bluuebunny/crossref_metadata_2025 huggingface dataset:
Frightened or Bothered
Authors: Settles Isis H. , Harrell Zaje A. T. , Buchanan NiCole T. , Yap Stevie C. Y.
Published: March 2011

The present study distinguishes between bothersome versus frightening sexual harassment appraisals and examines their relative strength as mediators of the relationship of sexual harassment intensity and perpetrator status with psychological distress. Using a sample of 6,304 men and women in the U.S. Armed Forces, the results indicated that sexual harassment intensity and perpetrator status were related to psychological distress. For men, bothersome appraisals mediated this relationship for two of the three sexual harassment subtypes examined and for perpetrator status; for women, bothersome appraisal was not a significant mediator. Frightening appraisals mediated the relationship for all sexual harassment subtypes and perpetrator status for both men and women, and accounted for significantly more of the relationship between sexual harassment intensity and distress than did bothersome appraisals for most analyses. However, mediating relationships were significantly stronger for men than for women. We discuss the utility of a multidimensional conceptualization of sexual harassment appraisals.
Biomechanical Comparison of 2 Different Locking Plate Fixation Methods in Vancouver B1 Periprosthetic Femur Fractures
Authors: Pletka Joshua D. , Marsland Daniel , Belkoff Stephen M. , Mears Simon C. , Kates Stephen L.
Published: March 2011

Locking plates are commonly used to treat fractures around a well-fixed femoral component. The optimal construct should provide sufficient fixation while minimizing soft-tissue dissection. The purpose of the current study was to determine whether plate length, working length, or bone mineral density affects survival of locking plate fixation for Vancouver type B1 periprosthetic hip fractures. A transverse osteotomy was created just distal to cemented femoral prostheses in 9 pairs of cadaveric femurs. Fractures were stabilized with long (20-hole) or short (12-hole) locking plates that were secured proximally with cables and screws and distally with screws only. Specimens were then cycled 10 000 times at 2500 N of axial force and 15 Nm of torque to simulate full weightbearing. A motion capture system was used to record fracture displacement during cycling. Failure occurred in 5 long and 3 short plates, with no significant differences found in the number of cycles to failure. For the specimens that survived, there were no significant differences found between long and short plates for displacement or rotation observed at the fracture site. A shorter working length was not associated with increased failure rate. Lower bone mineral density was significantly associated with failure ( P = .02). We concluded that long locked plates do not appear to offer a biomechanical advantage over short locking plates in terms of fixation survival, and that bone mineral density was a better predictor of failure than was the fixation construct type.
Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor
Authors: Redell Michele S. , Ruiz Marcos J. , Alonzo Todd A. , Gerbing Robert B. , Tweardy David J.
Published: March 2011

Acute myeloid leukemia (AML) is an aggressive malignancy with a relapse rate approaching 50%, despite aggressive chemotherapy. New therapies for AML are targeted at signal transduction pathways known to support blast survival, such as the Stat3 pathway. Aberrant activation of Stat3 has been demonstrated in many different malignancies, including AML, and this finding is frequently associated with more aggressive disease. The objectives of this study were: (1) to characterize Stat3 signaling patterns in AML cells lines and primary pediatric samples; and (2) to test the efficacy and potency of a novel Stat3 inhibitor in inducing apoptosis in AML cells. We found that Stat3 was constitutively activated in 6 of 7 AML cell lines and 6 of 18 primary pediatric AML samples. Moreover, constitutively phosphorylated Stat3 was frequent in samples with normal karyotype but uncommon in samples with t(8;21). Most cell lines and primary samples responded to G-CSF stimulation, although the sensitivity and magnitude of the response varied dramatically. Our novel small-molecule Stat3 inhibitor, C188-9, inhibited G-CSF–induced Stat3 phosphorylation, induced apoptosis in AML cell lines and primary samples, and inhibited AML blast colony formation with potencies in the low micromolar range. Therefore, Stat3 inhibition may be a valuable strategy for targeted therapies for AML.
Complement activation on platelet-leukocyte complexes and microparticles in enterohemorrhagic Escherichia coli–induced hemolytic uremic syndrome
Authors: Ståhl Anne-lie , Sartz Lisa , Karpman Diana
Published: March 2011

Hemolytic uremic syndrome (HUS) is commonly associated with Shiga toxin (Stx)–producing Escherichia coli O157:H7 infection. This study examined patient samples for complement activation on leukocyte-platelet complexes and microparticles, as well as donor samples for Stx and lipopolysaccharide (O157LPS)–induced complement activation on platelet-leukocyte complexes and microparticles. Results, analyzed by flow cytometry, showed that whole blood from a child with HUS had surface-bound C3 on 30% of platelet-monocyte complexes compared with 14% after recovery and 12% in pediatric controls. Plasma samples from 12 HUS patients were analyzed for the presence of microparticles derived from platelets, monocytes, and neutrophils. Acute-phase samples exhibited high levels of platelet microparticles and, to a lesser extent, monocyte microparticles, both bearing C3 and C9. Levels decreased significantly at recovery. Stx or O157LPS incubated with donor whole blood increased the population of platelet-monocyte and platelet-neutrophil complexes with surface-bound C3 and C9, an effect enhanced by costimulation with Stx and O157LPS. Both Stx and O157LPS induced the release of C3- and C9-bearing microparticles from platelets and monocytes. Released microparticles were phagocytosed by neutrophils. The presence of complement on platelet-leukocyte complexes and microparticles derived from these cells suggests a role in the inflammatory and thrombogenic events that occur during HUS.
Adenosine modifies the balance between membrane and soluble forms of Flt-1
Authors: Leonard Frederique , Devaux Yvan , Vausort Melanie , Ernens Isabelle , Rolland-Turner Magali , Wagner Daniel R
Published: March 2011

VEGFR-1 (or Flt-1) exists under a sFlt-1 or a mFlt-1 form. sFlt-1 is antiangiogenic, and mFlt-1 is proangiogenic. The cardioprotective nucleoside Ado is proangiogenic, but its effects on Flt-1 are unknown and were tested in this study. In primary human macrophages from healthy volunteers, Ado inhibited sFlt-1 expression induced by LPS (–43%, P=0.006), HS, and IL-1β but not hypoxia. This effect was also observed in macrophages from patients with acute MI (–33%, P<0.001). It was reproduced by the A2A Ado receptor agonist CGS21680 and abrogated by the A2A antagonist SCH58261. Conversely, Ado increased mFlt-1 expression, thus switching sFlt-1 from the soluble toward the membrane form. This switch was also present in macrophages from acute MI patients (P<0.001). Assessment of HIF-1α nuclear translocation and activation together with siRNA experiments suggested that the effect of Ado on Flt-1 involves HIF-1α. In conclusion, Ado down-regulates sFlt-1 and up-regulates mFlt-1 production, an effect that indicates that Ado may be used to stimulate angiogenesis in the heart.
Differential Impacts of Insulin-Like Growth Factor-Binding Protein-3 (IGFBP-3) in Epithelial IGF-Induced Lung Cancer Development
Authors: Kim Woo-Young , Kim Mi-Jung , Moon Hojin , Yuan Ping , Kim Jin-Soo , Woo Jong-Kyu , Zhang Guangcheng , Suh Young-Ah , Feng Lei , Behrens Carmen , Van Pelt Carolyn S. , Kang Hyunseok , Lee J. Jack , Hong Waun-Ki , Wistuba Ignacio I. , Lee Ho-Young
Published: March 2011

The IGF axis has been implicated in the risk of various cancers. We previously reported a potential role of tissue-derived IGF in lung tumor formation and progression. However, the role of IGF-binding protein (IGFBP)-3, a major IGFBP, on the activity of tissue-driven IGF in lung cancer development is largely unknown. Here, we show that IGF-I, but not IGF-II, protein levels in non-small-cell lung cancer (NSCLC) were significantly higher than those in normal and hyperplastic bronchial epithelium. We found that IGF-I and IGFBP-3 levels in NSCLC tissue specimens were significantly correlated with phosphorylated IGF-IR (pIGF-IR) expression. We investigated the impact of IGFBP-3 expression on the activity of tissue-driven IGF-I in lung cancer development using mice carrying lung-specific human IGF-I transgene (Tg), a germline-null mutation of IGFBP-3, or both. Compared with wild-type (BP3+/+) mice, mice carrying heterozygous (BP3+/−) or homozygous (BP3−/−) deletion of IGFBP-3 alleles exhibited decreases in circulating IGFBP-3 and IGF-I. Unexpectedly, IGFTg mice with 50% of physiological IGFBP-3 (BP3+/−; IGFTg) showed higher levels of pIGF-IR/IR and a greater degree of spontaneous or tobacco carcinogen [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]-induced lung tumor development and progression than did the IGFTg mice with normal (BP3+/+;IGFTg) or homozygous deletion of IGFBP-3 (BP3−/−; IGFTg). These data show that IGF-I is overexpressed in NSCLC, leading to activation of IGF-IR, and that IGFBP-3, depending on its expression level, either inhibits or potentiates IGF-I actions in lung carcinogenesis.
Gap Junctions between Neuronal Inputs But Not Gonadotropin-Releasing Hormone Neurons Control Estrous Cycles in the Mouse
Authors: Campbell Rebecca E. , Ducret Eric , Porteous Robert , Liu Xinhuai , Herde Michel K. , Wellerhaus Kerstin , Sonntag Stephan , Willecke Klaus , Herbison Allan E.
Published: March 2011

The role of gap junctions in the neural control of fertility remains poorly understood. Using acute brain slices from adult GnRH-green fluorescent protein transgenic mice, individual GnRH neurons were filled with a mixture of fluorescent dextran and neurobiotin. No dye transfer was found between any GnRH neurons, although approximately 30% of GnRH neurons exchanged neurobiotin with closely apposed cells. Dual electrophysiological recordings from pairs of GnRH neurons revealed an absence of electrical coupling. Using adult connexin 36 (Cx36)-cyan fluorescent protein transgenic mice, Cx36 was identified in cells within several hypothalamic brain regions, including 64% of preoptic area kisspeptin neurons but not in GnRH neurons. To assess the potential role of Cx36 in non-GnRH neurons within the GnRH neuronal network (i.e. neurons providing afferent inputs to GnRH neurons), a calmodulin kinase IIα-Cre (CKC)-LoxP strategy was used to generate mice with a neuron-specific deletion of Cx36 beginning in the first postnatal week. Mutant female mice exhibited normal puberty onset but disordered estrous cyclicity, although their fecundity was normal as was their estrogen-negative and -positive feedback mechanisms. The effects of adult deletion of Cx36 from neurons were assessed using a tamoxifen-dependent inducible CKC-Cx36 transgenic strategy. Mutant mice exhibited the same reproductive phenotype as the CKC-Cx36 animals. Together these observations demonstrate that there is no gap junctional coupling between GnRH neurons. However, it is apparent that other neurons within the GnRH neuronal network, potentially the preoptic kisspeptin neurons, are dependent on Cx36 gap junctions and that this is critical for normal estrous cyclicity.
Playing Fair: Fairness Beliefs and Health Policy Preferences in the United States
Authors: Lynch Julia , Gollust Sarah E.
Published: March 2011

Conventional wisdom suggests that the best way to persuade Americans to support changes in health care policy is to appeal to their self-interest — particularly to concerns about their economic and health security. An alternative strategy, framing problems in the health care system to emphasize inequalities, could also, however, mobilize public support for policy change by activating underlying attitudes about the unfairness or injustice of these inequalities. In this article, we draw on original data from a nationally representative survey to describe Americans' beliefs about fairness in the health domain, including their perceptions of the fairness of particular inequalities in health and health care. We then assess the influence of these fairness considerations on opinions about the appropriate role of private actors versus government in providing health insurance. Respondents believe inequalities in access to and quality of health care are more unfair than unequal health outcomes. Even after taking into account self-interest considerations and the other usual suspects driving policy opinions, perceptions of the unfairness of inequalities in health care strongly influence respondents' preferences for government provision of health insurance.
Challenging Custom: Rethinking National Population Surveillance Policy in a Global Public Health Age
Authors: Katz Rebecca , Rosenbaum Sara
Published: March 2011

This article examines the current state of disease surveillance and reporting in the United States and seeks to answer two central questions: first, whether the increasing emphasis on the global importance of public health policies compels a fundamental reexamination of the long-standing deferential approach to state power where matters of population health surveillance are concerned and, second, how the nation's long-standing deferential legal customs might be modified to address the growing emphasis on global public health policy that is undergirded by technological advances. We examine the International Health Regulations, or IHR (2005), and suggest that these regulations offer a powerful impetus for reevaluating U.S. legal custom concerning the policy and practice of population health surveillance, not only as a matter of U.S. law but also as a core dimension of U.S. legal obligations to other nations, as embodied in international agreements and treaties. We find that if the political will exists to change the domestic disease surveillance and reporting system, the federal government has the power to act. Questions remain, however, about whether the public health and legislative communities are willing to challenge current customs or even if they desire to do so.
Victims into Emblems: Images of the Ránquil Massacre in Chilean National Narratives, 1934–2004
Authors: Mallon Florencia E.
Published: March 2011

This article explores the multiple ways in which the 1934 massacre of peasants in Ránquil in the Chilean Andean region of Lonquimay has been remembered and explained in Chile across the twentieth and the beginning of the twenty-first centuries. With the rise of the left and internal Communist Party debates in the 1930s, Ránquil first became an emblem of popular resistance and the unity between Mapuche and non-Mapuche peasants who were willing to sacrifice all in the name of revolution. During the Popular Unity government of Salvador Allende, Ránquil was one of several massacres transformed into narratives of popular heroism that were used as emblems to support the construction of a new and more inclusive national community. Yet because of Ránquil's unique location along the southern frontier where Chilean expansion into Mapuche territory created a rupture in the national imaginary that has yet to be closed, the presence of Mapuche peasants in the massacre continues to be debated until the present day. Ránquil is therefore an especially meaningful example of how debates over memory can serve as windows into the deeper conflicts and anxieties present in any society.
Coordinated regulation of differentiation and proliferation of embryonic cardiomyocytes by a jumonji (Jarid2)-cyclin D1 pathway
Authors: Nakajima Kuniko , Inagawa Masayo , Uchida Chiharu , Okada Kumiko , Tane Shoji , Kojima Mizuyo , Kubota Misae , Noda Masatsugu , Ogawa Satoko , Shirato Haruki , Sato Michio , Suzuki-Migishima Rika , Hino Toshiaki , Satoh Yukio , Kitagawa Masatoshi , Takeuchi Takashi
Published: March 2011

In general, cell proliferation and differentiation show an inverse relationship, and are regulated in a coordinated manner during development. Embryonic cardiomyocytes must support embryonic life by functional differentiation such as beating, and proliferate actively to increase the size of the heart. Therefore, progression of both proliferation and differentiation is indispensable. It remains unknown whether proliferation and differentiation are related in these embryonic cardiomyocytes. We focused on abnormal phenotypes, such as hyperproliferation, inhibition of differentiation and enhanced expression of cyclin D1 in cardiomyocytes of mice with mutant jumonji (Jmj, Jarid2), which encodes the repressor of cyclin D1. Analysis of Jmj/cyclin D1 double mutant mice showed that Jmj was required for normal differentiation and normal expression of GATA4 protein through cyclin D1. Analysis of transgenic mice revealed that enhanced expression of cyclin D1 decreased GATA4 protein expression and inhibited the differentiation of cardiomyocytes in a CDK4/6-dependent manner, and that exogenous expression of GATA4 rescued the abnormal differentiation. Finally, CDK4 phosphorylated GATA4 directly, which promoted the degradation of GATA4 in cultured cells. These results suggest that CDK4 activated by cyclin D1 inhibits differentiation of cardiomyocytes by degradation of GATA4, and that initiation of Jmj expression unleashes the inhibition by repression of cyclin D1 expression and allows progression of differentiation, as well as repression of proliferation. Thus, a Jmj-cyclin D1 pathway coordinately regulates proliferation and differentiation of cardiomyocytes.
Different Forms of Self-Control Share a Neurocognitive Substrate
Authors: Tabibnia Golnaz , Monterosso John R. , Baicy Kate , Aron Adam R. , Poldrack Russell A. , Chakrapani Shruthi , Lee Buyean , London Edythe D.
Published: March 2011

Psychological and neurocognitive studies have suggested that different kinds of self-control may share a common psychobiological component. If this is true, performance in affective and nonaffective inhibitory control tasks in the same individuals should be correlated and should rely upon integrity of this region. To test this hypothesis, we acquired high-resolution magnetic resonance images from 44 healthy and 43 methamphetamine-dependent subjects. Individuals with methamphetamine dependence were tested because of prior findings that they suffer inhibitory control deficits. Gray matter structure of the inferior frontal gyrus was assessed using voxel-based morphometry. Subjects participated in tests of motor and affective inhibitory control (stop-signal task and emotion reappraisal task, respectively); and methamphetamine-dependent subjects provided self-reports of their craving for methamphetamine. Performance levels on the two inhibitory control tasks were correlated with one another and with gray matter intensity in the right pars opercularis region of the inferior frontal gyrus in healthy subjects. Gray matter intensity of this region was also correlated with methamphetamine craving. Compared with healthy subjects, methamphetamine-dependent subjects exhibited lower gray matter intensity in this region, worse motor inhibitory control, and less success in affect regulation. These findings suggest that self-control in different psychological domains involves a common substrate in the right pars opercularis, and that successful self-control depends on integrity of this substrate.
The Small GTPase RhoA Is Required to Maintain Spinal Cord Neuroepithelium Organization and the Neural Stem Cell Pool
Authors: Herzog Dominik , Loetscher Pirmin , van Hengel Jolanda , Knüsel Sebastian , Brakebusch Cord , Taylor Verdon , Suter Ueli , Relvas João B.
Published: March 2011

The regulation of adherens junctions (AJs) is critical for multiple events during CNS development, including the formation and maintenance of the neuroepithelium. We have addressed the role of the small GTPase RhoA in the developing mouse nervous system using tissue-specific conditional gene ablation. We show that, in the spinal cord neuroepithelium, RhoA is essential to localize N-cadherin and β-catenin to AJs and maintain apical–basal polarity of neural progenitor cells. Ablation of RhoA caused the loss of AJs and severe abnormalities in the organization of cells within the neuroepithelium, including decreased neuroepithelial cell proliferation and premature cell-cycle exit, reduction of the neural stem cell pool size, and the infiltration of neuroepithelial cells into the lumen of the ventricle. We also show that, in the absence of RhoA, its effector, mammalian diaphanous-related formin1 (mDia1), does not localize to apical AJs in which it likely stabilizes intracellular adhesion by promoting local actin polymerization and microtubule organization. Furthermore, expressing a dominant-negative form of mDia1 in neural stem/progenitor cells results in a similar phenotype compared with that of the RhoA conditional knock-out, namely the loss of AJs and apical polarity. Together, our data show that RhoA signaling is necessary for AJ regulation and for the maintenance of mammalian neuroepithelium organization preventing precocious cell-cycle exit and differentiation.
Orientation Decoding Depends on Maps, Not Columns
Authors: Freeman Jeremy , Brouwer Gijs Joost , Heeger David J. , Merriam Elisha P.
Published: March 2011

The representation of orientation in primary visual cortex (V1) has been examined at a fine spatial scale corresponding to the columnar architecture. We present functional magnetic resonance imaging (fMRI) measurements providing evidence for a topographic map of orientation preference in human V1 at a much coarser scale, in register with the angular-position component of the retinotopic map of V1. This coarse-scale orientation map provides a parsimonious explanation for why multivariate pattern analysis methods succeed in decoding stimulus orientation from fMRI measurements, challenging the widely held assumption that decoding results reflect sampling of spatial irregularities in the fine-scale columnar architecture. Decoding stimulus attributes and cognitive states from fMRI measurements has proven useful for a number of applications, but our results demonstrate that the interpretation cannot assume decoding reflects or exploits columnar organization.
The Role of the Medial Prefrontal Cortex in Innate Fear Regulation in Infants, Juveniles, and Adolescents
Authors: Chan Thomas , Kyere Kwaku , Davis Brian R. , Shemyakin Alexei , Kabitzke Patricia A. , Shair Harry N. , Barr Gordon A. , Wiedenmayer Christoph P.
Published: March 2011

In adult animals, the medial prefrontal cortex (mPFC) plays a significant role in regulating emotions and projects to the amygdala and periaqueductal gray (PAG) to modulate emotional responses. However, little is known about the development of this neural circuit and its relevance to unlearned fear in pre-adulthood. To address these issues, we examined the mPFC of 14-d-old (infants), 26-d-old (juveniles), and 38- to 42-d-old (adolescents) rats to represent different developmental and social milestones. The expression patterns of the neuronal marker FOS were used to assess neurological activity. Muscimol, a GABA agonist, was used to inactivate the prelimbic and infralimbic mPFC subdivisions (400 ng in 200 nl). Animals were exposed to either a threatening or nonthreatening stimulus that was ecologically relevant and age specific. Freezing was measured as an indicator of innate fear behavior. The data indicated that the mPFC is neither active nor responsive to innate fear in infant rats. In juveniles, the prelimbic mPFC became responsive in processing aversive sensory stimulation but did not regulate freezing behavior. Finally, during adolescence, inactivation of the prelimbic mPFC significantly attenuated freezing and decreased FOS expression in the ventral PAG. Surprisingly, across all ages, there were no significant differences in FOS levels in the medial and basolateral/lateral amygdala when either mPFC subdivision was inactivated. Together, unlearned fear has a unique developmental course with different brain areas involved in unlearned fear in the immature animal than the adult. In particular, the mPFC neural circuitry is different in young animals and progressively develops more capacities as the animal matures.
Is the Medial Posterior Parietal Area V6A a Single Functional Area?
Authors: Gamberini Michela , Galletti Claudio , Bosco Annalisa , Breveglieri Rossella , Fattori Patrizia
Published: March 2011

The visuomotor medial posterior parietal area V6A has been recently subdivided into two cytoarchitectonic sectors called V6Ad and V6Av (Luppino et al., 2005). The aim of the present study was to recognize whether these two cortical sectors show different functional profiles. Fourteen hemispheres from eight animals (Macaca fascicularis) were included in this study, for a total of 3828 extracellularly recorded neurons assigned to areas V6Ad or V6Av on cytoarchitectural basis. The sensitivity of recorded neurons to sensory- and motor-related activities was checked with a series of functional tests performed on behaving animals. We found that cells sensitive to visual stimuli were more represented in V6Av and cells sensitive to somatosensory stimuli were more represented in V6Ad. Visual cells directly encoding spatial locations (real-position cells) were present only in V6Av. Cells encoding basic visual and somatic properties as well as different aspects of reaching and grasping activities were present in both sectors of V6A, although with different incidence. Cells that had reach-related activity enhanced by visual feedback and grasping neurons activated by whole-hand prehension were more concentrated in V6Av. Conversely, reaching neurons inhibited by visual feedback and grasping neurons activated by precision grip were more represented in V6Ad. Although V6Av and V6Ad show partly different functional profiles, our data support the idea that V6A is a single functional area involved in the control of reach-to-grasp movements, with the dorsal sector (V6Ad) more involved in the somatomotor control and the ventral sector (V6Av) in the visual control of reaching and grasping actions.
Egr-1 TransactivatesBimGene Expression to Promote Neuronal Apoptosis
Authors: Xie Bo , Wang Chong , Zheng Zhihao , Song Bin , Ma Chi , Thiel Gerald , Li Mingtao
Published: March 2011

The proapoptotic BH3-only protein Bim is a crucial regulator of neuronal apoptosis. Previous studies have indicated the involvement of the c-Jun, FOXO1/3a, and B/C-Myb transcription factors in the regulation of Bim during neuronal apoptosis. However, the mechanism underlying the transcriptional regulation of Bim in activity deprivation-induced neuronal apoptosis has remained unclear. The present study demonstrates that early growth response 1 (Egr-1), rather than c-Jun, FOXO1/3a, or B/C-Myb, directly transactivatesBimgene expression to mediate apoptosis of rat cerebellar granule neurons. We showed that Egr-1 was sufficient and necessary for neuronal apoptosis. Suppression of Egr-1 activity using dominant-negative mutant or knockdown of Egr-1 using small interfering RNAs led to a decrease in Bim expression, whereas overexpression of Egr-1 resulted in induction of Bim. Deletion and site-directed mutagenesis of the Bim promoter revealed thatBimtranscriptional activation depends primarily on a putative Egr-binding sequence between nucleotides −56 and −47 upstream of the start site. We also showed that Egr-1 binding to this sequence increased in response to activity deprivationin vitroandin vivo. Moreover, inhibition of Egr-1 binding to theBimpromoter, by mithramycin A and chromomycin A3, reduced the activity deprivation-induced increases inBimpromoter activity and mRNA and protein levels and protected neurons from apoptosis, further supporting the Egr-1-mediated transactivation ofBim. Additionally, Bim overcame the Egr-1 knockdown-mediated inhibition of apoptosis, whereas Bim knockdown impaired the increase in apoptosis induced by Egr-1. These findings establishBimas an Egr-1 target gene in neurons, uncovering a novel Egr-1/Bim pathway by which activity deprivation induces neuronal apoptosis.
A Nuclear Variant of ErbB3 Receptor Tyrosine Kinase Regulates Ezrin Distribution and Schwann Cell Myelination
Authors: Adilakshmi Tadepalli , Ness-Myers Jennifer , Madrid-Aliste Carlos , Fiser Andras , Tapinos Nikos
Published: March 2011

Reciprocal interactions between glia and neurons are essential for the proper organization and function of the nervous system. Recently, the interaction between ErbB receptors (ErbB2 and ErbB3) on the surface of Schwann cells and neuronal Neuregulin-1 (NRG1) has emerged as the pivotal signal that controls Schwann cell development, association with axons, and myelination. To understand the function of NRG1–ErbB2/3 signaling axis in adult Schwann cell biology, we are studying the specific role of ErbB3 receptor tyrosine kinase (RTK) since it is the receptor for NRG1 on the surface of Schwann cells. Here, we show that alternative transcription initiation results in the formation of a nuclear variant of ErbB3 (nuc-ErbB3) in rat primary Schwann cells. nuc-ErbB3 possesses a functional nuclear localization signal sequence and binds to chromatin. Using chromatin immunoprecipitation (ChIP)–chip arrays, we identified the promoters that associate with nuc-ErbB3 and clustered the active promoters in Schwann cell gene expression. nuc-ErbB3 regulates the transcriptional activity of ezrin and HMGB1 promoters, whereas inhibition of nuc-ErbB3 expression results in reduced myelination and altered distribution of ezrin in the nodes of Ranvier. Finally, we reveal that NRG1 regulates the translation of nuc-ErbB3 in rat Schwann cells. For the first time, to our knowledge, we show that alternative transcription initiation from a gene that encodes a RTK is capable to generate a protein variant of the receptor with a distinct role in molecular and cellular regulation. We propose a new concept for the molecular regulation of myelination through the expression and distinct role of nuc-ErbB3.
Different Fear States Engage Distinct Networks within the Intercalated Cell Clusters of the Amygdala
Authors: Busti Daniela , Geracitano Raffaella , Whittle Nigel , Dalezios Yannis , Mańko Miroslawa , Kaufmann Walter , Sätzler Kurt , Singewald Nicolas , Capogna Marco , Ferraguti Francesco
Published: March 2011

Although extinction-based therapies are among the most effective treatments for anxiety disorders, the neural bases of fear extinction remain still essentially unclear. Recent evidence suggests that the intercalated cell masses of the amygdala (ITCs) are critical structures for fear extinction. However, the neuronal organization of ITCs and how distinct clusters contribute to different fear states are still entirely unknown. Here, by combining whole-cell patch-clamp recordings and biocytin labeling with full anatomical reconstruction of the filled neurons and ultrastructural analysis of their synaptic contacts, we have elucidated the cellular organization and efferent connections of one of the main ITC clusters in mice. Our data showed an unexpected heterogeneity in the axonal pattern of medial paracapsular ITC (Imp) neurons and the presence of three distinct neuronal subtypes. Functionally, we observed that the Imp was preferentially activated during fear expression, whereas extinction training and extinction retrieval activated the main ITC nucleus (IN), as measured by quantifying Zif268 expression. This can be explained by the IPSPs evoked in the IN after Imp stimulation, most likely through the GABAergic monosynaptic innervation of IN neurons by one subtype of Imp cells, namely the medial capsular-projecting (MCp)–Imp neurons. MCp–Imp neurons also target large ITC cells that surround ITC clusters and express the metabotropic glutamate receptor 1α. These findings reveal a distinctive participation of ITC clusters to different fear states and the underlying anatomical circuitries, hence shedding new light on ITC networks and providing a novel framework to elucidate their role in fear expression and extinction.
Neural Computations Governing Spatiotemporal Pooling of Visual Motion Signals in Humans
Authors: Webb Ben S. , Ledgeway Timothy , Rocchi Francesca
Published: March 2011

The brain estimates visual motion by decoding the responses of populations of neurons. Extracting unbiased motion estimates from early visual cortical neurons is challenging because each neuron contributes an ambiguous (local) representation of the visual environment and inherently variable neural response. To mitigate these sources of noise, the brain can pool across large populations of neurons, pool the response of each neuron over time, or a combination of the two. Recent psychophysical and physiological work points to a flexible motion pooling system that arrives at different computational solutions over time and for different stimuli. Here we ask whether a single, likelihood-based computation can accommodate the flexible nature of spatiotemporal motion pooling in humans. We examined the contribution of different computations to human observers' performance on two global visual motion discriminations tasks, one requiring the combination of motion directions over time and another requiring their combination in different relative proportions over space and time. Observers' perceived direction of global motion was accurately predicted by a vector average readout of direction signals accumulated over time and a maximum likelihood readout of direction signals combined over space, consistent with the notion of a flexible motion pooling system that uses different computations over space and time. Additional simulations of observers' performance with a population decoding model revealed a more parsimonious solution: flexible spatiotemporal pooling could be accommodated by a single computation that optimally pools motion signals across a population of neurons that accumulate local motion signals on their receptive fields at a fixed rate over time.
Trpv1Reporter Mice Reveal Highly Restricted Brain Distribution and Functional Expression in Arteriolar Smooth Muscle Cells
Authors: Cavanaugh Daniel J. , Chesler Alexander T. , Jackson Alexander C. , Sigal Yaron M. , Yamanaka Hiroki , Grant Rebecca , O'Donnell Dajan , Nicoll Roger A. , Shah Nirao M. , Julius David , Basbaum Allan I.
Published: March 2011

The heat and capsaicin receptor, TRPV1, is required for the detection of painful heat by primary afferent pain fibers (nociceptors), but the extent to which functional TRPV1 channels are expressed in the CNS is debated. Because previous evidence is based primarily on indirect physiological responses to capsaicin, here we genetically modified theTrpv1locus to reveal, with excellent sensitivity and specificity, the distribution of TRPV1 in all neuronal and non-neuronal tissues. In contrast to reports of widespread and robust expression in the CNS, we find that neuronal TRPV1 is primarily restricted to nociceptors in primary sensory ganglia, with minimal expression in a few discrete brain regions, most notably in a contiguous band of cells within and adjacent to the caudal hypothalamus. We confirm hypothalamic expression in the mouse using several complementary approaches, includingin situhybridization, calcium imaging, and electrophysiological recordings. Additionalin situhybridization experiments in rat, monkey, and human brain demonstrate that the restricted expression of TRPV1 in the CNS is conserved across species. Outside of the CNS, we find TRPV1 expression in a subset of arteriolar smooth muscle cells within thermoregulatory tissues. Here, capsaicin increases calcium uptake and induces vasoconstriction, an effect that likely counteracts the vasodilation produced by activation of neuronal TRPV1.
Die Supply Chain als regelungstechnische Aufgabe
Authors: Beyer Jürgen
Published: March 2011

Die Anwendung regelungstechnischer Methoden in der Supply Chain verspricht neben dem Erkenntnisgewinn auch die Möglichkeit, deren dynamisches Verhalten gezielt zu beeinflussen. Hierzu wird ein zeitdiskretes stochastisches Prozessmodell im Zustandsraum formuliert, das eine einfache Behandlung von Totzeiten ermöglicht. Nach einer Analyse des Prozesses hinsichtlich Stabilitätseigenschaften und dem Übertragungsverhalten der Erwartungswerte und Kovarianzen wird ein Zustandsregler zur Festlegung des Bestellverhaltens entworfen. Dieser Ansatz erlaubt die Kontrolle der Mittelwerte und Streuungen aller internen Zustände der Supply Chain.
Kooperative Wegplanung für dynamisch konfigurierbare Transportmodule
Authors: Krühn Tobias , Heiserich Gerd
Published: March 2011

Kleinskalige multidirektionale Transportmodule sind in der Lage, durch dynamische Gruppenbildung eine Vielzahl unterschiedlicher Transportaufgaben zu erfüllen. Stückgüter können auf einer flächig angeordneten Modulmatrix entlang beliebiger Transportwege bewegt werden. Das in diesem Beitrag vorgestellte Verfahren zur kooperativen Wegplanung basiert auf einem vollständig dezentralen Ansatz, bei dem die einzelnen Elemente durch eine einfache Zustandsübergangsfunktion charakterisiert sind, aus der sich ein effizientes Verhalten des Gesamtsystems ergibt.
Uso de medicamentos por pessoas com deficiências em áreas do estado de São Paulo
Authors: Castro Shamyr Sulyvan , Pelicioni Americo Focesi , Cesar Chester Luiz Galvão , Carandina Luana , Barros Marilisa Berti de Azevedo , Alves Maria Cecilia Goi Porto , Goldbaum Moisés
Published: March 2011

OBJETIVO: Analisar o consumo de medicamentos e os principais grupos terapêuticos consumidos por pessoas com deficiências físicas, auditivas ou visuais. MÉTODOS: Estudo transversal em que foram analisados dados do Inquérito Multicêntrico de Saúde no Estado de São Paulo (ISA-SP) em 2002 e do Inquérito de Saúde no Município de São Paulo (ISA-Capital), realizado em 2003. Os entrevistados que referiram deficiências foram estudados segundo as variáveis que compõem o banco de dados: área, sexo, renda, faixa etária, raça, consumo de medicamentos e tipos de medicamentos consumidos. RESULTADOS: A percentagem de consumo entre as pessoas com deficiência foi de: 62,8% entre os visuais; 60,2% entre os auditivos e 70,1% entre os físicos. As pessoas com deficiência física consumiram 20% mais medicamentos que os não-deficientes. Entre as pessoas com deficiência visual, os medicamentos mais consumidos foram os diuréticos, agentes do sistema renina-angiotensina e analgésicos. Pessoas com deficiência auditiva utilizaram mais analgésicos e agentes do sistema renina-angiotensina. Entre indivíduos com deficiência física, analgésicos, antitrombóticos e agentes do sistema renina-angiotensina foram os medicamentos mais consumidos. CONCLUSÕES: Houve maior consumo de medicamentos entre as pessoas com deficiências quando comparados com os não-deficientes, sendo os indivíduos com deficiência física os que mais consumiram fármacos, seguidos de deficientes visuais e auditivos.
Consórcio intermunicipal para a aquisição de medicamentos: impacto no desabastecimento e no custo
Authors: Amaral Silvâni Maria Sehnem do , Blatt Carine Raquel
Published: March 2011

O estudo analisa o impacto de consórcio para a aquisição de medicamentos no desabastecimento e no custo dos medicamentos do Componente da Assistência Farmacêutica Básica do município de Indaial, SC. Observou-se uma redução aproximada de 12,0% de 2008 para 2007, e de 48,0% de 2009 para 2007 no número de itens que apresentaram falta em pelo menos um dia; a redução foi de 33% no custo total de aquisição quando comparada a aquisição pelo consórcio (2009) com a aquisição municipal (2007), e de 18% quando comparada aos valores médios do Banco de Preço em Saúde do Ministério da Saúde/2009. A aquisição de medicamentos pelo consórcio diminuiu o desabastecimento e apresentou economia, possibilitando aquisição de maior quantidade de produtos com a mesma disponibilidade de recursos.
"A wild and wondrous ride": CDC field epidemiologists in the east Pakistan smallpox and cholera epidemics of 1958
Authors: Greenough Paul
Published: March 2011

In mid-April of 1958 the Government of Pakistan summoned the press to announce a grave need for international aid to cope with smallpox and cholera epidemics in East Pakistan. In response, and with the backing of the US State Department, Dr. Alexander D. Langmuir, chief epidemiologist of the CDC, led a team of epidemiologists to assist authorities in Dacca strengthen their immunization programs. Langmuir's superiors hoped for a Cold War advantage, but he saw an opportunity for trainees in the Epidemic Intelligence Service to learn about public health in a developing country. Langmuir later described the episode as a "wild and wondrous ride," but it had been more like a nightmare: the East Pakistan health department had collapsed; a popular movement had taken over vaccination and squandered vaccine supplies; hostile journalists had questioned the Americans' deeper motives; and a professional rivalry opened between the Americans and a British epidemiologist named Aidan Cockburn. By the time the epidemic subsided in July 1958, 30 million Bengalis had been vaccinated for smallpox but another 20,000 had succumbed to the disease. This episode was CDC's first sustained foreign intervention, a precursor to its extensive role in the 1970s helping WHO eradicate smallpox from Bangladesh.
Small(pox) success?
Authors: Birn Anne-Emanuelle
Published: March 2011

The 30th anniversary of the World Health Organization's (WHO) official certification of smallpox eradication was marked by a slew of events hailing the campaign's dramatic tale of technological and organizational triumph against an ancient scourge. Yet commemorations also serve as moments of critical reflection. This article questions the acclaim showered upon smallpox eradication as the single greatest public health success in history. It examines how and why smallpox eradication and WHO's concurrent social justice-oriented primary health care approach (following from the Declaration of Alma-Ata) became competing paradigms. It synthesizes critiques of eradication's shortcomings and debunks some of the myths surrounding the global eradication campaign as a public health priority and necessity, and as a Cold War victory of cooperation. The article concludes with thoughts on integrating technical and social-political aspects of health within the context of welfare states as the means to achieving widespread and enduring global public health success.
Acyclovir‐Induced Immune Thrombocytopenia in a Patient with Herpes Zoster of the Trigeminal Nerve
Authors: Katsenos Stamatis , Gkolias Dimitrios , Nikolopoulou Melita
Published: March 2011

Acyclovir has been widely used as an antiviral agent for the treatment of infections caused by herpes simplex and varicella‐zoster viruses. The drug is usually well tolerated; however, rarely, adverse effects may be severe, including neuropsychiatric reactions, gastrointestinal disturbances, skin lesions, renal disorders, and dyscrasias. We describe a 20–year‐old man who was treated with intravenous acyclovir 5 mg/kg every 8 hours for a herpes zoster infection (shingles) that involved painful vesicular lesions and skin eruptions along the third branch of trigeminal nerve. Despite favorable improvement of his cutaneous lesions, the patient developed severe thrombocytopenia within 5 days of starting acyclovir. The drug was discontinued, and the patient's condition improved by using a supportive therapeutic approach. An extensive workup for detection of acyclovir‐dependent platelet antibodies indicated positive results, implicating acyclovir as a cause of thrombocytopenia. In addition, the temporal relationship between the start of acyclovir and the onset of thrombocytopenia, along with the exclusion of the other most frequently occurring known causes of thrombocytopenia, established a definitive diagnosis of acyclovir‐induced immune thrombocytopenia. To our knowledge, this is the first well‐documented report of isolated severe immune thrombocytopenia induced by acyclovir. Clinicians should be aware of this rare potential adverse reaction, as prompt diagnosis is the cornerstone of appropriate management.
Hepatotoxicity Associated with Chinese Skullcap Contained in Move Free Advanced Dietary Supplement: Two Case Reports and Review of the Literature
Authors: Linnebur Sunny A. , Rapacchietta Olivia C. , Vejar Maria
Published: March 2011

Move Free Advanced is a widely available dietary supplement in the United States, marketed to comfort sore joints and improve flexibility and mobility. This product contains glucosamine, chondroitin, hyaluronic acid, and Uniflex proprietary extract, which is a combination of Chinese skullcap and black catechu. We describe two patients who developed hepatotoxicity after ingesting a Move Free Advanced product. In both patients, the hepatotoxicity resolved after discontinuation of the supplement. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 6 for both patients) between the patients' development of hepatotoxicity and the Move Free Advanced supplement. Based on a review of the literature, the herbal extract Chinese skullcap is the most likely cause of the hepatotoxicity. To our knowledge, these two cases are the first to be published regarding possible hepatotoxicity associated with Move Free Advanced. Patients seeking dietary supplements for osteoarthritis may want to avoid glucosamine‐chondroitin products such as Move Free Advanced that also contain Chinese skullcap.
Severe Postoperative Immune‐Mediated Coagulopathy Associated with Bovine Thrombin Exposure
Authors: Rodgers George M. , Kraiss Larry W.
Published: March 2011

Immune‐mediated coagulopathy is a known risk of bovine‐derived topical thrombin exposure and is the subject of a black‐box warning in the package inserts of bovine‐derived topical thrombin products. The manifestation of coagulopathy due to bovine thrombin exposure may range from abnormal laboratory values without clinical sequelae to severe bleeding, which can be fatal in rare instances and result in significant consumption of blood and blood products, and significantly higher treatment costs. We describe a 76–year‐old woman who developed severe hemorrhagic complications after surgical exposure to bovine‐derived topical thrombin. The patient was initially diagnosed with disseminated intravascular coagulation with an accompanying coagulopathy. Despite resolution of the disseminated intravascular coagulation, the patient continued to experience episodic hemorrhages accompanied by positive coagulation mixing studies and clotting factor assays indicating a significantly reduced factor V activity (< 5% of normal) that confirmed an ongoing immune‐mediated coagulopathy. The presence of a factor V inhibitor was confirmed by inhibitor titer assay. After a critical care hospitalization of 64 days that required the use of 282 units of blood products and two reoperations for hemorrhage, the patient was discharged home. Immune‐mediated coagulopathy resulting from bovine thrombin exposure can result in clinically severe bleeding in some patients. As illustrated by the consumption of health care resources in this case report, should such a coagulopathy develop, the costs may be considerable.