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Sample records for medullary circuitry regulating

  1. Neuronal Circuitry Mechanisms Regulating Adult Mammalian Neurogenesis

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    Song, Juan; Olsen, Reid H.J.; Sun, Jiaqi; Ming, Guo-li; Song, Hongjun

    2017-01-01

    The adult mammalian brain is a dynamic structure, capable of remodeling in response to various physiological and pathological stimuli. One dramatic example of brain plasticity is the birth and subsequent integration of newborn neurons into the existing circuitry. This process, termed adult neurogenesis, recapitulates neural developmental events in two specialized adult brain regions: the lateral ventricles of the forebrain. Recent studies have begun to delineate how the existing neuronal circuits influence the dynamic process of adult neurogenesis, from activation of quiescent neural stem cells (NSCs) to the integration and survival of newborn neurons. Here, we review recent progress toward understanding the circuit-based regulation of adult neurogenesis in the hippocampus and olfactory bulb. PMID:27143698

  2. Corticostriatal circuitry in regulating diseases characterized by intrusive thinking.

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    Kalivas, Benjamin C; Kalivas, Peter W

    2016-03-01

    Intrusive thinking triggers clinical symptoms in many neuropsychiatric disorders. Using drug addiction as an exemplar disorder sustained in part by intrusive thinking, we explore studies demonstrating that impairments in corticostriatal circuitry strongly contribute to intrusive thinking. Neuroimaging studies have long implicated this projection in cue-induced craving to use drugs, and preclinical models show that marked changes are produced at corticostriatal synapses in the nucleus accumbens during a relapse episode. We delineate an accumbens microcircuit that mediates cue-induced drug seeking becoming an intrusive event. This microcircuit harbors many potential therapeutic targets. We focus on preclinical and clinical studies, showing that administering N-acetylcysteine restores uptake of synaptic glutamate by astroglial glutamate transporters and thereby inhibits intrusive thinking. We posit that because intrusive thinking is a shared endophenotype in many disorders, N-acetylcysteine has positive effects in clinical trials for a variety of neuropsychiatric disorders, including drug addiction, gambling, trichotillomania, and depression.

  3. Regulating Critical Period Plasticity: Insight from the Visual System to Fear Circuitry for Therapeutic Interventions

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    Elisa M. Nabel

    2013-11-01

    Full Text Available Early temporary windows of heightened brain plasticity called critical periods developmentally sculpt neural circuits and contribute to adult behavior. Regulatory mechanisms of visual cortex development –the preeminent model of experience-dependent critical period plasticity- actively limit adult plasticity and have proved fruitful therapeutic targets to reopen plasticity and rewire faulty visual system connections later in life. Interestingly, these molecular mechanisms have been implicated in the regulation of plasticity in other functions beyond vision. Applying mechanistic understandings of critical period plasticity in the visual cortex to fear circuitry may provide a conceptual framework for developing novel therapeutic tools to mitigate aberrant fear responses in post traumatic stress disorder. In this review, we turn to the model of experience-dependent visual plasticity to provide novel insights for the mechanisms regulating plasticity in the fear system. Fear circuitry, particularly fear memory erasure, also undergoes age-related changes in experience-dependent plasticity. We consider the contributions of molecular brakes that halt visual critical period plasticity to circuitry underlying fear memory erasure. A major molecular brake in the visual cortex, perineuronal net formation, recently has been identified in the development of fear systems that are resilient to fear memory erasure. The roles of other molecular brakes, myelin-related Nogo receptor signaling and Lynx family proteins– endogenous inhibitors for nicotinic acetylcholine receptor, are explored in the context of fear memory plasticity. Such fear plasticity regulators, including epigenetic effects, provide promising targets for therapeutic interventions.

  4. Medullary raphe nuclei activate the lumbosacral defecation center through the descending serotonergic pathway to regulate colorectal motility in rats.

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    Nakamori, Hiroyuki; Naitou, Kiyotada; Horii, Yuuki; Shimaoka, Hiroki; Horii, Kazuhiro; Sakai, Hiroki; Yamada, Akihiro; Furue, Hidemasa; Shiina, Takahiko; Shimizu, Yasutake

    2018-03-01

    Colorectal motility is regulated by two defecation centers located in the brain and spinal cord. In previous studies, we have shown that administration of serotonin (5-HT) in the lumbosacral spinal cord causes enhancement of colorectal motility. Because spinal 5-HT is derived from neurons of the medullary raphe nuclei, including the raphe magnus, raphe obscurus, and raphe pallidus, we examined whether stimulation of the medullary raphe nuclei enhances colorectal motility via the lumbosacral defecation center. Colorectal pressure was recorded with a balloon in vivo in anesthetized rats. Electrical stimulation of the medullary raphe nuclei failed to enhance colorectal motility. Because GABAergic neurons can be simultaneously activated by the raphe stimulation and released GABA masks accelerating actions of the raphe nuclei on the lumbosacral defecation center, a GABA A receptor antagonist was preinjected intrathecally to manifest excitatory responses. When spinal GABA A receptors were blocked by the antagonist, electrical stimulation of the medullary raphe nuclei increased colorectal contractions. This effect of the raphe nuclei was inhibited by intrathecal injection of 5-hydroxytryptamine type 2 (5-HT 2 ) and type 3 (5-HT 3 ) receptor antagonists. In addition, injection of a selective 5-HT reuptake inhibitor in the lumbosacral spinal cord augmented the raphe stimulation-induced enhancement of colorectal motility. Transection of the pelvic nerves, but not transection of the colonic nerves, prevented the effect of the raphe nuclei on colorectal motility. These results demonstrate that activation of the medullary raphe nuclei causes augmented contractions of the colorectum via 5-HT 2 and 5-HT 3 receptors in the lumbosacral defecation center. NEW & NOTEWORTHY We have shown that electrical stimulation of the medullary raphe nuclei causes augmented contractions of the colorectum via pelvic nerves in rats. The effect of the medullary raphe nuclei on colorectal motility is

  5. Sympathetic nerve-derived ATP regulates renal medullary blood flow via vasa recta pericytes

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    Scott S Wildman

    2013-10-01

    Full Text Available Pericyte cells are now known to be a novel locus of blood flow control, being able to regulate capillary diameter via their unique morphology and expression of contractile proteins. We have previously shown that exogenous ATP causes constriction of vasa recta via renal pericytes, acting at a variety of membrane bound P2 receptors on descending vasa recta, and therefore may be able to regulate medullary blood flow (MBF. Regulation of MBF is essential for appropriate urine concentration and providing essential oxygen and nutrients to this region of high, and variable, metabolic demand. Various sources of endogenous ATP have been proposed, including from epithelial, endothelial and red blood cells in response to stimuli such as mechanical stimulation, local acidosis, hypoxia, and exposure to various hormones. Extensive sympathetic innervation of the nephron has previously been shown, however the innervation reported has focused around the proximal and distal tubules, and ascending loop of Henle. We hypothesise that sympathetic nerves are an additional source of ATP acting at renal pericytes and therefore regulate MBF. Using a rat live kidney slice model in combination with video imaging and confocal microscopy techniques we firstly show sympathetic nerves in close proximity to vasa recta pericytes in both the outer and inner medulla. Secondly, we demonstrate pharmacological stimulation of sympathetic nerves in situ (by tyramine evokes pericyte-mediated vasoconstriction of vasa recta capillaries; inhibited by the application of the P2 receptor antagonist suramin. Lastly, tyramine-evoked vasoconstriction of vasa recta by pericytes is significantly less than ATP-evoked vasoconstriction. Sympathetic innervation may provide an additional level of functional regulation in the renal medulla that is highly localized. It now needs to be determined under which physiological/pathophysiological circumstances that sympathetic innervation of renal pericytes is

  6. CXCR4 Regulates Extra-Medullary Myeloma through Epithelial-Mesenchymal-Transition-like Transcriptional Activation

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    Aldo M. Roccaro

    2015-07-01

    Full Text Available Extra-medullary disease (EMD in multiple myeloma (MM is associated with poor prognosis and resistance to chemotherapy. However, molecular alterations that lead to EMD have not been well defined. We developed bone marrow (BM- and EMD-prone MM syngeneic cell lines; identified that epithelial-to-mesenchymal transition (EMT transcriptional patterns were significantly enriched in both clones compared to parental cells, together with higher levels of CXCR4 protein; and demonstrated that CXCR4 enhanced the acquisition of an EMT-like phenotype in MM cells with a phenotypic conversion for invasion, leading to higher bone metastasis and EMD dissemination in vivo. In contrast, CXCR4 silencing led to inhibited tumor growth and reduced survival. Ulocuplumab, a monoclonal anti-CXCR4 antibody, inhibited MM cell dissemination, supported by suppression of the CXCR4-driven EMT-like phenotype. These results suggest that targeting CXCR4 may act as a regulator of EMD through EMT-like transcriptional modulation, thus representing a potential therapeutic strategy to prevent MM disease progression.

  7. A CRY-BIC negative-feedback circuitry regulating blue light sensitivity of Arabidopsis.

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    Wang, Xu; Wang, Qin; Han, Yun-Jeong; Liu, Qing; Gu, Lianfeng; Yang, Zhaohe; Su, Jun; Liu, Bobin; Zuo, Zecheng; He, Wenjin; Wang, Jian; Liu, Bin; Matsui, Minami; Kim, Jeong-Il; Oka, Yoshito; Lin, Chentao

    2017-11-01

    Cryptochromes are blue light receptors that regulate various light responses in plants. Arabidopsis cryptochrome 1 (CRY1) and cryptochrome 2 (CRY2) mediate blue light inhibition of hypocotyl elongation and long-day (LD) promotion of floral initiation. It has been reported recently that two negative regulators of Arabidopsis cryptochromes, Blue light Inhibitors of Cryptochromes 1 and 2 (BIC1 and BIC2), inhibit cryptochrome function by blocking blue light-dependent cryptochrome dimerization. However, it remained unclear how cryptochromes regulate the BIC gene activity. Here we show that cryptochromes mediate light activation of transcription of the BIC genes, by suppressing the activity of CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), resulting in activation of the transcription activator ELONGATED HYPOCOTYL 5 (HY5) that is associated with chromatins of the BIC promoters. These results demonstrate a CRY-BIC negative-feedback circuitry that regulates the activity of each other. Surprisingly, phytochromes also mediate light activation of BIC transcription, suggesting a novel photoreceptor co-action mechanism to sustain blue light sensitivity of plants under the broad spectra of solar radiation in nature. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  8. Sensitive Periods of Emotion Regulation: Influences of Parental Care on Frontoamygdala Circuitry and Plasticity

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    Gee, Dylan G.

    2016-01-01

    Early caregiving experiences play a central role in shaping emotional development, stress physiology, and refinement of limbic circuitry. Converging evidence across species delineates a sensitive period of heightened neuroplasticity when frontoamygdala circuitry is especially amenable to caregiver inputs early in life. During this period, parental…

  9. Brainstem circuitry regulating phasic activation of trigeminal motoneurons during REM sleep.

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    Christelle Anaclet

    2010-01-01

    Full Text Available Rapid eye movement sleep (REMS is characterized by activation of the cortical and hippocampal electroencephalogram (EEG and atonia of non-respiratory muscles with superimposed phasic activity or twitching, particularly of cranial muscles such as those of the eye, tongue, face and jaw. While phasic activity is a characteristic feature of REMS, the neural substrates driving this activity remain unresolved. Here we investigated the neural circuits underlying masseter (jaw phasic activity during REMS. The trigeminal motor nucleus (Mo5, which controls masseter motor function, receives glutamatergic inputs mainly from the parvocellular reticular formation (PCRt, but also from the adjacent paramedian reticular area (PMnR. On the other hand, the Mo5 and PCRt do not receive direct input from the sublaterodorsal (SLD nucleus, a brainstem region critical for REMS atonia of postural muscles. We hypothesized that the PCRt-PMnR, but not the SLD, regulates masseter phasic activity during REMS.To test our hypothesis, we measured masseter electromyogram (EMG, neck muscle EMG, electrooculogram (EOG and EEG in rats with cell-body specific lesions of the SLD, PMnR, and PCRt. Bilateral lesions of the PMnR and rostral PCRt (rPCRt, but not the caudal PCRt or SLD, reduced and eliminated REMS phasic activity of the masseter, respectively. Lesions of the PMnR and rPCRt did not, however, alter the neck EMG or EOG. To determine if rPCRt neurons use glutamate to control masseter phasic movements, we selectively blocked glutamate release by rPCRt neurons using a Cre-lox mouse system. Genetic disruption of glutamate neurotransmission by rPCRt neurons blocked masseter phasic activity during REMS.These results indicate that (1 premotor glutamatergic neurons in the medullary rPCRt and PMnR are involved in generating phasic activity in the masseter muscles, but not phasic eye movements, during REMS; and (2 separate brainstem neural circuits control postural and cranial muscle

  10. Thyroid cancer - medullary carcinoma

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    Thyroid - medullary carcinoma; Cancer - thyroid (medullary carcinoma); MTC; Thyroid nodule - medullary ... National Cancer Institute. PDQ thyroid cancer treatment. Bethesda, ... February 4, 2016. www.cancer.gov/cancertopics/pdq/treatment/ ...

  11. Role of basal ganglia in sleep-wake regulation: neural circuitry and clinical significance

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    Ramalingam Vetrivelan

    2010-11-01

    Full Text Available Researchers over the last decade have made substantial progress towards understanding the roles of dopamine and the basal ganglia in the control of sleep-wake behavior. In this review, we outline recent advancements regarding dopaminergic modulation of sleep through the basal ganglia (BG and extra-BG sites. Our main hypothesis is that dopamine promotes sleep by its action on the D2 receptors in the BG and promotes wakefulness by its action on D1 and D2 receptors in the extra-BG sites. This hypothesis implicates dopamine depletion in the BG (such as in Parkinson’s disease in causing frequent nighttime arousal and overall insomnia. Furthermore, the arousal effects of psychostimulants (methamphetamine, cocaine and modafinil may be linked to the ventral periaquductal grey (vPAG dopaminergic circuitry targeting the extra-BG sleep-wake network.

  12. Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise.

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    Antoine Lutz

    2008-03-01

    Full Text Available Recent brain imaging studies using functional magnetic resonance imaging (fMRI have implicated insula and anterior cingulate cortices in the empathic response to another's pain. However, virtually nothing is known about the impact of the voluntary generation of compassion on this network. To investigate these questions we assessed brain activity using fMRI while novice and expert meditation practitioners generated a loving-kindness-compassion meditation state. To probe affective reactivity, we presented emotional and neutral sounds during the meditation and comparison periods. Our main hypothesis was that the concern for others cultivated during this form of meditation enhances affective processing, in particular in response to sounds of distress, and that this response to emotional sounds is modulated by the degree of meditation training. The presentation of the emotional sounds was associated with increased pupil diameter and activation of limbic regions (insula and cingulate cortices during meditation (versus rest. During meditation, activation in insula was greater during presentation of negative sounds than positive or neutral sounds in expert than it was in novice meditators. The strength of activation in insula was also associated with self-reported intensity of the meditation for both groups. These results support the role of the limbic circuitry in emotion sharing. The comparison between meditation vs. rest states between experts and novices also showed increased activation in amygdala, right temporo-parietal junction (TPJ, and right posterior superior temporal sulcus (pSTS in response to all sounds, suggesting, greater detection of the emotional sounds, and enhanced mentation in response to emotional human vocalizations for experts than novices during meditation. Together these data indicate that the mental expertise to cultivate positive emotion alters the activation of circuitries previously linked to empathy and theory of mind in

  13. Expression and regulation of M-type K+channel in PC12 cells and rat adrenal medullary cells.

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    Harada, Keita; Matsuoka, Hidetada; Inoue, Masumi

    2018-02-27

    M-type K + channels contribute to the resting membrane potential in the sympathetic ganglion neurons of various animals, whereas their expression in adrenal medullary (AM) cells has been controversial. The present experiment aims to explore the expression of M channels comprising the KCNQ2 subunit in the rat AM cell and its immortalized cell line PC12 cells at the protein level and how its expression in PC12 cells is regulated. The KCNQ2 isoform was recognized in homogenates of PC12 cells but not the rat adrenal medullae by immunoblotting and KCNQ2-like immunoreactivity (IR) was detected in PC12 cells but not in rat AM cells. When the PC12 cells were maintained in a dexamethasone-containing medium, KCNQ2-like IR in the cells was suppressed, whereas the removal of fetal bovine serum from the culture medium for 1 day resulted in an increase in KCNQ2-like IR. A similar enhancement occurred when PC12 cells were cultured under conditions where glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) activities were suppressed. These morphological findings were confirmed in functional analysis. The cells cultured in the presence of an inhibitor of either GR or MR exhibited larger amplitudes of Ca 2+ signal in response to an M channel inhibitor than did the cells in its absence, whereas the resting Ca 2+ level in the former was lower than that in the latter. These results indicate that the M channel is not expressed in rat AM cells and this absence of expression may be ascribed to the suppression by glucocorticoid activity.

  14. The Calcium-Induced Regulation in the Molecular and Transcriptional Circuitry of Human Inflammatory Response and Autoimmunity

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    Ivo R. de Seabra Rodrigues Dias

    2018-01-01

    Full Text Available Rheumatoid arthritis synovial fibroblasts (RASFs are fundamental effector cells in RA driving the joint inflammation and deformities. Celastrol is a natural compound that exhibits a potent anti-arthritic effect promoting endoplasmic reticulum (ER stress mediated by intracellular calcium (Ca2+ mobilization. Ca2+ is a second messenger regulating a variety of cellular processes. We hypothesized that the compound, celastrol, affecting cytosolic Ca2+ mobilization could serve as a novel strategy to combat RA. To address this issue, celastrol was used as a molecular tool to assay the inflammatory gene expression profile regulated by Ca2+. We confirmed that celastrol treatment mobilized cytosolic Ca2+ in patient-derived RASFs. It was found that 23 genes out of 370 were manipulated by Ca2+ mobilization using an inflammatory and autoimmunity PCR array following independent quantitative PCR validation. Most of the identified genes were downregulated and categorized into five groups corresponding to their cellular responses participating in RA pathogenesis. Accordingly, a signaling network map demonstrating the possible molecular circuitry connecting the functions of the products of these genes was generated based on literature review. In addition, a bioinformatics analysis revealed that celastrol-induced Ca2+ mobilization gene expression profile showed a novel mode of action compared with three FDA-approved rheumatic drugs (methotrexate, rituximab and tocilizumab. To the best of our knowledge, this is a pioneer work charting the Ca2+ signaling network on the regulation of RA-associated inflammatory gene expression.

  15. The Endocannabinoid System and Its Role in Regulating the Intrinsic Neural Circuitry of the Gastrointestinal Tract.

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    Trautmann, Samantha M; Sharkey, Keith A

    2015-01-01

    Endocannabinoids are important neuromodulators in the central nervous system. They regulate central transmission through pre- and postsynaptic actions on neurons and indirectly through effects on glial cells. Cannabinoids (CBs) also regulate neurotransmission in the enteric nervous system (ENS) of the gastrointestinal (GI) tract. The ENS consists of intrinsic primary afferent neurons, interneurons, and motor neurons arranged in two ganglionated plexuses which control all the functions of the gut. Increasing evidence suggests that endocannabinoids are potent neuromodulators in the ENS. In this review, we will highlight key observations on the localization of CB receptors and molecules involved in the synthesis and degradation of endocannabinoids in the ENS. We will discuss endocannabinoid signaling mechanisms, endocannabinoid tone and concepts of CB receptor metaplasticity in the ENS. We will also touch on some examples of enteric neural signaling in relation neuromuscular, secretomotor, and enteroendocrine transmission in the ENS. Finally, we will briefly discuss some key future directions. © 2015 Elsevier Inc. All rights reserved.

  16. Topology and Control of the Cell-Cycle-Regulated Transcriptional Circuitry

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    Haase, Steven B.; Wittenberg, Curt

    2014-01-01

    Nearly 20% of the budding yeast genome is transcribed periodically during the cell division cycle. The precise temporal execution of this large transcriptional program is controlled by a large interacting network of transcriptional regulators, kinases, and ubiquitin ligases. Historically, this network has been viewed as a collection of four coregulated gene clusters that are associated with each phase of the cell cycle. Although the broad outlines of these gene clusters were described nearly 20 years ago, new technologies have enabled major advances in our understanding of the genes comprising those clusters, their regulation, and the complex regulatory interplay between clusters. More recently, advances are being made in understanding the roles of chromatin in the control of the transcriptional program. We are also beginning to discover important regulatory interactions between the cell-cycle transcriptional program and other cell-cycle regulatory mechanisms such as checkpoints and metabolic networks. Here we review recent advances and contemporary models of the transcriptional network and consider these models in the context of eukaryotic cell-cycle controls. PMID:24395825

  17. Brainstem and spinal cord circuitry regulating REM sleep and muscle atonia.

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    Martina Krenzer

    Full Text Available Previous work has suggested, but not demonstrated directly, a critical role for both glutamatergic and GABAergic neurons of the pontine tegmentum in the regulation of rapid eye movement (REM sleep.To determine the in vivo roles of these fast-acting neurotransmitters in putative REM pontine circuits, we injected an adeno-associated viral vector expressing Cre recombinase (AAV-Cre into mice harboring lox-P modified alleles of either the vesicular glutamate transporter 2 (VGLUT2 or vesicular GABA-glycine transporter (VGAT genes. Our results show that glutamatergic neurons of the sublaterodorsal nucleus (SLD and glycinergic/GABAergic interneurons of the spinal ventral horn contribute to REM atonia, whereas a separate population of glutamatergic neurons in the caudal laterodorsal tegmental nucleus (cLDT and SLD are important for REM sleep generation. Our results further suggest that presynaptic GABA release in the cLDT-SLD, ventrolateral periaqueductal gray matter (vlPAG and lateral pontine tegmentum (LPT are not critically involved in REM sleep control.These findings reveal the critical and divergent in vivo role of pontine glutamate and spinal cord GABA/glycine in the regulation of REM sleep and atonia and suggest a possible etiological basis for REM sleep behavior disorder (RBD.

  18. Medullary Sponge Kidney

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    ... tubes, inside a fetus’ kidneys. In a normal kidney , urine flows through these tubules as the kidney is being formed during a ... not fully understand the cause of medullary sponge kidney or why cysts form in the tubules during fetal development. Even though medullary sponge kidney ...

  19. Homeodomain-interacting protein kinase 2, a novel autoimmune regulator interaction partner, modulates promiscuous gene expression in medullary thymic epithelial cells.

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    Rattay, Kristin; Claude, Janine; Rezavandy, Esmail; Matt, Sonja; Hofmann, Thomas G; Kyewski, Bruno; Derbinski, Jens

    2015-02-01

    Promiscuous expression of a plethora of tissue-restricted Ags (TRAs) by medullary thymic epithelial cells (mTECs) plays an essential role in T cell tolerance. Although the cellular mechanisms by which promiscuous gene expression (pGE) imposes T cell tolerance have been well characterized, the underlying molecular mechanisms remain poorly understood. The autoimmune regulator (AIRE) is to date the only validated molecule known to regulate pGE. AIRE is part of higher-order multiprotein complexes, which promote transcription, elongation, and splicing of a wide range of target genes. How AIRE and its partners mediate these various effects at the molecular level is still largely unclear. Using a yeast two-hybrid screen, we searched for novel AIRE-interacting proteins and identified the homeodomain-interacting protein kinase 2 (HIPK2) as a novel partner. HIPK2 partially colocalized with AIRE in nuclear bodies upon cotransfection and in human mTECs in situ. Moreover, HIPK2 phosphorylated AIRE in vitro and suppressed the coactivator activity of AIRE in a kinase-dependent manner. To evaluate the role of Hipk2 in modulating the function of AIRE in vivo, we compared whole-genome gene signatures of purified mTEC subsets from TEC-specific Hipk2 knockout mice with control mice and identified a small set of differentially expressed genes. Unexpectedly, most differentially expressed genes were confined to the CD80(lo) mTEC subset and preferentially included AIRE-independent TRAs. Thus, although it modulates gene expression in mTECs and in addition affects the size of the medullary compartment, TEC-specific HIPK2 deletion only mildly affects AIRE-directed pGE in vivo. Copyright © 2015 by The American Association of Immunologists, Inc.

  20. MEDULLARY THYROID CARCINOMA

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    V. S. Medvedev

    2013-01-01

    Full Text Available Medullary thyroid carcinoma belongs to orphan diseases affecting a small part of the population. Multicenter trials are required to elaborate a diagnostic algorithm, to define treatment policy, and to predict an outcome.

  1. PROJECTIONS FROM THE ROSTRAL PARVOCELLULAR RETICULAR-FORMATION TO PONTINE AND MEDULLARY NUCLEI IN THE RAT - INVOLVEMENT IN AUTONOMIC REGULATION AND OROFACIAL MOTOR CONTROL

    NARCIS (Netherlands)

    TERHORST, GJ; COPRAY, JCVM; LIEM, RSB; VANWILLIGEN, JD

    1991-01-01

    The efferent connections of the rostral parvocellular reticular formation to pontine and medullary nuclei in the rat were studied with anterogradely transported Phaseolus vulgaris leucoagglutinin. Dense innervations from the rostral parvocellular reticular formation were found in the mesencephalic

  2. Regulations of gene expression in medullary thymic epithelial cells required for preventing the onset of autoimmune diseases

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    Taishin eAkiyama

    2013-08-01

    Full Text Available Elimination of potential self-reactive T cells in the thymus is crucial for preventing the onset of autoimmune diseases. Epithelial cell subsets localized in thymic medulla (mTECs contribute to this process by supplying a wide range of self-antigens that are otherwise expressed in a tissue-specific manner (TSAs. Expression of some TSAs in mTECs is controlled by the autoimmune regulator (AIRE protein, of which dysfunctional mutations are the causative factor of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED. In addition to the elimination of self-reactive T cells, recent studies indicated roles of mTECs in the development of Foxp3-positive regulatory T cells, which suppress autoimmunity and excess immune reactions in peripheral tissues. The TNF family cytokines, RANK ligand, CD40 ligand and lymphotoxin were found to promote the differentiation of AIRE- and TSA-expressing mTECs. Furthermore, activation of NF-κB is essential for mTEC differentiation. In this mini-review, we focus on molecular mechanisms that regulate induction of AIRE and TSA expression and discuss possible contributions of these mechanisms to prevent the onset of autoimmune diseases.

  3. POWER SUPPLY PROTECTIVE CIRCUITRY.

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    A recommendation a corrective action plan was made as a solution to the high cost of common and protective circuitry in terms, of reliability of the power supply types A, B, C, D and E in the Minuteman system. (Author)

  4. Genome-wide location analysis reveals distinct transcriptional circuitry by paralogous regulators Foxa1 and Foxa2.

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    Irina M Bochkis

    Full Text Available Gene duplication is a powerful driver of evolution. Newly duplicated genes acquire new roles that are relevant to fitness, or they will be lost over time. A potential path to functional relevance is mutation of the coding sequence leading to the acquisition of novel biochemical properties, as analyzed here for the highly homologous paralogs Foxa1 and Foxa2 transcriptional regulators. We determine by genome-wide location analysis (ChIP-Seq that, although Foxa1 and Foxa2 share a large fraction of binding sites in the liver, each protein also occupies distinct regulatory elements in vivo. Foxa1-only sites are enriched for p53 binding sites and are frequently found near genes important to cell cycle regulation, while Foxa2-restricted sites show only a limited match to the forkhead consensus and are found in genes involved in steroid and lipid metabolism. Thus, Foxa1 and Foxa2, while redundant during development, have evolved divergent roles in the adult liver, ensuring the maintenance of both genes during evolution.

  5. Genome-Wide Location Analysis Reveals Distinct Transcriptional Circuitry by Paralogous Regulators Foxa1 and Foxa2

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    Bochkis, Irina M.; Schug, Jonathan; Ye, Diana Z.; Kurinna, Svitlana; Stratton, Sabrina A.; Barton, Michelle C.; Kaestner, Klaus H.

    2012-01-01

    Gene duplication is a powerful driver of evolution. Newly duplicated genes acquire new roles that are relevant to fitness, or they will be lost over time. A potential path to functional relevance is mutation of the coding sequence leading to the acquisition of novel biochemical properties, as analyzed here for the highly homologous paralogs Foxa1 and Foxa2 transcriptional regulators. We determine by genome-wide location analysis (ChIP-Seq) that, although Foxa1 and Foxa2 share a large fraction of binding sites in the liver, each protein also occupies distinct regulatory elements in vivo. Foxa1-only sites are enriched for p53 binding sites and are frequently found near genes important to cell cycle regulation, while Foxa2-restricted sites show only a limited match to the forkhead consensus and are found in genes involved in steroid and lipid metabolism. Thus, Foxa1 and Foxa2, while redundant during development, have evolved divergent roles in the adult liver, ensuring the maintenance of both genes during evolution. PMID:22737085

  6. NPR-9, a Galanin-Like G-Protein Coupled Receptor, and GLR-1 Regulate Interneuronal Circuitry Underlying Multisensory Integration of Environmental Cues in Caenorhabditis elegans.

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    Jason C Campbell

    2016-05-01

    Full Text Available C. elegans inhabit environments that require detection of diverse stimuli to modulate locomotion in order to avoid unfavourable conditions. In a mammalian context, a failure to appropriately integrate environmental signals can lead to Parkinson's, Alzheimer's, and epilepsy. Provided that the circuitry underlying mammalian sensory integration can be prohibitively complex, we analyzed nematode behavioral responses in differing environmental contexts to evaluate the regulation of context dependent circuit reconfiguration and sensorimotor control. Our work has added to the complexity of a known parallel circuit, mediated by interneurons AVA and AIB, that integrates sensory cues and is responsible for the initiation of backwards locomotion. Our analysis of the galanin-like G-protein coupled receptor NPR-9 in C. elegans revealed that upregulation of galanin signaling impedes the integration of sensory evoked neuronal signals. Although the expression pattern of npr-9 is limited to AIB, upregulation of the receptor appears to impede AIB and AVA circuits to broadly prevent backwards locomotion, i.e. reversals, suggesting that these two pathways functionally interact. Galanin signaling similarly plays a broadly inhibitory role in mammalian models. Moreover, our identification of a mutant, which rarely initiates backwards movement, allowed us to interrogate locomotory mechanisms underlying chemotaxis. In support of the pirouette model of chemotaxis, organisms that did not exhibit reversal behavior were unable to navigate towards an attractant peak. We also assessed ionotropic glutamate receptor GLR-1 cell-specifically within AIB and determined that GLR-1 fine-tunes AIB activity to modify locomotion following reversal events. Our research highlights that signal integration underlying the initiation and fine-tuning of backwards locomotion is AIB and NPR-9 dependent, and has demonstrated the suitability of C. elegans for analysis of multisensory integration

  7. Medullary carcinoma of the colon

    DEFF Research Database (Denmark)

    Fiehn, Anne-Marie Kanstrup; Grauslund, Morten; Glenthøj, Anders

    2015-01-01

    Medullary carcinoma of the colon is a rare variant of colorectal cancer claimed to have a more favorable prognosis than conventional adenocarcinomas. The histopathologic appearance may be difficult to distinguish from poorly differentiated adenocarcinoma. The study aimed to evaluate the diagnostic...... differences in CK20 (p = 0.005) expression and in the rate of BRAF mutations (p = 0.0035). In conclusion, medullary carcinomas of the colon are difficult to discriminate from poorly differentiated adenocarcinoma even with the help of immunohistochemical and molecular analyses. This raises the question whether...

  8. Medullary Sponge Kidney on Retrograde Pyelography

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    Huang, Tsung-Yi; Lin, Jih-Pin

    2014-01-01

    A woman aged 31 had recurrent urinary tract infection with bloody urine. A series image of medullary sponge kidney presented by intravenous urography (IVU) was detected dynamically by retrograde pyelography (RP). Other than ultrasonography and IVU, RP is also a reliable method to detect medullary sponge kidney. PMID:24855603

  9. Medullary sponge kidney associated with congenital hemihypertrophy.

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    Indridason, O S; Thomas, L; Berkoben, M

    1996-08-01

    Medullary sponge kidney is a developmental disorder characterized by ectatic and cystic malformation of the collecting ducts and tubules. Clinical manifestations include urinary tract infections, renal stones, and hematuria. It can be associated with other developmental disorders. A case of medullary sponge kidney associated with congenital hemihypertrophy, complicated by nephrocalcinosis and nephrolithiasis, is reported here.

  10. Medullary carcinoma of the thyroid

    International Nuclear Information System (INIS)

    Samuel, A.M.; Pradhan, S.A.; D'Cruz, A.; Shah, D.H.

    1999-01-01

    Medullary thyroid carcinoma is a biologically distinct form of thyroid cancer and accounts for 5-10% of all thyroid neoplasms. Twenty percent of MTC can occur in a familial setting either by itself or as part of the multiple endocrine neoplasm syndromes. A disciplined approach is necessary in the work-up of these patients to rule out coexistent endocrine tumors (pheochromocytomas and parathyroid). Cacitonin is a sensitive tumor marker secreted by MTC that is of prognostic value and important in the follow-up of patients. Surgery is the mainstay of treatment with a total thyroidectomy and centre compartment clearance being the minimum for patients without cervical adenopathy. Radiotherapy has a limited role and is only indicated as a palliative measure in patients with advanced/metastatic disease not amenable to surgery

  11. Renal acidification defects in medullary sponge kidney

    DEFF Research Database (Denmark)

    Osther, P J; Hansen, A B; Røhl, H F

    1988-01-01

    Thirteen patients with medullary sponge kidney underwent a short ammonium chloride loading test to investigate their renal acidification capacity. All but 1 presented with a history of recurrent renal calculi and showed bilateral widespread renal medullary calcification on X-ray examination. Nine...... patients had some form of renal acidification defect; 8 had the distal type of renal tubular acidosis, 2 the complete and 6 the incomplete form. One patient had proximal renal tubular acidosis. These findings, which suggest that renal acidification defects play an important role in the pathogenesis...... of renal calculi in medullary sponge kidney, have considerable therapeutic implications....

  12. Decreased GABAA receptor binding in the medullary serotonergic system in the sudden infant death syndrome.

    Science.gov (United States)

    Broadbelt, Kevin G; Paterson, David S; Belliveau, Richard A; Trachtenberg, Felicia L; Haas, Elisabeth A; Stanley, Christina; Krous, Henry F; Kinney, Hannah C

    2011-09-01

    γ-Aminobutyric acid (GABA) neurons in the medulla oblongata help regulate homeostasis, in part through interactions with the medullary serotonergic (5-HT) system. Previously, we reported abnormalities in multiple 5-HT markers in the medullary 5-HT system of infants dying from sudden infant death syndrome (SIDS), suggesting that 5-HT dysfunction is involved in its pathogenesis. Here, we tested the hypothesis that markers of GABAA receptors are decreased in the medullary 5-HT system in SIDS cases compared with controls. Using tissue receptor autoradiography with the radioligand H-GABA, we found 25% to 52% reductions in GABAA receptor binding density in 7 of 10 key nuclei sampled of the medullary 5-HT system in the SIDS cases (postconceptional age [PCA] = 51.7 ± 8.3, n = 28) versus age-adjusted controls (PCA = 55.3 ± 13.5, n = 8) (p ≤ 0.04). By Western blotting, there was 46.2% reduction in GABAAα3 subunit levels in the gigantocellularis (component of the medullary 5-HT system) of SIDS cases (PCA = 53.9 ± 8.4, n = 24) versus controls (PCA = 55.3 ± 8.3, n = 8) (56.8% standard in SIDS cases vs 99.35% in controls; p = 0.026). These data suggest that medullary GABAA receptors are abnormal in SIDS infants and that SIDS is a complex disorder of a homeostatic network in the medulla that involves deficits of the GABAergic and 5-HT systems.

  13. Optogenetic mapping of brain circuitry

    Science.gov (United States)

    Augustine, George J.; Berglund, Ken; Gill, Harin; Hoffmann, Carolin; Katarya, Malvika; Kim, Jinsook; Kudolo, John; Lee, Li M.; Lee, Molly; Lo, Daniel; Nakajima, Ryuichi; Park, Min Yoon; Tan, Gregory; Tang, Yanxia; Teo, Peggy; Tsuda, Sachiko; Wen, Lei; Yoon, Su-In

    2012-10-01

    Studies of the brain promise to be revolutionized by new experimental strategies that harness the combined power of optical techniques and genetics. We have mapped the circuitry of the mouse brain by using both optogenetic actuators that control neuronal activity and optogenetic sensors that detect neuronal activity. Using the light-activated cation channel, channelrhodopsin-2, to locally photostimulate neurons allows high-speed mapping of local and long-range circuitry. For example, with this approach we have mapped local circuits in the cerebral cortex, cerebellum and many other brain regions. Using the fluorescent sensor for chloride ions, Clomeleon, allows imaging of the spatial and temporal dimensions of inhibitory circuits in the brain. This approach allows imaging of both conventional "phasic" synaptic inhibition as well as unconventional "tonic" inhibition. The combined use of light to both control and monitor neural activity creates unprecedented opportunities to explore brain function, screen pharmaceutical agents, and potentially to use light to ameliorate psychiatric and neurological disorders.

  14. Genetics Home Reference: medullary cystic kidney disease type 1

    Science.gov (United States)

    ... Medullary cystic kidney disease type 1 Medullary cystic kidney disease type 1 Printable PDF Open All Close All ... is direct-to-consumer genetic testing? What is precision medicine? What is newborn screening? New Pages Pelizaeus-Merzbacher- ...

  15. Medullary Thyroid Carcinoma Program | Center for Cancer Research

    Science.gov (United States)

    Medullary Thyroid Carcinoma Program Multiple endocrine neoplasia (MEN) types 2A and 2B are rare genetic diseases, which lead to the development of medullary thyroid cancer, usually in childhood. Surgery is the only standard treatment.

  16. Recovery of Dysphagia in Lateral Medullary Stroke

    Directory of Open Access Journals (Sweden)

    Hitesh Gupta

    2014-01-01

    Full Text Available Lateral medullary stroke is typically associated with increased likelihood of occurrence of dysphagia and exhibits the most severe and persistent form. Worldwide little research exists on dysphagia in brainstem stroke. An estimated 15% of all patients admitted to stroke rehabilitation units experience a brainstem stroke out of which about 47% suffer from dysphagia. In India, a study showed that 22.3% of posterior circulation stroke patients develop dysphagia. Dearth of literature on dysphagia and its outcome in brainstem stroke particularly lateral medullary stroke motivated the author to present an actual case study of a patient who had dysphagia following a lateral medullary infarct. This paper documents the severity and management approach of dysphagia in brainstem stroke, with traditional dysphagia therapy and VitalStim therapy. Despite being diagnosed with a severe form of dysphagia followed by late treatment intervention, the patient had complete recovery of the swallowing function.

  17. 17β-Estradiol modulates cell proliferation of medullary cords during ovarian differentiation of the Lepidochelys olivacea sea turtle.

    Science.gov (United States)

    Díaz-Hernández, Verónica; Vázquez-Gómez, Alma; Marmolejo-Valencia, Alejandro; Montaño, Luis Manuel; Merchant-Larios, Horacio

    2017-11-15

    In turtles undergoing temperature sex determination (TSD), bipotential gonads express Sox9 in medullary cords at both female- (FPT) and male-producing temperatures (MPT). Subsequently, when the sex fate of medullary cords becomes dimorphic, at FPT, Sox9 is downregulated, whereas at MPT, its expression is maintained. Medullary cords in the ovary turn into ovarian lacuna, whereas in the testis they differentiate as seminiferous cords. When embryos of Lepidochelys olivacea sea turtle are incubated at MPT and treated with estradiol, Sox9 expression persists in the medullary cords in the form of tiny ovotestis-like formations. The perturbed development of the treated gonads is due to a significant decrease in the number of proliferating cells. This suggests that the disturbed effect caused by exogenous estradiol may be due to a conflict between the gene networks regulated by temperature and the increased level of endogenous estrogens, induced by the treatment. Here, we decided to use fadrozole and fulvestrant, an aromatase inhibitor and an estrogen-receptor antagonist, respectively, to provide insights into the role played by endogenous estrogens in regulating the cell proliferation of the two main gonadal compartments: the medullary cords and the cortex. Comparing cell proliferation patterns, our current results suggest that the endogenous estrogens are involved in determining the sex fate of medullary cords, by repressing proliferation. Interestingly, our results showed that endogenous estradiol levels are unnecessary for the thickening of the ovarian cortex. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Intraoperative neurophysiology of the conus medullaris and cauda equina.

    Science.gov (United States)

    Kothbauer, Karl F; Deletis, Vedran

    2010-02-01

    Intraoperative neurophysiological techniques are becoming routine tools for neurosurgical practice. Procedures affecting the lumbosacral nervous system are frequent in adult and pediatric neurosurgery. This review provides an overview of the techniques utilized in cauda and conus operations. Two basic methodologies of intraoperative neurophysiological testing are utilized during surgery in the lumbosacral spinal canal. Mapping techniques help identify functional neural structures, namely, nerve roots and their respective spinal levels. Monitoring is referred to as the technology to continuously assess the functional integrity of pathways and reflex circuits. For mapping direct electrical stimulation of a structure within the surgical field and recording at a distant site, usually a muscle is the most commonly used setup. Sensory nerve roots or spinal cord areas can be mapped by stimulation of a distant sensory nerve or skin area and recording from a structure within the surgical field. Continuous monitoring of the motor system is done with motor evoked potentials. These are evoked by transcranial electrical stimulation and recorded from lower extremity and sphincter muscles. Presence or absence of muscle responses are the monitored parameters. To monitor the sensory pathways, sensory potentials evoked by tibial, peroneal, or pudendal nerve stimulation and recorded from the dorsal columns with a spinal electrode or as cortical responses from scalp electrodes are used. Amplitudes and latencies of these responses are measured for interpretation. The bulbocavernosus reflex, with stimulation of the pudendal nerve and recording from the external anal sphincter, is used for continuous monitoring of the reflex circuitry. The presence of absence of this response is the pertinent parameter monitored. Stimulation of individual dorsal nerve roots is used to identify those segments that generate spastic activity and which may be cut during selective dorsal rhizotomy

  19. Schwannosis induced medullary compression in VACTERL syndrome.

    LENUS (Irish Health Repository)

    Treacy, A

    2011-10-21

    A 7-year-old boy with a history of VACTERL syndrome was found collapsed in bed. MRI had shown basilar invagination of the skull base and narrowing of the foramen magnum. Angulation, swelling and abnormal high signal at the cervicomedullary junction were felt to be secondary to compression of the medulla. Neuropathologic examination showed bilateral replacement of the medullary tegmentum by an irregularly circumscribed cellular lesion which was composed of elongated GFAP\\/S 100-positive cells with spindled nuclei and minimal atypia. The pathologic findings were interpreted as intramedullary schwannosis with mass effect. Schwannosis, is observed in traumatized spinal cords where its presence may represent attempted, albeit aberrant, repair by inwardly migrating Schwann cells ofperipheral origin. In our view the compressive effect of the basilar invagination on this boy\\'s medulla was of sufficient magnitude to have caused tumoral medullary schwannosis with resultant intermittent respiratory compromise leading to reflex anoxic seizures.

  20. Recurrent intramedullary epidermoid cyst of conus medullaris.

    LENUS (Irish Health Repository)

    Fleming, Christina

    2011-01-01

    Spinal intramedullary epidermoid cyst is a rare condition. Recurrent epidermoid cyst in the spine cord is known to occur. The authors describe a case of recurrent conus medullaris epidermoid cyst in a 24-year-old female. She initially presented at 7 years of age with bladder disturbance in the form of diurnal enuresis and recurrent urinary tract infection. MRI lumbar spine revealed a 4 cm conus medullaris epidermoid cyst. Since the initial presentation, the cyst had recurred seven times in the same location and she underwent surgical intervention in the form of exploration and debulking. This benign condition, owing to its anatomical location, has posed a surgical and overall management challenge. This occurrence is better managed in a tertiary-care centre requiring multi-disciplinary treatment approach.

  1. Recovery of Dysphagia in Lateral Medullary Stroke

    OpenAIRE

    Gupta, Hitesh; Banerjee, Alakananda

    2014-01-01

    Lateral medullary stroke is typically associated with increased likelihood of occurrence of dysphagia and exhibits the most severe and persistent form. Worldwide little research exists on dysphagia in brainstem stroke. An estimated 15% of all patients admitted to stroke rehabilitation units experience a brainstem stroke out of which about 47% suffer from dysphagia. In India, a study showed that 22.3% of posterior circulation stroke patients develop dysphagia. Dearth of literature on dysphagia...

  2. Medullary breast carcinoma: anatomo-radiological correlation

    Energy Technology Data Exchange (ETDEWEB)

    Matheus, Valeria Soares; Canella, Ellyete de Oliveira; Djahjah, Maria Celia Resende; Koch, Hilton Augusto [Instituto Nacional de Cancer (INCa), Rio de Janeiro, RJ (Brazil); Kestelman, Fabiola Procaci [Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ (Brazil); Instituto Nacional de Cancer (INCa), Rio de Janeiro, RJ (Brazil)]. E-mail: msavaleria@yahoo.com

    2008-11-15

    To evaluate radiological findings in patients submitted to surgical treatment for medullary breast cancer at Instituto Nacional de Cancer (INCa), Rio de Janeiro, RJ, Brazil, correlating them with histological results. A retrospective descriptive study was developed with patients submitted to surgery at INCa, in the period from January 1997 to December 2006, for identifying the presence of medullary breast carcinoma and analyzing radiological findings. Among 21,287 patients diagnosed with carcinoma, 76 (0.357%) had typical medullary breast carcinoma. The age range of these patients was 32-81 years (mean = 59.1 years). Mammography demonstrated lesions in 19 of these patients, 17 (89.5%) of them with masses, and 2 with focal asymmetry. Among the patients with masses, 15 (88.1%) presented with high density and 2 (11.9%) with isodensity. Twelve patients presented sonographic findings, 11 (91.6%) of them with hypoechoic masses, and one with an anechoic mass with areas of cystic degeneration. Nodular mass was the predominant radiological finding (89.5%), 88.1% of them corresponding to masses with high density and circumscribed margins. Despite the radiological characteristics of benignity, a solid, fast growing, highly dense mass with circumscribed margins should be further investigated to confirm the diagnosis. (author)

  3. Medullary breast carcinoma: anatomo-radiological correlation

    International Nuclear Information System (INIS)

    Matheus, Valeria Soares; Canella, Ellyete de Oliveira; Djahjah, Maria Celia Resende; Koch, Hilton Augusto; Kestelman, Fabiola Procaci

    2008-01-01

    To evaluate radiological findings in patients submitted to surgical treatment for medullary breast cancer at Instituto Nacional de Cancer (INCa), Rio de Janeiro, RJ, Brazil, correlating them with histological results. A retrospective descriptive study was developed with patients submitted to surgery at INCa, in the period from January 1997 to December 2006, for identifying the presence of medullary breast carcinoma and analyzing radiological findings. Among 21,287 patients diagnosed with carcinoma, 76 (0.357%) had typical medullary breast carcinoma. The age range of these patients was 32-81 years (mean = 59.1 years). Mammography demonstrated lesions in 19 of these patients, 17 (89.5%) of them with masses, and 2 with focal asymmetry. Among the patients with masses, 15 (88.1%) presented with high density and 2 (11.9%) with isodensity. Twelve patients presented sonographic findings, 11 (91.6%) of them with hypoechoic masses, and one with an anechoic mass with areas of cystic degeneration. Nodular mass was the predominant radiological finding (89.5%), 88.1% of them corresponding to masses with high density and circumscribed margins. Despite the radiological characteristics of benignity, a solid, fast growing, highly dense mass with circumscribed margins should be further investigated to confirm the diagnosis. (author)

  4. Nephronophthisis and medullary cystic kidney disease complex

    Directory of Open Access Journals (Sweden)

    Stanišić Marijana

    2005-01-01

    Full Text Available Background. Nephronophthisis and medullary cystic kidney disease complex refers to the genetic heterogeneous group of inherited tubulointerstital nephritis. Nephronophthisis comprises at last 3 clinical manifestations, has the autosomal recessive pattern of inheritance, appears early in life and is the most frequent inherited kidney disease that causes terminal renal failure in childhood, while medullary cystic kidney disease has the autosomal dominant pattern of inheritance, is less frequent, and terminal renal failure appears later in life. These two forms have similar clinical and morphological findings but extrarenal manifestations, the median ages of occurrence of terminal renal failure, and siblings presence help us distinguish these diseases. Case report. In this article we illustrated the case of a 20- years old patient with the suspicion of having complex nephornophthisis and medullary cystic kidney disease based upon mild renal failure, seen in routinely taken laboratory findings and bilateral cysts in corticomedullary region of the kidneys verified on abdominal ultrasound examination. Conclusion. This disease should rise suspicion in children or adolescents with progressive renal failure, a typical clinical manifestation, blood and urine samples results, bilateral cysts in the corticomedullary region of the kidneys seen during ultrasound examination of the kidneys and family inheritance.

  5. Convergence and cross talk in urogenital neural circuitries.

    Science.gov (United States)

    Hubscher, C H; Gupta, D S; Brink, T S

    2013-10-01

    Despite common comorbidity of sexual and urinary dysfunctions, the interrelationships between the neural control of these functions are poorly understood. The medullary reticular formation (MRF) contributes to both mating/arousal functions and micturition, making it a good site to test circuitry interactions. Urethane-anesthetized adult Wistar rats were used to examine the impact of electrically stimulating different nerve targets [dorsal nerve of the penis (DNP) or clitoris (DNC); L6/S1 trunk] on responses of individual extracellularly recorded MRF neurons. The effect of bladder filling on MRF neurons was also examined, as was stimulation of DNP on bladder reflexes via cystometry. In total, 236 MRF neurons responded to neurostimulation: 102 to DNP stimulation (12 males), 64 to DNC stimulation (12 females), and 70 to L6/S1 trunk stimulation (12 males). Amplitude thresholds were significantly different at DNP (15.0 ± 0.6 μA), DNC (10.5 ± 0.7 μA), and L6/S1 trunk (54.2 ± 4.6 μA), whereas similar frequency responses were found (max responses near 30-40 Hz). In five males, filling/voiding cycles were lengthened with DNP stimulation (11.0 ± 0.9 μA), with a maximal effective frequency plateau beginning at 30 Hz. Bladder effects lasted ≈ 2 min after DNP stimulus offset. Many MRF neurons receiving DNP/DNC input responded to bladder filling (35.0% and 68.3%, respectively), either just before (43%) or simultaneously with (57%) the voiding reflex. Taken together, MRF-evoked responses with neurostimulation of multiple nerve targets along with different responses to bladder infusion have implications for the role of MRF in multiple aspects of urogenital functions.

  6. Cellular transport of l-arginine determines renal medullary blood flow in control rats, but not in diabetic rats despite enhanced cellular uptake capacity.

    Science.gov (United States)

    Persson, Patrik; Fasching, Angelica; Teerlink, Tom; Hansell, Peter; Palm, Fredrik

    2017-02-01

    Diabetes mellitus is associated with decreased nitric oxide bioavailability thereby affecting renal blood flow regulation. Previous reports have demonstrated that cellular uptake of l-arginine is rate limiting for nitric oxide production and that plasma l-arginine concentration is decreased in diabetes. We therefore investigated whether regional renal blood flow regulation is affected by cellular l-arginine uptake in streptozotocin-induced diabetic rats. Rats were anesthetized with thiobutabarbital, and the left kidney was exposed. Total, cortical, and medullary renal blood flow was investigated before and after renal artery infusion of increasing doses of either l-homoarginine to inhibit cellular uptake of l-arginine or N ω -nitro- l-arginine methyl ester (l-NAME) to inhibit nitric oxide synthase. l-Homoarginine infusion did not affect total or cortical blood flow in any of the groups, but caused a dose-dependent reduction in medullary blood flow. l-NAME decreased total, cortical and medullary blood flow in both groups. However, the reductions in medullary blood flow in response to both l-homoarginine and l-NAME were more pronounced in the control groups compared with the diabetic groups. Isolated cortical tubular cells displayed similar l-arginine uptake capacity whereas medullary tubular cells isolated from diabetic rats had increased l-arginine uptake capacity. Diabetics had reduced l-arginine concentrations in plasma and medullary tissue but increased l-arginine concentration in cortical tissue. In conclusion, the reduced l-arginine availability in plasma and medullary tissue in diabetes results in reduced nitric oxide-mediated regulation of renal medullary hemodynamics. Cortical blood flow regulation displays less dependency on extracellular l-arginine and the upregulated cortical tissue l-arginine may protect cortical hemodynamics in diabetes. Copyright © 2017 the American Physiological Society.

  7. Signal conditioning circuitry design for instrumentation systems.

    Energy Technology Data Exchange (ETDEWEB)

    Larsen, Cory A.

    2012-01-01

    This report details the current progress in the design, implementation, and validation of the signal conditioning circuitry used in a measurement instrumentation system. The purpose of this text is to document the current progress of a particular design in signal conditioning circuitry in an instrumentation system. The input of the signal conditioning circuitry comes from a piezoresistive transducer and the output will be fed to a 250 ksps, 12-bit analog-to-digital converter (ADC) with an input range of 0-5 V. It is assumed that the maximum differential voltage amplitude input from the sensor is 20 mV with an unknown, but presumably high, sensor bandwidth. This text focuses on a specific design; however, the theory is presented in such a way that this text can be used as a basis for future designs.

  8. Packaging and interconnection for superconductive circuitry

    International Nuclear Information System (INIS)

    Anacker, W.

    1976-01-01

    A three dimensional microelectronic module packaged for reduced signal propagation delay times including a plurality of circuit carrying means, which may comprise unbacked chips, with integrated superconductive circuitry thereon is described. The circuit carrying means are supported on their edges and have contact lands in the vicinity of, or at, the edges to provide for interconnecting circuitry. The circuit carrying means are supported by supporting means which include slots to provide a path for interconnection wiring to contact the lands of the circuit carrying means. Further interconnecting wiring may take the form of integrated circuit wiring on the reverse side of the supporting means. The low heat dissipation of the superconductive circuitry allows the circuit carrying means to be spaced approximately no less than 30 mils apart. The three dimensional arrangement provides lower random propagation delays than would a planar array of circuits

  9. Role of the Oxytocin Receptor Expressed in the Rostral Medullary Raphe in Thermoregulation During Cold Conditions

    OpenAIRE

    Kasahara, Yoshiyuki; Tateishi, Yuko; Hiraoka, Yuichi; Otsuka, Ayano; Mizukami, Hiroaki; Ozawa, Keiya; Sato, Keisuke; Hidema, Shizu; Nishimori, Katsuhiko

    2015-01-01

    Recent papers have reported that oxytocin (Oxt) and the oxytocin receptor (Oxtr) may be involved in the regulation of food intake in mammals. We therefore suspected the Oxt/Oxtr system to be involved in energy homeostasis. In previous studies, we found a tendency toward obesity in Oxtr-deficient (Oxtr ?/?) mice, as well as impaired thermoregulation when these mice were exposed to cold conditions. In the present study, we observed the expression of Oxtr in the rostral medullary raphe (RMR), th...

  10. Medullary carcinoma of the thyroid - an unusual case of hyalinizing ...

    African Journals Online (AJOL)

    Medullary thyroid carcinoma is a neoplasm occurring in sporadic and familial patterns. A rare variant of medullary thyroid carcinoma shows microscopic features similar to hyalinizing trabecular adenoma of thyroid. Detection of this variant requires a high index of suspicion and immunohistochemical confirmation by ...

  11. MR imaging of medullary streaks in osteosclerosis: a case report

    International Nuclear Information System (INIS)

    Lee, Hak Soo; Joo, Kyung Bin; Park, Tae Soo; Song, Ho Taek; Kim, Yong Soo; Park, Dong Woo; Park, Choong Ki

    2000-01-01

    We present a case of medullary sclerosis of the appendicular skeleton in a patient with chronic renal insufficiency for whom MR imaging findings were characteristic. T1- and T2-weighted MR images showed multiple vertical lines (medullary streaks) of low signal intensity in the metaphyses and diaphyses of the distal femur and proximal tibia

  12. OCTREOTIDE FOR MEDULLARY-THYROID CARCINOMA ASSOCIATED DIARRHEA

    NARCIS (Netherlands)

    SMID, WM; DULLAART, RPF

    Medullary thyroid carcinoma associated diarrhoea can be disabling. A 75-yr-old man with metastatic medullary thyroid carcinoma and refractory diarrhoea is described. Subcutaneous administration of the somatostatin analogue, octreotide, 100-mu-g thrice daily, resulted in a sustained improvement in

  13. Renal medullary carcinoma with an ophthalmic metastasis

    Directory of Open Access Journals (Sweden)

    Christine Ibilibor

    2017-01-01

    Full Text Available Renal medullary carcinoma (RMC is a rare, aggressive primary renal malignancy that classically occurs in adolescent males with sickle cell trait and universally presents with metastatic disease at presentation. We report a case of medullary carcinoma in a young man with likely ophthalmic metastasis. We also review relevant literature available to date. The patient is a 20-year-old African-American male with a past medical history significant to for sickle cell trait who presented to the University Medical Center with cough and the right eye pain for 1 month as well as painless gross hematuria for 1 week. A chest and abdominal computed tomography showed a 7 cm hypodense right renal mass with bilateral hilar adenopathy, and multiple bilateral pulmonary nodules. A renal biopsy was performed and showed RMC. Ophthalmic exam revealed the right retinal hemorrhage concerning for a metastatic lesion. Palliative chemotherapy was offered to the patient, however, he and his family chose to enroll in hospice care considering his poor prognosis. He subsequently passed away 33 days after presentation. To our knowledge, there is only one other case of ophthalmic metastasis in a patient with metastatic RMC. Thus, we present this case to contribute to current literature regarding orbital metastasis in this largely fatal disease.

  14. Medullary sponge kidney and isolated hemihyperplasia

    Directory of Open Access Journals (Sweden)

    P S Priyamvada

    2014-01-01

    Full Text Available The term hemihyperplasia refers to an enlargement of body parts beyond the normal asymmetry. Hemihyperplasia can be isolated or associated with various well-described malformation syndromes. Medullary sponge kidney (MSK has been described with isolated and syndromic hemihyperplasia; the actual prevalence is not known The hemi hypertrophy can be so subtle that it may be easily overlooked. MSK need not be limited to the side of hemihyperplasia - most often it is bilateral. Around 33 cases has been reported from different parts of the world of which 15 cases are isolated hemi hyperplasia (IHH, the remaining occurring in the context of various malformation syndromes So far only one case has been reported from India. We report a case of IHH involving right side of the body, recurrent renal stones, incomplete distal renal tubular acidosis hypercalciuria and imaging showing bilateral MSKs.

  15. Carcinoma medular do rim Renal medullary carcinoma

    Directory of Open Access Journals (Sweden)

    Paulo Guilherme de Oliveira Salles

    2006-04-01

    Full Text Available É relatado caso de paciente de 24 anos, portador de traço falciforme, com imagem sólida no rim direito, submetido a nefrectomia radical que revelou tumor, cujo exame anatomopatológico permitiu o diagnóstico de carcinoma medular do rim. Os autores discutem aspectos dessa neoplasia, tais como freqüência, patogênese, apresentação clínica, histopatologia e evolução.We report the case of a 24-year-old patient who presented a left kidney tumor that was diagnosed as a medullary renal cell carcinoma. The following aspects of this neoplasia are discussed in this communication: frequency, pathogenesis, clinical presentation, histopathological findings, differential diagnosis and follow-up.

  16. Roentgenological findings of histiocytic medullary reticulosis in the lung

    International Nuclear Information System (INIS)

    Kim, Soon Yong; Lim, Jae Hoon; Suh, Soo Jhi

    1981-01-01

    Histiocytic medullary reticulosis, known as malignant histiocytosis, is a disorder characterized by a systemic proliferation of morphologically abnormal histiocytes with prominent erythrophagocytosis. Fever, wasting, lymphadenopathy, hepatosplenomegaly and pancytopenia are the main clinical pictures. Prognosis is very poor and invariably die within several months. Authors present radiological findings of pulmonary involvement in 5 cases of histologically proven histiocytic medullary reticulosis. The findings are progressive interstitial, alveolar or mixed infiltrations, small amount of pleural effusion, hilar and/or mediastinal lymph node enlargement and cardiomegaly. Histiocytic medullary reticulosis should be borne in mind in differential diagnosis of any patient who has unexplainable above radiological findings

  17. Optogenetic dissection of medial prefrontal cortex circuitry

    Directory of Open Access Journals (Sweden)

    Danai eRiga

    2014-12-01

    Full Text Available The medial prefrontal cortex (mPFC is critically involved in numerous cognitive functions, including attention, inhibitory control, habit formation, working memory and long-term memory. Moreover, through its dense interconnectivity with subcortical regions (e.g. thalamus, striatum, amygdala and hippocampus, the mPFC is thought to exert top-down executive control over the processing of aversive and appetitive stimuli. Because the mPFC has been implicated in the processing of a wide range of cognitive and emotional stimuli, it is thought to function as a central hub in the brain circuitry mediating symptoms of psychiatric disorders. New optogenetics technology enables anatomical and functional dissection of mPFC circuitry with unprecedented spatial and temporal resolution. This provides important novel insights in the contribution of specific neuronal subpopulations and their connectivity to mPFC function in health and disease states. In this review, we present the current knowledge obtained with optogenetic methods concerning mPFC function and dysfunction and integrate this with findings from traditional intervention approaches used to investigate the mPFC circuitry in animal models of cognitive processing and psychiatric disorders.

  18. Uptodate view on diagnostics and treatment of medullary thyroid cancer

    Directory of Open Access Journals (Sweden)

    D O Gazizova

    2013-09-01

    Full Text Available During last 4 years leading endocrine societies of the world published clinical recommendations on diag nostics and treatment of medullary thyroid cancer. The article covers most aspects of following patients with this pathology.

  19. The development of micromachined gyroscope structure and circuitry technology.

    Science.gov (United States)

    Xia, Dunzhu; Yu, Cheng; Kong, Lun

    2014-01-14

    This review surveys micromachined gyroscope structure and circuitry technology. The principle of micromachined gyroscopes is first introduced. Then, different kinds of MEMS gyroscope structures, materials and fabrication technologies are illustrated. Micromachined gyroscopes are mainly categorized into micromachined vibrating gyroscopes (MVGs), piezoelectric vibrating gyroscopes (PVGs), surface acoustic wave (SAW) gyroscopes, bulk acoustic wave (BAW) gyroscopes, micromachined electrostatically suspended gyroscopes (MESGs), magnetically suspended gyroscopes (MSGs), micro fiber optic gyroscopes (MFOGs), micro fluid gyroscopes (MFGs), micro atom gyroscopes (MAGs), and special micromachined gyroscopes. Next, the control electronics of micromachined gyroscopes are analyzed. The control circuits are categorized into typical circuitry and special circuitry technologies. The typical circuitry technologies include typical analog circuitry and digital circuitry, while the special circuitry consists of sigma delta, mode matching, temperature/quadrature compensation and novel special technologies. Finally, the characteristics of various typical gyroscopes and their development tendency are discussed and investigated in detail.

  20. The Development of Micromachined Gyroscope Structure and Circuitry Technology

    Directory of Open Access Journals (Sweden)

    Dunzhu Xia

    2014-01-01

    Full Text Available This review surveys micromachined gyroscope structure and circuitry technology. The principle of micromachined gyroscopes is first introduced. Then, different kinds of MEMS gyroscope structures, materials and fabrication technologies are illustrated. Micromachined gyroscopes are mainly categorized into micromachined vibrating gyroscopes (MVGs, piezoelectric vibrating gyroscopes (PVGs, surface acoustic wave (SAW gyroscopes, bulk acoustic wave (BAW gyroscopes, micromachined electrostatically suspended gyroscopes (MESGs, magnetically suspended gyroscopes (MSGs, micro fiber optic gyroscopes (MFOGs, micro fluid gyroscopes (MFGs, micro atom gyroscopes (MAGs, and special micromachined gyroscopes. Next, the control electronics of micromachined gyroscopes are analyzed. The control circuits are categorized into typical circuitry and special circuitry technologies. The typical circuitry technologies include typical analog circuitry and digital circuitry, while the special circuitry consists of sigma delta, mode matching, temperature/quadrature compensation and novel special technologies. Finally, the characteristics of various typical gyroscopes and their development tendency are discussed and investigated in detail.

  1. Introduction to European comments on "Medullary Thyroid Cancer

    DEFF Research Database (Denmark)

    Jarzab, Barbara; Feldt-Rasmussen, Ulla

    2013-01-01

    Guest Editors of Thyroid Research supplement devoted to medullary thyroid cancer present the history on how the discussion about "Medullary Thyroid Cancer: management guidelines of the American Thyroid Association" was initiated and subsequently widely commented before and during European Thyroid...... Association - Cancer Research Network Meeting in Lisbon. It is explained why it has been decided to publish the manuscripts within the supplement - to document voices from the discussion and popularize them....

  2. Medullary sponge kidney on axial computed tomography

    International Nuclear Information System (INIS)

    Ginalski, J.-M.; Schnyder, Pierre; Portmann, Luc; Jaeger, Philippe

    1991-01-01

    To evaluate features of medullary sponge kidney (MSK) on computed tomography (CT), 4-mm-thick axial slices without intravenous contrast material were 1st made in 13 patients through 24 kidneys which showed images of MSK on excretory urograms. On CT, papillary calcifications were found in 11 kidneys. In 5 of these, the calcifications were not detectable on plain films. Some hyperdense papillae (attenuation value 55-70 Hounsfield units) without calcification were found in 4 other kidneys. 9 kidneys appeared normal. 10 of the 14 kidneys were reexamined by a 2nd series of 4-mm-thick axial slices, 5 min after intravenous injection of 50 ml of Urografin. Images suggesting possible ectasia of precaliceal tubules were found in only 4 kidneys. These images appear much less obvious and characteristic on CT than on excretory urogram and do nothing more than suggest the possibility of MSK. In conclusion, the sensitivity of CT in the detection of MSK is markedly lower than that of excretory urography. In the most florid cases of the disease, CT can only show images suggesting the possibility of MSK. On the other hand, CT appears much more sensitive than plain films and tomograms of excretory in the detection of papillary calcifications, the most frequent complication of MSK. (author). 13 refs.; 3 figs

  3. Uptake of I-131 MIBG by medullary thyroid cancer

    International Nuclear Information System (INIS)

    Endo, K.; Koizumi, M.; Sakahara, H.

    1985-01-01

    I-131 MIBG scans are useful for the localization of pheochromocytoma and neuroblastoma with high catecholamine levels. Recently the authors have found that medullary thyroid cancer also showed an uptake of I-131 MIBG in both primary neck tumors and metastatic sites. Up to now scintigraphic studies were performed in 5 patients with medullary thyroid cancer. Scintigraphy was done at 24 and 48 hours after the administration of 0.5 mCi of I-131 MIBG, thyroid uptake of dissociated I-131 being prevented by Lugol's solution. Four out of 5 cases were familial type and uptake of I-131 MIBG was similarly observed in medullary thyroid cancer as well as in pheochromocytoma. Bone metastasis of medullary thyroid cancer was also detected with I-131 MIBG. However, one case of sporadic form was negative with I-131 MIBG, whereas there was a high uptake of Tc(V)-99m dimercaptosuccinic acid: a newly developed radiopharmaceutical for medullary thyroid cancer, visualizing a different uptake mechanism of both reagents (J Nucl Med 25: 323-325, 1984). After adrenalectomy high uptake of I-131 MIBG was still observed in medullary thyroid cancer, in spite of normal catecholamine levels. The tumor to blood ratio was estimated in vivo to be about several hundreds at 24 hours after the administration. These cells are of neural crest origin and the mechanism of uptake of I-131 MIBG may not be related to the catechamine uptake mechanism. This paper concludes that I-131 MIBG is useful not only for the localization but also for the treatment of medullary thyroid cancer, as preliminary performed in pheochromocytoma and neuroblastoma

  4. Mutant HABP2 Causes Non-Medullary Thyroid Cancer | Center for Cancer Research

    Science.gov (United States)

    The thyroid is a butterfly-shaped gland that lies at the base of the throat in front of the windpipe. A member of the endocrine system, the thyroid secretes hormones to regulate heart rate, blood pressure, temperature, and metabolism. Cancer of the thyroid is the most common endocrine cancer and the eighth most common cancer in the U.S. An estimated 63,450 Americans will be diagnosed with thyroid cancer this year. The vast majority is of follicular cell origin, and the remaining cancer originates from parafollicular cells, so called medullary thyroid cancer.

  5. Quantification of deep medullary veins at 7 T brain MRI

    Energy Technology Data Exchange (ETDEWEB)

    Kuijf, Hugo J.; Viergever, Max A.; Vincken, Koen L. [University Medical Center Utrecht, Image Sciences Institute, Utrecht (Netherlands); Bouvy, Willem H.; Razoux Schultz, Tom B.; Biessels, Geert Jan [University Medical Center Utrecht, Department of Neurology, Brain Center Rudolf Magnus, Utrecht (Netherlands); Zwanenburg, Jaco J.M. [University Medical Center Utrecht, Image Sciences Institute, Utrecht (Netherlands); University Medical Center Utrecht, Department of Radiology, Utrecht (Netherlands)

    2016-10-15

    Deep medullary veins support the venous drainage of the brain and may display abnormalities in the context of different cerebrovascular diseases. We present and evaluate a method to automatically detect and quantify deep medullary veins at 7 T. Five participants were scanned twice, to assess the robustness and reproducibility of manual and automated vein detection. Additionally, the method was evaluated on 24 participants to demonstrate its application. Deep medullary veins were assessed within an automatically created region-of-interest around the lateral ventricles, defined such that all veins must intersect it. A combination of vesselness, tubular tracking, and hysteresis thresholding located individual veins, which were quantified by counting and computing (3-D) density maps. Visual assessment was time-consuming (2 h/scan), with an intra-/inter-observer agreement on absolute vein count of ICC = 0.76 and 0.60, respectively. The automated vein detection showed excellent inter-scan reproducibility before (ICC = 0.79) and after (ICC = 0.88) visually censoring false positives. It had a positive predictive value of 71.6 %. Imaging at 7 T allows visualization and quantification of deep medullary veins. The presented method offers fast and reliable automated assessment of deep medullary veins. (orig.)

  6. Post-Aire maturation of thymic medullary epithelial cells involves selective expression of keratinocyte-specific autoantigens

    OpenAIRE

    Xiaoping eWang; Martti eLaan; Rudolf eBichele; Kai eKisand; Hamish S Scott; Hamish S Scott; Pärt ePeterson

    2012-01-01

    The autoimmune regulator (Aire)-directed ectopic expression of tissue-specific antigens (TSAs) by mature medullary thymic epithelial cells (mTECs) has been viewed as an essential mechanism in the induction of central tolerance. Recent data suggest that the survival of mTECs extends beyond the Aire+ cell population to form the post-Aire mTEC population and Hassall's corpuscles (HCs). The nature and function of these post-Aire epithelial cells and structures, however, have remained unidentified...

  7. Sudden death after medullary infarction—A case report

    Directory of Open Access Journals (Sweden)

    Yuh-Jen Wang

    2013-10-01

    Full Text Available Sudden death in a stable medullary infarction case frequently induces legal problems. Currently, the etiology of the most reported cases are not known because autopsy is rare. Here, we report one female patient with medullary infarction who experienced a sudden cardiopulmonary arrest during a brain magnetic resonance imaging (MRI study. The blood flow changes on the MRI indicated that her death resulted from the sudden collapse of systemic circulation. Dysautonomia, or sudden respiratory arrest resulting from brainstem dysfunction, was suspected. In this report, we present her cranial MRI findings and discuss the possible pathophysiology after reviewing the relevant literature. We also recommend certain tests for patients with medullary infarction to prevent the risk of sudden unexpected deaths.

  8. Synchronous multifocal medullary and papillary thyroid microcarcinoma detected by elastography.

    Science.gov (United States)

    Koudounarakis, Eleftherios; Karatzanis, Alexander; Chatzidakis, Alkiviadis; Tzardi, Maria; Velegrakis, George

    2014-01-01

    A few cases of concomitant medullary and papillary carcinoma in the same thyroid nodule have been described in the literature. However, the presence of multiple foci of both types of malignancy in the same gland is very rare. A 39 year-old female with multiple thyroid nodules, elevated serum calcitonin levels and elastographic findings suggestive of thyroid malignancy, underwent total thyroidectomy and central neck dissection. Histology revealed the presence of one focus of medullary and one focus of papillary carcinoma on each thyroid lobe. Subsequently, the patient underwent treatment with radioactive iodine. This is the third case of synchronous multifocal medullary and papillary thyroid carcinoma reported in the literature. Several theories for the simultaneous development of these malignant entities have been proposed. Ultrasound elastography can be a useful, noninvasive tool in the assessment of thyroid nodules. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Regulatory circuitry governing fungal development, drug resistance, and disease.

    Science.gov (United States)

    Shapiro, Rebecca S; Robbins, Nicole; Cowen, Leah E

    2011-06-01

    Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans, several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus, which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans, C. neoformans, and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease.

  10. How plastic are human spinal cord motor circuitries?

    DEFF Research Database (Denmark)

    Christiansen, Lasse; Lundbye-Jensen, Jesper; Perez, Monica A

    2017-01-01

    Human and animal studies have documented that neural circuitries in the spinal cord show adaptive changes caused by altered supraspinal and/or afferent input to the spinal circuitry in relation to learning, immobilization, injury and neurorehabilitation. Reversible adaptations following, e...

  11. Involvement of a chromatin modifier in response to mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cell injury: Probably an indirect action via the regulation of NFκB/FasL circuitry

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Shiwei [Department of Urology, 174th Hospital of PLA, Fujian 361001 (China); Dong, Yushu [Department of Neurosurgery, 463rd Hospital of PLA, Shenyang 110042 (China); Xu, Chun; Jiang, Liming; Chen, Yongjie; Jiang, Cheng [Department of Urology, 174th Hospital of PLA, Fujian 361001 (China); Hou, Wugang, E-mail: gangwuhou@163.com [Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032 (China); Li, Wei, E-mail: liweipepeyato@163.com [Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, Xi’an 710032 (China)

    2013-11-01

    Highlights: •MTA1 expression is upregulated in SCs upon MEHP treatment. •Knockdown of MTA1 in SCs impairs the MEHP-induced NFκB signaling activation. •Knockdown of MTA1 inhibits recruitment of NFκB onto FasL promoter in MEHP-treated SCs. -- Abstract: The Fas/FasL signaling pathway, controlled by nuclear factor-κB (NFκB) at the transcriptional level, is critical for triggering germ cell apoptosis in response to mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cell (SC) injury, but the exact regulation mechanism remain unknown. Here, we discovered that expression level of Metastasis associated protein 1 (MTA1), a component of the Mi-2/nucleosome remodeling and deacetylase complex, was upregulated in SCs during the early recovery after MEHP exposure. This expression change was in line with the dynamic changes in germ cell apoptosis in response to MEHP treatment. Furthermore, a knockdown of MTA1 by RNAi in SCs was found to impair the MEHP-induced early activation of NFκB pathway and abolish the recruitment of NFκB onto FasL promoter, which consequently diminished the MEHP-triggered FasL induction. Considering that Fas/FasL is a well characterized apoptosis initiating signaling during SCs injury, our results point to a potential “switch on” effect of MTA1, which may govern the activation of NFκB/FasL cascade in MEHP-insulted SCs. Overall, the MTA1/NFκB/FasL circuit may serve as an important defensive/repairing mechanism to help to control the germ cell quality after SCs injury.

  12. Development and aging of human spinal cord circuitries.

    Science.gov (United States)

    Geertsen, Svend Sparre; Willerslev-Olsen, Maria; Lorentzen, Jakob; Nielsen, Jens Bo

    2017-08-01

    The neural motor circuitries in the spinal cord receive information from our senses and the rest of the nervous system and translate it into purposeful movements, which allow us to interact with the rest of the world. In this review, we discuss how these circuitries are established during early development and the extent to which they are shaped according to the demands of the body that they control and the environment with which the body has to interact. We also discuss how aging processes and physiological changes in our body are reflected in adaptations of activity in the spinal cord motor circuitries. The complex, multifaceted connectivity of the spinal cord motor circuitries allows them to generate vastly different movements and to adapt their activity to meet new challenges imposed by bodily changes or a changing environment. There are thus plenty of possibilities for adaptive changes in the spinal motor circuitries both early and late in life. Copyright © 2017 the American Physiological Society.

  13. Conus Medullaris Arachnoid Cyst Presenting as Cauda Equina Syndrome.

    Science.gov (United States)

    Sharif, Salman; Afsar, Afifa; Qadeer, Mohsin

    2017-01-01

    Intradural arachnoid cysts are a rare cause of spinal cord and nerve root compression. Primarily, they are present in the thoracic region posteriorly. We report a 25-year-old man who had an intradural arachnoid cyst at the level of conus medullaris presenting with cauda equina syndrome, which is very rare.

  14. Is renal medullary carcinoma the seventh nephropathy in sickle cell ...

    African Journals Online (AJOL)

    Introduction: Previous studies had enlisted renal medullary carcinoma (RMC) as the seventh nephropathy in sickle cell disease (SCD). Clinical experience has contradicted this claim and this study is targeted at refuting or supporting this assumption. Objective: To estimate the prevalence of RMC and describe other renal ...

  15. Medullary thyroid cancer: RET testing of an archival material

    DEFF Research Database (Denmark)

    Godballe, Christian; Jørgensen, Gita; Gerdes, Anne-Marie

    2009-01-01

    Medullary thyroid carcinoma (MTC) might be sporadic (75%) or hereditary (25%). Until the mid nineties the diagnosis of hereditary MTC was based on family history, clinical evaluation, histological detection of C-cell hyperplasia and tumor multifocality. Patients and families with hereditary MTC...

  16. Medullary thyroid cancer: RET testing of an archival material

    DEFF Research Database (Denmark)

    Godballe, Christian; Jørgensen, Gita; Gerdes, Anne-Marie Axø

    2010-01-01

    Medullary thyroid carcinoma (MTC) might be sporadic (75%) or hereditary (25%). Until the mid nineties the diagnosis of hereditary MTC was based on family history, clinical evaluation, histological detection of C-cell hyperplasia and tumor multifocality. Patients and families with hereditary MTC...

  17. Oxytonergic circuitry sustains and enables creative cognition in humans

    Science.gov (United States)

    Baas, Matthijs; Roskes, Marieke; Sligte, Daniel J.; Ebstein, Richard P.; Chew, Soo Hong; Tong, Terry; Jiang, Yushi; Mayseless, Naama; Shamay-Tsoory, Simone G.

    2014-01-01

    Creativity enables humans to adapt flexibly to changing circumstances, to manage complex social relations and to survive and prosper through social, technological and medical innovations. In humans, chronic, trait-based as well as temporary, state-based approach orientation has been linked to increased capacity for divergent rather than convergent thinking, to more global and holistic processing styles and to more original ideation and creative problem solving. Here, we link creative cognition to oxytocin, a hypothalamic neuropeptide known to up-regulate approach orientation in both animals and humans. Study 1 (N = 492) showed that plasma oxytocin predicts novelty-seeking temperament. Study 2 (N = 110) revealed that genotype differences in a polymorphism in the oxytocin receptor gene rs1042778 predicted creative ideation, with GG/GT-carriers being more original than TT-carriers. Using double-blind placebo-controlled between-subjects designs, Studies 3–6 (N = 191) finally showed that intranasal oxytocin (vs matching placebo) reduced analytical reasoning, and increased holistic processing, divergent thinking and creative performance. We conclude that the oxytonergic circuitry sustains and enables the day-to-day creativity humans need for survival and prosperity and discuss implications. PMID:23863476

  18. Transitional circuitry for studying the properties of DNA

    Science.gov (United States)

    Trubochkina, N.

    2018-01-01

    The article is devoted to a new view of the structure of DNA as an intellectual scheme possessing the properties of logic and memory. The theory of transient circuitry, developed by the author for optimal computer circuits, revealed an amazing structural similarity between mathematical models of transition silicon elements and logic and memory circuits of solid state transient circuitry and atomic models of parts of DNA.

  19. Aire Downregulation Is Associated with Changes in the Posttranscriptional Control of Peripheral Tissue Antigens in Medullary Thymic Epithelial Cells

    OpenAIRE

    Oliveira, Ernna H.; Macedo, Claudia; Collares, Cristhianna V.; Freitas, Ana Carolina; Donate, Paula Barbim; Sakamoto-Hojo, Elza T.; Donadi, Eduardo A.; Passos, Geraldo A.

    2016-01-01

    Autoimmune regulator (Aire) is a transcriptional regulator of peripheral tissue antigens (PTAs) and microRNAs (miRNAs) in medullary thymic epithelial cells (mTECs). In this study, we tested the hypothesis that Aire also played a role as an upstream posttranscriptional controller in these cells and that variation in its expression might be associated with changes in the interactions between miRNAs and the mRNAs encoding PTAs. We demonstrated that downregulation of Aire in vivo in the thymuses ...

  20. Cysticercosis of conus medullaris: A case report and literature review

    Directory of Open Access Journals (Sweden)

    Saurabh K Verma

    2014-01-01

    Full Text Available "Neurocysticercosis" - involvement of the central nervous system (CNS by taenia solium, is one of the most common parasitic diseases of the CNS. However, spinal involvement by neurocysticercosis is uncommon. Spinal intramedullary cysticercosis involving the conus medullaris is an uncommon clinical condition, which may mimic an intramedullary tumor and can lead to irreversible neurological deficits if untreated. Here, we report a 31-year-old male patient with cysticercosis in the conus medullaris of the spinal cord. Magnetic resonance imaging revealed a well-defined round intramedullary lesion at D12-L1 vertebral levels, which was homogeneously hypointense on T1WI and hyperintense on T2WI with peripheral edema. Since the patient had progressive neurological deficits, surgery was performed to decompress the spinal cord. Histopathology examination of the removed lesion proved it to be cysticercosis. In this report, we also discuss the principles of diagnosis and treatment of intramedullary cysticercosis in combination with literature review.

  1. Circuitry linking the Csr and stringent response global regulatory systems.

    Science.gov (United States)

    Edwards, Adrianne N; Patterson-Fortin, Laura M; Vakulskas, Christopher A; Mercante, Jeffrey W; Potrykus, Katarzyna; Vinella, Daniel; Camacho, Martha I; Fields, Joshua A; Thompson, Stuart A; Georgellis, Dimitris; Cashel, Michael; Babitzke, Paul; Romeo, Tony

    2011-06-01

    CsrA protein regulates important cellular processes by binding to target mRNAs and altering their translation and/or stability. In Escherichia coli, CsrA binds to sRNAs, CsrB and CsrC, which sequester CsrA and antagonize its activity. Here, mRNAs for relA, spoT and dksA of the stringent response system were found among 721 different transcripts that copurified with CsrA. Many of the transcripts that copurified with CsrA were previously determined to respond to ppGpp and/or DksA. We examined multiple regulatory interactions between the Csr and stringent response systems. Most importantly, DksA and ppGpp robustly activated csrB/C transcription (10-fold), while they modestly activated csrA expression. We propose that CsrA-mediated regulation is relieved during the stringent response. Gel shift assays confirmed high affinity binding of CsrA to relA mRNA leader and weaker interactions with dksA and spoT. Reporter fusions, qRT-PCR and immunoblotting showed that CsrA repressed relA expression, and (p)ppGpp accumulation during stringent response was enhanced in a csrA mutant. CsrA had modest to negligible effects on dksA and spoT expression. Transcription of dksA was negatively autoregulated via a feedback loop that tended to mask CsrA effects. We propose that the Csr system fine-tunes the stringent response and discuss biological implications of the composite circuitry. © Published 2011. This article is a US Government work and is in the public domain in the USA.

  2. Medullary carcinoma arising in a thyroid with Hashimoto's disease.

    Science.gov (United States)

    Weiss, L M; Weinberg, D S; Warhol, M J

    1983-10-01

    A 51-year-old woman presented with a large goiter and on pathologic examination was found to have both Hashimoto's thyroiditis and medullary carcinoma of the thyroid. To our knowledge, this is the first well-documented case of the coexistence of these two entities in the same patient in the English literature. The association of Hashimoto's disease and carcinoma of the thyroid is reviewed and its relevance discussed.

  3. A Developmental Shift from Positive to Negative Connectivity in Human Amygdala-Prefrontal Circuitry

    Science.gov (United States)

    Gee, Dylan G.; Humphreys, Kathryn L.; Flannery, Jessica; Goff, Bonnie; Telzer, Eva H.; Shapiro, Mor; Hare, Todd A.; Bookheimer, Susan Y.; Tottenham, Nim

    2013-01-01

    Recent human imaging and animal studies highlight the importance of frontoamygdala circuitry in the regulation of emotional behavior and its disruption in anxiety-related disorders. While tracing studies have suggested changes in amygdala-cortical connectivity through the adolescent period in rodents, less is known about the reciprocal connections within this circuitry across human development, when these circuits are being fine-tuned and substantial changes in emotional control are observed. The present study examined developmental changes in amygdala-prefrontal circuitry across the ages of 4 to 22 years using task-based functional magnetic resonance imaging (fMRI). Results suggest positive amygdala-prefrontal connectivity in early childhood that switches to negative functional connectivity during the transition to adolescence. Amygdala-mPFC functional connectivity was significantly positive (greater than zero) among participants younger than ten, whereas functional connectivity was significantly negative (less than zero) among participants ten years and older, over and above the effect of amygdala reactivity. The developmental switch in functional connectivity was paralleled by a steady decline in amygdala reactivity. Moreover, the valence switch might explain age-related improvement in task performance and a developmentally normative decline in anxiety. Initial positive connectivity followed by a valence shift to negative connectivity provides a neurobiological basis for regulatory development and may present novel insight into a more general process of developing regulatory connections. PMID:23467374

  4. Direction-selective circuitry in rat retina develops independently of GABAergic, cholinergic and action potential activity.

    Directory of Open Access Journals (Sweden)

    Le Sun

    Full Text Available The ON-OFF direction selective ganglion cells (DSGCs in the mammalian retina code image motion by responding much more strongly to movement in one direction. They do so by receiving inhibitory inputs selectively from a particular sector of processes of the overlapping starburst amacrine cells, a type of retinal interneuron. The mechanisms of establishment and regulation of this selective connection are unknown. Here, we report that in the rat retina, the morphology, physiology of the ON-OFF DSGCs and the circuitry for coding motion directions develop normally with pharmacological blockade of GABAergic, cholinergic activity and/or action potentials for over two weeks from birth. With recent results demonstrating light independent formation of the retinal DS circuitry, our results strongly suggest the formation of the circuitry, i.e., the connections between the second and third order neurons in the visual system, can be genetically programmed, although emergence of direction selectivity in the visual cortex appears to require visual experience.

  5. Medullary Thyroid Carcinoma Presenting as a Predominantly Cystic Mass on Ultrasonography: A Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ja Young; Kim, Ah Hyun; Moon, Hee Jung; Kim, Eun Kyung; Kwak, Jin Young [Yonsei University College of Medicine, Seoul (Korea, Republic of); Choi, Jun Jeong [Wonju College of Medicine, Wonju (Korea, Republic of); Kim, Myung Hyun [Gangnam MizMedi Hospital, Seoul (Korea, Republic of)

    2012-03-15

    Most medullary thyroid carcinomas show suspicious malignant features such as hypoechogenicity, a spiculated margin and/or intranodular calcifications, which are well known features of papillary carcinoma. We report here on a case of medullary carcinoma that was seen as a predominantly cystic thyroid mass on ultrasonography. This type of case is not common in the literature and we discuss the way to diagnose a medullary thyroid carcinoma

  6. Multiple fracture of medullary tube during intramedullary nailing of long bone fractures.

    Science.gov (United States)

    Vakharia, M R; Lehto, S A; Mohler, D G

    2000-01-01

    Intramedullary nailing is an accepted treatment for the fixation of femoral and tibial shaft fractures. There is a low but significant incidence of intraoperative complications during intramedullary nailing. During this procedure, a medullary tube may be used to exchange the bent olive-tipped reaming guidewire for the straight guidewire. A review of the literature found only one report of a fracture of the medullary tube. Two cases in which the medullary tube fractured into multiple pieces are presented.

  7. [Autosomal recessive polycystic kidney disease and complex nephronophtisis medullary cystic disease].

    Science.gov (United States)

    2008-12-01

    Reseach during the past decade has led to the discovery that defects in some proteins that localize to primary cilia or the basal body are the main contributors to renal cyst development. Autosomal recessive polycystic disease and nephronophthisis- medullary cystic kidney disease are named ciliopathies. The cilium is a microtubule-based organelle that is found on most mammalian cells. Cilia-mediated hypothesis has evolved into the concept of cystogenesis, cilia bend by fluid initiate a calcium influx that prevents cyst formation. Cilia might sense stimuli in the cell enviroment and control cell polarity and mitosis. A new set of pathogenic mechanisms in renal cystic disease defined new therapeutic targets, control of intracellular calcium, inhibition of cAMP and down regulation cannonical Wnt signaling.

  8. Genome-wide gene expression profiling of homeodomain-interacting protein kinase 2 deficient medullary thymic epithelial cells

    Directory of Open Access Journals (Sweden)

    Kristin Rattay

    2015-12-01

    Full Text Available The establishment of central tolerance essentially depends on the promiscuous gene expression (pGE of a plethora of tissue restricted antigens by the medullary thymic epithelial cells. The antigens are presented to developing thymocytes in the thymus to select for non-self reactive T-cell receptors in order to prevent autoimmune reactions in the periphery. However the molecular regulation of tissue-restricted antigen expression is still poorly understood. The only regulator known to play a role in the transcriptional regulation so far is the autoimmune regulator (AIRE. AIRE is thought to act in a multi-protein complex, promoting transcription, elongation and splicing of target genes. Yet the full composition of this Aire-associated multi-protein complex and its mode of action remain to be elucidated. Here we describe the experimental details and controls of the gene array analysis on the impact of the homeodomain-interacting protein kinase 2 (Hipk2 on promiscuous gene expression in medullary thymic epithelial cells based on the analysis of newly generated TEC-specific Hipk2 conditional knockout mice. The changes in gene expression are presumably mediated through a regulatory effect of Hipk2 on AIRE as published in the study by Rattay and colleagues in the Journal of Immunology [1]. The gene array data reported in this paper have been deposited in the Gene Expression Omnibus (GEO database, www.ncbi.nlm.nih.gov/geo (accession no. GSE63432.

  9. Functional characterization of obesogenic neural circuitries

    NARCIS (Netherlands)

    Boender, A.J.

    2015-01-01

    Obesity can be characterized as a disorder in which affected individuals fail to properly regulate the balance between energy intake and expenditure. Recently, genome-wide association studies have identified over 30 genetic variants that associate with increased body weight and thus provide clues on

  10. Corticostriatal circuitry and habitual ethanol seeking

    Science.gov (United States)

    Barker, Jacqueline M.; Corbit, Laura H.; Robinson, Donita L.; Gremel, Christina M.; Gonzales, Rueben A.; Chandler, L. Judson

    2015-01-01

    The development of alcohol-use disorders is thought to involve a transition from casual alcohol use to uncontrolled alcohol-seeking behavior. This review will highlight evidence suggesting that the shift toward inflexible alcohol seeking that occurs across the development of addiction consists, in part, of a progression from goal-directed to habitual behaviors. This shift in “response strategy” is thought to be largely regulated by corticostriatal network activity. Indeed, specific neuroanatomical substrates within the prefrontal cortex and the striatum have been identified as playing opposing roles in the expression of actions and habits. A majority of the research on the neurobiology of habitual behavior has focused on non-drug reward seeking. Here, we will highlight recent research identifying corticostriatal structures that regulate the expression of habitual alcohol seeking and a comparison will be made when possible to findings for non-drug rewards. PMID:26059221

  11. Development and aging of human spinal cord circuitries

    DEFF Research Database (Denmark)

    Geertsen, Svend Sparre; Willerslev-Olsen, Maria; Lorentzen, Jakob

    2017-01-01

    development and to what extent they are shaped according to the demands of the body that they control and the environment that the body has to interact with. We also discuss how ageing processes and physiological changes in our body are reflected in adaptations of activity in the spinal cord motor circuitries....... The complex, multi-facetted connectivity of the spinal cord motor circuitries allow that they can be used to generate vastly different movements and that their activity can be adapted to meet new challenges imposed by bodily changes or a changing environment. There are thus plenty of possibilities...

  12. Medullary thyroid cancer: RET testing of an archival material

    DEFF Research Database (Denmark)

    Godballe, Christian; Jørgensen, Gita; Gerdes, Anne-Marie Axø

    2010-01-01

    Medullary thyroid carcinoma (MTC) might be sporadic (75%) or hereditary (25%). Until the mid nineties the diagnosis of hereditary MTC was based on family history, clinical evaluation, histological detection of C-cell hyperplasia and tumor multifocality. Patients and families with hereditary MTC m...... by testing of non-tumor tissue from patients with known hereditary MTC. This study shows that genetic testing of archival MTC material is technically possible and might be a way of identifying patients with previously not recognized hereditary MTC....

  13. Is thyroidectomy necessary in RET mutations carriers of the familial medullary thyroid carcinoma syndrome?

    DEFF Research Database (Denmark)

    Hansen, H S; Torring, H; Godballe, C

    2000-01-01

    BACKGROUND: The results and consequences of genetic testing in a family with familial medullary thyroid carcinoma (FMTC) are described. METHODS: In the screening of relatives, serum calcitonin is replaced by RET mutation analysis that was performed in families suspected of hereditary medullary th...

  14. The Development of Micromachined Gyroscope Structure and Circuitry Technology

    OpenAIRE

    Dunzhu Xia; Cheng Yu; Lun Kong

    2014-01-01

    This review surveys micromachined gyroscope structure and circuitry technology. The principle of micromachined gyroscopes is first introduced. Then, different kinds of MEMS gyroscope structures, materials and fabrication technologies are illustrated. Micromachined gyroscopes are mainly categorized into micromachined vibrating gyroscopes (MVGs), piezoelectric vibrating gyroscopes (PVGs), surface acoustic wave (SAW) gyroscopes, bulk acoustic wave (BAW) gyroscopes, micromachined electrostati...

  15. Progress toward the maintenance and repair of degenerating retinal circuitry.

    Science.gov (United States)

    Vugler, Anthony A

    2010-01-01

    Retinal diseases such as age-related macular degeneration and retinitis pigmentosa remain major causes of severe vision loss in humans. Clinical trials for treatment of retinal degenerations are underway and advancements in our understanding of retinal biology in health/disease have implications for novel therapies. A review of retinal biology is used to inform a discussion of current strategies to maintain/repair neural circuitry in age-related macular degeneration, retinitis pigmentosa, and Type 2 Leber congenital amaurosis. In age-related macular degeneration/retinitis pigmentosa, a progressive loss of rods/cones results in corruption of bipolar cell circuitry, although retinal output neurons/photoreceptive melanopsin cells survive. Visual function can be stabilized/enhanced after treatment in age-related macular degeneration, but in advanced degenerations, reorganization of retinal circuitry may preclude attempts to restore cone function. In Type 2 Leber congenital amaurosis, useful vision can be restored by gene therapy where central cones survive. Remarkable progress has been made in restoring vision to rodents using light-responsive ion channels inserted into bipolar cells/retinal ganglion cells. Advances in genetic, cellular, and prosthetic therapies show varying degrees of promise for treating retinal degenerations. While functional benefits can be obtained after early therapeutic interventions, efforts should be made to minimize circuitry changes as soon as possible after rod/cone loss. Advances in retinal anatomy/physiology and genetic technologies should allow refinement of future reparative strategies.

  16. The origin of behavioral bursts in decision-making circuitry.

    Directory of Open Access Journals (Sweden)

    Amanda Sorribes

    2011-06-01

    Full Text Available From ants to humans, the timing of many animal behaviors comes in bursts of activity separated by long periods of inactivity. Recently, mathematical modeling has shown that simple algorithms of priority-driven behavioral choice can result in bursty behavior. To experimentally test this link between decision-making circuitry and bursty dynamics, we have turned to Drosophila melanogaster. We have found that the statistics of intervals between activity periods in endogenous activity-rest switches of wild-type Drosophila are very well described by the Weibull distribution, a common distribution of bursty dynamics in complex systems. The bursty dynamics of wild-type Drosophila walking activity are shown to be determined by this inter-event distribution alone and not by memory effects, thus resembling human dynamics. Further, using mutant flies that disrupt dopaminergic signaling or the mushroom body, circuitry implicated in decision-making, we show that the degree of behavioral burstiness can be modified. These results are thus consistent with the proposed link between decision-making circuitry and bursty dynamics, and highlight the importance of using simple experimental systems to test general theoretical models of behavior. The findings further suggest that analysis of bursts could prove useful for the study and evaluation of decision-making circuitry.

  17. Bilateral Medial Medullary Stroke: A Challenge in Early Diagnosis

    Directory of Open Access Journals (Sweden)

    Amir M. Torabi

    2013-01-01

    Full Text Available Bilateral medial medullary stroke is a very rare type of stroke, with catastrophic consequences. Early diagnosis is crucial. Here, I present a young patient with acute vertigo, progressive generalized weakness, dysarthria, and respiratory failure, who initially was misdiagnosed with acute vestibular syndrome. Initial brain magnetic resonance imaging (MRI that was done in the acute phase was read as normal. Other possibilities were excluded by lumbar puncture and MRI of cervical spine. MR of C-spine showed lesion at medial medulla; therefore a second MRI of brain was requested, showed characteristic “heart appearance” shape at diffusion weighted (DWI, and confirmed bilateral medial medullary stroke. Retrospectively, a vague-defined hyperintense linear DWI signal at midline was noted in the first brain MRI. Because of the symmetric and midline pattern of this abnormal signal and similarity to an artifact, some radiologists or neurologists may miss this type of stroke. Radiologists and neurologists must recognize clinical and MRI findings of this rare type of stroke, which early treatment could make a difference in patient outcome. The abnormal DWI signal in early stages of this type of stroke may not be a typical “heart appearance” shape, and other variants such as small dot or linear DWI signal at midline must be recognized as early signs of stroke. Also, MRI of cervical spine may be helpful if there is attention to brainstem as well.

  18. MR imaging of medullary compression due to vertebral metastases

    International Nuclear Information System (INIS)

    Dooms, G.C.; Mathurin, P.; Maldague, B.; Cornelis, G.; Malghem, J.; Demeure, R.

    1987-01-01

    A prospective study was performed to assess the value of MR imaging for demonstrating medullary compression due to vertebral metastases in cancer patients clinically suspected of presenting with that complication. Twenty-five consecutive unselected patients were studied, and the MR imaging findings were confirmed by myelography, CT, and/or surgical and autopsy findings for each patient. The MR examinations were performed with a superconducting magnet (Philips Gyroscan S15) operating at 0.5-T. MR imaging demonstrated the metastases (single or multiple) mainly on T1- weighted images (TR = 0.45 sec and TE = 20 msec). Soft-tissue tumoral mass and/or deformity of a vertebral body secondary to metastasis, compressing the spinal cord, was equally demonstrated on T1- and heavily T2-weighted images (TR = 1.65 sec and TE = 100 msec). In the sagittal plane, MR imaging demonstrated the exact level of the compression (one or multiple levels) and its full extent. In conclusion, MR is the first imaging modality for studying cancer patients with clinically suspected medullary compression and obviates the need for more invasive procedures

  19. The architecture and conservation pattern of whole-cell control circuitry.

    Science.gov (United States)

    McAdams, Harley H; Shapiro, Lucy

    2011-05-27

    The control circuitry that directs and paces Caulobacter cell cycle progression involves the entire cell operating as an integrated system. This control circuitry monitors the environment and the internal state of the cell, including the cell topology, as it orchestrates orderly activation of cell cycle subsystems and Caulobacter's asymmetric cell division. The proteins of the Caulobacter cell cycle control system and its internal organization are co-conserved across many alphaproteobacteria species, but there are great differences in the regulatory apparatus' functionality and peripheral connectivity to other cellular subsystems from species to species. This pattern is similar to that observed for the "kernels" of the regulatory networks that regulate development of metazoan body plans. The Caulobacter cell cycle control system has been exquisitely optimized as a total system for robust operation in the face of internal stochastic noise and environmental uncertainty. When sufficient details accumulate, as for Caulobacter cell cycle regulation, the system design has been found to be eminently rational and indeed consistent with good design practices for human-designed asynchronous control systems. Copyright © 2011 Elsevier Ltd. All rights reserved.

  20. Medullary Thyroid Carcinoma: Targeted Therapies and Future Directions

    Directory of Open Access Journals (Sweden)

    Scott N. Pinchot

    2009-01-01

    Full Text Available Medullary thyroid cancer (MTC is a rare neuroendocrine neoplasm that accounts for approximately 5% of all thyroid malignancies. The natural history of MTC is characterized by early lymph node and distant metastases, making complete surgical cure often impossible. Conventional chemotherapy and external beam radiation have been largely ineffective in altering the natural history of MTC. Therefore, there is a great need to develop novel therapeutic strategies to affect symptom control and reduce tumor burden in patients with widely disseminated disease. Here, we review several pathways which have been shown to be vital in MTC tumorigenesis and focus on the pathways of interest for which targeted drug therapies are currently being developed.

  1. 2012 European Thyroid Association Guidelines for Metastatic Medullary Thyroid Cancer

    Directory of Open Access Journals (Sweden)

    V V Voskoboynikov

    2013-06-01

    Full Text Available Distant metastases are the main cause of death in patients with medullary thyroid cancer (MTC. These 21 recommendations focus on MTC patients with distant metastases and a detailed followup protocol of patients with biochemical or imaging evidence of disease, selection criteria for treatment, and treatment modalities, including local and systemic treatments based on the results of recent trials. Asymptomatic patients with low tumor burden and stable disease may benefit from local treatment modalities and can be followed up at regular intervals of time. Imaging is usually performed every 6–12 months, or at longer inter vals of time depending on the doubling times of serum calcitonin and carcinoembryonic antigen levels. Patients with symptoms, large tumor burden and progression on imaging should receive systemic treatment. Indeed, major progress has recently been achieved with novel targeted therapies using kinase inhibitors directed against RET and VEGFR, but further research is needed to improve the outcome of these patients.

  2. Central Brain Circuitry for Color-Vision-Modulated Behaviors.

    Science.gov (United States)

    Longden, Kit D

    2016-10-24

    Color is famous for not existing in the external world: our brains create the perception of color from the spatial and temporal patterns of the wavelength and intensity of light. For an intangible quality, we have detailed knowledge of its origins and consequences. Much is known about the organization and evolution of the first phases of color processing, the filtering of light in the eye and processing in the retina, and about the final phases, the roles of color in behavior and natural selection. To understand how color processing in the central brain has evolved, we need well-defined pathways or circuitry where we can gauge how color contributes to the computations involved in specific behaviors. Examples of such pathways or circuitry that are dedicated to processing color cues are rare, despite the separation of color and luminance pathways early in the visual system of many species, and despite the traditional definition of color as being independent of luminance. This minireview presents examples in which color vision contributes to behaviors dominated by other visual modalities, examples that are not part of the canon of color vision circuitry. The pathways and circuitry process a range of chromatic properties of objects and their illumination, and are taken from a variety of species. By considering how color processing complements luminance processing, rather than being independent of it, we gain an additional way to account for the diversity of color coding in the central brain, its consequences for specific behaviors and ultimately the evolution of color vision. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Bladder urine oxygen tension for assessing renal medullary oxygenation in rabbits: experimental and modeling studies

    OpenAIRE

    Sgouralis, Ioannis; Kett, Michelle M.; Ow, Connie P. C.; Abdelkader, Amany; Layton, Anita T.; Gardiner, Bruce S.; Smith, David W.; Lankadeva, Yugeesh R.; Evans, Roger G.

    2016-01-01

    Oxygen tension (Po2) of urine in the bladder could be used to monitor risk of acute kidney injury if it varies with medullary Po2. Therefore, we examined this relationship and characterized oxygen diffusion across walls of the ureter and bladder in anesthetized rabbits. A computational model was then developed to predict medullary Po2 from bladder urine Po2. Both intravenous infusion of [Phe2,Ile3,Orn8]-vasopressin and infusion of NG-nitro-l-arginine reduced urinary Po2 and medullary Po2 (8–1...

  4. A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and roadmap for future research

    Science.gov (United States)

    Phillips, Mary L; Swartz, Holly A.

    2014-01-01

    Objective This critical review appraises neuroimaging findings in bipolar disorder in emotion processing, emotion regulation, and reward processing neural circuitry, to synthesize current knowledge of the neural underpinnings of bipolar disorder, and provide a neuroimaging research “roadmap” for future studies. Method We examined findings from all major studies in bipolar disorder that used fMRI, volumetric analyses, diffusion imaging, and resting state techniques, to inform current conceptual models of larger-scale neural circuitry abnormalities in bipolar disorder Results Bipolar disorder can be conceptualized in neural circuitry terms as parallel dysfunction in bilateral prefrontal cortical (especially ventrolateral prefrontal cortical)-hippocampal-amygdala emotion processing and emotion regulation neural circuitries, together with an “overactive” left-sided ventral striatal-ventrolateral and orbitofrontal cortical reward processing circuitry, that result in characteristic behavioral abnormalities associated with bipolar disorder: emotional lability, emotional dysregulation and heightened reward sensitivity. A potential structural basis for these functional abnormalities are gray matter decreases in prefrontal and temporal cortices, amygdala and hippocampus, and fractional anisotropy decreases in white matter tracts connecting prefrontal and subcortical regions. Conclusion Neuroimaging studies of bipolar disorder clearly demonstrate abnormalities in neural circuitries supporting emotion processing, emotion regulation and reward processing, although there are several limitations to these studies. Future neuroimaging research in bipolar disorder should include studies adopting dimensional approaches; larger studies examining neurodevelopmental trajectories in bipolar disorder and at-risk youth; multimodal neuroimaging studies using integrated systems approaches; and studies using pattern recognition approaches to provide clinically useful, individual

  5. Are cardiac syndrome X, irritable bowel syndrome and reflex sympathetic dystrophy examples of lateral medullary ischaemic syndromes?

    Science.gov (United States)

    Syme, Paul

    2005-01-01

    Altered pain appreciation and autonomic function are hallmarks of Cardiac syndrome X, Irritable bowel syndrome and Reflex sympathetic dystrophy. Both pain appreciation and autonomic function are controlled by the lateral medulla. This hypothesis proposes that lateral medullary ischaemia at a microvascular level is responsible for these syndromes and could also be linked to other conditions where autonomic dysfunction is a major feature such as late-onset asthma, type 2 diabetes and essential hypertension. Autonomic function is controlled by the nucleus tractus solitarius, which acts as the main viscero-afferent nucleus in the brain stem regulating vagal tone. It is particularly susceptible to ischaemia since it is highly metabolically active and lies in a medullary arterial watershed zone. The anatomical route of the vertebral artery through cervical vertebra makes it vulnerable to injury from whiplash with or without any genetic predisposition to atheroma formation. This could make microvascular occlusion commonplace and a plausible explanation for the above syndromes. Ischaemia rather than infarction occurs because of the excellent collateral blood supply in the brainstem. In support of this hypothesis, a new Transcranial doppler ultrasonography arterial signal has been described called small vessel knock, the ultrasound signal of small vessel occlusion. Recent evidence has shown that ultrasound targeting of this signal in the vertebral artery improves clinical symptoms in these syndromes which supports this hypothesis. Two such cases are discussed.

  6. Affective neural circuitry during facial emotion processing in pediatric bipolar disorder.

    Science.gov (United States)

    Pavuluri, Mani N; O'Connor, Megan Marlow; Harral, Erin; Sweeney, John A

    2007-07-15

    Facial emotions are central to human interaction. Identifying pathophysiology in affect processing circuitry that supports the ability to assess facial emotions might facilitate understanding of affect regulation in pediatric bipolar disorder. Ten euthymic, unmedicated pediatric bipolar patients and 10 healthy control subjects matched for age, gender, race, socioeconomic status, and IQ were scanned with functional magnetic resonance imaging. Angry, happy, and neutral faces were presented in 30-sec blocks, with a 20-sec rest period between blocks. Subjects were asked to press a button when each face appeared, to ensure that attention was maintained on-task. In bipolar patients, in response to both angry and happy faces relative to neutral faces, we observed reduced activation of right rostral ventrolateral prefrontal cortex together with increased activity in right pregenual anterior cingulate, amygdala, and paralimbic cortex. Bipolar patients also showed reduced activation of visual areas in occipital cortex together with greater activation in higher-order visual perceptual areas, including superior temporal sulcus and fusiform gyrus with angry faces and posterior parietal cortex with happy faces. Findings document a disturbance in affective neurocircuitry in pediatric bipolar disorder. Reduced activation in ventrolateral prefrontal cortex might reflect diminished top-down control that leads to the observed exaggerated activation in amygdala and paralimbic areas. Changes in occipital areas might represent an effort to gate sensory input when affective responses to the faces could not be successfully modulated. Disturbances in affect processing circuitry could contribute to emotional dysregulation and social cognitive difficulties in bipolar youth.

  7. Medullary lesion revealed by MRI in a case of MS with respiratory arrest

    International Nuclear Information System (INIS)

    Mochizuki, A.; Yamanouchi, H.; Murata, M.; Nagura, H.; Kuzuhara, S.; Toyokura, Y.

    1988-01-01

    A 66-year-old MS patient who suffered respiratory arrest followed by complete remission is reported. Magnetic resonance imaging (MRI) revealed a medullary lesion. Clinicoradiological relationships are discussed. (orig.)

  8. Successful intraosseous infusion in the critically ill patient does not require a medullary cavity.

    LENUS (Irish Health Repository)

    McCarthy, Gerard

    2012-02-03

    OBJECTIVES: To demonstrate that successful intraosseous infusion in critically ill patients does not require bone that contains a medullary cavity. DESIGN: Infusion of methyl green dye via standard intraosseous needles into bones without medullary cavity-in this case calcaneus and radial styloid-in cadaveric specimens. SETTING: University department of anatomy. PARTICIPANTS: Two adult cadaveric specimens. MAIN OUTCOME MEASURES: Observation of methyl green dye in peripheral veins of the limb in which the intraosseous infusion was performed. RESULTS: Methyl green dye was observed in peripheral veins of the chosen limb in five out of eight intraosseous infusions into bones without medullary cavity-calcaneus and radial styloid. CONCLUSIONS: Successful intraosseous infusion does not always require injection into a bone with a medullary cavity. Practitioners attempting intraosseous access on critically ill patients in the emergency department or prehospital setting need not restrict themselves to such bones. Calcaneus and radial styloid are both an acceptable alternative to traditional recommended sites.

  9. Procalcitonin Levels Predict Clinical Course and Progression-Free Survival in Patients With Medullary Thyroid Cancer

    NARCIS (Netherlands)

    Walter, Martin A.; Meier, Christian; Radimerski, Tanja; Iten, Fabienne; Kraenzlin, Marius; Mueller-Brand, Jan; de Groot, Jan Willem B.; Kema, Ido P.; Links, Thera P.; Mueller, Beat

    2010-01-01

    BACKGROUND: Procalcitonin has been well established as an important marker of sepsis and systemic infection. The authors evaluated the diagnostic and predictive value of calcitonin and its prohormone procalcitonin in medullary thyroid cancer. METHODS: The authors systematically explored the ability

  10. Definitions of traumatic conus medullaris and cauda equina syndrome: a systematic literature review

    NARCIS (Netherlands)

    Brouwers, E.M.; Meent, H. van de; Curt, A.; Starremans, B.; Hosman, A.J.; Bartels, R.H.M.A.

    2017-01-01

    STUDY DESIGN: A systematic review. OBJECTIVES: Conus medullaris syndrome (CMS) and cauda equina syndrome (CES) are well-known neurological entities. It is assumed that these syndromes are different regarding neurological and functional prognosis. However, literature concerning spinal trauma is

  11. AT2 receptors mediate tonic renal medullary vasoconstriction in renovascular hypertension

    OpenAIRE

    Duke, Lisa M; Widdop, Robert E; Kett, Michelle M; Evans, Roger G

    2005-01-01

    Renal medullary blood flow is relatively insensitive to angiotensin II (Ang II)-induced vasoconstriction, due partly to AT1-mediated release of nitric oxide and/or prostaglandins. AT2-receptor activation appears to blunt AT1-mediated vasodilatation within the medullary circulation. This could affect long-term efficacy of antihypertensive pharmacotherapies targeting the renin/angiotensin system, particularly in Ang II-dependent forms of hypertension.We tested the effects of AT1- and AT2-recept...

  12. Two-dimensional Fourier analysis of the spongy medullary keratin of structurally coloured feather barbs

    Science.gov (United States)

    Prum, R. O.; Torres, R.; Williamson, S.; Dyck, J.

    1999-01-01

    We conducted two-dimensional (2D) discrete Fourier analyses of the spatial variation in refractive index of the spongy medullary keratin from four different colours of structurally coloured feather barbs from three species of bird: the rose-faced lovebird, Agapornis roseicollis (Psittacidae), the budgerigar, Melopsittacus undulatus (Psittacidae), and the Gouldian finch, Poephila guttata (Estrildidae). These results indicate that the spongy medullary keratin is a nanostructured tissue that functions as an array of coherent scatterers. The nanostructure of the medullary keratin is nearly uniform in all directions. The largest Fourier components of spatial variation in refractive index in the tissue are of the appropriate size to produce the observed colours by constructive interference alone. The peaks of the predicted reflectance spectra calculated from the 2D Fourier power spectra are congruent with the reflectance spectra measured by using microspectrophotometry. The alternative physical models for the production of these colours, the Rayleigh and Mie theories, hypothesize that medullary keratin is an incoherent array and that scattered waves are independent in phase. This assumption is falsified by the ring-like Fourier power spectra of these feathers, and the spacing of the scattering air vacuoles in the medullary keratin. Structural colours of avian feather barbs are produced by constructive interference of coherently scattered light waves from the optically heterogeneous matrix of keratin and air in the spongy medullary layer.

  13. Clinical study of 12 cases of medullary carcinoma of the breast

    International Nuclear Information System (INIS)

    Shibuya, Hitoshi; Sasaki, Kenichi; Yamamoto, Masaaki; Higaki, Nagato; Nakamura, Yukio

    2006-01-01

    Medullary carcinoma of the breast is a rare type breast cancer, and shows peculiar clinical features. In a series of 460 cases of breast cancer operated on at the hospital from 1975 to 2004, twelve (2.6%) cases were diagnosed as medullary carcinoma of the breast by postoperative pathological study. When the specimens from the twelve tumors were reevaluated according to the Ridolfi's subtype classification, six tumors were classified into typical medullary carcinoma (TMC) and the remaining six tumors into atypical medullary carcinoma (AMC). On mammography these tumors were visualized as homogeneously enhancing oval masses without calcification and the boundary was comparatively well-defined. US demonstrated well-defied masses with a heterogeneous, hypoechoic texture and with reinforcement of posterior echoes. The rate of lymph node metastasis was 33.3% in medullary carcinomas which was not significantly different from that of infiltrative ductal carcinomas experienced during the same period. The rate of a positivity of a hormone receptor was 8.3% in medullary carcinomas which was low in predominance in comparison with that of infiltrative ductal carcinomas. The positive rate for a HER2/neu (above2+) by the IHC method was 58%. An average observation period is 11 years, and all patients are alive. (author)

  14. Do egg-laying crocodilian (Alligator mississippiensis) archosaurs form medullary bone?

    Science.gov (United States)

    Schweitzer, M H; Elsey, R M; Dacke, C G; Horner, J R; Lamm, E-T

    2007-04-01

    It is beyond question that Mesozoic dinosaurs, like Aves and Crocodylia, are archosaurs. However, within the archosaurian clade, the origin and distribution of some major features are less clear, particularly with respect to reproductive physiology. Medullary bone, a highly mineralized, bony reproductive tissue present in the endosteal cavities of all extant egg-laying birds thus far examined, has recently been reported in Tyrannosaurus rex. Its presence or absence in extant crocodilians, therefore, may shed light on the timing of its evolutionary appearance. If medullary bone is present in all three taxa, it arose before the three lineages diverged. However, if medullary bone arose after this divergence, it may be present in both extinct dinosaurs and birds, or in birds only. If present in extinct dinosaurs and birds, but not crocodilians, it would indicate that it arose in the common ancestor of this clade, thus adding support to the closer phylogenetic relationship of dinosaurs and birds relative to crocodilians. Thus, the question of whether the crocodilian Alligator mississippiensis forms medullary bone during the production of eggs has important evolutionary significance. Our examination of long bones from several alligators (two alligators with eggs in the oviducts, one that had produced eggs in the past but was not currently in reproductive phase, an immature female and an adult male) shows no differences on the endosteal surfaces of the long bones, and no evidence of medullary bone, supporting the hypothesis that medullary bone first evolved in the dinosaur-bird line, after the divergence of crocodilians from this lineage.

  15. Role of nitric oxide and prostaglandin in the maintenance of cortical and renal medullary blood flow

    Directory of Open Access Journals (Sweden)

    S.I Gomez

    2008-02-01

    Full Text Available This study was undertaken in anesthetized dogs to evaluate the relative participation of prostaglandins (PGs and nitric oxide (NO in the maintenance of total renal blood flow (TRBF, and renal medullary blood flow (RMBF. It was hypothesized that the inhibition of NO should impair cortical and medullary circulation because of the synthesis of this compound in the endothelial cells of these two territories. In contrast, under normal conditions of perfusion pressure PG synthesis is confined to the renal medulla. Hence PG inhibition should predominantly impair the medullary circulation. The initial administration of 25 µM kg-1 min-1 NG-nitro-L-arginine methyl ester produced a significant 26% decrease in TRBF and a concomitant 34% fall in RMBF, while the subsequent inhibition of PGs with 5 mg/kg meclofenamate further reduced TRBF by 33% and RMBF by 89%. In contrast, the initial administration of meclofenamate failed to change TRBF, while decreasing RMBF by 49%. The subsequent blockade of NO decreased TRBF by 35% without further altering RMBF. These results indicate that initial PG synthesis inhibition predominantly alters the medullary circulation, whereas NO inhibition decreases both cortical and medullary flow. This latter change induced by NO renders cortical and RMBF susceptible to a further decrease by PG inhibition. However, the decrease in medullary circulation produced by NO inhibition is not further enhanced by subsequent PG inhibition.

  16. Implementing size-optimal discrete neural networks require analog circuitry

    Energy Technology Data Exchange (ETDEWEB)

    Beiu, V.

    1998-12-01

    This paper starts by overviewing results dealing with the approximation capabilities of neural networks, as well as bounds on the size of threshold gate circuits. Based on a constructive solution for Kolmogorov`s superpositions the authors show that implementing Boolean functions can be done using neurons having an identity transfer function. Because in this case the size of the network is minimized, it follows that size-optimal solutions for implementing Boolean functions can be obtained using analog circuitry. Conclusions and several comments on the required precision are ending the paper.

  17. Inducing nonlinear dynamic response via piezoelectric circuitry integration

    Science.gov (United States)

    Xu, J.; Tang, J.

    2014-04-01

    Owing to the two-way electro-mechanical coupling characteristics, piezoelectric transducers have been widely used as sensors and actuators in sensing and control applications. In this research, we explore the integration of piezoelectric transducer with the structure, in which the transducer is connected with a Wheatstone bridge based circuitry subjected to chaotic excitation. It is shown that a type of Wheatstone bridge circuit with proper parameters configuration can increase sensitivity in detecting structural anomaly. Such integration has the potential to significantly amplify the response change when the underlying structure is subject to property change. Comprehensive analytical and experimental studies are carried out to demonstrate the concept and validate the performance improvement.

  18. Medullary bone in fossils: function, evolution and significance in growth curve reconstructions of extinct vertebrates.

    Science.gov (United States)

    Prondvai, E

    2017-03-01

    Medullary bone (MB) is a special endosteal tissue forming in the bones of female birds during egg laying to serve as a labile calcium reservoir for building the hard eggshell. Therefore, the presence of MB reported in multiple nonavian dinosaurs is currently considered as evidence that those specimens were sexually mature females in their reproductive period. This interpretation has led to further inferences on species-specific growth strategies and related life-history aspects of these extinct vertebrates. However, a few studies questioned the reproductive significance of fossil MB by either regarding the tissue pathological or attributing alternative functions to it. This study reviews the general inferences on extinct vertebrates and discusses the primary role, distribution, regulation and adaptive significance of avian MB to point out important but largely overlooked uncertainties and inconsistencies in this matter. Emerging discordancy is demonstrated when the presence of MB vs. trade-off between growth and reproduction is used for interpreting dinosaurian growth curves. Synthesis of these data suggests that fossil MB was related to high calcium turnover rates but not exclusively to egg laying. Furthermore, revised application of Allosaurus growth data by modelling individual-based growth curves implies a much higher intraspecific variability in growth strategies, including timing of sexual maturation, than usually acknowledged. New hypotheses raised here to resolve these incongruences also propose new directions of research on the origin and functional evolution of this curious bone tissue. © 2016 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2016 European Society For Evolutionary Biology.

  19. Role of the oxytocin receptor expressed in the rostral medullary raphe in thermoregulation during cold conditions

    Directory of Open Access Journals (Sweden)

    Yoshiyuki eKasahara

    2015-11-01

    Full Text Available Recent papers have reported that oxytocin (Oxt and the oxytocin receptor (Oxtr may be involved in the regulation of food intake in mammals. We therefore suspected the Oxt/Oxtr system to be involved in energy homeostasis. In previous studies, we found a tendency toward obesity in Oxtr-deficient mice, as well as impaired thermoregulation when these mice were exposed to cold conditions. In the present study, we observed the expression of Oxtr in the rostral medullary raphe (RMR, the brain region known to control thermogenesis in brown adipose tissue. Through immunohistochemistry, we detected neurons expressing Oxtr and c-Fos in the RMR of mice exposed to cold conditions. Up to 40% of Oxtr-positive neurons in RMR were classified as glutamatergic neurons, as shown by immunostaining using anti-VGLUT3 antibody. In addition, mice with exclusive expression of Oxtr in the RMR were generated by injecting an AAV-Oxtr vector into the RMR region of Oxtr-deficient mice. We confirmed the recovery of thermoregulatory ability in the manipulated mice during exposure to cold conditions. Moreover, mice with RMR-specific expression of Oxtr lost the typical morphological change in brown adipose tissue observed in Oxtr-deficient mice. Additionally, increased expression of the β3-adrenergic receptor gene, Adrb3 was observed in brown adipose tissue. These results are the first to show the critical role of RMR Oxtr expression in thermoregulation during cold conditions.

  20. Modeling disease risk through analysis of physical interactions between genetic variants within chromatin regulatory circuitry.

    Science.gov (United States)

    Corradin, Olivia; Cohen, Andrea J; Luppino, Jennifer M; Bayles, Ian M; Schumacher, Fredrick R; Scacheri, Peter C

    2016-11-01

    SNPs associated with disease susceptibility often reside in enhancer clusters, or super-enhancers. Constituents of these enhancer clusters cooperate to regulate target genes and often extend beyond the linkage disequilibrium (LD) blocks containing risk SNPs identified in genome-wide association studies (GWAS). We identified 'outside variants', defined as SNPs in weak LD with GWAS risk SNPs that physically interact with risk SNPs as part of a target gene's regulatory circuitry. These outside variants further explain variation in target gene expression beyond that explained by GWAS-associated SNPs. Additionally, the clinical risk associated with GWAS SNPs is considerably modified by the genotype of outside variants. Collectively, these findings suggest a potential model in which outside variants and GWAS SNPs that physically interact in 3D chromatin collude to influence target transcript levels as well as clinical risk. This model offers an additional hypothesis for the source of missing heritability for complex traits.

  1. Nicotinic stimulation of catecholamine synthesis and tyrosine hydroxylase phosphorylation in cervine adrenal medullary chromaffin cells.

    Science.gov (United States)

    Knowles, P J; Douglas, S A; Bunn, S J

    2011-03-01

    The synthesis and secretion of catecholamines by the adrenal medulla is of major importance in the stress response. Tyrosine hydroxylase, the rate-limiting enzyme for catecholamine biosynthesis, has been extensively studied in adrenal medullary chromaffin cells from a number of species. Cervine chromaffin cells are of interest because the deer is known to be a relatively stress-prone reactive species. We report the first characterisation of tyrosine hydroxylase regulation in cervine chromaffin cells. Nicotinic receptor activation resulted in a time- and concentration-dependent increase in catecholamine synthesis, which was significantly reduced by the extracellular signal-regulated kinase (ERK)1/2 signalling pathway inhibitor PD98059 and the calcium/calmodulin protein kinase II inhibitor KN-93, but not by H89 or bisindolylmaleimide I, inhibitors of protein kinase A and C, respectively. Nicotinic stimulation also increased the phosphorylation of ERK1/2 and tyrosine hydroxylase. This latter response occurred on serine residues 19, 31 and 40 of the enzyme. The nicotinic-induced phosphorylation of ERK1/2 and serine 31 of tyrosine hydroxylase was suppressed by PD98059 but not bisindolylmaleimide I. These data indicate that nicotinic stimulation of tyrosine hydroxylase involves the phosphorylation of serine 31 via an ERK1/2-dependent, protein kinase C-independent pathway. Protein kinase C activation by phorbol 12-myristate 13-acetate also caused an ERK1/2-dependent increase in the serine 31 phosphorylation of tyrosine hydroxylase but, in contrast to the nicotinic response, was not accompanied by an increase in enzyme activity. Thus, ERK1/2-mediated serine 31 phosphorylation of tyrosine hydroxylase appears necessary but not sufficient for nicotinic activation of catecholamine synthesis in cervine chromaffin cells. These data present potentially important similarities and differences between the regulation of catecholamine synthesis in cervine and the more widely studied

  2. RET proto oncogene mutation detection and medullary thyroid carcinoma prevention.

    Science.gov (United States)

    Yeganeh, Marjan Zarif; Sheikholeslami, Sara; Hedayati, Mehdi

    2015-01-01

    Thyroid cancer is the most common endocrine neoplasia. The medullary thyroid carcinoma (MTC) is one of the most aggressive forms of thyroid malignancy,accounting for up to 10% of all types of this disease. The mode of inheritance of MTC is autosomal dominantly and gain of function mutations in the RET proto-oncogene are well known to contribute to its development. MTC occurs as hereditary (25%) and sporadic (75%) forms. Hereditary MTC has syndromic (multiple endocrine neoplasia type 2A, B; MEN2A, MEN2B) and non-syndromic (Familial MTC, FMTC) types. Over the last two decades, elucidation of the genetic basis of tumorigenesis has provided useful screening tools for affected families. Advances in genetic screening of the RET have enabled early detection of hereditary MTCs and prophylactic thyroidectomy for relatives who may not show any symptom sof the disease. In this review we emphasize the main RET mutations in syndromic and non syndromic forms of MTC, and focus on the importance of RET genetic screening for early diagnosis and management of MTC patients, based on American Thyroid Association guidelines and genotype-phenotype correlation.

  3. Advances and controversies in the management of medullary thyroid carcinoma.

    Science.gov (United States)

    Maia, Ana Luiza; Wajner, Simone Magagnin; Vargas, Carla Vaz Ferreira

    2017-01-01

    Medullary thyroid carcinoma (MTC) comprises approximately 4% of all malignant thyroid neoplasms. Although the majority of patients have a good prognosis, a subgroup of patients develops progressive disease and requires systemic therapy. Here, we focused on the current MTC therapeutic approaches and discussed the advantages and disadvantages of molecular targeted therapies. Targeted molecular therapies that inhibit RET and other tyrosine kinase receptors involved in angiogenesis have been shown to improve progression-free survival in patients with advanced MTC. Two drugs, vandetanib and cabozantinib, have been approved for the treatment of progressive or symptomatic MTC, and several others have exhibited variable efficacy. No tyrosine kinase inhibitor has been shown to improve survival. Although no definitive recommendation can currently be made, cumulative data indicate that knowledge of the tumor mutational profile may facilitate improvements in targeted therapy for MTC. Tyrosine kinase inhibitors are effective therapeutic agents for the treatment of progressive MTC. Nevertheless, it is not clear who will benefit the most from therapy, and the decision regarding when and how to initiate the treatment should be made based on the patient's medical history and tumor behavior. Hopefully, in the near future, molecular profiling of MTC can be used to determine the most effective molecular therapeutic target.

  4. Muscular metastasis heralding medullary carcinoma of the thyroid

    Directory of Open Access Journals (Sweden)

    Rawdha Tekaya

    2013-09-01

    Full Text Available Medullary thyroid carcinoma (MTC commonly metastasizes locally to the cervical lymph nodes and distantly to the liver, lungs and bones. Metastatic involvement of the muscles is extremely rare. We reported an unusual case of undiagnosed MTC presenting with symptoms related to metastatic lesions of the brachoradialis and the gluteus medius muscles. A 53-year-old man consulted for a painful mass of the right forearm and atrophy of the quadriceps. Ultrasonography revealed a heterogeneous collection in the forearm. Computed tomographic scan showed a mass in the right lung, an enlargement of mediastinal lymph nodes and solid masses in the right gluteus medius and the left iliopoas muscle extending to the left iliac bone. Pulmonary biopsies displayed findings consistent with metastatic MTC. Fine needle aspiration cytology from the right arm swelling revealed a lesion with the same calcitonin immunostaining patterns as the lung metastasis. The diagnosis of multiple metastases (lung, muscle and bone of MTC is established. The patient has received local radiation therapy and was planned for chemotherapy. Muscular metastases from MTC are rare and although their prognosis is poor, local treatment may be worthwhile.

  5. Targeted Therapy for Medullary Thyroid Cancer: A Review

    Directory of Open Access Journals (Sweden)

    S. R. Priya

    2017-10-01

    Full Text Available Medullary thyroid cancers (MTCs constitute between 2 and 5% of all thyroid cancers. The 10-year overall survival (OS rate of patients with localized disease is around 95% while that of patients with regional stage disease is about 75%. Only 20% of patients with distant metastases at diagnosis survive 10 years which is significantly lower than for differentiated thyroid cancers. Cases with regional metastases at presentation have high recurrence rates. Adjuvant external radiation confers local control but not improved OS. The management of residual, recurrent, or metastatic disease till a few years ago was re-surgery with local measures such as radiation. Chemotherapy was used with marginal benefit. The development of targeted therapy has brought in a major advantage in management of such patients. Two drugs—vandetanib and cabozantinib—have been approved for use in progressive or metastatic MTC. In addition, several drugs acting on other steps of the molecular pathway are being investigated with promising results. Targeted radionuclide therapy also provides an effective treatment option with good quality of life. This review covers the rationale of targeted therapy for MTC, present treatment options, drugs and methods under investigation, as well as an outline of the adverse effects and their management.

  6. Reward Circuitry Plasticity in Pain Perception and Modulation

    Directory of Open Access Journals (Sweden)

    Marcos F. DosSantos

    2017-11-01

    Full Text Available Although pain is a widely known phenomenon and an important clinical symptom that occurs in numerous diseases, its mechanisms are still barely understood. Owing to the scarce information concerning its pathophysiology, particularly what is involved in the transition from an acute state to a chronic condition, pain treatment is frequently unsatisfactory, therefore contributing to the amplification of the chronic pain burden. In fact, pain is an extremely complex experience that demands the recruitment of an intricate set of central nervous system components. This includes cortical and subcortical areas involved in interpretation of the general characteristics of noxious stimuli. It also comprises neural circuits that process the motivational-affective dimension of pain. Hence, the reward circuitry represents a vital element for pain experience and modulation. This review article focuses on the interpretation of the extensive data available connecting the major components of the reward circuitry to pain suffering, including the nucleus accumbens, ventral tegmental area, and the medial prefrontal cortex; with especial attention dedicated to the evaluation of neuroplastic changes affecting these structures found in chronic pain syndromes, such as migraine, trigeminal neuropathic pain, chronic back pain, and fibromyalgia.

  7. DNA-based random number generation in security circuitry.

    Science.gov (United States)

    Gearheart, Christy M; Arazi, Benjamin; Rouchka, Eric C

    2010-06-01

    DNA-based circuit design is an area of research in which traditional silicon-based technologies are replaced by naturally occurring phenomena taken from biochemistry and molecular biology. This research focuses on further developing DNA-based methodologies to mimic digital data manipulation. While exhibiting fundamental principles, this work was done in conjunction with the vision that DNA-based circuitry, when the technology matures, will form the basis for a tamper-proof security module, revolutionizing the meaning and concept of tamper-proofing and possibly preventing it altogether based on accurate scientific observations. A paramount part of such a solution would be self-generation of random numbers. A novel prototype schema employs solid phase synthesis of oligonucleotides for random construction of DNA sequences; temporary storage and retrieval is achieved through plasmid vectors. A discussion of how to evaluate sequence randomness is included, as well as how these techniques are applied to a simulation of the random number generation circuitry. Simulation results show generated sequences successfully pass three selected NIST random number generation tests specified for security applications.

  8. Bladder urine oxygen tension for assessing renal medullary oxygenation in rabbits: experimental and modeling studies

    Science.gov (United States)

    Sgouralis, Ioannis; Kett, Michelle M.; Ow, Connie P. C.; Abdelkader, Amany; Layton, Anita T.; Gardiner, Bruce S.; Smith, David W.; Lankadeva, Yugeesh R.

    2016-01-01

    Oxygen tension (Po2) of urine in the bladder could be used to monitor risk of acute kidney injury if it varies with medullary Po2. Therefore, we examined this relationship and characterized oxygen diffusion across walls of the ureter and bladder in anesthetized rabbits. A computational model was then developed to predict medullary Po2 from bladder urine Po2. Both intravenous infusion of [Phe2,Ile3,Orn8]-vasopressin and infusion of NG-nitro-l-arginine reduced urinary Po2 and medullary Po2 (8–17%), yet had opposite effects on renal blood flow and urine flow. Changes in bladder urine Po2 during these stimuli correlated strongly with changes in medullary Po2 (within-rabbit r2 = 0.87–0.90). Differences in the Po2 of saline infused into the ureter close to the kidney could be detected in the bladder, although this was diminished at lesser ureteric flow. Diffusion of oxygen across the wall of the bladder was very slow, so it was not considered in the computational model. The model predicts Po2 in the pelvic ureter (presumed to reflect medullary Po2) from known values of bladder urine Po2, urine flow, and arterial Po2. Simulations suggest that, across a physiological range of urine flow in anesthetized rabbits (0.1–0.5 ml/min for a single kidney), a change in bladder urine Po2 explains 10–50% of the change in pelvic urine/medullary Po2. Thus, it is possible to infer changes in medullary Po2 from changes in urinary Po2, so urinary Po2 may have utility as a real-time biomarker of risk of acute kidney injury. PMID:27385734

  9. Fifth ventricle: an unusual cystic lesion of the conus medullaris.

    Science.gov (United States)

    Liccardo, G; Ruggeri, F; De Cerchio, L; Floris, R; Lunardi, P

    2005-06-01

    Cystic dilatation of the fifth ventricle on its own is an extremely rare pathological event in adults whose pathogenesis is uncertain. The authors describe a personal case of 'fifth ventricle' and review the pertinent literature. To emphasize the importance of including the fifth ventricle in differential diagnosis of lesions of the conus medullaris to ensure proper treatment. Italy. A 30-year-old woman was referred to us for recurrent low back pain. The patient was assessed by clinical, electrophysiological (motor evoked potential, somatosensorial evoked potential and electromyography of the perineal and lower limb muscles) and urodynamic investigations as well as a magnetic resonance imaging (MRI) of the lumbar-sacral segment with and without gadolinium enhancement, subsequently extended to the entire vertebral column and brain. Follow-up consisted of periodic clinical evaluation and lumbar-sacral MRI after 1 and 2 years. General physical examination, electrophysiological and urodynamic investigations were all negative, confirming the subjective nature of the patient's symptoms. Lumbar-sacral MRI demonstrated the presence of a cyst lesion containing cerebrospinal fluid (CSF), which did not enhance after gadolinium, compatible with the diagnosis of the terminal ventricle. By extending the MRI investigation to the entire vertebral column and brain, it was possible to exclude an association with other malformations of the central nervous system. Clinical and radiological follow-up confirmed the nonevolutive nature of the lesion 1 and 2 years later. The lack of clinical symptoms and the stability of the radiological situation at 1 and 2 years follow-up motivated our choice of conservative treatment.

  10. Medullary Thyroid Cancer: It is a pain in the neck?

    Directory of Open Access Journals (Sweden)

    Marlon A. Guerrero, Sheila Lindsay, Insoo Suh, Menno R. Vriens, Elham Khanafshar, Wen T. Shen, Jessica Gosnell, Electron Kebebew, Quan-Yang Duh, Orlo H. Clark

    2011-01-01

    Full Text Available Background: Medullary thyroid cancer (MTC commonly presents with lymph node (LN metastases, and has a worse prognosis than papillary thyroid cancer (PTC. Tumor size and LN involvement have been shown to affect stage of disease; however, to our knowledge, ours is the first study that attempts to correlate anterior neck pain on presentation with the extent of disease.Methods: We performed a retrospective review of patients with MTC who underwent an operation from February 1998 through December 2008. We compared the symptom of anterior neck pain with the pathologic extent of disease. Our control group comprised patients who underwent an operation for PTC. Analysis was performed using the Fisher's exact test and the Mann-Whitney test.Results: Of the 109 patients with MTC, 50 (46% met our inclusion criteria. Of the 50 patients with MTC, 11 presented with neck pain, compared to 3 of the 50 patients with PTC (p = 0.041. Of those 11 patients, 9 (82% had LN involvement on final pathology, as compared with 14 (36% of the 39 without neck pain (p = 0.014. Of patients with neck pain, 18% were diagnosed at stage I to II and 82% at stage III to IV, compared to 64% at stage I to II and 36% at stage III to IV (p = 0.014.Conclusions: Our study demonstrates that more patients with MTC present with anterior neck pain than do patients with PTC and that patients with MTC and neck pain have an increased risk of LN metastases. The results of this study suggest that MTC patients, who present with concomitant neck pain, should undergo a total thyroidectomy, prophylactic bilateral central neck dissection, and ipsilateral lateral neck dissection.

  11. Medullary Thyroid Cancer: It is a pain in the neck?

    Science.gov (United States)

    Guerrero, Marlon A; Lindsay, Sheila; Suh, Insoo; Vriens, Menno R; Khanafshar, Elham; Shen, Wen T; Gosnell, Jessica; Kebebew, Electron; Duh, Quan-Yang; Clark, Orlo H

    2011-04-08

    Medullary thyroid cancer (MTC) commonly presents with lymph node (LN) metastases, and has a worse prognosis than papillary thyroid cancer (PTC). Tumor size and LN involvement have been shown to affect stage of disease; however, to our knowledge, ours is the first study that attempts to correlate anterior neck pain on presentation with the extent of disease. We performed a retrospective review of patients with MTC who underwent an operation from February 1998 through December 2008. We compared the symptom of anterior neck pain with the pathologic extent of disease. Our control group comprised patients who underwent an operation for PTC. Analysis was performed using the Fisher's exact test and the Mann-Whitney test. Of the 109 patients with MTC, 50 (46%) met our inclusion criteria. Of the 50 patients with MTC, 11 presented with neck pain, compared to 3 of the 50 patients with PTC (p = 0.041). Of those 11 patients, 9 (82%) had LN involvement on final pathology, as compared with 14 (36%) of the 39 without neck pain (p = 0.014). Of patients with neck pain, 18% were diagnosed at stage I to II and 82% at stage III to IV, compared to 64% at stage I to II and 36% at stage III to IV (p = 0.014). Our study demonstrates that more patients with MTC present with anterior neck pain than do patients with PTC and that patients with MTC and neck pain have an increased risk of LN metastases. The results of this study suggest that MTC patients, who present with concomitant neck pain, should undergo a total thyroidectomy, prophylactic bilateral central neck dissection, and ipsilateral lateral neck dissection.

  12. Medullary Thyroid Cancer: It is a pain in the neck?

    Science.gov (United States)

    Guerrero, Marlon A.; Lindsay, Sheila; Suh, Insoo; Vriens, Menno R.; Khanafshar, Elham; Shen, Wen T.; Gosnell, Jessica; Kebebew, Electron; Duh, Quan-Yang; Clark, Orlo H.

    2011-01-01

    Background: Medullary thyroid cancer (MTC) commonly presents with lymph node (LN) metastases, and has a worse prognosis than papillary thyroid cancer (PTC). Tumor size and LN involvement have been shown to affect stage of disease; however, to our knowledge, ours is the first study that attempts to correlate anterior neck pain on presentation with the extent of disease. Methods: We performed a retrospective review of patients with MTC who underwent an operation from February 1998 through December 2008. We compared the symptom of anterior neck pain with the pathologic extent of disease. Our control group comprised patients who underwent an operation for PTC. Analysis was performed using the Fisher's exact test and the Mann-Whitney test. Results: Of the 109 patients with MTC, 50 (46%) met our inclusion criteria. Of the 50 patients with MTC, 11 presented with neck pain, compared to 3 of the 50 patients with PTC (p = 0.041). Of those 11 patients, 9 (82%) had LN involvement on final pathology, as compared with 14 (36%) of the 39 without neck pain (p = 0.014). Of patients with neck pain, 18% were diagnosed at stage I to II and 82% at stage III to IV, compared to 64% at stage I to II and 36% at stage III to IV (p = 0.014). Conclusions: Our study demonstrates that more patients with MTC present with anterior neck pain than do patients with PTC and that patients with MTC and neck pain have an increased risk of LN metastases. The results of this study suggest that MTC patients, who present with concomitant neck pain, should undergo a total thyroidectomy, prophylactic bilateral central neck dissection, and ipsilateral lateral neck dissection. PMID:21509150

  13. Pretargeted radioimmunotherapy (pRAIT) in medullary thyroid cancer (MTC).

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Salaun, Pierre-Yves; Ansquer, Catherine; Drui, Delphine; Mirallié, Eric; Faivre-Chauvet, Alain; Barbet, Jacques; Goldenberg, David M; Chatal, Jean-François

    2012-06-01

    Prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival, based on prognostic factors, such as serum calcitonin doubling time (Ct DT). Pretargeted radioimmunotherapy (pRAIT) is a novel targeted radionuclide therapy, using a bispecific monoclonal antibody (BsMAb) and a radiolabeled bivalent hapten, designed to improve the therapeutic index and to deliver increased tumor-absorbed doses to relatively radioresistant solid tumors. Pretargeting has demonstrated a more favorable therapeutic index and clinical efficacy than directly labeled anti-carcinoembryonic antigen (CEA) MAb in preclinical MTC models. Moreover, two phase I/II clinical trials assessing anti-CEA × anti-DTPA-indium BsMAb (murine F6x734 and chimeric hMN14x734) with (131)I-di-DTPA-indium showed encouraging therapeutic results in progressive, metastatic, MTC patients, with an improved survival in intermediate- and high-risk (pre-pRAIT Ct DT, <2 years) patients, as compared to contemporaneous untreated patients (median overall survival, 110 months vs 61 months; P < 0.030). pRAIT efficacy has been recently confirmed in a prospective multicenter phase II study assessing hMN14x734 and (131)I-di-DTPA-indium in rapidly progressive MTC patients. New pRAIT compounds are now available with fully humanized, recombinant, trivalent BsMAb (anti-CEA TF2) and histamine-succinyl-glutamine (HSG) peptides. The HSG peptide allows easy and stable labeling with different radiometals, such as (177)Lu or (90)Y beta-emitters having favorable physical features for pRAIT or (68)Ga and (18)F positron-emitters, allowing the development of a highly sensitive and specific immuno-positron emission tomography method in MTC or other CEA-positive tumors.

  14. Pretargeted radioimmunotherapy in rapidly progressing, metastatic, medullary thyroid cancer.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Salaun, Pierre-Yves; Oudoux, Aurore; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques

    2010-02-15

    Medullary thyroid cancer (MTC) patients with localized residual disease and/or distant metastases may survive for several years or rapidly progress and die of their disease. Thus, highly reliable prognostic factors are needed for an early distinction between high-risk patients who need to be treated and low-risk patients who warrant a watch-and-wait approach. Calcitonin doubling time is an independent predictor of survival, with a high predictive value in a population of patients who have not normalized their calcitonin, even after repeated surgery. Several imaging methods should be proposed for patients with abnormal residual calcitonin levels persisting after complete surgery: ultrasonography and computed tomography (CT) for neck exploration, and CT for chest, abdomen, and pelvis. Magnetic resonance imaging (MRI) appears to have an advantage over CT for the detection of liver metastases from endocrine tumors. Moreover, MRI appears to be a sensitive imaging technique for detecting the spread of MTC to bone/bone marrow. 2-Fluoro-2-deoxy-D-glucose positron emission tomography/CT could be used for staging patients with progressive MTC, with possible prognostication by standard uptake value quantification. For systemic treatment of patients with rapidly progressing metastatic MTC, chemotherapy is not considered a valid therapeutic option. It is too early to evaluate the potential effectiveness of multikinase inhibitors, although interesting results of phase 2 studies have shown a transient stabilization in 30% to 50% of patients. Pretargeted radioimmunotherapy has been the only innovative treatment modality convincingly showing some survival benefit when compared with a historical untreated control group. (c) 2010 American Cancer Society.

  15. Neural control of adrenal medullary and cortical blood flow during hemorrhage

    International Nuclear Information System (INIS)

    Breslow, M.J.; Jordan, D.A.; Thellman, S.T.; Traystman, R.J.

    1987-01-01

    Hemorrhagic hypotension produces an increase in adrenal medullary blood flow and a decrease in adrenal cortical blood flow. To determine whether changes in adrenal blood flow during hemorrhage are neurally mediated, the authors compared blood flow responses following adrenal denervation (splanchnic nerve section) with changes in the contralateral, neurally intact adrenal. Carbonized microspheres labeled with 153 Gd, 114 In, 113 Sn, 103 Ru, 95 Nb or 46 Se were used. Blood pressure was reduced and maintained at 60 mmHg for 25 min by hemorrhage into a pressurized bottle system. Adrenal cortical blood flow decreased to 50% of control with hemorrhage in both the intact and denervated adrenal. Adrenal medullary blood flow increased to four times control levels at 15 and 25 min posthemorrhage in the intact adrenal, but was reduced to 50% of control at 3, 5, and 10 min posthemorrhage in the denervated adrenal. In a separate group of dogs, the greater splanchnic nerve on one side was electrically stimulated at 2, 5, or 15 Hz for 40 min. Adrenal medullary blood flow increased 5- to 10-fold in the stimulated adrenal but was unchanged in the contralateral, nonstimulated adrenal. Adrenal cortical blood flow was not affected by nerve stimulation. They conclude that activity of the splanchnic nerve profoundly affects adrenal medullary vessels but not adrenal cortical vessels and mediates the observed increase in adrenal medullary blood flow during hemorrhagic hypotension

  16. Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive.

    Science.gov (United States)

    Yun, Sanghee; Reynolds, Ryan P; Petrof, Iraklis; White, Alicia; Rivera, Phillip D; Segev, Amir; Gibson, Adam D; Suarez, Maiko; DeSalle, Matthew J; Ito, Naoki; Mukherjee, Shibani; Richardson, Devon R; Kang, Catherine E; Ahrens-Nicklas, Rebecca C; Soler, Ivan; Chetkovich, Dane M; Kourrich, Saïd; Coulter, Douglas A; Eisch, Amelia J

    2018-04-16

    Major depressive disorder (MDD) is considered a 'circuitopathy', and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal dysfunction. It is unknown whether stimulation of upstream hippocampal circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in mice and humans. Here we show that molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemogenetic stimulation of Ent neurons induce antidepressive-like effects in mice. Mechanistically, we show that Ent-stimulation-induced antidepressive-like behavior relies on the generation of new hippocampal neurons. Thus, controlled stimulation of Ent hippocampal afferents is antidepressive via increased hippocampal neurogenesis. These findings emphasize the power and potential of Ent glutamatergic afferent stimulation-previously well-known for its ability to influence learning and memory-for MDD treatment.

  17. Stretchable biocompatible electronics by embedding electrical circuitry in biocompatible elastomers.

    Science.gov (United States)

    Jahanshahi, Amir; Salvo, Pietro; Vanfleteren, Jan

    2012-01-01

    Stretchable and curvilinear electronics has been used recently for the fabrication of micro systems interacting with the human body. The applications range from different kinds of implantable sensors inside the body to conformable electrodes and artificial skins. One of the key parameters in biocompatible stretchable electronics is the fabrication of reliable electrical interconnects. Although very recent literature has reported on the reliability of stretchable interconnects by cyclic loading, work still needs to be done on the integration of electrical circuitry composed of rigid components and stretchable interconnects in a biological environment. In this work, the feasibility of a developed technology to fabricate simple electrical circuits with meander shaped stretchable interconnects is presented. Stretchable interconnects are 200 nm thin Au layer supported with polyimide (PI). A stretchable array of light emitting diodes (LEDs) is embedded in biocompatible elastomer using this technology platform and it features a 50% total elongation.

  18. Focusing on optic tectum circuitry through the lens of genetics

    Directory of Open Access Journals (Sweden)

    Nevin Linda M

    2010-09-01

    Full Text Available Abstract The visual pathway is tasked with processing incoming signals from the retina and converting this information into adaptive behavior. Recent studies of the larval zebrafish tectum have begun to clarify how the 'micro-circuitry' of this highly organized midbrain structure filters visual input, which arrives in the superficial layers and directs motor output through efferent projections from its deep layers. The new emphasis has been on the specific function of neuronal cell types, which can now be reproducibly labeled, imaged and manipulated using genetic and optical techniques. Here, we discuss recent advances and emerging experimental approaches for studying tectal circuits as models for visual processing and sensorimotor transformation by the vertebrate brain.

  19. Silent Synapse-Based Circuitry Remodeling in Drug Addiction.

    Science.gov (United States)

    Dong, Yan

    2016-05-01

    Exposure to cocaine, and likely other drugs of abuse, generates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-silent glutamatergic synapses in the nucleus accumbens. These immature synaptic contacts evolve after drug withdrawal to redefine the neurocircuital properties. These results raise at least three critical questions: (1) what are the molecular and cellular mechanisms that mediate drug-induced generation of silent synapses; (2) how are neurocircuits remodeled upon generation and evolution of drug-generated silent synapses; and (3) what behavioral consequences are produced by silent synapse-based circuitry remodeling? This short review analyzes related experimental results, and extends them to some speculations. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  20. Regulating Digital Power Supply.

    Science.gov (United States)

    The patent relates to a digital power supply regulator using pulse counts and a feedback servo loop. Analog MOS circuitry is extremely sensitive to...radiation and there are undesirable results when not placed in a suitable radiation-free environment. The present invention is a regulated power supply but

  1. Deciphering the transcriptional circuitry of microRNA genes expressed during human monocytic differentiation

    KAUST Repository

    Schmeier, Sebastian

    2009-12-10

    Background: Macrophages are immune cells involved in various biological processes including host defence, homeostasis, differentiation, and organogenesis. Disruption of macrophage biology has been linked to increased pathogen infection, inflammation and malignant diseases. Differential gene expression observed in monocytic differentiation is primarily regulated by interacting transcription factors (TFs). Current research suggests that microRNAs (miRNAs) degrade and repress translation of mRNA, but also may target genes involved in differentiation. We focus on getting insights into the transcriptional circuitry regulating miRNA genes expressed during monocytic differentiation. Results: We computationally analysed the transcriptional circuitry of miRNA genes during monocytic differentiation using in vitro time-course expression data for TFs and miRNAs. A set of TF?miRNA associations was derived from predicted TF binding sites in promoter regions of miRNA genes. Time-lagged expression correlation analysis was utilised to evaluate the TF?miRNA associations. Our analysis identified 12 TFs that potentially play a central role in regulating miRNAs throughout the differentiation process. Six of these 12 TFs (ATF2, E2F3, HOXA4, NFE2L1, SP3, and YY1) have not previously been described to be important for monocytic differentiation. The remaining six TFs are CEBPB, CREB1, ELK1, NFE2L2, RUNX1, and USF2. For several miRNAs (miR-21, miR-155, miR-424, and miR-17-92), we show how their inferred transcriptional regulation impacts monocytic differentiation. Conclusions: The study demonstrates that miRNAs and their transcriptional regulatory control are integral molecular mechanisms during differentiation. Furthermore, it is the first study to decipher on a large-scale, how miRNAs are controlled by TFs during human monocytic differentiation. Subsequently, we have identified 12 candidate key controllers of miRNAs during this differentiation process. 2009 Schmeier et al; licensee Bio

  2. Medullary carcinoma of the thyroid - an unusual case of hyalinizing trabecular adenoma - like variant (encapsulated

    Directory of Open Access Journals (Sweden)

    Madhusmita Jena

    2012-07-01

    Full Text Available Medullary thyroid carcinoma is a neoplasm occurring in sporadic and familial patterns. A rare variant of medullary thyroid carcinoma shows microscopic features similar to hyalinizing trabecular adenoma of thyroid. Detection of this variant requires a high index of suspicion and immunohistochemical confirmation by calcitonin positivity. We present a 36 years old female patient with a thyroid nodule, which, on microscopy, displayed an encapsulated tumor with elongated cells arranged in trabecular pattern separated by hyalinized fibrous septae simulating a hyalinizing trabecular adenoma. Also present were spindle cells arranged in an organoid fashion. Most of the cells showed salt and pepper chromatin pattern. The lesion was negative for amyloid but showed diffuse calcitonin positivity indicative of a tumor of C-cell origin i.e. medullary carcinoma of thyroid – hyalinizing trabecular variant.

  3. Vascular endothelial growth factor signaling is necessary for expansion of medullary microvessels during postnatal kidney development

    DEFF Research Database (Denmark)

    Robdrup Tinning, Anne; Jensen, Boye L; Johnsen, Iben

    2016-01-01

    for the development of the renal medullary microcirculation. Endothelial cell-specific immunolabeling of kidney sections from rats showed immature vascular bundles at postnatal day (P) 10 with subsequent expansion of bundles until P21. Medullary VEGF protein abundance coincided with vasa recta bundle formation....... In human fetal kidney tissue, immature vascular bundles appeared early in the third trimester (GA27-28) and expanded in size until term. Rat pups treated with the VEGF receptor-2 (VEGFR2) inhibitor vandetanib (100 mg·kg(-1)·day(-1)) from P7 to P12 or P10 to P16 displayed growth retardation and proteinuria....... Stereological quantification showed a significant reduction in total length (386 ± 13 vs. 219 ± 16 m), surface area, and volume of medullary microvessels. Vascular bundle architecture was unaffected. ANG II-AT1A/1B (-/-) mice kidneys displayed poorly defined vasa recta bundles whereas mice with collecting duct...

  4. Panmedullary edema with inferior olivary hypertrophy in bilateral medial medullary infarction.

    Science.gov (United States)

    Inoue, Yasuteru; Miyashita, Fumio; Koga, Masatoshi; Yamada, Naoaki; Toyoda, Kazunori; Minematsu, Kazuo

    2014-03-01

    Bilateral medial medullary infarction (MMI) is a rare type of stroke with poor outcomes. Inferior olivary nucleus hypertrophy results from a pathologic lesion in the Guillain-Mollaret triangle. The relationship between inferior olivary nucleus hypertrophy and the medullary lesion is obscure. To the best of our knowledge, only 1 autopsy case with unilateral medial medullary infarction that was associated with ipsilateral inferior olivary nucleus hypertrophy has been reported. We describe a rare case with acute infarction in the bilateral medial medulla oblongata accompanied by subacute bilateral inferior olivary nucleus hypertrophy and panmedullary edema. The hypertrophy appeared to have been caused by local ischemic damage to the termination of the central tegmental tract at the bilateral inferior olivary nucleus. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  5. 76 FR 72214 - Certain Semiconductor Chips with DRAM Circuitry, and Modules and Products Containing Same Receipt...

    Science.gov (United States)

    2011-11-22

    ... INTERNATIONAL TRADE COMMISSION [DN 2855] Certain Semiconductor Chips with DRAM Circuitry, and... the U.S. International Trade Commission has received a complaint entitled In Re Certain Semiconductor... United States after importation of certain semiconductor chips with dram circuitry, and modules and...

  6. Stitching Codeable Circuits: High School Students' Learning about Circuitry and Coding with Electronic Textiles

    Science.gov (United States)

    Litts, Breanne K.; Kafai, Yasmin B.; Lui, Debora A.; Walker, Justice T.; Widman, Sari A.

    2017-01-01

    Learning about circuitry by connecting a battery, light bulb, and wires is a common activity in many science classrooms. In this paper, we expand students' learning about circuitry with electronic textiles, which use conductive thread instead of wires and sewable LEDs instead of lightbulbs, by integrating programming sensor inputs and light…

  7. Unusual Metastasis of Medullary Thyroid Carcinoma to the Breast: A Cytological and Histopathological Correlation.

    Science.gov (United States)

    Tanwar, Parul; Gandhi, Jatin S; Sharma, Anila; Gupta, Manoj; Choudhary, Partha S

    2018-01-01

    Breast metastases are a relatively rare condition and account for approximately 0.5-2% of all breast tumors. Recognition of metastatic tumors in the breast is important because it would prevent unnecessary mutilating surgery and would lead to appropriate treatment of the primary tumor. Breast metastases from medullary thyroid cancer (MTC) are very rare with only 21 reported cases in the literature. Some MTCs mimic primary invasive lobular carcinoma of the breast histopathologically and radiologically, making the distinction between the two diagnostically challenging. We present the case of a 45-year-old female presenting with a lump breast, which was later found out to be metastasis from medullary carcinoma thyroid.

  8. Transient hyperechogenicity of the renal medullary pyramids: incidence in the healthy term newborn.

    Science.gov (United States)

    Khoory, B J; Andreis, I A; Vino, L; Fanos, V

    1999-01-01

    A screening program was performed on 1881 clinically healthy term newborns, aimed at detecting eventual pathological conditions not diagnosed during pregnancy. Seventy-three cases of transient hyperechogenicity of the renal medullary pyramids were observed, involving one or both kidneys with either sectorial or diffuse pattern. None of the neonates examined had evidence of renal dysfunction and follow-up ultrasound scans demonstrated complete resolution of the sonographic picture. Medullary hyperechogenicity is not rare in healthy term newborns (3.9%); it presents rapid resolution and should be considered in differential diagnosis of pathological conditions.

  9. Is thyroidectomy necessary in RET mutations carriers of the familial medullary thyroid carcinoma syndrome?

    DEFF Research Database (Denmark)

    Hansen, H S; Torring, H; Godballe, C

    2000-01-01

    BACKGROUND: The results and consequences of genetic testing in a family with familial medullary thyroid carcinoma (FMTC) are described. METHODS: In the screening of relatives, serum calcitonin is replaced by RET mutation analysis that was performed in families suspected of hereditary medullary...... thyroid carcinoma (MTC). In 4 of 10 families, mutation in exon 10 was found in codon 611. RESULTS: One hundred fifty persons belonging to 30 families were tested, of which 10 families were carriers of RET mutation in exon 10. In 1 of these families with MTC only, 2 brothers were gene carriers of a RET...

  10. Shear wave elastography in medullary thyroid carcinoma diagnostics

    Directory of Open Access Journals (Sweden)

    Katarzyna Dobruch-Sobczak

    2015-12-01

    Full Text Available Shear wave elastography (SWE is a modern method for the assessment of tissue stiffness. There has been a growing interest in the use of this technique for characterizing thyroid focal lesions, including preoperative diagnostics. Aim: The aim of the study was to assess the clinical usefulness of SWE in medullary thyroid carcinoma (MTC diagnostics. Materials and methods: A total of 169 focal lesions were identifi ed in the study group (139 patients, including 6 MTCs in 4 patients (mean age: 45 years. B-mode ultrasound and SWE were performed using Aixplorer (SuperSonic, Aix-en-Provence, with a 4–15 MHz linear probe. The ultrasound was performed to assess the echogenicity and echostructure of the lesions, their margin, the halo sign, the height/width ratio (H/W ratio, the presence of calcifi cations and the vascularization pattern. This was followed by an analysis of maximum and mean Young’s (E modulus values for MTC (EmaxLR, EmeanLR and the surrounding thyroid tissues (EmaxSR, EmeanSR, as well as mean E-values (EmeanLRz for 2 mm region of interest in the stiffest zone of the lesion. The lesions were subject to pathological and/or cytological evaluation. Results: The B-mode assessment showed that all MTCs were hypoechogenic, with no halo sign, and they contained micro- and/ or macrocalcifi cations. Ill-defi ned lesion margin were found in 4 out of 6 cancers; 4 out of 6 cancers had a H/W ratio > 1. Heterogeneous echostructure and type III vascularity were found in 5 out of 6 lesions. In the SWE, the mean value of EmaxLR for all of the MTCs was 89.5 kPa and (the mean value of EmaxSR for all surrounding tissues was 39.7 kPa Mean values of EmeanLR and EmeanSR were 34.7 kPa and 24.4 kPa, respectively. The mean value of EmeanLRz was 49.2 kPa. Conclusions: SWE showed MTCs as stiffer lesions compared to the surrounding tissues. The lesions were qualifi ed for fi ne needle aspiration biopsy based on B-mode assessment. However, the diagnostic algorithm

  11. Central cardiovascular actions of L-homocysteine microinjected into ventrolateral medullary autonomic areas of the rat.

    Science.gov (United States)

    Takemoto, Yumi

    2016-09-01

    Elevated L-homocysteine concentrations in the plasma and cerebrospinal fluid are related to cardiovascular and neuronal diseases, and could contribute to disease development. However, the central cardiovascular actions of L-homocysteine in two important autonomic regulating areas remain unknown: the rostral ventrolateral medulla (RVLM), including pre-sympathetic neurons, and the caudal ventrolateral medulla (CVLM), including interneurons projecting to pre-sympathetic neurons in the RVLM. Therefore, the aim of the current study was to examine the influence of L-homocysteine microinjected into the RVLM and CVLM areas on changes in arterial blood pressure (ABP) and heart rate (HR) of anesthetized rats, as well as the influence of ionotropic excitatory amino acid (iEAA) receptors on the central actions of L-homocysteine. L-Homocysteine solutions were microinjected into the RVLM and CVLM, which were defined according to pressor and depressor responses to L-glutamate microinjections, respectively. ABP and HR increased in the RVLM and decreased in the CVLM after microinjection with L-homocysteine, similar to L-glutamate, in a dose-dependent manner, suggesting mediation of EAA receptors. Prior microinjection of the N-methyl-D-aspartate (NMDA) iEAA receptor antagonist MK801, but not the non-NMDA receptor antagonist CNQX, abolished the observed responses to L-homocysteine in both the RVLM and CVLM. These results indicate the central cardiovascular actions of L-homocysteine via MK801-sensitive receptors of the medullary autonomic neurons in the rat RVLM and CVLM. It remains unknown if the central cardiovascular actions are related to cardiovascular diseases after endogenously and locally augmented L-homocysteine production by disordered metabolism. Further studies on functional significance of L-homocysteine may provide some clue to understand its toxic mechanism.

  12. New Drug Candidate Targeting the 4A1 Orphan Nuclear Receptor for Medullary Thyroid Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Lei Zhang

    2018-03-01

    Full Text Available Medullary thyroid cancer (MTC is a relatively rare thyroid cancer responsible for a substantial fraction of thyroid cancer mortality. More effective therapeutic drugs with low toxicity for MTC are urgently needed. Orphan nuclear receptor 4A1 (NR4A1 plays a pivotal role in regulating the proliferation and apoptosis of a variety of tumor cells. Based on the NR4A1 protein structure, 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA was identified from the Specs compounds database using the protein structure-guided virtual screening approach. Computationally-based molecular modeling studies suggested that IMCA has a high affinity for the ligand binding pocket of NR4A1. MTT [3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2-H-tetrazolium bromide] and apoptosis assays demonstrated that IMCA resulted in significant thyroid cancer cell death. Immunofluorescence assays showed that IMCA induced NR4A1 translocation from the nucleus to the cytoplasm in thyroid cancer cell lines, which may be involved in the cell apoptotic process. In this study, the quantitative polymerase chain reaction results showed that the IMCA-induced upregulation of sestrin1 and sestrin2 was dose-dependent in thyroid cancer cell lines. Western blot showed that IMCA increased phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK and decreased phosphorylation of ribosomal protein S6 kinase (p70S6K, which is the key enzyme in the mammalian target of rapamycin (mTOR pathway. The experimental results suggest that IMCA is a drug candidate for MTC therapy and may work by increasing the nuclear export of NR4A1 to the cytoplasm and the tumor protein 53 (p53-sestrins-AMPK-mTOR signaling pathway.

  13. A computational framework for ultrastructural mapping of neural circuitry.

    Directory of Open Access Journals (Sweden)

    James R Anderson

    2009-03-01

    Full Text Available Circuitry mapping of metazoan neural systems is difficult because canonical neural regions (regions containing one or more copies of all components are large, regional borders are uncertain, neuronal diversity is high, and potential network topologies so numerous that only anatomical ground truth can resolve them. Complete mapping of a specific network requires synaptic resolution, canonical region coverage, and robust neuronal classification. Though transmission electron microscopy (TEM remains the optimal tool for network mapping, the process of building large serial section TEM (ssTEM image volumes is rendered difficult by the need to precisely mosaic distorted image tiles and register distorted mosaics. Moreover, most molecular neuronal class markers are poorly compatible with optimal TEM imaging. Our objective was to build a complete framework for ultrastructural circuitry mapping. This framework combines strong TEM-compliant small molecule profiling with automated image tile mosaicking, automated slice-to-slice image registration, and gigabyte-scale image browsing for volume annotation. Specifically we show how ultrathin molecular profiling datasets and their resultant classification maps can be embedded into ssTEM datasets and how scripted acquisition tools (SerialEM, mosaicking and registration (ir-tools, and large slice viewers (MosaicBuilder, Viking can be used to manage terabyte-scale volumes. These methods enable large-scale connectivity analyses of new and legacy data. In well-posed tasks (e.g., complete network mapping in retina, terabyte-scale image volumes that previously would require decades of assembly can now be completed in months. Perhaps more importantly, the fusion of molecular profiling, image acquisition by SerialEM, ir-tools volume assembly, and data viewers/annotators also allow ssTEM to be used as a prospective tool for discovery in nonneural systems and a practical screening methodology for neurogenetics. Finally

  14. Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate.

    Science.gov (United States)

    Mansson, Robert; Welinder, Eva; Åhsberg, Josefine; Lin, Yin C; Benner, Christopher; Glass, Christopher K; Lucas, Joseph S; Sigvardsson, Mikael; Murre, Cornelis

    2012-12-18

    Recent studies have identified a number of transcriptional regulators, including E2A, early B-cell factor 1 (EBF1), FOXO1, and paired box gene 5 (PAX5), that promote early B-cell development. However, how this ensemble of regulators mechanistically promotes B-cell fate remains poorly understood. Here we demonstrate that B-cell development in FOXO1-deficient mice is arrested in the common lymphoid progenitor (CLP) LY6D(+) cell stage. We demonstrate that this phenotype closely resembles the arrest in B-cell development observed in EBF1-deficient mice. Consistent with these observations, we find that the transcription signatures of FOXO1- and EBF1-deficient LY6D(+) progenitors are strikingly similar, indicating a common set of target genes. Furthermore, we found that depletion of EBF1 expression in LY6D(+) CLPs severely affects FOXO1 mRNA abundance, whereas depletion of FOXO1 activity in LY6D(+) CLPs ablates EBF1 transcript levels. We generated a global regulatory network from EBF1 and FOXO1 genome-wide transcription factor occupancy and transcription signatures derived from EBF1- and FOXO1-deficient CLPs. This analysis reveals that EBF1 and FOXO1 act in a positive feedback circuitry to promote and stabilize specification to the B-cell lineage.

  15. A CREB-Sirt1-Hes1 Circuitry Mediates Neural Stem Cell Response to Glucose Availability

    Directory of Open Access Journals (Sweden)

    Salvatore Fusco

    2016-02-01

    Full Text Available Summary: Adult neurogenesis plays increasingly recognized roles in brain homeostasis and repair and is profoundly affected by energy balance and nutrients. We found that the expression of Hes-1 (hairy and enhancer of split 1 is modulated in neural stem and progenitor cells (NSCs by extracellular glucose through the coordinated action of CREB (cyclic AMP responsive element binding protein and Sirt-1 (Sirtuin 1, two cellular nutrient sensors. Excess glucose reduced CREB-activated Hes-1 expression and results in impaired cell proliferation. CREB-deficient NSCs expanded poorly in vitro and did not respond to glucose availability. Elevated glucose also promoted Sirt-1-dependent repression of the Hes-1 promoter. Conversely, in low glucose, CREB replaced Sirt-1 on the chromatin associated with the Hes-1 promoter enhancing Hes-1 expression and cell proliferation. Thus, the glucose-regulated antagonism between CREB and Sirt-1 for Hes-1 transcription participates in the metabolic regulation of neurogenesis. : Using a combination of in vitro and in vivo studies, Fusco et al. find that excess glucose impairs the self-renewal capacity of neural stem cells through a molecular circuit that involves the transcription factor CREB and Sirtuin 1. The authors suggest that this circuitry may link nutrient excess with neurodegeneration and brain aging. Keywords: neural stem cells, adult neurogenesis, CREB, Sirt-1, nutrients, metabolism, diabetes

  16. Epigenetic Regulation of Monocyte and Macrophage Function

    NARCIS (Netherlands)

    Hoeksema, Marten A.; de Winther, Menno P. J.

    2016-01-01

    Monocytes and macrophages are key players in tissue homeostasis and immune responses. Epigenetic processes tightly regulate cellular functioning in health and disease. Recent Advances: Recent technical developments have allowed detailed characterizations of the transcriptional circuitry underlying

  17. Cost-benefit decision circuitry: proposed modulatory role for acetylcholine.

    Science.gov (United States)

    Fobbs, Wambura C; Mizumori, Sheri J Y

    2014-01-01

    In order to select which action should be taken, an animal must weigh the costs and benefits of possible outcomes associate with each action. Such decisions, called cost-benefit decisions, likely involve several cognitive processes (including memory) and a vast neural circuitry. Rodent models have allowed research to begin to probe the neural basis of three forms of cost-benefit decision making: effort-, delay-, and risk-based decision making. In this review, we detail the current understanding of the functional circuits that subserve each form of decision making. We highlight the extensive literature by detailing the ability of dopamine to influence decisions by modulating structures within these circuits. Since acetylcholine projects to all of the same important structures, we propose several ways in which the cholinergic system may play a local modulatory role that will allow it to shape these behaviors. A greater understanding of the contribution of the cholinergic system to cost-benefit decisions will permit us to better link the decision and memory processes, and this will help us to better understand and/or treat individuals with deficits in a number of higher cognitive functions including decision making, learning, memory, and language. © 2014 Elsevier Inc. All rights reserved.

  18. Dentate Gyrus circuitry features improve performance of sparse approximation algorithms.

    Directory of Open Access Journals (Sweden)

    Panagiotis C Petrantonakis

    Full Text Available Memory-related activity in the Dentate Gyrus (DG is characterized by sparsity. Memory representations are seen as activated neuronal populations of granule cells, the main encoding cells in DG, which are estimated to engage 2-4% of the total population. This sparsity is assumed to enhance the ability of DG to perform pattern separation, one of the most valuable contributions of DG during memory formation. In this work, we investigate how features of the DG such as its excitatory and inhibitory connectivity diagram can be used to develop theoretical algorithms performing Sparse Approximation, a widely used strategy in the Signal Processing field. Sparse approximation stands for the algorithmic identification of few components from a dictionary that approximate a certain signal. The ability of DG to achieve pattern separation by sparsifing its representations is exploited here to improve the performance of the state of the art sparse approximation algorithm "Iterative Soft Thresholding" (IST by adding new algorithmic features inspired by the DG circuitry. Lateral inhibition of granule cells, either direct or indirect, via mossy cells, is shown to enhance the performance of the IST. Apart from revealing the potential of DG-inspired theoretical algorithms, this work presents new insights regarding the function of particular cell types in the pattern separation task of the DG.

  19. Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries.

    Science.gov (United States)

    Boeva, Valentina; Louis-Brennetot, Caroline; Peltier, Agathe; Durand, Simon; Pierre-Eugène, Cécile; Raynal, Virginie; Etchevers, Heather C; Thomas, Sophie; Lermine, Alban; Daudigeos-Dubus, Estelle; Geoerger, Birgit; Orth, Martin F; Grünewald, Thomas G P; Diaz, Elise; Ducos, Bertrand; Surdez, Didier; Carcaboso, Angel M; Medvedeva, Irina; Deller, Thomas; Combaret, Valérie; Lapouble, Eve; Pierron, Gaelle; Grossetête-Lalami, Sandrine; Baulande, Sylvain; Schleiermacher, Gudrun; Barillot, Emmanuel; Rohrer, Hermann; Delattre, Olivier; Janoueix-Lerosey, Isabelle

    2017-09-01

    Neuroblastoma is a tumor of the peripheral sympathetic nervous system, derived from multipotent neural crest cells (NCCs). To define core regulatory circuitries (CRCs) controlling the gene expression program of neuroblastoma, we established and analyzed the neuroblastoma super-enhancer landscape. We discovered three types of identity in neuroblastoma cell lines: a sympathetic noradrenergic identity, defined by a CRC module including the PHOX2B, HAND2 and GATA3 transcription factors (TFs); an NCC-like identity, driven by a CRC module containing AP-1 TFs; and a mixed type, further deconvoluted at the single-cell level. Treatment of the mixed type with chemotherapeutic agents resulted in enrichment of NCC-like cells. The noradrenergic module was validated by ChIP-seq. Functional studies demonstrated dependency of neuroblastoma with noradrenergic identity on PHOX2B, evocative of lineage addiction. Most neuroblastoma primary tumors express TFs from the noradrenergic and NCC-like modules. Our data demonstrate a previously unknown aspect of tumor heterogeneity relevant for neuroblastoma treatment strategies.

  20. Proximal Tubular Injury in Medullary Rays Is an Early Sign of Acute Tacrolimus Nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Diane Cosner

    2015-01-01

    Full Text Available Tacrolimus (FK506 is one of the principal immunosuppressive agents used after solid organ transplantations to prevent allograft rejection. Chronic renal injury induced by tacrolimus is characterized by linear fibrosis in the medullary rays; however, the early morphologic findings of acute tacrolimus nephrotoxicity are not well characterized. Kidney injury molecule-1 (KIM-1 is a specific injury biomarker that has been proven to be useful in the diagnosis of mild to severe acute tubular injury on renal biopsies. This study was motivated by a patient with acute kidney injury associated with elevated serum tacrolimus levels in whom KIM-1 staining was present only in proximal tubules located in the medullary rays in the setting of otherwise normal light, immunofluorescent, and electron microscopy. We subsequently evaluated KIM-1 expression in 45 protocol and 39 indicated renal transplant biopsies to determine whether higher serum levels of tacrolimus were associated with acute segment specific injury to the proximal tubule, as reflected by KIM-1 staining in the proximal tubules of the cortical medullary rays. The data suggest that tacrolimus toxicity preferentially affects proximal tubules in medullary rays and that this targeted injury is a precursor lesion for the linear fibrosis seen in chronic tacrolimus toxicity.

  1. Urinary acidification and urinary excretion of calcium and citrate in women with bilateral medullary sponge kidney

    DEFF Research Database (Denmark)

    Osther, P J; Mathiasen, Helle; Hansen, A B

    1994-01-01

    Urinary acidification ability, acid-base status and urinary excretion of calcium and citrate were evaluated in 10 women with bilateral medullary sponge kidney (MSK) and in 10 healthy women. Patients with MSK had higher fasting urine pH compared to normal controls (p

  2. Midbrain and medullary control of postinspiratory activity of the crural and costal diaphragm in vivo

    NARCIS (Netherlands)

    Subramanian, Hari H.; Holstege, Gert

    Subramanian HH, Holstege G. Midbrain and medullary control of postinspiratory activity of the crural and costal diaphragm in vivo. J Neurophysiol 105: 2852-2862, 2011. First published March 30, 2011; doi:10.1152/jn.00168.2011.-Studies on brain stem respiratory neurons suggest that eupnea consists of

  3. Kidney Involvement in Systemic Calcitonin Amyloidosis Associated With Medullary Thyroid Carcinoma

    NARCIS (Netherlands)

    Koopman, Timco; Niedlich-den Herder, Cindy; Stegeman, Coen A.; Links, Thera P.; Bijzet, Johan; Hazenberg, Bouke P. C.; Diepstra, Arjan

    A 52-year-old woman with widely disseminated medullary thyroid carcinoma developed nephrotic syndrome and slowly decreasing kidney function. A kidney biopsy was performed to differentiate between malignancy-associated membranous glomerulopathy and tyrosine kinase inhibitor-induced focal segmental

  4. Fewer Cancer Reoperations for Medullary Thyroid Cancer After Initial Surgery According to ATA Guidelines

    NARCIS (Netherlands)

    Verbeek, Hans H. G.; Meijer, Johannes A. A.; Zandee, Wouter T.; Kramp, Kelvin H.; Sluiter, Willem; Smit, Johannes W.; Kievit, Job; Links, Thera P.; Plukker, John Th M.

    Surgery is still the only curative treatment for medullary thyroid cancer (MTC). We evaluated clinical outcome in patients with locoregional MTC with regard to adequacy of treatment following ATA guidelines and number of sessions to first intended curative surgery in different hospitals. We reviewed

  5. Comparison of three radiolabelled peptide analogues for CCK-2 receptor scintigraphy in medullary thyroid carcinoma

    NARCIS (Netherlands)

    A.C. Fröberg (Alida); M. de Jong (Marion); B.A. Nock (Berthold); W.A.P. Breeman (Wouter); J.L. Erion (Jack); T. Maina (Theodosia); M. Verdijsseldonck (Marion); W.W. de Herder (Wouter); A. van der Lugt (Aad); P.P.M. Kooij (Peter); E.P. Krenning (Eric)

    2009-01-01

    textabstractPurpose: Cholecystokinin 2 (CCK-2) receptor overexpression has been demonstrated in a high percentage of medullary thyroid carcinomas (MTC). Analogous to somatostatin receptors, CCK-2 receptors might be viable targets for radionuclide scintigraphy and/or radionuclide therapy. Several

  6. Disseminated medullary thyroid carcinoma despite early thyroid surgery in the multiple endocrine neoplasia-2A syndrome

    NARCIS (Netherlands)

    van Santen, H. M.; Aronson, D. C.; van Trotsenburg, A. S. P.; ten Kate, F. J. W.; van de Wetering, M. D.; Wiersinga, W. M.; de Vijlder, J. J. M.; Vulsma, T.

    2005-01-01

    A 5 1/2-year-old boy, with a family history of multiple endocrine neoplasia (MEN)-2A syndrome, was evaluated for presence of MEN-2A and medullary thyroid carcinoma (MTC). DNA diagnostics confirmed MEN-2A. Basal (360 ng/L) and pentagastrin stimulated (430 ng/L) calcitonin (CT) levels were slightly

  7. Biochemical markers in the follow-up of medullary thyroid cancer

    NARCIS (Netherlands)

    de Groot, Jan Willem B.; Kema, Ido P.; Breukelman, Henk; van der Veer, Eveline; Wiggers, Theo; Plukker, John T. M.; Wolffenbuttel, Bruce H. R.; Links, Thera P.

    2006-01-01

    Medullary thyroid cancer (MTC) shares biochemical features with other neuroendocrine tumors but the particular characteristics are largely unexplored. We investigated the biochemical neuroendocrine profile of MTC and whether specific markers could be useful in follow-up. In addition to the standard

  8. Taking into care metastatic medullary compressions; Prise en charge des compressions medullaires metastatiques

    Energy Technology Data Exchange (ETDEWEB)

    Dupin, C.; Feuvret, L. [Groupe hospitalier Pitie-Salpetriere, 75 - Paris (France)

    2010-10-15

    As between 5 and 14 per cent of patients suffering from cancer will suffer from a metastatic medullary compression which severely impacts the vital and functional prognostic, the authors proposes an overview of the different techniques used to take these compressions into care: surgery, radiotherapy and cortico-therapy. They describe their positive and negative impacts. Short communication

  9. A Rare Case of Painful Trigeminal Neuropathy Secondary to Lateral Medullary Infarct: Neuroimaging and Electrophysiological Studies.

    Science.gov (United States)

    Huang, Ching-Tang; Lo, Chung-Ping; Chen, Ying-Chu; Tu, Min-Chien

    2015-06-01

    To report a rare case of painful trigeminal neuropathy after lateral medullary infarct and probe its underlying pathogenesis on the basis of neuroimaging and electrophysiological study. A 45-year-old man presented acute onset of unsteady gait followed by paroxysmal and electric shock-like headache in the distribution of ophthalmic branch of left trigeminal nerve in 2 days. Neurological examinations showed hypoesthesia in the distribution of mandibular branch of left trigeminal nerve and left appendicular ataxia. Muscle powers and deep tendon reflexes were normal. Brain magnetic resonance imaging revealed infarct within the left cerebellum and middle portion of dorsolateral medulla. Vascular compression at the root entry zone of trigeminal nerve was excluded. Painful trigeminal neuropathy secondary to lateral medullary infarct was diagnosed. Ancillary blink reflex study 3 days after the stroke event showed abnormal late responses (R2), either ipsilateral or contralateral, after stimulation of left supraorbital nerve, suggesting left medullary lesion. Followup study 3 weeks later demonstrated normalization in absolute latencies of bilateral late responses, in line with remission of pain paroxysms on low-dose gabapentin treatment. Painful trigeminal neuropathy attributed to lateral medullary infarct is a unique disease entity. Ophthalmic branch involvement, coexisting sensory deficits, absence of triggers, and rapid evolvement and remission are its characteristics. Our neuroimaging study delineated ischemic stroke pathology within descending tract and spinal nucleus of trigeminal nerve. Serial electrophysiological studies provide evidences supporting ephaptic transmission as the main pathogenesis concordant with dynamics of neuropathic pain and therapeutic implications.

  10. Vandetanib in advanced medullary thyroid cancer: review of adverse event management strategies

    DEFF Research Database (Denmark)

    Grande, Enrique; Kreissl, Michael C; Filetti, Sebastiano

    2013-01-01

    Vandetanib has recently demonstrated clinically meaningful benefits in patients with unresectable, locally advanced or metastatic medullary thyroid cancer (MTC). Given the potential for long-term vandetanib therapy in this setting, in addition to treatment for disease-related symptoms, effective ...

  11. Impacts of nitric oxide and superoxide on renal medullary oxygen transport and urine concentration

    Science.gov (United States)

    Edwards, Aurélie; Layton, Anita T.

    2015-01-01

    The goal of this study was to investigate the reciprocal interactions among oxygen (O2), nitric oxide (NO), and superoxide (O2−) and their effects on medullary oxygenation and urinary output. To accomplish that goal, we developed a detailed mathematical model of solute transport in the renal medulla of the rat kidney. The model represents the radial organization of the renal tubules and vessels, which centers around the vascular bundles in the outer medulla and around clusters of collecting ducts in the inner medulla. Model simulations yield significant radial gradients in interstitial fluid oxygen tension (Po2) and NO and O2− concentration in the OM and upper IM. In the deep inner medulla, interstitial fluid concentrations become much more homogeneous, as the radial organization of tubules and vessels is not distinguishable. The model further predicts that due to the nonlinear interactions among O2, NO, and O2−, the effects of NO and O2− on sodium transport, osmolality, and medullary oxygenation cannot be gleaned by considering each solute's effect in isolation. An additional simulation suggests that a sufficiently large reduction in tubular transport efficiency may be the key contributing factor, more so than oxidative stress alone, to hypertension-induced medullary hypoxia. Moreover, model predictions suggest that urine Po2 could serve as a biomarker for medullary hypoxia and a predictor of the risk for hospital-acquired acute kidney injury. PMID:25651567

  12. Closing the medullary canal after retrograde nail removal using a bioabsorbable bone plug: technical tip

    NARCIS (Netherlands)

    Schepers, T.; Vogels, L. M. M.

    2012-01-01

    We describe a simple technique for closure of the intra-articular opening after the removal of a retrograde femur nail. With the use of a gelatine bioabsorbable bone plug the medullary canal is closed, reducing leakage of blood and cancellous bone particles from the bone into the knee joint

  13. Clinico-pathological and prognostic findings on 27 cases of medullary thyroid carcinoma.

    Science.gov (United States)

    Gabsi, Azza; El Amine El Hadj, Olfa; Goucha, Aida; Said, Gritli; Laabidi, Besma; Gamoudi, Amor

    2017-02-01

    Medullary thyroid carcinoma is a rare tumor accounting for less than 10% of thyroid neoplasm. This tumor is characterized by important histological polymorphism which makes morphological diagnosis difficult and immunohistochemical study often necessary. We aim to perform a retrospective review of clinical and pathological characteristics of medullary carcinoma. We will discuss the place of immunohistochemistry in the positive diagnosis and as a prognostic factor. patients with thyroid medullary carcinoma diagnosed in department of pathology at carcinologic institute between 1998 and 2013 were retrospectively included. Clinic, radiologic and prognostic variables were assessed. Slides were reviewed for all the patients with confirmed tumors. Twenty-seven patients with CMT were identified. The average age was 55 years with predominance of males. The average consultation time was 16 months. The most common presentation symptom was a cervical lymph node. Total thyroidectomy was performed in 23 patients. Tumor was nodular and unique in 22 cases. The average size was 2.1 cm. CMT was of mixed type containing both medullary and papillary compound in four cases. Amyloid substance was present and abundant in 21cases. Positive staining for calcitonin was observed in 16 cases. Distant metastasis or metastatic lymph nodes was observed in eight cases with an average period of 42 months. Radiotherapy was performed in fifteen cases and two patients received chemotherapy. In the absence of amyloid deposits, immunohistochemical staining with calcitonin is useful to confirm the diagnosis. The prognosis of this entity is more pejorative than papillary thyroid carcinoma.

  14. Adenocarcinoma of the prostate and metastatic medullary compression. A retrospective study of 22 patients

    DEFF Research Database (Denmark)

    Honnens de Lichtenberg, M; Kvist, E; Hjortberg, P

    1992-01-01

    A retrospective study of 709 patients with prostatic cancer was carried out. Twenty-two developed medullary cord compression (an incidence of 3%). All but two of the 22 patients were treated by radiation and 10 had additional hormonal treatment. Ten had some benefit from the treatment, but only 2...

  15. Renal cortical and medullary blood flow during modest saline loading in humans

    DEFF Research Database (Denmark)

    Damkjær, M; Vafaee, M; Braad, P E

    2012-01-01

    Renal medullary blood flow (RMBF) is considered an important element of sodium homeostasis, but the experimental evidence is incongruent. Studies in anaesthetized animals generally support the concept in contrast to measurements in conscious animals. We hypothesized that saline-induced natriuresis...

  16. Application of difference gel electrophoresis to the identification of inner medullary collecting duct proteins.

    NARCIS (Netherlands)

    Hoffert, J.D.; Balkom, B.W.M. van; Chou, C.L.; Knepper, M.A.

    2004-01-01

    In this study, we present a standardized approach to purification of native inner medullary collecting duct (IMCD) cells from rat kidney for proteomic analysis and apply the approach to identification of abundant proteins utilizing two-dimensional difference gel electrophoresis (DIGE) coupled with

  17. VAC Therapy Direct to the Medullary Cavity for Chronic Tibial Osteomyelitis.

    Science.gov (United States)

    Miyamura, Satoshi; Tsuji, Shigeyoshi; Iwai, Takao; Hamada, Masayuki

    2016-06-01

    Vacuum-assisted wound closure (VAC) is useful for difficult wound beds, although sites where bleeding or infection is expected are usually regarded as problematic for this therapy. This report outlines the treatment of chronic tibial osteomyelitis (Cierny- Mader type III) due to mixed infection with Nocardia spp and Bacteroi- des fragilis by postoperative VAC therapy direct to the medullary cavity, followed by wound coverage with a gastrocnemius myocutaneous skin flap. A 64-year-old man developed chronic left tibial os- teomyelitis after a work injury. The nonviable tissues were debrided, including a sequestrum. Nocardia spp and B. fragilis were isolated from surgical bone specimens, and chronic tibial osteomyelitis due to mixed infection was diagnosed. Postoperatively, VAC therapy was performed directly to the open medullary cavity of the tibia and sub- sequently covered the residual soft tissue defect with a gastrocnemius myocutaneous flap. The authors could not find any English literature on VAC therapy direct to the medullary cavity combined with transplantation of a myocutaneous flap for osteomyelitis. Nocardia spp can cause a variety of infections, among which osteomyelitis occupies a relatively small percentage. This case raises the possibil- ity of treating chronic tibial osteomyelitis caused by mixed infection with Nocardia spp and B. fragilis by applying postoperative VAC ther- apy directly to the medullary cavity and covering the residual wound with a gastrocnemius myocutaneous flap.

  18. Layer 3 Excitatory and Inhibitory Circuitry in the Prefrontal Cortex: Developmental Trajectories and Alterations in Schizophrenia.

    Science.gov (United States)

    Hoftman, Gil D; Datta, Dibyadeep; Lewis, David A

    2017-05-15

    Convergent evidence suggests that schizophrenia is a disorder of neurodevelopment with alterations in both early and late developmental processes hypothesized to contribute to the disease process. Abnormalities in certain clinical features of schizophrenia, such as working memory impairments, depend on distributed neural circuitry including the dorsolateral prefrontal cortex (DLPFC) and appear to arise during the protracted maturation of this circuitry across childhood and adolescence. In particular, the neural circuitry substrate for working memory in primates involves the coordinated activity of excitatory pyramidal neurons and a specific population of inhibitory gamma-aminobutyric acid neurons (i.e., parvalbumin-containing basket cells) in layer 3 of the DLPFC. Understanding the relationships between the normal development of-and the schizophrenia-associated alterations in-the DLPFC circuitry that subserves working memory could provide new insights into the nature of schizophrenia as a neurodevelopmental disorder. Consequently, we review the following in this article: 1) recent findings regarding alterations of DLPFC layer 3 circuitry in schizophrenia, 2) the developmental refinements in this circuitry that occur during the period when the working memory alterations in schizophrenia appear to arise and progress, and 3) how various adverse environmental exposures could contribute to developmental disturbances of this circuitry in individuals with schizophrenia. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  19. AT(2) receptors mediate tonic renal medullary vasoconstriction in renovascular hypertension.

    Science.gov (United States)

    Duke, Lisa M; Widdop, Robert E; Kett, Michelle M; Evans, Roger G

    2005-02-01

    1. Renal medullary blood flow is relatively insensitive to angiotensin II (Ang II)-induced vasoconstriction, due partly to AT(1)-mediated release of nitric oxide and/or prostaglandins. AT(2)-receptor activation appears to blunt AT(1)-mediated vasodilatation within the medullary circulation. This could affect long-term efficacy of antihypertensive pharmacotherapies targeting the renin/angiotensin system, particularly in Ang II-dependent forms of hypertension. 2. We tested the effects of AT(1)- and AT(2)-receptor blockade on basal cortical and medullary laser Doppler flux (CLDF and MLDF), and on responses to renal arterial infusion of Ang II, in rats with 2 kidney, 1 clip (2K1C) hypertension and sham-operated controls. Studies were carried out in thiobutabarbital (175 mg kg(-1), i.p.) anaesthetised rats, 4 weeks after clipping, or sham surgery (n=6 in each of eight groups). 3. Candesartan (10 microg kg(-1) h(-1), intravenous (i.v.)) reduced mean arterial pressure ( approximately 17%) and increased CLDF ( approximately 24%), similarly in both sham and 2K1C rats, but did not significantly affect MLDF. PD123319 (1 mg kg(-1) h(-1), i.v.) increased basal MLDF (19%) in 2K1C but not sham rats, without significantly affecting other variables. 4. In sham rats, renal arterial infusion of Ang II (1-100 ng kg(-1) min(-1)) dose dependently decreased CLDF (up to 44%), but did not significantly affect MLDF. These effects were markedly blunted in 2K1C rats. After PD123319, Ang II dose dependently increased MLDF (up to 38%) in sham but not 2K1C rats. Candesartan abolished all effects of Ang II, including those seen after PD123319. 5. Our data indicate that AT(1) receptors mediate medullary vasodilatation, which is opposed by AT(2)-receptor activation. In 2K1C hypertension, AT(2)-receptor activation tonically constricts the medullary circulation.

  20. Lateral medullary infarction with cardiovascular autonomic dysfunction: an unusual presentation with review of the literature.

    Science.gov (United States)

    Huynh, Tridu R; Decker, Barbara; Fries, Timothy J; Tunguturi, Ajay

    2018-01-24

    We report an unusual case of lateral medullary infarction presenting with orthostatic hypotension with pre-syncope without vertigo or Horner's syndrome. Case report with review of the literature. A 67-year-old man presented with pre-syncope and ataxia without vertigo. Initial brain CT and MRI were normal. Neurological evaluation revealed right-beating nystagmus with left gaze, vertical binocular diplopia, right upper-extremity dysmetria, truncal ataxia with right axial lateropulsion, and right-facial and lower extremity hypoesthesia. Bedside blood pressure measurements disclosed orthostatic hypotension. He had normal sinus rhythm on telemetry and normal ejection fraction on echocardiogram. A repeat brain MRI disclosed an acute right dorsolateral medullary infarct. Autonomic testing showed reduced heart rate variability during paced deep breathing, attenuated late phase II and phase IV overshoot on Valsalva maneuver, and a fall of 25 mmHg of blood pressure at the end of a 10-min head-up tilt with no significant change in heart rate. These results were consistent with impaired sympathetic and parasympathetic cardiovascular reflexes. He was discharged to acute rehabilitation a week later with residual right dysmetria and ataxia. Lateral medullary infarctions are usually reported as partial presentations of classical lateral medullary syndrome with accompanying unusual symptoms ranging from trigeminal neuralgias to hiccups. Pre-syncope from orthostatic hypotension is a rare presentation. In the first 3-4 days, absence of early DWI MRI findings is possible in small, dorsolateral medullary infarcts with sensory disturbances. Physicians should be aware of this presentation, as early diagnosis and optimal therapy are associated with good prognosis.

  1. Development of impulse control circuitry in children of alcoholics.

    Science.gov (United States)

    Hardee, Jillian E; Weiland, Barbara J; Nichols, Thomas E; Welsh, Robert C; Soules, Mary E; Steinberg, Davia B; Zubieta, Jon-Kar; Zucker, Robert A; Heitzeg, Mary M

    2014-11-01

    Difficulty with impulse control is heightened in children with a family history of alcohol use disorders and is a risk factor for later substance problems. Cross-sectional functional magnetic resonance imaging studies have shown altered impulse control processing in adolescents with a positive family history, yet developmental trajectories have yet to be examined. Longitudinal functional magnetic resonance imaging was conducted in children of alcoholic families (family history positive [FH+]; n = 43) and children of control families (family history negative [FH-]; n = 30) starting at ages 7-12 years. Participants performed a go/no-go task during functional magnetic resonance imaging at intervals of 1-2 years, with two to four scans performed per subject. We implemented a repeated-measures linear model fit across all subjects to conduct a whole-brain search for developmental differences between groups. Performance improved with age in both groups, and there were no performance differences between groups. Significant between-group differences in linear age-related activation changes were found in the right caudate, middle cingulate, and middle frontal gyrus. Post hoc analyses revealed significant activation decreases with age in the caudate and middle frontal gyrus for FH- subjects and a significant increase with age in middle cingulate activation for FH+ subjects. Group differences were evident at age 7-12 years, even in alcohol- and drug-naïve participants, with FH+ subjects showing significantly blunted activation at baseline compared with FH- subjects. Differences in response inhibition circuitry are visible in FH+ individuals during childhood; these differences continue into adolescence, displaying trajectories that are inconsistent with development of normal response inhibition. These patterns precede problem drinking and may be a contributing factor for subsequent substance use problems. Copyright © 2014 Society of Biological Psychiatry. Published by

  2. Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism.

    Science.gov (United States)

    Gan, Zhenji; Rumsey, John; Hazen, Bethany C; Lai, Ling; Leone, Teresa C; Vega, Rick B; Xie, Hui; Conley, Kevin E; Auwerx, Johan; Smith, Steven R; Olson, Eric N; Kralli, Anastasia; Kelly, Daniel P

    2013-06-01

    The mechanisms involved in the coordinate regulation of the metabolic and structural programs controlling muscle fitness and endurance are unknown. Recently, the nuclear receptor PPARβ/δ was shown to activate muscle endurance programs in transgenic mice. In contrast, muscle-specific transgenic overexpression of the related nuclear receptor, PPARα, results in reduced capacity for endurance exercise. We took advantage of the divergent actions of PPARβ/δ and PPARα to explore the downstream regulatory circuitry that orchestrates the programs linking muscle fiber type with energy metabolism. Our results indicate that, in addition to the well-established role in transcriptional control of muscle metabolic genes, PPARβ/δ and PPARα participate in programs that exert opposing actions upon the type I fiber program through a distinct muscle microRNA (miRNA) network, dependent on the actions of another nuclear receptor, estrogen-related receptor γ (ERRγ). Gain-of-function and loss-of-function strategies in mice, together with assessment of muscle biopsies from humans, demonstrated that type I muscle fiber proportion is increased via the stimulatory actions of ERRγ on the expression of miR-499 and miR-208b. This nuclear receptor/miRNA regulatory circuit shows promise for the identification of therapeutic targets aimed at maintaining muscle fitness in a variety of chronic disease states, such as obesity, skeletal myopathies, and heart failure.

  3. Corticospinal tract insult alters GABAergic circuitry in the mammalian spinal cord

    Directory of Open Access Journals (Sweden)

    Jeffrey B. Russ

    2013-09-01

    Full Text Available During perinatal development, corticospinal tract (CST projections into the spinal cord help refine spinal circuitry. Although the normal developmental processes that are controlled by the arrival of corticospinal input are becoming clear, little is known about how perinatal cortical damage impacts specific aspects of spinal circuit development, particularly the inhibitory microcircuitry that regulates spinal reflex circuits. In this study, we sought to determine how ischemic cortical damage impacts the synaptic attributes of a well-characterized population of inhibitory, GABAergic interneurons, called GABApre neurons, which modulates the efficiency of proprioceptive sensory terminals in the sensorimotor reflex circuit. We found that putative GABApre interneurons receive CST input and, using an established mouse model of perinatal stroke, that cortical ischemic injury results in a reduction of CST density within the intermediate region of the spinal cord, where these interneurons reside. Importantly, CST alterations were restricted to the side contralateral to the injury. Within the synaptic terminals of the GABApre interneurons, we observed a dramatic upregulation of the 65-isoform of the GABA synthetic enzyme glutamic acid decarboxylase (GAD65. In accordance with the CST density reduction, GAD65 was elevated on the side of the spinal cord contralateral to cortical injury. This effect was not seen for other GABApre synaptic markers or in animals that received sham surgery. Our data reveal a novel effect of perinatal stroke that involves severe deficits in the architecture of descending spinal pathways, which in turn appear to promote molecular alterations in a specific spinal GABAergic circuit.

  4. Neurobiological Programming of Early Life Stress: Functional Development of Amygdala-Prefrontal Circuitry and Vulnerability for Stress-Related Psychopathology.

    Science.gov (United States)

    VanTieghem, Michelle R; Tottenham, Nim

    2017-04-25

    Early adverse experiences are associated with heighted vulnerability for stress-related psychopathology across the lifespan. While extensive work has investigated the effects of early adversity on neurobiology in adulthood, developmental approaches can provide further insight on the neurobiological mechanisms that link early experiences and long-term mental health outcomes. In the current review, we discuss the role of emotion regulation circuitry implicated in stress-related psychopathology from a developmental and transdiagnostic perspective. We highlight converging evidence suggesting that multiple forms of early adverse experiences impact the functional development of amygdala-prefrontal circuitry. Next, we discuss how adversity-induced alterations in amygdala-prefrontal development are associated with symptoms of emotion dysregulation and psychopathology. Additionally, we discuss potential mechanisms through which protective factors may buffer the effects of early adversity on amygdala-prefrontal development to confer more adaptive long-term outcomes. Finally, we consider limitations of the existing literature and make suggestions for future longitudinal and translational research that can better elucidate the mechanisms linking early adversity, neurobiology, and emotional phenotypes. Together, these findings may provide further insight into the neuro-developmental mechanisms underlying the emergence of adversity-related emotional disorders and facilitate the development of targeted interventions that can ameliorate risk for psychopathology in youth exposed to early life stress.

  5. 78 FR 53159 - Certain Semiconductor Chips With Dram Circuitry, and Modules and Products Containing Same: Notice...

    Science.gov (United States)

    2013-08-28

    ... INTERNATIONAL TRADE COMMISSION [Investigation No. 337-TA-819] Certain Semiconductor Chips With Dram Circuitry, and Modules and Products Containing Same: Notice of Commission Determination To Terminate the Investigation Based on Settlement AGENCY: U.S. International Trade Commission. ACTION: Notice...

  6. United in Diversity : A Physiological and Molecular Characterization of Subpopulations in the Basal Ganglia Circuitry

    OpenAIRE

    Viereckel, Thomas

    2017-01-01

    The Basal Ganglia consist of a number of different nuclei that form a diverse circuitry of GABAergic, dopaminergic and glutamatergic neurons. This complex network is further organized in subcircuits that govern limbic and motor functions in humans and other vertebrates. Due to the interconnection of the individual structures, dysfunction in one area or cell population can affect the entire network, leading to synaptic and molecular alterations in the circuitry as a whole. The studies in this ...

  7. Clinical relevance of18F-FDG PET and18F-DOPA PET in recurrent medullary thyroid carcinoma

    NARCIS (Netherlands)

    H.H.G. Verbeek (Hans H.); J.T. Plukker (John); K.P. Koopmans (Klaas Pieter); J. de Groot (Jan); R.M.W. Hofstra (Robert); A.C. Muller Kobold (Anneke); A.N.A. van der Horst-Schrivers (Anouk); A.H. Brouwers (A.); T.P. Links (Thera)

    2012-01-01

    textabstractThe transition from stable to progressive disease is unpredictable in patients with biochemical evidence of medullary thyroid carcinoma (MTC). Calcitonin and carcinoembryonic antigen (CEA) doubling times are currently the most reliable markers for progression, but for accurate

  8. Clinical Relevance of F-18-FDG PET and F-18-DOPA PET in Recurrent Medullary Thyroid Carcinoma

    NARCIS (Netherlands)

    Verbeek, Hans H. G.; Plukker, John T. M.; Koopmans, Klaas Pieter; de Groot, Jan Willem B.; Hofstra, Robert M. W.; Kobold, Anneke C. Muller; van der Horst-Schrivers, Anouk N. A.; Brouwers, Adrienne H.; Links, Thera P.

    2012-01-01

    The transition from stable to progressive disease is unpredictable in patients with biochemical evidence of medullary thyroid carcinoma (MTC). Calcitonin and carcinoembryonic antigen (CEA) doubling times are currently the most reliable markers for progression, but for accurate determination, serial

  9. Lessons from sleeping flies: insights from Drosophila melanogaster on the neuronal circuitry and importance of sleep.

    Science.gov (United States)

    Potdar, Sheetal; Sheeba, Vasu

    2013-06-01

    Sleep is a highly conserved behavior whose role is as yet unknown, although it is widely acknowledged as being important. Here we provide an overview of many vital questions regarding this behavior, that have been addressed in recent years using the genetically tractable model organism Drosophila melanogaster in several laboratories around the world. Rest in D. melanogaster has been compared to mammalian sleep and its homeostatic and circadian regulation have been shown to be controlled by intricate neuronal circuitry involving circadian clock neurons, mushroom bodies, and pars intercerebralis, although their exact roles are not entirely clear. We draw attention to the yet unanswered questions and contradictions regarding the nature of the interactions between the brain regions implicated in the control of sleep. Dopamine, octopamine, γ-aminobutyric acid (GABA), and serotonin are the chief neurotransmitters identified as functioning in different limbs of this circuit, either promoting arousal or sleep by modulating membrane excitability of underlying neurons. Some studies have suggested that certain brain areas may contribute towards both sleep and arousal depending on activation of specific subsets of neurons. Signaling pathways implicated in the sleep circuit include cyclic adenosine monophosphate (cAMP) and epidermal growth factor receptor-extracellular signal-regulated kinase (EGFR-ERK) signaling pathways that operate on different neural substrates. Thus, this field of research appears to be on the cusp of many new and exciting findings that may eventually help in understanding how this complex physiological phenomenon is modulated by various neuronal circuits in the brain. Finally, some efforts to approach the "Holy Grail" of why we sleep have been summarized.

  10. Unusual metastasis of medullary thyroid carcinoma to the breast: A cytological and histopathological correlation

    Directory of Open Access Journals (Sweden)

    Parul Tanwar

    2018-01-01

    Full Text Available Breast metastases are a relatively rare condition and account for approximately 0.5–2% of all breast tumors. Recognition of metastatic tumors in the breast is important because it would prevent unnecessary mutilating surgery and would lead to appropriate treatment of the primary tumor. Breast metastases from medullary thyroid cancer (MTC are very rare with only 21 reported cases in the literature. Some MTCs mimic primary invasive lobular carcinoma of the breast histopathologically and radiologically, making the distinction between the two diagnostically challenging. We present the case of a 45-year-old female presenting with a lump breast, which was later found out to be metastasis from medullary carcinoma thyroid.

  11. Life threatening medullary injury following adenoidectomy and local anesthetic infiltration of the operative bed.

    Science.gov (United States)

    Hershman, Eli; Halberthal, Michael; Goldsher, Dorit; Golz, Avishai; Bar-Joseph, Gad

    2009-02-01

    To draw attention to a rare, life threatening complication of a rather common procedure, namely medullary injury following adenoidectomy and local anesthetic infiltration of the operative bed. Case report. A tertiary pediatric critical care unit. A healthy 7-year-old girl underwent adenoidectomy and local anesthetic infiltration of the adenoid bed with lidocaine and adrenaline. In the recovery room, nystagmus, dysarthria, dyspnea, inability to cough and right hemiparesis were noticed. Because of her inability to remove secretions tracheal intubation was performed, followed by severe, life threatening respiratory failure. Tracheal intubation, hemodynamic support, prolonged mechanical ventilation, nitric oxide, and tracheostomy. In children, local anesthetic infiltration of the adenoid bed may cause life-threatening medullary injury and its routine use should be re-considered.

  12. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma

    Science.gov (United States)

    Asa, Sylvia L.; Dralle, Henning; Elisei, Rossella; Evans, Douglas B.; Gagel, Robert F.; Lee, Nancy; Machens, Andreas; Moley, Jeffrey F.; Pacini, Furio; Raue, Friedhelm; Frank-Raue, Karin; Robinson, Bruce; Rosenthal, M. Sara; Santoro, Massimo; Schlumberger, Martin; Shah, Manisha; Waguespack, Steven G.

    2015-01-01

    Introduction: The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association. Methods: The Task Force identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document. Results: The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC. Conclusions: The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendations to represent current, rational, and optimal medical practice. PMID:25810047

  13. [A case of solitary ectopic medullary carcinoma in the right submandibular region].

    Science.gov (United States)

    Kikutake, Takashi; Hosaka, Seiji; Fujita, Yasuhiko; Yoshida, Takahisa; Kawamoto, Shunji

    2013-11-01

    A 77-year-old woman consulted our hospital because of an indolent mass in the right submandibular region, which developed approximately 4 months previously. Ultrasonography revealed a 19.5×9.2 mm homogeneous low echoic mass in the submandibular region and a 9.8×3.1 mm low echoic mass in the left thyroid lobe. Blood examinations revealed high levels of carcinoembryonic antigen (CEA) and calcitonin. Analysis of the cytological specimens obtained from the submandibular tumors indicated class IV disease. First, we resected the mandibular tumor for diagnosis, and the specimen showed medullary carcinoma. Later, the patient underwent left thyroid lobe resection. The pathological diagnosis was adenomatous goiter. We report a rare case of ectopic medullary carcinoma in the right mandibular region.

  14. The potential value of somatostatin receptor scintigraphy in medullary thyroid carcinoma

    International Nuclear Information System (INIS)

    Doerr, U.; Bihl, H.; Frank-Raue, K.; Raue, F.; Sautter-Bihl, M.L.; Buhr, H.J.; Guzman, G.; Inst. de Neurocirugia, Investigationes Cerebrales 'Dr Asenjo' Santiago

    1993-01-01

    In a prospective study, ten patients with recurrent medullary thyroid carcinoma (markedly elevated calcitonin levels) were investigated by means of somatostatin receptor scintigraphy (SRS) with 111 In-pentetreotide. Scintigraphically, 30 sites of pathological uptake were found, mostly located in the neck and upper mediastinum. So far, 18 suspected tumour sites underwent histological examination and 14 of them could be verified as metastases of medullary thyroid carcinoma (MTC). The remaining four putative tumour lesions turned out to be false positive scintigraphic findings caused by chronic inflammation and somatostatin receptor positive tumours other than MTC. We conclude that SRS is a promising imaging modality for localization of MTC recurrence and may thus make a contribution to better management of this patient group. (Author)

  15. Depicting Medullary Thyroid Cancer Recurrence: The Past and the Future of Nuclear Medicine Imaging

    OpenAIRE

    Skoura, Evangelia

    2013-01-01

    Context: Inherited and sporadic medullary thyroid cancer (MTC) is an uncommon and medically challenging malignancy. Even if the extent of initial surgery is deemed adequate, the recurrence rate remains high, up to 50% in most series. Measurement of serum calcitonin is important in the follow-up of patients with MTC, and reliably reflects the existence of the disease. Evidence Acquisition: There is no single sensitive diagnostic imaging method to reveal all MTC recurrences or metastases. Conve...

  16. Histopathological and immunohistochemical findings of primary and metastatic medullary thyroid carcinoma in a young dog.

    Science.gov (United States)

    Piñeyro, Pablo; Vieson, Miranda D; Ramos-Vara, José A; Moon-Larson, Martha; Saunders, Geoffrey

    2014-01-01

    This report describes the gross, histological, and immunohistochemical features of medullary thyroid carcinoma (MTC) with pulmonary metastases in a young dog. Sheets of pleomorphic cells supported by fibrous stroma characterized the primary mass, while metastatic nodules had a neuroendocrine pattern. Despite differing histologic features, all masses showed marked immunoreactivity against calcitonin and multiple neuroendocrine markers consistent with MTC. Although MTC is a well-recognized entity, it may be difficult to distinguish this mass from other thyroid neoplasms, necessitating immunohistochemical characterization.

  17. Histopathological and immunohistochemical findings of primary and metastatic medullary thyroid carcinoma in a young dog

    OpenAIRE

    Piñeyro, Pablo; Vieson, Miranda D.; Ramos-Vara, José A.; Moon-Larson, Martha; Saunders, Geoffrey

    2014-01-01

    This report describes the gross, histological, and immunohistochemical features of medullary thyroid carcinoma (MTC) with pulmonary metastases in a young dog. Sheets of pleomorphic cells supported by fibrous stroma characterized the primary mass, while metastatic nodules had a neuroendocrine pattern. Despite differing histologic features, all masses showed marked immunoreactivity against calcitonin and multiple neuroendocrine markers consistent with MTC. Although MTC is a well-recognized enti...

  18. Glutamine uptake contributes to central sensitization in the medullary dorsal horn

    OpenAIRE

    Chiang, Chen Yu; Li, Zhaohui; Dostrovsky, Jonathan O.; Hu, James W.; Sessle, Barry J.

    2008-01-01

    Mustard oil application to tooth pulp produces central sensitization in rat medullary dorsal horn (MDH) nociceptive neurons, which has been implicated in persistent pain mechanisms. We found that superfusion onto MDH of methylaminoisobutyric acid, a competitive inhibitor of the neuronal system A transporter for presynaptic uptake of glutamine (a glutamate precursor released from astroglia), significantly depressed development of mustard oil-induced central sensitization in rat MDH nociceptive...

  19. Central sensitization in medullary dorsal horn involves gap junctions and hemichannels

    OpenAIRE

    Chiang, Chen Yu; Li, Zhaohui; Dostrovsky, Jonathan O.; Sessle, Barry J.

    2010-01-01

    Central sensitization is a fundamental mechanism contributing to acute and chronic pain conditions. Our previous studies have documented a glutamatergic-, purinergic- and glial-dependent central sensitization that can be induced in rat medullary dorsal horn (MDH) nociceptive neurons by mustard oil (MO) application to the tooth pulp. The present study demonstrated that carbenoxolone, a potent gap junction and hemichannel blocker, completely blocked all parameters of MO-induced central sensitiz...

  20. The influence of calcineurin inhibitors on renal medullary microcirculation: a novel approach to nephrotoxicity

    OpenAIRE

    Kelly, Mark Christopher

    2015-01-01

    The calcineurin inhibitors (CNIs), cyclosporine A (CsA) and tacrolimus (FK506), have revolutionized solid organ transplantation with their unprecedented ability to increase graft and patient survival. However, they have a plethora of unwanted side effects, of which nephrotoxicity is predominant. Renal cortical blood flow is majorly suppressed with administration of CsA and FK506, however the impact of these drugs on medullary blood flow is still unclear. \\ud It was previously thought that ren...

  1. The heart of the matter: Acute quadriplegia with respiratory paralysis - bilateral medial medullary infarction

    Directory of Open Access Journals (Sweden)

    Bhaskara P Shelley

    2017-01-01

    Full Text Available The clinicoradiologic correlate of bilateral medial medullary infarction is described. This is a rare clinical entity of vertebrobasilar stroke syndrome with catastrophic consequences and a poor functional prognosis. Since the initial symptom is quadriplegia, the clinical diagnosis without neuroimaging can be challenging with a potential for misdiagnosis as Guillain–Barré syndrome or brainstem encephalitis in the early stages. The teaching neuroimage of the “heart appearance” sign is revisited.

  2. Lateral Medullary Ischemic Infarct Caused by Posterior Inferior Cerebellar Artery Aneurysm

    Directory of Open Access Journals (Sweden)

    Muhammad Taimur Malik

    2017-12-01

    Full Text Available Posterior inferior cerebellar artery (PICA aneurysms are rare. The most common complication of intracranial aneurysms is rupture causing subarachnoid hemorrhage. Ischemic infarct, although more common in giant thrombosed aneurysms, is a very rare manifestation of small intracranial aneurysms. Here we describe a patient who presented with lateral medullary acute infarction associated with an ipsilateral, small (4 × 3.5 mm, unruptured and non-thrombosed PICA aneurysm.

  3. Medullary nephrocalcinosis and pancreatic calcifications demonstrated by ultrasound and CT in infants after treatment with ACTH

    Energy Technology Data Exchange (ETDEWEB)

    Rausch, H.P.; Hanefield, F.; Kaufmann, B.J.

    1984-10-01

    Thirteen patients who had undergone prolonged adrenocorticotropic hormone (ACTH) therapy for infantile spasms or encephalopathy were examined with sonography. Nine patients were seen to have appearances characteristic of medullary nephrocalcinosis. Five patients also showed a homogeneously increased echogenicity of the whole pancreas on sonography, and one of these showed increased density on computed tomography. Density measurements were in the range of calcific arterial within the papillae and pancreatic tissue. On abdominal survey radiographs, even in retrospect, no calcifications could be recognized.

  4. Adenocarcinoma of the prostate and metastatic medullary compression. A retrospective study of 22 patients

    DEFF Research Database (Denmark)

    Honnens de Lichtenberg, M; Kvist, E; Hjortberg, P

    1992-01-01

    A retrospective study of 709 patients with prostatic cancer was carried out. Twenty-two developed medullary cord compression (an incidence of 3%). All but two of the 22 patients were treated by radiation and 10 had additional hormonal treatment. Ten had some benefit from the treatment, but only 2...... of 19 regained their ability to walk. The need for immediate diagnosis and treatment is stressed....

  5. Irreducible tibial pilon fracture caused by incarceration of the fibula in the tibial medullary canal.

    Science.gov (United States)

    Ellanti, Prasad; Hammad, Yassir; Kosutic, Damir; Grieve, Philip P

    2012-01-01

    Fractures can be irreducible for several reasons, including soft tissue or bone fragment interposition. We report an unusual fracture configuration of a comminuted tibial pilon fracture in which the distal fibular shaft fragment was occupying the medullary canal of the proximal tibial shaft fragment and inhibiting reduction and fixation. To the best of our knowledge, this has not been previously reported in a published study. Copyright © 2012 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

  6. Factors affecting neurological outcome in traumatic conus medullaris and cauda equina injuries.

    Science.gov (United States)

    Kingwell, Stephen P; Curt, Armin; Dvorak, Marcel F

    2008-01-01

    The purpose of this review was to describe the relevant factors that influence neurological outcomes in patients who sustain traumatic conus medullaris injuries (CMIs) and cauda equina injuries (CEIs). Despite the propensity for spinal trauma to affect the thoracolumbar spine, few studies have adequately characterized the outcomes of CMIs and CEIs. Typically the level of neural axis injury is inferred from the spinal level of injury or the presenting neurological picture because no study from the spinal literature has specifically evaluated the location of the conus medullaris with respect to the level of greatest canal compromise. Furthermore, the conus medullaris is known to have a small but important variable location based on the spinal level. Patients with a CMI will typically present with variable lowerextremity weakness, absent lower-limb reflexes, and saddle anesthesia. The development of a mixed upper motor neuron and lower motor neuron syndrome may occur in patients with CMIs, whereas a CEI is a pure lower motor neuron injury. Many treatment options exist and should be individualized. Posterior decompression and stabilization offers at least equivalent neurological outcomes as nonoperative or anterior approaches and has the additional benefits of surgeon familiarity, shorter hospital stays, earlier rehabilitation, and ease of nursing care. Overall, CEIs and CMIs have similar outcomes, which include ambulatory motor function and a variable persistence of bowel, bladder, and potentially sexual dysfunctions.

  7. Effectiveness of Neuromuscular Electrical Stimulation on Patients With Dysphagia With Medullary Infarction.

    Science.gov (United States)

    Zhang, Ming; Tao, Tao; Zhang, Zhao-Bo; Zhu, Xiao; Fan, Wen-Guo; Pu, Li-Jun; Chu, Lei; Yue, Shou-Wei

    2016-03-01

    To evaluate and compare the effects of neuromuscular electrical stimulation (NMES) acting on the sensory input or motor muscle in treating patients with dysphagia with medullary infarction. Prospective randomized controlled study. Department of physical medicine and rehabilitation. Patients with dysphagia with medullary infarction (N=82). Participants were randomized over 3 intervention groups: traditional swallowing therapy, sensory approach combined with traditional swallowing therapy, and motor approach combined with traditional swallowing therapy. Electrical stimulation sessions were for 20 minutes, twice a day, for 5d/wk, over a 4-week period. Swallowing function was evaluated by the water swallow test and Standardized Swallowing Assessment, oral intake was evaluated by the Functional Oral Intake Scale, quality of life was evaluated by the Swallowing-Related Quality of Life (SWAL-QOL) Scale, and cognition was evaluated by the Mini-Mental State Examination (MMSE). There were no statistically significant differences between the groups in age, sex, duration, MMSE score, or severity of the swallowing disorder (P>.05). All groups showed improved swallowing function (P≤.01); the sensory approach combined with traditional swallowing therapy group showed significantly greater improvement than the other 2 groups, and the motor approach combined with traditional swallowing therapy group showed greater improvement than the traditional swallowing therapy group (Pdysphagia and improves quality of life for patients with dysphagia with medullary infarction. A sensory approach appears to be better than a motor approach. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  8. Wallenberg's lateral medullary syndrome: diffusion-weighted imaging findings

    Energy Technology Data Exchange (ETDEWEB)

    Kitis, O.; Calli, C.; Yunten, N.; Kocaman, A.; Sirin, H. [Ege Univ., Izmir (Turkey). Dept. of Radiology

    2004-02-01

    To investigate the efficacy of diffusion-weighted imaging in patients with Wallenberg's lateral medullary syndrome. Thirteen patients with Wallenberg's lateral medullary syndrome were examined with conventional and echoplanar diffusion-weighted magnetic resonance (MR) imaging in a 1.5 T magnetic resonance unit. MR examinations were obtained in the acute or subacute stage of clinical syndrome, and diffusion-weighted imaging (DWI) was considered to be positive for infarction when an increase in signal was seen on b = 1000 s/mm2 images in the posterolateral medullary localization. DWIs were positive in 12 patients in the acute or subacute stages of this clinical syndrome. A false-negative result was obtained in only one patient examined within the first day, 10 h after onset of the symptoms. In the visual evaluation of the DWI, the contrast between normal and infarcted brainstem area was better in the high b-value images than in the apparent diffusion coefficient map images. DWI is a valuable technique for examining patients presenting with the signs and symptoms of Wallenberg's syndrome and high b-value images can provide complementary data to T2-weighted images. However, because most of our case group were in either the acute or subacute stage, true sensitivity of the method in the hyperacute stage of the syndrome remains unclear.

  9. Ondine's Curse in a Patient with Unilateral Medullary and Bilateral Cerebellar Infarctions

    Directory of Open Access Journals (Sweden)

    Hui-Tzu Ho

    2005-11-01

    Full Text Available Central sleep apnea (CSA, also known as Ondine's curse (OC, is a phenomenon characterized by episodes of repeated apnea during sleep due to disorders of the central nervous system. We report a patient with CSA/OC due to right dorsolateral medullary and bilateral cerebellar infarctions that occurred in the clinical setting of right vertebral artery stenosis. Polysomnography (PSG showed repeated episodes of absence of nasal cannula flow accompanying cessation of thoracic and abdominal respiratory movements and a decline in blood oxygen saturation. The duration of apnea was as long as 12 seconds. Brain magnetic resonance (MR images showed acute infarctions involving the right dorsolateral medulla, bilateral cerebellar vermis and paramedian cerebellar hemispheres. MR angiography showed nonvisualization of the right vertebral artery. Transcranial Doppler sonography showed a high resistance flow profile in the right vertebral artery and normal flow patterns in the basilar artery and left vertebral artery. These findings suggest that the medullary and bilateral cerebellar infarcts were caused by stenosis/pseudo-occlusion of the right vertebral artery. Reduced respiratory afferent inputs to the dorsal respiratory group of medullary neurons, the nucleus tractus solitarius and reduced “automatic” components of the respiratory drive may play a role in the development of CSA/OC.

  10. Prominent deep medullary veins: a predictive biomarker for stroke risk from transient ischemic attack?

    Science.gov (United States)

    Duan, Yang; Xu, Zhihua; Li, Hongyi; Cai, Xiaonan; Chang, Cancan; Yang, Benqiang

    2018-05-01

    Background Deep medullary veins (DMVs) are a biomarker of severity and prognosis in patients with acute cerebral infarction. However, their clinical significance remains unclear in patients with transient ischemic attack (TIA). Purpose To determine whether prominent deep medullary veins (PDMVs) are a predictive biomarker for stroke risk after TIA. Material and Methods Clinical and imaging data of 49 patients with TIA and 49 sex- and age-matched controls were studied. PDMVs were defined as DMVs with a score of 3 (TDMVs) or asymmetric DMVs (ADMVs), and the relationship between PDMVs and clinical features was analyzed. The DMV score based on susceptibility weighted imaging (SWI) ranged from 0 (not visible) to 3 (very prominent) and was calculated for both hemispheres separately. A different score in each hemisphere was defined as ADMVs and an equal score was defined as symmetric DMVs. The asymmetry and score of DMVs were compared between the two groups and with respect to the time from TIA onset to imaging analysis. Results Agreement between neuroradiologists for the DMV asymmetry/score on SWI was excellent. The frequency of ADMVs and TDMVs was significantly higher in patients with TIA than controls ( P  0.05); PDMVs were not correlated with age, blood pressure, or diabetes. However, PDMVs were associated with the ABCD2 score (≥4), clinical symptoms, and duration of TIA (≥10 min). Conclusion Prominent deep medullary veins is a predictive biomarker for the risk of stroke in many patients having suffered from TIA.

  11. Role of 20-hydroxyeicosatetraenoic acid in mediating hypertension in response to chronic renal medullary endothelin type B receptor blockade.

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    Joshua S Speed

    Full Text Available BACKGROUND: The renal medullary endothelin (ET-1 system plays an important role in the control of sodium excretion and arterial pressure (AP through the activation of renal medullary ET-B receptors. We have previously shown that blockade of endothelin type B receptors (ET-B leads to salt-sensitive hypertension through mechanisms that are not fully understood. One possible mechanism is through a reduction in renal medullary production of 20-hydroxyeicosatetraenoic acid (20-HETE. 20-HETE, a metabolite of arachidonic acid, has natriuretic properties similar to ET-B activation. While these findings suggest a possible interaction between ET-B receptor activation and 20-HETE production, it is unknown whether blockade of medullary ET-B receptors in rats maintained on a high sodium intake leads to reductions in 20-HETE production. METHODOLOGY/PRINCIPAL FINDINGS: The effect of increasing sodium intake from low (NS = .8% to high (HS = 8% on renal medullary production of 20-HETE in the presence and absence of renal medullary ET-B receptor antagonism was examined. Renal medullary blockade of ET-B receptors resulted in salt sensitive hypertension. In control rats, blood pressure rose from 112.8±2.4 mmHg (NS to 120.7±9.3 mmHg (HS. In contrast, when treated with an ET-B receptor blocker, blood pressure was significantly elevated from 123.7±3.2 (NS to 164.2±7.1 (HS. Furthermore, increasing sodium intake was associated with elevated medullary 20-HETE (5.6±.8 in NS vs. 14.3±3.7 pg/mg in HS, an effect that was completely abolished by renal medullary ET-B receptor blockade (4.9±.8 for NS and 4.5±.6 pg/mg for HS. Finally, the hypertensive response to intramedullary ET-B receptor blockade was blunted in rats pretreated with a specific 20-HETE synthesis inhibitor. CONCLUSION: These data suggest that increases in renal medullary production of 20-HETE associated with elevating salt intake may be, in part, due to ET-B receptor activation within the renal

  12. AT2 receptors mediate tonic renal medullary vasoconstriction in renovascular hypertension

    Science.gov (United States)

    Duke, Lisa M; Widdop, Robert E; Kett, Michelle M; Evans, Roger G

    2005-01-01

    Renal medullary blood flow is relatively insensitive to angiotensin II (Ang II)-induced vasoconstriction, due partly to AT1-mediated release of nitric oxide and/or prostaglandins. AT2-receptor activation appears to blunt AT1-mediated vasodilatation within the medullary circulation. This could affect long-term efficacy of antihypertensive pharmacotherapies targeting the renin/angiotensin system, particularly in Ang II-dependent forms of hypertension. We tested the effects of AT1- and AT2-receptor blockade on basal cortical and medullary laser Doppler flux (CLDF and MLDF), and on responses to renal arterial infusion of Ang II, in rats with 2 kidney, 1 clip (2K1C) hypertension and sham-operated controls. Studies were carried out in thiobutabarbital (175 mg kg−1, i.p.) anaesthetised rats, 4 weeks after clipping, or sham surgery (n=6 in each of eight groups). Candesartan (10 μg kg−1 h−1, intravenous (i.v.)) reduced mean arterial pressure (∼17%) and increased CLDF (∼24%), similarly in both sham and 2K1C rats, but did not significantly affect MLDF. PD123319 (1 mg kg−1 h−1, i.v.) increased basal MLDF (19%) in 2K1C but not sham rats, without significantly affecting other variables. In sham rats, renal arterial infusion of Ang II (1–100 ng kg−1 min−1) dose dependently decreased CLDF (up to 44%), but did not significantly affect MLDF. These effects were markedly blunted in 2K1C rats. After PD123319, Ang II dose dependently increased MLDF (up to 38%) in sham but not 2K1C rats. Candesartan abolished all effects of Ang II, including those seen after PD123319. Our data indicate that AT1 receptors mediate medullary vasodilatation, which is opposed by AT2-receptor activation. In 2K1C hypertension, AT2-receptor activation tonically constricts the medullary circulation. PMID:15678096

  13. Aire downregulation is associated with changes in the posttranscriptional control of peripheral tissue antigens in medullary thymic epithelial cells.

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    Ernna Hérida Oliveira

    2016-11-01

    Full Text Available Autoimmune regulator (Aire is a transcriptional regulator of peripheral tissue antigens (PTAs and microRNAs (miRNAs in medullary thymic epithelial cells (mTECs. In this study, we tested the hypothesis that Aire also played a role as an upstream posttranscriptional controller in these cells and that variation in its expression might be associated with changes in the interactions between miRNAs and the mRNAs encoding PTAs. We demonstrated that downregulation of Aire in vivo in the thymuses of BALB/c mice imbalanced the large-scale expression of these two RNA species and consequently their interactions. The expression profiles of a large set of mTEC miRNAs and mRNAs isolated from the thymuses of mice subjected (or not to small-interfering (siRNA-induced Aire gene knockdown revealed that 87 miRNAs and 4,558 mRNAs were differentially expressed. The reconstruction of the miRNA-mRNA interaction networks demonstrated that interactions between these RNAs were under Aire influence and therefore changed when this gene was downregulated. Prior to Aire knockdown, only members of the miR-let-7 family interacted with a set of PTA mRNAs. Under Aire knockdown conditions, a larger set of miRNA families and their members established this type of interaction. Notably, no previously described Aire-dependent PTA interacted with the miRNAs, indicating that these PTAs were somehow refractory. The miRNA-mRNA interactions were validated by calculating the minimal free energy of the pairings between the miRNA seed regions and the mRNA 3´ UTRs and within the cellular milieu using the luciferase reporter gene assay. These results suggest the existence of a link between transcriptional and posttranscriptional control because Aire downregulation alters the miRNA-mRNA network controlling PTAs in mTEC cells.

  14. Aire Downregulation Is Associated with Changes in the Posttranscriptional Control of Peripheral Tissue Antigens in Medullary Thymic Epithelial Cells.

    Science.gov (United States)

    Oliveira, Ernna H; Macedo, Claudia; Collares, Cristhianna V; Freitas, Ana Carolina; Donate, Paula Barbim; Sakamoto-Hojo, Elza T; Donadi, Eduardo A; Passos, Geraldo A

    2016-01-01

    Autoimmune regulator (Aire) is a transcriptional regulator of peripheral tissue antigens (PTAs) and microRNAs (miRNAs) in medullary thymic epithelial cells (mTECs). In this study, we tested the hypothesis that Aire also played a role as an upstream posttranscriptional controller in these cells and that variation in its expression might be associated with changes in the interactions between miRNAs and the mRNAs encoding PTAs. We demonstrated that downregulation of Aire in vivo in the thymuses of BALB/c mice imbalanced the large-scale expression of these two RNA species and consequently their interactions. The expression profiles of a large set of mTEC miRNAs and mRNAs isolated from the thymuses of mice subjected (or not) to small-interfering-induced Aire gene knockdown revealed that 87 miRNAs and 4,558 mRNAs were differentially expressed. The reconstruction of the miRNA-mRNA interaction networks demonstrated that interactions between these RNAs were under Aire influence and therefore changed when this gene was downregulated. Prior to Aire-knockdown, only members of the miR-let-7 family interacted with a set of PTA mRNAs. Under Aire-knockdown conditions, a larger set of miRNA families and their members established this type of interaction. Notably, no previously described Aire-dependent PTA interacted with the miRNAs, indicating that these PTAs were somehow refractory. The miRNA-mRNA interactions were validated by calculating the minimal free energy of the pairings between the miRNA seed regions and the mRNA 3' UTRs and within the cellular milieu using the luciferase reporter gene assay. These results suggest the existence of a link between transcriptional and posttranscriptional control because Aire downregulation alters the miRNA-mRNA network controlling PTAs in mTEC cells.

  15. Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumor with lymph node metastasis: A case report

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    Sadat Alavi Mehr

    2011-12-01

    Full Text Available Abstract Introduction Papillary thyroid carcinoma and medullary thyroid carcinoma are two different thyroid neoplasia. The simultaneous occurrence of medullary thyroid carcinoma and papillary thyroid carcinoma as a collison tumor with metastases from both lesions in the regional lymph nodes is a rare phenomenon. Case presentation A 32-year-old Iranian man presented with a fixed anterior neck mass. Ultrasonography revealed two separate thyroid nodules as well as a suspicious neck mass that appeared to be a metastatic lesion. The results of thyroid function tests were normal, but the preoperative calcitonin serum value was elevated. Our patient underwent a total thyroidectomy with neck exploration. Two separate and ill-defined solid lesions grossly in the right lobe were noticed. Histological and immunohistochemical studies of these lesions suggested the presence of medullary thyroid carcinoma and papillary thyroid carcinoma. The lymph nodes isolated from a neck dissection specimen showed metastases from both lesions. Conclusions The concomitant occurrence of papillary thyroid carcinoma and medullary thyroid carcinoma and the exact diagnosis of this uncommon event are important. The treatment strategy should be reconsidered in such cases, and genetic screening to exclude multiple endocrine neoplasia 2 syndromes should be performed. For papillary thyroid carcinoma, radioiodine therapy and thyroid-stimulating hormone suppressive therapy are performed. However, the treatment of medullary thyroid carcinoma is mostly radical surgery with no effective adjuvant therapy.

  16. Toroidal transformer design program with application to inverter circuitry

    Science.gov (United States)

    Dayton, J. A., Jr.

    1972-01-01

    Estimates of temperature, weight, efficiency, regulation, and final dimensions are included in the output of the computer program for the design of transformers for use in the basic parallel inverter. The program, written in FORTRAN 4, selects a tape wound toroidal magnetic core and, taking temperature, materials, core geometry, skin depth, and ohmic losses into account, chooses the appropriate wire sizes and number of turns for the center tapped primary and single secondary coils. Using the program, 2- and 4-kilovolt-ampere transformers are designed for frequencies from 200 to 3200 Hz and the efficiency of a basic transistor inverter is estimated.

  17. Endothelin receptor A antagonism attenuates renal medullary blood flow impairment in endotoxemic pigs.

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    Johan Fenhammar

    Full Text Available BACKGROUND: Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors. METHODS AND FINDINGS: A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours. After two hours the animals were treated with the selective endothelin receptor type A antagonist TBC 3711 (2 mg⋅kg(-1, n = 8 or served as endotoxin-treated controls (n = 8. Renal artery blood flow, diuresis and creatinine clearance decreased in response to endotoxemia. Perfusion in the cortex, as measured by laser doppler flowmetry, was reduced in both groups, but TBC 3711 attenuated the decrease in the medulla (p = 0.002. Compared to control, TBC 3711 reduced renal oxygen extraction as well as cortical and medullary lactate/pyruvate ratios (p<0.05 measured by microdialysis. Furthermore, TBC 3711 attenuated the decline in renal cortical interstitial glucose levels (p = 0.02 and increased medullary pyruvate levels (p = 0.03. Decreased creatinine clearance and oliguria were present in both groups without any significant difference. CONCLUSIONS: These results suggest that endothelin released during endotoxemia acts via endothelin A receptors to impair renal medullary blood flow causing ischemia. Reduced renal oxygen extraction and cortical levels of lactate by TBC 3711, without effects on cortical blood flow, further suggest additional metabolic effects of endothelin type A receptor activation in this model of endotoxin induced acute kidney injury.

  18. Primary medullary hemorrhage in a patient with coagulopathy due to alcoholic cirrhosis: A case report.

    Science.gov (United States)

    Shen, Guangxun; Gao, Yu; Lee, Kwee-Yum; Nan, Guangxian

    2018-04-01

    Mild-to-moderate alcoholic cirrhosis of the liver is related to spontaneous intracerebral hemorrhage (ICH). In terms of spontaneous brainstem hemorrhage, pontine is considered as the most common site in contrast to medulla oblongata where the hemorrhage is rarely seen. This rare primary medullary hemorrhage has been attributed so far to vascular malformation (VM), anticoagulants, hypertension, hemorrhagic transformation, and other undetermined factors. Herein, we describe a 53-year-old patient with 35-year history of alcohol abuse was admitted for acute-onset isolated hemianesthesia on the right side. He was normotensive on admission. A neurological examination revealed isolated hemihypoaesthesia on the right side. He had no history of hypertension, and viral hepatitis, and nil use of anticoagulants. Brain computed tomography (CT) image demonstrated hemorrhagic lesion in dorsal and medial medulla oblongata which was ruptured into the fourth ventricle. Brain magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA) demonstrated no evidence of VM. The laboratory tests implied liver dysfunction, thrombocytopenia, and coagulation disorders. Abdominal ultrasound, and CT image showed a small, and nodular liver with splenomegaly, suggestive of moderate alcoholic cirrhosis. Liver protection therapy and the management of coagulation disorders. After 14 days, he was discharged with mild hemianesthesia but with more improved parameters in laboratory tests. At the 6-month follow-up, brain MRI, MRA, and non-contrast MRI showed no significant findings except for a malacic lesion. We conclude that the patient had alcoholic cirrhosis with coagulopathy, and this may have resulted in primary medullary hemorrhage. This is a first case to report alcoholic cirrhosis as etiology of primary medullary hemorrhage.

  19. Chronological changes of blink reflex and MRI in a patient with lateral medullary infarction

    International Nuclear Information System (INIS)

    Kawamura, Hirotsune; Amano, Keiichi; Tanikawa, Tatsuya; Kawabatake, Hiroko; Kubo, Osami; Kitamura, Koichi; Ono, Yuko

    1986-01-01

    Recently, the brainstem pathways of bilateral late reflexes (R2) of electrically elicited blink reflex have been well established. An afferent delay or block of the late reflexes is closely related to a lesion of the lateral medullary portion. The chronological alteration of blink reflex (BR) was studied to compare with radiological abnormalities on MRI in a patient with lateral medullary infarction on the right side. A diagnosis of Wallenberg syndrome was made clinically and location of the lesion was identified in detail by MRI. The infarcted region which was well demonstrated as an increased intensity area on SE images obtained 52 days after the onset of symptoms was much smaller than that on SE as well as on IR image 21 days after the onset of symptoms. Therefore, it was concluded that more than half of the increased intensity area on the SE images obtained 21 days after the onset of symptoms recovered from the condition of being extremely damaged by ischemia on the right lateral medullary portion in this patient. On the other hand, in the initial BR 26 days after the onset of symptoms, the late reflexes (R2) were consistently absent bilaterally when the affected side (right) was stimulated and normal when the normal side (left) was stimulated. This type of BR abnormality is compatible with an afferent block of late reflexes (R2). The early reflex (R1) was normal on either side. Whereas in the second BR at 55 days after the onset of symptoms, the late reflexes turned to be normal in latency when the right side was stimulated. This recovery of late reflexes after the stimulation of the supraorbital nerve on the affected side was thought to be relevant to the part of disappearance of increased intensity area on the SE images obtained 52 days after the onset of symptoms. (J.P.N.)

  20. Optogenetic deconstruction of sleep-wake circuitry in the brain

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    Antoine Adamantidis

    2010-01-01

    Full Text Available How does the brain regulate the sleep-wake cycle? What are the temporal codes of sleep- and wake-promoting neural circuits? How do these circuits interact with each other across the light/dark cycle? Over the past few decades, many studies from a variety of disciplines have made substantial progress in answering these fundamental questions. For example, neurobiologists have identified multiple, redundant wake-promoting circuits in the brainstem, hypothalamus, and basal forebrain. Sleep-promoting circuits have been found in the preoptic area and hypothalamus. One of the greatest challenges in recent years has been to selectively record and manipulate these sleep-wake centers in vivo with high spatial and temporal resolution. Recent developments in microbial opsin-based neuromodulation tools, collectively referred to as “optogenetics,” have provided a novel method to demonstrate causal links between neural activity and specific behaviors. Here, we propose to use optogenetics as a fundamental tool to probe the necessity, sufficiency, and connectivity of defined neural circuits in the regulation of sleep and wakefulness.

  1. Histamine-induced increases in cyclic AMP levels in bovine adrenal medullary cells.

    OpenAIRE

    Marley, P. D.; Thomson, K. A.; Jachno, K.; Johnston, M. J.

    1991-01-01

    1. The effect of histamine on cellular cyclic AMP levels in cultured bovine adrenal medullary cells has been studied. 2. Histamine (0.3-30 microM) increased cyclic AMP levels transiently, with a maximal response after 5 min, a smaller response after 20 min, and no increase seen after 80 or 180 min. The EC50 at 5 min was approximately 2 microM. Histamine had no effect on cyclic AMP release from the cells over 5 min, but increased it after 90 min. 3. The cyclic AMP response to 5 microM histamin...

  2. Conus medullaris syndrome due to an intradural disc herniation: A case report

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    Chaudhary Kshitij

    2008-01-01

    Full Text Available A 70-year-old male patient developed acute paraplegia due to conus medullaris compression secondary to extrusion of D12-L1 disc. After negative epidural examination intraoperatively, a durotomy was performed and an intradural disc fragment was excised. Patient did not regain ambulatory status at two-year follow-up. Intraoperative finding of negative extradural compression, tense swollen dura and CSF leak from ventral dura should alert the surgeon for the possibility of intradural disc herniation. A routine preoperative MRI is misleading and a high index of suspicion helps to avoid a missed diagnosis.

  3. Horner's Syndrome Incidental to Medullary Thyroid Carcinoma Excision: Case Report and Brief Literature Review

    Science.gov (United States)

    Mastronikolis, Nicholas S.; Spiliopoulou, Sofia P.; Zolota, Vassiliki; Papadas, Theodoros A.

    2016-01-01

    Horner's syndrome is characterized by a combination of ipsilateral miosis, blepharoptosis, enophthalmos, facial anhidrosis, and iris heterochromia in existence of congenital lesions. The syndrome results from a disruption of the ipsilateral sympathetic innervation of the eye and ocular adnexa at different levels. Though rare, thyroid and neck surgery could be considered as possible causes of this clinical entity. We present a case of Horner's syndrome in a patient after total thyroidectomy and neck dissection for medullary thyroid cancer with neck nodal disease and attempt a brief review of the relevant literature. PMID:27200201

  4. Horner’s Syndrome Incidental to Medullary Thyroid Carcinoma Excision: Case Report and Brief Literature Review

    Directory of Open Access Journals (Sweden)

    Nicholas S. Mastronikolis

    2016-01-01

    Full Text Available Horner’s syndrome is characterized by a combination of ipsilateral miosis, blepharoptosis, enophthalmos, facial anhidrosis, and iris heterochromia in existence of congenital lesions. The syndrome results from a disruption of the ipsilateral sympathetic innervation of the eye and ocular adnexa at different levels. Though rare, thyroid and neck surgery could be considered as possible causes of this clinical entity. We present a case of Horner’s syndrome in a patient after total thyroidectomy and neck dissection for medullary thyroid cancer with neck nodal disease and attempt a brief review of the relevant literature.

  5. Subjective Visual Vertical and Horizontal Abnormalities in a Patient with Lateral Medullary Syndrome-A Case Report

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    Amit Tyagi

    2015-01-01

    Full Text Available Introduction: Evaluation of persistent vertigo in post infarct patients is very important as the management depends on whether the cause is purely of central origin or due to associated vestibular affliction.   Case Report: A patient with left sided dorsolateral medullary syndrome and persistent vestibular symptoms was evaluated. Vestibular test battery showed abnormal smooth pursuit, bilateral hyperactive caloric responses, and abnormal dynamic subjective visual vertical and dynamic subjective visual horizontal tests.   Conclusion:  Dorsolateral medullary infarctions (Wallenberg’s syndrome typically cause a central vestibular tonus imbalance in the roll plane with ipsilateral deviations of perceived vertical orientation. The SVV and SVH tests may have a role in localizing the pathology in a patient with lateral medullary syndrome.

  6. 76 FR 79215 - Certain Semiconductor Chips With Dram Circuitry, and Modules and Products Containing Same...

    Science.gov (United States)

    2011-12-21

    ... INTERNATIONAL TRADE COMMISSION [Investigation No. 337-TA-819] Certain Semiconductor Chips With... importation, and the sale within the United States after importation of certain semiconductor chips with DRAM... semiconductor chips with DRAM circuitry, and modules and products containing same that infringe one or more of...

  7. Synaptic defects in the spinal and neuromuscular circuitry in a mouse model of spinal muscular atrophy.

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    Karen K Y Ling

    2010-11-01

    Full Text Available Spinal muscular atrophy (SMA is a major genetic cause of death in childhood characterized by marked muscle weakness. To investigate mechanisms underlying motor impairment in SMA, we examined the spinal and neuromuscular circuitry governing hindlimb ambulatory behavior in SMA model mice (SMNΔ7. In the neuromuscular circuitry, we found that nearly all neuromuscular junctions (NMJs in hindlimb muscles of SMNΔ7 mice remained fully innervated at the disease end stage and were capable of eliciting muscle contraction, despite a modest reduction in quantal content. In the spinal circuitry, we observed a ∼28% loss of synapses onto spinal motoneurons in the lateral column of lumbar segments 3-5, and a significant reduction in proprioceptive sensory neurons, which may contribute to the 50% reduction in vesicular glutamate transporter 1(VGLUT1-positive synapses onto SMNΔ7 motoneurons. In addition, there was an increase in the association of activated microglia with SMNΔ7 motoneurons. Together, our results present a novel concept that synaptic defects occur at multiple levels of the spinal and neuromuscular circuitry in SMNΔ7 mice, and that proprioceptive spinal synapses could be a potential target for SMA therapy.

  8. Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species

    Science.gov (United States)

    Gee, Dylan G.; Fetcho, Robert N.; Jing, Deqiang; Li, Anfei; Glatt, Charles E.; Drysdale, Andrew T.; Cohen, Alexandra O.; Dellarco, Danielle V.; Yang, Rui R.; Dale, Anders M.; Jernigan, Terry L.; Lee, Francis S.; Casey, B.J.

    2016-01-01

    Anxiety disorders peak in incidence during adolescence, a developmental window that is marked by dynamic changes in gene expression, endocannabinoid signaling, and frontolimbic circuitry. We tested whether genetic alterations in endocannabinoid signaling related to a common polymorphism in fatty acid amide hydrolase (FAAH), which alters endocannabinoid anandamide (AEA) levels, would impact the development of frontolimbic circuitry implicated in anxiety disorders. In a pediatric imaging sample of over 1,000 3- to 21-y-olds, we show effects of the FAAH genotype specific to frontolimbic connectivity that emerge by ∼12 y of age and are paralleled by changes in anxiety-related behavior. Using a knock-in mouse model of the FAAH polymorphism that controls for genetic and environmental backgrounds, we confirm phenotypic differences in frontoamygdala circuitry and anxiety-related behavior by postnatal day 45 (P45), when AEA levels begin to decrease, and also, at P75 but not before. These results, which converge across species and level of analysis, highlight the importance of underlying developmental neurobiology in the emergence of genetic effects on brain circuitry and function. Moreover, the results have important implications for the identification of risk for disease and precise targeting of treatments to the biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation. PMID:27001846

  9. Group Membership Modulates the Neural Circuitry Underlying Third Party Punishment.

    Science.gov (United States)

    Morese, Rosalba; Rabellino, Daniela; Sambataro, Fabio; Perussia, Felice; Valentini, Maria Consuelo; Bara, Bruno G; Bosco, Francesca M

    2016-01-01

    This research aims to explore the neural correlates involved in altruistic punishment, parochial altruism and anti-social punishment, using the Third-Party Punishment (TPP) game. In particular, this study considered these punishment behaviors in in-group vs. out-group game settings, to compare how people behave with members of their own national group and with members of another national group. The results showed that participants act altruistically to protect in-group members. This study indicates that norm violation in in-group (but not in out-group) settings results in increased activity in the medial prefrontal cortex and temporo-parietal junction, brain regions involved in the mentalizing network, as the third-party attempts to understand or justify in-group members' behavior. Finally, exploratory analysis during anti-social punishment behavior showed brain activation recruitment of the ventromedial prefrontal cortex, an area associated with altered regulation of emotions.

  10. Angiotensin II stimulates renin in inner medullary collecting duct cells via protein kinase C and independent of epithelial sodium channel and mineralocorticoid receptor activity.

    Science.gov (United States)

    Gonzalez, Alexis A; Liu, Liu; Lara, Lucienne S; Seth, Dale M; Navar, L Gabriel; Prieto, Minolfa C

    2011-03-01

    Collecting duct (CD) renin is stimulated by angiotensin (Ang) II, providing a pathway for Ang I generation and further conversion to Ang II. Ang II stimulates the epithelial sodium channel via the Ang II type 1 receptor and increases mineralocorticoid receptor activity attributed to increased aldosterone release. Our objective was to determine whether CD renin augmentation is mediated directly by Ang II type 1 receptor or via the epithelial sodium channel and mineralocorticoid receptor. In vivo studies examined the effects of epithelial sodium channel blockade (amiloride; 5 mg/kg per day) on CD renin expression and urinary renin content in Ang II-infused rats (80 ng/min, 2 weeks). Ang II infusion increased systolic blood pressure, medullary renin mRNA, urinary renin content, and intrarenal Ang II levels. Amiloride cotreatment did not alter these responses despite a reduction in the rate of progression of systolic blood pressure. In primary cultures of inner medullary CD cells, renin mRNA and (pro)renin protein levels increased with Ang II (100 nmol/L), and candesartan (Ang II type 1 receptor antagonist) prevented this effect. Aldosterone (10(-10) to 10(-7) mol/L) with or without amiloride did not modify the upregulation of renin mRNA in Ang II-treated cells. However, inhibition of protein kinase C with calphostin C prevented the Ang II-mediated increases in renin mRNA and (pro)renin protein levels. Furthermore, protein kinase C activation with phorbol 12-myristate 13-acetate increased renin expression to the same extent as Ang II. These data indicate that an Ang II type 1 receptor-mediated increase in CD renin is induced directly by Ang II via the protein kinase C pathway and that this regulation is independent of mineralocorticoid receptor activation or epithelial sodium channel activity.

  11. The involvement of medullary reticular formation in the hypotensive effect of extracts from seeds of Cassia tora.

    Science.gov (United States)

    Chan, S H; Koo, A; Li, K M

    In pentobarbital anesthetized rats, the medial portion of the medullary reticular formation has been identified to be directly involved in the hypotensive effect of extracts from the seeds of Cassia tora. This conclusion was drawn from the observed decrease in arterial blood pressure following local injection of extracts of this herb into this reticular site and from its inability to promote hypotension when the same reticular site has been electrolytically lesioned. The role of the medullary reticular formation in the Cassia tora-induced hypotension was suggested to be one which modulates the basic cardiovascular reflexes, favoring a decrease in vasomotor tone.

  12. Post-Aire maturation of thymic medullary epithelial cells involves selective expression of keratinocyte-specific autoantigens

    Directory of Open Access Journals (Sweden)

    Xiaoping eWang

    2012-03-01

    Full Text Available The autoimmune regulator (Aire-directed ectopic expression of tissue-specific antigens (TSAs by mature medullary thymic epithelial cells (mTECs has been viewed as an essential mechanism in the induction of central tolerance. Recent data suggest that the survival of mTECs extends beyond the Aire+ cell population to form the post-Aire mTEC population and Hassall's corpuscles (HCs. The nature and function of these post-Aire epithelial cells and structures, however, have remained unidentified. In this study, we characterized in detail the end-stage development of mTECs and HCs in both Aire-sufficient and Aire-deficient mice. In addition, using a transgenic mouse model in which the LacZ reporter gene is under the control of the endogenous Aire promoter, we purified and analyzed the post-Aire mTECs to characterize their function. We showed that the end-stage maturation of mTECs closely resembles that of keratinocytes and that the lack of Aire results in a marked block of mTEC differentiation, which is partially overcome by ligands for RANK and CD40. We also provide evidence that, during mTEC development, Aire is expressed only once and during a limited 1-2 day period. The following loss of Aire expression is accompanied by a quick downregulation of MHC class II and CD80, and of most of the Aire-dependent and Aire-independent TSAs, with the exception of keratinocyte-specific genes. In the final stage of maturation, the mTECs lose their nuclei to become HCs and specifically express desmogleins (DGs 1 and 3, which, via cross-presentation by APCs, may contribute to tolerance against these pemphigus vulgaris-related TSAs.

  13. Post-Aire Maturation of Thymic Medullary Epithelial Cells Involves Selective Expression of Keratinocyte-Specific Autoantigens

    Science.gov (United States)

    Wang, Xiaoping; Laan, Martti; Bichele, Rudolf; Kisand, Kai; Scott, Hamish S.; Peterson, Pärt

    2012-01-01

    The autoimmune regulator (Aire)-directed ectopic expression of tissue-specific antigens (TSAs) by mature medullary thymic epithelial cells (mTECs) has been viewed as an essential mechanism in the induction of central tolerance. Recent data suggest that the survival of mTECs extends beyond the Aire+ cell population to form the post-Aire mTEC population and Hassall’s corpuscles (HCs). The nature and function of these post-Aire epithelial cells and structures, however, have remained unidentified. In this study, we characterized in detail the end-stage development of mTECs and HCs in both Aire-sufficient and Aire-deficient mice. In addition, using a transgenic mouse model in which the LacZ reporter gene is under the control of the endogenous Aire promoter, we purified and analyzed the post-Aire mTECs to characterize their function. We showed that the end-stage maturation of mTECs closely resembles that of keratinocytes and that the lack of Aire results in a marked block of mTEC differentiation, which is partially overcome by ligands for RANK and CD40. We also provide evidence that, during mTEC development, Aire is expressed only once and during a limited 1–2 day period. The following loss of Aire expression is accompanied by a quick downregulation of MHC class II and CD80, and of most of the Aire-dependent and Aire-independent TSAs, with the exception of keratinocyte-specific genes. In the final stage of maturation, the mTECs lose their nuclei to become HCs and specifically express desmogleins (DGs) 1 and 3, which, via cross-presentation by APCs, may contribute to tolerance against these pemphigus vulgaris-related TSAs. PMID:22448160

  14. Aire knockdown in medullary thymic epithelial cells affects Aire protein, deregulates cell adhesion genes and decreases thymocyte interaction.

    Science.gov (United States)

    Pezzi, Nicole; Assis, Amanda Freire; Cotrim-Sousa, Larissa Cotrim; Lopes, Gabriel Sarti; Mosella, Maritza Salas; Lima, Djalma Sousa; Bombonato-Prado, Karina F; Passos, Geraldo Aleixo

    2016-09-01

    We demonstrate that even a partial reduction of Aire mRNA levels by siRNA-induced Aire knockdown (Aire KD) has important consequences to medullary thymic epithelial cells (mTECs). Aire knockdown is sufficient to reduce Aire protein levels, impair its nuclear location, and cause an imbalance in large-scale gene expression, including genes that encode cell adhesion molecules. These genes drew our attention because adhesion molecules are implicated in the process of mTEC-thymocyte adhesion, which is critical for T cell development and the establishment of central self-tolerance. Accordingly, we consider the following: 1) mTECs contribute to the elimination of self-reactive thymocytes through adhesion; 2) Adhesion molecules play a crucial role during physical contact between these cells; and 3) Aire is an important transcriptional regulator in mTECs. However, its role in controlling mTEC-thymocyte adhesion remains unclear. Because Aire controls adhesion molecule genes, we hypothesized that the disruption of its expression could influence mTEC-thymocyte interaction. To test this hypothesis, we used a murine Aire(+) mTEC cell line as a model system to reproduce mTEC-thymocyte adhesion in vitro. Transcriptome analysis of the mTEC cell line revealed that Aire KD led to the down-modulation of more than 800 genes, including those encoding for proteins involved in cell adhesion, i.e., the extracellular matrix constituent Lama1, the CAM family adhesion molecules Vcam1 and Icam4, and those that encode peripheral tissue antigens. Thymocytes co-cultured with Aire KD mTECs had a significantly reduced capacity to adhere to these cells. This finding is the first direct evidence that Aire also plays a role in controlling mTEC-thymocyte adhesion. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Influence of Bisphosphonate Treatment on Medullary Macrophages and Osteoclasts: An Experimental Study

    Directory of Open Access Journals (Sweden)

    Natalia Daniela Escudero

    2012-01-01

    Full Text Available Nitrogen-containing bisphosphonates are widely used for treating diverse bone pathologies. They are anticatabolic drugs that act on osteoclasts inhibiting bone resorption. It remains unknown whether the mechanism of action is by decreasing osteoclast number, impairing osteoclast function, or whether they continue to effectively inhibit bone resorption despite the increase in osteoclast number. There is increasing evidence that bisphosphonates also act on bone marrow cells like macrophages and monocytes. The present work sought to evaluate the dynamics of preosteoclast fusion and possible changes in medullary macrophage number in bisphosphonate-treated animals. Healthy female Wistar rats received olpadronate, alendronate, or vehicle during 5 weeks, and 5-bromo-2-deoxyuridine (BrdU on day 7, 28, or 34 of the experiment. Histomorphometric studies were performed to study femurs and evaluate: number of nuclei per osteoclast (N.Nu/Oc; number of BrdU-positive nuclei (N.Nu BrdU+/Oc; percentage of BrdU-positive nuclei per osteoclast (%Nu.BrdU+/Oc; medullary macrophage number (mac/mm2 and correlation between N.Nu/Oc and mac/mm2. Results showed bisphosphonate-treated animals exhibited increased N.Nu/Oc, caused by an increase in preosteoclast fusion rate and evidenced by higher N.Nu BrdU+/Oc, and significantly decreased mac/mm2. Considering the common origin of osteoclasts and macrophages, the increased demand for precursors of the osteoclast lineage may occur at the expense of macrophage lineage precursors.

  16. Renal medullary carcinoma: sonographic, computed tomography, magnetic resonance and angiographic findings

    Energy Technology Data Exchange (ETDEWEB)

    Khan, Ali E-mail: drkhan@primedia.co.uk; Thomas, Nigel; Costello, Brandon; Jobling, Louis; Kretser, Dan de; Broadfield, Emma; O' Shea, Sarah

    2000-07-01

    Renal medullary carcinoma is a recently described, highly aggressive tumour, occurring predominantly in young patients of African descent with sickle cell trait (SCT). All have been metastatic at surgery. Surgery, radiotherapy and chemotherapy do not appear to alter the course of the disease. The survival time is very short. Presentation is usually with haematuria, abdominal pain and weight loss. Forty-nine patients have been reported from the USA, of these 47 were African/Americans. The reports have mostly appeared in pathology journals. On review of the imaging findings reported in the radiological journals, it becomes apparent that it is possible for a radiologist to suggest a specific diagnosis in the appropriate demographic and clinical setting. Here the first British patient of Afro-Caribbean decent in whom a pre-operative diagnosis was suggested on the imaging findings of a centrally located renal pelvic tumour, encasing the pelvis on a background of SCT in a 28-year-old is described. It is expected that a high index of suspicion in the appropriate clinical setting may lead to earlier diagnosis, treatment and survival of patients. The patient is alive and reasonably well 9 months after surgery. The full range of imaging findings in renal medullary carcinoma are described.

  17. FSP1(+) fibroblast subpopulation is essential for the maintenance and regeneration of medullary thymic epithelial cells.

    Science.gov (United States)

    Sun, Lina; Sun, Chenming; Liang, Zhanfeng; Li, Hongran; Chen, Lin; Luo, Haiying; Zhang, Hongmei; Ding, Pengbo; Sun, Xiaoning; Qin, Zhihai; Zhao, Yong

    2015-10-08

    Thymic epithelial cells (TECs) form a 3-dimentional network supporting thymocyte development and maturation. Besides epithelium and thymocytes, heterogeneous fibroblasts are essential components in maintaining thymic microenvironments. However, thymic fibroblast characteristics, development and function remain to be determined. We herein found that thymic non-hematopoietic CD45(-)FSP1(+) cells represent a unique Fibroblast specific protein 1 (FSP1)(-)fibroblast-derived cell subset. Deletion of these cells in FSP1-TK transgenic mice caused thymus atrophy due to the loss of TECs, especially mature medullary TECs (MHCII(high), CD80(+) and Aire(+)). In a cyclophosphamide-induced thymus injury and regeneration model, lack of non-hematopoietic CD45(-)FSP1(+) fibroblast subpopulation significantly delayed thymus regeneration. In fact, thymic FSP1(+) fibroblasts released more IL-6, FGF7 and FSP1 in the culture medium than their FSP1(-) counterparts. Further experiments showed that the FSP1 protein could directly enhance the proliferation and maturation of TECs in the in vitro culture systems. FSP1 knockout mice had significantly smaller thymus size and less TECs than their control. Collectively, our studies reveal that thymic CD45(-)FSP1(+) cells are a subpopulation of fibroblasts, which is crucial for the maintenance and regeneration of TECs especially medullary TECs through providing IL-6, FGF7 and FSP1.

  18. [Medullary carcinoma experience in breast oncology unit of Hospital Juarez Mexico].

    Science.gov (United States)

    Jiménez-Villanueva, Xicoténcatl; Hernández-Rubio, Angela; García-Rodríguez, Francisco Mario; García, Rebeca Gil; Moreno-Eutimio, Mario; Herrera-Torre, Analy

    2014-01-01

    Medullary breast cancer is a rare type, considered of good prognosis. To know the epidemiological and clinical characteristics of the population attended in the Hospital Juarez de Mexico, to know if they are alike to described worldwide and if the treatments proposed internationally are applicable for this hospitable center. We performed a retrospective analysis. Reviewing the records with histopathologic diagnosis of medullary breast cancer from February 1993 to February 2011. Finding 41 patients in the oncology unit of the institution. We report an incidence of 3.04%, originating in 11 Mexican States, with a low to middle socioeconomic level in 39.02%. The average age at the time of diagnosis was 50 years. No family history was reported but some patients had medical history for type 2 diabetes, hypertension and previous breast cancer. 63.41% were menopausal. The average clinical size of the tumor was 58 mm. The 63% of the cases were located in the left breast. The 53.1% were clinical stages I and II, 46.3% were clinical stages III and in 9.6% of the cases primary tumor could not be assessed. Only 47% of the patients had positive axillary lynph nodes at diagnosis. The inmunohistochemestry was only reported in 14 of the 41 patients, according to the molecular classification of breast cancer: 8 were triple negative, 2 luminal A, 1 luminal B and 3 Her2neu. The Mexican population presents epidemiological and clinical characteristics similar to those patients described in other studies worldwide.

  19. Interest of MIBG scintigraphy in screening for pheochromocytoma in patients with medullary thyroid carcinoma

    International Nuclear Information System (INIS)

    Bonnin, F.; Lumbroso, J.; Schlumberger, M.; Megnigbeto, A.; Tenenbaum, F.; Leclere, J.; Travagli, J.P.; Gardet, P.; Parmentier, C.

    1995-01-01

    Adrenal medullary disease (AMD) is clinically silent in most patients with medullary thyroid carcinoma (MTC). During 16 years, a series of 174 MTC patients was screened yearly for AMD. Metaiodobenzylguanidine (MIBG) scans were performed in 54 cases (21 at diagnosis and 33 during the follow up of MTC) either systematically (43 cases) or in patients with biological or ultrasonographic signs of AMD (11 cases). AMD was discovered in ten patients: five patients were already known to have a type II multiple endocrine neoplasia (MEN-2); in five patients previously considered as having either a sporadic (four cases) or a familial type of isolated MTC (one case), the occurrence of AMD led to diagnose a MEN-2 a syndrome. In three cases, AMD was bilateral. MIBG scan were performed in nine of the ten patients with AMD. No false positive MIBG scan was observed in the series. All patients with positive MIBG scan had either elevated excretion of catecholamines and derivates. MIBG scan had a sensitivity of 0.9 and specificity of 1. MIBG should not be used as a screening test. In particular, MIBG scan should not be performed systematically neither at diagnosis nor during follow-up. But, in cases with suspicion of AMD, it provides important complementary functional information. (authors). 15 refs., 3 tabs., 2 figs

  20. Regulating prefrontal cortex activation

    DEFF Research Database (Denmark)

    Aznar, Susana; Klein, Anders Bue

    2013-01-01

    The prefrontal cortex (PFC) is involved in mediating important higher-order cognitive processes such as decision making, prompting thereby our actions. At the same time, PFC activation is strongly influenced by emotional reactions through its functional interaction with the amygdala...... and the striatal circuitry, areas involved in emotion and reward processing. The PFC, however, is able to modulate amygdala reactivity via a feedback loop to this area. A role for serotonin in adjusting for this circuitry of cognitive regulation of emotion has long been suggested based primarily on the positive...... pharmacological effect of elevating serotonin levels in anxiety regulation. Recent animal and human functional magnetic resonance studies have pointed to a specific involvement of the 5-hydroxytryptamine (5-HT)2A serotonin receptor in the PFC feedback regulatory projection onto the amygdala. This receptor...

  1. A Role for the Lateral Dorsal Tegmentum in Memory and Decision Neural Circuitry

    Science.gov (United States)

    Redila, Van; Kinzel, Chantelle; Jo, Yong Sang; Puryear, Corey B.; Mizumori, Sheri J.Y.

    2017-01-01

    A role for the hippocampus in memory is clear, although the mechanism for its contribution remains a matter of debate. Converging evidence suggests that hippocampus evaluates the extent to which context-defining features of events occur as expected. The consequence of mismatches, or prediction error, signals from hippocampus is discussed in terms of its impact on neural circuitry that evaluates the significance of prediction errors: Ventral tegmental area (VTA) dopamine cells burst fire to rewards or cues that predict rewards (Schultz et al., 1997). Although the lateral dorsal tegmentum (LDTg) importantly controls dopamine cell burst firing (Lodge & Grace, 2006) the behavioral significance of the LDTg control is not known. Therefore, we evaluated LDTg functional activity as rats performed a spatial memory task that generates task-dependent reward codes in VTA (Jo et al., 2013; Puryear et al., 2010) and another VTA afferent, the pedunculopontine nucleus (PPTg, Norton et al., 2011). Reversible inactivation of the LDTg significantly impaired choice accuracy. LDTg neurons coded primarily egocentric information in the form of movement velocity, turning behaviors, and behaviors leading up to expected reward locations. A subset of the velocity-tuned LDTg cells also showed high frequency bursts shortly before or after reward encounters, after which they showed tonic elevated firing during consumption of small, but not large, rewards. Cells that fired before reward encounters showed stronger correlations with velocity as rats moved toward, rather than away from, rewarded sites. LDTg neural activity was more strongly regulated by egocentric behaviors than that observed for PPTg or VTA cells that were recorded by Puryear et al. and Norton et al. While PPTg activity was uniquely sensitive to ongoing sensory input, all three regions encoded reward magnitude (although in different ways), reward expectation, and reward encounters. Only VTA encoded reward prediction errors. LDTg

  2. A neural circuitry that emphasizes spinal feedback generates diverse behaviours of human locomotion.

    Science.gov (United States)

    Song, Seungmoon; Geyer, Hartmut

    2015-08-15

    It is often assumed that central pattern generators, which generate rhythmic patterns without rhythmic inputs, play a key role in the spinal control of human locomotion. We propose a neural control model in which the spinal control generates muscle stimulations mainly through integrated reflex pathways with no central pattern generator. Using a physics-based neuromuscular human model, we show that this control network is sufficient to compose steady and transitional 3-D locomotion behaviours, including walking and running, acceleration and deceleration, slope and stair negotiation, turning, and deliberate obstacle avoidance. The results suggest feedback integration to be functionally more important than central pattern generation in human locomotion across behaviours. In addition, the proposed control architecture may serve as a guide in the search for the neurophysiological origin and circuitry of spinal control in humans. Neural networks along the spinal cord contribute substantially to generating locomotion behaviours in humans and other legged animals. However, the neural circuitry involved in this spinal control remains unclear. We here propose a specific circuitry that emphasizes feedback integration over central pattern generation. The circuitry is based on neurophysiologically plausible muscle-reflex pathways that are organized in 10 spinal modules realizing limb functions essential to legged systems in stance and swing. These modules are combined with a supraspinal control layer that adjusts the desired foot placements and selects the leg that is to transition into swing control during double support. Using physics-based simulation, we test the proposed circuitry in a neuromuscular human model that includes neural transmission delays, musculotendon dynamics and compliant foot-ground contacts. We find that the control network is sufficient to compose steady and transitional 3-D locomotion behaviours including walking and running, acceleration and

  3. Circuitry Linking the Catabolite Repression and Csr Global Regulatory Systems of Escherichia coli.

    Science.gov (United States)

    Pannuri, Archana; Vakulskas, Christopher A; Zere, Tesfalem; McGibbon, Louise C; Edwards, Adrianne N; Georgellis, Dimitris; Babitzke, Paul; Romeo, Tony

    2016-11-01

    Cyclic AMP (cAMP) and the cAMP receptor protein (cAMP-CRP) and CsrA are the principal regulators of the catabolite repression and carbon storage global regulatory systems, respectively. cAMP-CRP controls the transcription of genes for carbohydrate metabolism and other processes in response to carbon nutritional status, while CsrA binds to diverse mRNAs and regulates translation, RNA stability, and/or transcription elongation. CsrA also binds to the regulatory small RNAs (sRNAs) CsrB and CsrC, which antagonize its activity. The BarA-UvrY two-component signal transduction system (TCS) directly activates csrB and csrC (csrB/C) transcription, while CsrA does so indirectly. We show that cAMP-CRP inhibits csrB/C transcription without negatively regulating phosphorylated UvrY (P-UvrY) or CsrA levels. A crp deletion caused an elevation in CsrB/C levels in the stationary phase of growth and increased the expression of csrB-lacZ and csrC-lacZ transcriptional fusions, although modest stimulation of CsrB/C turnover by the crp deletion partially masked the former effects. DNase I footprinting and other studies demonstrated that cAMP-CRP bound specifically to three sites located upstream from the csrC promoter, two of which overlapped the P-UvrY binding site. These two proteins competed for binding at the overlapping sites. In vitro transcription-translation experiments confirmed direct repression of csrC-lacZ expression by cAMP-CRP. In contrast, cAMP-CRP effects on csrB transcription may be mediated indirectly, as it bound nonspecifically to csrB DNA. In the reciprocal direction, CsrA bound to crp mRNA with high affinity and specificity and yet exhibited only modest, conditional effects on expression. Our findings are incorporated into an emerging model for the response of Csr circuitry to carbon nutritional status. Csr (Rsm) noncoding small RNAs (sRNAs) CsrB and CsrC of Escherichia coli use molecular mimicry to sequester the RNA binding protein CsrA (RsmA) away from lower

  4. Calcitonin and carcinoembryonic antigen doubling times as prognostic factors in medullary thyroid carcinoma: a structured meta-analysis

    NARCIS (Netherlands)

    Meijer, Johannes A. A.; le Cessie, Saskia; van den Hout, Wilbert B.; Kievit, Job; Schoones, Johannes W.; Romijn, Johannes A.; Smit, Johannes W. A.

    2010-01-01

    In the management of patients with medullary thyroid carcinoma (MTC), calcitonin doubling time (dt) has gained interest as an independent predictor of recurrence and survival. To perform a structured meta-analysis of the diagnostic value of calcitonin dt, carcinoembryonic antigen (CEA) dt and the

  5. Lateral medullary syndrome following injury of the vestibular pathway to the core vestibular cortex: Diffusion tensor imaging study.

    Science.gov (United States)

    Yeo, Sang Seok; Jang, Sung Ho; Kwon, Jung Won

    2018-02-05

    The parieto-insular vestibular cortex (PIVC) is a core region of vestibular input into regions of the cortex. The vestibular nuclei have reciprocal connections with the PIVC. However, little is known about injury of the core vestibular pathway to the PIVC in patients with dorsolateral medullary infarctions. In this study, using diffusion tensor tractography (DTT), we investigated injury of the neural connections between the vestibular nuclei and the PIVC in patients with typical central vestibular disorder. Eight consecutive patients with lateral medullary syndrome and 10 control subjects were recruited for this study. To reconstruct the core vestibular pathway to the PIVC, we defined the seed region of interest (ROI) as the vestibular nuclei of the pons and the target ROI as the PIVC. Fractional anisotropy (FA), mean diffusivity (MD), and tract volume were measured. The core vestibular pathway to the PIVC showed significantly lower tract volume in patients compared with the control group (p0.05). In conclusion, injury of the core vestibular pathway to the PIVC was demonstrated in patients with lateral vestibular syndrome following dorsolateral medullary infarcts. We believe that analysis of the core vestibular pathway to the PIVC using DTT would be helpful in evaluating patients with lateral medullary syndrome. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. (18)F-Dihydroxyphenylalanine PET in patients with biochemical evidence of medullary thyroid cancer : Relation to tumor differentiation

    NARCIS (Netherlands)

    Koopmans, Klaas P.; de Groot, Jan Willem B.; Plukker, John T. M.; de Vries, Elisabeth G. E.; Kema, Ido P.; Sluiter, Wim J.; Jager, Pieter L.; Links, Thera P.

    Curative treatment for recurrent medullary thyroid cancer (MTC), diagnosed by rising serum calcitonin, is surgery, but tumor localization is difficult. Therefore, the value of (18)F-dihy-droxyphenylanaline PET ((18)F-DOPA PET), (18)F-FDG PET, (99m)Tc-V-di-mercaptosulfuricacid (DMSA-V) scintigraphy,

  7. Somatostatin receptor scintigraphy using (99m)Tc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma

    NARCIS (Netherlands)

    Czepczynski, Rafal; Parisella, Maria Gemma; Kosowicz, Jerzy; Mikolajczak, Renata; Ziemnicka, Katarzyna; Gryczynska, Maria; Sowinski, Jerzy; Signore, Alberto

    2007-01-01

    Purpose Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin

  8. Incorporation of radioactive sulfate (Na235SO4) by mouse adrenal medullary cells as shown by radioautography

    International Nuclear Information System (INIS)

    Munhoz, C.O.G.; Merzel, J.

    1977-01-01

    Preliminary radioautographic results, observed in the adreno-medullary cells of mice injected with radiosulfate, suggested that the cells might synthetize sulfur-containing compounds. Only further studies could make-clear if sulfate groups are linked to carbohydrate molecules and/or chromaffin granules [pt

  9. Sonographic assessment of normal renal parenchymal and medullary pyramid thicknesses among children in Enugu, Southeast, Nigeria

    International Nuclear Information System (INIS)

    Eze, C.U.; Akpan, V.P.; Nwadike, I.U.

    2016-01-01

    Background: Renal parenchymal thickness (RPT) and renal medullary pyramid thickness (MPT) are important renal size parameters. This study was aimed at establishing normograms for RPT and MPT with respect to age and somatometric parameters among children. Methods: This was a cross sectional study done in Enugu, Nigeria between May 2013 and April 2014. The subjects were 512 children aged 1–17 years scanned with ultrasound equipment with 3.5 MHz and 5 MHz curvilinear transducers. The RPT was measured perpendicularly to the long axis of the kidney from the medullary papilla to the renal capsule and MPT was measured from the apex to the base of the medullary pyramid on the same plane. The age and somatometric parameters of the subjects were recorded. Results: The mean ± SD of RPT and MPT for the right kidney were 12.62 ± 1.67 mm and 7.10 ± 0.92 mm and the left kidney were 12.81 ± 1.7 and 7.23 ± 0.94 mm respectively. There was a significant difference between the right and left RPT and MPT (p < 0.05). The right and left RPT correlated strongly with age, body surface area (BSA), height, and weight but moderately with body mass index (BMI). A moderate positive correlation was observed between MPT and age, BSA, height, and weight. However, a weak correlation was observed between MPT and BMI. Conclusion: Normograms of RPT and MPT in relation to age could be useful for grading hydronephrosis in children. - Highlights: • Sonography of RPT and MPT at the anterior longitudinal axis of the kidney is simple. • RPT and MPT Measurements are reliable within and between experienced sonographers. • No significant gender differences in RPT and MPT values exist in this study. • Significant differences exist between the right and left RPT and MPT measurements. • Normative values of RPT and MPT in relation to age in children are useful.

  10. Effects of aspirin on renal cortical and medullary tissues in rat embryos

    Directory of Open Access Journals (Sweden)

    Seyed Homayoon Sadraie

    2013-12-01

    Full Text Available Background: Aspirin is the drug of the century, and is a multifunctional drug and one of the most prescribed drugs in the world. Aspirin is a safe drug at low doses but also it has life-threatening side effects when administered at high doses. This study investi-gates the effects of aspirin on renal cortical and medullary tissue in rat embryos.Methods: In this study, 30 pregnant female rats were randomly divided into 6 groups. Control group with no intervention, sham group received 2 ml distilled water (as a sol-vent of aspirin received from days 8 to 20 of pregnancy, and four experimental groups received different doses of 75, 100, 200 and 300 mg/kg of aspirin by gavage. Pregnant rats were sacrificed on the twenty days of pregnancy and the fetuses were removed. Weight of the fetuses and placenta and Crown-Rump length were measured. Fetal kid-neys were fixed in formalin processed, sectioned and stained with Hematoxylin- Eosin. Thickness of renal cortical and medullary tissue by using a Motic hardware and soft-ware system were measured and recorded. A significance level of 0.05 was predeter-mined for all statistical analyses.Results: No apparent fetal anomalies were observed in experimental groups. In addi-tion, no significant differences were shown in the mean of fetal weight, placental weight, mean of Crown-Rump length in experimental groups 75, 200 and 300 mg/kg compared to control and sham groups. Mean fetal and placental weight in experimental group 100 significantly increased compared to control and sham groups. Mean ratio of renal cortex to renal medulla in experimental group 75, 100 and 300 were significantly decreased compared to control and sham groups (respectively P= 0.03, P= 0.013, P= 0.03.Conclusion: It seems that maternal use of aspirin during pregnancy can not cause fetal abnormalities. However, it can cause some changes in renal cortical and medullary tis-sue of rat embryos.

  11. Stitching Codeable Circuits: High School Students' Learning About Circuitry and Coding with Electronic Textiles

    Science.gov (United States)

    Litts, Breanne K.; Kafai, Yasmin B.; Lui, Debora A.; Walker, Justice T.; Widman, Sari A.

    2017-10-01

    Learning about circuitry by connecting a battery, light bulb, and wires is a common activity in many science classrooms. In this paper, we expand students' learning about circuitry with electronic textiles, which use conductive thread instead of wires and sewable LEDs instead of lightbulbs, by integrating programming sensor inputs and light outputs and examining how the two domains interact. We implemented an electronic textiles unit with 23 high school students ages 16-17 years who learned how to craft and code circuits with the LilyPad Arduino, an electronic textile construction kit. Our analyses not only confirm significant increases in students' understanding of functional circuits but also showcase students' ability in designing and remixing program code for controlling circuits. In our discussion, we address opportunities and challenges of introducing codeable circuit design for integrating maker activities that include engineering and computing into classrooms.

  12. Mechanisms of Long Non-Coding RNAs in the Assembly and Plasticity of Neural Circuitry.

    Science.gov (United States)

    Wang, Andi; Wang, Junbao; Liu, Ying; Zhou, Yan

    2017-01-01

    The mechanisms underlying development processes and functional dynamics of neural circuits are far from understood. Long non-coding RNAs (lncRNAs) have emerged as essential players in defining identities of neural cells, and in modulating neural activities. In this review, we summarized latest advances concerning roles and mechanisms of lncRNAs in assembly, maintenance and plasticity of neural circuitry, as well as lncRNAs' implications in neurological disorders. We also discussed technical advances and challenges in studying functions and mechanisms of lncRNAs in neural circuitry. Finally, we proposed that lncRNA studies would advance our understanding on how neural circuits develop and function in physiology and disease conditions.

  13. Adaptive Supply Voltage Management for Low Power Logic Circuitry Operating at Subthreshold

    OpenAIRE

    Rehan Ahmed

    2015-01-01

    With the rise in demand of portable hand held devices and with the rise in application of wireless sensor networks and RFID reduction of total power consumption has become a necessity. To save power we operate the logic circuitry of our devices at sub-threshold. In sub-threshold the drain current is exponentially dependent on the threshold voltage hence the threshold variation causes profound variation of ION and IOFF the ratio of which affect the speed of a circuit drastically. S...

  14. Functional role for cortical-striatal circuitry in modulating alcohol self-administration.

    Science.gov (United States)

    Jaramillo, Anel A; Randall, Patrick A; Stewart, Spencer; Fortino, Brayden; Van Voorhies, Kalynn; Besheer, Joyce

    2018-03-01

    The cortical-striatal brain circuitry is heavily implicated in drug-use. As such, the present study investigated the functional role of cortical-striatal circuitry in modulating alcohol self-administration. Given that a functional role for the nucleus accumbens core (AcbC) in modulating alcohol-reinforced responding has been established, we sought to test the role of cortical brain regions with afferent projections to the AcbC: the medial prefrontal cortex (mPFC) and the insular cortex (IC). Long-Evans rats were trained to self-administer alcohol (15% alcohol (v/v)+2% sucrose (w/v)) during 30 min sessions. To test the functional role of the mPFC or IC, we utilized a chemogenetic technique (hM4D i -Designer Receptors Activation by Designer Drugs) to silence neuronal activity prior to an alcohol self-administration session. Additionally, we chemogenetically silenced mPFC→AcbC or IC→AcbC projections, to investigate the role of cortical-striatal circuitry in modulating alcohol self-administration. Chemogenetically silencing the mPFC decreased alcohol self-administration, while silencing the IC increased alcohol self-administration, an effect absent in mCherry-Controls. Interestingly, silencing mPFC→AcbC projections had no effect on alcohol self-administration. In contrast, silencing IC→AcbC projections decreased alcohol self-administration, in a reinforcer-specific manner as there was no effect in rats trained to self-administer sucrose (0.8%, w/v). Additionally, no change in self-administration was observed in the mCherry-Controls. Together these data demonstrate the complex role of the cortical-striatal circuitry while implicating a role for the insula-striatal circuit in modulating ongoing alcohol self-administration. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Statins Promote Long-Term Recovery after Ischemic Stroke by Reconnecting Noradrenergic Neuronal Circuitry

    Directory of Open Access Journals (Sweden)

    Kyoung Joo Cho

    2015-01-01

    Full Text Available Inhibitors of HMG-CoA reductase (statins, widely used to lower cholesterol in coronary heart and vascular disease, are effective drugs in reducing the risk of stroke and improving its outcome in the long term. After ischemic stroke, cardiac autonomic dysfunction and psychological problems are common complications related to deficits in the noradrenergic (NA system. This study investigated the effects of statins on the recovery of NA neuron circuitry and its function after transient focal cerebral ischemia (tFCI. Using the wheat germ agglutinin (WGA transgene technique combined with the recombinant adenoviral vector system, NA-specific neuronal pathways were labeled, and were identified in the locus coeruleus (LC, where NA neurons originate. NA circuitry in the atorvastatin-treated group recovered faster than in the vehicle-treated group. The damaged NA circuitry was partly reorganized with the gradual recovery of autonomic dysfunction and neurobehavioral deficit. Newly proliferated cells might contribute to reorganizing NA neurons and lead anatomic and functional recovery of NA neurons. Statins may be implicated to play facilitating roles in the recovery of the NA neuron and its function.

  16. Impulsivity and aggression in schizophrenia: a neural circuitry perspective with implications for treatment.

    Science.gov (United States)

    Hoptman, Matthew J

    2015-06-01

    Elevations of impulsive behavior have been observed in a number of serious mental illnesses. These phenomena can lead to harmful behaviors, including violence, and thus represent a serious public health concern. Such violence is often a reason for psychiatric hospitalization, and it often leads to prolonged hospital stays, suffering by patients and their victims, and increased stigmatization. Despite the attention paid to violence, little is understood about its neural basis in schizophrenia. On a psychological level, aggression in schizophrenia has been primarily attributed to psychotic symptoms, desires for instrumental gain, or impulsive responses to perceived personal slights. Often, multiple attributions can coexist during a single aggressive incident. In this review, I discuss the neural circuitry associated with impulsivity and aggression in schizophrenia, with an emphasis on implications for treatment. Impulsivity appears to account for a great deal of aggression in schizophrenia, especially in inpatient settings. Urgency, defined as impulsivity in the context of strong emotion, is the primary focus of this article. It is elevated in several psychiatric disorders, and in schizophrenia, it has been related to aggression. Many studies have implicated dysfunctional frontotemporal circuitry in impulsivity and aggression in schizophrenia, and pharmacological treatments may act via that circuitry to reduce urgency and aggressive behaviors; however, more mechanistic studies are critically needed. Recent studies point toward manipulable neurobehavioral targets and suggest that cognitive, pharmacological, neuromodulatory, and neurofeedback treatment approaches can be developed to ameliorate urgency and aggression in schizophrenia. It is hoped that these approaches will improve treatment efficacy.

  17. Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

    Directory of Open Access Journals (Sweden)

    Dichter Gabriel S

    2012-07-01

    Full Text Available Abstract This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders, neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder, and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome. We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.

  18. A role for radiotherapy in the management of advanced medullary thyroid carcinoma: the Mayo Clinic experience

    Directory of Open Access Journals (Sweden)

    Jason A. Call

    2013-07-01

    Full Text Available Outcomes of external beam radiotherapy (EBRT in advanced medullary thyroid carcinoma\t(MTC\tare\tlargely\tunknown. Retrospective review of data from patients with MTC, diagnosed from June 1, 1970, through December 31, 2007. Overall survival and locoregional tumor control rates were calculated. Seventeen patients had adjuvant or palliative EBRT delivered to 41 sites. Six patients initially had adjuvant EBRT (median, 60.80 Gy; none had relapse in the treated area. Five patients with locoregional recurrence after surgery were treated (median, 59.40 Gy, and durable disease control was achieved in 3. Twelve patients received palliative EBRT to 29 sites of metastatic disease (median, 30.00 Gy, which provided sustained symptom relief at 45% of sites. Five- and ten- year overall survival rates were 44% and 19%, respectively. Adjuvant EBRT may be most effective for prevention of locoregional recurrence. EBRT may provide sustained control of advanced, metastatic disease in select patients.

  19. Smoldering medullary thyroid carcinoma liver metastasis 37 years after resection of an organ-confined tumor.

    Science.gov (United States)

    Waters, Kevin M; Ali, Syed Z; Erozan, Yener S; Olson, Matthew T

    2015-01-01

    Medullary thyroid carcinoma (MTC) is an uncommon thyroid tumor that usually behaves aggressively. After resection, serological surveillance for calcitonin and carcinoembryonic antigen (CEA) is used to prompt a radiographic search for metastatic disease. We report a case of a 65-year-old woman who presented with a large liver metastasis 37 years after she underwent thyroidectomy for organ-confined MTC. Her clinical course over that time showed a smoldering pattern in which she was symptom free until presentation even though her serum calcitonin and CEA concentrations were elevated for 17 years, and a small equivocal radiographic lesion in the liver was detected 10 years prior to presentation. Cytopathology from an ultrasound guided fine needle aspiration of the hepatic lesion was diagnostic for metastatic MTC. This case highlights the ability for smoldering residual MTC to suddenly transform to aggressive biological behavior after a long period of clinical remission. © 2014 Wiley Periodicals, Inc.

  20. CURRENT CAPABILITIES AND PROSPECTS OF CHEMORADIOTHERAPY FOR MEDULLARY THYROID CANCER (A LITERATURE REVIEW

    Directory of Open Access Journals (Sweden)

    I. S. Pimonova

    2017-01-01

    Full Text Available Medullary thyroid cancer (MTC is characterized by the most aggressive course among differentiated thyroid carcinomas and is accompanied by early and extensive metastasis. Up to 60 % of patients with MTC already have disseminated forms of the disease (stage III– IV by the moment of diagnosis. Overall five-year and ten-year survival of patients with MTC is 85–89 and 73–75 %, respectively, whereas five-year survival rate in patients with stage III–IV MTC is significantly lower and does not exceed 5–10 %. Therefore, treatment of disseminated forms of MTC is an extremely important problem in clinical oncology. The article gives an overview of Russian and foreign publications on the effectiveness of radiation and drug therapy for generalized MTC. Particular attention is paid to modern promising treatment strategies used for this category of patients, such as radionuclide therapy of bone metastases and targeted therapy with tyrosine kinase inhibitors.

  1. RET mutations in a large indian family with medullary thyroid carcinoma

    Directory of Open Access Journals (Sweden)

    D M Mahesh

    2014-01-01

    Full Text Available Background: Medullary thyroid carcinoma (MTC is a tumor arising from the para follicular (C cells of the thyroid gland and can occur either sporadically or as part of an inherited syndrome. A proportion of these cases carry an autosomal dominant mutation in the RET (REarranged during Transfection proto-oncogene. Screening for these mutations in the affected patients and the carriers ′′at risk′′ which includes the first-degree relatives is of utmost importance for early detection and prompt treatment including prophylactic thyroidectomy in cases that harbor these mutations. Results: This report presents details of screening and subsequent follow-up of a large Indian family, where the index case was found to carry p.Cys634Ser mutation involving exon 11 of the RET gene. These data are of value considering the paucity of information within the region in context of screening large families affected by these mutations.

  2. Neuroanatomical circuitry between kidney and rostral elements of brain: a virally mediated transsynaptic tracing study in mice.

    Science.gov (United States)

    Zhou, Ye-Ting; He, Zhi-Gang; Liu, Tao-Tao; Feng, Mao-Hui; Zhang, Ding-Yu; Xiang, Hong-Bing

    2017-02-01

    The identity of higher-order neurons and circuits playing an associative role to control renal function is not well understood. We identified specific neural populations of rostral elements of brain regions that project multisynaptically to the kidneys in 3-6 days after injecting a retrograde tracer pseudorabies virus (PRV)-614 into kidney of 13 adult male C57BL/6J strain mice. PRV-614 infected neurons were detected in a number of mesencephalic (e.g. central amygdala nucleus), telencephalic regions and motor cortex. These divisions included the preoptic area (POA), dorsomedial hypothalamus (DMH), lateral hypothalamus, arcuate nucleus (Arc), suprachiasmatic nucleus (SCN), periventricular hypothalamus (PeH), and rostral and caudal subdivision of the paraventricular nucleus of the hypothalamus (PVN). PRV-614/Tyrosine hydroxylase (TH) double-labeled cells were found within DMH, Arc, SCN, PeH, PVN, the anterodorsal and medial POA. A subset of neurons in PVN that participated in regulating sympathetic outflow to kidney was catecholaminergic or serotonergic. PRV-614 infected neurons within the PVN also contained arginine vasopressin or oxytocin. These data demonstrate the rostral elements of brain innervate the kidney by the neuroanatomical circuitry.

  3. Imaging of renal medullary carcinoma in children and young adults: a report from the Children's Oncology Group

    Energy Technology Data Exchange (ETDEWEB)

    Sandberg, Jesse K.; Khanna, Geetika [Washington University School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, MO (United States); Mullen, Elizabeth A. [Children' s Hospital Boston/Dana-Farber Cancer Institute, Department of Pediatric Oncology, Boston, MA (United States); Cajaiba, Mariana M.; Perlman, Elizabeth J. [Northwestern University Feinberg School of Medicine, Department of Pathology and Laboratory Medicine, Ann and Robert H. Lurie Children' s Hospital of Chicago, Chicago, IL (United States); Smith, Ethan A. [University of Michigan Health System, Section of Pediatric Radiology, C. S. Mott Children' s Hospital, Department of Radiology, Ann Arbor, MI (United States); Servaes, Sabah [Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); Geller, James I. [University of Cincinnati, Division of Pediatric Oncology, Cincinnati Children' s Hospital Medical Center, Cincinnati, OH (United States); Ehrlich, Peter F. [University of Michigan Health System, Section of Pediatric Surgery, C. S. Mott Children' s Hospital, Department of Surgery, Ann Arbor, MI (United States); Cost, Nicholas G. [University of Colorado School of Medicine, Division of Urology, Department of Surgery, Aurora, CO (United States); Dome, Jeffrey S. [Children' s National Medical Center, Division of Pediatric Oncology, Washington, DC (United States); Fernandez, Conrad V. [Dalhousie University and IWK Health Centre, Department of Pediatrics, Halifax, NS (Canada)

    2017-11-15

    Renal medullary carcinoma is a rare renal malignancy of childhood. There are no large series describing the imaging appearance of renal medullary carcinoma in children. To characterize the clinical and imaging features of pediatric renal medullary carcinoma at initial presentation. We retrospectively analyzed images of 25 pediatric patients with renal medullary carcinoma enrolled in the Children's Oncology Group renal tumors classification, biology and banking study (AREN03B2) from March 2006 to August 2016. Imaging findings of the primary mass, and patterns of locoregional and distant spread were evaluated in correlation with pathological and surgical findings. Median age at presentation was 13 years (range: 6-21 years), with a male predominance (3.2:1). The overall stage of disease at initial presentation was stage 1 in 1, stage 2 in 2 and stage 4 in 22. Maximum diameter of the primary renal mass ranged from 1.6 to 10.3 cm (mean: 6.6 cm) with a slight right side predilection (1.5:1). Enlarged (>1 cm short axis) retroperitoneal lymph nodes were identified at initial staging in 20/25 (80%) cases, 10 of which were histologically confirmed while the others did not undergo surgical sampling. Enlarged lymph nodes were also identified in the mediastinum (14/25; 56%) and supraclavicular regions (4/25; 16%). Metastatic disease was present in the lungs in 19/25 (76%) and liver in 6/25 (24%). The pattern of lung metastases was pulmonary lymphangitic carcinomatosis: 10 cases (9 bilateral, 1 unilateral), pulmonary nodules with indistinct margins: 6 cases, pulmonary nodules with distinct margins: 2 cases, while 1 case had pulmonary nodules with both indistinct and distinct margins. Pulmonary lymphangitic carcinomatosis was pathologically confirmed in 4/10 cases. All cases with pulmonary lymphangitic carcinomatosis had associated enlarged mediastinal lymph nodes. Renal medullary carcinoma in children and young adults presents at an advanced local and distant stage in the

  4. Imaging of renal medullary carcinoma in children and young adults: a report from the Children's Oncology Group

    International Nuclear Information System (INIS)

    Sandberg, Jesse K.; Khanna, Geetika; Mullen, Elizabeth A.; Cajaiba, Mariana M.; Perlman, Elizabeth J.; Smith, Ethan A.; Servaes, Sabah; Geller, James I.; Ehrlich, Peter F.; Cost, Nicholas G.; Dome, Jeffrey S.; Fernandez, Conrad V.

    2017-01-01

    Renal medullary carcinoma is a rare renal malignancy of childhood. There are no large series describing the imaging appearance of renal medullary carcinoma in children. To characterize the clinical and imaging features of pediatric renal medullary carcinoma at initial presentation. We retrospectively analyzed images of 25 pediatric patients with renal medullary carcinoma enrolled in the Children's Oncology Group renal tumors classification, biology and banking study (AREN03B2) from March 2006 to August 2016. Imaging findings of the primary mass, and patterns of locoregional and distant spread were evaluated in correlation with pathological and surgical findings. Median age at presentation was 13 years (range: 6-21 years), with a male predominance (3.2:1). The overall stage of disease at initial presentation was stage 1 in 1, stage 2 in 2 and stage 4 in 22. Maximum diameter of the primary renal mass ranged from 1.6 to 10.3 cm (mean: 6.6 cm) with a slight right side predilection (1.5:1). Enlarged (>1 cm short axis) retroperitoneal lymph nodes were identified at initial staging in 20/25 (80%) cases, 10 of which were histologically confirmed while the others did not undergo surgical sampling. Enlarged lymph nodes were also identified in the mediastinum (14/25; 56%) and supraclavicular regions (4/25; 16%). Metastatic disease was present in the lungs in 19/25 (76%) and liver in 6/25 (24%). The pattern of lung metastases was pulmonary lymphangitic carcinomatosis: 10 cases (9 bilateral, 1 unilateral), pulmonary nodules with indistinct margins: 6 cases, pulmonary nodules with distinct margins: 2 cases, while 1 case had pulmonary nodules with both indistinct and distinct margins. Pulmonary lymphangitic carcinomatosis was pathologically confirmed in 4/10 cases. All cases with pulmonary lymphangitic carcinomatosis had associated enlarged mediastinal lymph nodes. Renal medullary carcinoma in children and young adults presents at an advanced local and distant stage in the

  5. Imaging of renal medullary carcinoma in children and young adults: a report from the Children's Oncology Group.

    Science.gov (United States)

    Sandberg, Jesse K; Mullen, Elizabeth A; Cajaiba, Mariana M; Smith, Ethan A; Servaes, Sabah; Perlman, Elizabeth J; Geller, James I; Ehrlich, Peter F; Cost, Nicholas G; Dome, Jeffrey S; Fernandez, Conrad V; Khanna, Geetika

    2017-11-01

    Renal medullary carcinoma is a rare renal malignancy of childhood. There are no large series describing the imaging appearance of renal medullary carcinoma in children. To characterize the clinical and imaging features of pediatric renal medullary carcinoma at initial presentation. We retrospectively analyzed images of 25 pediatric patients with renal medullary carcinoma enrolled in the Children's Oncology Group renal tumors classification, biology and banking study (AREN03B2) from March 2006 to August 2016. Imaging findings of the primary mass, and patterns of locoregional and distant spread were evaluated in correlation with pathological and surgical findings. Median age at presentation was 13 years (range: 6-21 years), with a male predominance (3.2:1). The overall stage of disease at initial presentation was stage 1 in 1, stage 2 in 2 and stage 4 in 22. Maximum diameter of the primary renal mass ranged from 1.6 to 10.3 cm (mean: 6.6 cm) with a slight right side predilection (1.5:1). Enlarged (>1 cm short axis) retroperitoneal lymph nodes were identified at initial staging in 20/25 (80%) cases, 10 of which were histologically confirmed while the others did not undergo surgical sampling. Enlarged lymph nodes were also identified in the mediastinum (14/25; 56%) and supraclavicular regions (4/25; 16%). Metastatic disease was present in the lungs in 19/25 (76%) and liver in 6/25 (24%). The pattern of lung metastases was pulmonary lymphangitic carcinomatosis: 10 cases (9 bilateral, 1 unilateral), pulmonary nodules with indistinct margins: 6 cases, pulmonary nodules with distinct margins: 2 cases, while 1 case had pulmonary nodules with both indistinct and distinct margins. Pulmonary lymphangitic carcinomatosis was pathologically confirmed in 4/10 cases. All cases with pulmonary lymphangitic carcinomatosis had associated enlarged mediastinal lymph nodes. Renal medullary carcinoma in children and young adults presents at an advanced local and distant stage in the

  6. An fMRI study of the interface between affective and cognitive neural circuitry in pediatric bipolar disorder.

    Science.gov (United States)

    Pavuluri, Mani N; O'Connor, Megan Marlow; Harral, Erin M; Sweeney, John A

    2008-04-15

    The pathophysiology of pediatric bipolar disorder (PBD) impacts both affective and cognitive brain systems. Understanding disturbances in the neural circuits subserving these abilities is critical for characterizing developmental aberrations associated with the disorder and developing improved treatments. Our objective is to use functional neuroimaging with pediatric bipolar disorder patients employing a task that probes the functional integrity of attentional control and affect processing. Ten euthymic unmedicated pediatric bipolar patients and healthy controls matched for age, sex, race, socioeconomic status, and IQ were scanned using functional magnetic resonance imaging. In a pediatric color word matching paradigm, subjects were asked to match the color of a word with one of two colored circles below. Words had a positive, negative or neutral emotional valence, and were presented in 30-s blocks. In the negative affect condition, relative to the neutral condition, patients with bipolar disorder demonstrated greater activation of bilateral pregenual anterior cingulate cortex and left amygdala, and less activation in right rostral ventrolateral prefrontal cortex (PFC) and dorsolateral PFC at the junction of the middle frontal and inferior frontal gyri. In the positive affect condition, there was no reduced activation of PFC or increased amygdala activation. The pattern of reduced activation of ventrolateral PFC and greater amygdala activation in bipolar children in response to negative stimuli suggests both disinhibition of emotional reactivity in the limbic system and reduced function in PFC systems that regulate those responses. Higher cortical cognitive areas such as the dorsolateral PFC may also be adversely affected by exaggerated emotional responsivity to negative emotions. This pattern of functional alteration in affective and cognitive circuitry may contribute to the reduced capacity for affect regulation and behavioral self-control in pediatric bipolar

  7. Functional dysconnectivity of corticostriatal circuitry as a risk phenotype for psychosis.

    Science.gov (United States)

    Fornito, Alex; Harrison, Ben J; Goodby, Emmeline; Dean, Anna; Ooi, Cinly; Nathan, Pradeep J; Lennox, Belinda R; Jones, Peter B; Suckling, John; Bullmore, Edward T

    2013-11-01

    Dysregulation of corticostriatal circuitry has long been thought to be critical in the etiology of psychotic disorders, although the differential roles played by dorsal and ventral systems in mediating risk for psychosis have been contentious. To use resting-state functional magnetic resonance imaging to characterize disease-related, risk-related, and symptom-related changes of corticostriatal functional circuitry in patients with first-episode psychosis and their unaffected first-degree relatives. This case-control cross-sectional study was conducted at a specialist early psychosis clinic, GlaxoSmithKline Clinical Unit, and magnetic resonance imaging facility. Nineteen patients with first-episode psychosis, 25 of their unaffected first-degree relatives, and 26 healthy control subjects were included in this study. Voxelwise statistical parametric maps testing differences in the strength of functional connectivity between 6 striatal seed regions of interest (3 caudate and 3 putamen) per hemisphere and all other brain regions. Disease-related changes, reflecting differences between patients and control subjects, involved widespread dysregulation of corticostriatal systems characterized most prominently by a dorsal-to-ventral gradient of hypoconnectivity to hyperconnectivity between striatal and prefrontal regions. A similar gradient was evident in comparisons between relatives and control subjects, identifying it as a genetically inherited risk phenotype. In patients, functional connectivity in risk-affected and disease-affected dorsal frontostriatal circuitry correlated with the severity of both positive and negative symptoms. First-episode psychosis is associated with pronounced dysregulation of corticostriatal systems, characterized most prominently by hypoconnectivity of dorsal and hyperconnectivity of ventral frontostriatal circuits. These changes correlate with symptom severity and are also apparent in unaffected first-degree relatives, suggesting that they

  8. Presence of a nail in the medullary canal; is it enough to prevent femoral neck shortening in trochanteric fracture?

    Science.gov (United States)

    Song, Hyung Keun; Yoon, Han Kuk; Yang, Kyu Hyun

    2014-09-01

    Presence of a cephalomedullary nail (CMN) in the medullary canal has been thought as advantageous in the control of femoral neck shortening (FNS) and lag screw sliding in trochanteric fracture compared to extramedullary fixation system. However, researches on the factors that influence the degree of FNS after cephalomedullary nailing are lacking. We observed 95 patients (mean age, 75±2.8 years) with trochanteric fractures who were treated with a CMN, and evaluated the relationship between FNS and patient factors including age, gender, fracture type (AO/OTA), bone mineral density, medullary canal diameter, canal occupancy ratio (COR=nail size/canal diameter), and tip-apex distance using initial, immediate postoperative, and follow-up radiography. Univariate regression analyses revealed that the degree of FNS was significantly correlated with fracture type (A1 versus A3, pfracture type (pfracture.

  9. Impact of F DOPA-PET on therapeutic decision in endocrine tumours: digestive tumours, medullary thyroid cancer or pheochromocytoma

    International Nuclear Information System (INIS)

    Montravers, F.; Grahek, D.; Kerrou, K.; Gutman, F.; Beco, V. de; Nataf, V.; Balard, M.; Talbot, J.N.

    2006-01-01

    FDOPA-PET has been proposed for a decade in oncology, in particular in endocrine tumours. To the best of our knowledge, only one impact rate has been reported: 31% in 17 patients with digestive carcinoid tumours. We did a questionnaire survey to evaluate this impact reported by the referring clinician in 87 patients who had FDOPA PET due to digestive carcinoid tumour or another type of digestive endocrine tumour or a medullary thyroid cancer or a pheochromocytoma. The response rate to the survey was 87%. The overall impact of FDOPA PET on patient's management was 36%. Its value was greater for digestive carcinoid tumour and for medullary thyroid cancer; the number of patients with pheochromocytoma is still limited. In the other digestive endocrine tumours, a change in patient management was less frequent and FDOPA PET should be performed when the other examinations are inconclusive. (author)

  10. A case of thyroid medullary carcinoma with multiple painful bone metastases successfully treated with strontium-89 chloride

    International Nuclear Information System (INIS)

    Oshiro, Chiya; Kamigaki, Shunji; Arai, Takashi; Nakamura, Yukio; Fukunaga, Mutsumi; Ichida, Wakako; Ikeda, Hiroshi

    2012-01-01

    A 70-year-old man was diagnosed as thyroid medullary carcinoma with multiple bone metastases. He underwent total thyroidectomy and cervical lymph node dissection. After one year, the pain from his bone lesions was becoming severe. To relieve the pain, he was administered opioids and external-beam radiation therapy. However, he continued to have substantial multiple bone pain. We used combination therapy of strontium-89 chloride for the treatment of widespread multiple bone pain and external-beam radiation therapy for localized pain. That combination therapy was effective and improved the quality of life (QOL) of the patient. We used strontium-89 chloride four times within one year, and no serious side effects occurred during therapy. Our thoroughly investigated case suggests that strontium-89 therapy is one of the effective and safe therapies for patients with painful bone metastases of thyroid medullary carcinoma. (author)

  11. Topography of the medullary cone of the crab-eating fox (Cerdocyon thous Linnaeus, 1766: Case report

    Directory of Open Access Journals (Sweden)

    Luane Lopes Pinheiro

    2011-12-01

    Full Text Available The crab-eating fox is the most common Canidae of South America. In general, its diet varies according to the season and inhabited region. In this study, the medullary cone of the crab-eating fox was described because of interests in comparative anatomy, with the goal of providing information that could assist in epidural anesthesia, which cannot be efficiently practiced without knowledge of this anatomical region. We investigated an adult male from the Bauxite Mine (Paragominas, PA, which was dissected in the lumbosacral region. The medullary cone was 10.13 cm long; the base began at the L6 and the apex was at the S3. Considering that the specimen studied had nine lumbar and four sacral vertebrae, we conclude that the sacrococcygeal region is probably the most suitable place for epidural anesthesia.

  12. MR Imaging of Ventriculus Terminalis of The Conus Medullaris. A report of two operated patients and review of the literature

    Energy Technology Data Exchange (ETDEWEB)

    Dullerud, Reidar; Server, A. [Ullevaal Univ. Hospital, Oslo (Norway). Div. of Radiology; Berg-Johnsen, J. [The National Hospital, Oslo (Norway). Dept. of Neurosurgery

    2003-07-01

    We report on 2 patients in whom a cystic dilation of the conus medullaris was incidentally found at MR imaging carried out in the work-up for sciatica. The cysts were well circumscribed and had signal intensity identical to the CSF on both T1- and T2-weighted images. There was no evidence of contrast enhancement. None of the patients had specific symptoms related to the spinal cord. At surgery, no evidence of malignancy was seen in any of the patients. A benign cystic dilation, also called dilated ventriculus terminalis, occasionally can be seen in the conus medullaris as an incidental finding at thoracolumbar MR imaging. Unless the expansion per se indicates cyst drainage, these patients may be monitored by clinical and MR follow-up, avoiding surgery in a substantial number of cases.

  13. Microwave technology for waste management applications including disposition of electronic circuitry

    International Nuclear Information System (INIS)

    Wicks, G.G.; Clark, D.E.; Schulz, R.L.; Folz, D.C.

    1995-01-01

    Microwave technology is being developed nationally and internationally for a variety of environmental remediation purposes. These efforts include treatment and destruction of a vast array of gaseous, liquid and solid hazardous wastes as well as subsequent immobilization of selected components. Microwave technology provides an important contribution to an arsenal of existing remediation methods that are designed to protect the public and environment from undesirable consequences of hazardous materials. Applications of microwave energy for environmental remediation will be discussed. Emphasized will be a newly developed microwave process designed to treat discarded electronic circuitry and reclaim the precious metals within for reuse

  14. Neural Circuitry Based on Single Electron Transistors and Single Electron Memories

    Directory of Open Access Journals (Sweden)

    Aïmen BOUBAKER

    2014-05-01

    Full Text Available In this paper, we propose and explain a neural circuitry based on single electron transistors ‘SET’ which can be used in classification and recognition. We implement, after that, a Winner-Take-All ‘WTA’ neural network with lateral inhibition architecture. The original idea of this work is reflected, first, in the proposed new single electron memory ‘SEM’ design by hybridising two promising Single Electron Memory ‘SEM’ and the MTJ/Ring memory and second, in modeling and simulation results of neural memory based on SET. We prove the charge storage in quantum dot in two types of memories.

  15. Microwave Technology for Waste Management Applications Including Disposition of Electronic Circuitry

    International Nuclear Information System (INIS)

    Wicks, G.G.; Clark, D.E.; Schulz, R.L.

    1998-01-01

    Advanced microwave technology is being developed nationally and internationally for a variety of waste management and environmental remediation purposes. These efforts include treatment and destruction of a vast array of gaseous, liquid and solid hazardous wastes as well as subsequent immobilization of hazardous components into leach resistant forms. Microwave technology provides an important contribution to an arsenal of existing remediation methods that are designed to protect the public and environment from the undesirable consequences of hazardous materials. One application of special interest is the treatment of discarded electronic circuitry using a new hybrid microwave treatment process and subsequent reclamation of the precious metals within

  16. Induction of aldose reductase and sorbitol in renal inner medullary cells by elevated extracellular NaCl.

    OpenAIRE

    Bagnasco, S M; Uchida, S; Balaban, R S; Kador, P F; Burg, M B

    1987-01-01

    Aldose reductase [aldehyde reductase 2; alditol:NAD(P)+ 1-oxidoreductase, EC 1.1.1.21] catalyzes conversion of glucose to sorbitol. Although its activity is implicated in the progression of ocular and neurological complications of diabetes, the normal function of the enzyme in most cells is unknown. Both aldose reductase activity and substantial levels of sorbitol were previously reported in renal inner medullary cells. In this tissue, the extracellular NaCl concentration normally is high and...

  17. Intraoperative localization of recurrent medullary carcinoma of the thyroid using indium-111 pentetreotide and a nuclear surgical probe

    Energy Technology Data Exchange (ETDEWEB)

    Waddington, W.A. (Inst. of Nuclear Medicine, Univ. Coll., London Medical School (United Kingdom)); Kettle, A.G. (Dept. of Nuclear Medicine, Kent and Canterbury Hospital, Canterbury (United Kingdom)); Heddle, R.M. (Dept. of Surgery, Kent and Canterbury Hospital, Canterbury (United Kingdom)); Coakley, A.J. (Dept. of Nuclear Medicine, Kent and Canterbury Hospital, Canterbury (United Kingdom))

    1994-04-01

    A patient with recurrent medullary thyroid cancer in the neck in whom previous surgery for recurrence had been undertaken with only partial success had the diseased tissue localized preoperatively by indium-111 pentetreotide. Scanning with technetium-99m V dimercaptosuccinic acid and iodine-123 metaiodobenzylguanidine failed to localize the tumor. Utilization of a nuclear surgical probe after preoperative [sup 111]In pentetreotide allowed accurate surgical localization of the tumour tissue. (orig.)

  18. Survival improvement in patients with disseminated medullary thyroid carcinoma treated with 131I-MIBG therapy

    International Nuclear Information System (INIS)

    Mihaljevic, I.; Topuzovi, N.; Snajder, D.

    2015-01-01

    Full text of publication follows. Introduction and aim: The aim of this paper is to present our experience of 131 I-MIBG therapy in the cases of aggressive form of medullary thyroid carcinoma (MTC) with local and distant metastases. MTC is an uncommon thyroid tumor, accounting from 3-5% of all thyroid malignancies, and arises from para-follicular C cells which produce calcitonin (CT). Prognosis of MTC is related to tumor extension at disease detection, but long-term survival in patients with disseminated MTC is still unsatisfactory. Methods: 4 female patients with metastatic MTC (63, 69 and 2 patients aged 73 years), which already underwent total thyroidectomy and selective neck dissection, received therapy with 100 mCi 131 I-MIBG in our Institute. Patients had widespread disease with neck recurrences (all 4 cases), liver and bone metastases (2 cases) and lung metastases (1 case). All those patients received the therapy twice, second one 3 months up to 1 year after the first cycle. After therapy, whole body scintigraphy was performed; tumor marker levels (CT, carcinoembryonic antigen - CEA, neuron specific enolase - NSE, chromogranin A - CgA and pro-gastrin releasing peptide - pro-GRP) were measured before and after therapy. Results: in one patient we observed a slight decrease in CT level after first MIBG therapy, in another one a slight decrease in CEA serum level, and no lung metastases were visible on whole body scan after second 131 I-MIBG therapy. In one of the two remaining cases there was a significant decrease in CT serum level only after neck dissection. In all cases the patients reported an improvement in subjective symptom reduction. Conclusion: 131 I-MIBG therapy could provide additional benefit to patients with MTC and could improve overall survival, but more patient should be treated in order to define the true potential of the therapy. The aim of this paper is to present our experience of 131 I-MIBG therapy in the cases of aggressive form of

  19. Differential patterns of dynamic functional connectivity variability of striato-cortical circuitry in children with benign epilepsy with centrotemporal spikes.

    Science.gov (United States)

    Li, Rong; Liao, Wei; Yu, Yangyang; Chen, Heng; Guo, Xiaonan; Tang, Ye-Lei; Chen, Huafu

    2018-03-01

    Benign epilepsy with centrotemporal spikes (BECTS) is characterized by abnormal (static) functional interactions among cortical and subcortical regions, regardless of the active or chronic epileptic state. However, human brain connectivity is dynamic and associated with ongoing rhythmic activity. The dynamic functional connectivity (dFC) of the distinct striato-cortical circuitry associated with or without interictal epileptiform discharges (IEDs) are poorly understood in BECTS. Herein, we captured the pattern of dFC using sliding window correlation of putamen subregions in the BECTS (without IEDs, n = 23; with IEDs, n = 20) and sex- and age-matched healthy controls (HCs, n = 28) during rest. Furthermore, we quantified dFC variability using their standard deviation. Compared with HCs and patients without IEDs, patients with IEDs exhibited excessive variability in the dorsal striatal-sensorimotor circuitry related to typical seizure semiology. By contrast, excessive stability (decreased dFC variability) was found in the ventral striatal-cognitive circuitry (p < .05, GRF corrected). In addition, correlation analysis revealed that the excessive variability in the dorsal striatal-sensorimotor circuitry was related to highly frequent IEDs (p < .05, uncorrected). Our finding of excessive variability in the dorsal striatal-sensorimotor circuitry could be an indication of increased sensitivity to regional fluctuations in the epileptogenic zone, while excessive stability in the ventral striatal-cognitive circuitry could represent compensatory mechanisms that prevent or postpone cognitive impairments in BECTS. Overall, the differentiated dynamics of the striato-cortical circuitry extend our understanding of interactions among epileptic activity, striato-cortical functional architecture, and neurocognitive processes in BECTS. © 2017 Wiley Periodicals, Inc.

  20. Architecture of the femoral medullary canal and working length for intramedullary nailing. Biomechanic indications for dynamic nailing.

    Science.gov (United States)

    Steriopoulos, K; Psarakis, S A; Savakis, C; Papakitsou, E; Christakis, D; Velivasakis, E

    1997-10-01

    We classified human femoral intramedullary architecture into 3 types. The cortex in the first type is thick and the medullary canal narrow with an even and smooth translation towards the metaphysis. In the second type, the cortex is thin and the canal wider, also evenly distributed along the entire length, while in the third type the canal narrows just distal to the subtrochanteric region and similarly a few centimeters distally. Some medullary canals of the second type do not allow dynamic nailing, while canals of the third type presents some difficulties for unreamed nails. Most medullary canals belong to the first and second type and only few belong to type three. We performed comparative experimental loading in 11 pairs of cadaveric fractured femora fixed with static and dynamic nailing. Dynamic nailing was found to behave as safely as static ones in the presence of a sound femoral shaft central and peripheral to the fracture with a length twice the diameter of the femur at the fracture level. This could be checked intraoperatively with gentle rotation under image intensifier. In a clinical series, dynamic nailing was performed in about one quarter of the patients with femoral shaft fractures (18 of 72 patients) with excellent results.

  1. Activation of serotonergic neurons in the medullary caudal raphe shortens the laryngeal chemoreflex in anaesthetized neonatal rats.

    Science.gov (United States)

    Donnelly, William T; Xia, Luxi; Bartlett, Donald; Leiter, J C

    2017-08-01

    What is the central question of this study? Does activation of serotonergic neurons in the caudal medullary raphe, some of which project to the nucleus of the solitary tract, shorten the laryngeal chemoreflex? What is the main finding and its importance? We found that serotonin originating from neurons in the caudal raphe acts through a 5-HT 3 receptor located in the nucleus of the solitary tract to terminate reflex apnoea. Failure or deficiency of this arousal-related process is likely to be relevant to the pathogenesis of sudden infant death syndrome. Failure to terminate apnoea and arouse is likely to contribute to sudden infant death syndrome (SIDS). Serotonin is deficient in the brainstems of babies who have died of SIDS. We tested the hypothesis that activation of serotoninergic neurons in the caudal medullary raphe, some of which project to the nucleus of the solitary tract (NTS), would shorten the laryngeal chemoreflex (LCR). We studied anaesthetized neonatal rat pups between postnatal days 9 and 17. We injected 5-40 μl of water into the larynx to elicit the LCR and measured the duration of respiratory disruption. Microinjection of 50 nl of 100 μm AMPA into the caudal medullary raphe shortened the apnoeas (P serotonergic termination of apnoea is likely to be relevant to the pathogenesis of SIDS. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

  2. Medullary colonic carcinoma with microsatellite instability has lower survival compared with conventional colonic adenocarcinoma with microsatellite instability

    Directory of Open Access Journals (Sweden)

    Miguel A. Gómez-Álvarez

    2016-12-01

    Full Text Available Introduction: Colorectal medullary carcinoma (MC is a rare subtype of poorly differentiated adenocarcinoma (PDA with unclear prognostic significance. Microsatellite instable (MSI colorectal carcinomas have demonstrated better prognosis in clinical stage II. Aim: To analyze the survival and clinicopathological characteristics of MCs versus PDAs with MSI in clinical stage III. Material and methods: We studied 22 cases of PDAs with MSI versus 10 MCs. Results : Of the 10 MCs, 7 patients were men; the mean age was 57.8 ±5.6 years. The mean tumor size was 9.6 ±4.1 cm, and the primary site was the right colon in 9; 7 patients showed lymph node metastases (LNM and lymphovascular invasion (LVI. Of the 22 PDA cases, 12 (54.5% were women with a mean age of 75 ±16.1 years. The mean tumor size was 6.4 ±3.2 cm. Twelve (54.5% presented in the right colon, 21 (95.5% showed LNM and 7 (31.8% LVI. Follow-up was 32 ±8 months, with a 5-year overall survival of 42.9% for MCs and 76.6% for PDAs (p = 0.048. Univariate analysis found local recurrence (p = 0.001 and medullary subtype (p = 0.043 associated with lower survival. Conclusions : Medullary carcinomas were of greater tumor size and associated with more LVI and worse survival versus PDAs with MSI in stage III.

  3. Basolateral P2X receptors mediate inhibition of NaCl transport in mouse medullary thick ascending limb (mTAL)

    DEFF Research Database (Denmark)

    Marques, Rita D; de Bruijn, Pauline I.A.; Sørensen, Mads Vaarby

    2012-01-01

    the ATP-induced inhibition of transport was reduced. A comprehensive molecular search identified P2X(4), P2X(5) and P2X(1) receptor subunit mRNA in isolated mouse mTALs. These data define that basolateral ATP exerts a significant inhibition of Na(+) absorption in mouse mTAL. Pharmacological, molecular......Extracellular nucleotides regulate epithelial transport via luminal and basolateral P2 receptors. Renal epithelia express multiple P2 receptors, which mediate significant inhibition of solute absorption. Recently, we identified several P2 receptors in the medullary thick ascending limb (m......-stimulated mTALs transported at a rate of 1197 ± 104 µA/cm(2) (n=10), which was completely blockable with luminal furosemide (100 µM). Basolateral ATP (100 µM) acutely (1 minute) and reversibly reduced the absorptive I'(sc). After 2 minutes the reduction amounted to 24.4 ± 4.0% (n=10). The non-selective P2...

  4. H+, Water and Urea Transport in the Inner Medullary Collecting Duct and Their Role in the Prevention and Pathogenesis of Renal Stone Disease

    Science.gov (United States)

    Wall, Susan M.; Klein, Janet D.

    2008-09-01

    The inner medullary collecting duct (IMCD) is the final site within the kidney for the reabsorption of urea, water and electrolytes and for the secretion of H+ before the luminal fluid becomes the final urine. Transporters expressed in the IMCD contribute to the generation of the large ion gradients that exist between the interstitium and the collecting duct lumen. Thus, the luminal fluid within the human IMCD can reach an osmolality of 1200 mOsm/kg H2O and a pH of 4. This ability of the human nephron to concentrate and acidify the urine might predispose to stone formation. However, under treatment conditions that predispose to stone formation, such as during hypercalciuria, the kidney mitigates stone formation by reducing solute concentration by reducing H2O reabsorption. Moreover, the kidney attenuates stone formation by tightly controlling acid-base balance, which prevents the bone loss, hypocitraturia and hypercalciuria observed during metabolic acidosis by augmenting net H+ excretion by tightly regulating H+ transporter function and through luminal buffering, particularly with NH3. This article will review the ion transporters present in the mammalian IMCD and their role in the prevention and in the pathogenesis of renal stone formation.

  5. Reading acceleration training changes brain circuitry in children with reading difficulties

    Science.gov (United States)

    Horowitz-Kraus, Tzipi; Vannest, Jennifer J; Kadis, Darren; Cicchino, Nicole; Wang, Yingying Y; Holland, Scott K

    2014-01-01

    Introduction Dyslexia is characterized by slow, inaccurate reading. Previous studies have shown that the Reading Acceleration Program (RAP) improves reading speed and accuracy in children and adults with dyslexia and in typical readers across different orthographies. However, the effect of the RAP on the neural circuitry of reading has not been established. In the current study, we examined the effect of the RAP training on regions of interest in the neural circuitry for reading using a lexical decision task during fMRI in children with reading difficulties and typical readers. Methods Children (8–12 years old) with reading difficulties and typical readers were studied before and after 4 weeks of training with the RAP in both groups. Results In addition to improvements in oral and silent contextual reading speed, training-related gains were associated with increased activation of the left hemisphere in both children with reading difficulties and typical readers. However, only children with reading difficulties showed improvements in reading comprehension, which were associated with significant increases in right frontal lobe activation. Conclusions Our results demonstrate differential effects of the RAP on neural circuits supporting reading in both children with reading difficulties and typical readers and suggest that the intervention may stimulate use of typical neural circuits for reading and engage compensatory pathways to support reading in the developing brain of children with reading difficulties. PMID:25365797

  6. Multi-objective optimization of piezoelectric circuitry network for mode delocalization and suppression of bladed disk

    Science.gov (United States)

    Yoo, David; Tang, J.

    2017-04-01

    Since weakly-coupled bladed disks are highly sensitive to the presence of uncertainties, they can easily undergo vibration localization. When vibration localization occurs, vibration modes of bladed disk become dramatically different from those under the perfectly periodic condition, and the dynamic response under engine-order excitation is drastically amplified. In previous studies, it is investigated that amplified vibration response can be suppressed by connecting piezoelectric circuitry into individual blades to induce the damped absorber effect, and localized vibration modes can be alleviated by integrating piezoelectric circuitry network. Delocalization of vibration modes and vibration suppression of bladed disk, however, require different optimal set of circuit parameters. In this research, multi-objective optimization approach is developed to enable finding the best circuit parameters, simultaneously achieving both objectives. In this way, the robustness and reliability in bladed disk can be ensured. Gradient-based optimizations are individually developed for mode delocalization and vibration suppression, which are then integrated into multi-objective optimization framework.

  7. Nicotinic acetylcholine receptors in attention circuitry: the role of layer VI neurons of prefrontal cortex.

    Science.gov (United States)

    Proulx, Eliane; Piva, Matthew; Tian, Michael K; Bailey, Craig D C; Lambe, Evelyn K

    2014-04-01

    Cholinergic modulation of prefrontal cortex is essential for attention. In essence, it focuses the mind on relevant, transient stimuli in support of goal-directed behavior. The excitation of prefrontal layer VI neurons through nicotinic acetylcholine receptors optimizes local and top-down control of attention. Layer VI of prefrontal cortex is the origin of a dense feedback projection to the thalamus and is one of only a handful of brain regions that express the α5 nicotinic receptor subunit, encoded by the gene chrna5. This accessory nicotinic receptor subunit alters the properties of high-affinity nicotinic receptors in layer VI pyramidal neurons in both development and adulthood. Studies investigating the consequences of genetic deletion of α5, as well as other disruptions to nicotinic receptors, find attention deficits together with altered cholinergic excitation of layer VI neurons and aberrant neuronal morphology. Nicotinic receptors in prefrontal layer VI neurons play an essential role in focusing attention under challenging circumstances. In this regard, they do not act in isolation, but rather in concert with cholinergic receptors in other parts of prefrontal circuitry. This review urges an intensification of focus on the cellular mechanisms and plasticity of prefrontal attention circuitry. Disruptions in attention are one of the greatest contributing factors to disease burden in psychiatric and neurological disorders, and enhancing attention may require different approaches in the normal and disordered prefrontal cortex.

  8. Extensive Numerical Study and Circuitry Implementation of the Watt Governor Model

    Science.gov (United States)

    Marcondes, D. W. C.; Comassetto, G. F.; Pedro, B. G.; Vieira, J. C. C.; Hoff, A.; Prebianca, F.; Manchein, C.; Albuquerque, H. A.

    In this work we carry out extensive numerical study of a Watt centrifugal governor system model, and we also implement an electronic circuit by analog computation to experimentally solve the model. Our numerical results show the existence of self-organized stable periodic structures (SPSs) on parameter-space of the largest Lyapunov exponent and isospikes of time series of the Watt governor system model. A peculiar hierarchical organization and period-adding bifurcation cascade of the SPSs are observed, and this self-organized cascade accumulates on a periodic boundary. It is also shown that the periods of these structures organize themselves obeying the solutions of Diophantine equations. In addition, an experimental setup is implemented by a circuitry analogy of mechanical systems using analog computing technique to characterize the robustness of our numerical results. After applying an active control of chaos in the experiment, the effect of intrinsic experimental noise was minimized such that, the experimental results are astonishingly well in agreement with our numerical findings. We can also mention as another remarkable result, the application of analog computing technique to perform an experimental circuitry analysis in real mechanical problems.

  9. Testing the connections within face processing circuitry in Capgras delusion with diffusion imaging tractography

    Directory of Open Access Journals (Sweden)

    Maria A. Bobes

    2016-01-01

    Full Text Available Although Capgras delusion (CD patients are capable of recognizing familiar faces, they present a delusional belief that some relatives have been replaced by impostors. CD has been explained as a selective disruption of a pathway processing affective values of familiar faces. To test the integrity of connections within face processing circuitry, diffusion tensor imaging was performed in a CD patient and 10 age-matched controls. Voxel-based morphometry indicated gray matter damage in right frontal areas. Tractography was used to examine two important tracts of the face processing circuitry: the inferior fronto-occipital fasciculus (IFOF and the inferior longitudinal (ILF. The superior longitudinal fasciculus (SLF and commissural tracts were also assessed. CD patient did not differ from controls in the commissural fibers, or the SLF. Right and left ILF, and right IFOF were also equivalent to those of controls. However, the left IFOF was significantly reduced respect to controls, also showing a significant dissociation with the ILF, which represents a selective impairment in the fiber-tract connecting occipital and frontal areas. This suggests a possible involvement of the IFOF in affective processing of faces in typical observers and in covert recognition in some cases with prosopagnosia.

  10. Microstructural abnormalities in subcortical reward circuitry of subjects with major depressive disorder.

    Directory of Open Access Journals (Sweden)

    Anne J Blood

    2010-11-01

    Full Text Available Previous studies of major depressive disorder (MDD have focused on abnormalities in the prefrontal cortex and medial temporal regions. There has been little investigation in MDD of midbrain and subcortical regions central to reward/aversion function, such as the ventral tegmental area/substantia nigra (VTA/SN, and medial forebrain bundle (MFB.We investigated the microstructural integrity of this circuitry using diffusion tensor imaging (DTI in 22 MDD subjects and compared them with 22 matched healthy control subjects. Fractional anisotropy (FA values were increased in the right VT and reduced in dorsolateral prefrontal white matter in MDD subjects. Follow-up analysis suggested two distinct subgroups of MDD patients, which exhibited non-overlapping abnormalities in reward/aversion circuitry. The MDD subgroup with abnormal FA values in VT exhibited significantly greater trait anxiety than the subgroup with normal FA values in VT, but the subgroups did not differ in levels of anhedonia, sadness, or overall depression severity.These findings suggest that MDD may be associated with abnormal microstructure in brain reward/aversion regions, and that there may be at least two subtypes of microstructural abnormalities which each impact core symptoms of depression.

  11. Experimental Demonstration and Circuitry for a Very Compact Coil-Only Pulse Echo EMAT.

    Science.gov (United States)

    Rueter, Dirk

    2017-04-22

    This experimental study demonstrates for the first time a solid-state circuitry and design for a simple compact copper coil (without an additional bulky permanent magnet or bulky electromagnet) as a contactless electromagnetic acoustic transducer (EMAT) for pulse echo operation at MHz frequencies. A pulsed ultrasound emission into a metallic test object is electromagnetically excited by an intense MHz burst at up to 500 A through the 0.15 mm filaments of the transducer. Immediately thereafter, a smoother and quasi "DC-like" current of 100 A is applied for about 1 ms and allows an echo detection. The ultrasonic pulse echo operation for a simple, compact, non-contacting copper coil is new. Application scenarios for compact transducer techniques include very narrow and hostile environments, in which, e.g., quickly moving metal parts must be tested with only one, non-contacting ultrasound shot. The small transducer coil can be operated remotely with a cable connection, separate from the much bulkier supply circuitry. Several options for more technical and fundamental progress are discussed.

  12. Effects of Head Position on Perception of Gravity in Vestibular Neuritis and Lateral Medullary Infarction

    Directory of Open Access Journals (Sweden)

    Sung-Hee Kim

    2018-02-01

    Full Text Available ObjectiveInternal representation of gravity can be quantified by measuring the subjective visual vertical (SVV. Modulation of verticality perception during head tilts may be perturbed in vestibular disorders causing SVV tilts in the upright head position. This study aimed to determine the influence of head tilts on the estimation of SVV in acute vestibular disorders.MethodsWe measured the SVV in 37 patients with acute vestibular symptoms due to unilateral vestibular neuritis (VN (n = 28 and lateral medullary infarction (LMI (n = 9. Measurements of the SVV were performed under head upright, head tilt 30° and 60° in each direction. Seventeen normal subjects served as the control.ResultsIn controls, head tilt of 30° produced a contraversive shift of the SVV (the E-effect, and head tilt of 60° generated an ipsiversive shift (the A-effect. Patients with VN showed only the A-effect irrespective of the direction and amplitude of head tilt. Patients with LMI could estimate earth verticality accurately during head tilts. Patients with VN during the recovery phase showed the patterns of SVV modulation similar to those observed in the controls either with head upright or tilted.ConclusionGiven the absence of the E-effect in acute VN, the peripheral otolithic inputs appear to be essential in the perception of earth vertical during small static head tilts.

  13. Effects of Head Position on Perception of Gravity in Vestibular Neuritis and Lateral Medullary Infarction.

    Science.gov (United States)

    Kim, Sung-Hee; Kim, Ji-Soo

    2018-01-01

    Internal representation of gravity can be quantified by measuring the subjective visual vertical (SVV). Modulation of verticality perception during head tilts may be perturbed in vestibular disorders causing SVV tilts in the upright head position. This study aimed to determine the influence of head tilts on the estimation of SVV in acute vestibular disorders. We measured the SVV in 37 patients with acute vestibular symptoms due to unilateral vestibular neuritis (VN) ( n  = 28) and lateral medullary infarction (LMI) ( n  = 9). Measurements of the SVV were performed under head upright, head tilt 30° and 60° in each direction. Seventeen normal subjects served as the control. In controls, head tilt of 30° produced a contraversive shift of the SVV (the E-effect), and head tilt of 60° generated an ipsiversive shift (the A-effect). Patients with VN showed only the A-effect irrespective of the direction and amplitude of head tilt. Patients with LMI could estimate earth verticality accurately during head tilts. Patients with VN during the recovery phase showed the patterns of SVV modulation similar to those observed in the controls either with head upright or tilted. Given the absence of the E-effect in acute VN, the peripheral otolithic inputs appear to be essential in the perception of earth vertical during small static head tilts.

  14. Think of the Conus Medullaris at the Time of Diagnosis of Fetal Sacral Agenesis.

    Science.gov (United States)

    Mottet, Nicolas; Martinovic, Jelena; Baeza, Claire; Guimiot, Fabien; Bault, Jean-Philippe; Aubry, Marie Cécile; Riethmuller, Didier; Zerah, Michel; Cretolle, Celia; Benachi, Alexandra

    2017-01-01

    There is no precise prenatal indicator to refine an accurate prognosis in case of sacral agenesis and to define the diagnostic approach and outcome criteria in case of fetal sacral agenesis using 3 characteristics of the conus medullaris (CM): its position, its appearance, and associated spinal abnormalities. Ten cases of prenatally diagnosed sacral agenesis were included between 1995 and 2014 after collating ultrasound findings and prenatal computed tomography data. Two cases of total sacral agenesis and 8 of partial agenesis were included. There were 1 or more spinal abnormalities in 8/10 cases: 6 lipomas, 4 low-lying tethered cords, 2 diastematomyelias, and 1 syringomyelia. Three situations were distinguished: sacral agenesis with low-lying tethered cord, sacral agenesis with a truncated CM, and sacral agenesis with CM in place. If the sacral agenesis is isolated, a lipoma should be sought. Lipomas of the filum have a good prognosis, whereas lipomas of the CM cause neurological deficits in 1/3 of cases. When there is a low-lying tethered cord, a diastematomyelia or a syringomyelia may be associated. In truncated CM, there may be a severe form suggestive of caudal regression syndrome. Serious ultrasound signs are immobility of the lower limbs, talipes equinovarus, impaired bladder emptying, and dilatation of the upper urinary tract. A precise description of the morphology of the CM, its position, and associated spinal malformations are important in defining the neurological, urinary, gastrointestinal, and motor functions prognosis in cases of fetal sacral agenesis. © 2016 S. Karger AG, Basel.

  15. Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas

    Science.gov (United States)

    Moura, M M; Cavaco, B M; Pinto, A E; Domingues, R; Santos, J R; Cid, M O; Bugalho, M J; Leite, V

    2009-01-01

    Screening of REarranged during Transfection (RET) gene mutations has been carried out in different series of sporadic medullary thyroid carcinomas (MTC). RET-positive tumours seem to be associated to a worse clinical outcome. However, the correlation between the type of RET mutation and the patients' clinicopathological data has not been evaluated yet. We analysed RET exons 5, 8, 10–16 in fifty-one sporadic MTC, and found somatic mutations in thirty-three (64.7%) tumours. Among the RET-positive cases, exon 16 was the most frequently affected (60.6%). Two novel somatic mutations (Cys630Gly, c.1881del18) were identified. MTC patients were divided into three groups: group 1, with mutations in RET exons 15 and 16; group 2, with other RET mutations; group 3, having no RET mutations. Group 1 had higher prevalence (P=0.0051) and number of lymph node metastases (P=0.0017), and presented more often multifocal tumours (P=0.037) and persistent disease at last control (P=0.0242) than group 2. Detectable serum calcitonin levels at last screening (P=0.0119) and stage IV disease (P=0.0145) were more frequent in group 1, than in the other groups. Our results suggest that, among the sporadic MTC, cases with RET mutations in exons 15 and 16 are associated with the worst prognosis. Cases with other RET mutations have the most indolent course, and those with no RET mutations have an intermediate risk. PMID:19401695

  16. Depicting medullary thyroid cancer recurrence: the past and the future of nuclear medicine imaging.

    Science.gov (United States)

    Skoura, Evangelia

    2013-10-01

    Inherited and sporadic medullary thyroid cancer (MTC) is an uncommon and medically challenging malignancy. Even if the extent of initial surgery is deemed adequate, the recurrence rate remains high, up to 50% in most series. Measurement of serum calcitonin is important in the follow-up of patients with MTC, and reliably reflects the existence of the disease. There is no single sensitive diagnostic imaging method to reveal all MTC recurrences or metastases. Conventional morphologic imaging methods (U/S, CT, and MRI) and several methods of nuclear medicine have been used for this purpose with variable accuracy. The main role of nuclear medicine imaging is the detection of residual or recurrent tumor in the postoperative follow-up. In this review we present the radiopharmaceuticals used in the diagnosis of MTC recurrence, and comparison among them. The most used radiopharmaceuticals labelled with γ emitters are: Metaiodobenzylguanidine (MIBG), labelled with (131)I or (123)I, (111)In-pentetreotide (Octreoscan), 99mTc-pentavalent dimercaptosuccinic acid ((99m)Tc(V)-DMSA), and (99m)Tc-EDDA/HYNIC-Tyr3-Octreotide ( Tektrotyd). The radiopharmaceuticals labelled with a positron-emitting radionuclide (β+), suitable for positron emission tomography (PET) imaging are: (18)F-fluorodeoxyglucose ((18)F-FDG), (18)F-fluorodihydroxyphenylalanine (18F-DOPA), and 68Ga-labelled somatostatin analogues (68Ga-DOTATATE or DOTATOC).

  17. Cellular Signaling Pathway Alterations and Potential Targeted Therapies for Medullary Thyroid Carcinoma

    Directory of Open Access Journals (Sweden)

    Serena Giunti

    2013-01-01

    Full Text Available Parafollicular C-cell-derived medullary thyroid cancer (MTC comprises 3% to 4% of all thyroid cancers. While cytotoxic treatments have been shown to have limited efficacy, targeted molecular therapies that inhibit rearranged during transfection (RET and other tyrosine kinase receptors that are mainly involved in angiogenesis have shown great promise in the treatment of metastatic or locally advanced MTC. Multi-tyrosine kinase inhibitors such as vandetanib, which is already approved for the treatment of progressive MTC, and cabozantinib have shown distinct advantages with regard to rates of disease response and control. However, these types of tyrosine kinase inhibitor compounds are able to concurrently block several types of targets, which limits the understanding of RET as a specific target. Moreover, important resistances to tyrosine kinase inhibitors can occur, which limit the long-term efficacy of these treatments. Deregulated cellular signaling pathways and genetic alterations in MTC, particularly the activation of the RAS/mammalian target of rapamycin (mTOR cascades and RET crosstalk signaling, are now emerging as novel and potentially promising therapeutic treatments for aggressive MTC.

  18. Management and outcomes of patients with renal medullary carcinoma: a multicentre collaborative study.

    Science.gov (United States)

    Shah, Amishi Y; Karam, Jose A; Malouf, Gabriel G; Rao, Priya; Lim, Zita D; Jonasch, Eric; Xiao, Lianchun; Gao, Jianjun; Vaishampayan, Ulka N; Heng, Daniel Y; Plimack, Elizabeth R; Guancial, Elizabeth A; Fung, Chunkit; Lowas, Stefanie R; Tamboli, Pheroze; Sircar, Kanishka; Matin, Surena F; Kimryn Rathmell, W; Wood, Christopher G; Tannir, Nizar M

    2017-12-01

    To describe the management strategies and outcomes of patients with renal medullary carcinoma (RMC) and characterise predictors of overall survival (OS). RMC is a rare and aggressive malignancy that afflicts young patients with sickle cell trait; there are limited data on management to date. This is a study of patients with RMC who were treated in 2000-2015 at eight academic institutions in North America and France. The Kaplan-Meier method was used to estimate OS, measured from initial RMC diagnosis to date of death. Cox regression analysis was used to determine predictors of OS. In all, 52 patients (37 males) were identified. The median (range) age at diagnosis was 28 (9-48) years and 49 patients (94%) had stage III/IV. The median OS for all patients was 13.0 months and 38 patients (75%) had nephrectomy. Patients who underwent nephrectomy had superior OS compared to patients who were treated with systemic therapy only (median OS 16.4 vs 7.0 months, P 24 months. RMC carries a poor prognosis. Chemotherapy provides palliation and remains the mainstay of therapy, but 24 months, underscoring the need to develop more effective therapy for this rare tumour. In this study, nephrectomy was associated with improved OS. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

  19. Cutaneous Metastasis of Medullary Carcinoma Thyroid Masquerading as Subcutaneous Nodules Anterior Chest and Mandibular Region

    Directory of Open Access Journals (Sweden)

    Rahul Mannan

    2014-01-01

    Full Text Available Cutaneous metastasis of underlying primary malignancies can present to dermatologist with chief complaints of cutaneous lesions. The underlying malignancy is generally diagnosed much later after a complete assessment of the concerned case. Medullary carcinoma thyroid (MCT is a relatively uncommon primary neoplasia of the thyroid. Very few cases presenting as cutaneous metastases of MCT have been reported in the literature. Most of the cases which have been reported are of the papillary and the follicular types. We here report a case of a patient who presented in the dermatology clinic with the primary complaint of multiple subcutaneous nodules in anterior chest wall and left side of body of mandible. By systematic application of clinical and diagnostic skills these nodules were diagnosed as cutaneous metastasis of MCT bringing to the forefront a history of previously operated thyroid neoplasm. So clinically, the investigation of a flesh coloured subcutaneous nodule, presenting with a short duration, particularly in scalp, jaw, or anterior chest wall should include possibility of metastastic deposits. A dermatologist should keep a possibility of an internal organ malignancy in patients while investigating a case of flesh coloured subcutaneous nodules, presenting with short duration. A systematic application of clinical and diagnostic skills will eventually lead to such a diagnosis even when not suspected clinically at its primary presentation. A prompt and an emphatic diagnosis and treatment will have its bearing on the eventual outcome in all these patients.

  20. RET mutation heterogeneity in primary advanced medullary thyroid cancers and their metastases.

    Science.gov (United States)

    Romei, Cristina; Ciampi, Raffaele; Casella, Francesca; Tacito, Alessia; Torregrossa, Liborio; Ugolini, Clara; Basolo, Fulvio; Materazzi, Gabriele; Vitti, Paolo; Elisei, Rossella

    2018-02-09

    Medullary Thyroid Cancer (MTC) whose pathogenesis is strictly related to RET proto-oncogene alterations, has been shown to have a heterogenic RET mutation profile in subpopulations of MTC. The aim of our study was to investigate the RET somatic mutation profile in primary MTC and in the corresponding metastatic tissues in a series of advanced metastatic cases. This study demonstrated that in about 20% of cases a different RET mutation profile can be found when comparing primary tumor and its corresponding metastases. Furthermore in 8% of tumors, RET intratumor heterogeneity was observed We also showed that in some cases an imbalance of RET copy number was present. We confirmed a high prevalence (90%) of RET somatic mutations in advanced tumors. Fifty-six MTC patients (50 somatic and 6 hereditary cases) have been included in the study and a total of 209 specimens have been analysed by direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) has been used to investigate amplification/deletion of RET alleles. In conclusion, this study showed a genetic intra- and intertumor heterogeneity in MTC, But in only 20% of CASES These results could justify the relatively moderate level of aggressiveness of the disease with respect to more aggressive human tumors that are characterized by a high rate of mutation and heterogeneity.

  1. A Korean Family of Familial Medullary Thyroid Cancer with Cys618Ser RET Germline Mutation

    Science.gov (United States)

    Jung, Jinhyang; Uchino, Shinya; Lee, Youngha

    2010-01-01

    Familial medullary thyroid carcinoma (FMTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. An identifiable RET mutation can be detected in about 85% of FMTC families. The majority of germline mutations in FMTC have been found in exons 10 and 11 of the RET proto-oncogene, specifically within the cysteine codons 609, 611, 618, 620, and 634. We screened members of a large Korean family that had a history of FMTC by genetic analyses, and propose a therapeutic approach for managing the disorder. We report a RET mutation in exon10, codon 618 that causes substitution of a cysteine by a serine in the cysteine-rich domain of the RET receptor in a three-generation FMTC family composed of 30 members with 11 carriers. Nine of the gene carriers were clinically affected. The FMTC with cysteine RET mutations found in the Korean population is consistent with the clinical pattern reported worldwide; to date there have been no ethnic differences identified for FMTC. Our results suggest that this genetic profile might be associated with usually aggressive clinical course with regional lymph node metastasis but late onset of MTC. PMID:20119574

  2. Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors.

    Science.gov (United States)

    La Pietra, Valeria; Sartini, Stefania; Botta, Lorenzo; Antonelli, Alessandro; Ferrari, Silvia Martina; Fallahi, Poupak; Moriconi, Alessio; Coviello, Vito; Quattrini, Luca; Ke, Yi-Yu; Hsing-Pang, Hsieh; Da Settimo, Federico; Novellino, Ettore; La Motta, Concettina; Marinelli, Luciana

    2018-03-02

    It is now known that "gain of function" mutations of RET (REarranged during Transfection) kinase are specific and key oncogenic events in the onset of thyroid gland cancers such as the Medullary Thyroid Carcinoma (MTC). Although a number of RET inhibitors exist and are capable of inhibiting RET variants, in which mutations are outside the enzyme active site, the majority becomes dramatically ineffective when mutations are within the protein active site (V804L and V804M). Pursuing a receptor-based virtual screening against the kinase domain of RET, we found that compound 5 is able to inhibit efficiently both wild type and V804L mutant RET. Compound 5 was able to significantly reduce proliferation of both commercially available TT cell lines and surgical thyroid tissues obtained from patients with MTC and displayed a suitable drug-like profile, thus standing out as a promising candidate for further development towards the treatment of clinically unresponsive MTC. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  3. Sporadic minute medullary thyroid carcinoma with a double RET mutation: A case report.

    Science.gov (United States)

    Yamamoto, Hiroyuki; Ishii, Jun; Chiba, Tomohiro; Nakazato, Yoko; Hirano, Kouichi; Kamma, Hiroshi

    2017-11-01

    We describe a 74-year-old man with a nodular goiter accompanied by an incidental sporadic minute medullary thyroid carcinoma (MTC). Histopathologically, the MTC was a well-defined 1.7 mm tumor in the upper one-third right lobe, with solid cell nests (SCNs) adjacent to the MTC. C-cells were scattered mainly around the SCNs, but C-cell hyperplasia was not evident in the background thyroid. The MTC cell phenotype was immunohistochemically identical to background C-cells, but was completely different from the SCN main cells. Direct DNA analyses of isolated MTC paraffin-embedded specimens revealed two RET proto-oncogene missense point mutations in exon 11 (i.e., C630R and C634W). The non-tumor thyroid tissue did not reveal any mutations. This study reports the smallest case of sporadic MTC with a double RET somatic mutation, substantiating that RET mutations can occur during a very early stage of carcinogenesis. The combined presence of C630R and C634W represent a novel somatic mutation in sporadic MTC. The present case indicates that the sporadic MTC originated from the surrounding C-cells of the SCNs without C-cell hyperplasia and that the SCN main cells may not be able to develop into an MTC. © 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

  4. Antiproliferative and pro-apoptotic effects of Uncaria tomentosa in human medullary thyroid carcinoma cells.

    Science.gov (United States)

    Rinner, Beate; Li, Zeng Xia; Haas, Helga; Siegl, Veronika; Sturm, Sonja; Stuppner, Hermann; Pfragner, Roswitha

    2009-11-01

    Medullary thyroid carcinoma (MTC), a rare calcitonin-producing tumor, is derived from parafollicular C-cells of the thyroid and is characterized by constitutive Bcl-2 overexpression. The tumor is relatively insensitive to radiation therapy as well as conventional chemotherapy. To date, the only curative treatment is the early and complete surgical removal of all neoplastic tissue. In this study, the antiproliferative and pro-apoptotic effects of fractions obtained from Uncaria tomentosa (Willd.) DC, commonly known as uña de gato or cat's claw were investigated. Cell growth of MTC cells as well as enzymatic activity of mitochondrial dehydrogenase was markedly inhibited after treatment with different fractions of the plant. Furthermore, there was an increase in the expressions of caspase-3 and -7 and poly(ADP-ribose) polymerase (PARP) fraction, while bcl-2 overexpression remained constant. In particular, the alkaloids isopterpodine and pteropodine of U. tomentosa exhibited a significant pro-apoptotic effect on MTC cells, whereas the alkaloid-poor fraction inhibited cell proliferation but did not show any pro-apoptotic effects. These promising results indicate the growth-restraining and apoptotic potential of plant extracts against neuroendocrine tumors, which may add to existing therapies for cancer.

  5. The prognostic value of tumor markers doubling times in medullary thyroid carcinoma - preliminary report

    Directory of Open Access Journals (Sweden)

    Gawlik Tomasz

    2010-11-01

    Full Text Available Abstract Introduction Calcitonin (Ct and carcinoembrional antigen (CEA are widely used as tumor markers for the post-operative follow-up of patients with medullary thyroid carcinoma (MTC. In patients with elevated serum Ct and CEA their dynamics can be described by calculating the doubling time (DT - the time, they need to double the serum concentration. Previous reports concluded that the Ct and CEA DT have prognostic value in MTC patients. Patients and methods We retrospectively analyzed data of 70 MTC patients with elevated serum Ct or CEA. In total, doubling times were calculated and the DT of the less favorable marker was used to stratify the patients into the low- and high-risk group with the cut-off value of 2 years. The survival analysis was performed using Cox proportional hazard method. Results The doubling time Conclusions The calcitonin and carcinembrional antigen doubling times of less than two years are negative prognostic factors for MTC recurrence-free and total survival in patients with persistent or recurrent disease. They may be used as predictive factors for more intensive search of disease localization in asymptomatic hypercalcitoninemia and for therapy choice in symptomatic disease.

  6. Medullary and intrathecal injections of 17beta-estradiol in male rats.

    Science.gov (United States)

    Saleh, M C; Connell, B J; Saleh, T M

    2000-06-09

    The following experiments were designed to investigate the role of estrogen in central autonomic nuclei on autonomic tone and reflex control of heart rate. Male Sprague-Dawley rats were anesthetized with sodium thiobutabarbital (100 mg/kg) and instrumented to record blood pressure and heart rate. Efferent vagal and renal nerve activities were recorded and used to assess changes in parasympathetic and sympathetic tone, respectively. The cardiac baroreflex was evoked using a single bolus injection of phenylephrine (0.1 mg/kg) both before and following either intrathecal injection of estrogen (0.5 microM; 1 microl) to influence sympathetic preganglionic neurons of the intermediolateral cell column or bilateral injection of estrogen (0.5 microM; 100 nl/side) into the nucleus tractus solitarius, rostral ventrolateral medulla or nucleus ambiguus. The cardiac baroreflex was significantly enhanced following both intrathecal and medullary injections of estrogen. Efferent vagal nerve activity was significantly increased following injection of estrogen into the nucleus tractus solitarius, nucleus ambiguus and the intrathecal space. Renal sympathetic nerve activity was significantly depressed following injection of estrogen into the nucleus tractus solitarius, rostral ventrolateral medulla and the intrathecal space. In all cases, simultaneous injection of estrogen with the selective estrogen receptor antagonist, ICI 182,780 (1 pM) blocked all previously observed changes in baroreflex function and autonomic tone. These results demonstrate a role for estrogen in the reflex control of heart rate and as a central modulator of autonomic tone in male rats.

  7. Medullary Venous Hypertension Secondary to a Petrous Apex Dural Arteriovenous Fistula: A Case Report

    Directory of Open Access Journals (Sweden)

    Meghan Murphy

    2012-11-01

    Full Text Available Background: Dural arteriovenous fistulae (dAVF are common intracranial vascular lesions typically becoming symptomatic with cortical venous hypertension and possible hemorrhage. Here, we present a case illustration of a petrous apex dAVF with marked medullary venous hypertension and a unique clinical presentation. Methods: Case report. Results: A 72-year-old female, whose clinical progression was significant for altered mental status and progressive weakness, presented with diplopia, right leg paresis, and ataxia. Magnetic resonance imaging revealed edema involving the medulla. On digital subtraction cerebral angiogram, the patient was found to have a petrous apex dAVF, Cognard type IV. Following treatment with Onyx embolization, her symptoms rapidly improved, with complete resolution of diplopia and drastic improvement of her ataxia. Conclusion: The importance of this case is in the presentation and deterioration of the clinical exam, resembling an acute ischemic event. Further, this case illustrates that dAVF may cause venous hypertension with rapid onset of focal neurologic symptoms not exclusive to cortical locations.

  8. Changes of medullary hemopoiesis produced by chronic exposure to tritium oxide and external γ-radiation

    International Nuclear Information System (INIS)

    Murzina, L.D.; Muksinova, K.N.

    1982-01-01

    A comparative study of a chronic effect of tritium oxide ( 3 HOH) and external γ-radiation by 137 Cs on medullary hemopoiesis was conducted in experiments on Wistar rats. 3 HOH was administered for 3mos., 37x10 4 Bk per lg per of body mass daily (the absorbed dose 10.8 Gy), external irradiation was given in correlated values of dose rates and integral doses. Bone marrow depopulation was 1.9 times as deeper in rats exposed to 3 HOH as compared to that in irradiated rats. This difference is caused by early and stable inhibition of erythropoiesis with the administration of the radionuclide. The integral index showing the injuring effect of tritium on erythropoiesis was 4 times as high as compared to that of external γ-irradiation by 137 Cs. The time course of value of the proliferative pool of bone marrow granulocytes with the exposure to 2 types of radiation was monotypic. Differences in maturing and functioning granulocytic pools were marked in early time of the experiment

  9. Three-dimensional cytomorphology in fine needle aspiration biopsy of medullary thyroid carcinoma.

    Science.gov (United States)

    Chang, T C; Lai, S M; Wen, C Y; Hsiao, Y L; Huang, S H

    2001-01-01

    To elucidate three-dimensional (3-D) cytomorphology in fine needle aspiration biopsy (FNAB) of medullary thyroid carcinoma (MTC). ENAB was performed on tumors from five patients with MTC. The aspirate was stained and observed under a light microscope (LM). The aspirate was also fixed, dehydrated, critical point dried, spattered with gold ions and observed with a scanning electron microscope (SEM). For transmission electron microscopy (TEM), the specimen was fixed, dehydrated, embedded in an Epon mixture, cut with an ultramicrotome, mounted on copper grids, electron doubly stained with uranium acetate and lead citrate, and observed with TEM. Findings under SEM were correlated with those under LM and TEM. Under SEM, 3-D cytomorphology of MTC displayed a disorganized cellular arrangement with indistinct cell borders in three cases. The cell surface was uneven and had granular protrusions that corresponded to secretory granules observed under TEM. In one case with multiple endocrine neoplasia type IIB, there were abundant granules on the cell surface. In one case of sporadic MTC with multinucleated tumor giant cells and small cells, granular protrusions also were noted on the cell surface. Granular protrusion was a characteristic finding in FNAB of MTC tinder SEM and might be helpful in the differential diagnosis.

  10. High frequency of bone/bone marrow involvement in advanced medullary thyroid cancer.

    Science.gov (United States)

    Mirallié, E; Vuillez, J P; Bardet, S; Frampas, E; Dupas, B; Ferrer, L; Faivre-Chauvet, A; Murat, A; Charbonnel, B; Barbet, J; Goldenberg, D M; Chatal, J F; Kraeber-Bodéré, F

    2005-02-01

    High hematological toxicity has been observed with anti-carcinoembryonic antigen radioimmunotherapy (RIT) in medullary thyroid carcinoma (MTC), suggesting metastatic bone involvement (BI). This retrospective study evaluated the rate of BI in MTC patients enrolled in two phase-I/II RIT trials using anti-carcinoembryonic antigen x anti-diethylenetriamine pentaacetic acid bispecific antibodies and [(131)I]di-diethylenetriamine pentaacetic acid hapten. Thirty-five patients underwent bone scintigraphy, bone magnetic resonance imaging (MRI), and post-RIT immunoscintigraphy (IS). IS performed in MTC patients was compared with IS conducted in 12 metastatic colorectal carcinoma (CRC) patients. Quantitative analysis of bone uptake was performed in three MTC and three CRC patients. In the MTC group, bone scintigraphy detected BI in 56.6% of patients, MRI in 75.8%, and IS in 88.6%. BI was confirmed by undirected (random) bone marrow biopsy, by bone surgery, or by two positive imaging methods in 74.3% of the patients. Sensitivity per patient of bone scintigraphy, MRI, and IS were 72.7, 100, and 100%, respectively. In contrast, IS visualized BI in only 33.3% of CRC patients; bone uptake was lower in CRC than in MTC patients. Bone MRI combined with post-RIT IS disclosed a much higher BI rate in advanced MTC than previously reported in the literature.

  11. Ghrelin and obestatin in thyroid gland - immunohistochemical expression in nodular goiter, papillary and medullary cancer.

    Science.gov (United States)

    Gurgul, Edyta; Kasprzak, Aldona; Blaszczyk, Agata; Biczysko, Maciej; Surdyk-Zasada, Joanna; Seraszek-Jaros, Agnieszka; Ruchala, Marek

    2015-01-01

    Previous studies analyzing ghrelin and obestatin expression in thyroid gland tissue are not unanimous and are mostly related to ghrelin. The role of ghrelin and obestatin in the thyroid gland appears very interesting due to their probable involvement in cell proliferation. Furthermore, since the thyroid gland is associated with the maintenance of energy balance, the relationship between ghrelin, obestatin and thyroid function is worthy of consideration. The aim of the study was to assess ghrelin and obestatin immunocytochemical expression in nodular goiter (NG), papillary cancer (PTC) and medullary cancer (MTC). Analyzed samples included 9 cases of NG, 8 cases of PTC and 11 cases of MTC. The analysis of ghrelin and obestatin expression was performed by use of the immunohistochemical (IHC) EnVision system and evaluated with filter HSV software (quantitative morphometric analysis). Quantitative ghrelin expression in MTC cells was higher than in NG (p = 0.013) and correlated negatively with the size of the tumor (r= -0.829, p thyroid cell proliferation. The differences between ghrelin and obestatin immunoreactivity in benign and malignant thyroid tumors could support the theory of alternative transcription of the preproghrelin gene and independent production of ghrelin and obestatin.

  12. Bone densitometry by gamma ray attenuation measurement. Development of an apparatus for use on medullary casualties

    International Nuclear Information System (INIS)

    Berard, E.J.-J.

    1975-01-01

    We proposed to follow changes in the bone mineral content of medullary damage cases by measuring the attenuation of a monoenergetic gamma ray according to the Cameron and Sorenson technique. Apart from their high cost, existing instruments are not designed for this bedside observation of patients. Our aim was therefore to design and develop an easily portable, inexpensive apparatus. The γ radiation is supplied by a sealed 125 I source fitted with a narrow collimator. The battery-operated scintillation detector is that used to detect post-operative phlebites after injection of radio-fibrinogen. The source-detector unit can move to allow a transverse bone mineral content measurement. Data from the detector are processed electronically and the results given: - either graphically on a tracing board which gives an area proportional to the bone mineral content, - or numerically by means of an integrator computing this area and supplying the linear bone density directly. Experiments carried out in vivo showed the apparatus to be sensitive and the measurements reproducible, the results obtained being comparable with those of other authors. Using pieces of embalmed bone moreover an excellent correlation was observed between the bone mineral content obtained after incineration and the results displayed by our apparatus, which can therefore be calibrated [fr

  13. Parametric study of dielectric loaded surface plasmon polariton add-drop filters for hybrid silicon/plasmonic optical circuitry

    Science.gov (United States)

    Dereux, A.; Hassan, K.; Weeber, J.-C.; Djellali, N.; Bozhevolnyi, S. I.; Tsilipakos, O.; Pitilakis, A.; Kriezis, E.; Papaioannou, S.; Vyrsokinos, K.; Pleros, N.; Tekin, T.; Baus, M.; Kalavrouziotis, D.; Giannoulis, G.; Avramopoulos, H.

    2011-01-01

    Surface plasmons polaritons are electromagnetic waves propagating along the surface of a conductor. Surface plasmons photonics is a promising candidate to satisfy the constraints of miniaturization of optical interconnects. This contribution reviews an experimental parametric study of dielectric loaded surface plasmon waveguides ring resonators and add-drop filters within the perspective of the recently suggested hybrid technology merging plasmonic and silicon photonics on a single board (European FP7 project PLATON "Merging Plasmonic and Silicon Photonics Technology towards Tb/s routing in optical interconnects"). Conclusions relevant for dielectric loaded surface plasmon switches to be integrated in silicon photonic circuitry will be drawn. They rely on the opportunity offered by plasmonic circuitry to carry optical signals and electric currents through the same thin metal circuitry. The heating of the dielectric loading by the electric current enables to design low foot-print thermo-optical switches driving the optical signal flow.

  14. Microwave remediation of electronic circuitry waste and the resulting gaseous emissions

    Science.gov (United States)

    Schulz, Rebecca L.

    The global community has become increasingly dependent on computer and electronic technology. As a result, society is faced with an increasing amount of obsolete equipment and electronic circuitry waste. Electronic waste is generally disposed of in landfills. While convenient, this action causes a substantial loss of finite resources and poses an environmental threat as the circuit board components breakdown and are exposed to the elements. Hazardous compounds such as lead, mercury and cadmium may leach from the circuitry and find their way into the groundwater supply. For this dissertation, a microwave waste remediation system was developed. The system was designed to remove the organic components from a wide variety of electronic circuitry. Upon additional heating of the resulting ash material in an industrial microwave, a glass and metal product can be recovered. Analysis of the metal reveals the presence of precious metals (gold, silver) that can be sold to provide a return on investment. a glass and metal product can be recovered. Analysis of the metal reveals the presence of precious metals (gold, silver) that can be sold to provide a return on investment. Gaseous organic compounds that were generated as a result of organic removal were treated in a microwave off gas system that effectively reduced the concentration of the products emitted by several orders of magnitude, and in some cases completely destroying the waste gas. Upon further heating in an industrial microwave, a glass and metal product were recovered. In order to better understand the effects of processing parameters on the efficiency of the off-gas system, a parametric study was developed. The study tested the microwave system at 3 flow rates (10, 30, and 50 ft 3/min) and three temperatures (400, 700 and 1000°C. In order to test the effects of microwave energy, the experiments were repeated using a conventional furnace. While microwave energy is widely used, the mechanisms of interaction with

  15. Nucleic Acid Self-Assembly Circuitry Aided by Exonuclease III for Discrimination of Single Nucleotide Variants.

    Science.gov (United States)

    Zhang, Zhuo; Hsing, I-Ming

    2017-11-21

    Robust and rapid discrimination of one base mutations in nucleic acid sequences is important in clinical applications. Here, we report a hybridization-based assay exploiting nucleic acid self-assembly circuitry and enzyme exonuclease III (Exo III) for the differentiation of single nucleotide variants (SNVs). This one-step approach combines the merits of discrimination power of competitive DNA hybridization probes (probe + sink) with catalytic amplification assisted by Exo III. The phosphorothioate bonds modified on a wild-type (WT) specific sink inhibit the Exo III digestion; thus, subsequent catalytic amplification magnifies only the intended SNV targets. The integrated assay exhibits improved SNV discrimination rather than hybridization probes relying solely on competition or amplification and enables SNV detection at 1% abundance. Two frequent cancer-driver mutation sequences (EGFR-L861Q, NRAS-Q61K) were tested. Our strategy allows simple sequence design and can easily adapt to multianalyte SNV detections.

  16. Engineering nucleic acid structures for programmable molecular circuitry and intracellular biocomputation

    Science.gov (United States)

    Li, Jiang; Green, Alexander A.; Yan, Hao; Fan, Chunhai

    2017-11-01

    Nucleic acids have attracted widespread attention due to the simplicity with which they can be designed to form discrete structures and programmed to perform specific functions at the nanoscale. The advantages of DNA/RNA nanotechnology offer numerous opportunities for in-cell and in-vivo applications, and the technology holds great promise to advance the growing field of synthetic biology. Many elegant examples have revealed the potential in integrating nucleic acid nanostructures in cells and in vivo where they can perform important physiological functions. In this Review, we summarize the current abilities of DNA/RNA nanotechnology to realize applications in live cells and then discuss the key problems that must be solved to fully exploit the useful properties of nanostructures. Finally, we provide viewpoints on how to integrate the tools provided by DNA/RNA nanotechnology and related new technologies to construct nucleic acid nanostructure-based molecular circuitry for synthetic biology.

  17. Radiation-Hardened Circuitry Using Mask-Programmable Analog Arrays. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Britton, Jr., Charles L. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Ericson, Milton Nance [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Bobrek, Miljko [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Blalock, Benjamin [Univ. of Tennessee, Knoxville, TN (United States)

    2015-12-01

    As the recent accident at Fukushima Daiichi so vividly demonstrated, telerobotic technologies capable of withstanding high radiation environments need to be readily available to enable operations, repair, and recovery under severe accident scenarios where human entry is extremely dangerous or not possible. Telerobotic technologies that enable remote operation in high dose rate environments have undergone revolutionary improvement over the past few decades. However, much of this technology cannot be employed in nuclear power environments due the radiation sensitivity of the electronics and the organic insulator materials currently in use. This is the final report of the activities involving the NEET 2 project Radiation Hardened Circuitry Using Mask-Programmable Analog Arrays. We present a detailed functional block diagram of the proposed data acquisition system, the thought process leading to technical decisions, the implemented system, and the tested results from the systems. This system will be capable of monitoring at least three parameters of importance to nuclear reactor monitoring: temperature, radiation level, and pressure.

  18. cAMP-binding proteins in medullary tubules from rat kidney: effect of ADH

    International Nuclear Information System (INIS)

    Gapstur, S.M.; Homma, S.; Dousa, T.P.

    1988-01-01

    Little is known of the regulatory steps in the cellular action of vasopressin (AVP) on the renal epithelium, subsequent to the cAMP generation. We studied cAMP-binding proteins in the medullary collecting tubule (MCT) and the thick ascending limb of Henle's loop (MTAL) microdissected from the rat kidney by use of photoaffinity labeling. Microdissected tubules were homogenized and photoaffinity labeled by incubation with 1 microM 32P-labeled 8-azido-adenosine 3',5'-cyclic monophosphate (N3-8-[32P]-cAMP); the incorporated 32P was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Both in MCT and MTAL preparations, the analyses showed incorporation of N3-8-[32P]cAMP into two bands (Mr = 49,000 and Mr = 55,000) that comigrated with standards of the cAMP-dependent protein kinase regulatory subunits RI and RII. In MCT, most of the 32P (80%) was incorporated into RI, whereas in MTAL the 32P incorporated into RI and RII was equivalent. When freshly dissected MCT segments were incubated with 10(-12)-10(-6) M AVP, the subsequent photoaffinity labeling of RI with N3-8-[32P]cAMP was markedly diminished in a dose-dependent manner compared with controls. Our results suggest that cAMP binds in MCT and MTAL to regulatory subunits RI and RII of cAMP-dependent protein kinase. However, in MCT the dominant type of cAMP-dependent protein kinase appears to be type I. The outlined procedure is suitable to indirectly measure the occupancy of RI by endogenous cAMP generated in MCT cells in response to physiological levels (10(-12) M) of AVP

  19. Use of somatostatin analogue scintigraphy in the localization of recurrent medullary thyroid carcinoma

    International Nuclear Information System (INIS)

    Berna, L.; Catafau, A.; Mari, C.; Flotats, A.; Martin, J.C.; Estorch, M.; Carrio, I.; Chico, A.; Mato, E.; Matias-Guiu, X.; Alonso, C.; Mora, J.; Rodriguez-Espinosa, J.; Mauricio, D.

    1998-01-01

    Detection of recurrence of medullary thyroid carcinoma (MTC) remains a diagnostic problem. Increased serum tumour marker levels frequently indicate recurrence while conventional imaging techniques (CIT) are non-diagnostic. In this study, we performed indium-111 octreotide scintigraphy and CIT in a series of 20 patients with MTC presenting with elevated serum tumour markers after surgery. 111 In-octreotide whole-body studies detected 15 pathological uptake foci in 11 of the 20 patients studied and CIT detected 17 lesions in 11 of the 20 patients. Ten patients underwent reoperation, five of them with positive 111 In-octreotide scintigraphy and CIT and two with positive isotopic exploration and negative CIT. Surgical findings demonstrated that the results of isotopic study and CIT had been false-positive for MTC in one case (sarcoidosis). The six patients with true-positive 111 In-octreotide studies had significantly higher basal calcitonin (CT) and carcinoembryonic antigen (CEA) levels than the patients with negative isotopic studies. The expression of somatostatin receptor (SSTR) subtypes by PC-PCR could be investigated in four cases with a positive isotopic study. Among the three cases with a true-positive study, SSTR2, the SSTR subtype that preferentially binds to the somatostatin analogue octreotide, was detected in two, SSTR5 was demonstrated in the three, and SSTR3 was detected in one. No subtype of SSTR was detected in the case with a final diagnosis of sarcoidosis. We conclude that 111 In-octreotide has limited sensitivity in detecting recurrence in patients with MTC, although its sensitivity may improve with high serum CT levels. This radionuclide imaging technique should be employed when conventional imaging techniques are negative or inconclusive or when the presence of somatostatin receptors may provide the basis for treatment with somatostatin analogues. (orig.)

  20. Noncoding RNA blockade of autophagy is therapeutic in medullary thyroid cancer

    International Nuclear Information System (INIS)

    Gundara, Justin S; Zhao, JingTing; Gill, Anthony J; Lee, James C; Delbridge, Leigh; Robinson, Bruce G; McLean, Catriona; Serpell, Jonathan; Sidhu, Stan B

    2015-01-01

    Micro-RNAs are dysregulated in medullary thyroid carcinoma (MTC) and preliminary studies have shown that miRNAs may enact a therapeutic effect through changes in autophagic flux. Our aim was to study the in vitro effect of miR-9-3p on MTC cell viability, autophagy and to investigate the mRNA autophagy gene profile of sporadic versus hereditary MTC. The therapeutic role of miR-9-3p was investigated in vitro using human MTC cell lines (TT and MZ-CRC-1 cells), cell viability assays, and functional mechanism studies with a focus on cell cycle, apoptosis, and autophagy. Post-miR-9-3p transfection mRNA profiling of cell lines was performed using a customized, quantitative RT-PCR gene array card. This card was also run on clinical tumor samples (sporadic: n = 6; hereditary: n = 6) and correlated with clinical data. Mir-9-3p transfection resulted in reduced in vitro cell viability; an effect mediated through autophagy inhibition. This was accompanied by evidence of G2 arrest in the TT cell line and increased apoptosis in both cell lines. Atg5 was validated as a predicted miR-9-3p mRNA target in TT cells. Post-miR-9-3p transfection array studies showed a significant global decline in autophagy gene expression (most notably in PIK3C3, mTOR, and LAMP-1). Autophagy gene mRNAs were generally overexpressed in sporadic (vs. hereditary MTC) and Beclin-1 overexpression was shown to correlate with residual disease. Autophagy is a tumor cell survival mechanism in MTC that when disabled, is of therapeutic advantage. Beclin-1 expression may be a useful prognostic biomarker of aggressive disease

  1. Medullary thyroid carcinoma: Application of Thyroid Imaging Reporting and Data System (TI-RADS) Classification.

    Science.gov (United States)

    Yun, Gabin; Kim, Yeo Koon; Choi, Sang Il; Kim, Ji-Hoon

    2018-04-21

    To evaluate the applicability of ultrasound (US)-based Thyroid Imaging Reporting and Data System (TI-RADS) for evaluating medullary thyroid carcinoma (MTC). US images and medical records of patients with cytopathology-confirmed MTC between June 2003 and November 2016 were retrospectively reviewed. Four independent reviewers (two experienced and two inexperienced radiologists) evaluated 57 pre-operative US images of patients with MTC for shape, composition, echogenicity, margin, calcification of the MTC nodules, and categorized the nodules using TI-RADS classification. Weighted Kappa statistics was used to determine the inter-observer agreement of TI-RADS. Univariate and multivariate analyses were performed to assess US findings associated with lymph node metastasis. Ninety-five percent of nodules were classified as either high suspicion (68%) or intermediate suspicion (26%). The overall inter-rater agreement was good (Kappa 0.84, agreement 91.52%), and inexperienced reviewers also showed good agreements with the most experienced reviewer (weighted Kappa 0.73 and 0.81). According to the univariate analysis, TI-RADS category 5, shape, microcalcification, and extrathyroid extension were significantly associated with lymph node metastasis in MTC patients (p = 0.003, 0.008, 0.001, and 0.021, respectively). As per the multivariate analysis, the presence of microcalcification and the irregular shape of the nodule were significantly associated with metastatic lymph nodes in MTC patients (odds ratio, 26.6; 95% CI, 2.7-263.7, p = 0.005, odds ratio, 14.7; 95% CI, 1.3-170, p = 0.031, respectively). TI-RADS is applicable for the evaluation of MTC nodules with good inter-observer agreement.

  2. Postoperative Nomogram for Predicting Cancer-Specific Mortality in Medullary Thyroid Cancer.

    Science.gov (United States)

    Ho, Allen S; Wang, Lu; Palmer, Frank L; Yu, Changhong; Toset, Arnbjorn; Patel, Snehal; Kattan, Michael W; Tuttle, R Michael; Ganly, Ian

    2015-08-01

    Medullary thyroid cancer (MTC) is a rare thyroid cancer accounting for 5 % of all thyroid malignancies. The purpose of our study was to design a predictive nomogram for cancer-specific mortality (CSM) utilizing clinical, pathological, and biochemical variables in patients with MTC. MTC patients managed entirely at Memorial Sloan-Kettering Cancer Center between 1986 and 2010 were identified. Patient, tumor, and treatment characteristics were recorded, and variables predictive of CSM were identified by univariable analyses. A multivariable competing risk model was then built to predict the 10-year cancer specific mortality of MTC. All predictors of interest were added in the starting full model before selection, including age, gender, pre- and postoperative serum calcitonin, pre- and postoperative CEA, RET mutation status, perivascular invasion, margin status, pathologic T status, pathologic N status, and M status. Stepdown method was used in model selection to choose predictive variables. Of 249 MTC patients, 22.5 % (56/249) died from MTC, whereas 6.4 % (16/249) died secondary to other causes. Mean follow-up period was 87 ± 67 months. The seven variables with the highest predictive accuracy for cancer specific mortality included age, gender, postoperative calcitonin, perivascular invasion, pathologic T status, pathologic N status, and M status. These variables were used to create the final nomogram. Discrimination from the final nomogram was measured at 0.77 with appropriate calibration. We describe the first nomogram that estimates cause-specific mortality in individual patients with MTC. This predictive nomogram will facilitate patient counseling in terms of prognosis and subsequent clinical follow up.

  3. A cohort study on 10-year survival of sporadic medullary thyroid carcinoma with somatic RET mutation

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    Li-Lun Chuang

    2016-11-01

    Full Text Available Somatic rearranged during transfection (RET mutations are reported in 40–50% of sporadic medullary thyroid carcinoma (sMTC patients with prognostic significance. As there is a lack of somatic RET mutations reported previously for the Taiwanese population, we tried to assess the presence of somatic RET mutations and evaluate the potential outcome predictors for our sMTC patients. We collected data from seven sMTC patients from the years 1997 to 2005 and analyzed their clinic-pathological features up to 2015. All patients were still alive to follow up for 11∼18 years. Tumor DNAs were extracted to assess exons 10–11 and 13–16, and the intron-exon boundaries of the RET gene. Six cases (86% were screened positive of somatic RET gene mutations in hotspot regions, one at M918T, one at C620R, and three at C634S, with another two rare mutations at L629Q and V642I. Comparing the current tumor, node, metastases staging system, the 10-year survival outcomes for our sMTC patients was not predicted by serum calcitonin and/or carcinoembryonic antigen, surgical extent, and presence of the somatic RET gene mutations. The small cohort demonstrated a relatively good outcome of sMTC patients to survive >10 years. In addition, intensive treatment with total thyroidectomy with extensive neck lymph node dissection seemed to be the critical determinant of better survival outcome for sMTC patients.

  4. Selective Mitochondrial Uptake of MKT-077 Can Suppress Medullary Thyroid Carcinoma Cell Survival and

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    Dmytro Starenki

    2015-12-01

    Full Text Available BackgroundMedullary thyroid carcinoma (MTC is a neuroendocrine tumor mainly caused by mutations in the rearranged during transfection (RET proto-oncogene. Not all patients with progressive MTC respond to current therapy inhibiting RET, demanding additional therapeutic strategies. We recently demonstrated that disrupting mitochondrial metabolism using a mitochondria-targeted agent or by depleting a mitochondrial chaperone effectively suppressed human MTC cells in culture and in mouse xenografts by inducing apoptosis and RET downregulation. These observations led us to hypothesize that mitochondria are potential therapeutic targets for MTC. This study further tests this hypothesis using1-ethyl-2-[[3-ethyl-5-(3-methylbenzothiazolin-2-yliden]-4-oxothiazolidin-2-ylidenemethyl] pyridinium chloride (MKT-077, a water-soluble rhodocyanine dye analogue, which can selectively accumulate in mitochondria.MethodsThe effects of MKT-077 on cell proliferation, survival, expression of RET and tumor protein 53 (TP53, and mitochondrial activity were determined in the human MTC lines in culture and in mouse xenografts.ResultsMKT-077 induced cell cycle arrest in TT and MZ-CRC-1. Intriguingly, MKT-077 also induced RET downregulation and strong cell death responses in TT cells, but not in MZ-CRC-1 cells. This discrepancy was mainly due to the difference between the capacities of these cell lines to retain MKT-077 in mitochondria. The cytotoxicity of MKT-077 in TT cells was mainly attributed to oxidative stress while being independent of TP53. MKT-077 also effectively suppressed tumor growth of TT xenografts.ConclusionMKT-077 can suppress cell survival of certain MTC subtypes by accumulating in mitochondria and interfering with mitochondrial activity although it can also suppress cell proliferation via other mechanisms. These results consistently support the hypothesis that mitochondrial targeting has therapeutic potential for MTC.

  5. Early diagnosis of and surgical strategy for adrenal medullary disease in MEN II gene carriers

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    Jansson, S.; Tisell, L.E.; Fjaelling, M.L.; Lindberg, S.; Jacobsson, L.; Zachrisson, B.F.

    1988-01-01

    Sixteen multiple endocrine neoplasia type II (MEN II) gene carriers--12 who had undergone thyroidectomy because of medullary carcinoma of the thyroid and 4 whose thyroid glands had been removed because of C cell hyperplasia--were examined for the presence of pheochromocytomas. No patient had sought medical advice for pheochromocytoma symptoms. Fourteen patients had MEN IIa syndromes, one patient had a MEN IIb and another patient had a mixed syndrome of von Recklinghausen's neurofibromatosis and MEN II. Eight patients had undergone unilateral adrenalectomy for pheochromocytoma 11 +/- 4 years before. The patients underwent clinical examination, determination of the urinary excretion of catecholamines and metabolites, and /sup 131/I-metaiodobenzylguanidine (/sup 131/I-MIBG) and CAT scans. /sup 131/I-MIBG scanning was performed with images 1, 4, and 7 days after the radionuclide injection. In seven of eight patients who had undergone unilateral adrenalectomies, the /sup 131/I-MIBG scans showed accumulation of the radionuclide in the remaining adrenal gland. Bilateral adrenal accumulation of the radionuclide was demonstrated in seven of eight MEN IIa gene carriers who had not undergone adrenalectomy. Five patients, two of whom had undergone adrenalectomy, were found to have unilateral pheochromocytomas less than 2 cm in diameter. Only one of these five patients had an elevated excretion of urinary catecholamines. Between day 4 and day 7 after /sup 131/I-MIBG injection, adrenal glands with pheochromocytomas increased their relative accumulation of the radionuclide significantly more (p less than 0.02) than did adrenal glands without any demonstrable pheochromocytomas. All the pheochromocytomas were viewed by means of CAT scans.

  6. Lymph Node Metastases in Papillary and Medullary Thyroid Carcinoma Are Independent of Intratumoral Lymphatic Vessel Density

    Science.gov (United States)

    Pereira, Filipe; Pereira, Sofia S.; Mesquita, Marta; Morais, Tiago; Costa, Madalena M.; Quelhas, Pedro; Lopes, Carlos; Monteiro, Mariana P.; Leite, Valeriano

    2017-01-01

    Background Blood and lymph vessel invasion are well-recognized markers of tumor aggressiveness, as these are the routes that lead to metastases. Thyroid tumors, depending on the histological variant, tend to have distinctive biological behaviors and use different vascular routes to metastasize, yet the mechanisms underlying the metastatic process are still poorly understood. Objectives The aim of this study was to assess how the lymph vessel density (LVD) in different histological types of thyroid tumors, and in their surrounding tissue, correlate with the presence of lymph node metastases (LNM) and tumor pathological features. Methods Lymph vessels of papillary thyroid carcinomas (PTC), of the classical (CVPTC, n = 50) and follicular variants (FVPTC, n = 18), and medullary thyroid carcinomas (MTC, n = 34) were immunohistochemically stained against antigen D2-40. The stained area was quantified using a computerized morphometric analysis tool and correlated with the tumor pathological characteristics. Results LVD within all analyzed thyroid tumor subtypes was significantly lower than in the surrounding thyroid tissues (p < 0.001). Despite intratumoral LVD being significantly higher in CVPTC than in FVPTC, and peritumoral LVD being significantly higher in MTC than in PTC (p < 0.05), no correlations were found between LVD (either intratumoral or peritumoral) and the presence of lymph node metastasis. Conclusions As no LVD differences were found amongst thyroid tumors with or without LNM, dissemination is more likely to depend on the tumor ability to invade the abundant lymph vessel network of the surrounding thyroid tissue than on the ability of the tumor to promote de novo lymphangiogenesis. PMID:28589086

  7. Aire Expression Is Inherent to Most Medullary Thymic Epithelial Cells during Their Differentiation Program.

    Science.gov (United States)

    Kawano, Hiroshi; Nishijima, Hitoshi; Morimoto, Junko; Hirota, Fumiko; Morita, Ryoko; Mouri, Yasuhiro; Nishioka, Yasuhiko; Matsumoto, Mitsuru

    2015-12-01

    Aire in medullary thymic epithelial cells (mTECs) plays an important role in the establishment of self-tolerance. Because Aire(+) mTECs appear to be a limited subset, they may constitute a unique lineage(s) among mTECs. An alternative possibility is that all mTECs are committed to express Aire in principle, but Aire expression by individual mTECs is conditional. To investigate this issue, we established a novel Aire reporter strain in which endogenous Aire is replaced by the human AIRE-GFP-Flag tag (Aire/hAGF-knockin) fusion gene. The hAGF reporter protein was produced and retained very efficiently within mTECs as authentic Aire nuclear dot protein. Remarkably, snapshot analysis revealed that mTECs expressing hAGF accounted for >95% of mature mTECs, suggesting that Aire expression does not represent a particular mTEC lineage(s). We confirmed this by generating Aire/diphtheria toxin receptor-knockin mice in which long-term ablation of Aire(+) mTECs by diphtheria toxin treatment resulted in the loss of most mature mTECs beyond the proportion of those apparently expressing Aire. These results suggest that Aire expression is inherent to all mTECs but may occur at particular stage(s) and/or cellular states during their differentiation, thus accounting for the broad impact of Aire on the promiscuous gene expression of mTECs. Copyright © 2015 by The American Association of Immunologists, Inc.

  8. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer.

    Science.gov (United States)

    Wells, Samuel A; Gosnell, Jessica E; Gagel, Robert F; Moley, Jeffrey; Pfister, David; Sosa, Julie A; Skinner, Michael; Krebs, Annetta; Vasselli, James; Schlumberger, Martin

    2010-02-10

    PURPOSE There is no effective therapy for patients with distant metastasis of medullary thyroid carcinoma (MTC). Activating mutations in the RET proto-oncogene cause hereditary MTC, which provides a strong therapeutic rationale for targeting RET kinase activity. This open-label, phase II study assessed the efficacy of vandetanib, a selective oral inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, in patients with advanced hereditary MTC. METHODS Patients with unresectable locally advanced or metastatic hereditary MTC received initial treatment with once-daily oral vandetanib 300 mg. The dose was adjusted additionally in some patients on the basis of observed toxicity until disease progression or any other withdrawal criterion was met. The primary assessment was objective tumor response (by RECIST [Response Evaluation Criteria in Solid Tumors]). Results Thirty patients received initial treatment with vandetanib 300 mg/d. On the basis of investigator assessments, 20% of patients (ie, six of 30 patients) experienced a confirmed partial response (median duration of response at data cutoff, 10.2 months). An additional 53% of patients (ie, 16 of 30 patients) experienced stable disease at >/= 24 weeks, which yielded a disease control rate of 73% (ie, 22 of 30 patients). In 24 patients, serum calcitonin levels showed a 50% or greater decrease from baseline that was maintained for at least 4 weeks; 16 patients showed a similar reduction in serum carcinoembryonic antigen levels. The most common adverse events were diarrhea (70%), rash (67%), fatigue (63%), and nausea (63%). CONCLUSION In this study, vandetanib demonstrated durable objective partial responses and disease control with a manageable adverse event profile. These results demonstrate that vandetanib may provide an effective therapeutic option in patients with advanced hereditary MTC, a rare disease for which there has been no effective therapy.

  9. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer.

    Science.gov (United States)

    Robinson, Bruce G; Paz-Ares, Luis; Krebs, Annetta; Vasselli, James; Haddad, Robert

    2010-06-01

    Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinases that also inhibits rearranged during transfection kinase activity. Vandetanib (300 mg/d) has previously demonstrated antitumor activity in patients with advanced hereditary medullary thyroid cancer (MTC). This study investigated the efficacy and safety of 100 mg/d vandetanib in patients with advanced hereditary MTC. Eligible patients with unresectable, measurable, locally advanced, or metastatic hereditary MTC received 100 mg/d vandetanib. Upon disease progression, eligible patients could enter postprogression treatment with 300 mg/d vandetanib until a withdrawal criterion was met. The primary objective was to assess the objective response rate by response evaluation criteria in solid tumors. The study comprised 19 patients (13 males, six females; mean age 45 yr). Confirmed objective partial responses were observed in three patients, yielding an objective response rate of 16% (95% confidence interval 3.4-39.6). Stable disease lasting 24 wk or longer was reported in a further 10 patients (53%); the disease control rate was therefore 68% (95% confidence interval 43.4-87.4). Serum levels of calcitonin and carcinoembryonic antigen showed a sustained 50% or greater decrease from baseline in 16% (three of 19) and 5% (one of 19) of patients, respectively. Adverse events were predominantly grade 1 or 2 and consistent with previous vandetanib monotherapy studies. Vandetanib at a once-daily dose of 100 mg has clinically relevant antitumor activity in patients with locally advanced or metastatic hereditary MTC and an overall acceptable safety profile.

  10. Level of conus medullaris termination in adult population analyzed by kinetic magnetic resonance imaging.

    Science.gov (United States)

    Liu, An; Yang, Kaixiang; Wang, Daling; Li, Changqing; Ren, Zhiwei; Yan, Shigui; Buser, Zorica; Wang, Jeffrey C

    2017-07-01

    To investigate the change of conus medullaris termination (CMT) level in neutral, flexion and extension positions and to analyze the effects of age and gender on the CMT level. The midline sagittal T2-weighted kinetic magnetic resonance imaging (kMRI) study of 585 patients was retrospectively reviewed to identify the level of CMT. All patients were in an upright position. A straight line perpendicular to the long axis of the cord was drawn from the tip of the cord and then subtended to the adjacent vertebra or disk space. The CMT level was labeled in relation to the upper, middle and lower segments of adjacent vertebra or disk space and assigned values from 0 to 12 [0 = upper third of T12 (T12U), and 12 = upper third of L3 (L3U)]. All parameters were collected for neutral, flexion and extension positions. The level of CMT had the highest incidence (17.61%) at L1 lower (L1L) in neutral position, 17.44% at L1 upper (L1U) in flexion, and 16.92% at L1 middle (L1M) in extension with no significant differences among three positions (p > 0.05) in weight-bearing status. Moreover, the level of CMT was not correlated with age (p > 0.05). In terms of gender, the level of CMT was lower in women than in men in neutral position, flexion, and extension (p level of CMT in the neutral position was in accordance with previous cadaveric and supine-position MRI studies, and it did not change with flexion and extension. Women had lower CMT level than men, especially in the older population. This information can be very valuable when performing spinal anesthesia and spinal punctures.

  11. Trypanosoma cruzi Disrupts Thymic Homeostasis by Altering Intrathymic and Systemic Stress-Related Endocrine Circuitries

    Science.gov (United States)

    Lepletier, Ailin; de Carvalho, Vinicius Frias; e Silva, Patricia Machado Rodrigues; Villar, Silvina; Pérez, Ana Rosa; Savino, Wilson; Morrot, Alexandre

    2013-01-01

    We have previously shown that experimental infection caused by Trypanosoma cruzi is associated with changes in the hypothalamus-pituitary-adrenal axis. Increased glucocorticoid (GC) levels are believed to be protective against the effects of acute stress during infection but result in depletion of CD4+CD8+ thymocytes by apoptosis, driving to thymic atrophy. However, very few data are available concerning prolactin (PRL), another stress-related hormone, which seems to be decreased during T. cruzi infection. Considering the immunomodulatory role of PRL upon the effects caused by GC, we investigated if intrathymic cross-talk between GC and PRL receptors (GR and PRLR, respectively) might influence T. cruzi-induced thymic atrophy. Using an acute experimental model, we observed changes in GR/PRLR cross-activation related with the survival of CD4+CD8+ thymocytes during infection. These alterations were closely related with systemic changes, characterized by a stress hormone imbalance, with progressive GC augmentation simultaneously to PRL reduction. The intrathymic hormone circuitry exhibited an inverse modulation that seemed to counteract the GC-related systemic deleterious effects. During infection, adrenalectomy protected the thymus from the increase in apoptosis ratio without changing PRL levels, whereas an additional inhibition of circulating PRL accelerated the thymic atrophy and led to an increase in corticosterone systemic levels. These results demonstrate that the PRL impairment during infection is not caused by the increase of corticosterone levels, but the opposite seems to occur. Accordingly, metoclopramide (MET)-induced enhancement of PRL secretion protected thymic atrophy in acutely infected animals as well as the abnormal export of immature and potentially autoreactive CD4+CD8+ thymocytes to the periphery. In conclusion, our findings clearly show that Trypanosoma cruzi subverts mouse thymus homeostasis by altering intrathymic and systemic stress

  12. Interdisciplinary approaches of transcranial magnetic stimulation applied to a respiratory neuronal circuitry model.

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    Stéphane Vinit

    Full Text Available Respiratory related diseases associated with the neuronal control of breathing represent life-threatening issues and to date, no effective therapeutics are available to enhance the impaired function. The aim of this study was to determine whether a preclinical respiratory model could be used for further studies to develop a non-invasive therapeutic tool applied to rat diaphragmatic neuronal circuitry. Transcranial magnetic stimulation (TMS was performed on adult male Sprague-Dawley rats using a human figure-of-eight coil. The largest diaphragmatic motor evoked potentials (MEPdia were recorded when the center of the coil was positioned 6 mm caudal from Bregma, involving a stimulation of respiratory supraspinal pathways. Magnetic shielding of the coil with mu metal reduced magnetic field intensities and improved focality with increased motor threshold and lower amplitude recruitment curve. Moreover, transynaptic neuroanatomical tracing with pseudorabies virus (applied to the diaphragm suggest that connections exist between the motor cortex, the periaqueductal grey cell regions, several brainstem neurons and spinal phrenic motoneurons (distributed in the C3-4 spinal cord. These results reveal the anatomical substrate through which supraspinal stimulation can convey descending action potential volleys to the spinal motoneurons (directly or indirectly. We conclude that MEPdia following a single pulse of TMS can be successfully recorded in the rat and may be used in the assessment of respiratory supraspinal plasticity. Supraspinal non-invasive stimulations aimed to neuromodulate respiratory circuitry will enable new avenues of research into neuroplasticity and the development of therapies for respiratory dysfunction associated with neural injury and disease (e.g. spinal cord injury, amyotrophic lateral sclerosis.

  13. Neuroanatomical circuitry associated with exploratory eye movement in schizophrenia: a voxel-based morphometric study.

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    Linlin Qiu

    Full Text Available Schizophrenic patients present abnormalities in a variety of eye movement tasks. Exploratory eye movement (EEM dysfunction appears to be particularly specific to schizophrenia. However, the underlying mechanisms of EEM dysfunction in schizophrenia are not clearly understood. To assess the potential neuroanatomical substrates of EEM, we recorded EEM performance and conducted a voxel-based morphometric analysis of gray matter in 33 schizophrenic patients and 29 well matched healthy controls. In schizophrenic patients, decreased responsive search score (RSS and widespread gray matter density (GMD reductions were observed. Moreover, the RSS was positively correlated with GMD in distributed brain regions in schizophrenic patients. Furthermore, in schizophrenic patients, some brain regions with neuroanatomical deficits overlapped with some ones associated with RSS. These brain regions constituted an occipito-tempro-frontal circuitry involved in visual information processing and eye movement control, including the left calcarine cortex [Brodmann area (BA 17], the left cuneus (BA 18, the left superior occipital cortex (BA 18/19, the left superior frontal gyrus (BA 6, the left cerebellum, the right lingual cortex (BA 17/18, the right middle occipital cortex (BA19, the right inferior temporal cortex (BA 37, the right dorsolateral prefrontal cortex (BA 46 and bilateral precentral gyri (BA 6 extending to the frontal eye fields (FEF, BA 8. To our knowledge, we firstly reported empirical evidence that gray matter loss in the occipito-tempro-frontal neuroanatomical circuitry of visual processing system was associated with EEM performance in schizophrenia, which may be helpful for the future effort to reveal the underlying neural mechanisms for EEM disturbances in schizophrenia.

  14. An alternative pulse height correction method for pole zero cancellation circuitry

    International Nuclear Information System (INIS)

    Seino, T.; Takahashi, I.; Ishitsu, T.; Ueno, Y.; Kobashi, K.

    2012-01-01

    CdTe diode radiation detectors have a problem called the “polarization effect”, which causes CdTe performance to degrade with time. The pulsed bias voltage shutdown technique, in which a bias voltage is turned off and on quickly to recombine the accumulated charges, is used to suppress the effect. When this technique is used with a charge sensitive amplifier equipped with a pole zero cancellation (PZC) circuit, an extra dead time is observed. After a 40 ms shutdown, we have to wait for 130 ms (net 170 ms dead time) due to the saturation of the amplifier when equipped with a PZC stage while only 10 ms (net 50 ms dead time) is necessary without a PZC. However, PZC is essential to reduce the degradation of the energy resolution in high count rate conditions. Therefore, an alternative technique to avoid degrading the energy resolution in high count rate conditions without a PZC circuit was investigated. A present pulse height was corrected by using both the pulse heights and the elapsed times from the previous events. As a result, in a readout circuit having no PZC circuitry, an energy resolution of 4.7% for a 122 keV photo peak at a count rate of 20 kcps was obtained when using the correction, and a 9.1% one was obtained without the correction. In addition, an energy resolution of 2.7% for a 662 keV photo peak at a count rate of 21 kcps was obtained when using the correction, and a 5.3% one was obtained without the correction. It is shown that this new correction method has almost the same effect as PZC circuitry.

  15. Trigeminal-Rostral Ventromedial Medulla circuitry is involved in orofacial hyperalgesia contralateral to tissue injury

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    Chai Bryan

    2012-10-01

    Full Text Available Abstract Background Our previous studies have shown that complete Freund’s adjuvant (CFA-induced masseter inflammation and microinjection of the pro-inflammatory cytokine interleukin-1β (IL-1β into the subnucleus interpolaris/subnucleus caudalis transition zone of the spinal trigeminal nucleus (Vi/Vc can induce contralateral orofacial hyperalgesia in rat models. We have also shown that contralateral hyperalgesia is attenuated with a lesion of the rostral ventromedial medulla (RVM, a critical site of descending pain modulation. Here we investigated the involvement of the RVM-Vi/Vc circuitry in mediating contralateral orofacial hyperalgesia after an injection of CFA into the masseter muscle. Results Microinjection of the IL-1 receptor antagonist (5 nmol, n=6 into the ipsilateral Vi/Vc attenuated the CFA-induced contralateral hyperalgesia but not the ipsilateral hyperalgesia. Intra-RVM post-treatment injection of the NK1 receptor antagonists, RP67580 (0.5-11.4 nmol and L-733,060 (0.5-11.4 nmol, attenuated CFA-induced bilateral hyperalgesia and IL-1β induced bilateral hyperalgesia. Serotonin depletion in RVM neurons prior to intra-masseter CFA injection prevented the development of contralateral hyperalgesia 1–3 days after CFA injection. Inhibition of 5-HT3 receptors in the contralateral Vi/Vc with direct microinjection of the select 5-HT3 receptor antagonist, Y-25130 (2.6-12.9 nmol, attenuated CFA-induced contralateral hyperalgesia. Lesions to the ipsilateral Vc prevented the development of ipsilateral hyperalgesia but did not prevent the development of contralateral hyperalgesia. Conclusions These results suggest that the development of CFA-induced contralateral orofacial hyperalgesia is mediated through descending facilitatory mechanisms of the RVM-Vi/Vc circuitry.

  16. Regulation of body fat mass by the gut microbiota

    DEFF Research Database (Denmark)

    Schéle, Erik; Grahnemo, Louise; Anesten, Fredrik

    2016-01-01

    New insight suggests gut microbiota as a component in energy balance. However, the underlying mechanisms by which gut microbiota can impact metabolic regulation is unclear. A recent study from our lab shows, for the first time, a link between gut microbiota and energy balance circuitries in the h......New insight suggests gut microbiota as a component in energy balance. However, the underlying mechanisms by which gut microbiota can impact metabolic regulation is unclear. A recent study from our lab shows, for the first time, a link between gut microbiota and energy balance circuitries...

  17. Neuron class-specific requirements for Fragile X Mental Retardation Protein in critical period development of calcium signaling in learning and memory circuitry.

    Science.gov (United States)

    Doll, Caleb A; Broadie, Kendal

    2016-05-01

    Neural circuit optimization occurs through sensory activity-dependent mechanisms that refine synaptic connectivity and information processing during early-use developmental critical periods. Fragile X Mental Retardation Protein (FMRP), the gene product lost in Fragile X syndrome (FXS), acts as an activity sensor during critical period development, both as an RNA-binding translation regulator and channel-binding excitability regulator. Here, we employ a Drosophila FXS disease model to assay calcium signaling dynamics with a targeted transgenic GCaMP reporter during critical period development of the mushroom body (MB) learning/memory circuit. We find FMRP regulates depolarization-induced calcium signaling in a neuron-specific manner within this circuit, suppressing activity-dependent calcium transients in excitatory cholinergic MB input projection neurons and enhancing calcium signals in inhibitory GABAergic MB output neurons. Both changes are restricted to the developmental critical period and rectified at maturity. Importantly, conditional genetic (dfmr1) rescue of null mutants during the critical period corrects calcium signaling defects in both neuron classes, indicating a temporally restricted FMRP requirement. Likewise, conditional dfmr1 knockdown (RNAi) during the critical period replicates constitutive null mutant defects in both neuron classes, confirming cell-autonomous requirements for FMRP in developmental regulation of calcium signaling dynamics. Optogenetic stimulation during the critical period enhances depolarization-induced calcium signaling in both neuron classes, but this developmental change is eliminated in dfmr1 null mutants, indicating the activity-dependent regulation requires FMRP. These results show FMRP shapes neuron class-specific calcium signaling in excitatory vs. inhibitory neurons in developing learning/memory circuitry, and that FMRP mediates activity-dependent regulation of calcium signaling specifically during the early

  18. Three atypical manifestations of granulomatosis with polyangiitis: lateral medullary syndrome, anterior cheek mass and melting scleritis of eye.

    Science.gov (United States)

    Shenavandeh, Saeedeh; Petramfar, Peyman

    2017-01-01

    Granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis) is a vasculitis with various organ involvement. There have been a few cases of CNS stroke and rare cases of lateral medullary infarction (LMI) as a manifestation of GPA. Also there have been reports of sinuses, nose and laryngeal masses mistakenly referred as carcinomas and subsequently GPA was diagnosed in their pathological reports. Another severe fulminant manifestation can be necrotizing scleritis leading to perforation of sclera. Therefore, here we present some rare and fulminant manifestations of GPA in 3 separate cases for further emphasis of the unusual manifestations of GPA that should always be kept in mind.

  19. Acute coronary syndrome: a rare case of multiple endocrine neoplasia syndromes with pheochromocytoma and medullary thyroid carcinoma.

    Science.gov (United States)

    Maloberti, Alessadro; Meani, Paolo; Pirola, Roberto; Varrenti, Marisa; Boniardi, Marco; De Biase, Anna Maria; Vallerio, Paola; Bonacina, Edgardo; Mancia, Giuseppe; Loli, Paola; Giannattasio, Cristina

    2015-09-01

    Pheochromocytoma is a tumor arising from neuroectodermal chromaffin tissues in the adrenal gland or extra-adrenal paraganglia (paragangliomas). The prevalence of the tumor is 0.1%-0.6% in the hypertensive population, of which 10%-20% are malignant. Pheochromocytoma produces, stores, and secretes catecholamines, as well as leads to hypertensive crisis, arrhythmia, angina, and acute myocardial infarction without coronary artery diseases. We report a case of acute coronary syndrome (ACS) with a final diagnosis of multiple endocrine neoplasia with pheochromocytoma and medullary thyroid carcinoma (MTC).

  20. CHARACTERIZATION OF OZONE EMISSIONS FROM AIR CLEANERS EQUIPPED WITH OZONE GENERATORS AND SENSOR AND FEEDBACK CONTROL CIRCUITRY

    Science.gov (United States)

    The paper give results of a characterization of ozone emissions from air cleaners equipped with ozone generators and sensor and feedback control circuitry. Ozone emission rates of several consumer appliances, marketed as indoor air treatment or air purification systems, were det...

  1. Hematopoiesis stimulation test by interleukin 1α gene transfer in the Cynomolgus macaque: application to secondary medullary aplasia from an accidental irradiation

    International Nuclear Information System (INIS)

    De Revel, Th.

    2002-12-01

    After a description of the context of medullary aplasia (haematological radiobiology, radiation acute syndrome, therapeutic care), and an overview of knowledge about the interleukin-1 and medullary stroma cells, this research thesis aims at investigating therapeutic alternatives for radio-accidental aplasia. More precisely, it aims at defining means to get cytokines which are efficient for haematopoiesis. Interleukin-1 is chosen for its properties and tests are performed on a macaque with two approaches for gene transfer: an ex vivo transfer by retroviral vector enabling an integration in the target cell genome, and an in situ transfer by adeno-viral vector directly applied in the animal osseous medulla

  2. Enhanced antitumor activity of combined pretargeted radioimmunotherapy and paclitaxel in medullary thyroid cancer xenograft.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Saï-Maurel, Catherine; Campion, Loïc; Faivre-Chauvet, Alain; Mirallié, Eric; Chérel, Michel; Supiot, Stéphane; Barbet, Jacques; Chatal, Jean-François; Thédrez, Philippe

    2002-02-01

    A significant antitumor effect associated with moderate toxicity was obtained previously with anticarcinoembryonic antigen x antidiethylene-triaminepentaacetic acid (DTPA)-indium F6-734 bispecific antibody and iodine-131-labeled DTPA-indium bivalent hapten in an animal model of medullary thyroid cancer (MTC). The purpose of this study was to determine whether the cytotoxic agents doxorubicin and paclitaxel, also known as radiosensitizers, improve efficacy of pretargeted radioimmunotherapy (RIT) in experimental MTC. Nude mice bearing TT MTC xenograft were treated with F6-734 and iodine-131-labeled DTPA-indium bivalent hapten injected 48 h apart with or without doxorubicin or paclitaxel. The maximum tolerated dose (MTD) of RIT was 92.5 MBq (as determined previously) and that of doxorubicin and paclitaxel 200 and 1000 micrograms, respectively. A control group received no treatment. Animal weight, hematotoxicity, tumor volume, and serum calcitonin were monitored for 5 months. Tumor growth inhibition induced by drugs alone, RIT alone, or combined therapy was characterized by measuring relative tumor volume 20, 40, and 60 days after treatment to detect additivity or synergism. Mean tumor volume doubling time (MTVDT) was 13 +/- 4 days in the control group, 15 +/- 8 days in the group treated with the MTD of doxorubicin, and 32 +/- 13 days in the group treated with the MTD of paclitaxel. After RIT alone at 92.5 MBq, MTVDT was 86 +/- 22 days. After RIT at 74 MBq (80% of MTD), MTVDT was 56 +/- 10 days. MTVDT was not significantly different from this value after RIT plus doxorubicin, 60 +/- 16 days (65 and 100% of the respective single-agent MTDs). Combination of RIT with paclitaxel (65 and 100% of the respective single-agent MTDs) prolonged the suppression of tumor growth. One complete response was observed, and MTVDT was 114 +/- 44 days. This value was significantly longer than the value obtained with RIT alone at 74 MBq (P < 0.05) or with RIT combined with doxorubicin (P

  3. Somatostatin in medullary thyroid cancer. In vitro and in vivo studies.

    Science.gov (United States)

    Pacini, F; Elisei, R; Anelli, S; Basolo, F; Cola, A; Pinchera, A

    1989-03-15

    The authors evaluated the presence of somatostatin (SRIF) in the plasma and in the tumor tissue of a total of 22 patients with medullary thyroid cancer (MTC) and studied the effect of exogenous SRIF administration on basal and pentagastrin (PG)-stimulated plasma calcitonin (CT) and carcinoembryonic antigen (CEA) levels. Mean plasma SRIF concentrations were significantly higher than those found in normal controls, with five of 15 patients having plasma SRIF levels above the mean + 2 SD of normal controls. High immunoreactive SRIF concentrations were found in the extract of three tumor tissues but not in one follicular thyroid cancer or in one toxic diffuse goiter. By immunoperoxidase staining seven of 11 (63.6%) primary MTC and five of 13 (38.5%) metastases expressed SRIF antigen in a low number of cells and with a weak degree of staining. As expected, CT was expressed in almost 100% of the cases with positivity in most of the cells and strong degree of staining. Patients with positive SRIF staining in the primary tumor had longer survival than SRIF negative patients. Infusion of synthetic SRIF (11 micrograms/minute/45 minutes) produced a significant reduction of plasma CT (but not CEA) levels in 12 of the 15 patients submitted to this test. Maximal percent decrease of plasma CT ranged from 10.8% to 72.7% of the basal value and was usually observed between 30 and 45 minutes from the beginning of the infusion. When infused together with the injection of PG, SRIF was able to significantly (P less than 0.05) inhibit the PG-induced CT release in five of six patients tested. These results demonstrate the following: SRIF is present in a few cells of many primary MTC and less frequently in their metastases; tentatively, the expression of SRIF antigen in the tumor seems to be associated with longer survival; increased SRIF concentrations are found in the plasma of some patients with metastatic involvement; and treatment with exogenous SRIF reduces the basal and PG

  4. [Centro-medullary nailing in the complex fractures of the upper end of the humerus: preliminary results in 6 cases].

    Science.gov (United States)

    Jamal, Louaste; Cherrad, Taoufik; Bousbaa, Hicham; Wahidi, Mohammed; Amhajji, Larbi; Rachid, Khalid

    2016-01-01

    Antegrade intramedullary nailing has become the gold standard to treat two-, three-, and four-part cephalo-tuberosity fractures. We report a retrospective study of 6 patients who have undergone centro-medullary nailing since January 2012. Mean follow-up was 12 months; the average age was 57 years. Clinical evaluation was based on gross and weighted Constant and Murley score, based on the age and sex, compared to the "normal" body surface area. Radiological assessment allowed us to evaluate bone healing, the occurrence of osteonecrosis of femoral head or of post-traumatic arthrosis. Radiological examination focused even on the state of the tuberosities and on the existence or not of osteolysis of the greater tubercle of the humerus. It was also used to identify the criteria for good reduction, namely cephalic cap angle and diaphyseal axis (αF) in face views. All patients underwent the same surgical procedure. Constant and Murley score for all patients was 64.13 points. Weighted score based on age and sex was 73%. Joint mobility was estimated at an average of 116° for all patients in anterior elevation, 99.9° in lateral elevation, and 42° in external rotation. Average αF angle was 42°. All patients met criteria for good reduction, namely αF. Centro-medullary nailing allows simple and cost-effective bone synthesis with very promising functional results. Comminuted fractures and osteoporosis may limit these indications.

  5. BIOPSY PROVEN MEDULLARY SPONGE KIDNEY: Clinical findings, histopathology, and role of osteogenesis in stone and plaque formation

    Science.gov (United States)

    Evan, Andrew P.; Worcester, Elaine M.; Williams, James C.; Sommer, Andre J.; Lingeman, James E.; Phillips, Carrie L.; Coe, Fredric L.

    2015-01-01

    Medullary sponge kidney (MSK) is associated with recurrent stone formation, but the clinical phenotype is unclear because patients with other disorders may be incorrectly labeled MSK. We studied 12 patients with histologic findings pathognomonic of MSK. All patients had an endoscopically recognizable pattern of papillary malformation, which may be segmental or diffuse. Affected papillae are enlarged and billowy, due to markedly enlarged inner medullary collecting ducts (IMCD), which contain small, mobile ductal stones. Patients had frequent dilation of Bellini ducts, with occasional mineral plugs. Stones may form over white (Randall’s) plaque, but most renal pelvic stones are not attached, and have a similar morphology as ductal stones, which are a mixture of calcium oxalate and apatite. Patients had no abnormalities of urinary acidification or acid excretion; the most frequent metabolic abnormality was idiopathic hypercalciuria. Although both Runx2 and Osterix are expressed in papillae of MSK patients, no mineral deposition was seen at the sites of gene expression, arguing against a role of these genes in this process. Similar studies in idiopathic calcium stone formers showed no expression of these genes at sites of Randall’s plaque. The most likely mechanism for stone formation in MSK appears to be crystallization due to urinary stasis in dilated IMCD with subsequent passage of ductal stones into the renal pelvis where they may serve as nuclei for stone formation. PMID:25615853

  6. [Role of centro-medullary nailing in fractures of the distal quarter of the leg: about 30 cases].

    Science.gov (United States)

    Margad, Omar; Boukhris, Jalal; Sallahi, Hicham; Azriouil, Ouahb; Daoudi, Mohamed; Koulali, Khalid

    2017-01-01

    The fractures of the distal quarter of the leg are characterized by fracture line located at the level of the lower quarter of the tibia, according to Gerard and Evrard definition [1]. They are serious and pose problems for consolidation, immobilization and stability. We here describe our experience in the Department of Orthopaedics and Traumatology at the Avicenne Military Hospital, Marrakech. We report 30 cases of closed fractures of the lower quarter of the leg treated with centro-medullary nailing over a period of 10 years (January 2001-December 2010). Locked nailing was performed in 80% of cases and simple nailing was performed in the other cases. The average age of patients was 36 years. There was a clear male predominance (27 men, 3 women). The average time for consolidation was 17 weeks and functional outcomes were satisfactory. A single case of infection occurred 6 months after surgery (3.3%) and no other complication was reported. Malunion was detected in 30% of patients. Our epidemiological data and results were almost identical to those in the literature. Angular results were significantly lower than those obtained with the series of plates. By contrast, data on infections called for caution and some nails produced excellent angular results when nail fixation was stable. In the light of these results, codified indications for locked centro-medullary nailing should be extended to the fractures of the lower quarter of the leg, provided that stable fixation using double screw distal locking and primary osteosynthesis of distal fibula fractures are performed.

  7. Micromachined Silicon Stimulating Probes with CMOS Circuitry for Use in the Central Nervous System

    Science.gov (United States)

    Tanghe, Steven John

    1992-01-01

    Electrical stimulation in the central nervous system is a valuable technique for studying neural systems and is a key element in the development of prostheses for deafness and other disorders. This thesis presents a family of multielectrode probe structures, fulfilling the need for chronic multipoint stimulation tools essential for interfacing to the highly complex neural networks in the brain. These probes are batch-fabricated on silicon wafers, employing photoengraving techniques to precisely control the electrode site and array geometries and to allow the integration of on-chip CMOS circuitry for signal multiplexing and stimulus current generation. Silicon micromachining is used to define the probe shapes, which have typical shank dimensions of 3 mm in length by 100 mu m in width by 15 μm in thickness. Each shank supports up to eight planar iridium oxide electrode sites capable of delivering charge densities in excess of 3 mC/cm^2 during current pulse stimulation. Three active probe circuits have been designed with varied complexity and capability. All three can deliver biphasic stimulus currents through 16 sites using only 5 external leads, and they are all compatible with the same external control system. The most complex design interprets site addresses and stimulus current amplitudes from 16-bit words shifted into the probe at 4 MHz. Sixteen on-chip, biphasic, 8-bit digital-to-analog converters deliver analog stimulus currents in the range of +/- 254 muA to any combination of electrode sites. These DACs exhibit full-scale internal linearity to better than +/-1/2 LSB and can be calibrated by varying the positive power supply voltage. The entire probe circuit dissipates only 80 muW from +/-5 V supplies when not delivering stimulus currents, it includes several safety features, and is testable from the input pads. Test results from the fabricated circuits indicate that they all function properly at clocking frequencies as high as 10 MHz, meeting or exceeding

  8. Intranasal insulin modulates intrinsic reward and prefrontal circuitry of the human brain in lean women.

    Science.gov (United States)

    Kullmann, Stephanie; Frank, Sabine; Heni, Martin; Ketterer, Caroline; Veit, Ralf; Häring, Hans-Ulrich; Fritsche, Andreas; Preissl, Hubert

    2013-01-01

    There is accumulating evidence that food consumption is controlled by a wide range of brain circuits outside of the homeostatic system. Activation in these brain circuits may override the homeostatic system and also contribute to the enormous increase of obesity. However, little is known about the influence of hormonal signals on the brain's non-homeostatic system. Thus, selective insulin action in the brain was investigated by using intranasal application. We performed 'resting-state' functional magnetic resonance imaging in 17 healthy lean female subjects to assess intrinsic brain activity by fractional amplitude of low-frequency fluctuations (fALFF) before, 30 and 90 min after application of intranasal insulin. Here, we showed that insulin modulates intrinsic brain activity in the hypothalamus and orbitofrontal cortex. Furthermore, we could show that the prefrontal and anterior cingulate cortex response to insulin is associated with body mass index. This demonstrates that hormonal signals as insulin may reduce food intake by modifying the reward and prefrontal circuitry of the human brain, thereby potentially decreasing the rewarding properties of food. Due to the alarming increase in obesity worldwide, it is of great importance to identify neural mechanisms of interaction between the homeostatic and non-homeostatic system to generate new targets for obesity therapy. Copyright © 2012 S. Karger AG, Basel.

  9. The neural circuitry of visual artistic production and appreciation: A proposition

    Science.gov (United States)

    Chakravarty, Ambar

    2012-01-01

    The nondominant inferior parietal lobule is probably a major “store house” of artistic creativity. The ventromedial prefrontal lobe (VMPFL) is supposed to be involved in creative cognition and the dorsolateral prefrontal lobe (DLPFL) in creative output. The conceptual ventral and dorsal visual system pathways likely represent the inferior and superior longitudinal fasciculi. During artistic production, conceptualization is conceived in the VMPFL and the executive part is operated through the DLFPL. The latter transfers the concept to the visual brain through the superior longitudinal fasciculus (SLF), relaying on its path to the parietal cortex. The conceptualization at VMPFL is influenced by activity from the anterior temporal lobe through the uncinate fasciculus and limbic system pathways. The final visual image formed in the visual brain is subsequently transferred back to the DLPFL through the SLF and then handed over to the motor cortex for execution. During art appreciation, the image at the visual brain is transferred to the frontal lobe through the SLF and there it is matched with emotional and memory inputs from the anterior temporal lobe transmitted through the uncinate fasiculus. Beauty is perceived at the VMPFL and transferred through the uncinate fasciculus to the hippocampo–amygdaloid complex in the anterior temporal lobe. The limbic system (Papez circuit) is activated and emotion of appreciation is evoked. It is postulated that in practice the entire circuitry is activated simultaneously. PMID:22566716

  10. Super-Resolution Mapping of Neuronal Circuitry With an Index-Optimized Clearing Agent

    Directory of Open Access Journals (Sweden)

    Meng-Tsen Ke

    2016-03-01

    Full Text Available Super-resolution imaging deep inside tissues has been challenging, as it is extremely sensitive to light scattering and spherical aberrations. Here, we report an optimized optical clearing agent for high-resolution fluorescence imaging (SeeDB2. SeeDB2 matches the refractive indices of fixed tissues to that of immersion oil (1.518, thus minimizing both light scattering and spherical aberrations. During the clearing process, fine morphology and fluorescent proteins were highly preserved. SeeDB2 enabled super-resolution microscopy of various tissue samples up to a depth of >100 μm, an order of magnitude deeper than previously possible under standard mounting conditions. Using this approach, we demonstrate accumulation of inhibitory synapses on spine heads in NMDA-receptor-deficient neurons. In the fly medulla, we found unexpected heterogeneity in axon bouton orientations among Mi1 neurons, a part of the motion detection circuitry. Thus, volumetric super-resolution microscopy of cleared tissues is a powerful strategy in connectomic studies at synaptic levels.

  11. The emotional power of poetry: neural circuitry, psychophysiology and compositional principles.

    Science.gov (United States)

    Wassiliwizky, Eugen; Koelsch, Stefan; Wagner, Valentin; Jacobsen, Thomas; Menninghaus, Winfried

    2017-08-01

    It is a common experience-and well established experimentally-that music can engage us emotionally in a compelling manner. The mechanisms underlying these experiences are receiving increasing scrutiny. However, the extent to which other domains of aesthetic experience can similarly elicit strong emotions is unknown. Using psychophysiology, neuroimaging and behavioral responses, we show that recited poetry can act as a powerful stimulus for eliciting peak emotional responses, including chills and objectively measurable goosebumps that engage the primary reward circuitry. Importantly, while these responses to poetry are largely analogous to those found for music, their neural underpinnings show important differences, specifically with regard to the crucial role of the nucleus accumbens. We also go beyond replicating previous music-related studies by showing that peak aesthetic pleasure can co-occur with physiological markers of negative affect. Finally, the distribution of chills across the trajectory of poems provides insight into compositional principles of poetry. © The Author (2017). Published by Oxford University Press.

  12. Assessing Ink Transfer Performance of Gravure-Offset Fine-Line Circuitry Printing

    Science.gov (United States)

    Cheng, Hsien-Chie; Chen, You-Wei; Chen, Wen-Hwa; Lu, Su-Tsai; Lin, Shih-Ming

    2018-03-01

    In this study, the printing mechanism and performance of gravure-offset fine-line circuitry printing technology are investigated in terms of key printing parameters through experimental and theoretical analyses. First, the contact angles of the ink deposited on different substrates, blankets, and gravure metal plates are experimentally determined; moreover, their temperature and solvent content dependences are analyzed. Next, the ink solvent absorption and evaporation behaviors of the blankets at different temperatures, times, and numbers of printing repetitions are characterized by conducting experiments. In addition, while printing repeatedly, the surface characteristics of the blankets, such as the contact angle, vary with the amount of absorbed ink solvent, further affecting the ink transfer performance (ratio) and printing quality. Accordingly, the surface effect of the blanket due to ink solvent absorption on the ink contact angle is analyzed. Furthermore, the amount of ink transferred from the gravure plate to the blanket in the "off process" and from the blanket to the substrate in the "set process" is evaluated by conducting a simplified plate-to-plate experiment. The influences of loading rate (printing velocity), temperature, and solvent content on the ink transfer performance are addressed. Finally, the ink transfer mechanism is theoretically analyzed for different solvent contents using Surface Evolver. The calculation results are compared with those of the experiment.

  13. Tapping into rhythm generation circuitry in humans during simulated weightlessness conditions

    Science.gov (United States)

    Solopova, Irina A.; Selionov, Victor A.; Sylos-Labini, Francesca; Gurfinkel, Victor S.; Lacquaniti, Francesco; Ivanenko, Yuri P.

    2015-01-01

    An ability to produce rhythmic activity is ubiquitous for locomotor pattern generation and modulation. The role that the rhythmogenesis capacity of the spinal cord plays in injured populations has become an area of interest and systematic investigation among researchers in recent years, despite its importance being long recognized by neurophysiologists and clinicians. Given that each individual interneuron, as a rule, receives a broad convergence of various supraspinal and sensory inputs and may contribute to a vast repertoire of motor actions, the importance of assessing the functional state of the spinal locomotor circuits becomes increasingly evident. Air-stepping can be used as a unique and important model for investigating human rhythmogenesis since its manifestation is largely facilitated by a reduction of external resistance. This article aims to provide a review on current issues related to the “locomotor” state and interactions between spinal and supraspinal influences on the central pattern generator (CPG) circuitry in humans, which may be important for developing gait rehabilitation strategies in individuals with spinal cord and brain injuries. PMID:25741250

  14. The Impact of Ecological Niche on Adaptive Flexibility of Sensory Circuitry

    Directory of Open Access Journals (Sweden)

    Sarah L. Pallas

    2017-06-01

    Full Text Available Evolution and development are interdependent, particularly with regard to the construction of the nervous system and its position as the machine that produces behavior. On the one hand, the processes directing development and plasticity of the brain provide avenues through which natural selection can sculpt neural cell fate and connectivity, and on the other hand, they are themselves subject to selection pressure. For example, mutations that produce heritable perturbations in neuronal birth and death rates, transcription factor expression, or availability of axon guidance factors within sensory pathways can markedly affect the development of form and thus the function of stimulus decoding circuitry. This evolvability of flexible circuits makes them more adaptable to environmental variation. Although there is general agreement on this point, whether the sensitivity of circuits to environmental influence and the mechanisms underlying development and plasticity of sensory pathways are similar across species from different ecological niches has received almost no attention. Neural circuits are generally more sensitive to environmental influences during an early critical period, but not all niches afford the same access to stimuli in early life. Furthermore, depending on predictability of the habitat and ecological niche, sensory coding circuits might be more susceptible to sensory experience in some species than in others. Despite decades of work on understanding the mechanisms underlying critical period plasticity, the importance of ecological niche in visual pathway development has received little attention. Here, I will explore the relationship between critical period plasticity and ecological niche in mammalian sensory pathways.

  15. Taste Reward Circuitry Related Brain Structures Characterize Ill and Recovered Anorexia Nervosa and Bulimia Nervosa

    Science.gov (United States)

    Frank, Guido K.; Shott, Megan E.; Hagman, Jennifer O.; Mittal, Vijay A.

    2013-01-01

    Objective The pathophysiology of the eating disorder anorexia nervosa remains obscure, but structural brain alterations could be functionally important biomarkers. Here we assessed taste pleasantness and reward sensitivity in relation to brain structure, which might be related to food avoidance commonly seen in eating disorders. Method We used structural magnetic resonance brain imaging to study gray and white matter volumes in individuals with restricting type currently ill (n = 19) or recovered-anorexia nervosa (n = 24), bulimia nervosa (n= 19) and healthy control women (n=24). Results All eating disorder groups showed increased gray matter volume of the medial orbitofrontal cortex (gyrus rectus). Manually tracing confirmed larger gyrus rectus volume, and predicted taste pleasantness across all groups. The analyses also indicated other morphological differences between diagnostic categories: Ill and recovered-anorexia nervosa had increased right, while bulimia nervosa had increased left antero-ventral insula gray matter volumes compared to controls. Furthermore, dorsal striatum volumes were reduced in recovered-anorexia and bulimia nervosa, and predicted sensitivity to reward in the eating disorder groups. The eating disorder groups also showed reduced white matter in right temporal and parietal areas when compared to healthy controls. Notably, the results held when controlling for a range of covariates (e.g., age, depression, anxiety, medications). Conclusion Brain structure in medial orbitofrontal cortex, insula and striatum is altered in eating disorders and suggests altered brain circuitry that has been associated with taste pleasantness and reward value. PMID:23680873

  16. Contribution of olivofloccular circuitry developmental defects to atypical gaze in autism

    Science.gov (United States)

    Wegiel, Jerzy; Kuchna, Izabela; Nowicki, Krzysztof; Imaki, Humi; Wegiel, Jarek; Ma, Shuang Yong; Azmitia, Efrain C.; Banerjee, Probal; Flory, Michael; Cohen, Ira L.; London, Eric; Brown, W. Ted; Hare, Carolyn Komich; Wisniewski, Thomas

    2014-01-01

    Individuals with autism demonstrate atypical gaze, impairments in smooth pursuit, altered movement perception and deficits in facial perception. The olivofloccular neuronal circuit is a major contributor to eye movement control. This study of the cerebellum in 12 autistic and 10 control subjects revealed dysplastic changes in the flocculus of eight autistic (67%) and two control (20%) subjects. Defects of the oculomotor system, including avoidance of eye contact and poor or no eye contact, were reported in 88% of autistic subjects with postmortem-detected floccular dysplasia. Focal disorganization of the flocculus cytoarchitecture with deficit, altered morphology, and spatial disorientation of Purkinje cells (PCs); deficit and abnormalities of granule, basket, stellate and unipolar brush cells; and structural defects and abnormal orientation of Bergmann glia are indicators of profound disruption of flocculus circuitry in a dysplastic area. The average volume of PCs was 26% less in the dysplastic region than in the unaffected region of the flocculus (p<0.01) in autistic subjects. Moreover, the average volume of PCs in the entire cerebellum was 25% less in the autistic subjects than in the control subjects (p<0.001). Findings from this study and a parallel study of the inferior olive (IO) suggest that focal floccular dysplasia combined with IO neurons and PC developmental defects may contribute to oculomotor system dysfunction and atypical gaze in autistic subjects. PMID:23558308

  17. Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors.

    Science.gov (United States)

    Wei, Hongen; Chadman, Kathryn K; McCloskey, Daniel P; Sheikh, Ashfaq M; Malik, Mazhar; Brown, W Ted; Li, Xiaohong

    2012-06-01

    Abnormal immune responses have been reported to be associated with autism. A number of studies showed that cytokines were increased in the blood, brain, and cerebrospinal fluid of autistic subjects. Elevated IL-6 in autistic brain has been a consistent finding. However, the mechanisms by which IL-6 may be involved in the pathogenesis of autism are not well understood. Here we show that mice with elevated IL-6 in the brain display many autistic features, including impaired cognitive abilities, deficits in learning, abnormal anxiety traits and habituations, as well as decreased social interactions. IL-6 elevation caused alterations in excitatory and inhibitory synaptic formations and disrupted the balance of excitatory/inhibitory synaptic transmissions. IL-6 elevation also resulted in an abnormal change in the shape, length and distributing pattern of dendritic spines. These findings suggest that IL-6 elevation in the brain could mediate autistic-like behaviors, possibly through the imbalances of neural circuitry and impairments of synaptic plasticity. Published by Elsevier B.V.

  18. Gastric Medullary Carcinoma with Sporadic Mismatch Repair Deficiency and a TP53 R273C Mutation: An Unusual Case with Wild-Type BRAF

    Directory of Open Access Journals (Sweden)

    Brett M. Lowenthal

    2017-01-01

    Full Text Available Medullary carcinoma has long been recognized as a subtype of colorectal cancer associated with microsatellite instability and Lynch syndrome. Gastric medullary carcinoma is a very rare neoplasm. We report a 67-year-old male who presented with a solitary gastric mass. Total gastrectomy revealed a well-demarcated, poorly differentiated carcinoma with an organoid growth pattern, pushing borders, and abundant peritumoral lymphocytic response. The prior cytology was cellular with immunohistochemical panel consistent with upper gastrointestinal/pancreaticobiliary origin. Overall, the histopathologic findings were consistent with gastric medullary carcinoma. A mismatch repair panel revealed a mismatch repair protein deficient tumor with loss of MLH1 and PMS2 expression. BRAF V600E immunostain (VE1 and BRAF molecular testing were negative, indicating a wild-type gene. Tumor sequencing of MLH1 demonstrated a wild-type gene, while our molecular panel identified TP53 c.817C>T (p.R273C mutation. These findings were compatible with a sporadic tumor. Given that morphologically identical medullary tumors often occur in Lynch syndrome, it is possible that mismatch repair loss is an early event in sporadic tumors with p53 mutation being a late event. Despite having wild-type BRAF, this tumor is sporadic and unrelated to Lynch syndrome. This case report demonstrates that coordinate ancillary studies are needed to resolve sporadic versus hereditary rare tumors.

  19. Plasma levels of calcitonin in medullary thyroid carcinoma patients with and without the RET proto-oncogene mutations in exons 10 and 11

    Directory of Open Access Journals (Sweden)

    Samira Ehyayi

    2017-09-01

    Conclusion: Routine measurement of calcitonin has been investigated as a screening method for the diagnosis of medullary thyroid carcinoma patients. Nevertheless, additional data are required to definitely support routine measurement of calcitonin due to the role of RET proto-oncogene.

  20. Benefit of measuring basal serum calcitonin to detect medullary thyroid carcinoma in a Danish population with a high prevalence of thyroid nodules

    DEFF Research Database (Denmark)

    Hasselgren, Martin; Hegedüs, Laszlo; Godballe, Christian

    2009-01-01

    BACKGROUND: Routine measurement of serum calcitonin to detect medullary thyroid carcinoma (MTC) continues to be fiercely debated, although less attention has been paid to the positive predictive value (PPV) of this method. METHODS: We collected data from 959 patients with nontoxic nodular goiter...

  1. [Role of CT/111In-octreotide SPECT digital fusion imaging in the localization of loco-regional recurrence of medullary thyroid carcinoma

    NARCIS (Netherlands)

    Fiore, D.; Rubello, D.; Casara, D.; Pelizzo, M.R.; Franchi, A.; Muzzio, P.C.

    2004-01-01

    The case of a female patient affected by a sporadic medullary thyroid carcinoma (pT1N1aM0 at the onset) is reported. The patient had been initially treated by total thyroidectomy and lymphadenectomy of the central and lateral portions of the neck. During the following 30 years of follow-up, the

  2. Inhibitory synaptic transmission in isolated patches of membrane from cultured rat spinal cord and medullary neurons.

    Science.gov (United States)

    Lewis, C A; Faber, D S

    1996-07-01

    1. To quantify the variability in the characteristics of inhibitory glycinergic and GABAergic currents at single synaptic connections between cultured rat embryonic spinal cord or medullary neurons, we have used patch-clamp techniques to record miniature inhibitory postsynaptic currents (mIPSCs) in cell-attached patches. Experiments were performed with the patch pipette containing either a low-calcium internal saline to allow comparison with subsequent whole cell recordings or external saline with tetrodotoxin, DL-2-amino-5-phosphonovaleric acid, and 6-cyano-7-nitroquinoxaline-2,3-dione, a solution that is more appropriate for bathing a nerve terminal. 2. The mIPSCs recorded from the synapses restricted to the cell-attached patches were characterized by their times to peak, amplitudes, and time constants of decay. The degree of variability in these characteristics was quantified with the use of the following model-independent parameters: the coefficient of variation, skewness, and kurtosis. The distribution of time to peak values has a mean value of 5.6 +/- 0.5 (SE) ms, has the lowest coefficient of variation (0.33 +/- 0.01), is fairly symmetrical, and has a Gaussian shape with respect to peakedness. On the other hand, both the amplitude and decay time constant distributions are highly skewed and more peaked than Gaussian distributions. The mean amplitude is -6.6 +/- 0.6 pA with a coefficient of variation of 0.60 +/- 0.05, whereas the mean decay time constant is 22.8 +/- 1.0 ms with a coefficient of variation of 0.81 +/- 0.03. 3. The amplitude distributions for spontaneous inhibitory currents recorded from cell-attached patches are best fitted by the sum of multiple Gaussians. The coefficient of variation for the first Gaussian peak fitted to the amplitude distributions is 0.290 +/- 0.028. 4. Decay time distributions were consistently best fitted by the sum of four Gaussians with decay constants as follows: D1 = 5.7 +/- 0.2 ms (n = 12), D2 = 11.2 +/- 0.7 ms (n = 11

  3. Biodistribution and dosimetric study in medullary thyroid cancer xenograft using bispecific antibody and iodine-125-labeled bivalent hapten.

    Science.gov (United States)

    Hosono, M; Hosono, M N; Kraeber-Bodéré, F; Devys, A; Thédrez, P; Fiche, M; Gautherot, E; Barbet, J; Chatal, J F

    1998-09-01

    The purpose of this study was to evaluate biodistributions and absorbed doses of anti-carcinoembryonic antigen (CEA)/anti-diethylenetriamine pentaacetic acid (DTPA)-indium (anti-DTPA-In) bispecific monoclonal antibody (BsMAb) F6-734 and 125I-labeled DTPA-indium dimer hapten (125I-di-DTPA-In hapten) in athymic mice xenografted with human medullary thyroid cancer. Bispecific monoclonal antibodies F6-679 (anti-CEA/antihistamine) and G7A5-734 (antimelanoma/anti-di-DTPA-In) were used as irrelevant BsMAbs. Athymic mice inoculated with TT medullary thyroid cancer cells expressing CEA were administered BsMAbs F6-734, F6-679 or G7A5-734 and then, 48 hr later, 125I-di-DTPA-In hapten. Iodine-125-labeled F6 F(ab')2 fragment was injected into other groups of mice. Biodistributions were examined at 30 min and 5, 24, 48 and 96 hr after injection of 125I-di-DTPA-In hapten or 125I-labeled F6 F(ab')2. In mice injected with BsMAb F6-734 and 125I-di-DTPA-In hapten, tumor uptake was 9.1%+/-2.1%, 8.7%+/-3.5%, 8.0%+/-2.3%, 5.1%+/-0.9% and 3.5%+/-1.5% of the injected dose/g at 30 min and 5, 24, 48 and 96 hr, and tumor-to-blood, tumor-to-liver and tumor-to-kidney ratios were 37.0+/-12.5, 32.3+/-10.9 and 10.4+/-2.7 at 24 hr. Iodine-125-F6 F(ab')2 fragment showed a tumor uptake of 7.39% injected dose/g and tumor-to-blood, tumor-to-liver and tumor-to-kidney ratios of 1.8+/-0.6, 7.3+/-2.9 and 3.6+/-1.6 at 24 hr. In mice injected with F6-679 or G7A5-734, tumor uptake and tumor-to-normal tissue ratios were much lower than in the mice injected with F6-734. These results were confirmed by autoradiographic studies that demonstrated clear tumor-to-normal tissue contrast. This two-step targeting method seems very potent for the diagnosis and therapy of human medullary thyroid cancer and other CEA-producing tumors because it combines high tumor uptake and low normal tissue background.

  4. Genetic subtype differences in neural circuitry of food motivation in Prader-Willi syndrome.

    Science.gov (United States)

    Holsen, L M; Zarcone, J R; Chambers, R; Butler, M G; Bittel, D C; Brooks, W M; Thompson, T I; Savage, C R

    2009-02-01

    Differences in behavioral phenotypes between the two most common subtypes of Prader-Willi syndrome (PWS) (chromosome 15q deletions and maternal uniparental disomy 15 (UPD) indicate that distinct neural networks may be affected. Though both subtypes display hyperphagia, the deletion subgroup shows reduced behavioral inhibition around food, whereas those with UPD are generally more able to maintain cognitive control over food intake impulses. To examine the neural basis of phenotypic differences to better understand relationships between genetic subtypes and behavioral outcomes. We predicted greater food motivation circuitry activity in the deletion subtype and greater activity in higher order cognitive regions in the UPD group, especially after eating. Nine individuals with PWS due to UPD and nine individuals with PWS due to (type 2) deletion, matched for age, gender and body mass index, underwent functional magnetic resonance imaging (fMRI) while viewing food images during two food motivation states: one before (pre-meal) and one after (post-meal) eating a standardized 500 kcal meal. Both PWS subgroups showed greater activity in response to food pre- and post-meal compared with the healthy-weight group. Compared with UPD, the deletion subtype showed increased food motivation network activation both pre- and post-meal, especially in the medial prefrontal cortex (mPFC) and amygdala. In contrast, the UPD group showed greater activation than the deletion subtype post-meal in the dorsolateral prefrontal cortex (DLPFC) and parahippocampal gyrus (PHG). These preliminary findings are the first functional neuroimaging findings to support divergent neural mechanisms associated with behavioral phenotypes in genetic subtypes of PWS. Results are discussed within the framework of genetic mechanisms such as haploinsufficiency and gene dosage effects and their differential influence on deletion and UPD subtypes, respectively.

  5. Hyperleptinemia in Neonatally Overfed Female Rats Does Not Dysregulate Feeding Circuitry

    Directory of Open Access Journals (Sweden)

    Ilvana Ziko

    2017-10-01

    Full Text Available Neonatal overfeeding during the first weeks of life in male rats is associated with a disruption in the peripheral and central leptin systems. Neonatally overfed male rats have increased circulating leptin in the first 2 weeks of life, which corresponds to an increase in body weight compared to normally fed counterparts. These effects are associated with a short-term disruption in the connectivity of neuropeptide Y (NPY, agouti-related peptide (AgRP, and pro-opiomelanocortin (POMC neurons within the regions of the hypothalamus responsible for control of energy balance and food intake. Female rats that are overfed during the first weeks of their life experience similar changes in circulating leptin levels as well as in their body weight. However, it has not yet been studied whether these metabolic changes are associated with the same central effects as observed in males. Here, we hypothesized that hyperleptinemia associated with neonatal overfeeding would lead to changes in central feeding circuitry in females as it does in males. We assessed hypothalamic NPY, AgRP, and POMC gene expression and immunoreactivity at 7, 12, or 14 days of age, as well as neuronal activation in response to exogenous leptin in neonatally overfed and control female rats. Neonatally overfed female rats were hyperleptinemic and were heavier than controls. However, these metabolic changes were not mirrored centrally by changes in hypothalamic NPY, AGRP, and POMC fiber density. These findings are suggestive of sex differences in the effects of neonatal overfeeding and of differences in the ability of the female and male central systems to respond to changes in the early life nutritional environment.

  6. Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry.

    Science.gov (United States)

    Weder, Natalie; Zhang, Huiping; Jensen, Kevin; Yang, Bao Zhu; Simen, Arthur; Jackowski, Andrea; Lipschitz, Deborah; Douglas-Palumberi, Heather; Ge, Margrat; Perepletchikova, Francheska; O'Loughlin, Kerry; Hudziak, James J; Gelernter, Joel; Kaufman, Joan

    2014-04-01

    To determine whether epigenetic markers predict dimensional ratings of depression in maltreated children. A genome-wide methylation study was completed using the Illumina 450K BeadChip array in 94 maltreated and 96 healthy nontraumatized children with saliva-derived DNA. The 450K BeadChip does not include any methylation sites in the exact location as sites in candidate genes previously examined in the literature, so a test for replication of prior research findings was not feasible. Methylation in 3 genes emerged as genome-wide-significant predictors of depression: DNA-Binding Protein Inhibitor ID-3 (ID3); Glutamate Receptor, Ionotropic N-methyl-D-aspartate (NMDA) 1 (GRIN1); and Tubulin Polymerization Promoting Protein (TPPP) (p plasticity, and TPPP involved in neural circuitry development. Methylation in CpG sites in candidate genes were not predictors of depression at significance levels corrected for whole genome testing, but maltreated and control children did have significantly different β values after Bonferroni correction at multiple methylation sites in these candidate genes (e.g., BDNF, NR3C1, FKBP5). This study suggests that epigenetic changes in ID3, GRIN1, and TPPP genes, in combination with experiences of maltreatment, may confer risk for depression in children. The study adds to a growing body of literature supporting a role for epigenetic mechanisms in the pathophysiology of stress-related psychiatric disorders. Although epigenetic changes are frequently long lasting, they are not necessarily permanent. Consequently, interventions to reverse the negative biological and behavioral sequelae associated with child maltreatment are briefly discussed. Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

  7. Structural Alterations within Cerebellar Circuitry Are Associated with General Liability for Common Mental Disorders

    Science.gov (United States)

    Romer, Adrienne L.; Knodt, Annchen R.; Houts, Renate; Brigidi, Bartholomew D.; Moffitt, Terrie E.; Caspi, Avshalom; Hariri, Ahmad R.

    2017-01-01

    Accumulating mental health research encourages a shift in focus towards transdiagnostic dimensional features that are shared across categorical disorders. In support of this shift, recent studies have identified a general liability factor for psychopathology – sometimes called the ‘p factor’ – that underlies shared risk for a wide range of mental disorders. Identifying neural correlates of this general liability would substantiate its importance in characterizing the shared origins of mental disorders and help us begin to understand the mechanisms through which the ‘p factor’ contributes to risk. Here we first replicate the ‘p factor’ using cross-sectional data from a volunteer sample of 1,246 university students, and then, using high-resolution multimodal structural neuroimaging, demonstrate that individuals with higher ‘p factor’ scores show reduced structural integrity of white matter pathways, as indexed by lower fractional anisotropy values, uniquely within the pons. Whole-brain analyses further revealed that higher ‘p factor’ scores are associated with reduced gray matter volume in the occipital lobe and left cerebellar lobule VIIb, which is functionally connected with prefrontal regions supporting cognitive control. Consistent with the preponderance of cerebellar afferents within the pons, we observed a significant positive correlation between the white matter integrity of the pons and cerebellar gray matter volume associated with higher ‘p factor’ scores. The results of our analyses provide initial evidence that structural alterations in cortico-cerebellar circuitry supporting core functions related to the basic integration, coordination, and monitoring of information may contribute to a general liability for common mental disorders. PMID:28397842

  8. Flexible thin film circuitry enabling ubiquitous electronics via post-fabrication customization (Presentation Recording)

    Science.gov (United States)

    Cobb, Brian

    2015-09-01

    For decades, the electronics industry has been accurately described by Moore's Law, where the march towards increasing density and smaller feature sizes has enabled continuous cost reductions and performance improvements. With flexible electronics, this perpetual scaling is not foreseen to occur. Instead, the industry will be dominated by Wright's Law, first proposed in 1936, where increasing demand for high volumes of product will drive costs down. We have demonstrated thin film based circuitry compatible with flexible substrates with high levels of functionality designed for such a high volume industry. This includes a generic 8-bit microprocessor totaling more than 3.5k TFTs operating at 2.1 kHz. We have also developed a post fabrication programming technique via inkjet printing of conductive spots to form a one-time programmable instruction generator, allowing customization of the processor for a specific task. The combination demonstrates the possibility to achieve the high volume production of identical products necessary to reap the benefits promised by Wright's Law, while still retaining the individualization necessary for application differentiation. This is of particular importance in the area of item level identification via RFID, where low cost and individualized identification are necessary. Remotely powered RFID tags have been fabricated using an oxide semiconductor based TFT process. This process is compatible with the post-fabrication printing process to detail individual identification codes, with the goal of producing low cost, high volume flexible tags. The goal is to produce tags compatible with existing NFC communication protocols in order to communicate with readers that are already ubiquitous in the market.

  9. Effects of direct social experience on trust decisions and neural reward circuitry

    Directory of Open Access Journals (Sweden)

    Dominic S. Fareri

    2012-10-01

    Full Text Available The human striatum is integral for reward-processing and supports learning by linking experienced outcomes with prior expectations. Recent endeavors implicate the striatum in processing outcomes of social interactions, such as social approval/rejection, as well as in learning reputations of others. Interestingly, social impressions often influence our behavior with others during interactions. Information about an interaction partner’s moral character acquired from biographical information hinders updating of expectations after interactions via top down modulation of reward circuitry. An outstanding question is whether initial impressions formed through experience similarly modulate the ability to update social impressions at the behavioral and neural level. We investigated the role of experienced social information on trust behavior and reward-related BOLD activity. Participants played a computerized ball tossing game with three fictional partners manipulated to be perceived as good, bad or neutral. Participants then played an iterated trust game as investors with these same partners while undergoing fMRI. Unbeknownst to participants, partner behavior in the trust game was random and unrelated to their ball-tossing behavior. Participants’ trust decisions were influenced by their prior experience in the ball tossing game, investing less often with the bad partner compared to the good and neutral. Reinforcement learning models revealed that participants were more sensitive to updating their beliefs about good and bad partners when experiencing outcomes consistent with initial experience. Increased striatal and anterior cingulate BOLD activity for positive versus negative trust game outcomes emerged, which further correlated with model-derived prediction-error (PE learning signals. These results suggest that initial impressions formed from direct social experience can be continually shaped by consistent information through reward learning

  10. Coronary artery disease affects cortical circuitry associated with brain-heart integration during volitional exercise.

    Science.gov (United States)

    Norton, Katelyn N; Badrov, Mark B; Barron, Carly C; Suskin, Neville; Heinecke, Armin; Shoemaker, J Kevin

    2015-08-01

    This study tested the hypothesis that coronary artery disease (CAD) alters the cortical circuitry associated with exercise. Observations of changes in heart rate (HR) and in cortical blood oxygenation level-dependent (BOLD) images were made in 23 control subjects [control; 8 women; 63 ± 11 yr; mean arterial pressure (MAP): 90 ± 9 mmHg] (mean ± SD) and 17 similarly aged CAD patients (4 women; 59 ± 9 yr; MAP: 87 ± 10 mmHg). Four repeated bouts each of 30%, 40%, and 50% of maximal voluntary contraction (MVC) force (LAB session), and seven repeated bouts of isometric handgrip (IHG) at 40% MVC force (fMRI session), were performed, with each contraction lasting 20 s and separated by 40 s of rest. There was a main effect of group (P = 0.03) on HR responses across all IHG intensities. Compared with control, CAD demonstrated less task-dependent deactivation in the posterior cingulate cortex and medial prefrontal cortex, and reduced activation in the right anterior insula, bilateral precentral cortex, and occipital lobe (P < 0.05). When correlated with HR, CAD demonstrated reduced activation in the bilateral insula and posterior cingulate cortex, and reduced deactivation in the dorsal anterior cingulate cortex, and bilateral precentral cortex (P < 0.05). The increased variability in expected autonomic regions and decrease in total cortical activation in response to the IHG task are associated with a diminished HR response to volitional effort in CAD. Therefore, relative to similarly aged and healthy individuals, CAD impairs the heart rate response and modifies the cortical patterns associated with cardiovascular control during IHG. Copyright © 2015 the American Physiological Society.

  11. The role of the neural reward circuitry in self-referential optimistic belief updates.

    Science.gov (United States)

    Kuzmanovic, Bojana; Jefferson, Anneli; Vogeley, Kai

    2016-06-01

    People are motivated to adopt the most favorable beliefs about their future because positive beliefs are experienced as rewarding. However, it is so far inconclusive whether brain regions known to represent reward values are involved in the generation of optimistically biased belief updates. To address this question, we investigated neural correlates of belief updates that result in relatively better future outlooks, and therefore imply a positive subjective value of the judgment outcome. Participants estimated the probability of experiencing different adverse future events. After being provided with population base rates of these events, they had the opportunity to update their initial estimates. Participants made judgments concerning themselves or a similar other, and were confronted with desirable or undesirable base rates (i.e., lower or higher than their initial estimates). Belief updates were smaller following undesirable than desirable information, and this optimism bias was stronger for judgments regarding oneself than others. During updating, the positive value of self-related updates was reflected by neural activity in the subgenual ventromedial prefrontal cortex (vmPFC) that increased both with increasing sizes of favorable updates, and with decreasing sizes of unfavorable updates. During the processing of self-related undesirable base rates, increasing activity in a network including the dorsomedial PFC, hippocampus, thalamus and ventral striatum predicted decreasing update sizes. Thus, key regions of the neural reward circuitry contributed to the generation of optimistically biased self-referential belief updates. While the vmPFC tracked subjective values of belief updates, a network including the ventral striatum was involved in neglecting information calling for unfavorable updates. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Processing of pro-CGRP in a rat medullary thyroid carcinoma cell line transfected with protease inhibitors

    DEFF Research Database (Denmark)

    Johansen, Teit Eliot; Schifter, S; Vogel, Charlotte Katrine

    1991-01-01

    A rat medullary thyroid carcinoma cell line, CA77, was used to study the effect of a series of biosynthesized protease inhibitors on the proteolytic cleavage of the endogenously synthesized pro-CGRP. This cell line efficiently converted the pro-CGRP to mature CGRP as assessed by chromatography...... of cell extracts followed by radioimmunoassay for CGRP. CA77 cells were transfected with expression vectors encoding protease inhibitors: the Arg-serpins, alpha 1-antitrypsin Pittsburgh (358 Met----Arg) and plasminogen activator inhibitor 1, the Kazal type serine protease inhibitor, pancreatic secretory...... trypsin inhibitor, and the general thiol protease inhibitor, cystatin C. Only the chromatography of cell extracts from CA77 cells transfected with a plasmid encoding cystatin C showed an apparent higher content of unprocessed pro-CGRP as compared to non-transfected cells. No effect on pro-CGRP processing...

  13. Comparison of 99Tcm(V)-DMSA and 99Tcm-MIBI scintigraphy in medullary thyroid carcinoma

    International Nuclear Information System (INIS)

    Deng Bo; Xiao Huan; Chen Xiaofeng; Chen Huaming

    2004-01-01

    SPECT scintigraphy is used in 62 patients with medullary thyroid carcinoma (MTC), which are divided into two groups: 32 patients by 99 Tc m (V)-DMSA and 30 patients by 99 Tc m -MIBI. The qualitative analysis and half quantitative analysis are performed to the early and delayed images. Comparing the results with two groups, there is no difference in the masculine rate of MTC primary focus, but the results of 99 Tc m (V)-DMSA scintigraphy is obviously larger than 99 Tc m -MIBI by half quantitative analysis. The results show that the 99 Tc m (V)-DMSA scintigraphy is more predominant than the 99 Tc m -(V)-DMSA scintigraphy may be superior to 99 Tc m -MIBI in MTC primary focus and metastasis focus before surging for MTC patients. (authors)

  14. The affection of APA microcapsulation on catecholamine and leucine-enkephalin secretion from the bovine adrenal medullary chromaffin cells

    International Nuclear Information System (INIS)

    Guo Shuilong; Cui Xin; Luo Yun; Xue Yilong

    2002-01-01

    The affection of alginate-polylysine-alginate (APA) microcapsulation on catecholamine (CA) and leucine-enkephalin (L-EK) secretion from bovine adrenal medullary chromaffin cells was analysed. Encapsulating BCCs with the APA microcapsulation, the secretion of CA and L-EK in encapsulated BCCs was detected by high-performance liquid chromatography-electrochemical assay and radioimmunoassay, respectively. There is little difference between the encapsulated BCCs and the non-encapsulated BCCs in the secretion of epinephrine (E) and noradrenaline (NE) but the secretion of dopamine (DA) and L-EK in several points decline. The studies indicated that APA microcapsulation of BCCs didn't affect the secretion of E and NE, but did the secretion DA and L-EK in forepart

  15. Mild to moderate increase of serum calcitonin levels only in presence of large medullary thyroid cancer deposits.

    Science.gov (United States)

    Pelizzo, M R; Torresan, F; Da Roit, A; Merante Boschin, I; Chondrogiannis, S; Rampin, L; Colletti, P M; Vinjamury, S; Perkins, A J; Rubello, D

    2015-01-01

    Many open questions remain to be elucidated about the diagnosis, treatment and prognosis of medullary thyroid cancer (MTC). The most intriguing concerns the outcome of MTC patients after surgery. Great importance is usually given to serum calcitonin (Ct) and carcinoembryonic (CEA) levels. It is commonly believed that the higher are the levels of these tumor markers and their kinetics (double time and velocity of markers levels) the worst is the prognosis. However, this is not the rule, as there are huge MTC metastatic deposits characterized by low serum Ct and CEA levels, and this condition is not closely related to the outcome of the disease during post-surgical follow-up. A series is reported here of patients who have these characteristics, as well as a description of their prognosis and clinical outcome. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

  16. Laryngeal chondrosarcoma mimicking medullary thyroid carcinoma on fine-needle aspiration cytology: A case report of a diagnostic pitfall.

    Science.gov (United States)

    Vahidi, Shifteh; Amin, Khalid; Stewart, Jimmie

    2017-11-01

    Chondrosarcoma (CS) of larynx is a rare laryngeal tumor accounting about 1% of laryngeal malignancies. When CS arises from thyroid cartilage, it may clinically present as a thyroid nodule. Here we report a rare case of CS of thyroid cartilage misinterpreted as medullary thyroid carcinoma. The main aim of this case report is to emphasize the important role of accurate clinical history, appropriate physical examination, and proper localization of the tumor and clear definitive imaging in conjunction with interpretation of cytologic smears. When any of these roles are unclear, it may result in misinterpretation of the cytologic smears. In these unusual circumstances, when cytomorphologic features does not completely fit an entity, communication with the physician and the consideration of a broad differential diagnoses in the head and neck pathology may lead to correct diagnosis and avoid diagnostic pitfalls. Also in certain conditions, ancillary studies including laboratory tests are necessary for definitive classification. © 2017 Wiley Periodicals, Inc.

  17. P2Y2 receptor knock-out mice display normal NaCl absorption in medullary thick ascending limb

    DEFF Research Database (Denmark)

    Marques, Rita D; Praetorius, Helle A; Leipziger, Jens

    2013-01-01

    Local purinergic signals modulate renal tubular transport. Acute activation of renal epithelial P2 receptors causes inhibition of epithelial transport and thus, should favor increased water and salt excretion by the kidney. So far only a few studies have addressed the effects of extracellular...... nucleotides on ion transport in the thick ascending limb (TAL). In the medullary thick ascending limb (mTAL), basolateral P2X receptors markedly (~25%) inhibit NaCl absorption. Although this segment does express both apical and basolateral P2Y2 receptors, acute activation of the basolateral P2Y2 receptors had...... no apparent effect on transepithelial ion transport. Here we studied, if the absence of the P2Y2 receptor causes chronic alterations in mTAL NaCl absorption by comparing basal and AVP-stimulated transepithelial transport rates. We used perfused mouse mTALs to electrically measure NaCl absorption in juvenile...

  18. A review of the natural progression of medullary sponge kidney and a novel grading system based on intravenous urography findings.

    Science.gov (United States)

    Forster, J A; Taylor, J; Browning, A J; Biyani, C S

    2007-01-01

    Medullary sponge kidney (MSK) is a developmental abnormality of the medullary pyramids of the kidney, characterised by cystic dilatations of the collecting ducts. We investigated a cohort of patients with MSK to gain further information about its presentation, clinical course and treatment required. We devised a grading system based upon findings at diagnostic intravenous urography (IVU) and established a relationship between severity of IVU findings and severity of disease. The clinical notes and imaging of 29 patients with MSK were analysed. The severity of IVU findings was classified as follows: grade 1 (one calyx, unilateral), grade 2 (one calyx, bilateral), grade 3 (more than one calyx, unilateral) and grade 4 (more than one calyx, bilateral). The age range at diagnosis was 12-69 (mean 39), mean follow-up period was 12.7 years. Increasing grade of IVU findings correlated with more frequent symptomatic stone episodes (grade 1: 0.09 episodes per patient per year; grade 4: 0.34). Higher grade was also related to the number of hospital admissions (grade 1: 0.182 per patient per year; grade 4: 0.282) and the number of procedures required (either surgery or extracorporeal shock wave lithotripsy; grade 1: 0.0 interventions per patient per year; grade 4: 0.24). MSK presents over a wide age range and can cause long periods of intermittent episodes. Patients can be graded using a novel system based on IVU findings, which correlates with severity of disease. Management strategies such as intensity of follow-up can be modified using this grading. Copyright 2007 S. Karger AG, Basel.

  19. Poorly Differentiated Medullary Phenotype Predicts Poor Survival in Early Lymph Node-Negative Gastro-Esophageal Adenocarcinomas.

    Directory of Open Access Journals (Sweden)

    Christoph Treese

    Full Text Available 5-year survival rate in patients with early adenocarcinoma of the gastro-esophageal junction or stomach (AGE/S in Caucasian patients is reported to be 60-80%. We aimed to identify prognostic markers for patients with UICC-I without lymph-node involvement (N0.Clinical data and tissue specimen from patients with AGE/S stage UICC-I-N0, treated by surgery only, were collected retrospectively. Tumor size, lymphatic vessel or vein invasion, grading, classification systems (WHO, Lauren, Ming, expression of BAX, BCL-2, CDX2, Cyclin E, E-cadherin, Ki-67, TP53, TP21, SHH, Survivin, HIF1A, TROP2 and mismatch repair deficiency were analyzed using tissue microarrays and correlated with overall and tumor related survival.129 patients (48 female with a mean follow-up of 129.1 months were identified. 5-year overall survival was 83.9%, 5-year tumor related survival was 95.1%. Poorly differentiated medullary cancer subtypes (p<0.001 and positive vein invasion (p<0.001 were identified as risk factors for decreased overall-and tumor related survival. Ki-67 (p = 0.012 and TP53 mutation (p = 0.044 were the only immunohistochemical markers associated with worse overall survival but did not reach significance for decreased tumor related survival.In the presented study patients with AGE/S in stage UICC-I-N0 had a better prognosis as previously reported for Caucasian patients. Poorly differentiated medullary subtype was associated with reduced survival and should be considered when studying prognosis in these patients.

  20. Limbic-thalamo-cortical projections and reward-related circuitry integrity affects eating behavior: A longitudinal DTI study in adolescents with restrictive eating disorders.

    Directory of Open Access Journals (Sweden)

    Gaia Olivo

    Full Text Available Few studies have used diffusion tensor imaging (DTI to investigate the micro-structural alterations of WM in patients with restrictive eating disorders (rED, and longitudinal data are lacking. Twelve patients with rED were scanned at diagnosis and after one year of family-based treatment, and compared to twenty-four healthy controls (HCs through DTI analysis. A tract-based spatial statistics procedure was used to investigate diffusivity parameters: fractional anisotropy (FA and mean, radial and axial diffusivities (MD, RD and AD, respectively. Reduced FA and increased RD were found in patients at baseline in the corpus callosum, corona radiata and posterior thalamic radiation compared with controls. However, no differences were found between follow-up patients and controls, suggesting a partial normalization of the diffusivity parameters. In patients, trends for a negative correlation were found between the baseline FA of the right anterior corona radiata and the Eating Disorder Examination Questionnaire total score, while a positive trend was found between the baseline FA in the splenium of corpus callosum and the weight loss occurred between maximal documented weight and time of admission. A positive trend for correlation was also found between baseline FA in the right anterior corona radiata and the decrease in the Obsessive-Compulsive Inventory Revised total score over time. Our results suggest that the integrity of the limbic-thalamo-cortical projections and the reward-related circuitry are important for cognitive control processes and reward responsiveness in regulating eating behavior.

  1. The role of leptin in the regulation of energy balance and adiposity

    NARCIS (Netherlands)

    van Dijk, G

    2001-01-01

    Since its discovery, leptin (a 167-amino acid product of the OB gene) has quickly moved to the forefront as an important hormone for regulation of energy balance. It closes a feedback loop from adipose tissue to hypothalamic neuropeptide-containing neural circuitry involved in regulation of food

  2. Determining the Control Circuitry of Redox Metabolism at the Genome-Scale

    DEFF Research Database (Denmark)

    Federowicz, Stephen; Kim, Donghyuk; Ebrahim, Ali

    2014-01-01

    that are regulated during electron acceptor shifts. Here we propose a qualitative model that accounts for the full breadth of regulated genes by detailing how two global transcription factors (TFs), ArcA and Fnr of E. coli, sense key metabolic redox ratios and act on a genome-wide basis to regulate anabolic......-scale metabolic model to show that ArcA and Fnr regulate >80% of total metabolic flux and 96% of differential gene expression across fermentative and nitrate respiratory conditions. Based on the data, we propose a feedforward with feedback trim regulatory scheme, given the extensive repression of catabolic genes...

  3. Abnormal structure of fear circuitry in pediatric post-traumatic stress disorder.

    Science.gov (United States)

    Keding, Taylor J; Herringa, Ryan J

    2015-02-01

    Structural brain studies of adult post-traumatic stress disorder (PTSD) show reduced gray matter volume (GMV) in fear regulatory areas including the ventromedial prefrontal cortex (vmPFC) and hippocampus. Surprisingly, neither finding has been reported in pediatric PTSD. One possibility is that they represent age-dependent effects that are not fully apparent until adulthood. In addition, lower-resolution MRI and image processing in prior studies may have limited detection of such differences. Here we examine fear circuitry GMV, including age-related differences, using higher-resolution MRI in pediatric PTSD vs healthy youth. In a cross-sectional design, 3 T anatomical brain MRI was acquired in 27 medication-free youth with PTSD and 27 healthy non-traumatized youth of comparable age, sex, and IQ. Voxel-based morphometry was used to compare GMV in a priori regions including the medial prefrontal cortex and amygdala/hippocampus. Compared with healthy youth, PTSD youth had reduced GMV but no age-related differences in anterior vmPFC (BA 10/11, Z=4.5), which inversely correlated with PTSD duration. In contrast, although there was no overall group difference in hippocampal volume, a group × age interaction (Z=3.6) was present in the right anterior hippocampus. Here, age positively predicted hippocampal volume in healthy youth but negatively predicted volume in PTSD youth. Within the PTSD group, re-experiencing symptoms inversely correlated with subgenual anterior cingulate cortex (sgACC, Z=3.7) and right anterior hippocampus (Z=3.5) GMV. Pediatric PTSD is associated with abnormal structure of the vmPFC and age-related differences in the hippocampus, regions important in the extinction and contextual gating of fear. Reduced anterior vmPFC volume may confer impaired recovery from illness, consistent with its role in the allocation of attentional resources. In contrast, individual differences in sgACC volume were associated with re-experiencing symptoms, consistent with

  4. Radiation-Hardened Circuitry Using Mask-Programmable Analog Arrays. Report 3

    Energy Technology Data Exchange (ETDEWEB)

    Britton, Jr, Charles L. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Shelton, Jacob H. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Ericson, Milton Nance [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Blalock, Benjamin [Univ. of Tennessee, Knoxville, TN (United States)

    2015-03-01

    As the recent accident at Fukushima Daiichi so vividly demonstrated, telerobotic technologies capable of withstanding high radiation environments need to be readily available to enable operations, repair, and recovery under severe accident scenarios when human entry is extremely dangerous or not possible. Telerobotic technologies that enable remote operation in high dose rate environments have undergone revolutionary improvement over the past few decades. However, much of this technology cannot be employed in nuclear power environments because of the radiation sensitivity of the electronics and the organic insulator materials currently in use. This is a report of the activities involving Task 3 of the Nuclear Energy Enabling Technologies (NEET) 2 project Radiation Hardened Circuitry Using Mask-Programmable Analog Arrays [1]. Evaluation of the performance of the system for both pre- and post-irradiation as well as operation at elevated temperature will be performed. Detailed performance of the system will be documented to ensure the design meets requirements prior to any extended evaluation. A suite of tests will be developed which will allow evaluation before and after irradiation and during temperature. Selection of the radiation exposure facilities will be determined in the early phase of the project. Radiation exposure will consist of total integrated dose (TID) up to 200 kRad or above with several intermediate doses during test. Dose rates will be in various ranges determined by the facility that will be used with a target of 30 kRad/hr. Many samples of the pre-commercial devices to be used will have been tested in previous projects to doses of at least 300 kRad and temperatures up to 125C. The complete systems will therefore be tested for performance at intermediate doses. Extended temperature testing will be performed up to the limit of the commercial sensors. The test suite performed at each test point will consist of operational testing of the three basic

  5. Use of intra-medullary stacked nailing in the reduction of proximal plastic deformity in a pediatric Monteggia fracture:a case report

    OpenAIRE

    Lim, Jason; Huntley, James S

    2011-01-01

    Abstract Introduction In a Monteggia fracture dislocation, it is important to reduce the ulnar fracture completely. Extensive plastic deformation of the proximal ulna may make reduction by closed manipulation impossible. Case presentation We report the case of a four-year-old Caucasian boy in whom the plastic deformation of the proximal ulna was reduced, and this reduction was maintained, using intra-medullary stacked nailing. Conclusion The technique of stacked nailing is a useful addition t...

  6. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer

    DEFF Research Database (Denmark)

    Schlumberger, Martin J; Elisei, Rossella; Bastholt, Lars

    2009-01-01

    PURPOSE: This phase II study investigated the efficacy and tolerability of motesanib, an investigational, highly selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit in advanced medullary thyroid cancer (MTC). PATIENTS......%), hypertension (27%), and anorexia (27%). In pharmacokinetic analyses, motesanib trough concentrations were lower compared with differentiated thyroid cancer patients from the same study. CONCLUSION: Although the objective response rate was low, a significant proportion of MTC patients (81%) achieved stable...

  7. Demographic, clinical, and genetic characteristics of patients with medullary thyroid cancer in the past 16 years in Castilla-La Mancha.

    Science.gov (United States)

    Louhibi, Lynda; Marco, Amparo; Pinés, Pedro J; Padillo, José C; Gómez, Inés; Valero, Miguel A; Alramadán, Mubarak; Herranz, Sandra; Aguirre, Miguel; Hernández, Antonio

    2014-10-01

    Medullary thyroid cancer is a rare tumor that is more aggressive and has a worse prognosis than differentiated thyroid cancer. The purpose of this study was to report the demographic, clinical, and genetic characteristics of patients seen in the health care system of the community of Castilla-La Mancha over a 16-year period. Data were collected through a review of patients' medical records. The medical records of 58 patients (mean age at diagnosis, 51 years; range, 6-82 years; 63.8% women) were reviewed. Prevalence rate was 2.84 cases per 100,000 inhabitants, with a high variability between areas (range, 0-5.4 cases per 100,000 inhabitants). Familial cases accounted for 34.5% of all medullary thyroid cancers, and the most common mutation was C634Y. The condition was most commonly diagnosed following palpation of a cervical lump (70.6%). At diagnosis, 56 of 58 patients underwent ultrasound and 8 of 58 patients were tested for serum calcitonin. Tumor multicentricity was reported in 59 and 50% of patients with multiple endocrine neoplasia syndrome type 2A and 2B, respectively, and in no sporadic cases. Fifty-two percent of patients had an advanced stage (iii or iv) at diagnosis. Median follow-up was 36 months (interquartile range, 14-210); 11 patients were lost to follow-up. In Castilla-La Mancha, medullary thyroid cancer is diagnosed by cervical ultrasound, rather than calcitonin assay. There is a high prevalence of both familial and sporadic medullary thyroid cancer, and a significant variability in the type of proto-oncogen rearranged during transfection mutation as compared to the rest of the Spanish population. Copyright © 2013 SEEN. Published by Elsevier Espana. All rights reserved.

  8. FOXA and master transcription factors recruit Mediator and Cohesin to the core transcriptional regulatory circuitry of cancer cells

    Science.gov (United States)

    Fournier, Michèle; Bourriquen, Gaëlle; Lamaze, Fabien C.; Côté, Maxime C.; Fournier, Éric; Joly-Beauparlant, Charles; Caron, Vicky; Gobeil, Stéphane; Droit, Arnaud; Bilodeau, Steve

    2016-10-01

    Controlling the transcriptional program is essential to maintain the identity and the biological functions of a cell. The Mediator and Cohesin complexes have been established as central cofactors controlling the transcriptional program in normal cells. However, the distribution, recruitment and importance of these complexes in cancer cells have not been fully investigated. Here we show that FOXA and master transcription factors are part of the core transcriptional regulatory circuitry of cancer cells and are essential to recruit M ediator and Cohesin. Indeed, Mediator and Cohesin occupied the enhancer and promoter regions of actively transcribed genes and maintained the proliferation and colony forming potential. Through integration of publically available ChIP-Seq datasets, we predicted the core transcriptional regulatory circuitry of each cancer cell. Unexpectedly, for all cells investigated, the pioneer transcription factors FOXA1 and/or FOXA2 were identified in addition to cell-specific master transcription factors. Loss of both types of transcription factors phenocopied the loss of Mediator and Cohesin. Lastly, the master and pioneer transcription factors were essential to recruit Mediator and Cohesin to regulatory regions of actively transcribed genes. Our study proposes that maintenance of the cancer cell state is dependent on recruitment of Mediator and Cohesin through FOXA and master transcription factors.

  9. Left-right asymmetry defect in the hippocampal circuitry impairs spatial learning and working memory in iv mice.

    Directory of Open Access Journals (Sweden)

    Kazuhiro Goto

    Full Text Available Although left-right (L-R asymmetry is a fundamental feature of higher-order brain function, little is known about how asymmetry defects of the brain affect animal behavior. Previously, we identified structural and functional asymmetries in the circuitry of the mouse hippocampus resulting from the asymmetrical distribution of NMDA receptor GluR ε2 (NR2B subunits. We further examined the ε2 asymmetry in the inversus viscerum (iv mouse, which has randomized laterality of internal organs, and found that the iv mouse hippocampus exhibits right isomerism (bilateral right-sidedness in the synaptic distribution of the ε2 subunit, irrespective of the laterality of visceral organs. To investigate the effects of hippocampal laterality defects on higher-order brain functions, we examined the capacity of reference and working memories of iv mice using a dry maze and a delayed nonmatching-to-position (DNMTP task, respectively. The iv mice improved dry maze performance more slowly than control mice during acquisition, whereas the asymptotic level of performance was similar between the two groups. In the DNMTP task, the iv mice showed poorer accuracy than control mice as the retention interval became longer. These results suggest that the L-R asymmetry of hippocampal circuitry is critical for the acquisition of reference memory and the retention of working memory.

  10. Reward circuitry responsivity to food predicts future increases in body mass: moderating effects of DRD2 and DRD4.

    Science.gov (United States)

    Stice, Eric; Yokum, Sonja; Bohon, Cara; Marti, Nate; Smolen, Andrew

    2010-05-01

    To determine whether responsivity of reward circuitry to food predicts future increases in body mass and whether polymorphisms in DRD2 and DRD4 moderate these relations. The functional magnetic resonance imaging (fMRI) paradigm investigated blood oxygen level dependent activation in response to imagined intake of palatable foods, unpalatable foods, and glasses of water shown in pictures. DNA was extracted from saliva samples using standard salting-out and solvent precipitation methods. Forty-four adolescent female high school students ranging from lean to obese. Future increases in body mass index (BMI). Weaker activation of the frontal operculum, lateral orbitofrontal cortex, and striatum in response to imagined intake of palatable foods, versus imagined intake of unpalatable foods or water, predicted future increases in body mass for those with the DRD2 TaqIA A1 allele or the DRD4-7R allele. Data also suggest that for those lacking these alleles, greater responsivity of these food reward regions predicted future increases in body mass. This novel prospective fMRI study indicates that responsivity of reward circuitry to food increases risk for future weight gain, but that genes that impact dopamine signaling capacity moderate the predictive effects, suggesting two qualitatively distinct pathways to unhealthy weight gain based on genetic risk. 2010 Elsevier Inc. All rights reserved.

  11. Lateral hypothalamus, nucleus accumbens, and ventral pallidum roles in eating and hunger: interactions between homeostatic and reward circuitry

    Directory of Open Access Journals (Sweden)

    Daniel Charles Castro

    2015-06-01

    Full Text Available The study of the neural bases of eating behavior, hunger, and reward has consistently implicated the lateral hypothalamus (LH and its interactions with mesocorticolimbic circuitry, such as mesolimbic dopamine projections to nucleus accumbens (NAc and ventral pallidum (VP, in controlling motivation to eat. The NAc and VP play special roles in mediating the hedonic impact (‘liking’ and motivational incentive salience (‘wanting’ of food rewards, and their interactions with LH help permit regulatory hunger/satiety modulation of food motivation and reward. Here, we review some progress that has been made regarding this circuitry and its functions: the identification of localized anatomical hedonic hotspots within NAc and VP for enhancing hedonic impact; interactions of NAc/VP hedonic hotspots with specific LH signals such as orexin; an anterior-posterior gradient of sites in NAc shell for producing intense appetitive eating versus intense fearful reactions; and anatomically distributed appetitive functions of dopamine and mu opioid signals in NAc shell and related structures. Such findings help improve our understanding of NAc, VP, and LH interactions in mediating affective and motivation functions, including ‘liking’ and ‘wanting’ for food rewards.

  12. Uptake and localization of 131I-labeled anti-calcitonin immunoglobulins in rat medullary thyroid carcinoma tissue

    International Nuclear Information System (INIS)

    Gautvik, K.M.; Svindahl, K.; Skretting, A.; Stenberg, B.; Myhre, L.; Ekeland, A.; Johannesen, J.V.

    1982-01-01

    A medullary carcinoma of the thyroid gland (MCT) which has been transplanted repeatedly under the kidney capsule of Wag/Rij rats secretes calcitonin (CT) spontaneously. From 10-20 weeks after transplantation, immunoreactive serum calcitonin (iCT) is abnormally elevated and continues to rise parallel to tumor growth. The immunoglobulin fraction of the rabbit anti-CT antiserum raised against intact synthetic hormone, was purified and iodinated electrolytically. Specific activities of 131 I-labeled immunoglobulin of 0.008-0.014 mCi/μg protein were obtained with 80% preservation of CT binding activity. Wag/Rij rats with MCT tumor and increased serum iCT concentrations received intravenous injections of 131 I-labeled immunoglobulins (0.54-0.811 mCi). The distribution of radioactivity in the rats was followed for 14 days using external scintigraphy in combination with radioactivity measurements of blood and different organs at the end of the observation period. The distribution of /sup 113m/In was used as a marker for blood distribution. When the radioactivity ratios ( 131 I//sup 113m/In) in tumor and different organs were related to that of blood which was equal to unity, tumor tissue contained 3-6 times higher activity. Nonhyperimmune rabbit immunoglobulins or rabbit antirat prolactin immunoglobulins were not concentrated in MCT tissue, nor did anti-CT immunoglobulins localize in rat prolactin adenomas

  13. Uptake and localization of 131I-labeled anti-calcitonin immunoglobulins in rat medullary thyroid carcinoma tissue

    International Nuclear Information System (INIS)

    Gautvik, K.M.; Svindahl, K.; Skretting, A.; Stenberg, B.; Myhre, L.; Ekeland, A.; Johannesen, J.V.

    1982-01-01

    A medullary carcinoma of the thyroid gland (MCT) which has been transplanted repeatedly under the kidney capsule of Wag/Rij rats secretes calcitonin (CT) spontaneously. From 10--20 weeks after transplantation, immunoreactive serum calcitonin (iCT) is abnormally elevated and continues to rise parallel to tumor growth. The immunoglobulin fraction of the rabbit anti-CT antiserum raised against intact synthetic hormone, was purified and iodinated electrolytically. Specific activities of 131 I-labeled immunoglobulin of 0.008--0.014 mCi/microgram protein were obtained with 80% preservation of CT binding activity. Wag/Rig rats with MCT tumor and increased serum iCT concentrations received intravenous injections of 131 I-labeled immunoglobulins (0.054--0.811 mCi). The distribution of radioactivity in the rats was followed for 14 days using external scintigraphy in combination with radioactivity measurements of blood and different organs at the end of the observation period. The distribution of 113 mIn was used as a marker for blood distribution. When the radioactivity ratios ( 131 I/ 113 mIn) in tumor and different organs were related to that of blood which was set equal to unity, tumor tissue contained 3--6 times higher activity. Nonhyperimmune rabbit immunoglobulins or rabbit antirat prolactin immunoglobulins were not concentrated in MCT tissue, nor did anti-CT immunoglobulins localize in rat prolactin adenomas

  14. Radiosensitivity of hematopoietic stem cells in diffusion chamber cultures of the murine yolk sac and adult medullary tissue

    International Nuclear Information System (INIS)

    Weinberg, S.R.; Stohlman, F. Jr.

    1976-01-01

    The radiosensitivity of hematopoietic progenitor cells derived from the 10 1 / 2 day murine yolk sac and adult murine bone marrow have been compared. A yolk sac cell suspension was exposed to varying amounts of gamma radiation (0 to 950 R) and the index used for radiosensitivity was the proliferation and differentiation of these cells cultured for 10 days in the millipore diffusion chamber. The data provided evidence that the hematopoietically active embryonic yolk sac is less radiosensitive than the adult mouse tibial marrow cells. A 10 1 / 2 day yolk sac cell suspension (5.182 +- 0.601 x 10 6 cells per yolk sac) contained at least 2.8 +- 1.1 pluripotential stem cells (colony-forming units, CFU) and 242 +- 31 committed stem cells (colony-forming cells, CFC). The results suggest the existence of a hematopoietic stem cell compartment in the yolk sac which is markedly different from that found in adult medullary tissue. Furthermore, there is a difference between the expressions of the differentiation potential of precursor cells of extraembryonic and of adult origin when exposed to similar microenvironments

  15. Rapid response of hypercortisolism to vandetanib treatment in a patient with advanced medullary thyroid cancer and ectopic Cushing syndrome

    International Nuclear Information System (INIS)

    Pitoia Fabian; Bueno, Fernanda; Schmidt, Angelica; Lucas, Sabrina; Cross, Graciela

    2015-01-01

    Medullary thyroid carcinoma (MTC) may rarely present with paraneoplastic syndromes. Among the most frequent ones are the appearance of diarrhea and ectopic Cushing syndrome (ECS). The ECS in the context of MTC is usually present in patients with distant metastatic disease. The use of drugs such as ketoconazole, metyrapone, somatostatin analogs and etomidate have been ineffective alternatives to control hypercortisolism in these patients. Bilateral adrenalectomy is often required to manage this situation. Recently, the use of tyrosine kinase inhibitors has been shown to be a useful tool to achieve eucortisolism in patients with metastatic MTC and ECS. We present a patient with sporadic advanced persistent and progressive MTC with lymph node and liver metastases, which after 16 years of followup developed an ECS. After one month of 300 mg/day vandetanib treatment, a biochemical and clinical response of the ECS was achieved but it did not result in significant reduction of tumor burden. However the patient reached criteria for stable disease according to response evaluation criteria in solid tumors (RECIST 1.1) after 8 months of follow-up. (author)

  16. Radioimmunoassay of human calcitonin in serum and tissue from healthy individuals and patients with medullary carcinoma of the thyroid gland

    International Nuclear Information System (INIS)

    Gautvik, K.M.; Normann, T.; Teig, V.; Wille, S.Oe.; Brennhovd, I.O.; Christensen, I.

    1976-01-01

    A specific radioimmunological method for measurement of immunoreactive calcitonin (iCT) in human serum and tissue is described. Of healthy individuals of both sexes, 85 % had measurable iCT in serum (mean, 0.23 ng/ml). Of 29 patients who had received treatment for medullary carcinoma of the thyroid gland (MCT), 19 had increased serum iCT (0-60 ng/ml to205 ng/ml). Elevated serum iCT was also found preoperatively in 2 MCT patients. Eleven of the patients with abnormal elevations of serum iCT were alive 4 to 13 years after the operation. Concentration of iCT in extracts from MCT varied from 0.5 to 540 ng/ml wet weight. The diagnostic value of this method and its importance for pre- and post-operative evaluation of these patients are improved by the use of selective venous catheterization in basal state and during stimulation of CT secretion. (Auth.)

  17. Responses of medullary lateral line units of the rudd, Scardinius erythrophthalmus, and the nase, Chondrostoma nasus, to vortex streets.

    Science.gov (United States)

    Winkelnkemper, Jan; Kranz, Simon; Bleckmann, Horst

    2018-02-01

    Fish use their mechanosensory lateral line amongst others for the detection of vortices shed by an upstream object and/or for the detection of vortices caused by the tail fin movements of another fish. Thus, vortices are one type of hydrodynamic stimuli to which fish are exposed in their natural environment. We investigated the responses of medullary lateral line units of common rudd, Scardinius erythrophthalmus, and common nase, Chondrostoma nasus (Cyprinidae), to water flow (9.5-13.3 cm -1 ) that contained vortices (a Kármán vortex street) shed by an upstream cylinder (diameter 2 cm). The distance between the cylinder and the tip of the fish's snout varied between 8 and 24 cm. 21 out of 42 units (S. erythrophthalmus), respectively, 9 out of 39 units (Chondrostoma nasus) responded to the vortices shed by the cylinder. Up to a cylinder distance of 24 cm, interburst intervals revealed the vortex shedding frequency, i.e., burst frequency was similar to or identical with the vortex shedding frequency.

  18. Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer.

    Science.gov (United States)

    Sponziello, Marialuisa; Benvenuti, Silvia; Gentile, Alessandra; Pecce, Valeria; Rosignolo, Francesca; Virzì, Anna Rita; Milan, Melissa; Comoglio, Paolo M; Londin, Eric; Fortina, Paolo; Barnabei, Agnese; Appetecchia, Marialuisa; Marandino, Ferdinando; Russo, Diego; Filetti, Sebastiano; Durante, Cosimo; Verrienti, Antonella

    2018-03-01

    Whole exome sequencing (WES) was used to investigate two Italian siblings with wild-type RET genotype, who developed medullary thyroid cancers (MTCs) and, later, primary prostate and breast cancers, respectively. The proband's MTC harbored a p.Met918Thr RET mutation; his sister's MTC was RET/RAS wild-type. Both siblings had a germline mutation (p.Arg417Gln) in the extracellular Sema domain of the proto-oncogene MET. Experiments involving ectopic expression of MET p.Arg417Gln in MET-negative T47D breast cancer cells documented the mutant receptor's functionality and its ability to enhance cell migration and invasion. Our findings highlight a possible link between MET germline mutations and MTCs and suggest that MET p. Arg417Gln may promote an invasive malignant phenotype. The possibility that MTC can be driven/co-driven by a MET mutation has potential management implications, since the tyrosine-kinase inhibitor cabozantinib-approved for treating advanced MTCs-is a specific MET inhibitor. © 2017 Wiley Periodicals, Inc.

  19. Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma

    Directory of Open Access Journals (Sweden)

    Mehdi Hedayati

    2011-01-01

    Full Text Available Medullary thyroid carcinoma occurs in both sporadic (75% and hereditary (25% forms. The missense mutations of RET proto-oncogene in MTC development have been well demonstrated. To investigate the spectrum of predominant RET germline mutations in exons 10, 11, and 16 in hereditary MTC in Iranian population, 217 participants were included. Genomic DNAs were extracted from the leukocytes using the standard Salting Out/Proteinase K method. Mutation detection was performed through PCR-RFLP and DNA sequencing. In 217 participants, 43 missense mutations were identified in exons 10 (6%, 11 (13%, and 16 (0.9%. Moreover, a novel germline mutation was detected in exon 11 (S686N. Also four different polymorphisms were found in intron 16 in eight patients. The obtained data showed the frequency profile of RET mutations in Iranian individuals with MTC (19.8%. The most frequent mutation in our population was C634G whereas in most population it was C634R. Altogether, these results underline the importance of the genetic background of family members of any patient with MTC.

  20. Plasma Calcitonin Levels and miRNA323 Expression in Medullary Thyroid Carcinoma Patients with or without RET Mutation

    Science.gov (United States)

    Ehyaei, Samira; Hedayati, Mehdi; Zarif-Yeganeh, Marjan; Sheikholeslami, Sara; Ahadi, Mahsa; Amini, Sayed Asadollah

    2017-08-27

    Background: Medullary thyroid cancer (MTC) is an endocrine tumor featuring parafollicular or C-cell differentiation, with calcitonin as a specific biomarker in MTC diagnosis. Germline mutations in the RET proto-oncogene are considered responsible for its familial occurrence and somatic mutations can cause sporadic lesions. MicroRNAs can act as oncogenes or tumor suppressors by inhibiting the expression of target genes.. The aim of this study was to investigate relationships between plasma levels of calcitonin and miRNA323 expression in MTC patients with or without RET mutation. Methods: In this cross-sectional study, MTC lesions (based on pathological confirmation) were investigated. Genomic DNA was extracted and Exons 10 and 11 of RET were genotyped using PCR-sequencing. Division was into two groups of 43 cases each with or without mutation. Plasma levels of calcitonin were determined in both. Results: miRNA323 was measured using real-time-PCR. After performing normality tests, independent T-tests and Mann Whitney tests were used for the statistical comparison of parametric and nonparametric data, respectively. Plasma levels of calcitonin were significantly higher in MTC cases without a RET mutation compared to those with a mutation. Conclusion: There was no significant difference between the two groups regarding the expression of miRNA323 so that this parameter could not be used as a bio-index germ line mutations in MTCs. However, determination of calcitonin levels in plasma might be helpful in this regard. Creative Commons Attribution License

  1. Mutations of codon 918 in the RET proto-oncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Zedenius, J.; Svensson, A.; Baeckdahl, M.; Wallin, G. [Karolinska Hospital, Stockholm (Sweden)] [and others

    1995-10-01

    The hereditary multiple endocrine neoplasia syndromes types 2A and B (MEN 2A and B) were recently linked to germline mutations in the RET proto-oncogene, altering one of five cysteine residues in exon 10 or 11 (MEN 2A), or substituting a methionine for a threonine at codon 918 in exon 16 (MEN 2B). The latter mutation also occurs somatically in some sporadic medullary thyroid carcinomas (MTC), and has in a previous study been correlated with a less favorable clinical outcome. In the present study, 46 MTCs were selected for investigation of the codon 918 mutation. The mutation was found in 29 tumors (63%), and was significantly correlated with a poor outcome, with regard to distant metastasis or tumor recurrence (p<10{sup 4}). Two tumors showed multifocal growth and C-cell hyperplasia, and these patients were therefore also investigated for germline mutations in exons 10, 11 and 16. The codon 918 mutation was found only in the tumors, thus of somatic origin. The RET codon 918 mutation may have prognostic impact, and therefore preoperative assessment may influence decision-making in the treatment of patients suffering from MTC. 13 refs., 1 fig., 1 tab.

  2. High prevalence of exon 8 G533C mutation in apparently sporadic medullary thyroid carcinoma in Greece.

    Science.gov (United States)

    Sarika, H L; Papathoma, A; Garofalaki, M; Vasileiou, V; Vlassopoulou, B; Anastasiou, E; Alevizaki, M

    2012-12-01

    Genetic screening for ret mutation has become routine practice in the evaluation of medullary thyroid carcinoma (MTC). Approximately 25% of these tumours are familial, and they occur as components of the multiple endocrine neoplasia type 2 syndromes (MEN 2A and 2B) or familial MTC. In familial cases, the majority of mutations are found in exons 10, 11, 13, 14 or 15 of the ret gene. A rare mutation involving exon 8 (G533C) has recently been reported in familial cases of MTC in Brazil and Greece; some of these cases were originally thought to be sporadic. The aim of this study was to re-evaluate a series of sporadic cases of MTC, with negative family history, and screen them for germline mutations in exon 8. Genomic DNA was extracted from peripheral lymphocytes in 129 unrelated individuals who had previously been characterized as 'sporadic' based on the negative family history and negative screening for ret gene mutations. Samples were analysed in Applied Biosystems 7500 real-time PCR and confirmed by sequencing. The G533C exon 8 mutation was identified in 10 of 129 patients with sporadic MTC. Asymptomatic gene carriers were subsequently identified in other family members. In our study, we found that 7·75% patients with apparently sporadic MTC do carry G533C mutation involving exon 8 of ret. We feel that there is now a need to include exon 8 mutation screening in all patients diagnosed as sporadic MTC, in Greece. © 2012 Blackwell Publishing Ltd.

  3. Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration.

    Science.gov (United States)

    Plaas, Mario; Seppa, Kadri; Reimets, Riin; Jagomäe, Toomas; Toots, Maarja; Koppel, Tuuliki; Vallisoo, Tuuli; Nigul, Mait; Heinla, Indrek; Meier, Riho; Kaasik, Allen; Piirsoo, Andres; Hickey, Miriam A; Terasmaa, Anton; Vasar, Eero

    2017-08-31

    Wolfram syndrome (WS) is a rare autosomal-recessive disorder that is caused by mutations in the WFS1 gene and is characterized by juvenile-onset diabetes, optic atrophy, hearing loss and a number of other complications. Here, we describe the creation and phenotype of Wfs1 mutant rats, in which exon 5 of the Wfs1 gene is deleted, resulting in a loss of 27 amino acids from the WFS1 protein sequence. These Wfs1-ex5-KO232 rats show progressive glucose intolerance, which culminates in the development of diabetes mellitus, glycosuria, hyperglycaemia and severe body weight loss by 12 months of age. Beta cell mass is reduced in older mutant rats, which is accompanied by decreased glucose-stimulated insulin secretion from 3 months of age. Medullary volume is decreased in older Wfs1-ex5-KO232 rats, with the largest decreases at the level of the inferior olive. Finally, older Wfs1-ex5-KO232 rats show retinal gliosis and optic nerve atrophy at 15 months of age. Electron microscopy revealed axonal degeneration and disorganization of the myelin in the optic nerves of older Wfs1-ex5-KO232 rats. The phenotype of Wfs1-ex5-KO232 rats indicates that they have the core symptoms of WS. Therefore, we present a novel rat model of WS.

  4. Structure of a shear-thickening polysaccharide extracted from the New Zealand black tree fern, Cyathea medullaris.

    Science.gov (United States)

    Wee, May S M; Matia-Merino, Lara; Carnachan, Susan M; Sims, Ian M; Goh, Kelvin K T

    2014-09-01

    A shear-thickening water-soluble polysaccharide was purified from mucilage extracted from the fronds of the New Zealand black tree fern (Cyathea medullaris or 'mamaku' in Māori) and its structure characterised. Constituent sugar analysis by three complementary methods, combined with linkage analysis (of carboxyl reduced samples) and 1H and 13C nuclear magnetic resonance spectroscopy (NMR) revealed a glucuronomannan comprising a backbone of 4-linked methylesterified glucopyranosyl uronic acid and 2-linked mannopyranosyl residues, branched at O-3 of 45% and at both O-3 and O-4 of 53% of the mannopyranosyl residues with side chains likely comprising terminal xylopyranosyl, terminal galactopyranosyl, non-methylesterified terminal glucopyranosyl uronic acid and 3-linked glucopyranosyl uronic acid residues. The weight-average molecular weight of the purified polysaccharide was ∼1.9×10(6) Da as determined by size-exclusion chromatography coupled with multi-angle laser light scattering (SEC-MALLS). The distinctive rheological properties of this polysaccharide are discussed in relation to its structure. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Rapid response of hypercortisolism to vandetanib treatment in a patient with advanced medullary thyroid cancer and ectopic Cushing syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Pitoia Fabian; Bueno, Fernanda; Schmidt, Angelica; Lucas, Sabrina; Cross, Graciela, E-mail: fpitoia@intramed.net [Division de Endocrinologia, Hospital de Clinicas, Universidad de Buenos Aires Buenos Aires (Argentina)

    2015-08-15

    Medullary thyroid carcinoma (MTC) may rarely present with paraneoplastic syndromes. Among the most frequent ones are the appearance of diarrhea and ectopic Cushing syndrome (ECS). The ECS in the context of MTC is usually present in patients with distant metastatic disease. The use of drugs such as ketoconazole, metyrapone, somatostatin analogs and etomidate have been ineffective alternatives to control hypercortisolism in these patients. Bilateral adrenalectomy is often required to manage this situation. Recently, the use of tyrosine kinase inhibitors has been shown to be a useful tool to achieve eucortisolism in patients with metastatic MTC and ECS. We present a patient with sporadic advanced persistent and progressive MTC with lymph node and liver metastases, which after 16 years of followup developed an ECS. After one month of 300 mg/day vandetanib treatment, a biochemical and clinical response of the ECS was achieved but it did not result in significant reduction of tumor burden. However the patient reached criteria for stable disease according to response evaluation criteria in solid tumors (RECIST 1.1) after 8 months of follow-up. (author)

  6. Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate

    OpenAIRE

    Mansson, Robert; Welinder, Eva; Åhsberg, Josefine; Lin, Yin C.; Benner, Christopher; Glass, Christopher K.; Lucas, Joseph S.; Sigvardsson, Mikael; Murre, Cornelis

    2012-01-01

    Recent studies have identified a number of transcriptional regulators, including E2A, early B-cell factor 1 (EBF1), FOXO1, and paired box gene 5 (PAX5), that promote early B-cell development. However, how this ensemble of regulators mechanistically promotes B-cell fate remains poorly understood. Here we demonstrate that B-cell development in FOXO1-deficient mice is arrested in the common lymphoid progenitor (CLP) LY6D+ cell stage. We demonstrate that this phenotype closely resembles the arres...

  7. Alterations of the autoimmune regulator transcription factor and failure of central tolerance: APECED as a model.

    Science.gov (United States)

    Gallo, Vera; Giardino, Giuliana; Capalbo, Donatella; Palamaro, Loredana; Romano, Rosa; Santamaria, Francesca; Maio, Filomena; Salerno, Mariacarolina; Vajro, Pietro; Pignata, Claudio

    2013-01-01

    Self-nonself discrimination plays a key role in inducing a productive immunity and in preventing autoimmune reactions. Central tolerance within the thymus and peripheral tolerance in peripheral lymphoid organs lead to immunologic nonresponsiveness against self-components. The central tolerance represents the mechanism by which T cells binding with high avidity to self-antigens are eliminated through the so-called negative selection. Thymic medullary epithelial cells and medullary dendritic cells play a key role in this process, through the expression of a large number of tissue-specific self-antigens involving the transcription factor autoimmune regulator (AIRE). Mutations of AIRE result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, a rare autosomal recessive disease (OMIM 240300), which is the paradigm of a genetically determined failure of central tolerance and autoimmunity. This review focuses on recent advances in the molecular mechanisms of central tolerance, their alterations and clinical implication.

  8. Determining the control circuitry of redox metabolism at the genome-scale.

    Directory of Open Access Journals (Sweden)

    Stephen Federowicz

    2014-04-01

    Full Text Available Determining how facultative anaerobic organisms sense and direct cellular responses to electron acceptor availability has been a subject of intense study. However, even in the model organism Escherichia coli, established mechanisms only explain a small fraction of the hundreds of genes that are regulated during electron acceptor shifts. Here we propose a qualitative model that accounts for the full breadth of regulated genes by detailing how two global transcription factors (TFs, ArcA and Fnr of E. coli, sense key metabolic redox ratios and act on a genome-wide basis to regulate anabolic, catabolic, and energy generation pathways. We first fill gaps in our knowledge of this transcriptional regulatory network by carrying out ChIP-chip and gene expression experiments to identify 463 regulatory events. We then interfaced this reconstructed regulatory network with a highly curated genome-scale metabolic model to show that ArcA and Fnr regulate >80% of total metabolic flux and 96% of differential gene expression across fermentative and nitrate respiratory conditions. Based on the data, we propose a feedforward with feedback trim regulatory scheme, given the extensive repression of catabolic genes by ArcA and extensive activation of chemiosmotic genes by Fnr. We further corroborated this regulatory scheme by showing a 0.71 r(2 (p<1e-6 correlation between changes in metabolic flux and changes in regulatory activity across fermentative and nitrate respiratory conditions. Finally, we are able to relate the proposed model to a wealth of previously generated data by contextualizing the existing transcriptional regulatory network.

  9. Histamine modulation of the basal ganglia circuitry in the development of pathological grooming

    Science.gov (United States)

    Rapanelli, Maximiliano; Frick, Luciana

    2017-01-01

    Aberrant histaminergic function has been proposed as a cause of tic disorders. A rare mutation in the enzyme that produces histamine (HA), histidine decarboxylase (HDC), has been identified in patients with Tourette syndrome (TS). Hdc knockout mice exhibit repetitive behavioral pathology and neurochemical characteristics of TS, establishing them as a plausible model of tic pathophysiology. Where, when, and how HA deficiency produces these effects has remained unclear: whether the contribution of HA deficiency to pathogenesis is acute or developmental, and where in the brain the relevant consequences of HA deficiency occur. Here, we address these key pathophysiological questions, using anatomically and cellularly targeted manipulations in mice. We report that specific ablation or chemogenetic silencing of histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus leads to markedly elevated grooming, a form of repetitive behavioral pathology, and to elevated markers of neuronal activity in both dorsal striatum and medial prefrontal cortex. Infusion of HA directly into the striatum reverses this behavioral pathology, confirming that acute HA deficiency mediates the effect. Bidirectional chemogenetic regulation reveals that dorsal striatum neurons activated after TMN silencing are both sufficient to produce repetitive behavioral pathology and necessary for the full expression of the effect. Chemogenetic activation of TMN-regulated medial prefrontal cortex neurons, in contrast, increases locomotion and not grooming. These data confirm the centrality of striatal regulation by neurotransmitter HA in the adult in the production of pathological grooming. PMID:28584117

  10. In search of the next memory inside the circuitry from the oldest to the emerging non-volatile memories

    CERN Document Server

    Campardo, Giovanni

    2017-01-01

    This book provides students and practicing chip designers with an easy-to-follow yet thorough, introductory treatment of the most promising emerging memories under development in the industry. Focusing on the chip designer rather than the end user, this book offers expanded, up-to-date coverage of emerging memories circuit design. After an introduction on the old solid-state memories and the fundamental limitations soon to be encountered, the working principle and main technology issues of each of the considered technologies (PCRAM, MRAM, FeRAM, ReRAM) are reviewed and a range of topics related to design is explored: the array organization, sensing and writing circuitry, programming algorithms and error correction techniques are reviewed comparing the approach followed and the constraints for each of the technologies considered. Finally the issue of radiation effects on memory devices has been briefly treated. Additionally some considerations are entertained about how emerging memories can find a place in the...

  11. Revealing the Structural Neural Circuitry of Attention Deficit Hyperactivity Disorder With Diffusion MRI: Implications for Future Diagnosis and Treatment.

    Science.gov (United States)

    Adisetiyo, Vitria

    2018-04-01

    Rates of attention deficit hyperactivity disorder (ADHD) diagnosis and psychostimulant prescriptions continue to rise, yet there are no clear diagnostic tests or biomarkers for the disorder. The purpose of this article is to highlight the role of diffusion MRI in bolstering a neurobiologic conceptualization of ADHD and how this holds promise for optimizing future diagnosis. Diffusion MRI is a powerful neuroimaging tool for noninvasive assessment of the structural neural circuitry underlying brain function and behavior. Though the modality is still in its infancy, diffusion MRI studies are showing neural network disruption in ADHD consistent with findings from other imaging modalities. Given the mounting evidence of brain-behavior correlates in ADHD, it is likely that imaging-based biomarkers will one day be incorporated into clinical diagnosis and treatment evaluation. Until then, diffusion MRI findings serve to validate ADHD as a brain-based disorder with immediate public health implications for individuals with ADHD.

  12. Expression of the Autoimmune Regulator Gene and Its Relevance to the Mechanisms of Central and Peripheral Tolerance

    OpenAIRE

    Perniola, Roberto

    2012-01-01

    The autoimmune polyendocrine syndrome type 1 (APS-1) is a monogenic disease due to pathogenic variants occurring in the autoimmune regulator (AIRE) gene. Its related protein, AIRE, activates the transcription of genes encoding for tissue-specific antigens (TsAgs) in a subset of medullary thymic epithelial cells: the presentation of TsAgs to the maturating thymocytes induces the apoptosis of the autoreactive clones and constitutes the main form of central tolerance. Dysregulation of thymic AIR...

  13. Do cognitive measures and brain circuitry predict outcomes of exercise in Parkinson Disease: a randomized clinical trial.

    Science.gov (United States)

    King, L A; Peterson, D S; Mancini, M; Carlson-Kuhta, P; Fling, B W; Smulders, K; Nutt, J G; Dale, M; Carter, J; Winters-Stone, K M; Horak, F B

    2015-10-24

    There is emerging research detailing the relationship between balance/gait/falls and cognition. Imaging studies also suggest a link between structural and functional changes in the frontal lobe (a region commonly associated with cognitive function) and mobility. People with Parkinson's disease have important changes in cognitive function that may impact rehabilitation efficacy. Our underlying hypothesis is that cognitive function and frontal lobe connections with the basal ganglia and brainstem posture/locomotor centers are responsible for postural deficits in people with Parkinson's disease and play a role in rehabilitation efficacy. The purpose of this study is to 1) determine if people with Parkinson's disease can improve mobility and/or cognition after partaking in a cognitively challenging mobility exercise program and 2) determine if cognition and brain circuitry deficits predict responsiveness to exercise rehabilitation. This study is a randomized cross-over controlled intervention to take place at a University Balance Disorders Laboratory. The study participants will be people with Parkinson's disease who meet inclusion criteria for the study. The intervention will be 6 weeks of group exercise (case) and 6 weeks of group education (control). The exercise is a cognitively challenging program based on the Agility Boot Camp for people with PD. The education program is a 6-week program to teach people how to better live with a chronic disease. The primary outcome measure is the MiniBESTest and the secondary outcomes are measures of mobility, cognition and neural imaging. The results from this study will further our understanding of the relationship between cognition and mobility with a focus on brain circuitry as it relates to rehabilitation potential. This trial is registered at clinical trials.gov (NCT02231073).

  14. Ventilatory response to hypercapnia and hypoxia after extensive lesion of medullary serotonergic neurons in newborn conscious piglets.

    Science.gov (United States)

    Penatti, E M; Berniker, A V; Kereshi, B; Cafaro, C; Kelly, M L; Niblock, M M; Gao, H G; Kinney, H C; Li, A; Nattie, E E

    2006-10-01

    Acute inhibition of serotonergic (5-HT) neurons in the medullary raphé (MR) using a 5-HT(1A) receptor agonist had an age-dependent impact on the "CO(2) response" of piglets (33). Our present study explored the effect of chronic 5-HT neuron lesions in the MR and extra-raphé on the ventilatory response to hypercapnia and hypoxia in piglets, with possible implications on the role of 5-HT in the sudden infant death syndrome. We established four experimental groups. Group 1 (n = 11) did not undergo any treatment. Groups 2, 3, and 4 were injected with either vehicle or the neurotoxin 5,7-dihydroxytryptamine in the cisterna magna during the first week of life (group 2, n = 9; group 4, n = 11) or second week of life (group 3, n = 10). Ventilation was recorded in response to 5% CO(2) (all groups) and 12% O(2) (group 2) during wakefulness and sleep up to postnatal day 25. Surprisingly, the piglets did not reveal changes in their CO(2) sensitivity during early postnatal development. Overall, considerable lesions of 5-HT neurons (up to 65% decrease) in the MR and extra-raphé had no impact on the CO(2) response, regardless of injection time. Postlesion raphé plasticity could explain why we observed no effect. 5,7-Dihydroxytryptamine-treated males, however, did present a lower CO(2) response during sleep. Hypoxia significantly altered the frequency during sleep in lesioned piglets. Further studies are necessary to elucidate the role of plasticity, sex, and 5-HT abnormalities in sudden infant death syndrome.

  15. Imprinted ZnO nanostructure-based electrochemical sensing of calcitonin: A clinical marker for medullary thyroid carcinoma

    International Nuclear Information System (INIS)

    Patra, Santanu; Roy, Ekta; Madhuri, Rashmi; Sharma, Prashant K.

    2015-01-01

    Highlights: • Molecular imprinting-based sensor for medullary thyroid carcinoma marker was developed. • ZnO nanostructure was used as a platform for synthesis of imprinted polymer. • Imprinted polymer was prepared by ARGET–ATRP method. • A novel and biocompatible tyrosine amino acid derivative was used as monomer. • Linear working range is found from 9.99 ng L −1 to 7.919 mg L −1 with LOD 3.09 ng L −1 . - Abstract: The present work describes an exciting method for the selective and sensitive determination of calcitonin in human blood serum samples. Adopting the surface molecular imprinting technique, a calcitonin-imprinted polymer was prepared on the surface of the zinc oxide nanostructure. Firstly, a biocompatible tyrosine derivative as a monomer was grafted onto the surface of zinc oxide nanostructure followed by their polymerization on vinyl functionalized electrode surface by activator regenerated by electron transfer–atom transfer radical polymerization (ARGET–ATRP) technique. Such sensor can predict the small change in the concentration of calcitonin in the human body and it may also consider to be as cost-effective, renewable, disposable, and reliable for clinical studies having no such cross-reactivity and matrix effect from real samples. The morphologies and properties of the proposed sensor were characterized by scanning electron microscopy, cyclic voltammetry, difference pulse voltammetry and chronocoulometry. The linear working range was found to be 9.99 ng L −1 to 7.919 mg L −1 and the detection limit as low as 3.09 ± 0.01 ng L −1 (standard deviation for three replicate measurements) (S/N = 3)

  16. Somatostatin receptor scintigraphy using {sup 99m}Tc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Czepczynski, Rafal; Kosowicz, Jerzy; Ziemnicka, Katarzyna; Gryczynska, Maria; Sowinski, Jerzy [Poznan University of Medical Sciences, Department of Endocrinology, Przybyszewskiego 49, Poznan (Poland); Parisella, Maria G. [University Sapienza, Nuclear Medicine, Ospedale S. Andrea, Rome (Italy); Mikolajczak, Renata [Radioisotope Centre POLATOM, Otwock-Swierk (Poland); Signore, Alberto [University Sapienza, Nuclear Medicine, Ospedale S. Andrea, Rome (Italy); University of Groningen, Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen (Netherlands)

    2007-10-15

    Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin analogue {sup 99m}Tc-EDDA/HYNIC-TOC in MTC in comparison with other diagnostic techniques. Forty-five patients with MTC, aged 14-83 years, were investigated. Scintigraphy using {sup 99m}Tc-EDDA/HYNIC-TOC (Tektrotyd) was performed 2 and 4 h post injection of 740 MBq (20 mCi) of the tracer. Other imaging techniques were also applied and analysed in individual cases (ultrasonography, computed tomography, {sup 99m}Tc(V)-DMSA, {sup 131}I-MIBG, {sup 99m}Tc-MDP, {sup 111}In-DTPA-octreotide and {sup 18}F-FDG-PET) and compared with {sup 99m}Tc-EDDA/HYNIC-TOC. In group 1 (eight patients before thyroidectomy), uptake of the tracer was found in the primary tumours. In group 2 (six patients with remission), a false positive result was found in one patient; in the remaining five patients, no pathological foci were visualised. In group 3 (31 patients with post-surgical hypercalcitoninaemia), scintigraphy was true positive in 23 patients (74.2%): uptake in the thyroid bed was found in five patients, in the lymph nodes in 18 and in bone metastases in four. Using {sup 99m}Tc-EDDA/HYNIC-TOC scintigraphy, the overall sensitivity was 79.5%, specificity 83.3%, accuracy 80.0%, positive predictive value 96.9% and negative predictive value 38.5%. {sup 99m}Tc-EDDA/HYNIC-TOC is clinically useful for scintigraphy in the follow-up of patients with MTC. It can be used in clinical practice for preoperative evaluation, for localisation of local recurrence or distant metastases and particularly for therapy decision making. (orig.)

  17. Somatostatin receptor scintigraphy using 99mTc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma.

    Science.gov (United States)

    Czepczyński, Rafał; Parisella, Maria Gemma; Kosowicz, Jerzy; Mikołajczak, Renata; Ziemnicka, Katarzyna; Gryczyńska, Maria; Sowiński, Jerzy; Signore, Alberto

    2007-10-01

    Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin analogue (99m)Tc-EDDA/HYNIC-TOC in MTC in comparison with other diagnostic techniques. Forty-five patients with MTC, aged 14-83 years, were investigated. Scintigraphy using (99m)Tc-EDDA/HYNIC-TOC (Tektrotyd) was performed 2 and 4 h post injection of 740 MBq (20 mCi) of the tracer. Other imaging techniques were also applied and analysed in individual cases (ultrasonography, computed tomography, (99m)Tc(V)-DMSA, (131)I-MIBG, (99m)Tc-MDP, (111)In-DTPA-octreotide and (18)F-FDG-PET) and compared with (99m)Tc-EDDA/HYNIC-TOC. In group 1 (eight patients before thyroidectomy), uptake of the tracer was found in the primary tumours. In group 2 (six patients with remission), a false positive result was found in one patient; in the remaining five patients, no pathological foci were visualised. In group 3 (31 patients with post-surgical hypercalcitoninaemia), scintigraphy was true positive in 23 patients (74.2%): uptake in the thyroid bed was found in five patients, in the lymph nodes in 18 and in bone metastases in four. Using (99m)Tc-EDDA/HYNIC-TOC scintigraphy, the overall sensitivity was 79.5%, specificity 83.3%, accuracy 80.0%, positive predictive value 96.9% and negative predictive value 38.5%. (99m)Tc-EDDA/HYNIC-TOC is clinically useful for scintigraphy in the follow-up of patients with MTC. It can be used in clinical practice for preoperative evaluation, for localisation of local recurrence or distant metastases and particularly for therapy decision making.

  18. Demonstration of a potent RET transcriptional inhibitor for the treatment of medullary thyroid carcinoma based on an ellipticine derivative.

    Science.gov (United States)

    Kumarasamy, Vishnu Muthuraj; Sun, Daekyu

    2017-07-01

    Dominant-activating mutations in the RET (rearranged during transfection) proto-oncogene, which encodes a receptor tyrosine kinase, is often associated with the development of medullary thyroid carcinoma (MTC). The proximal promoter region of the RET gene consists of a guanine-rich sequence containing five runs of three consecutive guanine residues that serve as the binding site for transcriptional factors. As we have recently shown, this stretch of nucleotides in the promoter region is highly dynamic in nature and tend to form non-B DNA secondary structures called G-quadruplexes, which suppress the transcription of the RET gene. In the present study, ellipticine and its derivatives were identified as excellent RET G-quadruplex stabilizing agents. Circular dichroism (CD) spectroscopic studies revealed that the incorporation of a piperidine ring in an ellipticine derivative, NSC311153 improves its binding with the G-quadruplex structure and the stability induced by this compound is more potent than ellipticine. Furthermore, this compound also interfered with the transcriptional mechanism of the RET gene in an MTC derived cell line, TT cells and significantly decreased the endogenous RET protein expression. We demonstrated the specificity of NSC311153 by using papillary thyroid carcinoma (PTC) cells, the TPC1 cell line which lacks the G-quadruplex forming sequence in the promoter region due to chromosomal rearrangement. The RET downregulation selectively suppresses cell proliferation by inhibiting the intracellular Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways in the TT cells. In the present study, we also showed that the systemic administration of a water soluble NSC311153 analog in a mouse MTC xenograft model inhibited the tumor growth through RET downregulation.

  19. Prognostic Significance of Circulating RET M918T Mutated Tumor DNA in Patients With Advanced Medullary Thyroid Carcinoma.

    Science.gov (United States)

    Cote, Gilbert J; Evers, Caitlin; Hu, Mimi I; Grubbs, Elizabeth G; Williams, Michelle D; Hai, Tao; Duose, Dzifa Y; Houston, Michal R; Bui, Jacquelin H; Mehrotra, Meenakshi; Waguespack, Steven G; Busaidy, Naifa L; Cabanillas, Maria E; Habra, Mouhammed Amir; Luthra, Rajyalakshmi; Sherman, Steven I

    2017-09-01

    Interpretation of calcitonin measurement to predict the prognosis of medullary thyroid carcinoma (MTC) requires multiple measurements over an extended time period, making it an imperfect biomarker for evaluating prognosis or disease behavior. Single circulating cell-free DNA (cfDNA) values have been shown to be a valuable prognostic marker for several solid tumors. We tested the hypothesis that cfDNA containing the RET M918T mutation could be detected in the blood of patients with advanced MTC whose tumor harbored an M918T mutation and would be able to predict overall survival more reliably than calcitonin. The level of cfDNA containing RET M918T mutation was measured in the plasma of patients with MTC via droplet digital polymerase chain reaction. Patients had a confirmed sporadic MTC diagnosis, a serum calcitonin measurement >100 pg/mL, and tumor tissue biopsy results providing RET M918T mutation status. There were 75 patients included in this study, 50 of whom harbored an RET M918T mutation by tissue biopsy. RET M918T cfDNA was detected in 16 of 50 patients (32%) with a positive tissue biopsy. The detection of RET M918T cfDNA strongly correlated with worse overall survival and more accurately predicted a worse outcome than calcitonin doubling time. Liquid biopsy is able to detect RET M918T mutations in patient plasma with high specificity but low sensitivity. In patients with established somatic RET M918T mutations, the allelic fraction of circulating tumor DNA is prognostic for overall survival and may play a role in monitoring response to treatment. Copyright © 2017 Endocrine Society

  20. Central sensitization of nociceptive neurons in rat medullary dorsal horn involves purinergic P2X7 receptors.

    Science.gov (United States)

    Itoh, K; Chiang, C-Y; Li, Z; Lee, J-C; Dostrovsky, J O; Sessle, B J

    2011-09-29

    Central sensitization is a crucial process underlying the increased neuronal excitability of nociceptive pathways following peripheral tissue injury and inflammation. Our previous findings have suggested that extracellular adenosine 5'-triphosphate (ATP) molecules acting at purinergic receptors located on presynaptic terminals (e.g., P2X2/3, P2X3 subunits) and glial cells are involved in the glutamatergic-dependent central sensitization induced in medullary dorsal horn (MDH) nociceptive neurons by application to the tooth pulp of the inflammatory irritant mustard oil (MO). Since growing evidence indicates that activation of P2X7 receptors located on glia is involved in chronic inflammatory and neuropathic pain, the aim of the present study was to test in vivo for P2X7 receptor involvement in this acute inflammatory pain model. Experiments were carried out in anesthetized Sprague-Dawley male rats. Single unit recordings were made in MDH functionally identified nociceptive neurons for which mechanoreceptive field, mechanical activation threshold and responses to noxious stimuli were tested. We found that continuous intrathecal (i.t.) superfusion over MDH of the potent P2X7 receptor antagonists brilliant blue G and periodated oxidized ATP could each significantly attenuate the MO-induced MDH central sensitization. MDH central sensitization could also be produced by i.t. superfusion of ATP and even more effectively by the P2X7 receptor agonist benzoylbenzoyl ATP. Superfusion of the microglial blocker minocycline abolished the MO-induced MDH central sensitization, consistent with reports that dorsal horn P2X7 receptors are mostly expressed on microglia. In control experiments, superfusion over MDH of vehicle did not produce any significant changes. These novel findings suggest that activation of P2X7 receptors in vivo may be involved in the development of central sensitization in an acute inflammatory pain model. Copyright © 2011 IBRO. All rights reserved.

  1. Central α-adrenoceptors contribute to mustard oil-induced central sensitization in the rat medullary dorsal horn.

    Science.gov (United States)

    Wang, H; Xie, Y F; Chiang, C Y; Dostrovsky, J O; Sessle, B J

    2013-04-16

    Our previous studies have demonstrated that application of the inflammatory irritant mustard oil (MO) to the tooth pulp produces trigeminal central sensitization that includes increases in mechanoreceptive field size and responses to noxious stimuli and decrease in activation threshold in brainstem nociceptive neurons of trigeminal subnucleus caudalis (the medullary dorsal horn, MDH). The aim of the present study was to test if central noradrenergic processes are involved in the central sensitization of MDH neurons and if α1-adrenoceptors or α2-adrenoceptors or both are involved. In urethane/α-chloralose-anesthetized rats, the activity of extracellularly recorded and functionally identified single nociceptive neurons in the MDH was studied. Continuous intrathecal (i.t.) superfusion of the adrenergic modulator guanethidine and α-adrenoceptor blocker phentolamine or selective α1-adrenoceptor antagonist prazosin over the medulla strongly attenuated all three MO-induced parameters of central sensitization in the MDH nociceptive neurons, compared to phosphate-buffered saline (as vehicle control). In contrast, i.t. superfusion of the selective α2-adrenoceptor antagonist yohimbine had little effect on the mechanoreceptive field expansion and the decreased mechanical activation threshold, and indeed facilitated responses to noxious stimuli of sensitized nociceptive neurons. Superfusion of each of the four chemicals alone did not affect baseline nociceptive neuronal properties. These findings provide the first documentation of the involvement of central noradrenergic processes in MDH in the development of the central sensitization, and that α1- and α2-adrenoceptors may be differentially involved. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  2. Mitochondria-Targeted Nitroxide, Mito-CP, Suppresses Medullary Thyroid Carcinoma Cell Survival In Vitro and In Vivo

    Science.gov (United States)

    Starenki, Dmytro

    2013-01-01

    Context: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the RET proto-oncogene. For MTC therapy, the U.S. Food and Drug Administration recently approved vandetanib and cabozantinib, multikinase inhibitors targeting RET and other tyrosine kinase receptors of vascular endothelial growth factor, epidermal growth factor, or hepatocyte growth factor. Nevertheless, not all patients with the progressive MTC respond to these drugs, requiring the development of additional therapeutic modalities that have distinct activity. Objective: We aimed to evaluate mitochondria-targeted carboxy-proxyl (Mito-CP), a mitochondria-targeted redox-sensitive agent, for its tumor-suppressive efficacy against MTC. Design: In vitro cultures of 2 human MTC cell lines, TT and MZ-CRC-1, and TT xenografts in mice were treated with Mito-CP in comparison with vandetanib. The effects on cell survival/death, RET expression, mitochondrial integrity, and oxidative stress were determined. Results: Contrary to vandetanib, Mito-CP induced RET downregulation and strong cytotoxic effects in both cell lines in vitro, including caspase-dependent apoptosis. These effects were accompanied by mitochondrial membrane depolarization, decreased oxygen consumption, and increased oxidative stress in cells. Intriguingly, Mito-CP–induced cell death, but not RET downregulation, was partially inhibited by the reactive oxygen species scavenger, N-acetyl-cysteine, indicating that Mito-CP mediates tumor-suppressive effects via redox-dependent as well as redox-independent mechanisms. Orally administered Mito-CP effectively suppressed TT xenografts in mice, with an efficacy comparable to vandetanib and relatively low toxicity to animals. Conclusion: Our results suggest that Mito-CP can effectively suppress MTC cell growth/survival via a mechanism distinct from vandetanib effects. Mitochondrial targeting may be a potential strategy for MTC therapy. PMID:23509102

  3. Somatostatin receptor scintigraphy using 99mTc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma

    International Nuclear Information System (INIS)

    Czepczynski, Rafal; Kosowicz, Jerzy; Ziemnicka, Katarzyna; Gryczynska, Maria; Sowinski, Jerzy; Parisella, Maria G.; Mikolajczak, Renata; Signore, Alberto

    2007-01-01

    Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin analogue 99m Tc-EDDA/HYNIC-TOC in MTC in comparison with other diagnostic techniques. Forty-five patients with MTC, aged 14-83 years, were investigated. Scintigraphy using 99m Tc-EDDA/HYNIC-TOC (Tektrotyd) was performed 2 and 4 h post injection of 740 MBq (20 mCi) of the tracer. Other imaging techniques were also applied and analysed in individual cases (ultrasonography, computed tomography, 99m Tc(V)-DMSA, 131 I-MIBG, 99m Tc-MDP, 111 In-DTPA-octreotide and 18 F-FDG-PET) and compared with 99m Tc-EDDA/HYNIC-TOC. In group 1 (eight patients before thyroidectomy), uptake of the tracer was found in the primary tumours. In group 2 (six patients with remission), a false positive result was found in one patient; in the remaining five patients, no pathological foci were visualised. In group 3 (31 patients with post-surgical hypercalcitoninaemia), scintigraphy was true positive in 23 patients (74.2%): uptake in the thyroid bed was found in five patients, in the lymph nodes in 18 and in bone metastases in four. Using 99m Tc-EDDA/HYNIC-TOC scintigraphy, the overall sensitivity was 79.5%, specificity 83.3%, accuracy 80.0%, positive predictive value 96.9% and negative predictive value 38.5%. 99m Tc-EDDA/HYNIC-TOC is clinically useful for scintigraphy in the follow-up of patients with MTC. It can be used in clinical practice for preoperative evaluation, for localisation of local recurrence or distant metastases and particularly for therapy decision making. (orig.)

  4. Phase II trial of anticarcinoembryonic antigen pretargeted radioimmunotherapy in progressive metastatic medullary thyroid carcinoma: biomarker response and survival improvement.

    Science.gov (United States)

    Salaun, Pierre-Yves; Campion, Loïc; Bournaud, Claire; Faivre-Chauvet, Alain; Vuillez, Jean-Philippe; Taieb, David; Ansquer, Catherine; Rousseau, Caroline; Borson-Chazot, Françoise; Bardet, Stéphane; Oudoux, Aurore; Cariou, Bertrand; Mirallié, Eric; Chang, Chien-Hsing; Sharkey, Robert M; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques; Kraeber-Bodéré, Françoise

    2012-08-01

    The prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival based on such prognostic factors as serum calcitonin and carcinoembryonic antigen (CEA) doubling times (DTs). This prospective phase II multicenter trial evaluated the efficacy and safety of anti-CEA pretargeted radioimmunotherapy (pRAIT) in rapidly progressing metastatic MTC patients and also how serum biomarker DTs correlate with clinical outcome. From June 2004 to January 2008, 42 patients were treated with anti-CEA × anti-diethylenetriaminepentaacetic acid (DTPA) bispecific antibody (hMN-14 × m734) (40 mg/m(2)), followed by (131)I-di-DTPA-indium bivalent hapten (1.8 GBq/m(2)) 4-6 d later. The disease control rate (durable stabilization plus objective response) was 76.2%. Grade 3-4 hematologic toxicity was observed in 54.7% of patients and myelodysplastic syndrome in 2, including 1 heavily treated previously. After pRAIT, 21 of 37 assessed patients (56.7%) showed a significant impact on DT (≥100% increase of pre-pRAIT calcitonin or CEA DT or prolonged decrease of the biomarker concentration after pRAIT). Pre-pRAIT DT and post-pRAIT DT were significant independent predictors for overall survival (OS) from pRAIT (pre-pRAIT: hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.86; P = 0.016; and post-pRAIT: HR, 5.32; 95% CI, 1.63-17.36; P = 0.006) and OS from diagnosis (pre-pRAIT: HR, 0.21; 95% CI, 0.08-0.51; P = 0.001; and post-pRAIT: HR, 6.16; 95% CI, 1.81-20.98; P = 0.004). pRAIT showed antitumor activity, with manageable hematologic toxicity in progressive MTC. Increased biomarker DT after treatment correlated with increased OS.

  5. Bispecific antibody and iodine-131-labeled bivalent hapten dosimetry in patients with medullary thyroid or small-cell lung cancer.

    Science.gov (United States)

    Bardiès, M; Bardet, S; Faivre-Chauvet, A; Peltier, P; Douillard, J Y; Mahé, M; Fiche, M; Lisbona, A; Giacalone, F; Meyer, P; Gautherot, E; Rouvier, E; Barbet, J; Chatal, J F

    1996-11-01

    The purpose of this study was to estimate the dose delivered to tumor targets and normal tissues after two-step injection of an anti-CEA/anti-DTPA-In (F6-734) bispecific antibody and a 131I-labeled di-DTPA in-TL bivalent hapten in patients with medullary thyroid carcinoma (MTC) and small-cell lung cancer (SCLC). Five patients with persistent disease or recurrences of MTC and five patients with primary SCLC or relapse were studied. In a first step, 0.1 to 0.3 mg/kg of F6-734 bispecific antibody was injected intravenously. Four days later, 6 nmole (5.8 to 9.8 mCi) of 131I-labeled di-DTPA in-TL bivalent hapten were injected. Quantitative imaging was performed during one week after the second injection. All 5 patients with MTC showed positive immunoscintigraphy (IS). In the smallest visualized and resected tumor (0.8 g), the fraction of injected activity per gram (% ID/g) was 0.1% at Day 3. IS was positive in 4 of the 5 patients with SCLC. The volume of the smallest visualized SCLC tumor was estimated at 11 +/- 2 ml, and tumor uptake was about 0.009% ID/g. Tumor dose estimates ranged from 4.2 to 174 cGy/mCi in patients with MTC and from 1.7 to 8 cGy/mCi in patients with SCLC. High absorbed dose values were calculated for small MTC recurrences. For SCLC recurrences the values were smaller but in the same range as those obtained by other investigators with the one-step technique in lymphoma.

  6. Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma.

    Science.gov (United States)

    Barbet, Jacques; Campion, Loïc; Kraeber-Bodéré, Françoise; Chatal, Jean-François

    2005-11-01

    After unsuccessful surgery, medullary thyroid carcinoma (MTC) may be fatal or remain stable for decades, and precise survival predictors are needed. This study assesses the prognostic value of calcitonin and carcinoembryonic antigen (CEA) doubling-times (DT). This is a retrospective study on 65 MTC patients from 2.9-29.5 yr after surgery. Data registered in the database of the French Neuroendocrine Tumor Group were analyzed anonymously. All patients had abnormal calcitonin levels after total thyroidectomy and bilateral lymph node dissection. Calcitonin and CEA serum levels were measured during routine disease follow-up. To assess DT as prognostic factors, a patient population was extracted from the database. When calcitonin DT was less than 6 months, 5- and 10-yr survivals were three of 12 (25%) and one of 12 (8%), respectively; when between 6 months and 2 yr, 5- and 10-yr survivals were 11 of 12 (92%) and three of eight (37%), whereas all 41 patients with calcitonin DT greater than 2 yr were alive at the end of the study. Tumor-Node-Metastasis (TNM) stage, European Organization for Research and Treatment of Cancer (EORTC) score, and calcitonin DT were significant predictors of survival by univariate analysis, but only calcitonin DT remained an independent predictor of survival by multivariate analysis (P = 0.002) with a proportion of variance explained (PVE) of 37.4%. Calcitonin DT was a better predictor than CEA (PVE 63.3% and 47.0%, respectively). Calcitonin DT calculated using only the first four measurements was also an independent predictor of survival (P < 0.000001; PVE 40.4%). Calcitonin DT may be superior to initial clinical staging and among the most powerful prognostic indicators in MTC.

  7. Normal distribution and medullary-to-cortical shift of Nestin-expressing cells in acute renal ischemia.

    Science.gov (United States)

    Patschan, D; Michurina, T; Shi, H K; Dolff, S; Brodsky, S V; Vasilieva, T; Cohen-Gould, L; Winaver, J; Chander, P N; Enikolopov, G; Goligorsky, M S

    2007-04-01

    Nestin, a marker of multi-lineage stem and progenitor cells, is a member of intermediate filament family, which is expressed in neuroepithelial stem cells, several embryonic cell types, including mesonephric mesenchyme, endothelial cells of developing blood vessels, and in the adult kidney. We used Nestin-green fluorescent protein (GFP) transgenic mice to characterize its expression in normal and post-ischemic kidneys. Nestin-GFP-expressing cells were detected in large clusters within the papilla, along the vasa rectae, and, less prominently, in the glomeruli and juxta-glomerular arterioles. In mice subjected to 30 min bilateral renal ischemia, glomerular, endothelial, and perivascular cells showed increased Nestin expression. In the post-ischemic period, there was an increase in fluorescence intensity with no significant changes in the total number of Nestin-GFP-expressing cells. Time-lapse fluorescence microscopy performed before and after ischemia ruled out the possibility of engraftment by the circulating Nestin-expressing cells, at least within the first 3 h post-ischemia. Incubation of non-perfused kidney sections resulted in a medullary-to-cortical migration of Nestin-GFP-positive cells with the rate of expansion of their front averaging 40 microm/30 min during the first 3 h and was detectable already after 30 min of incubation. Explant matrigel cultures of the kidney and aorta exhibited sprouting angiogenesis with cells co-expressing Nestin and endothelial marker, Tie-2. In conclusion, several lines of circumstantial evidence identify a sub-population of Nestin-expressing cells with the mural cells, which are recruited in the post-ischemic period to migrate from the medulla toward the renal cortex. These migrating Nestin-positive cells may be involved in the process of post-ischemic tissue regeneration.

  8. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.

    Science.gov (United States)

    Wells, Samuel A; Robinson, Bruce G; Gagel, Robert F; Dralle, Henning; Fagin, James A; Santoro, Massimo; Baudin, Eric; Elisei, Rossella; Jarzab, Barbara; Vasselli, James R; Read, Jessica; Langmuir, Peter; Ryan, Anderson J; Schlumberger, Martin J

    2012-01-10

    There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC. Patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments. Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P = .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%). Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761).

  9. Imprinted ZnO nanostructure-based electrochemical sensing of calcitonin: A clinical marker for medullary thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Patra, Santanu; Roy, Ekta [Department of Applied Chemistry, Indian School of Mines, Dhanbad, Jharkhand 826 004 (India); Madhuri, Rashmi, E-mail: rshmmadhuri@gmail.com [Department of Applied Chemistry, Indian School of Mines, Dhanbad, Jharkhand 826 004 (India); Sharma, Prashant K. [Functional Nanomaterials Research Laboratory, Department of Applied Physics, Indian School of Mines, Dhanbad, Jharkhand 826 004 (India)

    2015-01-01

    Highlights: • Molecular imprinting-based sensor for medullary thyroid carcinoma marker was developed. • ZnO nanostructure was used as a platform for synthesis of imprinted polymer. • Imprinted polymer was prepared by ARGET–ATRP method. • A novel and biocompatible tyrosine amino acid derivative was used as monomer. • Linear working range is found from 9.99 ng L{sup −1} to 7.919 mg L{sup −1} with LOD 3.09 ng L{sup −1}. - Abstract: The present work describes an exciting method for the selective and sensitive determination of calcitonin in human blood serum samples. Adopting the surface molecular imprinting technique, a calcitonin-imprinted polymer was prepared on the surface of the zinc oxide nanostructure. Firstly, a biocompatible tyrosine derivative as a monomer was grafted onto the surface of zinc oxide nanostructure followed by their polymerization on vinyl functionalized electrode surface by activator regenerated by electron transfer–atom transfer radical polymerization (ARGET–ATRP) technique. Such sensor can predict the small change in the concentration of calcitonin in the human body and it may also consider to be as cost-effective, renewable, disposable, and reliable for clinical studies having no such cross-reactivity and matrix effect from real samples. The morphologies and properties of the proposed sensor were characterized by scanning electron microscopy, cyclic voltammetry, difference pulse voltammetry and chronocoulometry. The linear working range was found to be 9.99 ng L{sup −1} to 7.919 mg L{sup −1} and the detection limit as low as 3.09 ± 0.01 ng L{sup −1} (standard deviation for three replicate measurements) (S/N = 3)

  10. {sup 18}F-DOPA PET/CT in the diagnosis and localization of persistent medullary thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Archier, Aurelien; Mundler, Olivier [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, Marseille (France); Aix-Marseille University, European Center for Research in Medical Imaging, Marseille (France); Heimburger, Celine [University Hospitals of Strasbourg, Department of Biophysics and Nuclear Medicine, Strasbourg (France); Guerin, Carole; Palazzo, Fausto F.; Henry, Jean-Francois; Sebag, Frederic [Aix-Marseille University, Department of Endocrine Surgery, Conception Hospital, Marseille (France); Morange, Isabelle [Aix-Marseille University, Department of Endocrinology, Conception Hospital, Marseille (France); Schneegans, Olivier [Paul Strauss Cancer Center, Department of Nuclear Medicine, Strasbourg (France); Abdullah, Ahmad Esmaeel [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, Marseille (France); Imperiale, Alessio [University Hospitals of Strasbourg, Department of Biophysics and Nuclear Medicine, Strasbourg (France); ICube, UMR 7357 University of Strasbourg/CNRS and FMTS, Faculty of Medicine, Strasbourg (France); Taieb, David [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, Marseille (France); Aix-Marseille University, European Center for Research in Medical Imaging, Marseille (France); Institut Paoli-Calmettes, Inserm UMR1068 Marseille Cancerology Research Center, Marseille (France)

    2016-06-15

    To evaluate the performance of {sup 18}F-l-dihydroxyphenylalanine ({sup 18}F-DOPA) PET/CT in the detection of locoregional and distant medullary thyroid carcinoma (MTC) metastases and to compare imaging findings with histological data. We retrospectively evaluated 86 MTC patients with persistently high serum calcitonin levels after initial surgery who had undergone {sup 18}F-DOPA PET/CT between January 2007 and December 2014 in two referral centres. They were followed up for at least 6 months after the PET/CT assessment. The results were compared with histological data or with the findings obtained during follow-up using a complementary imaging modality. {sup 18}F-DOPA PET/CT was positive in 65 of the 86 patients, corresponding to a patient-based sensitivity of 75.6 %. Distant metastatic disease (M1) was seen in 29 patients including 11 with previously unknown metastases revealed only by PET/CT. Among the 36 patients without distant metastatic spread, 25 had nodal involvement limited to the neck, and 10 of these 25 patients underwent reoperation. The lymph node compartment-based sensitivity of {sup 18}F-DOPA PET/CT was 100 % in the two institutions but lesion-based sensitivity was only 24 %. Preoperative and postoperative median calcitonin levels were 405 pg/mL (range 128 - 1,960 pg/mL) and 259 pg/mL (range 33 - 1,516 pg/mL), respectively. None of the patients achieved normalization of serum calcitonin after reoperation. {sup 18}F-DOPA PET/CT enables early diagnosis of a significant number of patients with distant metastasis. It has a limited sensitivity in the detection of residual disease but provides high performance for regional analysis. A surgical compartment-oriented approach could be the approach of choice whatever the number of nodes revealed by {sup 18}F-DOPA PET/CT. (orig.)

  11. Foxn1 Is Dynamically Regulated in Thymic Epithelial Cells during Embryogenesis and at the Onset of Thymic Involution.

    Directory of Open Access Journals (Sweden)

    Kathy E O'Neill

    Full Text Available Thymus function requires extensive cross-talk between developing T-cells and the thymic epithelium, which consists of cortical and medullary TEC. The transcription factor FOXN1 is the master regulator of TEC differentiation and function, and declining Foxn1 expression with age results in stereotypical thymic involution. Understanding of the dynamics of Foxn1 expression is, however, limited by a lack of single cell resolution data. We have generated a novel reporter of Foxn1 expression, Foxn1G, to monitor changes in Foxn1 expression during embryogenesis and involution. Our data reveal that early differentiation and maturation of cortical and medullary TEC coincides with precise sub-lineage-specific regulation of Foxn1 expression levels. We further show that initiation of thymic involution is associated with reduced cTEC functionality, and proportional expansion of FOXN1-negative TEC in both cortical and medullary sub-lineages. Cortex-specific down-regulation of Foxn1 between 1 and 3 months of age may therefore be a key driver of the early stages of age-related thymic involution.

  12. Risperidone and Divalproex Differentially Engage the Fronto-Striato-Temporal Circuitry in Pediatric Mania: A Pharmacological Functional Magnetic Resonance Imaging Study

    Science.gov (United States)

    Pavuluri, Mani N.; Passarotti, Alessandra M.; Fitzgerald, Jacklynn M.; Wegbreit, Ezra; Sweeney, John A.

    2012-01-01

    Objective: The current study examined the impact of risperidone and divalproex on affective and working memory circuitry in patients with pediatric bipolar disorder (PBD). Method: This was a six-week, double-blind, randomized trial of risperidone plus placebo versus divalproex plus placebo for patients with mania (n = 21; 13.6 [plus or minus] 2.5…

  13. Active sodium-urea counter-transport is inducible in the basolateral membrane of rat renal initial inner medullary collecting ducts.

    OpenAIRE

    Kato, A; Sands, J M

    1998-01-01

    Rat inner medullary collecting ducts (IMCD3s) possess a luminal Na+-dependent, active urea secretory transport process, which is upregulated by water diuresis. In this study of perfused IMCDs microdissected from base (IMCD1), middle (IMCD2), or tip (IMCD3) of the inner medulla, we tested whether furosemide diuresis alters active urea transport. Rats received furosemide (10 mg/d s.c. for 3-4 d) and were compared with pair-fed control rats. Furosemide significantly decreased urine osmolality an...

  14. Use of intra-medullary stacked nailing in the reduction of proximal plastic deformity in a pediatric Monteggia fracture: a case report

    Directory of Open Access Journals (Sweden)

    Huntley James S

    2011-04-01

    Full Text Available Abstract Introduction In a Monteggia fracture dislocation, it is important to reduce the ulnar fracture completely. Extensive plastic deformation of the proximal ulna may make reduction by closed manipulation impossible. Case presentation We report the case of a four-year-old Caucasian boy in whom the plastic deformation of the proximal ulna was reduced, and this reduction was maintained, using intra-medullary stacked nailing. Conclusion The technique of stacked nailing is a useful addition to the armamentarium in the management of the potentially awkward Monteggia fracture.

  15. Pseudo-angiomatous liver metastasis of thyroid medullary carcinoma: multimodality diagnostic approach; Metastase hepatique pseudoangiomateuse d'un carcinome medullaire de la thyroide: approche diagnostique multimodalite

    Energy Technology Data Exchange (ETDEWEB)

    Imperiale, A.; Keomany, J.; Rust, E.; Constantinesco, A. [CHU de Strasbourg, Service de biophysique et medecine nucleaire, 67 (France); Greget, M. [CHU de Strasbourg, Service de radiologie 1, 67 (France); Chabrier, G.; Goichot, B. [CHU de Strasbourg, Service de medecine interne, endocrinologie et nutrition, 67 (France); Detour, J. [CHU de Strasbourg, Service de radiopharmacie, 67 (France); Pessaux, P. [CHU de Strasbourg, Service de chirurgie generale, hepatique et endocrinienne, 67 (France)

    2010-07-01

    Purpose: Illustrate the result of the diagnosis by multimodality imaging (MRI, scintigraphy {sup 123}I-Mibg, PET/CT{sup 18}F-F.D.G. and {sup 18}F-F DOPA) with liver metastasis looking like a single angioma in a patient with atypical medullary thyroid carcinoma. Conclusions: Angiomas must be taken into account in the differential diagnosis of liver metastasis of endocrine tumors, particularly in the case of small injuries where it may be difficult to differentiate a peripheral nodular contrast enhancement of a globular enhancement characteristics of angiomas. (N.C.)

  16. About 13 cases of medullary metastatic compression in breast cancer; A propos de 13 cas de compression medullaire metastatique du cancer du sein

    Energy Technology Data Exchange (ETDEWEB)

    Mahfoud, T.; Aassab, R.; Errihani, H. [Service d' oncologie medicale, Institut national d' oncologie, Rabat (Morocco); Mahfoud, T.; Khmamouche, M.R.; Debbagh, A.; Bazine, A.; Ichou, M. [Service d' oncologie medicale, Hopital militaire d' instruction Mohammed-V, Rabat (Morocco)

    2010-10-15

    As this issue is a diagnosis and therapeutic emergency, the authors report the development of a method to take into care medullary metastatic compression of the breast cancer. This study is based on 13 patients of a Rabat hospital over 3 years. Compressions have been observed by MRI. They have been treated by cortico-therapy and radiotherapy, but also by laminectomy in one case. The authors observed a improvement in terms of symptomatology, and a neurological recovery from the fourth week after the treatment. Short communication

  17. Circuitry linking the global Csr and σE-dependent cell envelope stress response systems.

    Science.gov (United States)

    Yakhnin, Helen; Aichele, Robert; Ades, Sarah E; Romeo, Tony; Babitzke, Paul

    2017-09-18

    CsrA of Escherichia coli is an RNA-binding protein that globally regulates a wide variety of cellular processes and behaviors including carbon metabolism, motility, biofilm formation, and the stringent response. CsrB and CsrC are sRNAs that sequester CsrA, thereby preventing CsrA-mRNA interaction. RpoE (σ E ) is the extracytoplasmic stress response sigma factor of E. coli Previous RNA-seq studies identified rpoE mRNA as a CsrA target. Here we explored the regulation of rpoE by CsrA and found that CsrA represses rpoE translation. Gel mobility shift, footprint and toeprint studies identified three CsrA binding sites in the rpoE leader transcript, one of which overlaps the rpoE Shine-Dalgarno (SD) sequence, while another overlaps the rpoE translation initiation codon. Coupled in vitro transcription-translation experiments showed that CsrA represses rpoE translation by binding to these sites. We further demonstrate that σ E indirectly activates transcription of csrB and csrC , leading to increased sequestration of CsrA such that repression of rpoE by CsrA is reduced. We propose that the Csr system fine-tunes the σ E -dependent cell envelope stress response. We also identified a 51 amino acid coding sequence whose stop codon overlaps the rpoE start codon, and demonstrate that rpoE is translationally coupled with this upstream open reading frame (ORF51). Loss of coupling reduces rpoE translation by more than 50%. Identification of a translationally coupled ORF upstream of rpoE suggests that this previously unannotated protein may participate in the cell envelope stress response. In keeping with existing nomenclature, we name ORF51 as rseD , resulting in an operon arrangement of rseD-rpoE-rseA-rseB-rseC IMPORTANCE CsrA posttranscriptionally represses genes required for bacterial stress responses, including the stringent response, catabolite repression, and the RpoS (σ S )-mediated general stress response. We show that CsrA represses translation of rpoE , encoding the

  18. Novel treatments of mood disorders based on brain circuitry (ECT, MST, TMS, VNS, DBS).

    Science.gov (United States)

    George, Mark S; Nahas, Ziad; Li, Xiangbao; Kozel, F Andrew; Anderson, Berry; Yamanaka, Kaori; Chae, Jeong-Ho; Foust, Milton J

    2002-10-01

    Advances in understanding the functional and structural anatomy of depression outlined in this issue set the stage for attempting to manipulate implicated brain regions as potential antidepressant therapies. On the one hand, these circuit- and device-based approaches to treating depression are not new. Electroconvulsive therapy (ECT) dates back to the beginning of modern biologic psychiatry with the discovery and rapid increase of first chemical (around 1910), and then later ECT. On the other hand, this area represents an important paradigm shift with treatments that are radical and different. A dizzying array of diverse technologies now allows researchers to stimulate the brain in undreamed of ways. However, the approaches described in this article are still considered experimental and are not approved for use in the United States by the Food and Drug Administration (FDA), except ECT, which predates the FDA. These device-based approaches to brain stimulation offer promise as potential acute and even longterm treatments. Additionally, the research determining whether and how these devices work to influence mood promises to help unravel the neurophysiology of mood regulation. These novel treatments are thus the translational tools to bridge from advances in brain imaging, into new treatments for depressed patients. Copyright 2002, Elsevier Science (USA). All rights reserved.

  19. Volatile solvents as drugs of abuse: focus on the cortico-mesolimbic circuitry.

    Science.gov (United States)

    Beckley, Jacob T; Woodward, John J

    2013-12-01

    Volatile solvents such as those found in fuels, paints, and thinners are found throughout the world and are used in a variety of industrial applications. However, these compounds are also often intentionally inhaled at high concentrations to produce intoxication. While solvent use has been recognized as a potential drug problem for many years, research on the sites and mechanisms of action of these compounds lags behind that of other drugs of abuse. In this review, we first discuss the epidemiology of voluntary solvent use throughout the world and then consider what is known about their basic pharmacology and how this may explain their use as drugs of abuse. We next present data from preclinical and clinical studies indicating that these substances induce common addiction sequelae such as dependence, withdrawal, and cognitive impairments. We describe how toluene, the most commonly studied psychoactive volatile solvent, alters synaptic transmission in key brain circuits such as the mesolimbic dopamine system and medial prefrontal cortex (mPFC) that are thought to underlie addiction pathology. Finally, we make the case that activity in mPFC circuits is a critical regulator of the mesolimbic dopamine system's ability to respond to volatile solvents like toluene. Overall, this review provides evidence that volatile solvents have high abuse liability because of their selective effects on critical nodes of the addiction neurocircuitry, and underscores the need for more research into how these compounds induce adaptations in neural circuits that underlie addiction pathology.

  20. Emotional regulation: implications for the psychobiology of psychotherapy.

    Science.gov (United States)

    Stein, Dan J

    2008-03-01

    A range of studies have contributed to understanding the psychobiology of emotional regulation. Functional imaging studies have demonstrated that cortico-limbic circuitry plays an important role in mediating processes such as reappraisal and suppression. Dorsolateral prefrontal cortex may be important in conscious reframing, while ventromedial prefrontal cortex and orbitofrontal cortex may be particularly important in emotion evaluation. Gene variants and early environments impact underlying emotional regulation and its neurobiology. It may be hypothesized that during interventions such as psychotherapy there are improvements in emotional regulation, together with the normalization of related psychobiological mechanisms.

  1. Medullary Thyroid Carcinoma in MEN2A: ATA Moderate- or High-Risk RET Mutations Do Not Predict Disease Aggressiveness.

    Science.gov (United States)

    Voss, Rachel K; Feng, Lei; Lee, Jeffrey E; Perrier, Nancy D; Graham, Paul H; Hyde, Samuel M; Nieves-Munoz, Frances; Cabanillas, Maria E; Waguespack, Steven G; Cote, Gilbert J; Gagel, Robert F; Grubbs, Elizabeth G

    2017-08-01

    High-risk RET mutations (codon 634) are associated with earlier development of medullary thyroid carcinoma (MTC) and presumed increased aggressiveness compared with moderate-risk RET mutations. To determine whether high-risk RET mutations are more aggressive. Retrospective cohort study using institutional multiple endocrine neoplasia type 2 registry. Tertiary cancer care center. Patients with MTC and moderate- or high-risk germline RET mutation. None (observational study). Proxies for aggressiveness were overall survival (OS) and time to distant metastatic disease (DMD). A total of 127 moderate-risk and 135 high-risk patients were included (n = 262). Median age at diagnosis was 42.3 years (range, 6.4 to 86.4 years; mean, 41.6 years) for moderate-risk mutations and 23.0 years (range, 3.7 to 66.8 years; mean, 25.6 years) for high-risk mutations (P < 0.0001). Moderate-risk patients had more T3/T4 tumors at diagnosis (P = 0.03), but there was no significant difference for N or M stage and no significant difference in OS (P = 0.40). From multivariable analysis for OS, increasing age [hazard ratio (HR), 1.05/y; 95% confidence interval (CI), 1.03 to 1.08], T3/T4 tumor (HR, 2.73; 95% CI, 1.22 to 6.11), and M1 status at diagnosis (HR, 3.93; 95% CI, 1.61 to 9.59) were significantly associated with worse OS but high-risk mutation was not (P = 0.40). No significant difference was observed for development of DMD (P = 0.33). From multivariable analysis for DMD, only N1 status at diagnosis was significant (HR, 2.10; 95% CI, 1.03 to 4.27). Patients with high- and moderate-risk RET mutations had similar OS and development of DMD after MTC diagnosis and therefore similarly aggressive clinical courses. High-risk connotes increased disease aggressiveness; thus, future guidelines should consider RET mutation classification by disease onset (early vs late) rather than by risk (high vs moderate). Copyright © 2017 Endocrine Society

  2. Effect of 3'UTR RET Variants on RET mRNA Secondary Structure and Disease Presentation in Medullary Thyroid Carcinoma.

    Directory of Open Access Journals (Sweden)

    Lucieli Ceolin

    Full Text Available The RET S836S variant has been associated with early onset and increased risk for metastatic disease in medullary thyroid carcinoma (MTC. However, the mechanism by which this variant modulates MTC pathogenesis is still open to discuss. Of interest, strong linkage disequilibrium (LD between RET S836S and 3'UTR variants has been reported in Hirschsprung's disease patients.To evaluate the frequency of the RET 3'UTR variants (rs76759170 and rs3026785 in MTC patients and to determine whether these variants are in LD with S836S polymorphism.Our sample comprised 152 patients with sporadic MTC. The RET S836S and 3'UTR (rs76759170 and rs3026785 variants were genotyped using Custom TaqMan Genotyping Assays. Haplotypes were inferred using the phase 2.1 program. RET mRNA structure was assessed by Vienna Package.The mean age of MTC diagnosis was 48.5±15.5 years and 57.9% were women. The minor allele frequencies of RET polymorphisms were as follows: S836S, 5.6%; rs76759170, 5.6%; rs3026785, 6.2%. We observed a strong LD among S836S and 3'UTR variants (|D'| = -1, r2 = 1 and |D'| = -1, r2 = 0,967. Patients harboring the S836S/3'UTR variants presented a higher percentage of lymph node and distant metastasis (P = 0.013 and P<0.001, respectively. Accordingly, RNA folding analyses demonstrated different RNA secondary structure predictions for WT(TCCGT, S836S(TTCGT or 3'UTR(GTCAC haplotypes. The S836S/3'UTR haplotype presented a greater number of double helices sections and lower levels of minimal free energy when compared to the wild-type haplotype, suggesting that these variants provides the most thermodynamically stable mRNA structure, which may have functional consequences on the rate of mRNA degradation.The RET S836S polymorphism is in LD with 3'UTR variants. In silico analysis indicate that the 3'UTR variants may affect the secondary structure of RET mRNA, suggesting that these variants might play a role in posttranscriptional control of the RET transcripts.

  3. Germline mutation of RET proto-oncogene’s exons 17 and 18 in Iranian medullary thyroid carcinoma patients

    Directory of Open Access Journals (Sweden)

    Marjan Zarif Yeganeh

    2017-03-01

    Full Text Available Background: Thyroid carcinoma is the most common endocrine malignancy. Medullary thyroid carcinoma (MTC approximately accounts for 5-10% of all thyroid carcinoma. Nowadays, it is obviously, the mutations in REarranged during transfection (RET proto-oncogene, especially, mutations in exons 10, 11 and 16 are associated with MTC pathogenesis and occurrence. Thus, early diagnosis of MTC by mutation detection in RET proto-oncogene allows to identify patients who do not have any developed symptoms. The aim of this study was to screening of germline mutations in RET proto-oncogene exons 17 and 18 in MTC patients and their first degree relatives in Iranian population. Methods: In this cross-sectional study, three hundred eleven participates (190 patients, 121 their relatives were referred to endocrine research center, Shahid Beheshti University of Medical Science during September 2013 until September 2015. The inclusion criteria were pathological and clinical diagnosis. After whole blood sampling, genomic DNA was extracted from peripheral blood leucocytes using the standard Salting Out/Proteinase K method. Nucleotide change detection in exons 17 and 18 was performed using PCR and direct DNA sequencing methods. Results: In this study, twenty missense mutations [CGC>TGC, c.2944C>T, p.Arg982Cys (rs17158558] which included 16 heterozygote and 4 homozygote mutations were found in codon 982 (exon 18. In the present study, 154 G>A (rs2742236 and 4 C>T (rs370072408 nucleotide changes were detected in exons 18 and intron 17 respectively. There was no mutation in exon 17. Conclusion: It seems that because of arginine to cysteine substitutions in RET tyrosine kinase protein structure and its polyphen score (0.955 and SIFT score (0.01 the mutation in codon 982 (exon 18 could be have pathogenic effects. On the other hands, the mentioned mutation frequency was 6.4% among MTC patients, so this mutation of exon 18 could be checked in genetic screening tests of RET

  4. ¹⁸F-FDG PET predicts survival after pretargeted radioimmunotherapy in patients with progressive metastatic medullary thyroid carcinoma.

    Science.gov (United States)

    Salaun, Pierre-Yves; Campion, Loïc; Ansquer, Catherine; Frampas, Eric; Mathieu, Cédric; Robin, Philippe; Bournaud, Claire; Vuillez, Jean-Philippe; Taieb, David; Rousseau, Caroline; Drui, Delphine; Mirallié, Eric; Borson-Chazot, Françoise; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques; Kraeber-Bodéré, Françoise

    2014-08-01

    PET is a powerful tool for assessing targeted therapy. Since (18)F-FDG shows a potential prognostic value in medullary thyroid carcinoma (MTC), this study evaluated (18)F-FDG PET alone and combined with morphological and biomarker evaluations as a surrogate marker of overall survival (OS) in patients with progressive metastatic MTC treated with pretargeted anti-CEA radioimmunotherapy (pRAIT) in a phase II clinical trial. Patients underwent PET associated with morphological imaging (CT and MRI) and biomarker evaluations, before and 3 and 6 months, and then every 6 months, after pRAIT for 36 months. A combined evaluation was performed using anatomic, metabolic and biomarker methods. The prognostic value of the PET response was compared with demographic parameters at inclusion including age, sex, RET mutation, time from initial diagnosis, calcitonin and CEA concentrations and doubling times (DT), SUVmax, location of disease and bone marrow involvement, and with response using RECIST, biomarker concentration variation, impact on DT, and combined methods. Enrolled in the study were 25 men and 17 women with disease progression. The median OS from pRAIT was 3.7 years (0.2 to 6.5 years) and from MTC diagnosis 10.9 years (1.7 to 31.5 years). After pRAIT, PET/CT showed 1 patient with a complete response, 4 with a partial response and 24 with disease stabilization. The combined evaluation showed 20 responses. For OS from pRAIT, univariate analysis showed the prognostic value of biomarker DT (P = 0.011) and SUVmax (P = 0.038) calculated before pRAIT and impact on DT (P = 0.034), RECIST (P = 0.009), PET (P = 0.009), and combined response (P = 0.004) measured after pRAIT. PET had the highest predictive value with the lowest Akaike information criterion (AIC 74.26) as compared to RECIST (AIC 78.06), biomarker variation (AIC 81.94) and impact on DT (AIC 79.22). No benefit was obtained by combining the methods (AIC 78.75). This result was confirmed by the

  5. {sup 18}F-FDG PET predicts survival after pretargeted radioimmunotherapy in patients with progressive metastatic medullary thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Salaun, Pierre-Yves; Robin, Philippe [University Hospital, Nuclear Medicine Department, Brest (France); Campion, Loic [ICO-Gauducheau Cancer Institute, Statistical Department, Nantes (France); Ansquer, Catherine; Mathieu, Cedric [University Hospital, Nuclear Medicine Department, Nantes (France); Frampas, Eric [University Hospital, Radiology Department, Nantes (France); Universite de Nantes, Nantes-Angers Cancer Research Center, Inserm, U 892, CNRS, UMR 6299, Nantes (France); Bournaud, Claire [University Hospital, Nuclear Medicine Department, Lyon (France); Vuillez, Jean-Philippe [University Hospital, Nuclear Medicine Department, Grenoble (France); Taieb, David [University Hospital, Nuclear Medicine Department, Marseille (France); Rousseau, Caroline [Universite de Nantes, Nantes-Angers Cancer Research Center, Inserm, U 892, CNRS, UMR 6299, Nantes (France); ICO-Rene Gauducheau, Nuclear Medicine Department, Nantes (France); Drui, Delphine [University Hospital, Endocrinology Department, Nantes (France); Mirallie, Eric [University Hospital, Surgery Department, Nantes (France); Borson-Chazot, Francoise [University Hospital, Endocrinology Department, Lyon (France); Goldenberg, David M. [IBC Pharmaceuticals, Inc., and Immunomedics, Inc., Morris Plains, NJ (United States); Center for Molecular Medicine and Immunology, Garden State Cancer Center, Morris Plains, NJ (United States); Chatal, Jean-Francois [GIP ARRONAX, Saint-Herblain (France); Barbet, Jacques [Universite de Nantes, Nantes-Angers Cancer Research Center, Inserm, U 892, CNRS, UMR 6299, Nantes (France); GIP ARRONAX, Saint-Herblain (France); Kraeber-Bodere, Francoise [University Hospital, Nuclear Medicine Department, Nantes (France); Universite de Nantes, Nantes-Angers Cancer Research Center, Inserm, U 892, CNRS, UMR 6299, Nantes (France); ICO-Rene Gauducheau, Nuclear Medicine Department, Nantes (France); Hotel Dieu University Hospital, Nuclear Medicine Department, Nantes (France)

    2014-08-15

    PET is a powerful tool for assessing targeted therapy. Since {sup 18}F-FDG shows a potential prognostic value in medullary thyroid carcinoma (MTC), this study evaluated {sup 18}F-FDG PET alone and combined with morphological and biomarker evaluations as a surrogate marker of overall survival (OS) in patients with progressive metastatic MTC treated with pretargeted anti-CEA radioimmunotherapy (pRAIT) in a phase II clinical trial. Patients underwent PET associated with morphological imaging (CT and MRI) and biomarker evaluations, before and 3 and 6 months, and then every 6 months, after pRAIT for 36 months. A combined evaluation was performed using anatomic, metabolic and biomarker methods. The prognostic value of the PET response was compared with demographic parameters at inclusion including age, sex, RET mutation, time from initial diagnosis, calcitonin and CEA concentrations and doubling times (DT), SUV{sub max}, location of disease and bone marrow involvement, and with response using RECIST, biomarker concentration variation, impact on DT, and combined methods. Enrolled in the study were 25 men and 17 women with disease progression. The median OS from pRAIT was 3.7 years (0.2 to 6.5 years) and from MTC diagnosis 10.9 years (1.7 to 31.5 years). After pRAIT, PET/CT showed 1 patient with a complete response, 4 with a partial response and 24 with disease stabilization. The combined evaluation showed 20 responses. For OS from pRAIT, univariate analysis showed the prognostic value of biomarker DT (P = 0.011) and SUV{sub max} (P = 0.038) calculated before pRAIT and impact on DT (P = 0.034), RECIST (P = 0.009), PET (P = 0.009), and combined response (P = 0.004) measured after pRAIT. PET had the highest predictive value with the lowest Akaike information criterion (AIC 74.26) as compared to RECIST (AIC 78.06), biomarker variation (AIC 81.94) and impact on DT (AIC 79.22). No benefit was obtained by combining the methods (AIC 78.75). This result was confirmed by the

  6. Hypothalamic neuroendocrine circuitry is programmed by maternal obesity: interaction with postnatal nutritional environment.

    Directory of Open Access Journals (Sweden)

    Hui Chen

    Full Text Available OBJECTIVE: Early life nutrition is critical for the development of hypothalamic neurons involved in energy homeostasis. We previously showed that intrauterine and early postnatal overnutrition programmed hypothalamic neurons expressing the appetite stimulator neuropeptide Y (NPY and suppressor proopiomelanocortin (POMC in offspring at weaning. However, the long-term effects of such programming and its interactions with post-weaning high-fat-diet (HFD consumption are unclear. RESEARCH DESIGN AND METHODS: Female Sprague Dawley rats were exposed to chow or HFD for 5 weeks before mating, throughout gestation and lactation. On postnatal day 1, litters were adjusted to 3/litter to induce postnatal overnutrition (vs. 12 in control. At postnatal day 20, half of the rats from each maternal group were weaned onto chow or HFD for 15 weeks. Hypothalamic appetite regulators, and fuel (glucose and lipid metabolic markers were measured. RESULTS: Offspring from obese dams gained more weight than those from lean dams independent of post-weaning diet. Maternal obesity interacted with post-weaning HFD consumption to cause greater levels of hyperphagia, adiposity, hyperlipidemia, and glucose intolerance in offspring. This was linked to increased hypothalamic NPY signaling and leptin resistance in adult offspring. Litter size reduction had a detrimental impact on insulin and adiponectin, while hypothalamic NPY and POMC mRNA expression were suppressed in the face of normal energy intake and weight gain. CONCLUSIONS: Maternal obesity, postnatal litter size reduction and post-weaning HFD consumption caused obesity via different neuroendocrine mechanism. There were strong additive effects of maternal obesity and post-weaning HFD consumption to increase the metabolic disorders in offspring.

  7. Neural circuitry mediating inflammation-induced central pain amplification in human experimental endotoxemia.

    Science.gov (United States)

    Benson, Sven; Rebernik, Laura; Wegner, Alexander; Kleine-Borgmann, Julian; Engler, Harald; Schlamann, Marc; Forsting, Michael; Schedlowski, Manfred; Elsenbruch, Sigrid

    2015-08-01

    To elucidate the brain mechanisms underlying inflammation-induced visceral hyperalgesia in humans, in this functional magnetic resonance imaging (fMRI) study we tested if intravenous administration of lipopolysaccharide (LPS) involves altered central processing of visceral pain stimuli. In this randomized, double-blind, placebo-controlled fMRI study, 26 healthy male subjects received either an intravenous injection of low-dose LPS (N=14, 0.4 ng/kg body weight) or placebo (N=12, control group). Plasma cytokines (TNF-α, IL-6), body temperature, plasma cortisol and mood were assessed at baseline and up to 6 h post-injection. At baseline and 2 h post-injection (test), rectal pain thresholds and painful rectal distension-induced blood oxygen level-dependent (BOLD) responses in brain regions-of-interest were assessed. To address specificity for visceral pain, BOLD responses to non-painful rectal distensions and painful somatic stimuli (i.e., punctuate mechanical stimulation) were also analyzed as control stimuli. Compared to the control group, LPS-treated subjects demonstrated significant and transient increases in TNF-α, IL-6, body temperature and cortisol, along with impaired mood. In response to LPS, rectal pain thresholds decreased in trend, along with enhanced up-regulation of rectal pain-induced BOLD responses within the posterior insula, dorsolateral prefrontal (DLPFC), anterior midcingulate (aMCC) and somatosensory cortices (all FWE-corrected ppain-induced neural activation in DLPFC and aMCC. No significant LPS effects were observed on neural responses to non-painful rectal distensions or mechanical stimulation. These findings support that peripheral inflammatory processes affect visceral pain thresholds and the central processing of sensory-discriminative aspects of visceral pain. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. The Dynamic Multisensory Engram: Neural Circuitry Underlying Crossmodal Object Recognition in Rats Changes with the Nature of Object Experience.

    Science.gov (United States)

    Jacklin, Derek L; Cloke, Jacob M; Potvin, Alphonse; Garrett, Inara; Winters, Boyer D

    2016-01-27

    Rats, humans, and monkeys demonstrate robust crossmodal object recognition (CMOR), identifying objects across sensory modalities. We have shown that rats' performance of a spontaneous tactile-to-visual CMOR task requires functional integration of perirhinal (PRh) and posterior parietal (PPC) cortices, which seemingly provide visual and tactile object feature processing, respectively. However, research with primates has suggested that PRh is sufficient for multisensory object representation. We tested this hypothesis in rats using a modification of the CMOR task in which multimodal preexposure to the to-be-remembered objects significantly facilitates performance. In the original CMOR task, with no preexposure, reversible lesions of PRh or PPC produced patterns of impairment consistent with modality-specific contributions. Conversely, in the CMOR task with preexposure, PPC lesions had no effect, whereas PRh involvement was robust, proving necessary for phases of the task that did not require PRh activity when rats did not have preexposure; this pattern was supported by results from c-fos imaging. We suggest that multimodal preexposure alters the circuitry responsible for object recognition, in this case obviating the need for PPC contributions and expanding PRh involvement, consistent with the polymodal nature of PRh connections and results from primates indicating a key role for PRh in multisensory object representation. These findings have significant implications for our understanding of multisensory information processing, suggesting that the nature of an individual's past experience with an object strongly determines the brain circuitry involved in representing that object's multisensory features in memory. The ability to integrate information from multiple sensory modalities is crucial to the survival of organisms living in complex environments. Appropriate responses to behaviorally relevant objects are informed by integration of multisensory object features

  9. Examination of Csr regulatory circuitry using epistasis analysis with RNA-seq (Epi-seq) confirms that CsrD affects gene expression via CsrA, CsrB and CsrC.

    Science.gov (United States)

    Potts, Anastasia H; Leng, Yuanyuan; Babitzke, Paul; Romeo, Tony

    2018-03-29

    The Csr global regulatory system coordinates gene expression in response to metabolic status. This system utilizes the RNA binding protein CsrA to regulate gene expression by binding to transcripts of structural and regulatory genes, thus affecting their structure, stability, translation, and/or transcription elongation. CsrA activity is controlled by sRNAs, CsrB and CsrC, which sequester CsrA away from other transcripts. CsrB/C levels are partly determined by their rates of turnover, which requires CsrD to render them susceptible to RNase E cleavage. Previous epistasis analysis suggested that CsrD affects gene expression through the other Csr components, CsrB/C and CsrA. However, those conclusions were based on a limited analysis of reporters. Here, we reassessed the global behavior of the Csr circuitry using epistasis analysis with RNA seq (Epi-seq). Because CsrD effects on mRNA levels were entirely lost in the csrA mutant and largely eliminated in a csrB/C mutant under our experimental conditions, while the majority of CsrA effects persisted in the absence of csrD, the original model accounts for the global behavior of the Csr system. Our present results also reflect a more nuanced role of CsrA as terminal regulator of the Csr system than has been recognized.

  10. Role of endothelin ET(A) and ET(B) receptor subtypes in the regulation of intrarenal blood flow and oxygen tension in rats.

    Science.gov (United States)

    Nitescu, Nicoletta; Grimberg, Elisabeth; Herlitz, Hans; Guron, Gregor

    2008-10-01

    The aim of the present study was to investigate the role of endothelin ET(A) and ET(B) receptors in the regulation of intrarenal blood flow and oxygen tension in normotensive Sprague-Dawley rats. Thiobutabarbital anaesthetized rats were divided into four groups (n = 6-9 per group): (i) saline (4 mL/kg per h); (ii) BQ123; (iii) BQ788; and (iv) BQ123 + BQ788. After baseline measurements, the ET(A) receptor antagonist BQ-123 (30 nmol/kg per min, i.v.) and/or the ET(B) receptor antagonist BQ-788 (30 nmol/kg per min, i.v.), was administered for a period of 60 min. Total renal blood flow (RBF), cortical and outer medullary perfusion (laser-Doppler flowmetry) and Po(2) (Clark-type microelectrodes) were analysed throughout. At baseline, there were no significant differences between groups in mean arterial pressure (MAP), RBF, cortical and outer medullary perfusion and Po(2). Infusion of BQ-788 reduced RBF, cortical perfusion and outer medullary Po(2) (P < 0.05) and increased renal vascular resistance (P < 0.05) compared with saline-treated and BQ123 + BQ788-infused groups. BQ-123 and coinfusion of BQ-123 + BQ-788 increased outer medullary perfusion compared with the saline-treated group (P < 0.05) without significantly affecting outer medullary Po(2) and MAP. Neither selective nor combined ET(A) and ET(B) receptor antagonism significantly affected renal cortical Po(2). In conclusion, in normotensive rats, ET(B) receptor antagonism caused renal vasoconstriction and reduced RBF and cortical perfusion. Furthermore, ET(B) receptor antagonism decreased outer medullary Po(2). These effects were mediated by ET(A) receptor activation and are not due to a lack of ET(B) receptor activation per se. Finally, BQ-123 increased renal outer medullary perfusion, suggesting a tonic vasoconstrictor effect of ET(A) receptors in the medulla of normotensive rats.

  11. Ikarisoside A inhibits acetylcholine-induced catecholamine secretion and synthesis by suppressing nicotinic acetylcholine receptor-ion channels in cultured bovine adrenal medullary cells.

    Science.gov (United States)

    Li, Xiaojia; Toyohira, Yumiko; Horisita, Takafumi; Satoh, Noriaki; Takahashi, Keita; Zhang, Han; Iinuma, Munekazu; Yoshinaga, Yukari; Ueno, Susumu; Tsutsui, Masato; Sata, Takeyoshi; Yanagihara, Nobuyuki

    2015-12-01

    Ikarisoside A is a natural flavonol glycoside derived from plants of the genus Epimedium, which have been used in Traditional Chinese Medicine as tonics, antirheumatics, and aphrodisiacs. Here, we report the effects of ikarisoside A and three other flavonol glycosides on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. We found that ikarisoside A (1-100 μM), but not icariin, epimedin C, or epimedoside A, concentration-dependently inhibited the secretion of catecholamines induced by acetylcholine, a physiological secretagogue and agonist of nicotinic acetylcholine receptors. Ikarisoside A had little effect on catecholamine secretion induced by veratridine and 56 mM K(+). Ikarisoside A (1-100 μM) also inhibited (22)Na(+) influx and (45)Ca(2+) influx induced by acetylcholine in a concentration-dependent manner similar to that of catecholamine secretion. In Xenopus oocytes expressing α3β4 nicotinic acetylcholine receptors, ikarisoside A (0.1-100 μM) directly inhibited the current evoked by acetylcholine. It also suppressed (14)C-catecholamine synthesis and tyrosine hydroxylase activity induced by acetylcholine at 1-100 μM and 10-100 μM, respectively. The present findings suggest that ikarisoside A inhibits acetylcholine-induced catecholamine secretion and synthesis by suppression of nicotinic acetylcholine receptor-ion channels in bovine adrenal medullary cells.

  12. Inhibition of /sup 22/Na influx by tricyclic and tetracyclic antidepressants and binding of (/sup 3/H)imipramine in bovine adrenal medullary cells

    Energy Technology Data Exchange (ETDEWEB)

    Arita, M.; Wada, A.; Takara, H.; Izumi, F.

    1987-10-01

    In bovine adrenal medullary cells we investigated the effects of antidepressants on ionic channels and secretion of catecholamines. Tricyclic (imipramine, amitriptyline and nortriptyline) and tetracyclic (maprotiline and mianserin) antidepressants inhibited carbachol-induced influx of /sup 22/Na, /sup 45/Ca and secretion of catecholamines (IC50, 14-96 microM). Influx of /sup 22/Na, /sup 45/Ca and secretion of catecholamines due to veratridine also were inhibited by these drugs (IC50, 10-17 microM). However, antidepressants did not suppress high concentration of K-induced 45Ca influx and catecholamine secretion, suggesting that antidepressants do not inhibit voltage-dependent Ca channels. (/sup 3/H)Imipramine bound specifically to adrenal medullary cells. Binding was saturable, reversible and with two different equilibrium dissociation constants (13.3 and 165.0 microM). Tricyclic and tetracyclic antidepressants competed for the specific binding of (/sup 3/H)imipramine at the same concentrations as they inhibited /sup 22/Na influx caused by carbachol or veratridine. Carbachol, d-tubocurarine, hexamethonium, tetrodotoxin, veratridine and scorpion venom did not inhibit the specific binding of (/sup 3/H)imipramine. These results suggest that tricyclic and tetracyclic antidepressants bind to two populations of binding sites which are functionally associated with nicotinic receptor-associated ionic channels and with voltage-dependent Na channels, and inhibit Na influx. Inhibition of Na influx leads to the reduction of Ca influx and catecholamine secretion caused by carbachol or veratridine.

  13. Inhibition of 22Na influx by tricyclic and tetracyclic antidepressants and binding of [3H]imipramine in bovine adrenal medullary cells

    International Nuclear Information System (INIS)

    Arita, M.; Wada, A.; Takara, H.; Izumi, F.

    1987-01-01

    In bovine adrenal medullary cells we investigated the effects of antidepressants on ionic channels and secretion of catecholamines. Tricyclic (imipramine, amitriptyline and nortriptyline) and tetracyclic (maprotiline and mianserin) antidepressants inhibited carbachol-induced influx of 22 Na, 45 Ca and secretion of catecholamines (IC50, 14-96 microM). Influx of 22 Na, 45 Ca and secretion of catecholamines due to veratridine also were inhibited by these drugs (IC50, 10-17 microM). However, antidepressants did not suppress high concentration of K-induced 45Ca influx and catecholamine secretion, suggesting that antidepressants do not inhibit voltage-dependent Ca channels. [ 3 H]Imipramine bound specifically to adrenal medullary cells. Binding was saturable, reversible and with two different equilibrium dissociation constants (13.3 and 165.0 microM). Tricyclic and tetracyclic antidepressants competed for the specific binding of [ 3 H]imipramine at the same concentrations as they inhibited 22 Na influx caused by carbachol or veratridine. Carbachol, d-tubocurarine, hexamethonium, tetrodotoxin, veratridine and scorpion venom did not inhibit the specific binding of [ 3 H]imipramine. These results suggest that tricyclic and tetracyclic antidepressants bind to two populations of binding sites which are functionally associated with nicotinic receptor-associated ionic channels and with voltage-dependent Na channels, and inhibit Na influx. Inhibition of Na influx leads to the reduction of Ca influx and catecholamine secretion caused by carbachol or veratridine

  14. Invasive medullary thymoma associated with myasthenia gravis: an unusual case Miastenia gravis em um paciente com timoma medular invasivo: relato de caso

    Directory of Open Access Journals (Sweden)

    JORGE S. REIS FILHO

    2000-12-01

    Full Text Available Thymomas are tumors characterized by a remarkable morphological heterogeneity and variable clinical behavior. This tumor has unique clinical associations, most notably with hematological abnormalities and myasthenia gravis. According with the Müller-Hermelink criteria, there are significant differences between the histological types of thymomas and the association with myasthenia gravis. Among the different histological types, medullary thymoma is the least frequent variant associated with this autoimmune disease. In this report we describe a case of medullary thymoma presenting in a 71-year- old woman with a myasthenic syndrome.Os timomas são tumores caracterizados por grande heterogeneidade morfológica e comportamento clínico variável. Este tumor apresenta associações clínicas singulares, principalmente com doenças hematológicas e com a miastenia gravis. De acordo com a classificação de Müller-Hermelink, existem diferenças significativas entre as variedades histológicas dos timomas e sua associação com a miastenia gravis. Entre os diferentes tipos histológicos, o timoma medular é a variante menos frequentemente associada com esta doença autoimune. Neste relato, nós descrevemos caso de timoma medular em uma paciente de 71 anos de idade com síndrome miastênica.

  15. Histopathological examination of bone debris from reaming of interlocking intra-medullary nail fixation of long bone fractures with concomitant head injury.

    Science.gov (United States)

    Khallaf, Fathy G; Kehinde, Elijah O

    2015-12-01

    The aim of study was to test, for the presence of osteoblasts in the reaming debris of intramedullary nailing of femoral and tibial fracture in patients with and without severe head injury. Two groups of patients were studied. Group A (n = 32) had long bone fractures in addition to having head injuries. Group B (n = 35) had only long bone fractures. The fractures in the 2 groups of patients was treated by inter medullary nailing. Osteoblasts in the debris of the inter medullary nailing was compared between the 2 groups of patients. The results demonstrated that histopathological specimens from reaming debris of fractured femur and tibia in patients with head injury showed osteoblasts in (82.9%) and in (27.5%) of patients with isolated long bone fractures (p fractures and concomitant head injury confirm fast and adequate healing in these patients and the presence of plenty of osteoblasts in their reaming debris may reflect a proof of accelerated fracture healing environment.

  16. When the Sense of Smell Meets Emotion: Anxiety-State-Dependent Olfactory Processing and Neural Circuitry Adaptation

    Science.gov (United States)

    Novak, Lucas R.; Gitelman, Darren R.

    2013-01-01

    Phylogenetically the most ancient sense, olfaction is characterized by a unique intimacy with the emotion system. However, mechanisms underlying olfaction–emotion interaction remain unclear, especially in an ever-changing environment and dynamic internal milieu. Perturbing the internal state with anxiety induction in human subjects, we interrogated emotion-state-dependent olfactory processing in a functional magnetic resonance imaging (fMRI) study. Following anxiety induction, initially neutral odors become unpleasant and take longer to detect, accompanied by augmented response to these odors in the olfactory (anterior piriform and orbitofrontal) cortices and emotion-relevant pregenual anterior cingulate cortex. In parallel, the olfactory sensory relay adapts with increased anxiety, incorporating amygdala as an integral step via strengthened (afferent or efferent) connections between amygdala and all levels of the olfactory cortical hierarchy. This anxiety-state-dependent neural circuitry thus enables cumulative infusion of limbic affective information throughout the olfactory sensory progression, thereby driving affectively charged olfactory perception. These findings could constitute an olfactory etiology model of emotional disorders, as exaggerated emotion–olfaction interaction in negative mood states turns innocuous odors aversive, fueling anxiety and depression with rising ambient sensory stress. PMID:24068799

  17. Mapping Compulsivity in the DSM-5 Obsessive Compulsive and Related Disorders: Cognitive Domains, Neural Circuitry, and Treatment

    Science.gov (United States)

    Apergis-Schoute, Annemieke M; Vaghi, Matilde M; Banca, Paula; Gillan, Claire M; Voon, Valerie; Chamberlain, Samuel R; Cinosi, Eduardo; Reid, Jemma; Shahper, Sonia; Bullmore, Edward T; Sahakian, Barbara J; Robbins, Trevor W

    2018-01-01

    Abstract Compulsions are repetitive, stereotyped thoughts and behaviors designed to reduce harm. Growing evidence suggests that the neurocognitive mechanisms mediating behavioral inhibition (motor inhibition, cognitive inflexibility) reversal learning and habit formation (shift from goal-directed to habitual responding) contribute toward compulsive activity in a broad range of disorders. In obsessive compulsive disorder, distributed network perturbation appears focused around the prefrontal cortex, caudate, putamen, and associated neuro-circuitry. Obsessive compulsive disorder-related attentional set-shifting deficits correlated with reduced resting state functional connectivity between the dorsal caudate and the ventrolateral prefrontal cortex on neuroimaging. In contrast, experimental provocation of obsessive compulsive disorder symptoms reduced neural activation in brain regions implicated in goal-directed behavioral control (ventromedial prefrontal cortex, caudate) with concordant increased activation in regions implicated in habit learning (presupplementary motor area, putamen). The ventromedial prefrontal cortex plays a multifaceted role, integrating affective evaluative processes, flexible behavior, and fear learning. Findings from a neuroimaging study of Pavlovian fear reversal, in which obsessive compulsive disorder patients failed to flexibly update fear responses despite normal initial fear conditioning, suggest there is an absence of ventromedial prefrontal cortex safety signaling in obsessive compulsive disorder, which potentially undermines explicit contingency knowledge and may help to explain the link between cognitive inflexibility, fear, and anxiety processing in compulsive disorders such as obsessive compulsive disorder. PMID:29036632

  18. Neurogenetic Impairments of Brain Reward Circuitry Links to Reward Deficiency Syndrome (RDS): Potential Nutrigenomic Induced Dopaminergic Activation

    Science.gov (United States)

    Blum, K; Oscar-Berman, M; Giordano, J; Downs, BW; Simpatico, T; Han, D; Femino, John

    2012-01-01

    Work from our laboratory in both in-patient and outpatient facilities utilizing the Comprehensive Analysis of Reported Drugs (CARD)™ found a significant lack of compliance to prescribed treatment medications and a lack of abstinence from drugs of abuse during active recovery. This unpublished, ongoing research provides an impetus to develop accurate genetic diagnosis and holistic approaches that will safely activate brain reward circuitry in the mesolimbic dopamine system. This editorial focuses on the neurogenetics of brain reward systems with particular reference to genes related to dopaminergic function. The terminology “Reward Deficiency Syndrome” (RDS), used to describe behaviors found to have an association with gene-based hypodopaminergic function, is a useful concept to help expand our understanding of Substance Use Disorder (SUD), process addictions, and other obsessive, compulsive and impulsive behaviors. This editorial covers the neurological basis of pleasure and the role of natural and unnatural reward in motivating and reinforcing behaviors. Additionally, it briefly describes the concept of natural dopamine D2 receptor agonist therapy coupled with genetic testing of a panel of reward genes, the Genetic Addiction Risk Score (GARS). It serves as a spring-board for this combination of novel approaches to the prevention and treatment of RDS that was developed from fundamental genomic research. We encourage further required studies. PMID:23264886

  19. Dorsal medial prefrontal cortex (MPFC) circuitry in rodent models of cocaine use: implications for drug addiction therapies.

    Science.gov (United States)

    Jasinska, Agnes J; Chen, Billy T; Bonci, Antonello; Stein, Elliot A

    2015-03-01

    Although the importance of the medial prefrontal cortex (MPFC) in cocaine addiction is well established, its precise contribution to cocaine seeking, taking and relapse remains incompletely understood. In particular, across two different models of cocaine self-administration, pharmacological or optogenetic activation of the dorsal MPFC has been reported to sometimes promote and sometimes inhibit cocaine seeking. We highlight important methodological differences between the two experimental paradigms and propose a framework to potentially reconcile the apparent discrepancy. We also draw parallels between these pre-clinical models of cocaine self-administration and human neuro-imaging studies in cocaine users, and argue that both lines of evidence point to dynamic interactions between cue-reactivity processes and control processes within the dorsal MPFC circuitry. From a translational perspective, these findings underscore the importance of interventions and therapeutics targeting not just a brain region, but a specific computational process within that brain region, and may have implications for the design and implementation of more effective treatments for human cocaine addiction. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

  20. Bilingualism yields language-specific plasticity in left hemisphere's circuitry for learning to read in young children.

    Science.gov (United States)

    Jasińska, K K; Berens, M S; Kovelman, I; Petitto, L A

    2017-04-01

    How does bilingual exposure impact children's neural circuitry for learning to read? Theories of bilingualism suggests that exposure to two languages may yield a functional and neuroanatomical adaptation to support the learning of two languages (Klein et al., 2014). To test the hypothesis that this neural adaptation may vary as a function of structural and orthographic characteristics of bilinguals' two languages, we compared Spanish-English and French-English bilingual children, and English monolingual children, using functional Near Infrared Spectroscopy neuroimaging (fNIRS, ages 6-10, N =26). Spanish offers consistent sound-to-print correspondences ("phonologically transparent" or "shallow"); such correspondences are more opaque in French and even more opaque in English (which has both transparent and "phonologically opaque" or "deep" correspondences). Consistent with our hypothesis, both French- and Spanish-English bilinguals showed hyperactivation in left posterior temporal regions associated with direct sound-to-print phonological analyses and hypoactivation in left frontal regions associated with assembled phonology analyses. Spanish, but not French, bilinguals showed a similar effect when reading Irregular words. The findings inform theories of bilingual and cross-linguistic literacy acquisition by suggesting that structural characteristics of bilinguals' two languages and their orthographies have a significant impact on children's neuro-cognitive architecture for learning to read. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells.

    Science.gov (United States)

    Iwata, Shigeru; Mikami, Yohei; Sun, Hong-Wei; Brooks, Stephen R; Jankovic, Dragana; Hirahara, Kiyoshi; Onodera, Atsushi; Shih, Han-Yu; Kawabe, Takeshi; Jiang, Kan; Nakayama, Toshinori; Sher, Alan; O'Shea, John J; Davis, Fred P; Kanno, Yuka

    2017-06-20

    Host defense requires the specification of CD4 + helper T (Th) cells into distinct fates, including Th1 cells that preferentially produce interferon-γ (IFN-γ). IFN-γ, a member of a large family of anti-pathogenic and anti-tumor IFNs, induces T-bet, a lineage-defining transcription factor for Th1 cells, which in turn supports IFN-γ production in a feed-forward manner. Herein, we show that a cell-intrinsic role of T-bet influences how T cells perceive their secreted product in the environment. In the absence of T-bet, IFN-γ aberrantly induced a type I IFN transcriptomic program. T-bet preferentially repressed genes and pathways ordinarily activated by type I IFNs to ensure that its transcriptional response did not evoke an aberrant amplification of type I IFN signaling circuitry, otherwise triggered by its own product. Thus, in addition to promoting Th1 effector commitment, T-bet acts as a repressor in differentiated Th1 cells to prevent abberant autocrine type I IFN and downstream signaling. Published by Elsevier Inc.

  2. Medullary cystic kidney disease

    Science.gov (United States)

    ... by: Charles Silberberg, DO, private practice specializing in nephrology, affiliated with New York Medical College, Division of Nephrology, Valhalla, NY. Review provided by VeriMed Healthcare Network. ...

  3. RET-Familial Medullary Thyroid Carcinoma Mutants Y791F and S891A Activate a Src/JAK/STAT3 Pathway, Independent of Glial Cell Line–Derived Neurotrophic Factor

    NARCIS (Netherlands)

    Plaza Menacho, Ivan; Koster, Roelof; Sloot, Almer M. van der; Quax, Wim J.; Osinga, Jan; Sluis, Tineke van der; Hollema, Harry; Burzynski, Grzegorz M.; Gimm, Oliver; Buys, Charles H.C.M.; Eggen, Bart J.L.; Hofstra, Robert M.W.

    2005-01-01

    The RET proto-oncogene encodes a receptor tyrosine kinase whose dysfunction plays a crucial role in the development of several neural crest disorders. Distinct activating RET mutations cause multiple endocrine neoplasia type 2A (MEN2A), type 2B (MEN2B), and familial medullary thyroid carcinoma

  4. RET-familial medullary thyroid carcinoma mutants Y791F and S891A activate a Src/JAK/STAT3 pathway, independent of glial cell line-derived neurotrophic factor

    NARCIS (Netherlands)

    Menacho, IP; Koster, R; van der Sloot, AM; Quax, WJ; Osinga, J; van der Sluis, T; Hollema, H; Burzynski, GM; Gimm, O; Buys, CHCM; Eggen, BJL; Hofstra, RMW

    2005-01-01

    The RET proto-oncogene encodes a receptor tyrosine kinase whose dysfunction plays a crucial role in the development of several neural crest disorders. Distinct activating RET mutations cause multiple endocrine neoplasia type 2A (MEN2A), type 2B (MEN2B), and familial medullary thyroid carcinoma

  5. The preparation and its believable effect of pentavalent ruenium-188 dimercaptosuccinic acid in a patient with medullary thyroid carcinoma

    International Nuclear Information System (INIS)

    Cheng Jingyi; Zhang Yingjing; Wan Danjing; Shao Peng; Wang Xincun; Jiang Changying

    2004-01-01

    Background: Dimercaptosuccinic acid (DMSA) forms a complex with pentavalent rhenium-188, known as 188 Re(V)-DMSA. This radiopharmaceutical has been shown to localize in a number of tumour types, most notably medullary thyroid carcinoma (MTC) and in bone metastases and other bone lesions. We have previously shown that 186 Re(V)-DMSA could be strongly uptaked by the lesion of MTC similar to that observed in the images of 99m Tc(V)-DMSA and had potential therapeutic value in these patients. Compared with 186Re, the 188Re has the advantages of its ready availability from a generator. Thus the aim of this study was to establish a method of reliable preparation of 188 Re(V)-DMSA and to evaluate its potential as a targeted radiotherapy agent to patient with MTC. Material and Method: The complex was prepared by reducing 188 Re in the presence of DMSA with stannous chloride at the condition of pH 1.5. The reaction was taken to completion by heating the complex in a boiling water bath for 30 minutes. Excess stannous chloride was required and the presence of hydrochloric acid didn't reduce the yield of labelling. A large dose of ascorbic acid was used to minimize autoradiolysis. The products were analysed with high-performance liquid chromatograms (HPLC) and thin layer chromatography (TLC) using a mobile phase consisting of n-butanol: acetic: water = 3:2:3 by volume. The TLC chromatograms were also visualized and quantified by gamma camera imaging. With the agreement, a patient who had a liver metastatic lesion from MTC but no symptoms (patient I) and another who had bone metastatic MTC and severe symptoms (patient II) were recruited . Both volunteers confirmed by a prior 99m Tc(V)-DMSA scan received a dose of 74 MBq of 188 Re(V)-DMSA and imaged at 3 hours with a GE Millennium VG ECT/CT. Results: The preparation had a good results with a labeling rate more than 95% and a stability in vitro more than 24 hours. The complex was a clear yellow solution which can be adjusted to p

  6. Regulation of chromatin states by drugs of abuse.

    Science.gov (United States)

    Walker, Deena M; Cates, Hannah M; Heller, Elizabeth A; Nestler, Eric J

    2015-02-01

    Drug addiction involves long-term behavioral abnormalities and gene expression changes throughout the mesolimbic dopamine system. Epigenetic mechanisms establish/maintain alterations in gene expression in the brain, providing the impetus for investigations characterizing how epigenetic processes mediate the effects of drugs of abuse. This review focuses on evidence that epigenetic events, specifically histone modifications, regulate gene expression changes throughout the reward circuitry. Drugs of abuse induce changes in histone modifications throughout the reward circuitry by altering histone-modifying enzymes, manipulation of which reveals a role for histone modification in addiction-related behaviors. There is a complex interplay between these enzymes, resulting in a histone signature of the addicted phenotype. Insights gained from these studies are key to identifying novel targets for diagnosis and therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. In Vitro Restoration of an Amyloid-Beta Altered Network Circuitry in a 'Mutated Biomimetic Acetylcholinesterase' Memristor/Memcapacitor Neural Prosthesis

    Directory of Open Access Journals (Sweden)

    John THORNTON

    2015-08-01

    Full Text Available Many diseases involve the ysregulation of acetylcholinesterase (ACHE causing inappropriate production of the neurotransmitter acetylcholine (ACH. Study of how the ACH actually restores a life threatening neural circuitry damage will provide valuable information for study Alzhermer’s disease. An artificial neuronal device was developed with nanostructured biomimetic mutated ACHE gorge membrane on gold chips having memristor/memcapacitor’s characteristics, served as a model for damaged brain circuitry prosthesis, compared before and after ACH treatments, for in vitro evaluation of the memory restoration in the presence of Amyloid-beta (Ab under the conditions of free from tracers and antibodies in NIST human serum. The results are presented in three categories in “Energy-Sensory” images. Before ACH treatments, images showed four stages of circuitry damages from non symptomatic to life threatening. After a 15 nM ACH treatment, the circuitry was restored due to the ACH removed Pathological High Frequency Oscillation (pHFO center during Slow- Waving Sleeping (SWS. After the prosthesis increased hydrophobicity, the High Frequency Oscillation (HFO was created. Results were compared between the recovered and the “normal brain”: 0.14 vs. 0.47 pJ/bit/µm3 for long-term and 14.0 vs.7.0 aJ/bit/µm3 for short-term memory restoration, respectively. The ratio of Rmax/Rmin value is 6.3-fold higher after the treatment of ACH compared without the treatment in the presence of Ab and the reentry sensitivity increased by 613.8- fold.

  8. Molt performance and bone density of cortical, medullary, and cancellous bone in laying hens during feed restriction or alfalfa-based feed molt.

    Science.gov (United States)

    Kim, W K; Donalson, L M; Bloomfield, S A; Hogan, H A; Kubena, L F; Nisbet, D J; Ricke, S C

    2007-09-01

    A study was conducted to evaluate the effects of alfalfa-based molt diets on molting performance and bone qualities. A total of 36 Single Comb White Leghorn hens were used for the study. There were 6 treatments: pretrial control (PC), fully fed (FF), feed withdrawal (FW), 90% alfalfa:10% layer ration (A90), 80% alfalfa:20% layer ration (A80), and 70% alfalfa:30% layer ration (A70). For the PC treatment, hens were euthanized by CO(2) gas, and bones were collected before molt was initiated. At the end of the 9-d molt period, hens were euthanized, and femurs and tibias were collected to evaluate bone qualities by peripheral quantitative computed tomography, mechanical testing, and conventional ash weights. The hens fed alfalfa-based molt diets and FW stopped laying eggs within 5 d after molt started, and all hens in these groups had reduced ovary weights compared with those of the FF hens. In the FW and A90 groups, total femur volumetric bone mineral densities (vBMD) at the midshaft were significantly lower, but those of the A80 and A70 groups were not significantly different from the values for the PC and FF hens. In cortical bone density, the midshaft tibial vBMD were significantly higher for FF and A70 hens than for PC hens. The medullary bone densities at the midshaft femur or tibia of the FW, A90, A80, and A70 hens were reduced compared with those of the PC hens. Femur cancellous densities at the distal femur for the FW and A90 hens were significantly reduced compared with those of the PC and FF hens. The FW, A80, and A70 hens yielded significantly higher elastic moduli, and the A80 hens had higher ultimate stress compared with the PC hens, suggesting that the mechanical integrity of the midshaft bone was maintained even though the medullary vBMD was reduced. These results suggest that alfalfa-based molt diets exhibit molt performance similar to FW, that medullary and cancellous bones are labile bone compartments during molting, and that alfalfa-based molt diets

  9. Effects of co-administration of ketamine and ethanol on the dopamine system via the cortex-striatum circuitry.

    Science.gov (United States)

    Liu, Qing; Xu, Tian-Yong; Zhang, Zhi-Bi; Leung, Chi-Kwan; You, Ding-Yun; Wang, Shang-Wen; Yi, Shuai; Jing, Qiang; Xie, Run-Fang; Li, Huifang-Jie; Zeng, Xiao-Feng

    2017-06-15

    Ketamine and ethanol are increasingly being used together as recreational drugs in rave parties. Their effects on the dopamine (DA) system remain largely unknown. This study aimed to investigate the effects of consuming two different concentrations of ketamine with and without alcohol on the DA system. We employed the conditioned place preference (CPP) paradigm to evaluate the rewarding effects of the combined administration of two different doses of ketamine (30mg/kg and 60mg/kg) with ethanol (0.3156g/kg). We evaluated the effects of the combined drug treatment on the transcriptional output of tyrosine hydroxylase (TH), dopa decarboxylase (DDC), synaptosomal-associated protein 25 (SNAP25), and vesicular monoamine transporter 2 (VMAT2) as well as protein expression level of brain-derived neurotrophic factor (BDNF) in rat prefrontal cortex (PFC) and striatum. We found that rats exhibited a dose-dependent, drug-paired, place preference to ketamine and ethanol associated with an elevated DA level in the striatum but not in the PFC. Moreover, treatment involving low- or high-dose ketamine with or without ethanol caused a differential regulatory response in the mRNA levels of the four DA metabolism genes and the cellular protein abundance of BDNF via the cortex-striatum circuitry. This study investigated the molecular mechanisms that occur following the combined administration of ketamine and ethanol in the DA system, which could potentially lead to alterations in the mental status and behavior of ketamine/ethanol users. Our findings may aid the development of therapeutic strategies for substance abuse patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. rsfMRI effects of KB220Z™ on Neural Pathways in Reward Circuitry of Abstinent Genotyped Heroin Addicts

    Science.gov (United States)

    Blum, Kenneth; Liu, Yijun; Wang, Wei; Wang, Yarong; Zhang, Yi; Oscar-Berman, Marlene; Smolen, Andrew; Febo, Marcelo; Han, David; Simpatico, Thomas; Cronjé, Frans J; Demetrovics, Zsolt; Gold, Mark S.

    2016-01-01

    Recently Willuhn et al. reported that cocaine use and even non-substance related addictive behavior, increases, as dopaminergic function is reduced. Chronic cocaine exposure has been associated with decreases in D2/D3 receptors, also associated with lower activation to cues in occipital cortex and cerebellum in a recent PET study from Volkow’s group. Therefore, treatment strategies, like dopamine agonist therapy, that might conserve dopamine function may be an interesting approach to relapse prevention in psychoactive drug and behavioral addictions. To this aim, we evaluated the effect of KB220Z™ on reward circuitry of ten heroin addicts undergoing protracted abstinence, an average 16.9 months. In a randomized placebo-controlled crossover study of KB220Z™ five subjects completed a triple blinded–experiment in which the subject, the person administering the treatment and the person evaluating the response to treatment were blinded as to which treatment any particular subject was receiving. In addition, nine subjects total were genotyped utilizing the GARSRX™ test. We preliminarily report that KB220Z ™ induced an increase in BOLD activation in caudate-accumbens-dopaminergic pathways compared to placebo following one-hour acute administration. Furthermore, KB220Z™ also reduced resting state activity in the putamen of abstinent heroin addicts. In the second phase of this pilot study of all ten abstinent heroin-dependent subjects, three brain regions of interest (ROIs) we observed to be significantly activated from resting state by KB220Z compared to placebo (P addiction by direct or indirect dopaminergic interaction. Due to small sample size, we caution definitive interpretation of these preliminary results and confirmation with additional research and ongoing rodent and human studies of KB220Z, is required. PMID:25526228

  11. Alterations in brain structures related to taste reward circuitry in ill and recovered anorexia nervosa and in bulimia nervosa.

    Science.gov (United States)

    Frank, Guido K; Shott, Megan E; Hagman, Jennifer O; Mittal, Vijay A

    2013-10-01

    The pathophysiology of anorexia nervosa remains obscure, but structural brain alterations could be functionally important biomarkers. The authors assessed taste pleasantness and reward sensitivity in relation to brain structure, which may be related to food avoidance commonly seen in eating disorders. The authors used structural MR imaging to study gray and white matter volumes in women with current restricting-type anorexia nervosa (N=19), women recovered from restricting-type anorexia nervosa (N=24), women with bulimia nervosa (N=19), and healthy comparison women (N=24). All eating disorder groups exhibited increased gray matter volume of the medial orbitofrontal cortex (gyrus rectus). Manual tracing confirmed larger gyrus rectus volume, and volume predicted taste pleasantness ratings across all groups. Analyses also indicated other morphological differences between diagnostic categories. Antero-ventral insula gray matter volumes were increased on the right side in the anorexia nervosa and recovered anorexia nervosa groups and on the left side in the bulimia nervosa group relative to the healthy comparison group. Dorsal striatum volumes were reduced in the recovered anorexia nervosa and bulimia nervosa groups and predicted sensitivity to reward in all three eating disorder groups. The eating disorder groups also showed reduced white matter in right temporal and parietal areas relative to the healthy comparison group. The results held when a range of covariates, such as age, depression, anxiety, and medications, were controlled for. Brain structure in the medial orbitofrontal cortex, insula, and striatum is altered in eating disorders and suggests altered brain circuitry that has been associated with taste pleasantness and reward value.

  12. Case report of severe Cushing's syndrome in medullary thyroid cancer complicated by functional diabetes insipidus, aortic dissection, jejunal intussusception, and paraneoplastic dysautonomia: remission with sorafenib without reduction in cortisol concentration.

    Science.gov (United States)

    Hammami, Muhammad M; Duaiji, Najla; Mutairi, Ghazi; Aklabi, Sabah; Qattan, Nasser; Abouzied, Mohei El-Din M; Sous, Mohamed W

    2015-09-09

    Normalization of cortisol concentration by multikinase inhibitors have been reported in three patients with medullary thyroid cancer-related Cushing's syndrome. Aortic dissection has been reported in three patients with Cushing's syndrome. Diabetes insipidus without intrasellar metastasis, intestinal intussusception, and paraneoplastic dysautonomia have not been reported in medullary thyroid cancer. An adult male with metastatic medullary thyroid cancer presented with hyperglycemia, hypernatremia, hypokalemia, hypertension, acne-like rash, and diabetes insipidus (urine volume >8 L/d, osmolality 190 mOsm/kg). Serum cortisol, adrenocorticoitropic hormone, dehydroepiandrostenedione sulfate, and urinary free cortisol were elevated 8, 20, 4.4, and 340 folds, respectively. Pituitary imaging was normal. Computed tomography scan revealed jejunal intussusception and incidental abdominal aortic dissection. Sorafenib treatment was associated with Cushing's syndrome remission, elevated progesterone (>10 fold), normalization of dehydroepiandrostenedione sulfate, but persistently elevated cortisol concentration. Newly-developed proximal lower limb weakness and decreased salivation were associated with elevated ganglionic neuronal acetylcholine receptor (alpha-3) and borderline P/Q type calcium channel antibodies. Extreme cortisol concentration may have contributed to aortic dissection and suppressed antidiuretic hormone secretion; which combined with hypokalemia due cortisol activation of mineralocorticoid receptors, manifested as diabetes insipidus. This is the first report of paraneoplastic dysautonomia and jejunal intussusception in medullary thyroid cancer, they may be related to medullary thyroid cancer's neuroendocrine origin and metastasis, respectively. Remission of Cushing's syndrome without measurable reduction in cortisol concentration suggests a novel cortisol-independent mechanism of action or assay cross-reactivity. Normalization of dehydroepiandrostenedione

  13. Oncocytic Variant of Medullary Thyroid Carcinoma: A Rare Case of Sporadic Multifocal and Bilateral RET Wild-Type Neoplasm with Revision of the Literature.

    Science.gov (United States)

    Vinciguerra, Gian Luca Rampioni; Noccioli, Niccolò; Cippitelli, Claudia; Minucci, Angelo; Capoluongo, Ettore; Bartolazzi, Armando

    2016-11-17

    Oncocytic variant of medullary thyroid carcinoma (OV-MTC) is a very unusual entity, up to date only 17 cases have been reported in the literature. MTC is a neuro-endocrine malignancy arising from the para-follicular C cells of the thyroid gland. It generally has a slight female predominance and appears as a single lesion. However in the Multiple Endocrine Neoplasia Syndrome 2, linked to the point mutation of RET oncogene, multifocal MTCs may also occur. Herein, we report the case of a 75 years old man with a rare form of sporadic multifocal and bilateral OV-MTC expressing wild-type RET gene. The histological and molecular features of this rare entity are presented and discussed with revision of the pertinent literature.

  14. Oncocytic variant of medullary thyroid carcinoma: a rare case of sporadic multifocal and bilateral RET wild-type neoplasm with revision of the literature

    Directory of Open Access Journals (Sweden)

    Gian Luca Rampioni Vinciguerra

    2016-12-01

    Full Text Available Oncocytic variant of medullary thyroid carcinoma (OV-MTC is a very unusual entity, up to date only 17 cases have been reported in the literature. MTC is a neuro-endocrine malignancy arising from the para-follicular C cells of the thyroid gland. It generally has a slight female predominance and appears as a single lesion. However in the Multiple Endocrine Neoplasia Syndrome 2, linked to the point mutation of RET oncogene, multifocal MTCs may also occur. Herein, we report the case of a 75 years old man with a rare form of sporadic multifocal and bilateral OV-MTC expressing wild-type RET gene. The histological and molecular features of this rare entity are presented and discussed with revision of the pertinent literature.

  15. A rare mutation in the RET-protooncogen associated with mixed medullary-follicular micro-carcinoma of the thyroid gland

    Energy Technology Data Exchange (ETDEWEB)

    Richter, K.; Huwe, A.; Boldt, H.; Dresel, S. [Nuklearmedizinische Klinik, HELIOS-Klinikum Berlin-Buch (Germany); Geipel, D. [St.-Hedwig-Krankenhaus, Bereich Endokrine Chirurgie (Germany); Mairinger, T. [Inst. fuer Pathologie, HELIOS-Klinikum Emil von Behring (Germany); Schwabe, M. [Inst. fuer Pathologie, Charite Berlin Campus Mitte (Germany)

    2008-07-01

    Medullary thyroid carcinoma (MTC) arises from parafollicular C-cells of the thyroid and accounts for 1% to 10% of all thyroid cancers (1). MTC can be sporadic or hereditary. Hereditary MTC represents 20% to 30% of all MTC with an autosomal dominant pattern of transmission and a high degree of penetrance (>90%). It can be transmitted as a single entity (sporadic), familial MTC (FMTC), or it can arise as part of a multiple endocrine neoplasia (MEN) syndrome type 2A or 2B. Both genders are equally affected. (1, 9) The identification of hereditary MTC has been facilitated in recent years by the direct analysis of germline point mutations of the RET(rearranged during transfection)-protooncogene, a 21 exon gene that encodes a plasma membrane-bound tyrosine kinase receptor, localised on chromosome 10q11.2, which is expressed in tissues derived from the neural crest. To date codon mutations in nine different exons were identified (7, 8, 16, 22, 29) causing MEN 2A (MTC in combination with pheochromocytoma and hyperparathyroidism, including rare variants with Hirschsprung's disease and cutaneous lichen amyloidosis), FMTC (MTC as a sole disease phenotype) and MEN 2B (MTC in combination with pheochromocytoma, multiple mucosa neuromas, and marfanoid habitus). The most common mutation, accounting for over 80% of all mutations associated with MEN 2A (or Sipple's) syndrome affects codon 634 in exon 11 of the RET-protooncogene. Other mutations affect codon 630 in exon 11, and codons 609, 611, 618, 620 in exon 10 - they also cause FMTC, although some have a classic MEN 2A syndrome. 5% to 10% of families with FMTC have mutations that affect codons 768, 790, 791 in exon 13: codons 804, 844 in exon 14, and codon 891 in exon 15 (3, 4, 10). The much more aggressive MEN 2B is caused by a single mutation converting a methionine into a threonine at codon 918 in exon 16, and has been identified in approximately 95% of patients with MEN 2B. Other rare mutations associated with MEN 2

  16. Hybridization of biomedical circuitry

    Science.gov (United States)

    Rinard, G. A.

    1978-01-01

    The design and fabrication of low power hybrid circuits to perform vital signs monitoring are reported. The circuits consist of: (1) clock; (2) ECG amplifier and cardiotachometer signal conditioner; (3) impedance pneumobraph and respiration rate processor; (4) hear/breath rate processor; (5) temperature monitor; and (6) LCD display.

  17. Analysis of Newly Identified and Rare Synonymous Genetic Variants in the RET Gene in Patients with Medullary Thyroid Carcinoma in Polish Population.

    Science.gov (United States)

    Sromek, Maria; Czetwertyńska, Małgorzata; Tarasińska, Magdalena; Janiec-Jankowska, Aneta; Zub, Renata; Ćwikła, Maria; Nowakowska, Dorota; Chechlińska, Magdalena

    2017-09-01

    Gain-of-function germline mutations of the RET proto-oncogene are responsible for initiation of carcinogenesis within the thyroid gland and development of hereditary form of medullary thyroid carcinoma and MEN2 syndrome. Genotype-phenotype correlations are established for most RET mutations, but the importance of the synonymous changes in this gene remains debatable. We aimed to analyze RET gene variants in Polish population. Genetic testing for the RET gene variants was performed with standard methods in 585 people aged 1-85, including 448 patients with medullary thyroid carcinoma and 131 of their first- and second-degree relatives, as well as six patients suspected of MTC/MEN2. Besides the most frequent synonymous changes, p.Leu769Leu, p.Ser836Ser, and p.Ser904Ser, four rare changes-c.1827C>T (p.Cys609Cys), c.2364C>T (p.Ile788Ile), c.2418C>T (p.Tyr806Tyr), and c.2673G>A (p.Ser891Ser)-were found in the RET gene, in the Polish population. Two of the rare changes, p.Cys609Cys and p.Ile788Ile, had not been previously described. The frequency of molecular synonymous variants in the general population was evaluated by testing 400 anonymous blood samples of neonates. Our findings may contribute to a better understanding of the genetic diversity of the RET gene and the involvement of synonymous variants in this diversity.

  18. Somatic mutations of the ret Protooncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumor recurrence

    Energy Technology Data Exchange (ETDEWEB)

    Romei, C.; Elisei, R.; Pinchera, A. [Univ. of Pisa (Italy)] [and others

    1996-04-01

    Germline point mutations in exons 10, 11, and 16 of the ret protooncogene have been identified as causative in multiple endocrine neoplasia type 2 and in familial medullary thyroid carcinoma (MTC). Somatic point mutations of the same gene, exclusively associated with codon 918 of exon 16, have also been reported in few cases of sporadic medullary thyroid carcinoma. We analyzed the blood and tumor DNA of 19 patients with sporadic MTC and 6 patients with primary parathyroid adenoma for point mutations at exons 10, 11, and 16 of the ret protooncogene by restriction analysis of the PCR-amplified product and by sequence analysis of exons 10 and 11. A Cys{sup 634}{r_arrow}Tyr mutation was found in both the tumoral and blood DNA of one patient, indicating that he was affected by an hereditary form of MTC, erroneously considered sporadic. In the other 18 patients with MTC, somatic point mutations of ret were found in 8 cases (44.4%). In 5 cases the mutation affected exon 16 (Met{sup 918}{r_arrow}Thr), and in 3 cases it affected exon 11 (Cys{sup 634}{r_arrow}Arg in 1 and Cys{sup 634}{r_arrow}Trp in 2); these 3 mutations were confirmed by sequence analysis. The remaining 10 patients had no mutation in exon 10 by either restriction analysis or sequence analysis. Clinical data showed that 75% of the patients whose tumor carried ret mutation had tumor recurrence and/or increased serum calcitonin concentrations during the postsurgical follow-up period as opposed to 10% of the patients without mutations (P < 0.02, by {chi}{sup 2} analysis). No ret mutation was found in the tumoral DNA from parathyroid adenomas. Our findings indicate that the somatic ret point mutation frequently found in sporadic MTC may affect not only exon 16 but also exon 11 and is associated with less favorable clinical outcome. 14 refs., 2 figs., 3 tabs.

  19. Renal medullary AA amyloidosis, hepatocyte dissociation and multinucleated hepatocytes in a 14-year-old free-ranging lioness (Panthera leo

    Directory of Open Access Journals (Sweden)

    J.H. Williams

    2005-06-01

    Full Text Available A 14-year-old lioness, originating from Etosha in Namibia, and a member of a pride in Pilanesberg National Park since translocation in 1994, was euthanased due to fight-related vertebral fracture and spinal injury, incurred approximately 6-8 weeks previously. Blood specimens collected at the time of death showed mild anaemia and a leukogram reflecting stress and chronic infection. Necropsy conducted within 2 hours of death was on a dehydrated, emaciated animal with hindquarter wasting and chronic traumatic friction injuries from dragging her hindlegs. There was cellulitis in the region of bite-wounds adjacent to the thoraco-lumbar vertebral fracture, at which site there was spinal cord compression, and there was marked intestinal helminthiasis. The outer renal medullae appeared pale and waxy and the liver was macroscopically unremarkable. Histopathology and electron microscopy of the kidneys revealed multifocal to coalescing deposits of proximal medullary interstitial amyloid, which fluoresced strongly with thioflavine T, and was sensitive to potassium permanganate treatment prior to Congo Red staining, thus indicating inflammatory (AA origin. There was diffuse hepatocyte dissociation, as well as numerous binucleated and scattered multinucleated (up to 8 nuclei/cell hepatocytes, with swollen hepatocyte mitochondria, in liver examined light microscopically. Ultrastructurally, the mono-, bi- and multinucleated hepatocytes contained multifocal irregular membrane-bound accumulations of finely-granular, amorphous material both intra-cytoplasmically and intra-nuclearly, as well as evidence of irreversible mitochondrial injury. The incidence and relevance in cats and other species of amyloidosis, particularly with renal medullary distribution, as well as of hepatocyte dissociation and multinucleation, as reported in selected literature, is briefly overviewed and their occurrence in this lioness is discussed.

  20. Renal medullary AA amyloidosis, hepatocyte dissociation and multinucleated hepatocytes in a 14-year-old free-ranging lioness (Panthera leo).

    Science.gov (United States)

    Williams, J H; Van Wilpe, E; Momberg, M

    2005-06-01

    A 14-year-old lioness, originating from Etosha in Namibia, and a member of a pride in Pilanesberg National Park since translocation in 1994, was euthanased due to fight-related vertebral fracture and spinal injury, incurred approximately 6-8 weeks previously. Blood specimens collected at the time of death showed mild anaemia and a leukogram reflecting stress and chronic infection. Necropsy conducted within 2 hours of death was on a dehydrated, emaciated animal with hindquarter wasting and chronic traumatic friction injuries from dragging her hindlegs. There was cellulitis in the region of bite-wounds adjacent to the thoraco-lumbar vertebral fracture, at which site there was spinal cord compression, and there was marked intestinal helminthiasis. The outer renal medullae appeared pale and waxy and the liver was macroscopically unremarkable. Histopathology and electron microscopy of the kidneys revealed multifocal to coalescing deposits of proximal medullary interstitial amyloid, which fluoresced strongly with thioflavine T, and was sensitive to potassium permanganate treatment prior to Congo Red staining, thus indicating inflammatory (AA) origin. There was diffuse hepatocyte dissociation, as well as numerous binucleated and scattered multinucleated (up to 8 nuclei/cell) hepatocytes, with swollen hepatocyte mitochondria, in liver examined light microscopically. Ultrastructurally, the mono-, bi- and multinucleated hepatocytes contained multifocal irregular membrane-bound accumulations of finely-granular, amorphous material both intra-cytoplasmically and intra-nuclearly, as well as evidence of irreversible mitochondrial injury. The incidence and relevance in cats and other species of amyloidosis, particularly with renal medullary distribution, as well as of hepatocyte dissociation and multinucleation, as reported in selected literature, is briefly overviewed and their occurrence in this lioness is discussed.

  1. A framework for the first-person internal sensation of visual perception in mammals and a comparable circuitry for olfactory perception in Drosophila.

    Science.gov (United States)

    Vadakkan, Kunjumon I

    2015-01-01

    Perception is a first-person internal sensation induced within the nervous system at the time of arrival of sensory stimuli from objects in the environment. Lack of access to the first-person properties has limited viewing perception as an emergent property and it is currently being studied using third-person observed findings from various levels. One feasible approach to understand its mechanism is to build a hypothesis for the specific conditions and required circuit features of the nodal points where the mechanistic operation of perception take place for one type of sensation in one species and to verify it for the presence of comparable circuit properties for perceiving a different sensation in a different species. The present work explains visual perception in mammalian nervous system from a first-person frame of reference and provides explanations for the homogeneity of perception of visual stimuli above flicker fusion frequency, the perception of objects at locations different from their actual position, the smooth pursuit and saccadic eye movements, the perception of object borders, and perception of pressure phosphenes. Using results from temporal resolution studies and the known details of visual cortical circuitry, explanations are provided for (a) the perception of rapidly changing visual stimuli, (b) how the perception of objects occurs in the correct orientation even though, according to the third-person view, activity from the visual stimulus reaches the cortices in an inverted manner and (c) the functional significance of well-conserved columnar organization of the visual cortex. A comparable circuitry detected in a different nervous system in a remote species-the olfactory circuitry of the fruit fly Drosophila melanogaster-provides an opportunity to explore circuit functions using genetic manipulations, which, along with high-resolution microscopic techniques and lipid membrane interaction studies, will be able to verify the structure

  2. Disrupted Structural and Functional Connectivity in Prefrontal-Hippocampus Circuitry in First-Episode Medication-Naïve Adolescent Depression.

    Directory of Open Access Journals (Sweden)

    Haiyang Geng

    Full Text Available Evidence implicates abnormalities in prefrontal-hippocampus neural circuitry in major depressive disorder (MDD. This study investigates the potential disruptions in prefrontal-hippocampus structural and functional connectivity, as well as their relationship in first-episode medication-naïve adolescents with MDD in order to investigate the early stage of the illness without confounds of illness course and medication exposure.Diffusion tensor imaging and resting-state functional magnetic resonance imaging (rs-fMRI data were acquired from 26 first-episode medication-naïve MDD adolescents and 31 healthy controls (HC. Fractional anisotropy (FA values of the fornix and the prefrontal-hippocampus functional connectivity was compared between MDD and HC groups. The correlation between the FA value of fornix and the strength of the functional connectivity in the prefrontal cortex (PFC region showing significant differences between the two groups was identified.Compared with the HC group, adolescent MDD group had significant lower FA values in the fornix, as well as decreased functional connectivity in four PFC regions. Significant negative correlations were observed between fornix FA values and functional connectivity from hippocampus to PFC within the HC group. There was no significant correlation between the fornix FA and the strength of functional connectivity within the adolescent MDD group.First-episode medication-naïve adolescent MDD showed decreased structural and functional connectivity as well as deficits of the association between structural and functional connectivity shown in HC in the PFC-hippocampus neural circuitry. These findings suggest that abnormal PFC-hippocampus neural circuitry may present in the early onset of MDD and play an important role in the neuropathophysiology of MDD.

  3. Thyroid medullary carcinoma and PET/CT with {sup 18}F-DOPA in the post surgery follow up: preliminary results; Carcinome medullaire de la thyroide et TEP/TDM a la {sup 18}F-DOPA dans le suivi post-chirurgical: resultats preliminaires

    Energy Technology Data Exchange (ETDEWEB)

    Keomany, J.; Rust, E.; Constantinesco, A.; Imperiale, A. [CHU de Strasbourg, Service de biophysique et medecine nucleaire, 67 (France); Detour, J. [CHU de Strasbourg, Service de radiopharmacie, 67 (France); Chabrier, G.; Goichot, B. [CHU de Strasbourg, Service de medecine interne, endocrinologie et nutrition, 67 (France); Schneegans, O. [FNCLCC Paul-Strauss, 67 - Strasbourg (France)

    2010-07-01

    Purpose: to study the contribution of the PET/CT with {sup 18}F DOPA in the therapy follow-up of patients with a history of medullary thyroid carcinoma and biological suspicion of residual disease or recurrence. Conclusions: The preliminary results show the interest of the PET/CT with {sup 18}F DOPA in the therapy follow-up and the management of patients suffering of medullary thyroid carcinoma in biological relapse. (N.C.)

  4. Carcinoma medular da mama: correlação anátomo-radiológica Medullary breast carcinoma: anatomo-radiological correlation

    Directory of Open Access Journals (Sweden)

    Valéria Soares Matheus

    2008-12-01

    Full Text Available OBJETIVO: Avaliar as características radiológicas do câncer de mama medular em pacientes submetidas a tratamento cirúrgico no Instituto Nacional de Câncer (INCA - Ministério da Saúde, Rio de Janeiro, RJ, correlacionando os achados com estudo histopatológico. MATERIAIS E MÉTODOS: Foi realizado estudo descritivo retrospectivo de mulheres submetidas a tratamento cirúrgico no INCA, no período de janeiro de 1997 a dezembro de 2006, para identificação das pacientes com carcinoma medular e análise dos achados radiológicos. RESULTADOS: Foram identificadas 21.287 pacientes com diagnóstico de carcinoma neste período, sendo 76 pacientes com diagnóstico de carcinoma medular típico (0,357%. Nessas pacientes selecionadas, a idade média foi de 51,9 anos (32 a 81 anos. Dezenove pacientes apresentavam lesão na mamografia, sendo 17 (89,5% nódulos e 2 assimetrias focais (10,5%. Entre as pacientes com nódulo, 15 (88,1% apresentavam alta densidade e 2 eram isodensos (11,9%. Doze pacientes apresentavam achados ultra-sonográficos e, destas, 11 (91,6% apresentavam nódulos hipoecóicos. Foi observada uma paciente com nódulo anecóico com áreas de degeneração cística. CONCLUSÃO: O nódulo foi o achado radiológico dominante (89,5%, dos quais 88,1% apresentaram nódulos com alta densidade e margens circunscritas. Apesar das características radiológicas de benignidade, um nódulo com alta densidade, sólido, margens circunscritas e crescimento rápido deve ser investigado para confirmar o diagnóstico.OBJECTIVE: To evaluate radiological findings in patients submitted to surgical treatment for medullary breast cancer at Instituto Nacional de Câncer (INCA, Rio de Janeiro, RJ, Brazil, correlating them with histological results. MATERIALS AND METHODS: A retrospective descriptive study was developed with patients submitted to surgery at INCA, in the period from January 1997 to December 2006, for identifying the presence of medullary breast

  5. EHD4 is a novel regulator of urinary water homeostasis.

    Science.gov (United States)

    Rahman, Shamma S; Moffitt, Alexandra E J; Trease, Andrew J; Foster, Kirk W; Storck, Matthew D; Band, Hamid; Boesen, Erika I

    2017-12-01

    The Eps15-homology domain-containing (EHD) protein family comprises 4 members that regulate endocytic recycling. Although the kidney expresses all 4 EHD proteins, their physiologic roles are largely unknown. This study focused on EHD4, which we found to be expressed differentially across nephron segments with the highest expression in the inner medullary collecting duct. Under baseline conditions, Ehd4 -/- [EHD4-knockout (KO)] mice on a C57Bl/6 background excreted a higher volume of more dilute urine than control C57Bl/6 wild-type (WT) mice while maintaining a similar plasma osmolality. Urine excretion after an acute intraperitoneal water load was significantly increased in EHD4-KO mice compared to WT mice, and although EHD4-KO mice concentrated their urine during 24-h water restriction, urinary osmolality remained significantly lower than in WT mice, suggesting that EHD4 plays a role in renal water handling. Total aquaporin 2 (AQP2) and phospho-S256-AQP2 (pAQP2) protein expression in the inner medulla was similar in the two groups in baseline conditions. However, localization of both AQP2 and pAQP2 in the renal inner medullary principal cells appeared more dispersed, and the intensity of apical membrane staining for AQP2 was reduced significantly (by ∼20%) in EHD4-KO mice compared to WT mice in baseline conditions, suggesting an important role of EHD4 in trafficking of AQP2. Together, these data indicate that EHD4 play important roles in the regulation of water homeostasis.-Rahman, S. S., Moffitt, A. E. J., Trease, A. J., Foster, K. W., Storck, M. D., Band, H., Boesen, E. I. EHD4 is a novel regulator of urinary water homeostasis. © FASEB.

  6. Sodium-bicarbonate cotransporter NBCn1 in the kidney medullary thick ascending limb cell line is upregulated under acidic conditions and enhances ammonium transport.

    Science.gov (United States)

    Lee, Soojung; Lee, Hye Jeong; Yang, Han Soo; Thornell, Ian M; Bevensee, Mark O; Choi, Inyeong

    2010-09-01

    In this study, we examined the effect of bicarbonate transporters on ammonium/ammonia uptake in the medullary thick ascending limb cell line ST-1. Cells were treated with 1 mm ouabain and 0.2 mM bumetanide to minimize carrier-mediated NH(4)(+) transport, and the intracellular accumulation of (14)C-methylammonium/methylammonia ((14)C-MA) was determined. In CO(2)/HCO(3)(-)-free solution, cells at normal pH briefly accumulated (14)C-MA over 7 min and reached a plateau. In CO(2)/HCO(3)(-) solution, however, cells markedly accumulated (14)C-MA over the experimental period of 30 min. This CO(2)/HCO(3)(-)-dependent accumulation was reduced by the bicarbonate transporter blocker, 4,4-diisothiocyanatostilbene-2,2-disulfonate (DIDS; 0.5 mM). Replacing Cl(-) with gluconate reduced the accumulation, but the reduction was more substantial in the presence of DIDS. Incubation of cells at pH 6.8 (adjusted with NaHCO(3) in 5% CO(2)) for 24 h lowered the mean steady-state intracellular pH to 6.96, significantly lower than 7.28 for control cells. The presence of DIDS reduced (14)C-MA accumulation in control conditions but had no effect after acidic incubation. Immunoblotting showed that NBCn1 was upregulated after acidic incubation and in NH(4)Cl-containing media. The Cl(-)-HCO(3)(-) exchanger AE2 was present, but its expression remained unaffected by acidic incubation. Expressed in Xenopus oocytes, NBCn1 increased carrier-mediated (14)C-MA transport, which was abolished by replacing Na(+). Two-electrode voltage clamp of oocytes exhibited negligible current after NH(4)Cl application. These results suggest that DIDS-sensitive HCO(3)(-) extrusion normally governs NH(4)(+)/NH(3) uptake in the medullary thick ascending limb cells. We propose that, in acidic conditions, DIDS-sensitive HCO(3)(-) extrusion is inactivated, while NBCn1 is upregulated to stimulate NH(4)(+) transport.

  7. The endosomal trafficking factors CORVET and ESCRT suppress plasma membrane residence of the renal outer medullary potassium channel (ROMK).

    Science.gov (United States)

    Mackie, Timothy D; Kim, Bo-Young; Subramanya, Arohan R; Bain, Daniel J; O'Donnell, Allyson F; Welling, Paul A; Brodsky, Jeffrey L

    2018-03-02

    Protein trafficking can act as the primary regulatory mechanism for ion channels with high open probabilities, such as the r enal o uter m edullary (ROMK) channel. ROMK, also known as Kir1.1 (KCNJ1), is the major route for potassium secretion into the pro-urine and plays an indispensable role in regulating serum potassium and urinary concentrations. However, the cellular machinery that regulates ROMK trafficking has not been fully defined. To identify regulators of the cell-surface population of ROMK, we expressed a pH-insensitive version of the channel in the budding yeast Saccharomyces cerevisiae We determined that ROMK primarily resides in the endoplasmic reticulum (ER), as it does in mammalian cells, and is subject to ER-associated degradation (ERAD). However, sufficient ROMK levels on the plasma membrane rescued growth on low-potassium medium of yeast cells lacking endogenous potassium channels. Next, we aimed to identify the biological pathways most important for ROMK regulation. Therefore, we used a synthetic genetic array to identify non-essential genes that reduce the plasma membrane pool of ROMK in potassium-sensitive yeast cells. Genes identified in this screen included several members of the endosomal complexes required for transport (ESCRT) and the class-C core vacuole/endosome tethering (CORVET) complexes. Mass spectroscopy analysis confirmed that yeast cells lacking an ESCRT component accumulate higher potassium concentrations. Moreover, silencing of ESCRT and CORVET components increased ROMK levels at the plasma membrane in HEK293 cells. Our results indicate that components of the post-endocytic pathway influence the cell-surface density of ROMK and establish that components in this pathway modulate channel activity.

  8. A case of sporadic medullary cystic kidney disease type 1 (MCKD1) with kidney enlargement complicated by IgA nephropathy.

    Science.gov (United States)

    Suzuki, Taihei; Iyoda, Masayuki; Yamaguchi, Yutaka; Shibata, Takanori

    2015-07-01

    Medullary cystic kidney disease (MCKD) is a progressive tubulointerstitial nephropathy, and it leads to end-stage kidney disease (ESKD). It is an autosomal dominant inherited disease, and is categorized into two types according to the localizing chromosome and timing of ESKD onset. Its pathogenesis has not been revealed clearly, thus accumulation of the cases is very valuable. We report here the first reported case of MCKD with kidney enlargement complicated by IgA nephropathy. A 70-year-old male was admitted to our hospital because of renal dysfunction and bilateral kidney enlargement. He was diagnosed as having MCKD complicated by IgA nephropathy (IgA-N) by renal biopsy. We speculated that he had MCKD type 1 on the basis of the late onset of renal failure and no significant evidence of mutation in the UMOD gene that is associated with MCKD type 2. Thereafter, his kidney function decreased progressively and he started to receive hemodialysis. This is an interesting case of MCKD1 in terms of its sporadic nature, kidney enlargement, and complication of IgA-N. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

  9. A rapid screening method for the detection of mutations in the RET proto-oncogene in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma families

    Energy Technology Data Exchange (ETDEWEB)

    Marsh, D.J.; Andrew, S.; Richardson, A.L. [Royal North Shore Hospital, St. Leonards (Australia)]|[Univ. of Sydney, New South Wales (Australia)] [and others

    1994-09-15

    Multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid carcinoma (FMTC) are autosomal dominant inherited cancer syndromes with incomplete penetrance. Following the identification of mutations in the RET proto-oncogene that segregate with the disease phenotype in MEN2A, MEN2B, and FMTC, genetic screening of individuals with mutations in RET may be performed. The authors have employed restriction endonuclease digestion of polymerase chain reaction products as an alternative to sequence analysis for rapid identification of mutant gene carriers in families in which MEN2A and RMTC are segregating. Twenty-one Australasian MEN2A and FMTC families have been screened for mutations in a cysteine-rich region of the RET proto-oncogene. Seven independent mutations were identified in key individuals in 16 of these families. The authors have identified a mutation in codon 620, 2053 T {r_arrow}C (Cys620Arg), and two mutations in codon 634 of exon 11 of RET, 2095 T {r_arrow} C (Cys634Arg) and 2096 G {r_arrow} A (Cys634Tyr), all three of which were present in both MEN2A and FMTC families. 7 refs., 1 fig., 1 tab.

  10. [Study of RET protooncogene in multiple endocrine neoplasm 2A and in familial medullary thyroid carcinoma. Clinical pathological findings in asymptomatic carriers].

    Science.gov (United States)

    Belli, Susana; Storani, María E; Dourisboure, Ricardo J; Podestá, Ernesto J; Solano, Angela R

    2003-01-01

    Twenty five percent of the medullary thyroid carcinoma (MTC) is hereditary and 5% is familiar (FMTC), or considered as multiple endocrine neoplasia (MEN) type 2A (17%) or 2B (3%). These diseases are the result of the autosomic dominant inheritance of a mutation in the RET protooncogene, in one out of 12 different known codons. We analyzed 7 families (2 MEN 2A and 5 FMTC). Six mutations were detected in the most frequent codon, 634 (2 MEN 2A y 4 FMTC) and one family with FMTC presented a novel mutation: a transition T > C at codon 630, resulting a C630A change. Among 57 individuals studied, 25 (43.85%) presented the mutation. Seven (28%) were asymptomatic carriers, including 5 children aged 11 +/- 3.2 years. The children underwent total thyroidectomy. The histopathologic examination showed C cells hyperplasia and microcarcinoma focus in both lobes, even in the presence of normal, basal or pentagastrine stimulated, calcitonine levels. In conclusion, we describe a germine novel mutation in the RET protooncogene: C630A; and the corresponding findings of C-cell disease in gene mutated carriers that emphasize the importance of prophylactic thyroidectomy as soon as the molecular diagnosis is confirmed.

  11. Neural Tissue Motion Impacts Cerebrospinal Fluid Dynamics at the Cervical Medullary Junction: A Patient-Specific Moving-Boundary Computational Model.

    Science.gov (United States)

    Pahlavian, Soroush Heidari; Loth, Francis; Luciano, Mark; Oshinski, John; Martin, Bryn A

    2015-12-01

    Central nervous system (CNS) tissue motion of the brain occurs over 30 million cardiac cycles per year due to intracranial pressure differences caused by the pulsatile blood flow and cerebrospinal fluid (CSF) motion within the intracranial space. This motion has been found to be elevated in type 1 Chiari malformation. The impact of CNS tissue motion on CSF dynamics was assessed using a moving-boundary computational fluid dynamics (CFD) model of the cervical-medullary junction (CMJ). The cerebellar tonsils and spinal cord were modeled as rigid surfaces moving in the caudocranial direction over the cardiac cycle. The CFD boundary conditions were based on in vivo MR imaging of a 35-year old female Chiari malformation patient with ~150-300 µm motion of the cerebellar tonsils and spinal cord, respectively. Results showed that tissue motion increased CSF pressure dissociation across the CMJ and peak velocities up to 120 and 60%, respectively. Alterations in CSF dynamics were most pronounced near the CMJ and during peak tonsillar velocity. These results show a small CNS tissue motion at the CMJ can alter CSF dynamics for a portion of the cardiac cycle and demonstrate the utility of CFD modeling coupled with MR imaging to help understand CSF dynamics.

  12. Stimulatory effect of nobiletin, a citrus polymethoxy flavone, on catecholamine synthesis through Ser19 and Ser40 phosphorylation of tyrosine hydroxylase in cultured bovine adrenal medullary cells.

    Science.gov (United States)

    Zhang, Han; Yanagihara, Nobuyuki; Toyohira, Yumiko; Takahashi, Keita; Inagaki, Hirohide; Satoh, Noriaki; Li, Xiaoja; Goa, Xiumei; Tsutsui, Masato; Takahaishi, Kojiro

    2014-01-01

    We previously reported the dual effects of nobiletin, a compound of polymethoxy flavones found in citrus fruits, on catecholamine secretion in cultured bovine adrenal medullary cells. Here, we report the effects of nobiletin on catecholamine synthesis in the cells. Nobiletin increased the synthesis of (14)C-catecholamines from [(14)C]tyrosine in a time (20-30 min)- and concentration (1.0-100 μM)-dependent manner. Nobiletin (10-100 μM) also activated tyrosine hydroxylase activity. The stimulatory effect of nobiletin on (14)C-catecholamine synthesis was not observed when extracellular Ca(2+) was not present in the incubation medium. Protein kinase inhibitors including H-89, an inhibitor of cyclic AMP-dependent protein kinase, and KN-93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinase II, suppressed the stimulatory effects of nobiletin on catecholamine synthesis as well as tyrosine hydroxylase activity. Nobiletin also induced the phosphorylation of tyrosine hydroxylase at Ser(19) and Ser(40). Nobiletin (1.0-100 μM) inhibited (14)C-catecholamine synthesis induced by acetylcholine. The present findings suggest that nobiletin, by itself, stimulates catecholamine synthesis through tyrosine hydroxylase phosphorylation at Ser(19) and Ser(40), whereas it inhibits catecholamine synthesis induced by acetylcholine in bovine adrenal medulla.

  13. Generation of a tenascin-C-CreER2 knockin mouse line for conditional DNA recombination in renal medullary interstitial cells.

    Directory of Open Access Journals (Sweden)

    Wenjuan He

    Full Text Available Renal medullary interstitial cells (RMIC are specialized fibroblast-like cells that exert important functions in maintaining body fluid homeostasis and systemic blood pressure. Here, we generated a RMIC specific tenascin-C promoter driven inducible CreER2 knockin mouse line with an EGFP reporter. Similar as endogenous tenascin-C expression, the reporter EGFP expression in the tenascin-C-CreER2(+/- mice was observed in the inner medulla of the kidney, and co-localized with COX2 but not with AQP2 or AQP1, suggesting selective expression in RMICs. After recombination (tenascin-C-CreER2(+/-/ROSA26-lacZ(+/- mice + tamoxifen, β-gal activity was restricted to the cells in the inner medulla of the kidney, and didn't co-localize with AQP2, consistent with selective Cre recombinase activity in RMICs. Cre activity was not obvious in other major organs or without tamoxifen treatment. This inducible RMIC specific Cre mouse line should therefore provide a novel tool to manipulate genes of interest in RMICs.

  14. Prenatal evaluation of the conus medullaris position in normal fetuses and fetuses with spina bifida occulta using three-dimensional ultrasonography.

    Science.gov (United States)

    Lei, Ting; Xie, Hong-Ning; Zheng, Ju; Feng, Jie-Ling; Du, Liu; Wang, Nan

    2014-06-01

    This study aimed to assess the fetal conus medullaris (CM) position with three-dimensional (3D) ultrasonography and its use in detecting and diagnosing spina bifida occulta (SBO). We examined 150 normal fetuses (gestational age, 20-38 weeks) and 14 fetuses with SBO. All fetuses underwent prenatal 3D ultrasonography, and the CM position in relation to the vertebral body was evaluated using volume contrast imaging. Intra- and inter-observer agreements were assessed using weighted kappa. The correlation between gestational age and CM level was determined by linear regression analysis. Operators successfully located the CM position in 145 cases. The CM was at L3 or higher in all normal group cases. A linear relationship was noted between gestational age (X) and CM position (Y) (Y = 0.118X + 6.011, R(2)  = 0.679, P < 0.001). The weighted kappa values for intra- and inter-observer agreement were 1.0 and 0.788, respectively. The CM was located at L3 in one case and lower than L3 in 13 cases in the SBO group. All values were below the fifth percentile for the normal group. Three-dimensional ultrasonography may accurately determine the CM vertebral level. Prenatal evaluation of the CM position may improve the detection and diagnosis of SBO. © 2014 John Wiley & Sons, Ltd.

  15. Secretive and proliferative tumor profile helps to select the best imaging technique to identify postoperative persistent or relapsing medullary thyroid cancer.

    Science.gov (United States)

    Faggiano, A; Grimaldi, F; Pezzullo, L; Chiofalo, M G; Caracò, C; Mozzillo, N; Angeletti, G; Santeusanio, F; Lombardi, G; Colao, A; Avenia, N; Ferolla, P

    2009-03-01

    In patients with postoperative persistent medullary thyroid cancer (MTC), the tumor detection rate is generally low for most of the imaging techniques now available. The aim of this study was to investigate if the clinico-biological profile of the tumor may indicate which imaging technique to perform in order to identify postoperative persistent or relapsing MTC foci. Thirty-five consecutive MTC patients with detectable and progressively increasing postoperative serum concentrations of calcitonin were enrolled in the study. The detection rates of 18F-deoxy-d-glucose (FDG)-positron emission tomography (PET), somatostatin receptor scintigraphy (SRS), and 131I-metaiodobenzylguanidine scintigraphy (MIBG) were compared in relation with calcitonin and carcinoembryonic antigen serum concentrations, Ki-67 score and results of conventional imaging techniques (CIT). FDG-PET positivity was significantly associated with calcitonin serum concentrations >400 pg/ml and Ki-67 score >2.0% (P800 pg/ml (Ptechnique to use in the follow-up of patients with MTC. A Ki-67 score >2.0% suggests to perform a FDG-PET in addition to conventional imaging. Calcitonin secretion predicts both FDG-PET and SRS uptake but SRS positivity is generally found only in patients with well defined MTC lesions that are also detectable at the conventional imaging examination. MIBG outcome is not predicted by any clinico-biological factors here investigated.

  16. Role of 188Re(V)DMSA in the diagnosis and therapy of medullary thyroid carcinoma: a pilot study in an animal model

    International Nuclear Information System (INIS)

    Learoyd, D.L.; Roach, P.J.; Snowdon, G.M.; Dadachova, K.; Moreau, A.M.; Robinson, B.G.

    1999-01-01

    Full text: 99 Tc m (V)DMSA has been reported to be highly sensitive in the diagnosis of medullary thyroid cancer (MTC). Rhenium-188, a beta emitter, has potential for therapy of MTC. However, initial studies with 188 Re indicate high renal uptake which may interfere with potential therapeutic applications of this radiopharmaceutical. A modified radiolabelling method has been shown to reduced the renal uptake of 188 Re(V)DMSA in control animals. The aims of this study were to determine whether there is uptake of modified 188 Re(V)DMSA in nude mice injected with an MTC cell line and whether there is potential for MTC therapy. Two groups of mice were injected in the left flank (SC) with TT cell line, and in mice showing tumour growth a low-dose (400 kBq) of 188 Re(V)DMSA was injected via a tail vein 8 weeks later. Biodistribution was performed on several mice and several others were given 'therapy' injections (8 MBq) to determine whether tumour shrinkage could be objectively observed. Tracer uptake was highest in bone and kidneys but tumour uptake was relatively low. However, no new tumour growth was seen in any of the mice subsequent to therapy injections and 1 mouse showed complete remission within 5 weeks of injection. Further animal and human studies will need to be performed to determine the potential role of this modified 118 Re(V)DMSA in patients with MTC

  17. Food-Related Neural Circuitry in Prader-Willi Syndrome: Response to High- versus Low-Calorie Foods

    Science.gov (United States)

    Dimitropoulos, Anastasia; Schultz, Robert T.

    2008-01-01

    Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hyperphagia and food preoccupations. Although dysfunction of the hypothalamus likely has a critical role in hyperphagia, it is only one of several regions involved in the regulation of eating. The purpose of this research was to examine food-related neural circuitry…

  18. Market, Regulation, Market, Regulation

    DEFF Research Database (Denmark)

    Frankel, Christian; Galland, Jean-Pierre

    2015-01-01

    This paper focuses on the European Regulatory system which was settled both for opening the Single Market for products and ensuring the consumers' safety. It claims that the New Approach and Standardization, and the Global Approach to conformity assessment, which suppressed the last technical...... barriers to trade in Europe, realized the free movement of products by organizing progressively several orders of markets and regulation. Based on historical and institutional documents, on technical publications, and on interviews, this article relates how the European Commission and the Member States had...... alternatively recourse to markets and to regulations, at the three main levels of the New Approach Directives implementation. The article focuses also more specifically on the Medical Devices sector, not only because this New Approach sector has long been controversial in Europe, and has recently been concerned...

  19. Food motivation circuitry hypoactivation related to hedonic and nonhedonic aspects of hunger and satiety in women with active anorexia nervosa and weight-restored women with anorexia nervosa.

    Science.gov (United States)

    Holsen, Laura M; Lawson, Elizabeth A; Blum, Justine; Ko, Eunice; Makris, Nikos; Fazeli, Pouneh K; Klibanski, Anne; Goldstein, Jill M

    2012-09-01

    Previous studies have provided evidence of food motivation circuitry dysfunction in individuals with anorexia nervosa. However, methodological limitations present challenges to the development of a cohesive neurobiological model of anorexia nervosa. Our goal was to investigate the neural circuitry of appetite dysregulation across states of hunger and satiety in active and weight-restored phases of anorexia nervosa using robust methodology to advance our understanding of potential neural circuitry abnormalities related to hedonic and nonhedonic state and trait. We scanned women with active anorexia nervosa, weight-restored women with anorexia nervosa and healthy-weight controls on a 3-T Siemens magnetic resonance scanner while they viewed images of high- and low-calorie foods and objects before (premeal) and after (postmeal) eating a 400 kcal meal. We enrolled 12 women with active disease, 10 weight-restored women with anorexia nervosa and 11 controls in our study. Compared with controls, both weight-restored women and those with active disease demonstrated hypoactivity premeal in the hypothalamus, amygdala and anterior insula in response to high-calorie foods (v. objects). Postmeal, hypoactivation in the anterior insula persisted in women with active disease. Percent signal change in the anterior insula was positively correlated with food stimuli ratings and hedonic and nonhedonic appetite ratings in controls, but not women with active disease. Our findings are limited by a relatively small sample size, which prevented the use of an analysis of variance model and exploration of interaction effects, although our substantial effect sizes of between-group differences suggest adequate power for our statistical analysis approach. Participants taking psychotropic medications were included. Our data provide evidence of potential state and trait hypoactivations in food motivation regions involved in the assessment of food's reward value and integration of these with

  20. Transforming growth factor-beta, but not ciliary neurotrophic factor, inhibits DNA synthesis of adrenal medullary cells in vitro

    DEFF Research Database (Denmark)

    Wolf, N; Krohn, K; Bieger, S

    1999-01-01

    by the neuroendocrine chromaffin cells, which also express the transforming growth factor-beta receptor type II. In contrast to the developmentally related sympathetic neurons, chromaffin cells continue to proliferate throughout postnatal life. Using 5-bromo-2'-deoxyuridine pulse labeling and tyrosine hydroxylase......Transforming growth factor-betas are members of a superfamily of multifunctional cytokines regulating cell growth and differentiation. Their functions in neural and endocrine cells are not well understood. We show here that transforming growth factor-betas are synthesized, stored and released...... immunocytochemistry as a marker for young postnatal rat chromaffin cells, we show that treatment with fibroblast growth factor-2 (1 nM) and insulin-like growth factor-II (10 nM) increased the fraction of 5-bromo-2'-deoxyuridine-labeled nuclei from 1% to about 40% of the cells in the absence of serum. In the presence...