pulp bleachability was not impaired by WXL xylan deposition but was slightly negatively affected by BXL xylan. Pulp beatability was improved by both WXL and BXL xylan deposition. The deposited xylan was more stable across bleaching and beating with the WXL xylan than the BXL xylan deposits. At low energy consumption, the deposited xylan improved pulp physical and mechanical properties. Xylan extraction by CCE with subsequent deposition in the oxygen delignification is an interesting technique to manufacture eucalypt pulps of high xylan content. The potential for industrial application is high as no significant modification of current pulp mill installations is needed.
Study of Novel Selective mGlu2 Agonist in the Temporo-Ammonic Input to CA1 Neurons Reveals Reduced mGlu2 Receptor Expression in a Wistar Substrain with an Anxiety-Like Phenotype
Authors: Ceolin Laura , Kantamneni Sriharsha , Barker Gareth R. I. , Hanna Lydia , Murray Laura , Warburton E. Clea , Robinson Emma S. J. , Monn James A. , Fitzjohn Stephen M. , Collingridge Graham L. , Bortolotto Zuner A. , Lodge David
Published: May 2011

Group II metabotropic receptors (mGluRs) regulate central synaptic transmission by modulating neurotransmitter release. However, the lack of pharmacological tools differentiating between mGlu2 and mGlu3 receptors has hampered identification of the roles of these two receptor subtypes. We have used LY395756 [(1SR,2SR,4RS,5RS,6SR)-2-amino-4-methylbicyclo[3.1.0]-hexane2,6-dicarboxylic], an agonist at mGlu2 receptors and an antagonist at mGlu3 receptors in cell lines, to investigate the roles of these receptors in the temporo-ammonic path from entorhinal cortex to CA1–stratum lacunosum moleculare in rat hippocampal slices. Surprisingly, the degree of inhibition of the field EPSP induced by LY395756 fell into two distinct groups, with EC50values of <1 μmand >100 μm. In “sensitive” slices, LY395756 had additive actions with a mixed mGlu2/mGlu3 agonist, DCG-IV [(2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine], whereas in “insensitive” slices, LY395756 reduced the effect of DCG-IV, with an IC50of ∼1 μm. This separation into sensitive and insensitive slices could be explained by LY395756 acting as an mGlu2 agonist and mGlu3 antagonist, respectively, a finding supported by data from mice lacking these receptors. The heterogeneity was correlated with differences in expression levels of mGlu2 receptors within our Wistar colony and other Wistar substrains. The initial search for a behavioral correlate indicated that rats lacking mGlu2 receptors showed anxiety-like behavior in open-field and elevated plus maze assays. These findings have implications for rat models of psychiatric disease and are especially pertinent given that mGlu2 receptors are targets for compounds under development for anxiety.
The Schizophrenia Risk Allele C of theTCF4rs9960767 Polymorphism Disrupts Sensorimotor Gating in Schizophrenia Spectrum and Healthy Volunteers
Authors: Quednow Boris B. , Ettinger Ulrich , Mössner Rainald , Rujescu Dan , Giegling Ina , Collier David A. , Schmechtig Anne , Kühn Kai-Uwe , Möller Hans-Jürgen , Maier Wolfgang , Wagner Michael , Kumari Veena
Published: May 2011

In a large-scale meta-analysis, it has been recently shown that the transcription factor 4 (TCF4) gene is among the most prominent susceptibility genes for schizophrenia. Moreover, transgenic mice overexpressingTCF4in the brain display a reduction of sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR). PPI is heritable and has been established as an important translational endophenotype of schizophrenia. We therefore investigated the impact of the schizophrenia susceptibility geneTCF4(rs9960767) on sensorimotor gating of the ASR in healthy humans and in patients with a schizophrenia spectrum disorder. We assessed PPI, startle reactivity, and habituation of the ASR in two independent samples. The first sample consisted of 107 healthy volunteers from London, UK. The second sample was a schizophrenia spectrum group (n= 113) of 73 schizophrenia patients and 40 individuals at high risk for schizophrenia from Bonn, Germany (total samplen= 220). In both samples, PPI was strongly decreased in carriers of the schizophrenia risk allele C of theTCF4gene (meta-analysis across both samples:p= 0.00002), whereas startle reactivity and habituation were unaffected byTCF4genotype. Sensorimotor gating is modulated byTCF4genotype, indicating an influential role ofTCF4gene variations in the development of early information-processing deficits in schizophrenia.
Homeostatic Plasticity in the Visual Thalamus by Monocular Deprivation
Authors: Krahe Thomas E. , Guido William
Published: May 2011

Monocular deprivation (MD) is a classic paradigm for experience-dependent cortical plasticity. One form is known as homeostatic plasticity, in which neurons innervated by the deprived eye show a remarkable capacity to compensate for degraded visual signals in an attempt to stabilize network activity. Although the evidence supporting homeostatic plasticity in visual cortex is extensive, it remains unclear whether neurons in subcortical visual structures respond to MD in a similar manner. Here we examined whether cells in the dorsal lateral geniculate nucleus (dLGN), the thalamic relay between the retina and visual cortex, show similar forms of experience-dependent homeostatic plasticity following MD. Two-week-old mice were monocularly deprived for a period of 5–7 d and miniature EPSCs (mEPSCs) were obtained from cells located in dLGN regions receiving input from the deprived or nondeprived eye. We found that MD promotes increases in the frequency and amplitude of mEPSCs and were restricted to the monocular segment contralateral to the deprived eye. These changes were accompanied by an increase in the probability of glutamate release at corticothalamic terminals that arise from the deprived visual cortex. Our findings indicate that homeostatic synaptic regulation from MD extends beyond cortical circuitry and shed light on how the brain modulates and integrates activity in the face of altered sensory experience.
Heterogeneous Representations in the Superior Parietal Lobule Are Common across Reaches to Visual and Proprioceptive Targets
Authors: McGuire Leah M. M. , Sabes Philip N.
Published: May 2011

The planning and control of sensory-guided movements requires the integration of multiple sensory streams. Although the information conveyed by different sensory modalities is often overlapping, the shared information is represented differently across modalities during the early stages of cortical processing. We ask how these diverse sensory signals are represented in multimodal sensorimotor areas of cortex in macaque monkeys. Although a common modality-independent representation might facilitate downstream readout, previous studies have found that modality-specific representations in multimodal cortex reflect upstream spatial representations. For example, visual signals have a more eye-centered representation. We recorded neural activity from two parietal areas involved in reach planning, area 5 and the medial intraparietal area (MIP), as animals reached to visual, combined visual and proprioceptive, and proprioceptive targets while fixing their gaze on another location. In contrast to other multimodal cortical areas, the same spatial representations are used to represent visual and proprioceptive signals in both area 5 and MIP. However, these representations are heterogeneous. Although we observed a posterior-to-anterior gradient in population responses in parietal cortex, from more eye-centered to more hand- or body-centered representations, we do not observe the simple and discrete reference frame representations suggested by studies that focused on identifying the “best-match” reference frame for a given cortical area. In summary, we find modality-independent representations of spatial information in parietal cortex, although these representations are complex and heterogeneous.
Functional Organization of the Thalamic Input to the Thalamic Reticular Nucleus
Authors: Lam Ying-Wan , Sherman S. Murray
Published: May 2011

Most axons connecting the thalamus and cortex in both directions pass through the thalamic reticular nucleus (TRN), a thin layer of GABAergic cells adjacent to the thalamus, and innervate neurons there. The TRN, therefore, is in a strategic location to regulate thalamocortical communication. We recorded neurons of the somatosensory region of the TRN in a thalamocortical slice preparation and studied the spatial organization of their thalamic input using laser scanning photostimulation. We show that the thalamoreticular pathway is organized topographically for most neurons. The somatosensory region of the TRN can be organized into three tiers. From the inner (thalamoreticular) border to the outer, in a manner roughly reciprocal to the reticulothalamic pathway, each of these tiers receives its input from one of the somatosensory relays of the thalamus—the posterior medial, ventroposterior medial, and ventroposterior lateral nuclei. What is surprising is that approximately a quarter of the recorded neurons received input from multiple thalamic regions usually located in different nuclei. These neurons distribute evenly throughout the thickness of the TRN. Our results, therefore, suggest that there exist a subpopulation of TRN neurons that receive convergent inputs from multiple thalamic sources and engage in more complex patterns of inhibition of relay cells. We propose these neurons enable the TRN to act as an externally driven “searchlight” that integrates cortical and subcortical inputs and then inhibits or disinhibits specific thalamic relay cells, so that appropriate information can get through the thalamus to the cortex.
The Requirement for Enhanced CREB1 Expression in Consolidation of Long-Term Synaptic Facilitation and Long-Term Excitability in Sensory Neurons ofAplysia
Authors: Liu Rong-Yu , Cleary Leonard J. , Byrne John H.
Published: May 2011

Accumulating evidence suggests that the transcriptional activator cAMP response element-binding protein 1 (CREB1) is important for serotonin (5-HT)-induced long-term facilitation (LTF) of the sensorimotor synapse inAplysia. Moreover,creb1is among the genes activated by CREB1, suggesting a role for this protein beyond the induction phase of LTF. The time course of the requirement for CREB1 synthesis in the consolidation of long-term facilitation was examined using RNA interference techniques in sensorimotor cocultures. Injection of CREB1 small-interfering RNA (siRNA) immediately or 10 h after 5-HT treatment blocked LTF when measured at 24 and 48 h after treatment. In contrast, CREB1 siRNA did not block LTF when injected 16 h after 5-HT treatment. These results demonstrate thatcreb1expression must be sustained for a relatively long time to support the consolidation of LTF. In addition, LTF is also accompanied by a long-term increase in the excitability (LTE) of sensory neurons (SNs). Because LTE was observed in the isolated SN after 5-HT treatment, this long-term change was intrinsic to that element of the circuit. LTE was blocked when CREB1 siRNA was injected into isolated SNs immediately after 5-HT treatment. These data suggest that 5-HT-induced CREB1 synthesis is required for consolidation of both LTF and LTE.
Common Alzheimer's Disease Risk Variant Within theCLUGene Affects White Matter Microstructure in Young Adults
Authors: Braskie Meredith N. , Jahanshad Neda , Stein Jason L. , Barysheva Marina , McMahon Katie L. , de Zubicaray Greig I. , Martin Nicholas G. , Wright Margaret J. , Ringman John M. , Toga Arthur W. , Thompson Paul M.
Published: May 2011

There is a strong genetic risk for late-onset Alzheimer's disease (AD), but so far few gene variants have been identified that reliably contribute to that risk. A newly confirmed genetic risk allele C of the clusterin (CLU) gene variant rs11136000 is carried by ∼88% of Caucasians. The C allele confers a 1.16 greater odds of developing late-onset AD than the T allele. AD patients have reductions in regional white matter integrity. We evaluated whether theCLUrisk variant was similarly associated with lower white matter integrity in healthy young humans. Evidence of early brain differences would offer a target for intervention decades before symptom onset. We scanned 398 healthy young adults (mean age, 23.6 ± 2.2 years) with diffusion tensor imaging, a variation of magnetic resonance imaging sensitive to white matter integrity in the living brain. We assessed genetic associations using mixed-model regression at each point in the brain to map the profile of these associations with white matter integrity. Each C allele copy of theCLUvariant was associated with lower fractional anisotropy—a widely accepted measure of white matter integrity—in multiple brain regions, including several known to degenerate in AD. These regions included the splenium of the corpus callosum, the fornix, cingulum, and superior and inferior longitudinal fasciculi in both brain hemispheres. Young healthy carriers of theCLUgene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing AD later in life.
Distractibility in Daily Life Is Reflected in the Structure and Function of Human Parietal Cortex
Authors: Kanai Ryota , Dong Mia Yuan , Bahrami Bahador , Rees Geraint
Published: May 2011

We all appreciate that some of our friends and colleagues are more distractible than others. This variability can be captured by pencil and paper questionnaires in which individuals report such cognitive failures in their everyday life. Surprisingly, these self-report measures have high heritability, leading to the hypothesis that distractibility might have a basis in brain structure. In a large sample of healthy adults, we demonstrated that a simple self-report measure of everyday distractibility accurately predicted gray matter volume in a remarkably focal region of left superior parietal cortex. This region must play a causal role in reducing distractibility, because we found that disrupting its function with transcranial magnetic stimulation increased susceptibility to distraction. Finally, we showed that the self-report measure of distractibility reliably predicted our laboratory-based measure of attentional capture. Our findings distinguish a critical mechanism in the human brain causally involved in avoiding distractibility, which, importantly, bridges self-report judgments of cognitive failures in everyday life and a commonly used laboratory measure of distractibility to the structure of the human brain.
Neuroanatomical Phenotype of Klinefelter Syndrome in Childhood: A Voxel-Based Morphometry Study
Authors: Bryant Daniel M. , Hoeft Fumiko , Lai Song , Lackey John , Roeltgen David , Ross Judith , Reiss Allan L.
Published: May 2011

Klinefelter syndrome (KS) is a genetic disorder characterized by a supernumerary X chromosome. As such, KS offers a naturally occurring human model for the study of both X-chromosome gene expression and androgen on brain development. Previous neuroimaging studies have revealed neuroanatomical variations associated with KS, but have differed widely with respect to subject inclusion criteria, including mosaicism, pubertal status, and history of testosterone replacement therapy (TRT), all factors likely to influence neurodevelopment. We conducted a voxel-based morphometry study of regional gray and white matter (GM and WM, respectively) volumes in 31 KS males (mean age, 9.69 ± 1.70 years) and 36 typically developing (TD) male controls (10.99 ± 1.72 years). None of the participants with KS had received TRT, and all were prepubertal and had nonmosaic 47,XXY karyotypes. After controlling for age, males with KS showed trends (0.05 <p< 0.10) for significantly reduced total gray matter volume (TGMV) and total white matter volume (TWMV), relative to TD males. After controlling for TGMV and age, the KS group had significantly increased sensorimotor and parietal-occipital GM and significantly reduced amygdalar, hippocampal, insular, temporal, and inferior frontal GM relative to TD controls. After controlling for TWMV and age, the KS group had significantly increased left parietal WM as well as significantly reduced frontal and temporal WM. These findings are indicative of a characteristic prepubertal neuroanatomical phenotype that may be associated with cognitive-behavioral features of KS. This work offers new insight into the relationships among X-chromosome gene expression, neuroanatomy, and cognitive-behavioral functions impaired in KS, including language and attention.
Spinal Protein Kinase M ζ Underlies the Maintenance Mechanism of Persistent Nociceptive Sensitization
Authors: Asiedu Marina N. , Tillu Dipti V. , Melemedjian Ohannes K. , Shy Adia , Sanoja Raul , Bodell Bryce , Ghosh Sourav , Porreca Frank , Price Theodore J.
Published: May 2011

Sensitization of the pain pathway is believed to promote clinical pain disorders. We hypothesized that the persistence of a sensitized state in the spinal dorsal horn might depend on the activity of protein kinase M ζ (PKMζ), an essential mechanism of late long-term potentiation (LTP). To test this hypothesis, we used intraplantar injections of interleukin-6 (IL-6) in mice to elicit a transient allodynic state that endured ∼3 d. After the resolution of IL-6-induced allodynia, a subsequent intraplantar injection of prostaglandin E2(PGE2) or intrathecal injection of the metabotropic glutamate receptor 1/5 (mGluR1/5) agonist DHPG (dihydroxyphenylglycol) precipitated allodynia and/or nocifensive responses. Intraplantar injection of IL-6 followed immediately by intrathecal injection of a PKMζ inhibitor prevented the expression of subsequent PGE2-induced allodynia. Inhibitors of protein translation were effective in preventing PGE2-induced allodynia when given immediately after IL-6, but not after the initial allodynia had resolved. In contrast, spinal PKMζ inhibition completely abolished both prolonged allodynia to hindpaw PGE2and enhanced nocifensive behaviors evoked by intrathecal mGluR1/5 agonist injection after the resolution of IL-6-induced allodynia. Moreover, spinal PKMζ inhibition prevented the enhanced response to subsequent stimuli following resolution of hypersensitivity induced by plantar incision. The present findings demonstrate that the spinal cord encodes an engram for persistent nociceptive sensitization that is analogous to molecular mechanisms of late LTP and suggest that spinally directed PKMζ inhibitors may offer therapeutic benefit for injury-induced pain states.
BACE1 Activity Is Modulated by Cell-Associated Sphingosine-1-Phosphate
Authors: Takasugi Nobumasa , Sasaki Tomoki , Suzuki Kunimichi , Osawa Satoko , Isshiki Hayato , Hori Yukiko , Shimada Naoaki , Higo Takuya , Yokoshima Satoshi , Fukuyama Tohru , Lee Virginia M.-Y. , Trojanowski John Q. , Tomita Taisuke , Iwatsubo Takeshi
Published: May 2011

Sphingosine kinase (SphK) 1 and 2 phosphorylate sphingosine to generate sphingosine-1-phosphate (S1P), a pluripotent lipophilic mediator implicated in a variety of cellular events. Here we show that the activity of β-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for amyloid-β peptide (Aβ) production, is modulated by S1P in mouse neurons. Treatment by SphK inhibitor, RNA interference knockdown of SphK, or overexpression of S1P degrading enzymes decreased BACE1 activity, which reduced Aβ production. S1P specifically bound to full-length BACE1 and increased its proteolytic activity, suggesting that cellular S1P directly modulates BACE1 activity. Notably, the relative activity of SphK2 was upregulated in the brains of patients with Alzheimer's disease. The unique modulatory effect of cellular S1P on BACE1 activity is a novel potential therapeutic target for Alzheimer's disease.
Dorsally and Ventrally Derived Oligodendrocytes Have Similar Electrical Properties but Myelinate Preferred Tracts
Authors: Tripathi Richa B. , Clarke Laura E. , Burzomato Valeria , Kessaris Nicoletta , Anderson Patrick N. , Attwell David , Richardson William D.
Published: May 2011

In the developing spinal cord, most oligodendrocyte precursors (OLPs) arise from the ventral ventricular zone (VZ) under the influence of Sonic Hedgehog, but a minority are generated from the dorsal VZ in a Hedgehog-independent manner. In the developing forebrain too, OLPs arise from both the ventral and the dorsal VZ. It is not known whether dorsally and ventrally derived oligodendrocyte (OL) lineage cells have different properties. We generated a dual reporter mouse line to color code ventrally and dorsally derived OLPs (vOLPs and dOLPs) and their differentiated oligodendrocyte progeny (vOLs and dOLs) for functional studies. We found that ∼80% of OL lineage cells in the postnatal spinal cord and ∼20% in the corpus callosum are ventrally derived. In both spinal cord and corpus callosum, vOLPs and dOLPs had indistinguishable electrical properties, as did vOLs and dOLs. However, vOLPs and dOLPs had different migration and settling patterns. In the spinal cord, vOLPs appeared early and spread uniformly throughout the cord, whereas dOLPs arrived later and remained mainly in the dorsal and dorsolateral funiculi. During adulthood, corticospinal and rubrospinal tracts became myelinated mainly by dOLs, even though vOLs dominated these tracts during early postnatal life. Thus, dOLPs are electrically similar to vOLPs but appear to outcompete them for dorsal axons.
Roles of Nucleus Accumbens Core and Shell in Incentive-Cue Responding and Behavioral Inhibition
Authors: Ambroggi Frederic , Ghazizadeh Ali , Nicola Saleem M. , Fields Howard L.
Published: May 2011

The nucleus accumbens (NAc) is involved in many reward-related behaviors. The NAc has two major components, the core and the shell. These two areas have different inputs and outputs, suggesting that they contribute differentially to goal-directed behaviors. Using a discriminative stimulus (DS) task in rats and inactivating the NAc by blocking excitatory inputs with glutamate antagonists, we dissociated core and shell contributions to task performance. NAc core but not shell inactivation decreased responding to a reward-predictive cue. In contrast, inactivation of either subregion induced a general behavioral disinhibition. This reveals that the NAc actively suppresses actions inappropriate to the DS task. Importantly, selective inactivation of the shell but not core significantly increased responding to the nonrewarded cue. To determine whether the different contributions of the NAc core and shell depend on the information encoded in their constituent neurons, we performed electrophysiological recording in rats performing the DS task. Although there was no firing pattern unique to either core or shell, the reward-predictive cue elicited more frequent and larger magnitude responses in the NAc core than in the shell. Conversely, more NAc shell neurons selectively responded to the nonrewarded stimulus. These quantitative differences might account for the different behavioral patterns that require either core or shell. Neurons with similar firing patterns could also have different effects on behavior due to their distinct projection targets.
Hyperactivity in the Ventral Cochlear Nucleus after Cochlear Trauma
Authors: Vogler Darryl P. , Robertson Donald , Mulders Wilhelmina H. A. M.
Published: May 2011

The emergence of hyperactivity in the form of elevated spontaneous firing rates after cochlear trauma has been well documented in a number of central auditory structures, including the auditory cortex, inferior colliculus, and dorsal subdivision of the cochlear nucleus. This hyperactivity is of interest as a possible neural substrate of tinnitus. Whether the ventral subdivision of the cochlear nucleus shows hyperactivity has never been investigated despite the fact that, like the dorsal division, it also receives direct input from the damaged cochlea and supplies major ascending inputs to brainstem and midbrain auditory centers. We investigated spontaneous neuronal firing rates in the ventral cochlear nucleus in a guinea pig model of cochlear trauma in which we have shown that hyperactivity consistently develops in the inferior colliculus (Mulders and Robertson, 2009). The mean spontaneous firing rates of ventral cochlear nucleus neurons was significantly elevated compared to sham controls. This hyperactivity was more evident in primary-like and onset categories of neurons. Hyperactivity in the ventral subdivision of cochlear nucleus therefore needs to be considered in relation to neural models of the genesis of tinnitus.
A Neural Mechanism Mediating the Impact of Episodic Prospection on Farsighted Decisions
Authors: Benoit Roland G. , Gilbert Sam J. , Burgess Paul W.
Published: May 2011

Humans can vividly imagine possible future events. This faculty, episodic prospection, allows the simulation of distant outcomes and desires. Here, we provide evidence for the adaptive function of this capacity and elucidate its neuronal basis. Participants either imagined specific events of spending money (e.g., £35 in 180 days at a pub), or merely estimated what the money could purchase in the scenario. Imagining the future biased subsequent monetary decisions toward choices associated with a higher long-term pay-off. It thus effectively attenuated temporal discounting, i.e., the propensity to devalue rewards with a delay until delivery. Using functional magnetic resonance imaging, we implicate the medial rostral prefrontal cortex (mrPFC) in this effect. Blood oxygen level-dependent signal in this region predicted future-oriented choices on a trial-by-trial basis. Activation reflected the reward magnitude of imagined episodes, and greater reward sensitivity was related to less discounting. This effect was also associated with increased mrPFC–hippocampal coupling. The data suggest that mrPFC uses information conveyed by the hippocampus to represent the undiscounted utility of envisaged events. The immediate experience of the delayed reward value might then bias toward farsighted decisions.
Spinocerebellar Ataxia Type 13 Mutant Potassium Channel Alters Neuronal Excitability and Causes Locomotor Deficits in Zebrafish
Authors: Issa Fadi A. , Mazzochi Christopher , Mock Allan F. , Papazian Diane M.
Published: May 2011

Whether changes in neuronal excitability can cause neurodegenerative disease in the absence of other factors such as protein aggregation is unknown. Mutations in the Kv3.3 voltage-gated K+channel cause spinocerebellar ataxia type 13 (SCA13), a human autosomal-dominant disease characterized by locomotor impairment and the death of cerebellar neurons. Kv3.3 channels facilitate repetitive, high-frequency firing of action potentials, suggesting that pathogenesis in SCA13 is triggered by changes in electrical activity in neurons. To investigate whether SCA13 mutations alter excitabilityin vivo, we expressed the human dominant-negative R420H mutant subunit in zebrafish. The disease-causing mutation specifically suppressed the excitability of Kv3.3-expressing, fast-spiking motor neurons during evoked firing and fictive swimming and, in parallel, decreased the precision and amplitude of the startle response. The dominant-negative effect of the mutant subunit on K+current amplitude was directly responsible for the reduced excitability and locomotor phenotype. Our data provide strong evidence that changes in excitability initiate pathogenesis in SCA13 and establish zebrafish as an excellent model system for investigating how changes in neuronal activity impair locomotor control and cause cell death.
Stress-Related Methylation of the Catechol-O-Methyltransferase Val158Allele Predicts Human Prefrontal Cognition and Activity
Authors: Ursini Gianluca , Bollati Valentina , Fazio Leonardo , Porcelli Annamaria , Iacovelli Luisa , Catalani Assia , Sinibaldi Lorenzo , Gelao Barbara , Romano Raffaella , Rampino Antonio , Taurisano Paolo , Mancini Marina , Di Giorgio Annabella , Popolizio Teresa , Baccarelli Andrea , De Blasi Antonio , Blasi Giuseppe , Bertolino Alessandro
Published: May 2011

DNA methylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT) Val158allele in rs4680 is associated with differential enzyme activity, stress responsivity, and prefrontal activity during working memory (WM), and it creates a CpG dinucleotide. We report that methylation of the Val158allele measured from peripheral blood mononuclear cells (PBMCs) of Val/Val humans is associated negatively with lifetime stress and positively with WM performance; it interacts with stress to modulate prefrontal activity during WM, such that greater stress and lower methylation are related to reduced cortical efficiency; and it is inversely related to mRNA expression and protein levels, potentially explaining thein vivoeffects. Finally, methylation ofCOMTin prefrontal cortex and that in PBMCs of rats are correlated. The relationship of methylation of theCOMTVal158allele with stress, gene expression, WM performance, and related brain activity suggests that stress-related methylation is associated with silencing of the gene, which partially compensates the physiological role of the high-activity Val allele in prefrontal cognition and activity. Moreover, these results demonstrate how stress-related DNA methylation of specific functional alleles impacts directly on human brain physiology beyond sequence variation.
Managing the Student‐Parent Dilemma: Mothers and Fathers in Higher Education
Authors: Estes Danielle K.
Published: May 2011

In this article, I explore how student‐parents draw on cultural discourses associated with parenthood and education when talking about their child care choices and schooling experiences. Unlike many other studies, I include the voices of both fathers and mothers. College students have extraordinary demands on their time, and their instructors do not generally expect them to be parents. Some students feel that in fact they are expected to be bad parents, bad students, or both. The use of accounts allows student‐parents to assert they are good parents even as they spend less time with their children and make their schoolwork a priority some of the time. As they modify their understandings of their capabilities as parents and students in this setting, they come to see themselves differently. They potentially change others' understandings of what good parents and good students are as well. Both the parent identity and the student identity change in the context of the university.
Coming of Age in the Bubble: Suburban Adolescents' Use of a Spatial Metaphor as a Symbolic Boundary
Authors: Kato Yuki
Published: May 2011

This article explores how suburban middle‐class adolescents use a spatial metaphor, “bubble,” as a symbolic boundary. The narratives about the bubble, collected through focus group discussions and ethnographic observations, show consensus among the teenagers about the socioeconomic and cultural superiority of the community, but they also reveal opposing views on its moral status. I also find that the teens use the same metaphor to draw moral distinctions among their peers, based on whether they align their identity with the norms and values the bubble symbolizes. I argue that the adolescents living in this community develop a strong place identity, even when they identify flaws with it, because their mundane references to the bubble provide them with an opportunity to critically examine the implication of their middle‐class status.
Why Parents Pay for College: The Good Parent, Perceptions of Advantage, and the Intergenerational Transfer of Opportunity
Authors: Holmstrom Lynda Lytle , Karp David A. , Gray Paul S.
Published: May 2011

This article asks how parents think about the cost of a college education for their children. Based on data from more than ninety in‐depth interviews with upper‐middle‐class parents and children, it is clear that grooming children for college and then paying for their education is intimately linked with ideas about being a “good parent.” We present data on three related aspects of parents' consciousness about paying for college. First, data are presented on how parents view the benefits of college for their children. Second, data illustrate how parents think about the obligations associated with paying. Third, we report on what parents expect in return for their efforts and expenditures. Data also indicate that parents' views are contingent on their perceived ability to pay for the increasing costs of higher education. We conclude by considering how the implicit contract between upper‐middle‐class parents and children may change as new economic and structural uncertainties increase parents' anxieties and challenge their abilities to see themselves as good parents.
Getting Away from It All: The Construction and Management of Temporary Identities on Vacation
Authors: Stein Karen
Published: May 2011

When individuals go on vacation they take on a temporary “vacation identity.” Vacationers use props, behaviors, and interactions with traveling companions to define and bound the experience as separate and different from everyday life. Data are drawn from twenty in‐depth interviews and participant observation with sixty international tourists in China during the summer of 2008. Vacationers' participation in rites and routines and impression management techniques helped them construct a personally meaningful, yet short‐lived identity. The results underscore the influence of others in identity construction and point to the importance of a nonpresent other in creating and presenting identities.