Sample records for rat medullary raphe

  1. Differences between three inbred rat strains in number of K+ channel-immunoreactive neurons in the medullary raphé nucleus.

    Riley, D; Dwinell, M; Qian, B; Krause, K L; Bonis, J M; Neumueller, S; Marshall, B D; Hodges, M R; Forster, H V


    Ventilatory sensitivity to hypercapnia is greater in Dahl salt-sensitive (SS) rats than in Fawn Hooded hypertensive (FHH) and Brown Norway (BN) inbred rats. Since pH-sensitive potassium ion (K(+)) channels are postulated to contribute to the sensing and signaling of changes in CO(2)-H(+) in chemosensitive neurons, we tested the hypothesis that there are more pH-sensitive K(+) channel-immunoreactive (ir) neurons within the medullary raphé nuclei of the highly chemosensitive SS rats than in the other two strains. Medullary tissues from male and female BN, FHH, and SS rats were stained with cresyl violet or with antibodies targeting TASK-1, K(v)1.4, and Kir2.3 channels. K(+) channel-ir neurons were quantified and compared with the total neurons in the region. The total number of neurons in the medullary raphé 1) was greater in male FHH than the other male rats, 2) did not differ among the female rats, and 3) did not differ between sexes. The average number of K(+) channel-ir neurons per section was 30-60 neurons higher in the male SS than in the other rat strains. In contrast, for the females, the number of K(+) channel-ir neurons was greatest in the BN. We also found significant differences in the number of K(+) channel-ir neurons between sexes in SS (males > females) and BN (females > males) rats, but not the FHH strain. Our findings support the hypothesis for males but not for females, suggesting that both genetic background and sex are determinants of K(+) channel immunoreactivity of medullary raphé neurons, and that the expression of pH-sensitive K(+) channels in the medullary raphé does not correlate with the ventilatory sensitivity to hypercapnia.

  2. Effect of extracellular acid–base disturbances on the intracellular pH of neurones cultured from rat medullary raphe or hippocampus

    Bouyer, Patrice; Bradley, Stefania Risso; Zhao, Jinhua; Wang, Wengang; Richerson, George B; Boron, Walter F


    Previous reports suggest that an important characteristic of chemosensitive neurones is an unusually large change of steady-state intracellular pH in response to a change in extracellular pH (ΔpHi/ΔpHo). To determine whether such a correlation exists between neurones from the medullary raphe (a chemosensitive brain region) and hippocampus (a non-chemosensitive region), we used BCECF to monitor pHi in cultured neurones subjected to extracellular acid–base disturbances. In medullary raphe neurones, respiratory acidosis (5% → 9% CO2) caused a rapid fall in pHi (ΔpHi ∼0.2) with no recovery and a large ΔpHi/ΔpHo of 0.71. Hippocampal neurones had a similar response, but with a slightly lower ΔpHi/ΔpHo (0.59). We further investigated a possible link between pHi regulation and chemosensitivity by following the pHi measurements on medullary raphe neurones with an immunocytochemistry for tryptophan hydroxylase (a marker of serotonergic neurones). We found that the ΔpHi/ΔpHo of 0.69 for serotonergic neurones (which are stimulated by acidosis) was not different from either the ΔpHi/ΔpHo of 0.75 for non-serotonergic neurones (most of which are not chemosensitive), or from the ΔpHi/ΔpHo of hippocampal neurones. For both respiratory alkalosis (5% → 3% CO2) and metabolic alkalosis (22 mm → 35 mm HCO3−), ΔpHi/ΔpHo was 0.42–0.53 for all groups of neurones studied. The only notable difference between medullary raphe and hippocampal neurones was in response to metabolic acidosis (22 mm → 14 mm HCO3−), which caused a large pHi decrease in ∼80% of medullary raphe neurones (ΔpHi/ΔpHo = 0.71), but relatively little pHi decrease in 70% of the hippocampal neurones (ΔpHi/ΔpHo = 0.09). Our comparison of medullary raphe and hippocampal neurones indicates that, except in response to metabolic acidosis, the neurones from the chemosensitive region do not have a uniquely high ΔpHi/ΔpHo. Moreover, regardless of whether neurones were cultured from the

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

    Yoshiyuki eKasahara


    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.

  4. Mescaline increases startle responding equally in normal and raphe-lesioned rats.

    Geyer, M A; Rose, G J; Petersen, L R


    To test the possible involvement of serotonin-containing cells of the midbrain in mediating the effects of mescaline on startle responding, electrolytic lesions were made in either the dorsal or median raphe nucleus in rats. Decreases in either striatal or hippocampal tryptophan hydroxylase activity confirmed the effectiveness of the lesions. One week later, startle was measured in response to 30 air-puff stimuli for each rat. Median, but not dorsal, raphe lesions increased startle magnitudes throughout the test session. The following day each group was divided into matched halves and were given 60 trials, 30 minutes after intraperitoneal injection of either saline or 10 mg/kg mescaline. Despite the large differences in baseline startle among the groups, mescaline produced comparable 25% increases in startle magnitudes in both sham- and raphe-lesioned animals. This result fails to support the hypothesis that increased startle responding produced by mescaline is mediated by the midbrain raphe nuclei.

  5. Effects of Acupuncture on Monoamine Neurotransmitters in Raphe Nuclei in Obese Rats

    魏群利; 刘志诚


    Effects of acupuncture on the levels of neurotransmitters in the raphe nuclei were investigated in obese rats. It was found that the levels of tryptophan (Trp) and 5-hydroxyindoleacetic acid (5-HIAA) were increased, and 5-hydroxytryptamine (5-HT) level and 5-HT/5-HIAA ratio decreased in the raphe nuclei of the obese group as compared with the normal group; and that acupuncture could produce weight reduction, increase the 5-HT level and 5-HT/5-HIAA ratio, and decrease the contents of Trp and 5-HIAA, but did not change the levels of dopamine (DA) and noradrenaline (NA). It is indicated that benign regulative action of acupuncture on 5-HT and its metabolism in the raphe nuclei is possibly one of the factors for reducing weight by acupuncture.

  6. Distributive characteristics of projection from vestibular nuclei to nucleus raphe magnus in rats

    Jingyu Sun; Yulin Dong; Fuxing Zhang; Jianhua Qiu; Yunqing Li


    BACKGROUND: Morphological studies have confirmed that vestibular nuclei accepts serotoninergic projections from nucleus raphe magnus, nucleus raphes pallidus, etc. But it is still unclear whether there is bi-directional association between vestibular nuclei and nucleus raphe magnus.OBJECTIVE: To observe the characteristics of projective fibers from vestibular nuclei to nucleus raphe magnus using tetramethyl rhodamine (TMR) in rats, so as to provide more sufficient morphological evidence of neural association from vestibular nuclei. DESIGN: An observational experiment. SETTING: Department of Anatomy (K.K. Leung Brain Research Center), the Fourth Military Medical University of Chinese PLA. MATERIALS: Eighteen male SD rats of clean degree, weighing 250-280 g, were provided by the Experimental Animal Center of the Fourth Military Medical University of Chinese PLA. METHODS: The experiments were carried out in the laboratory of Department of Anatomy (K.K. Leung Brain Research Center), the Fourth Military Medical University of Chinese PLA from September 2006 to January 2007. All the rats were anesthetized with intraperitoneal injection of pentobarbital sodium, then according to the coordinates on the rat brain atlas, 0.1 μL TMR (100 g/L) was injected into nucleus raphes magnus via the tip of glass microtubule by means of microinjection. Seven days later, the rats were anesthetized, then perfused and fixed to remove brain, and then frozen coronal brain sections were prepared.The retrogradely labeled neurons in the injected and projected sites were observed under fluorescence microscope. Light filters with evoked wave length of 540-553 nm and emission wave length≥1 580 nm were selected to observe the orange TMR-labeled neurons. All the sections were observed and counted under the fluorescence microscope.MAIN OUTCOME MEASURES: Characteristics and number of retrogradely labeled neurons at different sites of nuclei. RESULTS: Totally 18 SD rats were enrolled, 9 of them were

  7. Dorsal and median Raphe nuclei projection to MD of Thalamus in rat: A retrograde tracer study

    Pas Bakhsh P


    Full Text Available In order to understand the function of mammalians serotonin system, we have to know the anatomical structure, because physiological changes are influenced through the anatomical changes. A number of thalamic nuclei are associated with functions known to be influenced by serotonergic input in brainstem, among them mediodorsal thalamic nucleus has relationship with limbic system and prefrontal cortex. The precise topographical projections of mesencephalic raphe nuclei to the MD nucleus of thalamus were identified in the rat using horseradish peroxidase (HRP retrograde tracing substance. Injection of HRP in MD labeled a large number of neurons in rostral to caudal part of dorsal raphe nucleus. It exhibited a strong number of neurons in ipsilateral part of DR and a few cells in its contralateral part. Numerously labeled cells were also observed ipsilateral in rostral and medial part of MnR (86% and a few cells in it's contralateral part. The present study has provided that the MD innervation by DR is more greater in density than that observed at the MnR. Upon these results and previous study, mesencephalic raphe nuclei are involved in several specific functions of thalamus as limbic system behavioral mechanism. A much more detailed knowledge is needed to show topographic relationships between mesencephalic raphe nuclei and forebrain.

  8. Single-prolonged stress induces apoptosis in dorsal raphe nucleus in the rat model of posttraumatic stress disorder

    Liu Dongjuan


    Full Text Available Abstract Introduction Post-traumatic stress disorder (PTSD is an anxiety disorder that develops after exposure to a life-threatening traumatic experience. Meta-analyses of the brainstem showed that midsagittal area of the pons was significantly reduced in patients with PTSD, suggesting a potential apoptosis in dorsal raphe nucleus after single-prolonged stress (SPS. The aim of this study is to investigate whether SPS induces apoptosis in dorsal raphe nucleus in PTSD rats, which may be a possible mechanism of reduced volume of pons and density of gray matter. Methods In this study, rats were randomly divided into 1d, 7d and 14d groups after SPS along with the control group. The apoptosis rate was determined using annexin V-FITC/PI double-labeled flow cytometry (FCM. Levels of Cytochrome c (Cyt-C was examined by Western blotting. Expression of Cyt-C on mitochondria in the dorsal raphe nucleus neuron was determined by enzymohistochemistry under transmission electron microscopy (TEM. The change of thiamine monophosphatase (TMP levels was assessed by enzymohistochemistry under light microscope and TEM. Morphological changes of the ultrastructure of the dorsal raphe nucleus neuron were determined by TEM. Results Apoptotic morphological alterations were observed in dorsal raphe nucleus neuron for all SPS-stimulate groups of rats. The apoptosis rates were significantly increased in dorsal raphe nucleus neuron of SPS rats, along with increased release of cytochrome c from the mitochondria into the cytoplasm, increased expression of Cyt-C and TMP levels in the cytoplasm, which reached to the peak of increase 7 days of SPS. Conclusions The results indicate that SPS induced Cyt-C released from mitochondria into cytosol and apoptosis in dorsal raphe nucleus neuron of rats. Increased TMP in cytoplasm facilitated the clearance of apoptotic cells. We propose that this presents one of the mechanisms that lead to reduced volume of pons and gray matter associated

  9. Nitric oxide in the nucleus raphe magnus modulates cutaneous blood flow in rats during hypothermia

    Masoumeh Kourosh Arami


    Full Text Available Objective(s: Nucleus Raphe Magnus (NRM that is involved in the regulation of body temperature contains nitric oxide (NO synthase. Considering the effect of NO on skin blood flow control, in this study, we assessed its thermoregulatory role within the raphe magnus. Materials and Methods: To this end, tail blood flow of male Wistar rats was measured by laser doppler following the induction of hypothermia. Results: Intra-NRM injection of SNP (exogenous NO donor, 0.1- 0.2 μl, 0.2 nM increased the blood flow. Similarly, unilateral microinjection of glutamate (0.1- 0.2 μl, 2.3 nM into the nucleus increased the blood flow. This effectof L-glutamate was reduced by prior intra NRM administrationof NO synthase inhibitor NG-methyl-L-arginine or NG-nitro-L-argininemethyl ester (L-NAME, 0.1 µl, 100 nM. Conclusion: It is concluded that NO modulates the thermoregulatory response of NRM to hypothermia and may interactwith excitatory amino acids in central skin blood flow regulation.

  10. Effect of arginine vasopressin in the nucleus raphe magnus on antinociception in the rat.

    Yang, Jun; Chen, Jian-Min; Liu, Wen-Yan; Song, Cao-You; Wang, Cheng-Hai; Lin, Bao-Cheng


    Previous work has shown that arginine vasopressin (AVP) regulates antinociception through brain nuclei rather than the spinal cord and peripheral organs. The present study investigated the nociceptive effect of AVP in the nucleus raphe magnus (NRM) of the rat. Microinjection of AVP into the NRM increased pain threshold in a dose-dependent manner, while local administration of AVP-receptor antagonist-d(CH2)5Tyr(Et)DAVP decreased the pain threshold. Pain stimulation elevated AVP concentration in the NRM perfuse liquid. NRM pretreatment with AVP-receptor antagonist completely reversed AVP's effect on pain threshold in the NRM. The data suggest that AVP in the NRM is involved in antinociception.

  11. Role of glutamatergic receptors located in the nucleus raphe magnus on antinociceptive effect of morphine microinjected into the nucleus cuneiformis of rat.

    Haghparast, Abbas; Soltani-Hekmat, Ava; Khani, Abbas; Komaki, Alireza


    Neurons in the nucleus cuneiformis (CnF), located just ventrolateral to the periaqueductal gray, project to medullary nucleus raphe magnus (NRM), which is a key medullary relay for descending pain modulation and is critically involved in opioid-induced analgesia. Previous studies have shown that antinociceptive response of CnF-microinjected morphine can be modulated by the specific subtypes of glutamatergic receptors within the CnF. In this study, we evaluated the role of NMDA and kainate/AMPA receptors that are widely distributed within the NRM on morphine-induced antinociception elicited from the CnF. Hundred and five male Wistar rats weighing 250-300 g were used. Morphine (10, 20 and 40 microg) and NMDA receptor antagonist, MK-801 (10 microg) or kainate/AMPA receptor antagonist, DNQX (0.5 microg) in 0.5 microl saline were stereotaxically microinjected into the CnF and NRM, respectively. The latency of tail-flick response was measured at set intervals (2, 7, 12, 17, 22, 27 min after microinjection) by using an automated tail-flick analgesiometer. The results showed that morphine microinjection into the CnF dose-dependently causes increase in tail-flick latency (TFL). MK-801 microinjected into the NRM, just 1 min before morphine injection into the CnF, significantly attenuated antinociceptive effects of morphine. On the other hand, DNQX microinjected into the NRM, significantly increased TFL after local application of morphine into the CnF. We suggest that morphine related antinociceptive effect elicited from the CnF is mediated, in part, by NMDA receptor at the level of the NRM whereas kainite/AMPA receptor has a net inhibitory influence at the same pathway.

  12. Neurones in the adult rat anterior medullary velum.

    Ibrahim, M; Menoud, P A; Celio, M R


    The presence of neurones in the rat anterior medullary velum (AMV) has been investigated by using antibodies to the calcium-binding proteins, parvalbumin (PV), calretinin (CR), and calbindin-D28k (CB). Disparate populations of mainly GABAergic neurones were located in the rostral and caudal regions of the AMV. The rostral region of the AMV was characterised by GABAergic CR-labelled or PV-labelled neurones. CR-labelled neurones were bipolar or multipolar with round to ovoid somata (diameters between 8 and 12 microm), and rostrocaudally running dendrites forming a network. PV-labelled neurones had round somata (diameters between 6 and 10 microm) and were bi-tufted, with beaded dendrites. Both CR-labelled and PV-labelled dendrites formed punctate pericellular associations with unlabelled somatic profiles. In the caudal region of the AMV, PV-labelled neurones were GABAergic, multipolar cells, having round somata (diameters between 9 and 12 microm), with either beaded or nonbeaded dendrites forming a network of interconnecting dendrites. PV-labelled pericellular associations were made around both PV-labelled and unlabelled somatic profiles. CR labelled unipolar brush cells (UBCs) were not GABAergic. UBCs were characterised by a round to oval somata (10-15 microm in diameter) from which a single primary dendrite emerged to form a distal expansion having small terminal dendrites. From the distal expansion, there also appeared to be CR-labelled processes emanating and extending for up to 250 microm. CB occasionally labelled "Purkinje-like cells" (PLCs). The rat AMV is a more complex structure than first envisaged with the presence of predominantly inhibitory neurones expressing different calcium-binding proteins. Functional and anatomic aspects of this circuitry are further discussed.

  13. Functional mapping of the cardiorespiratory effects of dorsal and median raphe nuclei in the rat

    Alvarenga R.M.


    Full Text Available The dorsal (DRN and median (MRN raphe nuclei are important sources of serotonergic innervation to the forebrain, projecting to sites involved in cardiovascular regulation. These nuclei have been mapped using electrical stimulation, which has the limitation of stimulating fibers of passage. The present study maps these areas with chemical stimulation, investigating their influence on cardiorespiratory parameters. Urethane-anesthetized (1.2 g/kg, iv male Wistar rats (280-300 g were instrumented for pulsatile and mean blood pressure (MBP, heart rate, renal nerve activity, and respiratory frequency recordings. Microinjections of L-glutamate (0.18 M, 50-100 nl with 1% Pontamine Sky Blue were performed within the DRN or the MRN with glass micropipettes. At the end of the experiments the sites of microinjection were identified. The majority of sites within the MRN (86.1% and DRN (85.4% evoked pressor responses when stimulated (DRN: deltaMBP = +14.7 ± 1.2; MRN: deltaMBP = +13.6 ± 1.3 mmHg. The changes in renal nerve activity and respiratory rate caused by L-glutamate were +45 ± 11 and +42 ± 9% (DRN; P < 0.05%, +40 ± 10 and +29 ± 7% (MRN, P < 0.05, respectively. No significant changes were observed in saline-microinjected animals. This study shows that: a the blood pressure increases previously observed by electrical stimulation within the raphe are due to activation of local neurons, b this pressor effect is due to sympathoexcitation because the stimulation increased renal sympathetic activity but did not produce tachycardia, and c the stimulation of cell bodies in these nuclei also increases the respiratory rate.

  14. Opioid microinjection into raphe magnus modulates cardiorespiratory function in mice and rats.

    Hellman, Kevin M; Mendelson, Scott J; Mendez-Duarte, Marco A; Russell, James L; Mason, Peggy


    The raphe magnus (RM) participates in opioid analgesia and contains pain-modulatory neurons with respiration-related discharge. Here, we asked whether RM contributes to respiratory depression, the most prevalent lethal effect of opioids. To investigate whether opioidergic transmission in RM produces respiratory depression, we microinjected a mu-opioid receptor agonist, DAMGO, or morphine into the RM of awake rodents. In mice, opioid microinjection produced sustained decreases in respiratory rate (170 to 120 breaths/min), as well as heart rate (520 to 400 beats/min). Respiratory sinus arrhythmia, indicative of enhanced parasympathetic activity, was prevalent in mice receiving DAMGO microinjection. We performed similar experiments in rats but observed no changes in breathing rate or heart rate. Both rats and mice experienced significantly more episodes of bradypnea, indicative of impaired respiratory drive, after opioid microinjection. During spontaneous arousals, rats showed less tachycardia after opioid microinjection than before microinjection, suggestive of an attenuated sympathetic tone. Thus, activation of opioidergic signaling within RM produces effects beyond analgesia, including the unwanted destabilization of cardiorespiratory function. These adverse effects on homeostasis consequent to opioid microinjection imply a role for RM in regulating the balance of sympathetic and parasympathetic tone.

  15. Maternal ethanol administration inhibits 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe of rat offspring.

    Kim, Eun-Kyung; Lee, Myoung-Hwa; Kim, Hong; Sim, Young-Je; Shin, Mal-Soon; Lee, Sam-Jun; Yang, Hye-Young; Chang, Hyun-Kyung; Lee, Taeck-Hyun; Jang, Mi-Hyeon; Shin, Min-Chul; Lee, Hee-Hyuk; Kim, Chang-Ju


    Maternal ethanol consumption during pregnancy has a detrimental effect on the central nervous system (CNS) development of fetus. 5-Hydroxytryptamine (5-HT) is an important neurotransmitter and/or neuromodulator in the mammalian CNS. Tryptophan hydroxylase (TPH) is the rate limiting enzyme of 5-HT synthesis. Ethanol is known to induce neuropsychiatric disorders by alteration of the central serotonergic system. In the present study, the effects of maternal ethanol intake on the 5-HT synthesis and the TPH expression in the dorsal raphe of rat offspring were investigated. The present results show that the synthesis of 5-HT and the expression of TPH in the dorsal raphe of rat offspring were suppressed by maternal ethanol intake and that the suppressive effect of alcohol was more potent in the 5 weeks old rat pups compared to the 3 weeks old rat pups. Based on the present study, it can be suggested that the pathogenesis of ethanol-induced neuropsychological disorders involves ethanol-induced suppression on the 5-HT synthesis and the TPH expression in the dorsal raphe of offspring.

  16. Effect of sex steroid hormones on the number of serotonergic neurons in rat dorsal raphe nucleus.

    Kunimura, Yuyu; Iwata, Kinuyo; Iijima, Norio; Kobayashi, Makito; Ozawa, Hitoshi


    Disorders caused by the malfunction of the serotonergic system in the central nervous system show sex-specific prevalence. Many studies have reported a relationship between sex steroid hormones and the brain serotonergic system; however, the interaction between sex steroid hormones and the number of brain neurons expressing serotonin has not yet been elucidated. In the present study, we determined whether sex steroid hormones altered the number of serotonergic neurons in the dorsal raphe nucleus (DR) of adult rat brains. Animals were divided into five groups: ovariectomized (OVX), OVX+low estradiol (E2), OVX+high E2, castrated males, and intact males. Antibodies against 5-hydroxytryptamine (5-HT, serotonin) and tryptophan hydroxylase (Tph), an enzyme for 5-HT synthesis, were used as markers of 5-HT neurons, and the number of 5-HT-immunoreactive (ir) or Tph-ir cells was counted. We detected no significant differences in the number of 5-HT-ir or Tph-ir cells in the DR among the five groups. By contrast, the intensity of 5-HT-ir showed significant sex differences in specific subregions of the DR independent of sex steroid levels, suggesting that the manipulation of sex steroid hormones after maturation does not affect the number and intensive immunostaining of serotonergic neurons in rat brain. Our results suggest that, the sexual dimorphism observed in the serotonergic system is due to factors such as 5-HT synthesis, transportation, and degradation but not to the number of serotonergic neurons.

  17. Reversible inactivation of rostral nucleus raphe pallidus attenuates acute autonomic responses but not their habituation to repeated audiogenic stress in rats.

    Nyhuis, Tara J; Masini, Cher V; Taufer, Kirsten L; Day, Heidi E W; Campeau, Serge


    The medullary nucleus raphe pallidus (RPa) mediates several autonomic responses evoked by acute stress exposure, including tachycardia and hyperthermia. The present study assessed whether the RPa contributes to the decline/habituation of these responses observed during repeated audiogenic stress. Adult male rats were implanted with cannulae aimed at the RPa, and abdominal E-mitters that wirelessly acquire heart rate and core body temperature. After surgical recovery, animals were injected with muscimol or vehicle (aCSF) in the RPa region, followed by 30 min of 95-dBA loud noise or no noise control exposures on 3 consecutive days at 24-h intervals. Forty-eight hours after the third exposure, animals were exposed to an additional, but injection-free, loud noise or no noise test to assess habituation of hyperthermia and tachycardia. Three days later, rats were restrained for 30-min to evaluate their ability to display normal acute autonomic responses following the repeated muscimol injection regimen. The results indicated that the inhibition of cellular activity induced by the GABAA-receptor agonist muscimol centered in the RPa region reliably attenuated acute audiogenic stress-evoked tachycardia and hyperthermia, compared with vehicle-injected rats. Animals in the stress groups exhibited similar attenuated tachycardia and hyperthermia during the injection-free fourth audiogenic stress exposure, and displayed similar and robust increases in these responses to the subsequent restraint test. These results suggest that cellular activity in neurons of the RPa region is necessary for the expression of acute audiogenic stress-induced tachycardia and hyperthermia, but may not be necessary for the acquisition of habituated tachycardic responses to repeated stress.

  18. [Medullary layer activity of the rat adrenals after a flight on the Kosmos-1129 biosatellite].

    Kvetnanský, R; Blazicek, P; Tigranian, R A


    After a 18.5-day space flight on Cosmos-1129 rat adrenals were investigated for the concentration of catecholamines and activity of enzymes involved in their synthesis, i.e. tyrosine hydroxylase, dopamine-beta-hydroxylase, and phenyl ethanol amine-N-methyl transferase. It was found that inflight the sympatho-adreno-medullary system of rats was not exposed to a prolonged or strong stressogenic effect. Postflight the rats showed an increased reactivity to the immobilization stress.

  19. Nicotine increases GABAergic input on rat dorsal raphe serotonergic neurons through alpha7 nicotinic acetylcholine receptor.

    Hernández-Vázquez, F; Chavarría, K; Garduño, J; Hernández-López, S; Mihailescu, S P


    The dorsal raphe nucleus (DRN) contains large populations of serotonergic (5-HT) neurons. This nucleus receives GABAergic inhibitory afferents from many brain areas and from DRN interneurons. Both GABAergic and 5-HT DRN neurons express functional nicotinic acetylcholine receptors (nAChRs). Previous studies have demonstrated that nicotine increases 5-HT release and 5-HT DRN neuron discharge rate by stimulating postsynaptic nAChRs and by increasing glutamate and norepinephrine release inside DRN. However, the influence of nicotine on the GABAergic input to 5-HT DRN neurons was poorly investigated. Therefore, the aim of this work was to determine the effect of nicotine on GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) of 5-HT DRN neurons and the subtype of nAChR(s) involved in this response. Experiments were performed in coronal slices obtained from young Wistar rats. GABAergic sIPSCs were recorded from post hoc-identified 5-HT DRN neurons with the whole cell voltage patch-clamp technique. Administration of nicotine (1 μM) increased sIPSC frequency in 72% of identified 5-HT DRN neurons. This effect was not reproduced by the α4β2 nAChR agonist RJR-2403 and was not influenced by TTX (1 μM). It was mimicked by the selective agonist for α7 nAChR, PNU-282987, and exacerbated by the positive allosteric modulator of the same receptor, PNU-120596. The nicotine-induced increase in sIPSC frequency was independent on voltage-gated calcium channels and dependent on Ca(2+)-induced Ca(2+) release (CICR). These results demonstrate that nicotine increases the GABAergic input to most 5-HT DRN neurons, by activating α7 nAChRs and producing CICR in DRN GABAergic terminals.

  20. Excitatory amino acid receptor blockade within the caudal pressor area and rostral ventrolateral medulla alters cardiovascular responses to nucleus raphe obscurus stimulation in rats

    Silva N.F.


    Full Text Available Pressor responses elicited by stimulation of the nucleus raphe obscurus (NRO depend on the integrity of the rostral ventrolateral medulla (RVLM. Therefore, to test the participation of excitatory amino acid (EAA receptors in the cardiovascular responses evoked by NRO stimulation (1 ms, 100 Hz, 40-70 µA, for 10 s, the EAA antagonist kynurenic acid (Kyn was microinjected at different sites in the ventrolateral medullar surface (2.7 nmol/200 nl of male Wistar rats (270-320 g, N = 39 and NRO stimulation was repeated. The effects of NRO stimulation were: hypertension (deltaMAP = +43 ± 1 mmHg, P<0.01, bradycardia (deltaHR = -30 ± 7 bpm, P<0.01 and apnea. Bilateral microinjection of Kyn into the RVLM, which did not change baseline parameters, almost abolished the bradycardia induced by NRO stimulation (deltaHR = -61 ± 3 before vs -2 ± 3 bpm after Kyn, P<0.01, N = 7. Unilateral microinjection of Kyn into the CVLM did not change baseline parameters or reduce the pressor response to NRO stimulation (deltaMAP = +46 ± 5 before vs +48 ± 5 mmHg after Kyn, N = 6. Kyn bilaterally microinjected into the caudal pressor area reduced blood pressure and heart rate and almost abolished the pressor response to NRO stimulation (deltaMAP = +46 ± 4 mmHg before vs +4 ± 2 mmHg after Kyn, P<0.01, N = 7. These results indicate that EAA receptors on the medullary ventrolateral surface play a role in the modulation of the cardiovascular responses induced by NRO stimulation, and also suggest that the RVLM participates in the modulation of heart rate responses and that the caudal pressor area modulates the pressor response following NRO stimulation.

  1. Effect of prenatal stress on memory, nicotine withdrawal and 5HT1A expression in raphe nuclei of adult rats.

    Said, N; Lakehayli, S; El Khachibi, M; El Ouahli, M; Nadifi, S; Hakkou, F; Tazi, A


    Maternal distress has often been associated with cognitive deficiencies and drug abuse in rats. This study examined these behavioral effects in offspring of mothers stressed during gestation. To this end, pregnant dams were subjected to daily electric foot shocks during the last 10 days of pregnancy. We measured litter parameters and body weights of the descendants after weaning (21 days) and at adulthood (80 days). Afterwards, prenatally stressed and control rats' performances in the novel object recognition test were compared in order to evaluate their memory while others underwent the Water consumption test to assess the nicotine withdrawal intensity after perinatal manipulations. Meanwhile, another set of rats were sacrificed and 5HT1A receptors' mRNA expression was measured in the raphe nuclei by quantitative Real Time PCR. We noticed no significant influence of maternal stress on litter size and body weight right after weaning. However, control rats were heavier than the stressed rats in adulthood. The results also showed a significant decrease in the recognition score in rats stressed in utero compared to the controls. Moreover, a heightened anxiety symptom was observed in the prenatally stressed offspring following nicotine withdrawal. Additionally, the Real Time PCR method revealed that prenatal stress induced a significant decrease in 5HT1A receptors' levels in the raphe nuclei. Nicotine had a similar effect on these receptors' expression in both nicotine-treated control and prenatally stressed groups. Taken together, these findings suggest that the cognitive functions and drug dependence can be triggered by early adverse events in rats.

  2. Upregulation of the dorsal raphe nucleus-prefrontal cortex serotonin system by chronic treatment with escitalopram in hyposerotonergic Wistar-Kyoto rats

    Yamada, Makiko; Kawahara, Yukie; Kaneko, Fumi; Kishikawa, Yuki; Sotogaku, Naoki; Poppinga, Wilfred J.; Folgering, Joost H. A.; Dremencov, Eliyahu; Kawahara, Hiroshi; Nishi, Akinori


    Wistar-Kyoto (WKY) rats are sensitive to chronic stressors and exhibit depression-like behavior. Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons projecting to the prefrontal cortex (PFC) comprise the important neurocircuitry underlying the pathophysiology of depression. To evaluate the DRN-PFC 5

  3. Evidence that PGE2 in the dorsal and median raphe nuclei is involved in LPS-induced anorexia in rats.

    Kopf, Brigitte S; Langhans, Wolfgang; Geary, Nori; Hrupka, Brian; Asarian, Lori


    Anorexia is an element of the acute-phase immune response. Its mechanisms remain poorly understood. Activation of inducible cyclooxygenase-2 (COX-2) in blood-brain-barrier endothelial cells and subsequent release of prostaglandins (e.g., prostaglandin E2, PGE2) may be involved. Therefore, we sought to relate the effects of prostaglandins on the anorexia following gram-negative bacterial lipopolysaccharide treatment (LPS) to neural activity in the dorsal and median raphe nuclei (DRN and MnR) in rats. COX-2 antagonist (NS-398, 10mg/kg; IP) administration prior to LPS (100μg/kg; IP) prevented anorexia and reduced c-Fos expression the DRN, MnR, nucleus tractus solitarii and several related forebrain areas. These data indicate that COX-2-mediated prostaglandin synthesis is necessary for LPS anorexia and much of the initial LPS-induced neural activation. Injection of NS-398 into the DRN and MnR (1ng/site) attenuated LPS-induced anorexia to nearly the same extent as IP NS-398, suggesting that prostaglandin signaling in these areas is necessary for LPS anorexia. Because the DRN and MnR are sources of major serotonergic projections to the forebrain, these data suggest that serotonergic neurons originating in the midbrain raphe play an important role in acute-phase response anorexia.

  4. Effects on serotonin of (-)nicotine and dimethylphenylpiperazinium in the dorsal raphe and nucleus accumbens of freely behaving rats.

    Ma, Z; Strecker, R E; McKenna, J T; Thakkar, M M; McCarley, R W; Tao, R


    The aim of this study was to investigate the neurochemical mechanism underlying the effect of nicotine and dimethylphenylpiperazinium (DMPP) on 5-hydroxytryptamine (5-HT) release in the dorsal raphe nucleus and nucleus accumbens of freely behaving rats. For comparison, lobeline, cytisine and RJR-2403 were also investigated. It was found that all drugs, when infused locally, evoked an increase of 5-HT in the dorsal raphe nucleus. However, the magnitudes of the 5-HT increase were comparatively different between the drugs in the ranking of their potency: DMPP>RJR 2403>nicotine>lobeline>cytisine. Both methyllycaconitine, a nicotinic acetylcholine receptor (nAChR) antagonist and methyllycaconitine, a selective alpha7-containing nAChR antagonist blocked the effects of nicotine and DMPP, suggesting that alpha7 subunit mediated the increases in 5-HT. However, DMPP was reported to increase 5-HT using non-nAChR mechanism [Lendvai B, Sershen H, Lajtha A, Santha E, Baranyi M, Vizi ES (1996) Differential mechanisms involved in the effect of nicotinic agonists DMPP and lobeline to release [3H]5-HT from rat hippocampal slices. Neuropharmacology 35:1769-1777]. To test if 5-HT carriers were involved, a selective 5-HT reuptake inhibitor citalopram (1 microM) was infused into the dorsal raphe nucleus before administration of nicotine or DMPP. As a result, citalopram significantly blocked the effect of DMPP, whereas it had no influence on nicotine. Finally, the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was used to test whether the increases in 5-HT were depolarization-dependent. Administration of 8-OH-DPAT (0.1 mg/kg, s.c.) produced significant decreases in 5-HT in the animals treated with nicotine. In contrast, the effect of DMPP was not altered by 8-OH-DPAT, suggesting that the increases in 5-HT were independent of cell membrane depolarization. In conclusion, there are different mechanisms involved in nicotine- and DMPP-evoked increases in 5-HT. This

  5. Selective vulnerability of the medullary thick ascending limb to anoxia in the isolated perfused rat kidney.

    Brezis, M; Rosen, S.; Silva, P.; Epstein, F H


    A specific anatomical lesion sharply localized to the cells of the medullary thick ascending limbs (mTAL) and characterized by mitochondrial swelling progressing to nuclear pyknosis and cell death is elicited reproducibly in isolated rat kidneys perfused for 15 or 90 min with cell-free albumin-Ringer's medium gassed with 5% CO2, 95% O2 (O2 content, 1.5 vol/100 ml). The lesion, involving about half of mTALs, appears first in mTALs removed from vascular bundles and near the inner medulla, areas...

  6. Effect of MDMA-Induced Axotomy on the Dorsal Raphe Forebrain Tract in Rats: An In Vivo Manganese-Enhanced Magnetic Resonance Imaging Study.

    Chuang-Hsin Chiu

    Full Text Available 3,4-Methylenedioxymethamphetamine (MDMA, also known as "Ecstasy", is a common recreational drug of abuse. Several previous studies have attributed the central serotonergic neurotoxicity of MDMA to distal axotomy, since only fine serotonergic axons ascending from the raphe nucleus are lost without apparent damage to their cell bodies. However, this axotomy has never been visualized directly in vivo. The present study examined the axonal integrity of the efferent projections from the midbrain raphe nucleus after MDMA exposure using in vivo manganese-enhanced magnetic resonance imaging (MEMRI. Rats were injected subcutaneously six times with MDMA (5 mg/kg or saline once daily. Eight days after the last injection, manganese ions (Mn2+ were injected stereotactically into the raphe nucleus, and a series of MEMRI images was acquired over a period of 38 h to monitor the evolution of Mn2+-induced signal enhancement across the ventral tegmental area, the medial forebrain bundle (MFB, and the striatum. The MDMA-induced loss of serotonin transporters was clearly evidenced by immunohistological staining consistent with the Mn2+-induced signal enhancement observed across the MFB and striatum. MEMRI successfully revealed the disruption of the serotonergic raphe-striatal projections and the variable effect of MDMA on the kinetics of Mn2+ accumulation in the MFB and striatum.

  7. Estradiol Valerate and Remifemin ameliorate ovariectomy-induced decrease in a serotonin dorsal raphe-preoptic hypothalamus pathway in rats.

    Wang, Wenjuan; Cui, Guangxia; Jin, Biao; Wang, Ke; Chen, Xing; Sun, Yu; Qin, Lihua; Bai, Wenpei


    Perimenopausal syndromes begin as ovarian function ceases and the most common symptoms are hot flushes. Data indicate that the projections of serotonin to hypothalamus may be involved in the mechanism of hot flushes. Therefore, the aim of this study is to investigate the potential role of the serotonin dorsal raphe-preoptic hypothalamus pathway for hot flushes in an animal model of menopause. We determined the changes in serotonin expression in the dorsal raphe (DR) and preoptic anterior hypothalamus (POAH) in ovariectomized rats. We also explored the therapeutical effects of estradiol valerate and Remifemin in this model. Eighty female Sprague-Dawley rats were randomly assigned to sham-operated (SHAM) group, ovariectomy (OVX) group with vehicle, ovariectomy with estradiol valerate treatment (OVX+E) group and ovariectomy with Remifemin (OVX+ICR) group. Serotonin expression was evaluated in the DR and POAH using immunofluorescence and quantified in the DR using an enzyme-linked immunosorbent assay (ELISA). Apoptosis was analyzed in the DR by TUNEL assay. The number of serotonin immunoreactive neurons and the level of serotonin expression in the DR decreased significantly following OVX compared to the SHAM group. No TUNEL-positive cells were detected in the DR in any group. In addition, following OVX, the number of serotonin-positive fibers decreased significantly in the ventromedial preoptic nucleus (VMPO), especially in the ventrolateral preoptic nucleus (VLPO). Treatment with either estradiol or Remifemin for 4 weeks countered the OVX-induced decreases in serotonin levels in both the DR and the hypothalamus, with levels in the treated rats similar to those in the SHAM group. A fluorescently labeled retrograde tracer was injected into the VLPO at the 4-week time point. A significantly lower percentage of serotonin with CTB double-labeled neurons in CTB-labeled neurons was demonstrated after ovariectomy, and both estradiol and Remifemin countered this OVX

  8. Dorsal raphe nucleus of brain in the rats flown in space inflight and postflight alteration of structure

    Krasnov, I.

    The structure of brain dorsal raphe nucleus (DRN) was studied in the rats flown in space aboard Space Shuttle "Columbia" (STS-58, SLS-2 program) and dissected on day 13 of the mission ("inflight" rats) and in 5-6 hours after finishing 14-day flight ("postflight" rats). The brain of "inflight" rats were excised after decapitation, sectioned sagitally halves of brain were fixed by immersion in 2,5 % glutaraldehyde in 0.1 M cacodylate buffer pH 7.3 at 4°C and kept in the flight at 4°C. After landing the brain frontal 0.5 mm sections from DRN area were osmificated and embedded in araldite at NASA ARC. The brains of "postflight": and control rats were underwent to the same procedure. Electronmicroscopical analysis, computer morphometry and glial cell count were performed at Moscow. In DRN neuropil of "inflight" rats the most part of axo-dendritic synapses were surrounded by glia cell processes and had decreased electron density of pre- and postsynaptic membrane and pronounced diminution of synaptic vesicle amount while dendrites were characterized by decrease in matrix electron density and microtubule quantity that in total indicates the decline of afferent flow reaching DRN neurons in microgravity. In DRN neurons of "inflight" rats all mitochondria were characterized by evenly increased dimensions, decreased matrix electron density, small amount of short and far- between located cristae and enlarged intermembrane and intercristae spaces, that in total points out low level of coupling of oxidation to phosphorilation, decrease in energy supply of neuron. Amount of ribosome in cytoplasm was significantly decreased indicating lower lever of biosynthetic processes. The last is supported by diminished dimensions of neuronal body, nucleus and nucleolus (place of r RNA synthesis), cross section area of that were reduced in DRN neurons of "inflight" rats by 18.8 % (p < 0.01), 11.1 % and 26.6 % (p <0,005) correspondingly. Ultrastructure and dimensions of intracellular

  9. Excitatory and inhibitory behavioral responses to the pharmacological stimulation of serotonergic function in dorsalis raphe lesioned rats.

    Rodríguez Echandía, E L; González, A S; Fóscolo, M R; Broitman, S T


    Neurotoxin-induced lesions of 5-HT neurons produce supersensitivity of 5-HT1 receptors without affecting 5-HT2 receptor binding in the brain. This model was used in the present work to analyze the role of 5-HT receptor subtypes in the mechanism controlling the excitatory and inhibitory behavioral responses to the pharmacological stimulation of 5-HT systems. Dorsalis raphe (DR) lesions were made by stereotaxic injection of kainic acid. At day 30 after injection DR-and control rats displayed similar baseline behavior in hole board tests. Three days later DR-and control rats received an ip injection of fluoxetine (5 or 10 mg/kg) 30 min before injecting ip 5-HTP(15 or 30 mg/kg). Immediately before and after each ip injection the excitatory response (myoclonic syndrome) was evaluated. DR-and control-group showed similar scores of myoclonus in response to fluoxetine-5-HTP. The inhibitory response was investigated in hole board trials performed 30 min after the second ip injection. The DR lesion potentiated the behavioral depressive effect of fluoxetine-5-HTP. In agreement with data in the literature the DR lesion caused 74.9% loss of forebrain 5-HT and 75% increases of 3H-5HT binding in cortex membranes. Most components of the excitatory response, which remained unchanged in the DR-lesioned rats, might be related to 5-HT2 receptors. The increased inhibitory response to 5-HT stimulation in DR-lesioned rats would be due to the supersensitivity of 5-HT1 receptors.

  10. Evidence for the existence of FGFR1-5-HT1A heteroreceptor complexes in the midbrain raphe 5-HT system.

    Borroto-Escuela, Dasiel O; Narvaez, Manuel; Pérez-Alea, Mileidys; Tarakanov, Alexander O; Jiménez-Beristain, Antonio; Mudó, Giuseppa; Agnati, Luigi F; Ciruela, Francisco; Belluardo, Natale; Fuxe, Kjell


    The ascending midbrain 5-HT neurons known to contain 5-HT1A autoreceptors may be dysregulated in depression due to a reduced trophic support. With in situ proximity ligation assay (PLA) and supported by co-location of the FGFR1 and 5-HT1A immunoreactivities in midbrain raphe 5-HT cells, evidence for the existence of FGFR1-5-HT1A heteroreceptor complexes were obtained in the dorsal and median raphe nuclei of the Sprague-Dawley rat. Their existence in the rat medullary raphe RN33B cell cultures was also established. After combined FGF-2 and 8-OH-DPAT treatment, a marked and significant increase in PLA positive clusters was found in the RN33B cells. Similar results were reached upon coactivation by agonists in HEK293T cells using the Fluorescent Resonance Energy Transfer (FRET) technique resulting in increased FRETmax and reduced FRET50 values. The heteroreceptor complex formation was dependent on TMV of the 5-HT1A receptor since it was blocked by incubation with TMV but not with TMII. Taken together, the 5-HT1A autoreceptors by being recruited into a FGFR1-5-HT1A heteroreceptor complex in the midbrain raphe 5-HT nerve cells may develop a novel function, namely a trophic role in many midbrain 5-HT neuron systems originating from the dorsal and medianus raphe nuclei.

  11. Cholinergic modulation of primary afferent glutamatergic transmission in rat medullary dorsal horn neurons.

    Jeong, Seok-Gwon; Choi, In-Sun; Cho, Jin-Hwa; Jang, Il-Sung


    Although muscarinic acetylcholine (mACh) receptors are expressed in trigeminal ganglia, it is still unknown whether mACh receptors modulate glutamatergic transmission from primary afferents onto medullary dorsal horn neurons. In this study, we have addressed the cholinergic modulation of primary afferent glutamatergic transmission using a conventional whole cell patch clamp technique. Glutamatergic excitatory postsynaptic currents (EPSCs) were evoked from primary afferents by electrical stimulation of trigeminal tract and monosynaptic EPSCs were recorded from medullary dorsal horn neurons of rat horizontal brain stem slices. Muscarine and ACh reversibly and concentration-dependently decreased the amplitude of glutamatergic EPSCs and increased the paired-pulse ratio. In addition, muscarine reduced the frequency of miniature EPSCs without affecting the current amplitude, suggesting that muscarine acts presynaptically to decrease the probability of glutamate release onto medullary dorsal horn neurons. The muscarine-induced decrease of glutamatergic EPSCs was significantly occluded by methoctramine or AF-DX116, M2 receptor antagonists, but not pirenzepine, J104129 and MT-3, selective M1, M3 and M4 receptor antagonists. The muscarine-induced decrease of glutamatergic EPSCs was highly dependent on the extracellular Ca2+ concentration. Physostigmine and clinically available acetylcholinesterase inhibitors, such as rivastigmine and donepezil, significantly shifted the concentration-inhibition relationship of ACh for glutamatergic EPSCs. These results suggest that muscarine acts on presynaptic M2 receptors to inhibit glutamatergic transmission by reducing the Ca2+ influx into primary afferent terminals, and that M2 receptor agonists and acetylcholinesterase inhibitors could be, at least, potential targets to reduce nociceptive transmission from orofacial tissues.

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

    Seyed Homayoon Sadraie


    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.

  13. Processing of pro-CGRP in a rat medullary thyroid carcinoma cell line transfected with protease inhibitors

    Johansen, Teit Eliot; Schifter, S; Vogel, Charlotte Katrine


    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...

  14. Strontium is a biased agonist of the calcium-sensing receptor in rat medullary thyroid carcinoma 6-23 cells

    Thomsen, Alex Rojas Bie; Worm, Jesper; Jacobsen, Stine Engesgaard


    of CaSR is poorly understood, the objective of the present study was to investigate biased signaling of CaSR by using rat medullary thyroid carcinoma 6-23 cells as a model of thyroid parafollicular C-cells. By doing concentration-response experiments we focused on the ability of two well known Ca...

  15. Calretinin is present in non-pyramidal cells of the rat hippocampus--III. Their inputs from the median raphe and medial septal nuclei.

    Acsády, L; Halasy, K; Freund, T F


    The subcortical innervation of a recently described subpopulation of non-pyramidal neurons, containing the calcium binding protein, calretinin, was investigated in the rat hippocampus using the anterograde tracer Phaseolus vulgaris-leucoagglutinin and double immunocytochemistry for calretinin and serotonin at the light and electron microscopic levels. Our results show that the GABAergic component of the septohippocampal pathway and the serotonergic raphe afferents establish multiple synaptic contacts with the calretinin-immunoreactive interneurons. The majority of the targets of both pathways were spine-free calretinin neurons known to innervate the dendritic region of the principal cells, but the GABAergic septal pathway was found to terminate also on the spiny neurons of stratum lucidum of the CA3 region and in the dentate hilus. The present results demonstrate that the serotonergic raphe-hippocampal and the GABAergic septohippocampal pathways are able to modulate dendritic inhibition of principal cells via calretinin-containing GABAergic interneurons.

  16. 5-HT7 receptor modulates GABAergic transmission in the rat dorsal raphe nucleus and controls cortical release of serotonin

    Magdalena eKusek


    Full Text Available The 5-HT7 receptor is one of the several serotonin (5-HT receptor subtypes that are expressed in the dorsal raphe nucleus (DRN. Some earlier findings suggested that 5-HT7 receptors in the DRN were localized on GABAergic interneurons modulating the activity of 5-HT projection neurons. The aim of the present study was to find out how the 5-HT7 receptor modulates the GABAergic synaptic input to putative 5-HT DRN neurons, and whether blockade of the 5-HT7 receptor would affect the release of 5-HT in the target structure. Male Wistar rats with microdialysis probes implanted in the prefrontal cortex (PFC received injections of the 5-HT7 receptor antagonist (2R-1-[(3-hydroxyphenylsulfonyl]-2-[2-(4-methyl-1 piperidinylethyl]pyrrolidine hydrochloride (SB 269970, which induced an increase in the levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA in the PFC. In another set of experiments whole-cell recordings from presumed projection neurons were carried out using DRN slices. SB 269970 application resulted in depolarization and in an increase in the firing frequency of the cells. In order to activate 5-HT7 receptors, 5-carboxamidotryptamine (5-CT was applied in the presence of N-[2-[4-(2-methoxyphenyl-1piperazinyl]ethyl]-N-2- pyridinylcyclohexanecarboxamide (WAY100635. Hyperpolarization of cells and a decrease in the firing frequency were observed after activation of the 5-HT7 receptor. Blockade of 5-HT7 receptors caused

  17. Heterozygous disruption of renal outer medullary potassium channel in rats is associated with reduced blood pressure.

    Zhou, Xiaoyan; Zhang, Zuo; Shin, Myung Kyun; Horwitz, Sarah Beth; Levorse, John M; Zhu, Lei; Sharif-Rodriguez, Wanda; Streltsov, Denis Y; Dajee, Maya; Hernandez, Melba; Pan, Yi; Urosevic-Price, Olga; Wang, Li; Forrest, Gail; Szeto, Daphne; Zhu, Yonghua; Cui, Yan; Michael, Bindhu; Balogh, Leslie Ann; Welling, Paul A; Wade, James B; Roy, Sophie; Sullivan, Kathleen A


    The renal outer medullary potassium channel (ROMK, KCNJ1) mediates potassium recycling and facilitates sodium reabsorption through the Na(+)/K(+)/2Cl(-) cotransporter in the loop of Henle and potassium secretion at the cortical collecting duct. Human genetic studies indicate that ROMK homozygous loss-of-function mutations cause type II Bartter syndrome, featuring polyuria, renal salt wasting, and hypotension; humans heterozygous for ROMK mutations identified in the Framingham Heart Study have reduced blood pressure. ROMK null mice recapitulate many of the features of type II Bartter syndrome. We have generated an ROMK knockout rat model in Dahl salt-sensitive background by using zinc finger nuclease technology and investigated the effects of knocking out ROMK on systemic and renal hemodynamics and kidney histology in the Dahl salt-sensitive rats. The ROMK(-/-) pups recapitulated features identified in the ROMK null mice. The ROMK(+/-) rats, when challenged with a 4% salt diet, exhibited a reduced blood pressure compared with their ROMK(+/+) littermates. More importantly, when challenged with an 8% salt diet, the Dahl salt-sensitive rats with 50% less ROMK expression showed increased protection from salt-induced blood pressure elevation and signs of protection from renal injury. Our findings in ROMK knockout Dahl salt-sensitive rats, together with the previous reports in humans and mice, underscore a critical role of ROMK in blood pressure regulation.

  18. Studying the Effect of Hydro- alcoholic Extract of Valeriana officinalis on the Number and Size of Raphe Magnus Neurons in Mature Rats

    Nahid Sadeghi


    Full Text Available Introduction & Objective: Effective materials from Valerian officinalis L. have too much usage in the pharmacological industry. It is used as a sedative, anticonvulsion, and antidepressant drug. Serotonin has a widespread role in vital function such as sleep, awareness and calmness. In this study we evaluated the effect of hydrochloric extract of valerian on number and size of raphe magnus neurons in adult rat. Materials & Methods:In this experimental study, which was conducted at Yasuj University of Medical Sciences in 2009, forty adult Wistar rats, each 170-250 gr, were divided randomly into four groups (one control group and three experimental groups. The animals were injected daily for one month with doses of 300, 400 and 600 mg/kg of the extract. The control group just received distilled water. After transcardial perfusion, the whole brain was separated, then 10 µm sections of the brain stem were prepared, and hematoxylin and eosin (H&E staining were done. Number and size of raphe magna neurons were observed under light microscope. The gathered data were analyzed by the SPSS software using One-way ANOVA and LSD. Results: The control group did not statistically show significant changes in number of raphe magna neurons. Comparison of the means of long and short diameter neurons showed significant increases in experimental groups with control group (P<0.05. In experimental groups the neuron nucleuses were more euchromatic than the control group. Conclusion: Hydrochloric extract of valerian has no effect on raphe magnus neurons, but it is effective on neurons' size. It can be concluded that the extract increases both neurons activity and serotonin secretion.

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

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


    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.

  20. Changes in firing rate and firing pattern of midbrain dopaminergic neurons after lesioning of the dorsal raphe nucleus by 5,7-drhydroxytryptamine in adult rats


    Objective To study the effect of serotonergic efferent projection of the dorsal raphe nucleus(DRN)on the activity of substantia nigra pars compacta(SNc)and ventral tegmenta area(VTA)dopaminergic neurons after lesioning of the DRN by the neurotoxin 5,7-drhydroxytryptamine(5,7-DHT)in rat.Methods The changes in the firing rate and firing pattern of SNc and VTA dopaminergic neurons were observed with extracellular recording in control and the lesioned rats.Results The results showed that the mean firing rates o...

  1. Galanin subtype 1 and subtype 2 receptors mediate opposite anxiety-like effects in the rat dorsal raphe nucleus.

    Morais, J S; Souza, M M; Campanha, T M N; Muller, C J T; Bittencourt, A S; Bortoli, V C; Schenberg, L C; Beijamini, V


    About 40% of the dorsal raphe nucleus (DRN) neurons co-express serotonin (5-HT) and galanin. Serotonergic pathways from the DRN to the amygdala facilitate learned anxiety, while those from the DRN to the dorsal periaqueductal grey matter (DPAG) impair innate anxiety. Previously, we showed that galanin infusion in the DRN of rats induces anxiolytic effect by impairing inhibitory avoidance without changing escape behaviour in the elevated T-maze (ETM). Here, we evaluated: (1) which galanin receptors would be involved in the anxiolytic effect of galanin in the DRN of rats tested in the ETM; (2) the effects of galanin intra-DRN on panic-like behaviours evoked by electrical stimulation of the DPAG. The activation of DRN GAL1 receptors by M617 (1.0 and 3.0nmol) facilitated inhibitory avoidance, whereas the activation of GAL2 receptors by AR-M1896 (3.0nmol) impaired the inhibitory avoidance in the ETM, suggesting an anxiogenic and an anxiolytic-like effect respectively. Both agonists did not change escape behaviour in the ETM or locomotor activity in the open field. The anxiolytic effect of AR-M1896 was attenuated by the prior administration of WAY100635 (0.18nmol), a 5-HT1A antagonist. Galanin (0.3nmol) administered in the DRN increased discreetly flight behaviours induced by electrical stimulation of the DPAG, suggesting a panicolytic effect. Together, our results showed that galanin mediates opposite anxiety responses in the DRN by activation of GAL1 and GAL2 receptors. The anxiolytic effect induced by activation of Gal2 receptors may depend on serotonergic tone. Finally, the role of galanin in panic related behaviours remains uncertain. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. [Characteristics of distribution of nitric oxide synthase containing neurons in the medullary cardiovascular centers of dogs and rats].

    Datsenko, V V; Pavliuchenko, V B; Moĭbenko, O O; Piliavs'kyĭ, O I; Kostiukov, O I; Maĭs'kyĭ, V O


    The aim of the study was to characterize species-related differences in the distribution of nitric oxide synthase (NOS)-containing neurons in the medullary structures of dogs and rats involved in the regulation of the sympathetic or parasympathetic drives. Two main results have been obtained, namely: (i) the average number of NOS-containing neurons in the dorsomedial and ventrolateral medulla per section in dog was larger than that in rat, while the density of the positive cells in the both regions in dog was less than that in rat. (ii) Within the dorsal motor nucleus of vagus a lot of NOS-containing cells (preganglionic vagal neurons) were observed only in dog. Differences in the distribution of NO-generating neurons in the medullary cardiovascular centers, and heterogeneity in the basal level of NO release may contribute to the peculiarities of the hemodynamic responses induced by NOS inhibitors in these species.

  3. Neurotoxicity of prenatal alcohol exposure on medullary pre-Bötzinger complex neurons in neonatal rats

    Ming-li Ji; Yun-hong Wu; Zhi-bin Qian


    Prenatal alcohol exposure disrupts the development of normal fetal respiratory function, but whether it perturbs respiratory rhythmical discharge activity is unclear. Furthermore, it is un-known whether the 5-hydroxytryptamine 2A receptor (5-HT2AR) is involved in the effects of prenatal alcohol exposure. In the present study, pregnant female rats received drinking water containing alcohol at concentrations of 0%, 1%, 2%, 4%, 8% or 10% (v/v) throughout the gestation period. Slices of the medulla from 2-day-old neonatal rats were obtained to record respiratory rhythmical discharge activity. 5-HT2AR protein and mRNA levels in the pre-Bötzing-er complex of the respiratory center were measured by western blot analysis and quantitative RT-PCR, respectively. Compared with the 0% alcohol group, respiratory rhythmical discharge activity in medullary slices in the 4%, 8% and 10% alcohol groups was decreased, and the reduc-tion was greatest in the 8% alcohol group. Respiratory rhythmical discharge activity in the 10%alcohol group was irregular. Thus, 8% was the most effective alcohol concentration at attenuating respiratory rhythmical discharge activity. These ifndings suggest that prenatal alcohol exposure attenuates respiratory rhythmical discharge activity in neonatal rats by downregulating 5-HT2AR protein and mRNA levels.

  4. 5-HT7 receptor modulates GABAergic transmission in the rat dorsal raphe nucleus and controls cortical release of serotonin.

    Kusek, Magdalena; Sowa, Joanna; Kamińska, Katarzyna; Gołembiowska, Krystyna; Tokarski, Krzysztof; Hess, Grzegorz


    The 5-HT7 receptor is one of the several serotonin (5-HT) receptor subtypes that are expressed in the dorsal raphe nucleus (DRN). Some earlier findings suggested that 5-HT7 receptors in the DRN were localized on GABAergic interneurons modulating the activity of 5-HT projection neurons. The aim of the present study was to find out how the 5-HT7 receptor modulates the GABAergic synaptic input to putative 5-HT DRN neurons, and whether blockade of the 5-HT7 receptor would affect the release of 5-HT in the target structure. Male Wistar rats with microdialysis probes implanted in the prefrontal cortex (PFC) received injections of the 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride (SB 269970), which induced an increase in the levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in the PFC. In another set of experiments whole-cell recordings from presumed projection neurons were carried out using DRN slices. SB 269970 application resulted in depolarization and in an increase in the firing frequency of the cells. In order to activate 5-HT7 receptors, 5-carboxamidotryptamine (5-CT) was applied in the presence of N-[2-[4-(2-methoxyphenyl)-1piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635). Hyperpolarization of cells and a decrease in the firing frequency were observed after activation of the 5-HT7 receptor. Blockade of 5-HT7 receptors caused a decrease in the mean frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), while its activation induced an increase. The mechanism of these effects appears to involve tonically-active 5-HT7 receptors modulating firing and/or GABA release from inhibitory interneurons which regulate the activity of DRN serotonergic projection neurons.

  5. 5-HT1A autoreceptor modulation of locomotor activity induced by nitric oxide in the rat dorsal raphe nucleus

    L.B. Gualda


    Full Text Available The dorsal raphe nucleus (DRN is the origin of ascending serotonergic projections and is considered to be an important component of the brain circuit that mediates anxiety- and depression-related behaviors. A large fraction of DRN serotonin-positive neurons contain nitric oxide (NO. Disruption of NO-mediated neurotransmission in the DRN by NO synthase inhibitors produces anxiolytic- and antidepressant-like effects in rats and also induces nonspecific interference with locomotor activity. We investigated the involvement of the 5-HT1A autoreceptor in the locomotor effects induced by NO in the DRN of male Wistar rats (280-310 g, N = 9-10 per group. The NO donor 3-morpholinosylnomine hydrochloride (SIN-1, 150, and 300 nmol and the NO scavenger S-3-carboxy-4-hydroxyphenylglycine (carboxy-PTIO, 0.1-3.0 nmol were injected into the DRN of rats immediately before they were exposed to the open field for 10 min. To evaluate the involvement of the 5-HT1A receptor and the N-methyl-D-aspartate (NMDA glutamate receptor in the locomotor effects of NO, animals were pretreated with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylaminotetralin (8-OH-DPAT, 8 nmol, the 5-HT1A receptor antagonist N-(2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY-100635, 0.37 nmol, and the NMDA receptor antagonist DL-2-amino-7-phosphonoheptanoic acid (AP7, 1 nmol, followed by microinjection of SIN-1 into the DRN. SIN-1 increased the distance traveled (mean ± SEM in the open-field test (4431 ± 306.1 cm; F7,63 = 2.44, P = 0.028 and this effect was blocked by previous 8-OH-DPAT (2885 ± 490.4 cm or AP7 (3335 ± 283.5 cm administration (P < 0.05, Duncan test. These results indicate that 5-HT1A receptor activation and/or facilitation of glutamate neurotransmission can modulate the locomotor effects induced by NO in the DRN.

  6. Effects of electroacupuncture on orphanin FQ immunoreactivity and preproorphanin FQ mRNA in nucleus of raphe magnus in the neuropathic pain rats.

    Ma, Fei; Xie, Hong; Dong, Zhi-Qiang; Wang, Yan-Qing; Wu, Gen-Cheng


    Orphanin FQ (OFQ) is an endogenous ligand for opioid receptor-like-1 (ORL1) receptor. Previous studies have shown that both OFQ immunoreactivity and preproorphanin FQ (ppOFQ) mRNA expression could be observed in the brain regions involved in pain modulation, e.g., nucleus of raphe magnus (NRM), dorsal raphe nucleus (DRN), and ventrolateral periaqueductal gray (vlPAG). It was reported that electroacupuncture (EA) has analgesic effect on neuropathic pain, and the analgesic effect was mediated by the endogenous opioid peptides. In the present study, we investigated the effects of EA on the changes of OFQ in the neuropathic pain rats. In the sciatic nerve chronic constriction injury (CCI) model, we investigated the changes of ppOFQ mRNA and OFQ immunoreactivity in NRM after EA by in situ hybridization (ISH) and immunohistochemistry methods, respectively. Then, the ppOFQ mRNA-positive and OFQ immunoreactive cells were counted under a computerized image analysis system. The results showed that expression of ppOFQ mRNA decreased and OFQ immunoreactivity increased after EA treatment in the neuropathic pain rats. These results indicated that EA modulated OFQ synthesis and OFQ peptide level in NRM of the neuropathic pain rats.

  7. Axon-glial relations during regeneration of axons in the adult rat anterior medullary velum.

    Berry, M; Hunter, A S; Duncan, A; Lordan, J; Kirvell, S; Tsang, W L; Butt, A M


    The anterior medullary velum (AMV) of adult Wistar rats was lesioned in the midsagittal plane, transecting all decussating axons including those of the central projection of the IVth nerve. At selected times up to 200 days after transection, the degenerative and regenerative responses of axons and glia were analyzed using transmission and scanning electron microscopy and immunohistochemistry. In particular, both the capacity of oligodendrocytes to remyelinate regenerated fibers and the stability of the CNS/PNS junctional zone of the IVth nerve rootlet were documented. Transected central AMV axons exhibited four patterns of fiber regeneration in which fibers grew: rostrocaudally in the reactive paralesion neuropil (Group 1); randomly within the AMV (Group 2); into the ipsilateral IVth nerve rootlet, after turning at the lesion edge and growing recurrently through the old degenerated contralateral central trochlear nerve trajectory (Group 3); and ectopically through paralesion tears in the ependyma onto the surface of the IVth ventricle (Group 4). Group 1-3 axons regenerated unperturbed through degenerating central myelin, reactive astrocytes, oligodendrocytes, microglia, and large accumulations of hematogenous macrophages. Only Group 3 axons survived long term in significant numbers, and all became myelinated by oligodendrocytes, ultimately establishing thin sheaths with relatively normal nodal gaps and intersegmental myelin sheath lengths. Schwann cells at the CNS/PNS junction of the IVth nerve rootlet did not invade the CNS, but astrocyte processes grew across the junction into the PNS portion of the IVth nerve. The basal lamina of the junctional glia limitans remained stable throughout the experimental period.

  8. Axon-myelin sheath relations of oligodendrocyte unit phenotypes in the adult rat anterior medullary velum.

    Butt, A M; Ibrahim, M; Berry, M


    Axon-oligodendrocyte relations of Rip-immunolabelled and dye-injected oligodendrocyte units are characterised in the adult rat anterior medullary velum (AMV). Each oligodendrocyte unit comprised the oligodendrocyte cell body, processes and the internodal myelin segments they support. Oligodendrocyte units corresponded to classically described type I/II or type III/IV unit phenotypes which respectively myelinated discrete populations of small and large diameter axons, delineated by a myelinated fire diameter of 2-4 microns (diameter of the axon plus its myelin sheath). Within units, mean fibre diameter was directly related to mean internodal length and inversely related to the number of myelin sheaths in the unit. The relationship between fibre diameter and internodal length was retained in units which myelinated axons of different diameters, indicating that axon diameter was an important determinant of the longitudinal dimensions of myelin sheaths. We also show that type III/IV units maintained a far greater volume of myelin than type I/II units. It was concluded that type I/II and III/IV oligodendrocytes represent two functionally and morphologically distinct phenotypes whose distribution densities were determined by the diameter and spatial dispersion of axons.

  9. Excitotoxic median raphe lesions aggravate working memory storage performance deficits caused by scopolamine infusion into the dentate gyrus of the hippocampus in the inhibitory avoidance task in rats

    Babar E.


    Full Text Available The interactions between the median raphe nucleus (MRN serotonergic system and the septohippocampal muscarinic cholinergic system in the modulation of immediate working memory storage performance were investigated. Rats with sham or ibotenic acid lesions of the MRN were bilaterally implanted with cannulae in the dentate gyrus of the hippocampus and tested in a light/dark step-through inhibitory avoidance task in which response latency to enter the dark compartment immediately after the shock served as a measure of immediate working memory storage. MRN lesion per se did not alter response latency. Post-training intrahippocampal scopolamine infusion (2 and 4 µg/side produced a more marked reduction in response latencies in the lesioned animals compared to the sham-lesioned rats. Results suggest that the immediate working memory storage performance is modulated by synergistic interactions between serotonergic projections of the MRN and the muscarinic cholinergic system of the hippocampus.

  10. Oligodendrocytes and the control of myelination in vivo: new insights from the rat anterior medullary velum.

    Butt, A M; Berry, M


    The rat anterior medullary velum (AMV) is representative of the brain and spinal cord, overall, and provides an almost two-dimensional preparation for investigating axon-glial interactions in vivo. Here, we review some of our findings on axon-oligodendrocyte unit relations in our adult, development, and injury paradigms: (1) adult oligodendrocytes are phenotypically heterogeneous, conforming to Del Rio Hortega's types I-IV, whereby differences in oligodendrocyte morphology, metabolism, myelin sheath radial and longitudinal dimensions, and biochemistry correlate with the diameters of axons in the unit; (2) oligodendrocytes derive from a common premyelinating oligodendrocyte phenotype, and divergence of types I-IV is related to the age they emerge and the presumptive diameter of axons in the unit; (3) during myelination, axon-oligodendrocyte units progress through a sequence of maturation phases, related to axon contact, ensheathment, establishment of internodal myelin sheaths, and finally the radial growth and compaction of the myelin sheath; (4) we provide direct in vivo evidence that platelet-derived growth factor-AA (PDGF-AA), fibroblast growth factor (FGF-2), and insulin-like growth factor-I (IGF-I) differentially regulate these events, by injecting the growth factors into the cerebrospinal fluid of neonatal rat pups; (5) in lesioned adult AMV, transected central nervous system (CNS) axons regenerate through the putatively inhibitory environment of the glial scar, but remyelination by oligodendrocytes is incomplete, indicating that axon-oligodendrocyte interactions are defective; and (6) in the adult AMV, cells expressing the NG2 chondroitin sulphate have a presumptive adult oligodendrocyte progenitor antigenic phenotype, but are highly complex cells and send processes to contact axolemma at nodes of Ranvier, suggesting they subserve a specific perinodal function. Thus, axons and oligodendrocyte lineage cells form interdependent functional units, but

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

    Takemoto, Yumi


    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. 5,7-DHT lesion of the dorsal raphe nuclei impairs object recognition but not affective behavior and corticosterone response to stressor in the rat.

    Lieben, Cindy K J; Steinbusch, Harry W M; Blokland, Arjan


    Previous studies with acute tryptophan depletion, leading to transient central 5-HT reductions, showed no effects on affective behavior but impaired object memory. In the present study, the behavioral effects of a 5,7-dihydroxytryptamine (5,7-DHT) lesion in the dorsal raphe were evaluated in animal models of anxiety (open field test), depression (forced swimming test), behavioral inhibition (discrete fixed interval test) and cognition (object recognition task). The corticosterone response to a stress condition was examined at several intervals after 5,7-DHT treatment. The substantial reduction in neuronal 5-HT markers in the dorsal raphe did not affect anxiety-related, depressive-like or impulsive behavior. Compared to the SHAM group, the lesioned rats showed a lower response latency to obtain a reward, indicating a quick and accurate reaction to a stimulus. No differences were found in the progressive ratio test for food motivation. A marked impairment in object recognition was found. The 5,7-DHT treatment did not affect the corticosterone response to a stressful situation. Overall, these results corroborate studies with acute tryptophan depletion suggesting a role of 5-HT in object memory, but not affective behavior.

  13. Effects of perinatal protein malnutrition and fenfluramine action on food intake and neuronal activation in the hypothalamus and raphe nuclei of neonate rats.

    Ferro Cavalcante, Taisy Cinthia; Marcelino da Silva, Amanda Alves; Amaral Almeida, Larissa Cavalcanti do; Tavares, Gabriel Araújo; de Farias Campina, Renata Cristinny; do Nascimento, Elizabeth; Lopes de Souza, Sandra


    In neonatal rats, hunger and satiety responses occur particularly via dehydration and gastric distention, respectively. The control of food intake in newborns is yet to be fully consolidated, particularly with respect to the participation of the hypothalamic nuclei and their relationship with the serotonergic pathway. Moreover, it is unclear how the environmental stressors in early life, like undernutrition, interfere in these events. Therefore, this study examined the serotonin-system's impact on food intake in rat neonates at postnatal day (P) 10 and P18 and the manner in which protein undernutrition during pregnancy and lactation interferes in this behavior. To accomplish this, Wistar rats were used, nutritionally manipulated by a diet having two protein levels, (8% and 17%) during pregnancy and lactation, to form the Control (n=10) and Low protein groups (n=10). At 10 and 18 postnatal days pups received an acute dose of fenfluramine (3mg/kg) or saline (0.9% NaCl) and subjected to milk consumption testing and then perfused to obtain the brains for the analysis of cell activation of the immunoreactive c-Fos in the hypothalamic and raphe nuclei. At 10days a reduction in weight gain was observed in both groups. On comparison of the neuronal activation for the paraventricular nucleus, an increased activation in response to fenfluramine was observed. At 18days, the weight gain percentage differed between the groups according to the nutritional manipulation, in which the control animals had no significant change while the undernourished presented increased weight gain with the use of fenfluramine. The marking of c-Fos in response to fenfluramine in the hypothalamic and raphe nuclei revealed, an especially lower activation of the PVN, MnR and DR compared intra-group. However when evaluating the effect of undernutrition, marking activation was observed to increase in all the nuclei analyzed, in the hypothalamus and raphe. Data from this study indicate that the action of

  14. Selective myelin defects in the anterior medullary velum of the taiep mutant rat.

    Song, J; Goetz, B D; Kirvell, S L; Butt, A M; Duncan, I D


    The taiep rat is a myelin mutant in which initial hypomyelination is followed by progressive demyelination of the CNS. An in vitro study suggests that accumulation of microtubules within oligodendrocytes is the cause of the taiep myelin defects (Song et al., 1999). In this article, we analyze microtubule accumulation in relation to taiep myelin defects in vivo in the anterior medullary velum (AMV), a CNS tissue that enables entire oligodendrocyte units to be resolved. Immunohistochemical analysis demonstrated notably high levels of beta-tubulin and the microtubule associated protein tau in the somata and processes of taiep oligodendrocytes. This was correlated with markedly reduced expression of the myelin proteins, proteolipid protein (PLP), myelin basic protein (MBP), 2',3 -cyclic nucleotide 3'-phosphodiesterase, and both large (L) and small (S) isoforms of myelin-associated glycoprotein (MAG). Moreover, PLP and L-MAG, which are dependent on the microtubule system for intracellular transport, accumulated in the perinuclear cytoplasm of the taiep oligodendrocyte. The myelin deficit was most marked in the area of the AMV populated by the small somata oligodendrocytes that have fine long processes that support numerous myelin sheaths of small diameter axons. Type III/IV oligodendrocytes, which have large somata and short processes that support a small number of myelin sheaths of large diameter axons, were also affected to a certain degree in compact myelin sheath formation. These results support the hypothesis that myelin loss and oligodendrocyte disruption in the taiep mutant result from a defect in the microtubule system that transports myelin components from the somata to the myelin sheath.

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

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


    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.

  16. Relationship between myelin sheath diameter and internodal length in axons of the anterior medullary velum of the adult rat.

    Ibrahim, M; Butt, A M; Berry, M


    Relations between myelin sheath diameters and internodal lengths were measured in whole mounts of osmium stained intact anterior medullary velum (AMV) from glutaraldehyde perfused adult rats. The AMV is a sheet of CNS tissue which roofs the IVth ventricle and contains fascicles of myelinated fibres which arise mainly from the nucleus of the IVth cranial nerve. These fibers displayed a broad range of myelin sheath external diameters and internodal lengths, from 4 microns. Our results indicated that small and large calibre fibres may have different myelin sheath diameter-internodal length interrelations.

  17. 5-HT7 receptor modulates GABAergic transmission in the rat dorsal raphe nucleus and controls cortical release of serotonin

    Magdalena eKusek; Joanna eSowa; Katarzyna eKamińska; Krystyna eGołembiowska; Krzysztof eTokarski; Grzegorz eHess


    The 5-HT7 receptor is one of the several serotonin (5-HT) receptor subtypes that are expressed in the dorsal raphe nucleus (DRN). Some earlier findings suggested that 5-HT7 receptors in the DRN were localized on GABAergic interneurons modulating the activity of 5-HT projection neurons. The aim of the present study was to find out how the 5-HT7 receptor modulates the GABAergic synaptic input to putative 5-HT DRN neurons, and whether blockade of the 5-HT7 receptor would affect the release of 5-...

  18. Anti-nociceptive effects of calcitonin gene-related peptide in nucleus raphe magnus of rats: an effect attenuated by naloxone.

    Huang, Y; Brodda-Jansen, G; Lundeberg, T; Yu, L C


    The present study investigated the role of calcitonin gene-related peptide (CGRP) on nociception in nucleus raphe magnus (NRM) and the interaction between CGRP and opioid peptides in NRM of rats. CGRP-like immunoreactivity was found at a concentration of 6.0+/-0. 77 pmol/g in NRM tissue of ten samples of rats, suggesting that it may contribute to physiological responses orchestrated by the NRM. The hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation increased significantly after intra-NRM administration of 0.5 or 1 nmol of CGRP in rats, but not 0.25 nmol. The anti-nociceptive effect induced by CGRP was antagonized by following intra-NRM injection of 1 nmol of the CGRP receptor antagonist CGRP8-37. Furthermore, the CGRP-induced anti-nociceptive effect was attenuated by following intra-NRM administration of 6 nmol of naloxone. The results indicate that CGRP and its receptors play an important role in anti-nociception, and there is a possible interaction between CGRP and opioid peptides in NRM of rats.

  19. In Vivo Effect of a 5-HT7 Receptor Agonist on 5-HT Neurons and GABA Interneurons in the Dorsal Raphe Nuclei of Sham and PD Rats.

    Wang, Shuang; Zhao, Yan; Gao, Jie; Guo, Yufang; Wang, Xiang; Huo, Jian; Wei, Ping; Cao, Jian


    The 5-hydroxytryptamine (5-HT; serotonin) neurotransmission is severely affected by the degeneration of nigrostriatal dopaminergic neurons. Here, we report the effects of the systemic administration of the 5-HT7 receptor agonist AS-19. In sham rats, the mean response of the 5-HT neurons in the dorsal raphe nucleus (DRN) to systemic AS-19 was excitatory and the mean response of the γ-aminobutyric acid (GABA) interneurons was inhibitory. In Parkinson disease (PD) rats, the same dose did not affect the 5-HT neurons and only high doses (640 μg/kg intravenous) were able to the increase GABA interneuron activity. These results indicate that DRN 5-HT neurons and GABA interneurons are regulated by the activation of 5-HT7 receptors and that the degeneration of the nigrostriatal pathway leads to decreased responses of these neurons to AS-19, which in turn suggests that the 5-HT7 receptors on 5-HT neurons and GABA interneurons in PD rats are dysfunctional and downregulated.

  20. Distinct effect of orphanin FQ in nucleus raphe magnus and nucleus reticularis gigantocellularis on the rat tail flick reflex.

    Yang, Z; Zhang, Y; Wu, G


    The aim of the present study is to investigate the effects of orphanin FQ (OFQ) microinjected into the nucleus raphe magnus (NRM) and the nucleus reticularis gigantocellularis (NGC) on pain modulation. The tail-flick latency (TFL) was used as a behavioral index of nociceptive responsiveness. The result showed microinjection of OFQ into the NRM significantly increased the TFL, whereas microinjection of OFQ into the NGC decreased the TFL, suggesting the analgesic effect of OFQ in the NRM and the hyperalgesic effect of OFQ in the NGC. As there are three classes of putative pain modulating neurons in the rostral ventromedial medulla (RVM), the hyperalgesic or analgesic effect of OFQ in the RVM might depend upon the different class of the neurons being acted.

  1. HV1 acts as a sodium sensor and promotes superoxide production in medullary thick ascending limb of Dahl salt-sensitive rats.

    Jin, Chunhua; Sun, Jingping; Stilphen, Carly A; Smith, Susan M E; Ocasio, Hiram; Bermingham, Brent; Darji, Sandip; Guha, Avirup; Patel, Roshan; Geurts, Aron M; Jacob, Howard J; Lambert, Nevin A; O'Connor, Paul M


    We previously characterized a H(+) transport pathway in medullary thick ascending limb nephron segments that when activated stimulated the production of superoxide by nicotinamide adenine dinucleotide phosphate oxidase. Importantly, the activity of this pathway was greater in Dahl salt-sensitive rats than salt-resistant (SS.13(BN)) rats, and superoxide production was enhanced in low Na(+) media. The goal of this study was to determine the molecular identity of this pathway and its relationship to Na(+). We hypothesized that the voltage-gated proton channel, HV1, was the source of superoxide-stimulating H(+) currents. To test this hypothesis, we developed HV1(-/-) null mutant rats on the Dahl salt-sensitive rat genetic background using zinc-finger nuclease gene targeting. HV1 could be detected in medullary thick limb from wild-type rats. Intracellular acidification using an NH4Cl prepulse in 0 sodium/BaCl2 containing media resulted in superoxide production in thick limb from wild-type but not HV1(-/-) rats (Pthick limb and peritoneal macrophages only when HV1 was present. When fed a high-salt diet, blood pressure, outer medullary renal injury (tubular casts), and oxidative stress (4-hydroxynonenal staining) were significantly reduced in HV1(-/-) rats compared with wild-type Dahl salt-sensitive rats. We conclude that HV1 is expressed in medullary thick ascending limb and promotes superoxide production in this segment when intracellular Na(+) is low. HV1 contributes to the development of hypertension and renal disease in Dahl salt-sensitive rats.

  2. Reciprocal connections between CART-immunoreactive, hypothalamic paraventricular neurons and serotonergic dorsal raphe cells in the rat: Light microscopic study.

    Lee, Ji S; Lee, Hyun S


    Based on the overlapping physiological roles of cocaine- and amphetamine-regulated transcript (CART) peptides and serotonin, the present study examined the anatomical connection between the hypothalamic paraventricular nucleus (PVN) and the dorsal raphe (DR). The first series of experiments were performed to investigate descending projections from the CART-immunoreactive (CART-ir) PVN to serotonergic DR cells. CART-ir varicosities made contact with serotonergic DR neurons. An anterograde tracing study revealed that varicosities originating from the PVN formed close appositions to serotonergic neuronal profiles along the entire rostro-caudal extent of the DR. A retrograde study demonstrated that CART neurons projecting to the DR were mainly localized in the caudal parvicellular PVN, comprising approximately 3.0%±0.4% (n=8) of total CART cells. A second series of experiments was performed to investigate ascending projections from the DR to CART-ir PVN cells. Serotonin transporter-ir boutons made contact with CART-ir PVN neurons. Anterograde tracing revealed that varicosities originating from the DR formed close appositions to CART-ir PVN cells. Retrograde examination demonstrated that serotonergic neurons projecting to the parvicellular PVN were located along the entire rostro-caudal extent of the DR. The present observation provided an anatomical basis for accumulating evidence in the literature that suggests a functional interaction between the CART and serotonin systems during the regulation of energy balance, emotional behavior, and arousal.

  3. Biochemical subtypes of oligodendrocyte in the anterior medullary velum of the rat as revealed by the monoclonal antibody Rip.

    Butt, A M; Ibrahim, M; Ruge, F M; Berry, M


    Oligodendrocytes were studied in the anterior medullary velum (AMV) of the rat using the monoclonal antibody Rip, an oligodendrocyte marker of unknown function. Confocal microscopic imaging of double immunofluorescent labelling with antibodies to Rip and carbonic anhydrase II (CAII) revealed two biochemically and morphologically distinct populations of oligodendrocyte which were either Rip+CAII+ or Rip+CAII-. Double immunofluorescent labelling with Rip and myelin basic protein (MBP) or glial fibrillary acidic protein (GFAP) provided direct evidence that Rip-labelled cells were phenotypically oligodendrocytes and confirmed that Rip did not recognise astrocytes. Oligodendrocytes which were Rip+CAII+ supported numerous myelin sheaths for small diameter axons, whilst Rip+CAII- oligodendrocytes supported fewer myelin sheaths for large diameter axons. Morphologically, Rip+CAII+ oligodendrocytes corresponded to types I or II of classical nomenclature, whilst Rip+CAII- oligodendrocytes corresponded to types III and IV. The results demonstrated a biochemical difference between oligodendrocytes which myelinated small and large diameter fibres.

  4. The serotonin 5-HT7 receptor agonist LP-44 microinjected into the dorsal raphe nucleus suppresses REM sleep in the rat.

    Monti, Jaime M; Leopoldo, Marcello; Jantos, Héctor


    The effects of LP-44, a selective 5-HT7 receptor agonist, and of SB-269970, a selective 5-HT7 receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The 5-HT7 receptor ligands were microinjected directly into the dorsal raphe nucleus (DRN) during the light period of the 12-h light/12-h dark cycle. Infusion of LP-44 (1.25-5.0 mM) into the DRN induced a significant reduction of rapid-eye-movement sleep (REMS) and of the number of REM periods. Similar effects were observed after the direct administration into the DRN of SB-269970 (0.5-1.0 mM). Pretreatment with a dose of SB-269970 (0.5 mM) that significantly affects sleep variables antagonized the LP-44 (2.5 mM)-induced suppression of REMS and of the number of REM periods. It is proposed that the suppression of REMS after microinjection of LP-44 into the DRN is related, at least in part, to the activation of GABAergic neurons in the DRN that contribute to long projections that reach, among others, the laterodorsal and pedunculopontine tegmental nuclei involved in the promotion of REMS.

  5. Electrolytic lesion of the nucleus raphe magnus reduced the antinociceptive effects of bilateral morphine microinjected into the nucleus cuneiformis in rats.

    Haghparast, Abbas; Ordikhani-Seyedlar, Mehdi; Ziaei, Maryam


    Several lines of investigation show that the rostral ventromedial medulla is a critical relay for midbrain regions, including the nucleus cuneiformis (CnF), which control nociception at the spinal cord. There is some evidence that local stimulation or morphine administration into the CnF produces the effective analgesia through the nucleus raphe magnus (NRM). The present study tries to determine the effect of morphine-induced analgesia following microinjection into the CnF in the absence of NRM. Seven days after the cannulae implantation, morphine was microinjected bilaterally into the CnF at the doses of 0.25, 1, 2.5, 5, 7.5 and 10 microg/0.3 microl saline per side. The morphine-induced antinociceptive effect measured by tail-flick test at 30, 60, 90 and 120 min after microinjection. The results showed that bilateral microinjection of morphine into the CnF dose-dependently causes increase in tail-flick latency (TFL). The 50% effective dose of morphine was determined and microinjected into the CnF (2.5 microg/0.3 microl saline per side) in rats after NRM electrolytic lesion (1 mA, 30 s). Lesion of the NRM significantly decreased TFLs, 30 (Peffects through the opioid receptors in the CnF. It is also appeared that morphine-induced antinociception decreases following the NRM lesion but it seems that there are some other descending pain modulatory pathways that activate in the absence of NRM.

  6. Inhibitory modulation of chemoreflex bradycardia by stimulation of the nucleus raphe obscurus is mediated by 5-HT3 receptors in the NTS of awake rats.

    Weissheimer, Karin Viana; Machado, Benedito H


    Several studies demonstrated the involvement of 5-hydroxytryptamine (5-HT) and its different receptor subtypes in the modulation of neurotransmission of cardiovascular reflexes in the nucleus tractus solitarii (NTS). Moreover, anatomic evidence suggests that nucleus raphe obscurus (ROb) is a source of 5-HT-containing terminals within the NTS. In the present study we investigated the possible changes in the cardiovascular responses to peripheral chemoreceptor activation by potassium cyanide (KCN, i.v.) following ROb stimulation with L-glutamate (10 nmol/50 nL) and also whether 5-HT3 receptors in the caudal commissural NTS are involved in this neuromodulation. The results showed that stimulation of the ROb with L-glutamate in awake rats (n=15) produced a significant reduction in the bradycardic response 30 s after the microinjection (-182+/-19 vs -236+/-10 bpm; Wilcoxon test) but no changes in the pressor response to peripheral chemoreceptor activation (43+/-4 vs 51+/-3 mmHg; two-way ANOVA) in relation to the control. Microinjection of 5--HT3 receptors antagonist granisetron (500 pmol/50 nL), but not the vehicle, into the caudal commissural NTS bilaterally prevented the reduction of chemoreflex bradycardia in response to microinjection of L-glutamate into ROb. These data indicate that 5-HT-containing projections from ROb to the NTS play an inhibitory neuromodulatory role in the chemoreflex evoked bradycardia by releasing 5-HT and activating 5-HT3 receptors in the caudal NTS.

  7. Tolerance to repeated stress in rats with lesions of the serotoninergic neurons of the Median Raphe Nucleus and chronically treated with imipramine.

    Silva, K; Carvalho, M C; Padovan, C M


    Repeated exposure to aversive events leads to the development of tolerance to stress, which involves the serotonergic pathway originated in the Median Raphe Nucleus (MnRN) to the Dorsal Hippocampus (DH). However, it is not clear whether these lesion-induced deficits can be attenuated by treatment with antidepressants. Therefore, the aim of this work was to investigate the effects of chronic treatment with Imipramine (IMI) in rats with lesions in the MnRN and exposed to restraint stress. Male Wistar rats with or without neurochemical lesions of the MnRN serotonergic neurons with the neurotoxin 5,7-DHT were submitted to acute (2h) or chronic restraint (2h/day/seven consecutive days) and treated with saline (1 ml/kg) or imipramine (15 mg/kg) via intraperitoneal twice a day during the same period. In acutely restrained rats, stress occurred on the last day of treatment. Test in the elevated plus maze (EPM) was performed 24h later. After EPM test, animals were sacrificed and had their brains removed. Dorsal hippocampus and striatum were dissected and the levels of 5-HT and 5-hydroxy-indoleacetic acid (5-HIAA) measured by HPLC analysis. Our results showed that in control rats exposure to acute restraint stress decreased exploration of the open and enclose arms of the EPM, an effect that was attenuated by imipramine. In rats with 5,7-DHT lesions, acute restraint did not change the exploration of the EPM, independently of the treatment. On the other hand, when chronically restrained, saline treated rat with 5,7-DHT lesion showed a reduced exploration of the open arms of the EPM. This effect was attenuated by simultaneous treatment with imipramine. HPLC analysis showed significantly decreases on 5-HT and 5-HIAA levels in the hippocampus, but not in the striatum. These later results confirm that 5,7-DHT lesions of the MnRN had significant impact on the serotonergic projections to the dorsal hippocampus which seems to be essential for the development of tolerance to repeated

  8. Involvement of ATP in noxious stimulus-evoked release of glutamate in rat medullary dorsal horn: a microdialysis study.

    Kumar, Naresh; Cherkas, Pavel S; Chiang, C Y; Dostrovsky, Jonathan O; Sessle, Barry J; Coderre, Terence J


    Our electrophysiological studies have shown that both purinergic and glutamatergic receptors are involved in central sensitization of nociceptive neurons in the medullary dorsal horn (MDH). Here we assessed the effects of intrathecal administration of apyrase (a nucleotide degrading enzyme of endogenous adenosine 5-triphosphate [ATP]), a combination of apyrase and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, an adenosine A1 receptor antagonist), or 2,3-O-2,4,6-trinitrophenyl-adenosine triphosphate (TNP-ATP, a P2X1, P2X3, P2X2/3 receptor antagonist) on the release of glutamate in the rat MDH evoked by application of mustard oil (MO) to the molar tooth pulp. In vivo microdialysis was used to dialyse the MDH every 5 min, and included 3 basal samples, 6 samples after drug treatment and 12 samples following application of MO. Tooth pulp application of MO induced a significant increase in glutamate release in the MDH. Superfusion of apyrase or TNP-ATP alone significantly reduced the MO-induced glutamate release in the MDH, as compared to vehicle. Furthermore, the suppressive effects of apyrase on glutamate release were reduced by combining it with DPCPX. This study demonstrates that application of an inflammatory irritant to the tooth pulp induces glutamate release in the rat MDH in vivo that may be reduced by processes involving endogenous ATP and adenosine. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. Medullary Endocannabinoids Contribute to the Differential Resting Baroreflex Sensitivity in Rats with Altered Brain Renin-Angiotensin System Expression.

    Schaich, Chris L; Grabenauer, Megan; Thomas, Brian F; Shaltout, Hossam A; Gallagher, Patricia E; Howlett, Allyn C; Diz, Debra I


    CB1 cannabinoid receptors are expressed on vagal afferent fibers and neurons within the solitary tract nucleus (NTS), providing anatomical evidence for their role in arterial baroreflex modulation. To better understand the relationship between the brain renin-angiotensin system (RAS) and endocannabinoid expression within the NTS, we measured dorsal medullary endocannabinoid tissue content and the effects of CB1 receptor blockade at this brain site on cardiac baroreflex sensitivity (BRS) in ASrAOGEN rats with low glial angiotensinogen, normal Sprague-Dawley rats and (mRen2)27 rats with upregulated brain RAS expression. Mass spectrometry revealed higher levels of the endocannabinoid 2-arachidonoylglycerol in (mRen2)27 compared to ASrAOGEN rats (2.70 ± 0.28 vs. 1.17 ± 0.09 ng/mg tissue; P < 0.01), while Sprague-Dawley rats had intermediate content (1.85 ± 0.27 ng/mg tissue). Microinjection of the CB1receptor antagonist SR141716A (36 pmol) into the NTS did not change cardiac BRS in anesthetized Sprague-Dawley rats (1.04 ± 0.05 ms/mmHg baseline vs. 1.17 ± 0.11 ms/mmHg after 10 min). However, SR141716A in (mRen2)27 rats dose-dependently improved BRS in this strain: 0.36 pmol of SR141716A increased BRS from 0.43 ± 0.03 to 0.71 ± 0.04 ms/mmHg (P < 0.001), and 36 pmol of SR141716A increased BRS from 0.47 ± 0.02 to 0.94 ± 0.10 ms/mmHg (P < 0.01). In contrast, 0.36 pmol (1.50 ± 0.12 vs. 0.86 ± 0.08 ms/mmHg; P < 0.05) and 36 pmol (1.38 ± 0.16 vs. 0.46 ± 0.003 ms/mmHg; P < 0.01) of SR141716A significantly reduced BRS in ASrAOGEN rats. These observations reveal differential dose-related effects of the brain endocannabinoid system that influence cardiovagal BRS in animals with genetic alterations in the brain RAS.

  10. Control of exercise-induced muscular glycogenolysis by adrenal medullary hormones in rats

    Richter, Erik; Galbo, H; Christensen, N J


    or continued swimming to exhaustion. The exercise-induced muscular glycogenolysis was markedly impeded by adrenodemedullation but not by sympathectomy. During the first 75 min of exercise, hepatic glycogenolysis was decreased in adrenodemedullated rats compared with sham-operated rats, and blood glucose only...... increased in the latter. At exhaustion, plasma insulin and glucagon were higher and lower, respectively, in adrenodemedullated rats than in sham-operated rats, whereas blood glucose did not differ significantly between these groups. During prolonged swimming in rats, adrenomedullary hormones enhance...

  11. Medullary schistosomiasis

    Lia Pappamikail


    Full Text Available Background: Schistosomal infestation of the central nervous system is a rare cause of cord compression, although a predominant one in endemic areas. Case Description: A 38-year-old male, native of Ivory Coast, with a history of 1 month of progressive paraparesis, neurogenic bladder, diminished deep tendon reflexes of the lower limbs, and sensory level. The magnetic resonance imaging (MRI showed a medullary lesion at D4-D5 level, suggestive of an intramedullary tumor. Laminotomy of D3 to D5 and excision of a grayish white lesion according to a preliminary histopathologic review suggestive of a high grade glioma. Definitive histopathology review established the diagnosis of medullary schistosomiasis. Conclusion: Schistosomal myeloradiculopathy should be considered in patients presenting with cord compression or features of transverse myelitis, especially in patients from endemic areas or low social economic settlements.

  12. Projection patterns of lateral hypothalamic, cocaine- and amphetamine-regulated transcript (CART) neurons to the dorsal raphe and/or the locus coeruleus in the rat.

    Yoon, Ye S; Lee, Hyun S


    The present study was designed to reveal the projection patterns of lateral hypothalamic (LH), cocaine- and amphetamine-regulated transcript (CART) neurons to the dorsal raphe (DR) and/or the locus coeruleus (LC) in the rat. After the injection of Red or Green Retrobeads into the DR or LC, LH sections were immunostained for CART and/or melanin-concentrating hormone (MCH). First, CART-immunoreactive axon terminals formed close appositions to the DR (or LC) neuronal profiles. Second, a subpopulation of CART neurons containing MCH projected to the monoaminergic nuclei; the majority of labeled neurons were observed in the dorsal hypothalamic area, the dorsal part of the posterior hypothalamic area, and the zona incerta. Cells were also observed in the perifornical part of the LH, the dorsomedial hypothalamic nucleus, the peduncular and the magnocellular parts of the LH. Of the total population of DR (or LC)-projecting cells, CART/MCH co-containing neurons were 9.5% ± 1.6% (or 10.8% ± 1.3% for LC). Finally, a subset of CART (or MCH) neurons provided divergent axon collaterals to the DR and the LC. Of the entire CART (or MCH) cell population, 3.9% ± 0.8% (or 5.6% ± 1.0% for MCH) sent axon collaterals to the DR/LC. CART/MCH co-containing neurons projecting to the DR or LC might be involved in the feeding-related regulation of arousal, stress-related responses, and emotional behaviors. Thus, CART (or MCH) cells that send divergent axon collaterals to the DR/LC might have a simultaneous (and possibly more efficient) way to exert their specific influences on the aminergic nuclei.

  13. Retrograde study of CART- or NPY-neuronal projection from the hypothalamic arcuate nucleus to the dorsal raphe and/or the locus coeruleus in the rat.

    Yoon, Ye S; Lee, Ji S; Lee, Hyun S


    The present study was designed to reveal cocaine- and amphetamine-regulated transcript (CART)- or neuropeptide Y (NPY)-immunoreactive neuronal projections from the hypothalamic arcuate nucleus (Arc) to the dorsal raphe (DR) and/or the locus coeruleus (LC) in the rat. Our results demonstrated that CART or NPY axon terminals formed close appositions to the neuronal profiles in the DR and the LC. Thus, arcuate sections were immunostained for the CART or NPY after the injections of green RetroBeads(™) into the DR and red tracer into the LC (or vice versa). First, retrogradely-labeled CART cells were mainly observed in the lateral Arc without colchicine. Of the total population of arcuate CART neurons, DR- and LC-projecting cells were 5.7% ± 0.9% and 6.6% ± 0.7%, respectively. In addition, a subset (3.3% ± 0.7%) of CART neurons provided divergent axon collaterals to the DR and the LC. Second, retrogradely-labeled NPY cells were observed in lateral or ventral borders of the medial Arc only after colchicine injection. Of the entire NPY cell population, DR- and LC-projecting neurons were 1.5% ± 0.3% and 1.3% ± 0.3%, respectively. Only a scanty proportion (0.1% ± 0.0%) sent axon collaterals to the DR and the LC. These observations suggested that arcuate CART or NPY system might have a potential influence on the brainstem monoaminergic nuclei, modulating their roles in feeding, nociception, emotional behaviors, arousal, and stress responses. Furthermore, a portion of arcuate CART neurons (along with only a few NPY cells) sending divergent axon collaterals to the DR/LC might have a simultaneous (and possibly more efficient) way to exert their specific influences on the monoaminergic nuclei.

  14. Prior cold water swim stress alters immobility in the forced swim test and associated activation of serotonergic neurons in the rat dorsal raphe nucleus.

    Drugan, R C; Hibl, P T; Kelly, K J; Dady, K F; Hale, M W; Lowry, C A


    Prior adverse experience alters behavioral responses to subsequent stressors. For example, exposure to a brief swim increases immobility in a subsequent swim test 24h later. In order to determine if qualitative differences (e.g. 19°C versus 25°C) in an initial stressor (15-min swim) impact behavioral, physiological, and associated neural responses in a 5-min, 25°C swim test 24h later, rats were surgically implanted with biotelemetry devices 1 week prior to experimentation then randomly assigned to one of six conditions (Day 1 (15 min)/Day 2 (5 min)): (1) home cage (HC)/HC, (2) HC/25°C swim, (3) 19°C swim/HC, (4) 19°C swim/25°C swim, (5) 25°C swim/HC, (6) 25°C swim/25°C swim. Core body temperature (Tb) was measured on Days 1 and 2 using biotelemetry; behavior was measured on Day 2. Rats were transcardially perfused with fixative 2h following the onset of the swim on Day 2 for analysis of c-Fos expression in midbrain serotonergic neurons. Cold water (19°C) swim on Day 1 reduced Tb, compared to both 25°C swim and HC groups on Day 1, and, relative to rats exposed to HC conditions on Day 1, reduced the hypothermic response to the 25°C swim on Day 2. The 19°C swim on Day 1, relative to HC exposure on Day 1, increased immobility during the 5-min swim on Day 2. Also, 19°C swim, relative to HC conditions, on Day 1 reduced swim (25°C)-induced increases in c-Fos expression in serotonergic neurons within the dorsal and interfascicular parts of the dorsal raphe nucleus. These results suggest that exposure to a 5-min 19°C cold water swim, but not exposure to a 5-min 25°C swim alters physiological, behavioral and serotonergic responses to a subsequent stressor.

  15. Stimulation of rat cranial dura mater with potassium chloride causes CGRP release into the cerebrospinal fluid and increases medullary blood flow.

    Dux, Mária; Will, Christine; Eberhardt, Mirjam; Fischer, Michael J M; Messlinger, Karl


    Primary headaches may be accompanied by increased intracranial blood flow induced by the release of the potent vasodilator calcitonin gene-related peptide (CGRP) from activated meningeal afferents. We aimed to record meningeal and medullary blood flow simultaneously and to localize the sites of CGRP release in rodent preparations in vivo and ex vivo. Blood flow in the exposed rat parietal dura mater and the medulla oblongata was recorded by laser Doppler flowmetry, while the dura was stimulated by topical application of 60mM potassium chloride (KCl). Samples of jugular venous plasma and cerebrospinal fluid (CSF) collected from the cisterna magna were analysed for CGRP concentrations using an enzyme immunoassay. In a hemisected rat skull preparation lined with dura mater the CGRP releasing effect of KCl superfusion was examined. Superfusion of the dura mater with KCl decreased meningeal blood flow unless alpha-adrenoceptors were blocked by phentolamine, whereas the medullary blood flow was increased. The same treatment caused increased CGRP concentrations in jugular plasma and CSF and induced significant CGRP release in the hemisected rat skull preparation. Anaesthesia of the trigeminal ganglion by injection of lidocaine reduced increases in medullary blood flow and CGRP concentration in the CSF upon meningeal KCl application. CGRP release evoked by depolarisation of meningeal afferents is accompanied by increased blood flow in the medulla oblongata but not the dura mater. This discrepancy can be explained by the smooth muscle depolarising effect of KCl and the activation of sympathetic vasoconstrictor mechanisms. The medullary blood flow response is most likely mediated by CGRP released from activated central terminals of trigeminal afferents. Increased blood supply of the medulla oblongata and CGRP release into the CSF may also occur in headaches accompanying vigorous activation of meningeal afferents.

  16. Thyroid cancer - medullary carcinoma

    Thyroid - medullary carcinoma; Cancer - thyroid (medullary carcinoma); MTC; Thyroid nodule - medullary ... in children and adults. Unlike other types of thyroid cancer, MTC is less likely to be caused by ...

  17. Human medullary responses to cooling and rewarming the skin: a functional MRI study.

    McAllen, Robin M; Farrell, Michael; Johnson, John M; Trevaks, David; Cole, Leonie; McKinley, Michael J; Jackson, Graeme; Denton, Derek A; Egan, Gary F


    A fall in skin temperature precipitates a repertoire of thermoregulatory responses that reduce the likelihood of a decrease in core temperature. Studies in animals suggest that medullary raphé neurons are essential for cold-defense, mediating both the cutaneous vasoconstrictor and thermogenic responses to ambient cooling; however, the involvement of raphé neurons in human thermoregulation has not been investigated. This study used functional MRI with an anatomically guided region of interest (ROI) approach to characterize changes in the blood oxygen level-dependent (BOLD) signal within the human medulla of nine normal subjects during non-noxious cooling and rewarming of the skin by a water-perfused body suit. An ROI covering 4.9 +/- 0.3 mm(2) in the ventral midline of the medulla immediately caudal to the pons (the rostral medullary raphé) showed an increase in BOLD signal of 3.9% (P medullary cross section at the same level (area, 126 +/- 15 mm(2)) showed no significant change in mean BOLD signal with cooling (+0.2%, P > 0.05). These findings demonstrate that human rostral medullary raphé neurons are selectively activated in response to a thermoregulatory challenge and point to the location of thermoregulatory neurons homologous to those of the raphé pallidus nucleus in rodents.

  18. Cellular localization of adenine receptors in the rat kidney and their functional significance in the inner medullary collecting duct.

    Kishore, Bellamkonda K; Zhang, Yue; Gevorgyan, Haykanush; Kohan, Donald E; Schiedel, Anke C; Müller, Christa E; Peti-Peterdi, János


    The Gi-coupled adenine receptor (AdeR) binds adenine with high affinity and potentially reduces cellular cAMP levels. Since cAMP is an important second messenger in the renal transport of water and solutes, we localized AdeR in the rat kidney. Real-time RT-PCR showed higher relative expression of AdeR mRNA in the cortex and outer medulla compared with the inner medulla. Immunoblots using a peptide-derived and affinity-purified rabbit polyclonal antibody specific for an 18-amino acid COOH-terminal sequence of rat AdeR, which we generated, detected two bands between ∼30 and 40 kDa (molecular mass of native protein: 37 kDa) in the cortex, outer medulla, and inner medulla. These bands were ablated by preadsorption of the antibody with the immunizing peptide. Immunofluorescence labeling showed expression of AdeR protein in all regions of the kidney. Immunoperoxidase revealed strong labeling of AdeR protein in the cortical vasculature, including the glomerular arterioles, and less intense labeling in the cells of the collecting duct system. Confocal immunofluorescence imaging colocalized AdeR with aquaporin-2 protein to the apical plasma membrane in the collecting duct. Functionally, adenine (10 μM) significantly decreased (P < 0.01) 1-deamino-8-d-arginine vasopressin (10 nM)-induced cAMP production in ex vivo preparations of inner medullary collecting ducts, which was reversed by PSB-08162 (20 μM, P < 0.01), a selective antagonist of AdeR. Thus, we demonstrated the expression of AdeR in the renal vasculature and collecting ducts and its functional relevance. This study may open a new avenue for the exploration of autocrine/paracrine regulation of renal vascular and tubular functions by the nucleobase adenine in health and disease.

  19. Transepithelial water and urea permeabilities of isolated perfused Munich-Wistar rat inner medullary thin limbs of Henle's loop.

    Nawata, C Michele; Evans, Kristen K; Dantzler, William H; Pannabecker, Thomas L


    To better understand the role that water and urea fluxes play in the urine concentrating mechanism, we determined transepithelial osmotic water permeability (Pf) and urea permeability (Purea) in isolated perfused Munich-Wistar rat long-loop descending thin limbs (DTLs) and ascending thin limbs (ATLs). Thin limbs were isolated either from 0.5 to 2.5 mm below the outer medulla (upper inner medulla) or from the terminal 2.5 mm of the inner medulla. Segment types were characterized on the basis of structural features and gene expression levels of the water channel aquaporin 1, which was high in the upper DTL (DTLupper), absent in the lower DTL (DTLlower), and absent in ATLs, and the Cl-(1) channel ClCK1, which was absent in DTLs and high in ATLs. DTLupper Pf was high (3,204.5 ± 450.3 μm/s), whereas DTLlower showed very little or no osmotic Pf (207.8 ± 241.3 μm/s). Munich-Wistar rat ATLs have previously been shown to exhibit no Pf. DTLupper Purea was 40.0 ± 7.3 × 10(-5) cm/s and much higher in DTLlower (203.8 ± 30.3 × 10(-5) cm/s), upper ATL (203.8 ± 35.7 × 10(-5) cm/s), and lower ATL (265.1 ± 49.8 × 10(-5) cm/s). Phloretin (0.25 mM) did not reduce DTLupper Purea, suggesting that Purea is not due to urea transporter UT-A2, which is expressed in short-loop DTLs and short portions of some inner medullary DTLs close to the outer medulla. In summary, Purea is similar in all segments having no osmotic Pf but is significantly lower in DTLupper, a segment having high osmotic Pf. These data are inconsistent with the passive mechanism as originally proposed.

  20. Axon-glial relationships in the anterior medullary velum of the adult rat.

    Berry, M; Ibrahim, M; Carlile, J; Ruge, F; Duncan, A; Butt, A M


    The anterior medullary velum is a thin sheet of CNS tissue which roofs the rostral part of the IVth ventricle and contains fascicles of myelinated fibres which, in part, arise from the nucleus of the IVth cranial nerve. This study used histochemical, immunohistochemical, and intracellular dye-injection techniques to describe cellular interrelationships in the velum in whole-mounts and in sections. Rip antibody-stained whole mounts provided a unique description of both oligodendrocyte units (defined as an oligodendrocyte and the complement of myelinated internodal segments it forms), and consecutive myelin sheaths along the same axon. A broad range of unit morphologies was categorised into four arbitrary groups, according to classical criteria, which comprised small cells supporting the short, thin myelin sheaths of 15-30 small diameter axons (Type I), through intermediate types (II & III), to the largest cells forming the long, thick myelin sheaths of 1-3 large diameter axons. Rip antibody and ferric ion-ferrocyanide staining, together with intracellular dye injection, revealed oligodendrocyte process branching patterns and their mode of engagement of myelin sheaths, nodes of Ranvier, and the spatial disposition of the outer cytoplasmic rims of myelin sheaths. The latter formed a conspicuous spiral ridge on the exterior surface of myelin sheaths which connected with the paranodal loops at each heminode. Large bundles of axons decussated through the velum, the bulk of which were IVth nerve fibres which constituted the IVth nerve rootlet. The PNS/CNS transitional zone of the IVth nerve was located 0.25-0.50 mm along the root, where astrocytic end-feet defined an abrupt margin, convex towards the periphery, where the heminodes of central and peripheral myelin were apposed, and where the basal lamina tubes of the Schwann cell units were discontinued. The basal processes of ependymal cells lining the ventricular wall of the velum, passed between axon bundles before

  1. Antinociception induced by intravenous dipyrone (metamizol) upon dorsal horn neurons: involvement of endogenous opioids at the periaqueductal gray matter, the nucleus raphe magnus, and the spinal cord in rats.

    Vazquez, Enrique; Hernandez, Norma; Escobar, William; Vanegas, Horacio


    Microinjection of dipyrone (metamizol) into the periaqueductal gray matter (PAG) in rats causes antinociception. This is mediated by endogenous opioidergic circuits located in the PAG itself, in the nucleus raphe magnus and adjacent structures, and in the spinal cord. The clinical relevance of these findings, however, is unclear. Therefore, in the present study, dipyrone was administered intravenously, and the involvement of endogenous opioidergic circuits in the so-induced antinociception was investigated. In rats, responses of dorsal spinal wide-dynamic range neurons to mechanical noxious stimulation of a hindpaw were strongly inhibited by intravenous dipyrone (200 mg/kg). This effect was abolished by microinjection of naloxone (0.5 microg/0.5 microl) into the ventrolateral and lateral PAG or into the nucleus raphe magnus or by direct application of naloxone (50 microg/50 microl) onto the spinal cord surface above the recorded neuron. These results show that dipyrone, a non-opioid analgesic with widespread use in Europe and Latin America, when administered in a clinically relevant fashion causes antinociception by activating endogenous opioidergic circuits along the descending pain control system.

  2. Corticotropin-releasing factor enhances locomotion and medullary neuronal firing in an amphibian.

    Lowry, C A; Rose, J D; Moore, F L


    Corticotropin-releasing factor (CRF) administration has been shown to act centrally to enhance locomotion in rats and amphibians. In the present study we used an amphibian, the roughskin newt (Taricha granulosa), to characterize changes in medullary neuronal activity associated with CRF-induced walking and swimming in animals chronically implanted with fine-wire microelectrodes. Neuronal activity was recorded from the raphe and adjacent reticular region of the rostral medulla. Under baseline conditions most of the recorded neurons showed low to moderate amounts of neuronal activity during periods of immobility and pronounced increases in firing that were time-locked with episodes of walking. These neurons sometimes showed further increases in discharge during swimming. Injections of CRF but not saline into the lateral ventricle produced a rapidly appearing increase in walking and pronounced changes (mostly increases) in firing rates of the medullary neurons. CRF produced diverse changes in patterns of firing in different neurons, but for these neurons as a group, the effects of CRF showed a close temporal association with the onset and expression of the peptide's effect on locomotion. In neurons that were active exclusively during movement prior to CRF treatment, the post-CRF increase in firing was evident during episodes of walking; in other neurons that also were spontaneously active during immobility prior to CRF infusion, post-CRF activity changes were evident during immobility as well as during episodes of locomotion. Thus, a principal effect of CRF was to potentiate the level of neuronal firing in a population of medullary neurons with locomotor-related properties. Due to the route of administration CRF may have acted on multiple central nervous system sites to enhance locomotion, but the results are consistent with neurophysiological effects involving medullary locomotion-regulating neurons.

  3. Transformation of adrenal medullary chromaffin cells increases asthmatic susceptibility in pups from allergen-sensitized rats

    Feng Jun-Tao


    Full Text Available Abstract Background Studies have shown that epinephrine release is impaired in patients with asthma. The pregnancy of female rats (dams with asthma promotes in their pups the differentiation of adrenal medulla chromaffin cells (AMCCs into sympathetic neurons, mediated by nerve growth factor, which leads to a reduction in epinephrine secretion. However, the relatedness between the alteration of AMCCs and increased asthma susceptibility in such offspring has not been established. Methods In this study, we observed the effects of allergization via ovalbumin on rat pups born of asthmatic dams. Results Compared to the offspring of untreated controls, bronchial hyperreactivity and airway inflammation were more severe in the pups from sensitized (asthmatic dams. In pups exposed to nerve growth factor (NGF in utero these effects were aggravated further, but the effects were blocked in pups whose dams had been treated with anti-NGF. Furthermore, alterations in AMCC phenotype corresponded to the degree of bronchial hyperreactivity and lung lesions of the different treatment groups. Such AMCC alterations included degranulation of chromaffin granules, reduction of epinephrine and phenylethanolamine-n-methyl transferase, and elevation of NGF and peripherin levels. Conclusions Our results present evidence that asthma during the pregnancy of rat dams promotes asthma susceptibility in their offspring, and that the transformation of AMCCs to neurons induced by NGF plays an important role in this process.

  4. The relationship between developing oligodendrocyte units and maturing axons during myelinogenesis in the anterior medullary velum of neonatal rats.

    Butt, A M; Ibrahim, M; Berry, M


    Myelinogenesis was investigated in whole-mounted anterior medullary vela from rats aged postnatal day (P) 10-12, using double immunofluorescence labelling with Rip and anti-neurofilament 200 (NF200) antibodies, to identify oligodendrocytes and axons, respectively. A number of discrete phases of maturation of oligodendrocyte units were recognised. (1) Promyelinating oligodendrocytes co-expressed Rip and Myelin basic Protein and formed axonal associations, prior to ensheathment. (2) Transitional oligodendrocytes contained both ensheathing and non-ensheating processes. (3) Myelinating oligodendrocytes were established after a period of remodelling (in which non-ensheathing processes were lost), appearing as oligodendrocyte unit morphological phenotypes with a definitive number of incipient myelin sheaths. (4) Maturation of myelinating oligodendrocytes was defined as the establishment of internodal sheath lengths and the redistrubution of myelin basic protein from the cell somata and radial processes into the myelin sheaths only. Myelination was probably related to the maturational state of the axons, since it was initiated when the latter had attained a critical diameter of between approximately 0.2 and 0.4 micron, coincident with the expression of NF200. Oligodendrocyte differentiation and myelination of the AMV were asynchronous and multifocal, and at P10: (1) axons which were destined to be of the largest calibre in the adult AMV were already myelinated by early developing oligodendrocytes, whilst those which were destined to be the smallest calibre in the adult were unmyelinated, but ultimately became ensheathed by late developing oligoendrocytes; (2) axons were sequentially ensheathed by early developing myelinating oligodendrocytes and late developing promyelinating oligodendrocytes; (3) all axons were small calibre; (4) oligodendrocyte units exhibited polymorphism. Thus, the development of oligodendrocyte morphological phenotypes was not related solely to

  5. Central sensitization of nociceptive neurons in rat medullary dorsal horn involves purinergic P2X7 receptors.

    Itoh, K; Chiang, C-Y; Li, Z; Lee, J-C; Dostrovsky, J O; Sessle, B J


    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.

  6. Electro-acupuncture stimulation to a hindpaw and a hind leg produces different reflex responses in sympathoadrenal medullary function in anesthetized rats.

    Mori, H; Uchida, S; Ohsawa, H; Noguchi, E; Kimura, T; Nishijo, K


    The effects of electro-acupuncture stimulation (EAS) of two different areas of a hindlimb with different stimulus intensities on sympathoadrenal medullary functions were examined in anesthetized artificially ventilated rats. Two needles of 160 microm diameter and about 5 mm apart were inserted about 5 mm deep into a hindpaw (Chungyang, S42) or a hind leg (Tsusanli, S36) and current of various intensities passed to excite various afferent nerve fiber groups at a repetition rate of 20 Hz and pulse duration of 0.5 ms for 30-60 s. Fiber groups of afferent nerves stimulated in a hindlimb were monitored by recording evoked action potentials from the afferents innervating the areas stimulated. The sympathoadrenal medullary functions were monitored by recording adrenal sympathetic efferent nerve activity and secretion rates of catecholamines from the adrenal medulla. EAS of a hindpaw at a stimulus strength sufficient to excite the group III and IV somatic afferent fibers produced reflex increases in both adrenal sympathetic efferent nerve activity and the secretion rate of catecholamines. EAS of a hind leg at a stimulus strength sufficient to excite the group III and IV afferent fibers produced reflex responses of either increases or decreases in sympathoadrenal medullary functions. All responses of adrenal sympathetic efferent nerve activity were lost after cutting the afferent nerves ipsilateral to the stimulated areas, indicating that the responses are the reflexes whose afferents nerve pathway is composed of hindlimb somatic nerves. It is concluded that electro-acupuncture stimulation of a hindpaw causes an excitatory reflex, while that of a hind leg causes either excitatory or inhibitory reflex of sympathoadrenal medullary functions, even if both group III and IV somatic afferent fibers are stimulated.

  7. Renal tubular and adrenal medullary tumors in the 2-year rat study with canagliflozin confirmed to be secondary to carbohydrate (glucose) malabsorption in the 15-month mechanistic rat study.

    De Jonghe, Sandra; Johnson, Mark D; Mamidi, Rao N V S; Vinken, Petra; Feyen, Bianca; Lammens, Godelieve; Proctor, Jim


    During preclinical development of canagliflozin, an SGLT2 inhibitor, treatment-related pheochromocytomas, renal tubular tumors (RTT), and testicular Leydig cell tumors were reported in the 2-year rat toxicology study. In a previous 6-month rat mechanistic study, feeding a glucose free diet prevented canagliflozin effects on carbohydrate malabsorption as well as the increase in cell proliferation in adrenal medulla and kidneys, implicating carbohydrate malabsorption as the mechanism for tumor formation. In this chronic study male Sprague-Dawley rats were dosed orally with canagliflozin at high dose-levels (65 or 100 mg/kg/day) for 15 months and received either a standard diet or a glucose-free diet. Canagliflozin-dosed rats on standard diet showed presence of basophilic renal tubular tumors (6/90) and an increased incidence of adrenal medullary hyperplasia (35/90), which was fully prevented by feeding a glucose-free diet (no RTT's; adrenal medullary hyperplasia in ≤5/90). These data further confirm that kidney and adrenal medullary tumors in the 2-year rat study were secondary to carbohydrate (glucose) malabsorption and were not due to a direct effect of canagliflozin on these target tissues. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Interaction of medullary P2 and glutamate receptors mediates the vasodilation in the hindlimb of rat.

    Korim, Willian Seiji; Ferreira-Neto, Marcos L; Pedrino, Gustavo R; Pilowsky, Paul M; Cravo, Sergio L


    In the nucleus tractus solitarii (NTS) of rats, blockade of extracellular ATP breakdown to adenosine reduces arterial blood pressure (AP) increases that follow stimulation of the hypothalamic defense area (HDA). The effects of ATP on NTS P2 receptors, during stimulation of the HDA, are still unclear. The aim of this study was to determine whether activation of P2 receptors in the NTS mediates cardiovascular responses to HDA stimulation. Further investigation was taken to establish if changes in hindlimb vascular conductance (HVC) elicited by electrical stimulation of the HDA, or activation of P2 receptors in the NTS, are relayed in the rostral ventrolateral medulla (RVLM); and if those responses depend on glutamate release by ATP acting on presynaptic terminals. In anesthetized and paralyzed rats, electrical stimulation of the HDA increased AP and HVC. Blockade of P2 or glutamate receptors in the NTS, with bilateral microinjections of suramin (10 mM) or kynurenate (50 mM) reduced only the evoked increase in HVC by 75 % or more. Similar results were obtained with the blockade combining both antagonists. Blockade of P2 and glutamate receptors in the RVLM also reduced the increases in HVC to stimulation of the HDA by up to 75 %. Bilateral microinjections of kynurenate in the RVLM abolished changes in AP and HVC to injections of the P2 receptor agonist α,β-methylene ATP (20 mM) into the NTS. The findings suggest that HDA-NTS-RVLM pathways in control of HVC are mediated by activation of P2 and glutamate receptors in the brainstem in alerting-defense reactions.

  9. Medullary Sponge Kidney

    ... Sponge Kidney? Complications of medullary sponge kidney include hematuria, or blood in the urine kidney stones urinary ... both kidneys. Complications of medullary sponge kidney include hematuria, or blood in the urine kidney stones urinary ...

  10. 5,7-dihydroxytryptamine lesions of dorsal and median raphé nuclei and performance in the social interaction test of anxiety and in a home-cage aggression test.

    File, S E; Hyde, J R; MacLeod, N K


    Micro-injections of the neurotoxin 5,7-dihydroxytryptamine into the dorsal raphe nucleus produced a behavioural profile in the social interaction test of anxiety similar to that seen in rats treated chronically with benzodiazepines. Neurotoxin injections into the median raphé nucleus did not produce a profile significantly different from that of the controls. In the control rats and in the rats with lesions of the median raphé nucleus, ACTH1-24 (corticotrophin) significantly reduced active social interactions, whereas it was without effect on the rats with lesions of the dorsal raphé nucleus. In the home-cage intruder test, the median raphé-lesioned rats submitted less to the intruder and stood and jumped on him more often than did the controls. The dorsal raphé-lesioned rats showed significantly fewer interactions of all kinds, compared with control rats when an intruder was placed in their home cages.

  11. Age-related hypertension and salt sensitivity are associated with unique cortico-medullary distribution of D1R, AT1R, and NADPH-oxidase in FBN rats

    Pokkunuri, Indira; Chugh, Gaurav; Rizvi, Imran; Asghar, Mohammad


    We examined effects of normal (NS) and high salt (HS) on blood pressure (BP) and cortico-medullary distribution of dopamine D1 receptor (D1R), angiotensin AT1 receptor (AT1R), NADPH oxidase-gp91phox, and sodium transporters (NHE-3, Na, K ATPase) in adult and aged rats. Aged rats fed with NS diet had higher BP, which further increased with HS. HS increased D1R mRNA and protein levels in cortex and medulla of adult rats. NS or HS fed-aged rats had higher AT1R and gp91phox mRNA levels in cortex ...


    G. R. Hassanzadeh G. Behzadi


    Full Text Available The ascending serotonergic projections are derived mainly from mesencephalic raphe nuclei. Topographical projections from mesencephalic raphe nuclei to the striatum were examined in the rat by the retrograde transport technique of HRP (horseradish peroxidase. In 29 rats stereotaxically injection of HRP enzyme were performed in dorsal and ventral parts of striatum separately. The extent of the injection sites and distribution of retrogradely labeled neuronal cell bodies were drawed on representative sections using a projection microscope. Following ipsilateral injection of HRP into the dorsal striatum, numerous labeled neurons were seen in rostral portion of dorsal raphe (DR nucleus. In the same level the cluster of labeled neurons were hevier through caudal parts of DR. A few neurons were also located in lateral wing of DR. More caudally some labeled neurons were found in lateral, medial line of DR. In median raphe nucleus (MnR the labeled neurons were scattered only in median portion of this nucleus. The ipsilateral injection of HRP into the ventral region of striatum resulted on labeling of numerous neurons in rostral, caudal and lateral portions of DR. Through the caudal extension of DR on 4th ventricle level, a large number of labeled neurons were distributed along the ventrocaudal parts of DR. In MnR, labeled neurons were observed only in median part of this nucleus. These findings suggest the mesencephalic raphe nuclei projections to caudo-putamen are topographically organized. In addition dorsal and median raphe nuclei have a stronger projection to the ventral striatum.

  13. Gene expression changes in serotonin, GABA-A receptors, neuropeptides and ion channels in the dorsal raphe nucleus of adolescent alcohol-preferring (P) rats following binge-like alcohol drinking.

    McClintick, Jeanette N; McBride, William J; Bell, Richard L; Ding, Zheng-Ming; Liu, Yunlong; Xuei, Xiaoling; Edenberg, Howard J


    Alcohol binge-drinking during adolescence is a serious public health concern with long-term consequences. We used RNA sequencing to assess the effects of excessive adolescent ethanol binge-drinking on gene expression in the dorsal raphe nucleus (DRN) of alcohol preferring (P) rats. Repeated binges across adolescence (three 1h sessions across the dark-cycle per day, 5 days per week for 3 weeks starting at 28 days of age; ethanol intakes of 2.5-3 g/kg/session) significantly altered the expression of approximately one-third of the detected genes. Multiple neurotransmitter systems were altered, with the largest changes in the serotonin system (21 of 23 serotonin-related genes showed decreased expression) and GABA-A receptors (8 decreased and 2 increased). Multiple neuropeptide systems were also altered, with changes in the neuropeptide Y and corticotropin-releasing hormone systems similar to those associated with increased drinking and decreased resistance to stress. There was increased expression of 21 of 32 genes for potassium channels. Expression of downstream targets of CREB signaling was increased. There were also changes in expression of genes involved in inflammatory processes, axonal guidance, growth factors, transcription factors, and several intracellular signaling pathways. These widespread changes indicate that excessive binge drinking during adolescence alters the functioning of the DRN and likely its modulation of many regions of the central nervous system, including the mesocorticolimbic system.

  14. Platelet-derived growth factor delays oligodendrocyte differentiation and axonal myelination in vivo in the anterior medullary velum of the developing rat.

    Butt, A M; Hornby, M F; Kirvell, S; Berry, M


    The AA dimeric form of platelet-derived growth factor (PDGF-AA) is implicated in the differentiation of cells of the oligodendrocyte lineage, which express PDGF receptors of the alpha subunit type (PDGF-alphaR). In the present study, we show that a single injection of PDGF-AA into the cerebrospinal fluid of neonatal rats delays oligodendrocyte differentiation and interrupts the progress of myelination in the anterior medullary velum (AMV), a white matter tract roofing the IVth ventricle of the brain. PDGF-AA or saline was injected intrathecally in postnatal day (P) 7 rats, and the AMV was subsequently removed and immunolabelled with the oligodendrocyte-specific antibody Rip, at P9, P12, and P21, corresponding to postinjection days (PID) 2, 5, and 14. At P9 (PID2), myelination was retarded in PDGF-AA-treated rats as opposed to saline-treated controls but progressed rapidly after P12 (PID5). Quantification supported the qualitative observations that PDGF-AA mediated an acute decrease in the number of Rip+ oligodendrocytes at P9-12, which largely recovered by P21, suggesting that PDGF-AA may have delayed recruitment of myelinating oligodendrocytes. However, the definitive number of Rip+ oligodendrocytes in the AMV was not increased, suggesting that its action as a promoter of early oligodendrocyte survival may not ultimately affect the definitive number of myelinating oliogdendrocytes in vivo. We discuss the possibilities that excess PDGF-AA may have acted on early oligodendrocytes (precursors or preoligodendrocytes) to either (1) delay their differentiation by maintaining them in the cell cycle or (2) accelerate their differentiation, which may result in premature cell death in the absence of synchronised survival signals. This study supports a role for PDGF-AA in the timing of oligodendrocyte differentiation in vivo, as has been shown in vitro.

  15. High potassium promotes mutual interaction between (pro)renin receptor and the local renin-angiotensin-aldosterone system in rat inner medullary collecting duct cells.

    Xu, Chuanming; Fang, Hui; Zhou, Li; Lu, Aihua; Yang, Tianxin


    (Pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD) with unclear functional implication. It is not known whether CD PRR is regulated by high potassium (HK). Here, we aimed to investigate the effect of HK on PRR expression and its role in regulation of aldosterone synthesis and release in the CD. In primary rat inner medullary CD cells, HK augmented PRR expression and soluble PPR (sPRR) release in a time- and dose-dependent manner, which was attenuated by PRR small interfering RNA (siRNA), eplerenone, and losartan. HK upregulated aldosterone release in parallel with an increase of CYP11B2 (cytochrome P-450, family 11, subfamily B, polypeptide 2) protein expression and upregulation of medium renin activity, both of which were attenuated by a PRR antagonist PRO20, PRR siRNA, eplerenone, and losartan. Similarly, prorenin upregulated aldosterone release and CYP11B2 expression, both of which were attenuated by PRR siRNA. Interestingly, a recombinant sPRR (sPRR-His) also stimulated aldosterone release and CYP11B2 expression. Taken together, we conclude that HK enhances a local renin-angiotensin-aldosterone system (RAAS), leading to increased PRR expression, which in turn amplifies the response of the RAAS, ultimately contributing to heightened aldosterone release.


    V. S. Medvedev


    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.

  17. Chronic Inhibition of Renal Outer Medullary Potassium Channel Not Only Prevented but Also Reversed Development of Hypertension and End-Organ Damage in Dahl Salt-Sensitive Rats.

    Zhou, Xiaoyan; Forrest, Michael J; Sharif-Rodriguez, Wanda; Forrest, Gail; Szeto, Daphne; Urosevic-Price, Olga; Zhu, Yonghua; Stevenson, Andra S; Zhou, Yuchen; Stribling, Sloan; Dajee, Maya; Walsh, Shawn P; Pasternak, Alexander; Sullivan, Kathleen A


    The renal outer medullary potassium (ROMK) channel mediates potassium recycling and facilitates sodium reabsorption through the Na(+)/K(+)/2Cl(-) cotransporter in the loop of Henle and potassium secretion at the cortical collecting duct. Evidence from the phenotype of humans and rodents with functional ROMK deficiency supports the contention that selective ROMK inhibitors (ROMKi) will represent a novel diuretic with potential of therapeutic benefit for hypertension. ROMKi have recently been synthesized by Merck & Co, Inc. The present studies were designed to examine the effects of ROMKi B on systemic hemodynamics, renal function and structure, and vascular function in Dahl salt-sensitive rats. Four experimental groups-control, high-salt diet alone; ROMKi B 3 mg·kg(-)(1)·d(-)(1); ROMKi B 10 mg·kg(-)(1)·d(-)(1); and hydrochlorothiazide 25 mg·kg(-)(1)·d(-)(1)-were included in prophylactic (from week 1 to week 9 on high-salt diet) and therapeutic studies (from week 5 to week 9 on high-salt diet), respectively. ROMKi B produced sustained blood pressure reduction and improved renal and vascular function and histological alterations induced by a high-salt diet. ROMKi B was superior to hydrochlorothiazide at reducing blood pressure. Furthermore, ROMKi B provided beneficial effects on both the plasma lipid profile and bone mineral density. Chronic ROMK inhibition not only prevented but also reversed the development of hypertension and end-organ damage in Dahl salt-sensitive rats. Our findings suggest a potential utility of ROMKi B as a novel antihypertensive agent, particularly for the treatment of the salt-sensitive hypertension patient population. © 2016 American Heart Association, Inc.

  18. Co-existence of calcium-binding proteins and γ-aminobutyric acid or glycine in neurons of the rat medullary dorsal horn

    王文; 武胜昔; 李云庆


    Background We investigated the co-expression of calbindin-D28k (CB), calretinin (CR) and parvalbumin (PV, a combination of the three is referred to as CaBPs) with γ-aminobutyric acid (GABA) or glycine in neurons of the rat medullary dorsal horn (MDH).Methods Immunofluorescence histochemical double-staining for CaBPs and GABA or glycine was performed on the sections from rat MDH.Results CB-, CR-, PV-, GABA- and glycine-like immunoreactive (LI) neurons were differentially observed in all layers of the MDH, but particularly in lamina Ⅱ. Neurons that exhibited immunoreactivity for both CaBPs and GABA or glycine were also observed mainly in lamina Ⅱ. A few of them were found in laminae I and III. The percentages of neurons which co-expressed CB/GABA or CB/glycine out of the total numbers of CB- and GABA-LI neurons or CB- and glycine-LI neurons were 5.3% and 12.1% or 4.1% and 10.0%, respectively. The ratios of CR/GABA or CR/glycine co-existing neurons out of the total numbers of CR- and GABA-LI neurons or CR- and glycine-LI neurons were 5.8% and 7.6% or 4.4% and 7.1%, respectively. The rates of PV/GABA or PV/glycine co-localized neurons out of the total numbers of PV- and GABA-LI neurons or PV- and glycine-LI neurons were 11.1% and 5.1% or 9.9% and 5.1%, respectively. Conclusion The results indicate that some neurons in the MDH contain both CaBPs and GABA or glycine.

  19. Catecholamine secretion by chemical hypoxia in guinea-pig, but not rat, adrenal medullary cells: differences in mitochondria.

    Harada, K; Endo, Y; Warashina, A; Inoue, M


    The effects of mitochondrial inhibitors (CN(-), a complex IV inhibitor and CCCP, protonophore) on catecholamine (CA) secretion and mitochondrial function were explored functionally and biochemically in rat and guinea-pig adrenal chromaffin cells. Guinea-pig chromaffin cells conspicuously secreted CA in response to CN(-) or CCCP, but rat cells showed a little, if any, secretory response to either of them. The resting metabolic rates in rat adrenal medullae did not differ from those in guinea-pig adrenal medullae. On the other hand, the time course of depolarization of the mitochondrial membrane potential (ΔΨm) in guinea-pig chromaffin cells in response to CN(-) was slower than that in rat chromaffin cells, and this difference was abolished by oligomycin, an F1F0-ATPase inhibitor. The extent of CCCP-induced decrease in cellular ATP in guinea-pig chromaffin cells, which was indirectly measured using a Mg(2+) indicator, was smaller than that in rat chromaffin cells. Relative expression levels of F1F0-ATPase inhibitor factor in guinea-pig adrenal medullae were smaller than in rat adrenal medullae, and the opposite was true for F1F0-ATPase α subunit. The present results indicate that guinea-pig chromaffin cells secrete more CA in response to a mitochondrial inhibitor than rat chromaffin cells and this higher susceptibility in the former is accounted for by a larger extent of reversed operation of F1F0-ATPase with the consequent decrease in ATP under conditions where ΔΨm is depolarized.

  20. Protein kinase C gamma interneurons in the rat medullary dorsal horn: distribution and synaptic inputs to these neurons, and subcellular localization of the enzyme.

    Peirs, Cédric; Patil, Sudarshan; Bouali-Benazzouz, Rabia; Artola, Alain; Landry, Marc; Dallel, Radhouane


    The γ isoform of protein kinase C (PKCγ), which is concentrated in interneurons in the inner part of lamina II (IIi ) of the dorsal horn, has been implicated in the expression of tactile allodynia. Lamina IIi PKCγ interneurons were shown to be activated by tactile inputs and to participate in local circuits through which these inputs can reach lamina I, nociceptive output neurons. That such local circuits are gated by glycinergic inhibition and that A- and C-fibers low threshold mechanoreceptors (LTMRs) terminate in lamina IIi raise the general issue of synaptic inputs to lamina IIi PKCγ interneurons. Combining light and electron microscopic immunochemistry in the rat spinal trigeminal nucleus, we show that PKCγ-immunoreactivity is mostly restricted to interneurons in lamina IIi of the medullary dorsal horn, where they constitute 1/3 of total neurons. The majority of synapses on PKCγ-immunoreactive interneurons are asymmetric (likely excitatory). PKCγ-immunoreactive interneurons appear to receive exclusively myelinated primary afferents in type II synaptic glomeruli. Neither large dense core vesicle terminals nor type I synaptic glomeruli, assumed to be the endings of unmyelinated nociceptive terminals, were found on these interneurons. Moreover, there is no vesicular glutamate transporter 3-immunoreactive bouton, specific to C-LTMRs, on PKCγ-immunoreactive interneurons. PKCγ-immunoreactive interneurons contain GABAA ergic and glycinergic receptors. At the subcellular level, PKCγ-immunoreactivity is mostly concentrated on plasma membranes, close to, but not within, postsynaptic densities. That only myelinated primary afferents were found to contact PKCγ-immunoreactive interneurons suggests that myelinated, but not unmyelinated, LTMRs play a critical role in the expression of mechanical allodynia.

  1. Differential expression of the L- and S-isoforms of myelin associated glycoprotein (MAG) in oligodendrocyte unit phenotypes in the adult rat anterior medullary velum.

    Butt, A M; Ibrahim, M; Gregson, N; Berry, M


    We have previously demonstrated differences in the expression of carbonic anhydrase II (CAII) in oligodendrocyte units myelinating small and large diameter fibres in the anterior medullary velum (AMV) of the adult rat (each unit comprises the cell body, processes and myelin sheaths). Others have indicated that myelin composition may also vary with respect to myelin basic protein (MBP) and proteolipid protein (PLP), and the small (S)- and large (L)-isoforms of myelin associated glycoprotein (MAG). In this study, we have determined the expression of myelin proteins in oligodendrocyte unit phenotypes I-IV, which myelinate fibres ranging in diameter from 0.3-12 microns diameter in the AMV, by using double immunolabelling for Rip, which labels entire units, and MBP, PLP, myelin oligodendrocyte glycoprotein (MOG), L-MAG and S-MAG. We show differences in the expression of L- and S-MAG in units which myelinate different diameter fibres: (1) type I/II units myelinating small diameter fibres had a L-MAG+/S-MAG-/CAII+ phenotype; (2) type II/III units myelinating different diameter fibres had a L-MAG+/S-MAG+/CAII+ phenotype; (3) type III/IV units myelinated large diameter fibres had a L-MAG+/S-MAG+/CAII- phenotype. All units, irrespective of fibre diameter, expressed Rip, MBP, PLP and MOG. The results indicate that type I-IV units may be variants of a single oligodendrocyte population and that phenotypic differences are determined by the diameter of fibres within the unit. The possible significance of metabolic and biochemical differences between oligodendrocytes myelinating small and large diameter axons are discussed with reference to the pathology of demyelination.

  2. 中缝大核NO和5-HT对大鼠胃运动的影响%A Study on Impact of Nitrogen Monoxidum in Nucleus Raphes Magnus and Serotonin on Gastric Motility of Rats



    目的:研究中缝大核一氧化氮(NO)和五羟色胺(5-HT)对大鼠胃运动的影响.方法:采用SD大鼠中缝大核(NRM)微量注射药物,记录胃运动收缩的幅度和频率.结果:中缝大核微量注射5-HT,能明显增强胃运动;中缝大核内预先注入精氨酸(L-Arg),可完全反转5-HT对胃运动的增强效应;中缝大核内预先注入一氧化氮合酶抑制剂(L-NAME),对5-HT增强胃运动的作用无影响,与生理盐水和5-HT的效应无显著差异,胃收缩频率均无明显变化.结论:NRM微量注入5-HT对胃运动有显著加强作用,NO可调制5-HT的作用.%Objective: To study the impact of nitrogen monoxidum (NO) in nucleus raphes magnus (NRM) and serotonin (5-HT) on gastric motility in rats. Methods: To record amplitude and frequency of gastric contraction in SD rats after micro-injection of NO and 5-HT in NRM. Result: Injection of 5-HT into NRM increased the amplitude of gastric contraction; Injection of L-Arg into NRM in advance could reverse the increase effect of 5-HT;lnjection of an inhibitor of NO synthethase, L-NAME, into NRM in advance caused no change of the effect of 5-HT, and showed no remarkable difference from the effect of normal saline or 5-HT. Conclusions: The Injection of 5-HT into NRM could increase the amplitude of gastric contraction, and NO could regulate the effect of 5-HT on gastric motility.

  3. Analgesia induced by morphine microinjected into the nucleus raphe magnus: effects on tonic pain.

    Dualé, Christian; Sierralta, Fernando; Dallel, Radhouane


    One of the possible sites of action of the analgesic effect of morphine is the Nucleus Raphe Magnus, as morphine injected into this structure induces analgesia in transient pain models. In order to test if morphine in the Nucleus Raphe Magnus is also analgesic in a tonic pain model, 5 microg of morphine or saline (control) were microinjected into the Nucleus Raphe Magnus of the rat. Analgesic effects were assessed following nociceptive stimulation using transient heating of the tail (phasic pain) and subcutaneous orofacial injection of 1.5 % formalin (tonic pain). While morphine was strongly analgesic for the tail-flick response (p Magnus is not the exclusive site of action of morphine-induced analgesia in clinical conditions.

  4. Medullary ventrolateral nitric oxide mediates the cardiac effect of electroacupuncture at "Neiguan" acupoint on acute myocardial ischemia in rats.

    Lu, Juan-Xiu; Zhou, Pei-Hua; Wang, Jin; Li, Xia; Cao, Yin-Xiang; Zhou, Xu; Zhu, Da-Nian


    Experiments were performed on male Sprague-Dawley (SD) rats anesthetized with a mixture of urethane and chloralose. A rat model of acute myocardial ischemia (AMI) was made by ligation of the left anterior descending branch of the coronary artery (LAD). After the LAD ligation, the ischemia area of the left ventricular wall became somewhat pale immediately. Under a light microscope, the pathological examination revealed that all the cells were swollen and in red color when the cardiac section was stained with hematoxylin basic fuchsin picric acid (HBFP), which indicated a typical change in the myocardial ischemia. In the AMI model, it was found that cardiac functions were markedly attenuated, such as decreases in the heart rate (HR), mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), maximal rate for left ventricular pressure rising and declining (+/-dp/dt(max)), velocity of contractile element (V(CE)) and total area of cardiac force loop (L(0)), and an increase in the left ventricular end diastolic pressure (LVEDP). In such AMI rats, application of electroacupuncture (EA) at "Neiguan" acupoints (Pe 6) for 20 min could obviously improve the above-mentioned cardiac functions. After microinjection of nitro-L-arginine (L-NNA), an inhibitor of nitric oxide synthase (NOS), was made into the rostral ventrolateral medulla (RVLM), the curative effect of EA on myocardial ischemia was reduced significantly or abolished, while after microinjection of normal saline of the same volume was made into the RVLM, the improving effect of EA remained. These results suggest that the effect of EA on myocardial ischemia is possibly mediated by the nitric oxide (NO) in the RVLM.

  5. Lesion of medullary catecholaminergic neurons is associated with cardiovascular dysfunction in rotenone-induced Parkinson's disease rats.

    Zhang, Zhaoqiang; Du, Xixun; Xu, Huamin; Xie, Junxia; Jiang, Hong


    In recent years, non-motor symptoms have been recognised as of vital importance in Parkinson's disease (PD); among these, cardiovascular dysfunctions are commonly seen in PD patients before their motor signs. The role of cardiovascular dysfunction in the progression of PD pathology, and its underlying mechanisms, are largely unknown. In the present study, in rotenone-induced PD rats, there was a gradual reduction in the number of nigral tyrosine hydroxylase-immunoreactive (TH-ir) neurons after 7, 14 and 21 days treatment. With the 56% reduction in striatal dopamine content and 52% loss of TH-ir neurons on the 14th day, the rats showed motor dysfunctions. However, from ECG power spectra, reductions in normalised low-frequency power and in the low-frequency power : high-frequency power ratio, as well as in mean blood pressure, were observed as early as the 3rd day. Plasma norepinephrine (NE) and epinephrine (E) levels were decreased by 39% and 26% respectively at the same time. Pearson's correlation analysis showed that both plasma NE and plasma E levels were positively correlated with MBP. Our results also showed that the loss of catecholaminergic neurons in the rostral ventrolateral medulla (RVLM), but not in the caudal ventrolateral medulla or the nucleus tractus solitarii, emerged earlier than the loss of nigral dopaminergic neurons. This suggests that dysfunction of catecholaminergic neurons in the RVLM might account for the reduced sympathetic activity, MBP and plasma catecholamine levels in the early stages of PD.

  6. Changes in firing rate and firing pattern of midbrain dopaminergic neurons after lesioning of the dorsal raphe nucleus by 5,7-drhydroxytryptamine in adult rats

    Wang Shuang; Liu Jian; Wang Tao; Han Lingna; Zhang Qiaojun; Li Qiang


    Objective To study the effect of serotonergic efferent projection of the dorsal rophe nucleus (DRN) on the activity of substantia nigro pars compacta (SNc) and ventral tegmenta area (VTA) dopaminergic neurons after lesioning of the DRN by the neurotoxin 5,7-drhydroxytryptamine (5,7-DHT) in rot. Methods The changes in the firing rote and firing pattern of SNc and VTA dopaminergic neurons were observed with extrocellular recording in control and the lesioned rats. Results The results showed that the mean firing rotes of the fast-firing dopaminergic neurons of the SNc in control and the lesioned rots were (5.34±0. 13 ) Hz (n = 23 ) and ( 7.13±0. 49 ) Hz (n=37), respectively. The mean firing rote of the fast-firing dopaminergic neurons of the SNc in the lesioned rats was significantly increased when compared to that of control rots (P<0.01), while the mean firing rote of the slow-firing dopaminergic neurons of the SNc did not change. The mean firing rotes of dopaminergic neurons of the VTA in control and the lesioned rots were (5.27±0. 38)Hz (n=35) and (3.6±0.2)Hz (n=52), respectively. Lesioning of the DRN induced a significant decrease in the mean firing rote of dopaminergic neurons of the VTA. The firing pattern of SNc and VTA dopaminergic neurons changed towards a more bursting or irrgular firing after the lesioning. Conlusion These data suggest that the serotonergic efferent projections of the DRN significantly affect the activity of SNe and VTA dopaminergic neurons.

  7. Projections of medullary and pontine noradrenergic neurons to the horizontal limb of the nucleus of diagonal band in the rat.

    Senatorov, V V; Renaud, L P


    Recent investigations in the rat have implicated a noradrenergic innervation to the horizontal nucleus of the diagonal band of Broca as a critical link in a neural circuit that conveys baroreceptor information centrally to inhibit the firing of vasopressin-secreting neurons in the hypothalamic supraoptic nucleus. In this study we used small intra-diagonal band injections of a retrograde tracer, rhodamine latex microspheres, in combination with tyrosine hydroxylase histochemistry to identify brainstem noradrenergic cells contributing to this innervation. In three cases where tracer injections were limited to the horizontal limb of the diagonal band, we observed 20-50 double-labelled neurons ipsilaterally in the dorsal part of the locus coeruleus (A6) and the caudal nucleus tractus solitarius (A2), and bilaterally in the caudal ventrolateral medulla (A1). Double-labelled neurons were also noted in the ventral tegmental area (dopaminergic A10 cell group). Although all major brainstem noradrenergic cell groups contribute fibers to the horizontal limb of the nucleus of diagonal band, data from physiological studies suggest that the noradrenergic A2 neurons in the nucleus tractus solitarius are the most likely pathway through which it receives this baroreceptor information.

  8. Contribution of Ca2+-dependent conductances to membrane potential fluctuations of medullary respiratory neurons of newborn rats in vitro.

    Onimaru, Hiroshi; Ballanyi, Klaus; Homma, Ikuo


    Ca2+-dependent conductances were studied in respiratory interneurons in the brainstem-spinal cord preparation of newborn rats. omega-Conotoxin-GVIA attenuated evoked postsynaptic potentials, spontaneous or evoked inspiratory spinal nerve activity and blocked spike afterhyperpolarization. Furthermore, omega-conotoxin-GVIA augmented rhythmic drive potentials of pre-inspiratory and inspiratory neurons and increased respiratory-related spike frequency of pre-inspiratory cells with no effect on inspiratory hyperpolarization. In contrast, omega-agatoxin-IVA depressed drive potentials of pre-inspiratory and inspiratory neurons and attenuated inspiratory hyperpolarization and spike frequency of pre-inspiratory cells. It did not affect spike shape and exerted only minor, non-significant, attenuating effects on spontaneous or evoked nerve bursts or evoked postsynaptic potentials. Nifedipine diminished drive potentials and spike frequency of pre-inspiratory neurons and shortened drive potentials in some cells. omega-Conotoxin-MVIIC attenuated drive potentials and intraburst firing rate of pre-inspiratory neurons and decreased substantially respiratory frequency. Respiratory rhythm disappeared following combined application of omega-conotoxin-GVIA, omega-conotoxin-MVIIC, omega-agatoxin-IVA and nifedipine. Apamin potentiated drive potentials and abolished spike afterhyperpolarization, whereas charybdotoxin and tetraethylammonium prolonged spike duration without effect on shape of drive potentials. The results show that specific sets of voltage-activated L-, N- and P/Q-type Ca2+ channels determine the activity of particular subclasses of neonatal respiratory neurons, whereas SK- and BK-type K+ channels attenuate drive potentials and shorten spikes, respectively, independent of cell type. We hypothesize that modulation of spontaneous activity of pre-inspiratory neurons via N-, L- and P/Q-type Ca2+ channels is important for respiratory rhythm or pattern generation.

  9. Neurokinin-1 Receptor-Immunopositive Neurons in the Medullary Dorsal Horn Provide Collateral Axons to both the Thalamus and Parabrachial Nucleus in Rats.

    Li, Xu; Ge, Shun-Nan; Li, Yang; Wang, Han-Tao


    It has been suggested that the trigemino-thalamic and trigemino-parabrachial projection neurons in the medullary dorsal horn (MDH) are highly implicated in the sensory-discriminative and emotional/affective aspects of orofacial pain, respectively. In previous studies, some neurons were reported to send projections to both the thalamus and parabrachial nucleus by way of collaterals in the MDH. However, little is known about the chemoarchitecture of this group of neurons. Thus, in the present study, we determined whether the neurokinin-1 (NK-1) receptor, which is crucial for primary orofacial pain signaling, was expressed in MDH neurons co-innervating the thalamus and parabrachial nucleus. Vesicular glutamate transporter 2 (VGLUT2) mRNA, a biomarker for the subgroup of glutamatergic neurons closely related to pain sensation, was assessed in trigemino-parabrachial projection neurons in the MDH. After stereotactic injection of fluorogold (FG) and cholera toxin subunit B (CTB) into the ventral posteromedial thalamic nucleus (VPM) and parabrachial nucleus (PBN), respectively, triple labeling with fluorescence dyes for FG, CTB and NK-1 receptor (NK-1R) revealed that approximately 76 % of the total FG/CTB dually labeled neurons were detected as NK-1R-immunopositive, and more than 94 % of the triple-labeled neurons were distributed in lamina I. In addition, by FG retrograde tract-tracing combined with fluorescence in situ hybridization (FISH) for VGLUT2 mRNA, 54, 48 and 70 % of FG-labeled neurons in laminae I, II and III, respectively, of the MDH co-expressed FG and VGLUT2 mRNA. Thus, most of the MDH neurons co-innervating the thalamus and PBN were glutamatergic. Most MDH neurons providing the collateral axons to both the thalamus and parabrachial nucleus in rats were NK-1R-immunopositive and expressed VGLUT2 mRNA. NK-1R and VGLUT2 in MDH neurons may be involved in both sensory-discriminative and emotional/affective aspects of orofacial pain processing.

  10. Pediatric Medullary Thyroid Carcinoma

    Starenki, Dmytro; Park, Jong-In


    Medullary thyroid carcinoma (MTC), which originates from thyroid parafollicular C cells, accounts for 3 to 5% of thyroid malignancies. MTC occurs either sporadically or in an inherited autosomal dominant manner. Hereditary MTC occurs as a familial MTC or as a part of multiple endocrine neoplasia (MEN) type 2A and B syndromes. A strong genotype-phenotype correlation has been observed between hereditary MTC and germ-line ?gain of function? mutations of the RET proto-oncogene. Most cases of pedi...

  11. AF64A诱导的大鼠大缝际核胆碱能神经损伤改变吗啡的镇痛作用%Effect of morphine-induced antinociception is altered by AF64A-induced lesions on cholinergic neurons in rat nucleus raphe magnus

    Kenji ABE; Kota ISHIDA; Masatoshi KATO; Toshiro SHIGENAGA; Kyoji TAGUCHI; Tadashi MIYATAKE


    AIM: To examine the role of cholinergic neurons in the nucleus raphe magnus (NRM) in noxious heat stimulationand in the effects of morphine-induced antinociception by rats. METHODS: After the cholinergic neuron selectivetoxin, AF64A, was microinjected into the NRM, we examined changes in the antinociceptive threshold and effectsof morphine (5 mg/kg, ip) using the hot-plate (HP) and tail-flick (TF) tests. RESULTS: Systemic administration ofmorphine inhibited HP and TF responses in control rats. Microinjection of AF64A (2 nmol/site) into the NRMsignificantly decreased the threshold of HP response after 14 d, whereas the TF response was not affected. Mor-phine-induced antinociception was significantly attenuated in rats administered AF64A. Extracellular acetylcholinewas attenuated after 14 d to below detectable levels in rats given AF64A. Naloxone (1 μg/site) microinjected intocontrol rat NRM also antagonized the antinociceptive effect of systemic morphine. CONCLUSION: These find-ings suggest that cbolinergic neuron activation in the NRM modulates the antinociceptive effect of morphine simul-taneously with the opiate system.

  12. Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation

    Josefine Storm Witteveen


    Full Text Available Besides its ‘classical’ neurotransmitter function, serotonin (5-HT has been found to also act as a neurodevelopmental signal. During development, the 5-HT projection system represents one of the earliest neurotransmitter systems to innervate the brain. One of the targets of the 5-HT projection system, originating in the brainstem raphe nuclei, is the medial prefrontal cortex (mPFC, an area involved in higher cognitive functions and important in the etiology of many neurodevelopmental disorders. Little is known however about the exact role of 5-HT and its signaling molecules in the formation of the raphe-prefrontal network. Using explant essays, we here studied the role of the 5-HT transporter (5-HTT, an important modulator of the 5-HT signal, in rostral raphe-prefrontal network formation. We found that the chemotrophic nature of the interaction between the origin (rostral raphe cluster and a target (mPFC of the 5-HT projection system was affected in rats lacking the 5-HTT (5-HTT-/-. While 5-HTT deficiency did not affect the dorsal raphe 5-HT-positive outgrowing neurites, the median raphe 5-HT neurites switched from a strong repulsive to an attractive interaction when co-cultured with the mPFC. Furthermore, the fasciculation of the mPFC outgrowing neurites was dependent on the amount of 5-HTT. In the mPFC of 5-HTT-/- pups, we observed clear differences in 5-HT innervation and the identity of a class of projection neurons of the mPFC. In the absence of the 5-HTT, the 5-HT innervation in all subareas of the early postnatal mPFC increased dramatically and the number of Satb2-positive callosal projection neurons was decreased. Together, these results suggest a 5-HTT dependency during early development of these brain areas and in the formation of the raphe-prefrontal network. The tremendous complexity of the 5-HT projection system and its role in several neurodevelopmental disorders highlights the need for further research in this largely

  13. Exposure to an open-field arena increases c-Fos expression in a subpopulation of neurons in the dorsal raphe nucleus, including neurons projecting to the basolateral amygdaloid complex

    Hale, M.W.; Hay-Schmidt, A.; Mikkelsen, J.D.


    Serotonergic systems in the dorsal raphe nucleus are thought to play an important role in the regulation of anxiety states. To investigate responses of neurons in the dorsal raphe nucleus to a mild anxiety-related stimulus, we exposed rats to an open-field, under low-light or high-light conditions....... Treatment effects on c-Fos expression in serotonergic and non-serotonergic cells in the midbrain raphe nuclei were determined 2 h following open-field exposure or home cage control (CO) conditions. Rats tested under both light conditions responded with increases in c-Fos expression in serotonergic neurons...... within subdivisions of the midbrain raphe nuclei compared with CO rats. However, the total numbers of serotonergic neurons involved were small suggesting that exposure to the open-field may affect a subpopulation of serotonergic neurons. To determine if exposure to the open-field activates a subset...

  14. [Local GABA-ergic modulation of serotonergic neuron activity in the nucleus raphe magnus].

    Iniushkin, A N; Merkulova, N A; Orlova, A O; Iniushkina, E M


    In voltage-clamp experimental on slices of the rat brainstem the effects of 5-HT and GABA on serotonergic neurons of nucleus raphe magnus were investigated. Local applications of 5-HT induced an increase in IPCSs frequency and amplitude in 45% of serotonergic cells. The effect suppressed by the blocker of fast sodium channels tetradotoxin. Antagonist of GABA receptor gabazine blocked IPSCs in neurons both sensitive and non-sensitive to 5-HT action. Applications of GABA induced a membrane current (I(GABA)), which was completely blocked by gabazine. The data suggest self-control of the activity of serotonergic neurons in nucleus raphe magnus by negative feedback loop via local GABAergic interneurons.

  15. Pediatric Medullary Thyroid Carcinoma.

    Starenki, Dmytro; Park, Jong-In

    Medullary thyroid carcinoma (MTC), which originates from thyroid parafollicular C cells, accounts for 3 to 5% of thyroid malignancies. MTC occurs either sporadically or in an inherited autosomal dominant manner. Hereditary MTC occurs as a familial MTC or as a part of multiple endocrine neoplasia (MEN) type 2A and B syndromes. A strong genotype-phenotype correlation has been observed between hereditary MTC and germ-line "gain of function" mutations of the RET proto-oncogene. Most cases of pediatric MTC are hereditary whereas sporadic MTC is rare in children and is usually diagnosed in adults. Therefore, MTC in children is most often diagnosed in the course of a familial genetic investigation. The standard treatment of MTC mainly requires surgery involving total thyroidectomy and central neck node dissection before extrathyroidal extension occurs. To prevent MTC development in hereditary syndromes, prophylactic thyroidectomy is performed in presymptomatic patients. An appropriate age at which the surgery should take place is determined based upon the data from genotyping, serum calcitonin measurements, and ultrasonography. For the treatment of advanced MTC cases, the broad spectrum receptor tyrosine kinase inhibitors vandetanib and cabozantinib, which also inhibit RET, are used although they are not always effective.

  16. Medullary sponge kidney.

    Gambaro, Giovanni; Danza, Francesco M; Fabris, Antonia


    After it was first described in 1939, medullary sponge kidney (MSK) received relatively little attention. This was because it was believed to have a low prevalence and because it was considered a benign condition. Studies in recent years have been changing these convictions however, hence the present review. Insight has been obtained on the genetic basis of this disease, supporting the hypothesis that MSK is due to a disruption at the 'ureteric bud-metanephric mesenchyme' interface. This explains why so many tubular defects coexist in this disease, and particularly a distal tubular acidification defect of which the highly prevalent metabolic bone disease is one very important consequence. In addition to the typical clinical phenotype of recurrent stone disease, other clinical profiles have now been recognized, that is, an indolent, almost asymptomatic MSK, and a rare form characterized by intractable, excruciating pain. Findings suggest the need for a more comprehensive clinical characterization of MSK patients. The genetic grounds for the condition warrant further investigation, and reliable methods are needed to diagnose MSK.

  17. Midbrain raphe stimulation improves behavioral and anatomical recovery from fluid-percussion brain injury.

    Carballosa Gonzalez, Melissa M; Blaya, Meghan O; Alonso, Ofelia F; Bramlett, Helen M; Hentall, Ian D


    The midbrain median raphe (MR) and dorsal raphe (DR) nuclei were tested for their capacity to regulate recovery from traumatic brain injury (TBI). An implanted, wireless self-powered stimulator delivered intermittent 8-Hz pulse trains for 7 days to the rat's MR or DR, beginning 4-6 h after a moderate parasagittal (right) fluid-percussion injury. MR stimulation was also examined with a higher frequency (24 Hz) or a delayed start (7 days after injury). Controls had sham injuries, inactive stimulators, or both. The stimulation caused no apparent acute responses or adverse long-term changes. In water-maze trials conducted 5 weeks post-injury, early 8-Hz MR and DR stimulation restored the rate of acquisition of reference memory for a hidden platform of fixed location. Short-term spatial working memory, for a variably located hidden platform, was restored only by early 8-Hz MR stimulation. All stimulation protocols reversed injury-induced asymmetry of spontaneous forelimb reaching movements tested 6 weeks post-injury. Post-mortem histological measurement at 8 weeks post-injury revealed volume losses in parietal-occipital cortex and decussating white matter (corpus callosum plus external capsule), but not hippocampus. The cortical losses were significantly reversed by early 8-Hz MR and DR stimulation, the white matter losses by all forms of MR stimulation. The generally most effective protocol, 8-Hz MR stimulation, was tested 3 days post-injury for its acute effect on forebrain cyclic adenosine monophosphate (cAMP), a key trophic signaling molecule. This procedure reversed injury-induced declines of cAMP levels in both cortex and hippocampus. In conclusion, midbrain raphe nuclei can enduringly enhance recovery from early disseminated TBI, possibly in part through increased signaling by cAMP in efferent targets. A neurosurgical treatment for TBI using interim electrical stimulation in raphe repair centers is suggested.

  18. Origin and evolution of the canal raphe system in diatoms.

    Ruck, Elizabeth C; Theriot, Edward C


    One lineage of pennate diatoms has a slit through the siliceous cell wall, called a "raphe," that functions in motility. Raphid pennate diatoms number in the perhaps tens of thousands of species, with the diversity of raphe forms potentially matching this number. Three lineages-the Bacillariales, Rhopalodiales, and Surirellales-possess a complex and presumably highly derived raphe that is physically separated from the cell interior, most often by a set of siliceous braces. Because the relationship among these three lineages is unclear, the number of origins of the canal raphe system and the homology of it and its constitutive parts among these lineages, is equally unclear. We reconstructed the phylogeny of raphid pennate diatoms and included, for the first time, members of all three canal raphid diatom lineages, and used the phylogeny to test specific hypotheses about the origin of the canal raphe. The canal raphe appears to have evolved twice, once in the common ancestor of Bacillariales and once in the common ancestor of Rhopalodiales and Surirellales, which form a monophyletic group in our analyses. These results recommend careful follow-up morphogenesis studies of the canal raphe in these two lineages to determine the underlying developmental basis for this remarkable case of parallel evolution.

  19. Renal acidification defects in medullary sponge kidney

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


    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...... of renal calculi in medullary sponge kidney, have considerable therapeutic implications....

  20. Medullary carcinoma of the colon

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


    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...

  1. Connections between 5-HT-containing terminals and 5-HT2A receptor and γ-aminobutyric acid or glycine co-existed neurons in the rat medullary dorsal horn

    LI Hui; LI Yun-qing


    Objective: To investigate the connections between serotonin (5-HT)-containing terminals and 5-HT2A receptor (5-HT2AR)/γ-aminobutyric acid (GABA) or 5-HT2AR/glycine co-existed neurons in the rat medullary dorsal horn (MDH).Methods: Immunofluorescence histochemical triple-staining for 5-HT, 5-HT2AR, GABA or glycine. Results: 5-HT-immunoreaetive fibers and terminals were chiefly located in the superficial laminae (laminae Ⅰ and Ⅱ) of the MDH. Neurons exhibiting 5-HT2AR-, GABA- or glycine-immunoreactivities were mainly observed in the superficial laminae. Some 5-HT2AR-immunopositive neurons also exhibited GABA- or glycine-immunoreaetivities. 5-HT-containing terminals made close contacts with 5-HT2AR/GABA or 5-HT2AR/glycine co-existed neurons. Conclusion: 5-HT2AR/GABA or 5-HT2AR /glycine co-exist in some of the neurons in the superficial laminae of the MDH. 5-HT-immunoreactive terminals form close connections with 5-HT2AR/GABA or 5-HT2AR/glycine co-existed neurons.

  2. Nitric oxide and superoxide transport in a cross section of the rat outer medulla. I. Effects of low medullary oxygen tension

    Edwards, Aurélie; Layton, Anita T


    ...) on the distribution of nitric oxide (NO), superoxide (O(2)(-)) and total peroxynitrite (ONOO), we developed a mathematical model that simulates the transport of those species in a cross section of the rat OM...

  3. Activation of dorsal raphe serotonin neurons is necessary for waiting for delayed rewards.

    Miyazaki, Kayoko W; Miyazaki, Katsuhiko; Doya, Kenji


    The forebrain serotonergic system is a crucial component in the control of impulsive behaviors. We previously reported that the activity of serotonin neurons in the midbrain dorsal raphe nucleus increased when rats performed a task that required them to wait for delayed rewards. However, the causal relationship between serotonin neural activity and the tolerance for the delayed reward remained unclear. Here, we test whether the inhibition of serotonin neural activity by the local application of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin in the dorsal raphe nucleus impairs rats' tolerance for delayed rewards. Rats performed a sequential food-water navigation task that required them to visit food and water sites alternately via a tone site to get rewards at both sites after delays. During the short (2 s) delayed reward condition, the inhibition of serotonin neural activity did not significantly influence the numbers of reward choice errors (nosepoke at an incorrect reward site following a conditioned reinforcer tone), reward wait errors (failure to wait for the delayed rewards), or total trials (sum of reward choice errors, reward wait errors, and acquired rewards). By contrast, during the long (7-11 s) delayed reward condition, the number of wait errors significantly increased while the numbers of total trials and choice errors did not significantly change. These results indicate that the activation of dorsal raphe serotonin neurons is necessary for waiting for long delayed rewards and suggest that elevated serotonin activity facilitates waiting behavior when there is the prospect of forthcoming rewards.

  4. Activity of Raphé Serotonergic Neurons Controls Emotional Behaviors

    Anne Teissier


    Full Text Available Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior, together suggesting that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function.

  5. Clinical correlates of raphe serotonergic dysfunction in early Parkinson's disease.

    Qamhawi, Zahi; Towey, David; Shah, Bina; Pagano, Gennaro; Seibyl, John; Marek, Kenneth; Borghammer, Per; Brooks, David James; Pavese, Nicola


    Post-mortem and neuroimaging studies suggest that the serotonergic system, which originates from the brainstem raphe nuclei, is disrupted in Parkinson's disease. This could contribute to the occurrence of non-motor symptoms and tremor, which are only partially explained by dopamine loss. However, the level of involvement of the serotonergic raphe nuclei in early Parkinson's disease is still debated. (123)I-FP-CIT single photon emission computed tomography is a marker of dopamine and serotonin transporter availability. While (123)I-FP-CIT binds primarily to dopamine transporters in the striatum, its binding in the brainstem raphe nuclei reflects serotonin transporter availability. We interrogated baseline single photon emission computed tomography scans of subjects recruited by the Parkinson's Progression Markers Initiative to determine: (i) the integrity of the brainstem raphe nuclei in early Parkinson's disease; and (ii) whether raphe serotonin transporter levels correlate with severity of tremor and symptoms of fatigue, depression, and sleep disturbance. Three hundred and forty-five patients with early drug-naïve Parkinson's disease, 185 healthy controls, and 56 subjects with possible Parkinson's disease without evidence of dopaminergic deficit were included. In the Parkinson's disease cohort, 37 patients had a tremulous, 106 patients had a pure akinetic-rigid, and 202 had a mixed phenotype. Patients with Parkinson's disease had significantly lower serotonin transporter availability in the brainstem raphe nuclei compared to controls (P disease individually had reduced signals. Raphe serotonin transporter availability over the entire Parkinson's disease cohort were associated with rest tremor amplitude (β = -0.106, P disease subgroup had significantly lower raphe serotonin transporter availability but less severe striatal dopaminergic deficits compared to akinetic-rigid patients with no resting tremor (P disease. We conclude that the raphe nuclei are affected in

  6. Basolateral membrane Na+/H+ exchange enhances HCO3- absorption in rat medullary thick ascending limb: evidence for functional coupling between basolateral and apical membrane Na+/H+ exchangers.

    Good, D W; George, T; Watts, B A


    The role of basolateral membrane Na+/H+ exchange in transepithelial HCO3- absorption (JHCO3) was examined in the isolated, perfused medullary thick ascending limb (MTAL) of the rat. In Na(+)-free solutions, addition of Na+ to the bath resulted in a rapid, amiloride-sensitive increase in intracellular pH. In MTALs perfused and bathed with solutions containing 146 mM Na+ and 25 mM HCO3-, bath addition of amiloride (1 mM) or 5-(N-ethyl-N-isopropyl) amiloride (EIPA, 50 microM) reversibly inhibited JHCO3 by 50%. Evidence that the inhibition of JHCO3 by bath amiloride was the result of inhibition of Na+/H+ exchange included the following: (i) the IC50 for amiloride was 5-10 microM, (ii) EIPA was a 50-fold more potent inhibitor than amiloride, (iii) the inhibition by bath amiloride was Na+ dependent, and (iv) significant inhibition was observed with EIPA as low as 0.1 microM. Fifty micromolar amiloride or 1 microM EIPA inhibited JHCO3 by 35% when added to the bath but had no effect when added to the tubule lumen, indicating that addition of amiloride to the bath did not directly inhibit apical membrane Na+/H+ exchange. In experiments in which apical Na+/H+ exchange was assessed from the initial rate of cell acidification following luminal EIPA addition, bath EIPA secondarily inhibited apical Na+/H+ exchange activity by 46%. These results demonstrate basolateral membrane Na+/H+ exchange enhances transepithelial HCO3- absorption in the MTAL. This effect appears to be the result of cross-talk in which an increase in basolateral membrane Na+/H+ exchange activity secondarily increases apical membrane Na+/H+ exchange activity. PMID:8618934

  7. PDGF-alpha receptor and myelin basic protein mRNAs are not coexpressed by oligodendrocytes in vivo: a double in situ hybridization study in the anterior medullary velum of the neonatal rat.

    Butt, A M; Hornby, M F; Ibrahim, M; Kirvell, S; Graham, A; Berry, M


    Platelet-derived growth factor (PDGF) is a growth-regulatory dimer with A and B subunits. PDGF-AA, acting via PDGF receptors of the alpha-unit subtype (PDGF-alphaR), is implicated in the differentiation of oligodendrocyte precursors and in the survival of newly formed oligodendrocytes, which gradually lose expression of PDGF-alphaR. However, it is unclear whether terminally differentiated oligodendrocytes express PDGF-alphaR in vivo. To address this question, and to help clarify the role of PDGF-AA in late oligodendrocyte differentiation, we have used double in situ hybridization with digoxigenin- and fluorescein-labeled riboprobes to relate PDGF-alphaR mRNA and myelin basic protein (MBP) mRNA expression in the isolated intact anterior medullary velum (AMV) of rats ages Postnatal Day (P) 10-12 and P30-32. In parallel experiments, AMV were immunolabeled with the oligodendrocyte-specific monoclonal antibody Rip to provide information on oligodendrocyte development and the extent of myelination. At P10, the AMV contained tracts in which axons ranged from unmyelinated to fully myelinated, whereas myelination was complete in P30-32 AMV. The first oligodendrocytes to express MBP mRNA or Rip were promyelinating oligodendrocytes, which had a "star-burst" morphology and had not yet begun to form myelin sheaths. As myelination proceeded, MBP mRNA became dispersed throughout oligodendrocyte units, comprising cell somata, processes, and internodal myelin sheaths. By P30-32, MBP mRNA had been redistributed to the myelin sheaths only, reflecting a change in the site of protein synthesis in mature myelinated axon tracts. At no stage of oligodendrocyte differentiation did we observe cellular coexpression of mRNA for PDGFalphaR and MBP. Our results indicated that oligodendrocytes lost the expression of PDGFalphaR prior to gaining that of myelin gene products, and preclude an action of PDGF-AA on Rip+/MBP+ star-burst promyelinating oligodendrocytes. The spatial and temporal

  8. Coordinated response of renal medullary enzymes regulating net sorbitol production in diuresis and antidiuresis.

    Sands, J M; Schrader, D C


    The renal response to changes in hydration includes variation in intracellular sorbitol, a major inner medullary osmolyte. To examine the mechanism for changes in net sorbitol production, we measured activities of enzymes regulating sorbitol production (aldose reductase) and degradation (sorbitol dehydrogenase) in untreated, water diuretic, and antidiuretic (water restriction and/or vasopressin administration) rats. Collecting duct segments dissected from collagenase-treated kidneys of Sprague-Dawley rats were divided into outer medullary and three distinct inner medullary regions. Aldose reductase activity increased during antidiuresis and decreased during diuresis. In contrast, sorbitol dehydrogenase activity was very low during antidiuresis and increased during diuresis. These changes in enzyme activity were found after 3 days, but not after 1 day, of water diuresis/antidiuresis. Enzyme activity changed only in the deepest 50% of the inner medullary collecting duct. Thus, there is coordinated regulation of aldose reductase and sorbitol dehydrogenase activities so that (a) during water diuresis, aldose reductase activity decreases while sorbitol dehydrogenase activity increases; and (b) during antidiuresis (water restriction and/or vasopressin administration), aldose reductase activity increases while sorbitol dehydrogenase activity remains low. We conclude that long-term osmoregulation in response to physiologic stimuli involves both aldose reductase and sorbitol dehydrogenase activities in rat terminal inner medullary collecting duct segments.

  9. Cellular effects of swim stress in the dorsal raphe nucleus.

    Kirby, Lynn G; Pan, Yu-Zhen; Freeman-Daniels, Emily; Rani, Shobha; Nunan, John D; Akanwa, Adaure; Beck, Sheryl G


    Swim stress regulates forebrain 5-hydroxytryptamine (5-HT) release in a complex manner and its effects are initiated in the serotonergic dorsal raphe nucleus (DRN). The purpose of this study was to examine the effects of swim stress on the physiology of DRN neurons in conjunction with 5-HT immunohistochemistry. Basic membrane properties, 5-HT(1A) and 5-HT(1B) receptor-mediated responses and glutamatergic excitatory postsynaptic currents (EPSCs) were measured using whole-cell patch clamp techniques. Rats were forced to swim for 15min and 24h later DRN brain slices were prepared for electrophysiology. Swim stress altered the resting membrane potential, input resistance and action potential duration of DRN neurons in a neurochemical-specific manner. Swim stress selectively elevated glutamate EPSC frequency in 5-HT DRN neurons. Swim stress non-selectively reduced EPSC amplitude in all DRN cells. Swim stress elevated the 5-HT(1B) receptor-mediated inhibition of glutamatergic synaptic activity that selectively targeted 5-HT cells. Non-5-HT DRN neurons appeared to be particularly responsive to the effects of a milder handling stress. Handling elevated EPSC frequency, reduced EPSC decay time and enhanced a 5-HT(1B) receptor-mediated inhibition of mEPSC frequency selectively in non-5-HT DRN cells. These results indicate that swim stress has both direct, i.e., changes in membrane characteristics, and indirect effects, i.e., via glutamatergic afferents, on DRN neurons. These results also indicate that there are distinct local glutamatergic afferents to neurochemically specific populations of DRN neurons, and furthermore that these distinct afferents are differentially regulated by swim stress. These cellular changes may contribute to the complex effects of swim stress on 5-HT neurotransmission and/or the behavioral changes underlying the forced swimming test model of depression.

  10. Role of serotonin transporter inhibition in the regulation of tryptophan hydroxylase in brainstem raphe nuclei: time course and regional specificity.

    MacGillivray, L; Lagrou, L M; Reynolds, K B; Rosebush, P I; Mazurek, M F


    Drugs that selectively inhibit the serotonin transporter (SERT) are widely prescribed for treatment of depression and a range of anxiety disorders. We studied the time course of changes in tryptophan hydroxylase (TPH) in four raphe nuclei after initiation of two different SERT inhibitors, citalopram and fluoxetine. In the first experiment, groups of Sprague-Dawley rats received daily meals of rice pudding either alone (n=9) or mixed with citalopram 5 mg/kg/day (n=27). Rats were sacrificed after 24 h, 7 days or 28 days of treatment. Sections of dorsal raphe nucleus (DRN), median raphe nucleus (MRN), raphe magnus nucleus (RMN) and caudal linear nucleus (CLN) were processed for TPH immunohistochemistry. Citalopram induced a significant reduction in DRN TPH-positive cell counts at 24 h (41%), 7 days (38%) and 28 days (52%). Similar reductions in TPH-positive cell counts were also observed at each timepoint in the MRN and in the RMN. In the MRN, citalopram resulted in significant reductions at 24 h (26%), 7 days (16%) and 28 days (23%). In the RMN, citalopram induced significant reductions of TPH-positive cell counts at 24 h (45%), 7 days (34%) and 28 days (43%). By contrast, no significant differences between control and treatment groups were observed in the CLN at any of the time points that we studied. To investigate whether these changes would occur with other SERT inhibitors, we conducted a second experiment, this time with a 28-day course of fluoxetine. As was observed with citalopram, fluoxetine induced significant reductions of TPH cell counts in the DRN (39%), MRN (38%) and RMN (41%), with no significant differences in the CLN. These results indicate that SERT inhibition can alter the regulation of TPH, the rate limiting enzyme for serotonin biosynthesis. This persistent and regionally specific downregulation of serotonin biosynthesis may account for some of the clinical withdrawal symptoms associated with drugs that inhibit SERT.

  11. Raphe nuclei in three cartilaginous fishes, Hydrolagus colliei, Heterodontus francisci, and Squalus acanthias.

    Stuesse, S L; Stuesse, D C; Cruce, W L


    The vertebrate reticular formation, containing over 30 nuclei in mammals, is a core brainstem area with a long evolutionary history. However, not all reticular nuclei are equally old. Nuclei that are widespread among the vertebrate classes are probably ones that evolved early. We describe raphe nuclei in the reticular formation of three cartilaginous fishes that diverged from a common ancestor over 350 million years ago. These fishes are Hydrolagus colliei, a holocephalan, Squalus acanthias, a small-brained shark, and Heterodontus francisci, a large-brained shark. Nuclear identification was based on immunohistochemical localization of serotonin and leu-enkephalin, on brainstem location, and on cytoarchitectonics. Raphe nuclei are clustered in inferior and superior cell groups, but within these groups individual nuclei can be identified: raphe pallidus, raphe obscurus, and raphe magnus in the inferior group and raphe pontis, raphe dorsalis, raphe centralis superior, and raphe linearis in the superior group. Hydrolagus lacked a dorsal raphe nucleus, but the nucleus was present in the sharks. The majority of immunoreactive cells are found in the superior group, especially in raphe centralis superior, but immunoreactive cells are present from spinal cord to caudal mesencephalon. The distribution and cytoarchitectonics of serotoninergic and enkephalinergic cells are similar to each other, but raphe nuclei contain fewer enkephalinergic than serotoninergic cells. The cytoarchitectonics of immunoreactive raphe cells in cartilaginous fishes are remarkably similar to those described for raphe nuclei in mammals; however, the lack of a raphe dorsalis in Hydrolagus indicates that either it evolved later than the other raphe nuclei or it was lost in holocephalan fishes.

  12. Hashimoto's Thyroiditis and Medullary Carcinoma of Thyroid.

    Dasgupta, S; Chakrabarti, S; Mandal, P K; Das, S


    Hashimoto's thyroiditis (HT) has been found to be associated with lymphoma, papillary carcinoma and Hürthle cell neoplasms of thyroid. In contrast, there are only a few reports of co-existence of HT with medullary carcinoma of thyroid. An overall prevalence of medullary carcinoma of only 0.35% has been reported in HT patients. Such a rare combination is being presented here. A 33 year old female presented with history of goiter for one year. Fine needle aspiration cytology (FNAC) of the swelling revealed cytological features suggestive of medullary carcinoma of thyroid. Histopathological examination of total thyroidectomy specimen revealed Hashimoto's thyroiditis along with medullary carcinoma of thyroid. Although Hashimoto's thyroiditis can uncommonly co-exist with thyroid neoplasm, its association with medullary carcinoma is extremely rare and hence being presented.

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

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


    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 m

  14. Hindbrain raphe stimulation boosts cyclic adenosine monophosphate and signaling proteins in the injured spinal cord.

    Carballosa-Gonzalez, Melissa M; Vitores, Alberto; Hentall, Ian D


    Early recovery from incomplete spinal cord contusion is improved by prolonged stimulation of the hindbrain's serotonergic nucleus raphe magnus (NRM). Here we examine whether increases in cyclic adenosine monophosphate (cAMP), an intracellular signaling molecule with several known restorative actions on damaged neural tissue, could play a role. Subsequent changes in cAMP-dependent phosphorylation of protein kinase A (PKA) and PKA-dependent phosphorylation of the transcription factor "cAMP response element-binding protein" (CREB) are also analyzed. Rats with moderate weight-drop injury at segment T8 received 2h of NRM stimulation beginning three days after injury, followed immediately by separate extraction of cervical, thoracic and lumbar spinal cord for immunochemical assay. Controls lacked injury, stimulation or both. Injury reduced cAMP levels to under half of normal in all three spinal regions. NRM stimulation completely restored these levels, while producing no significant change in non-injured rats. Pretreatment with the 5-HT7 receptor antagonist pimozide (1 mg/kg, intraperitoneal) lowered cAMP in non-injured rats to injury amounts, which were unchanged by NRM stimulation. The phosphorylated fraction of PKA (pPKA) and CREB (pCREB) was reduced significantly in all three regions after SCI and restored by NRM stimulation, except for pCREB in lumbar segments. In conclusion, SCI produces spreading deficits in cAMP, pPKA and pCREB that are reversible by Gs protein-coupled 5-HT receptors responding to raphe-spinal activity, although these signaling molecules are not reactive to NRM stimulation in normal tissue. These findings can partly explain the benefits of NRM stimulation after SCI. © 2013 Published by Elsevier B.V.

  15. Effect of Acupuncture Combined with Antidepressant on Behavioral Changes, and mRNA Expression of 5-Hydroxytryptamine Receptors in Nucleus Raphes Dorsalis of Sleep Deprivation Depression Rats%针药结合对抑郁症睡眠障碍大鼠行为学与中缝背核5-羟色胺受体mRNA表达的影响

    俞裕天; 袁青; 陈津岩; 谢津津; 郎建英; 麦嘉玲; 曾晓林; 汪满霞; 薛尔平


    Objective To investigate the effect of acupuncture combined with antidepressant on behavioral changes and 5-hydroxytryptamine 1A and 2A receptor ( 5-HT1AR and 5-HT2AR) mRNA expression in nucleus raphes dorsalis (NRD) of sleep deprivation depression (SDD) rats. Methods Eight normal Sprague Dawley (SD) rats were caged together without any stimulus or treatment, serving as the normal group. Thirty-two SD rats were given solitary raise for 21 days, together with chronic unpredictable mild stress ( CUMS) and rapid eye movement ( REM) sleep deprivation to establish the model. Twenty-eight rats completed the modeling successfully, and were divided into model group, acupuncture group, medicine group, and combination group, 7 rats in each group. Rats in the model group were given modeling treatment but without any intervention. Rats in the acupuncture group were given acupuncture on acupoint Yintang, Shenting and bilateral Taichong, acupuncture stimulation lasting 15 s every 10 min and acupuncture retention for 20 min in each day. Rats in the medicine group were given gastric gavage of Zoloft solution (0.83 mg·kg-1·d-1) and Alprazolam solution (0.067 mg· kg-1·d-1) , and rats in the combination group were given both acupuncture and medicine intervention. The intervention for the three intervention groups lasted for 7 days. Results Compared with the normal group, body weight, Open-field scores and sucrose preference of the model rats were significantly decreased on modeling day 7, 14, 21 (P<0.05). On modeling day 28, body weight and Open-field scores of each intervention group were significantly increased compared with those of the model group (P<0.05), and Open-field scores of combination group differed from those of acupuncture group and medicine group ( P<0.05). Only sucrose preference of combination group was improved significantly compared with the model group (P<0.05). Compared with the model group, NRD 5-HT1AR mRNA expression level was increased in the combination

  16. Kinase inhibitors for advanced medullary thyroid carcinoma

    Martin Schlumberger


    Full Text Available The recent availability of molecular targeted therapies leads to a reconsideration of the treatment strategy for patients with distant metastases from medullary thyroid carcinoma. In patients with progressive disease, treatment with kinase inhibitors should be offered.

  17. Swim stress differentially blocks CRF receptor mediated responses in dorsal raphe nucleus.

    Lamy, Christophe M; Beck, Sheryl G


    Modulation of the serotonergic (5-HT) neurotransmitter system arising from the dorsal raphe nucleus (DR) is thought to support the behavioral effects of swim stress, i.e., immobility. In vivo pharmacological and anatomical studies suggest that corticotropin-releasing factor (CRF) and γ-aminobutyric acid (GABA) synaptic transmission closely interact to set the response of the DR to swim stress. To investigate the cellular basis of these physiological mechanisms the effects of ovine CRF (oCRF) on GABA(A)-dependent miniature inhibitory postsynaptic currents (mIPSCs) in 5-HT and non-5-HT DR neurons in acute mesencephalic slices obtained from rats either naïve or 24h after a 15 min swim stress session were tested. In this study, the effect of swim stress alone was to decrease the holding current, i.e., hyperpolarize the neuron, and to increase the amplitude and charge of mIPSCs recorded from non-5-HT neurons. Ovine CRF (10 nM) induced an increase in mIPSC frequency in 5-HT neurons recorded from naïve rats, an effect that was suppressed by swim stress. The inward current elicited by oCRF in both 5-HT and non-5-HT neurons was also blocked by swim stress. Ovine CRF increased mIPSCs amplitude and charge in both 5-HT and non-5-HT neurons, but this effect was not modified by swim stress. In concert with our previous findings that swim stress decreased input resistance, action potential threshold and action potential duration and increased glutamatergic synaptic activity the overall primary effect of swim stress is to increase the excitability of 5-HT neurons. These data provide a mechanism at the cellular level for the immobility induced by swim stress and identifies critical components of the raphe circuitry responsible for the altered output of 5-HT neurons induced by swim stress.

  18. Male median raphe cysts: serial retrospective analysis and histopathological classification

    Shao I-Hung


    Full Text Available Abstract Background To review the clinical and pathological characteristics of median raphe cysts and to classify the lesions according to pathogenesis and histopathological findings. Methods The medical records of patients who were diagnosed with median raphe cysts between 2001 and 2010 were reviewed to document the clinical presentation and pathological findings of the cysts. Results Most patients were asymptomatic; however, 9 patients had inflammatory or infectious cysts that were tender or painful. Four patients who had cysts on the parameatus and distal prepuce had difficulty voiding. Hematuria and hematospermia were noted in 2 cases. Thirty-one cysts were lined with an urothelium-like epithelium, and a squamous epithelium lining was found in 3 cases. In 2 cases, a well-formed mucinous glandular structure was observed. The other 20 cysts consisted of mixed epithelia. After excision of the cysts under local or general anesthesia, an urethral fistula developed as a complication in only 1 case. Conclusions Median raphe cysts are benign lesions formed due to tissue trapping during the development of urethral folds. The cysts can be defined into 4 types based on pathological findings: urethral, epidermoid, glandular, and mixed. The associated symptoms and signs should be taken into consideration when determining the treatment for the cysts. Virtual slides The virtual slide(s for this article can be found here: http//

  19. Systemic pregabalin attenuates sensorimotor responses and medullary glutamate release in inflammatory tooth pain model.

    Narita, N; Kumar, N; Cherkas, P S; Chiang, C Y; Dostrovsky, J O; Coderre, T J; Sessle, B J


    Our previous studies have demonstrated that application of inflammatory irritant mustard oil (MO) to the tooth pulp induces medullary glutamate release and central sensitization in the rat medullary dorsal horn (MDH), as well as nociceptive sensorimotor responses in craniofacial muscles in rats. There is recent evidence that anticonvulsant drugs such as pregabalin that influence glutamatergic neurotransmission are effective in several pain states. The aim of this study was to examine whether systemic administration of pregabalin attenuated glutamate release in the medulla as well as these nociceptive effects reflected in increased electromyographic (EMG) activity induced by MO application to the tooth pulp. Male adult rats were anesthetized with isofluorane (1.0-1.2%), and jaw and tongue muscle EMG activities were recorded by needle electrodes inserted bilaterally into masseter and anterior digastric muscles and into the genioglossus muscle, and also the medullary release of glutamate was assessed by in vivo microdialysis. Pregabalin or vehicle control (isotonic saline) was administered 30 min before the pulpal application of MO or vehicle control (mineral oil). Application of mineral oil to the maxillary first molar tooth pulp produced no change in baseline EMG activity and glutamate release. However, application of MO to the pulp significantly increased both the medullary release of glutamate and EMG activity in the jaw and tongue muscles for several minutes. In contrast, pre-medication with pregabalin, but not vehicle control, significantly and dose-dependently attenuated the medullary glutamate release and EMG activity in these muscles after MO application to the tooth pulp (analysis of variance (ANOVA), ppain model, and that it may prove useful for the treatment of orofacial inflammatory pain states. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome.

    Duncan, Jhodie R; Garland, Marianne; Myers, Michael M; Fifer, William P; Yang, May; Kinney, Hannah C; Stark, Raymond I


    During pregnancy, exposure to nicotine and other compounds in cigarette smoke increases the risk of the sudden infant death syndrome (SIDS) two- to fivefold. Serotonergic (5-HT) abnormalities are found, in infants who die of SIDS, in regions of the medulla oblongata known to modulate cardiorespiratory function. Using a baboon model, we tested the hypothesis that prenatal exposure to nicotine alters 5-HT receptor and/or transporter binding in the fetal medullary 5-HT system in association with cardiorespiratory dysfunction. At 87 (mean) days gestation (dg), mothers were continuously infused with saline (n = 5) or nicotine (n = 5) at 0.5 mg/h. Fetuses were surgically instrumented at 129 dg for cardiorespiratory monitoring. Cesarean section delivery and retrieval of fetal medulla were performed at 161 (mean) dg for autoradiographic analyses of nicotinic and 5-HT receptor and transporter binding. In nicotine-exposed fetuses, high-frequency heart rate variability was increased 55%, possibly reflecting increases in the parasympathetic control of heart rate. This effect was more pronounced with greater levels of fetal breathing and age. These changes in heart rate variability were associated with increased 5-HT(1A) receptor binding in the raphé obscurus (P = 0.04) and increased nicotinic receptor binding in the raphé obscurus and vagal complex (P < 0.05) in the nicotine-exposed animals compared with controls (n = 6). The shift in autonomic balance in the fetal primate toward parasympathetic predominance with chronic exposure to nicotine may be related, in part, to abnormal 5-HT-nicotine alterations in the raphé obscurus. Thus increased risk for SIDS due to maternal smoking may be partly related to the effects of nicotine on 5-HT and/or nicotinic receptors.

  1. Distinct Contributions of Median Raphe Nucleus to Contextual Fear Conditioning and Fear-Potentiated Startle

    Silva, R. C. B.; Cruz, A. P. M.; Avanzi, V.; Landeira-Fernandez, J.; Brandão, M. L.


    Ascending 5-HT projections from the median raphe nucleus (MRN), probably to the hippocampus, are implicated in the acquisition of contextual fear (background stimuli), as assessed by freezing behavior. Foreground cues like light, used as a conditioned stimulus (CS) in classical fear conditioning, also cause freezing through thalamic transmission to the amygdala. As the MRN projects to the hippocampus and amygdala, the role of this raphe nucleus in fear conditioning to explicit cues remains to be explained. Here we analyzed the behavior of rats with MRN electrolytic lesions in a contextual conditioning situation and in a fear-potentiated startle procedure. The animals received MRN electrolytic lesions either before or on the day after two consecutive training sessions in which they were submitted to 10 conditioning trials, each in an experimental chamber (same context) where they. received foot-shocks (0.6 mA, 1 sec) paired to a 4-sec light CS. Seven to ten days later, the animals were submitted to testing sessions for assessing conditioned fear when they were placed for five shocks, and the duration of contextual freezing was recorded. The animals were then submitted to a fear-potentiated startle in response to a 4-sec light-CS, followed by white noise (100 dB, 50 ms). Control rats (sham) tested in the same context showed more freezing than did rats with pre- or post-training MRN lesions. Startle was clearly potentiated in the presence of light CS in the sham-lesioned animals. Whereas pretraining lesions reduced both freezing and fear-potentiated startle, the post-training lesions reduced only freezing to context, without changing the fear-potentiated startle. In a second experiment, neurotoxic lesions of the MRN with local injections of N-methyl-D-aspartate or the activation of 5-HT1A somatodendritic auto-receptors of the MRN by microinjections of the 5-HT1A receptor agonist 8-hydroxy- 2-(di-n-propylamino)tetralin (8-OH-DPAT) before the training sessions also

  2. Medullary Thyroid Carcinoma Program | Center for Cancer Research

    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.

  3. Social separation and diazepam withdrawal increase anxiety in the elevated plus-maze and serotonin turnover in the median raphe and hippocampus.

    dos Santos, Lucinéia; de Andrade, Telma G C S; Graeff, Frederico G


    The present work aimed to evaluate the effects of social separation for 14 days (chronic stress) and of withdrawal from a 14-day treatment with diazepam (acute stress) on the exploratory behaviour of male rats in the elevated plus-maze and on serotonin (5-hydroxytryptamine) turnover in different brain structures. Social separation had an anxiogenic effect, evidenced by fewer entries into, and less time spent on the open arms of the elevated plus-maze. Separation also selectively increased 5-hydroxytryptamine turnover in the hippocampus and median raphe nucleus. Diazepam withdrawal had a similar anxiogenic effect in grouped animals and increased 5-hydroxytryptamine turnover in the same brain structures. Chronic treatment with imipramine during the 14 days of separation prevented the behavioural and neurochemical changes caused by social separation. It is suggested that the increase in anxiety determined by both acute and chronic stress is mediated by the activation of the median raphe nucleus-hippocampal 5-hydroxytryptamine pathway.

  4. Descending inhibitory modulation of nucleus raphes magnus in cardiac nociception in rats and its pathway%中缝大核对大鼠心脏伤害性感受的下行抑制性调控作用及其调控通路

    孙娜; 牛利刚; 孔令恒; 朱娟霞; 徐燕; 杜剑青


    Objective To observe the cardiosomatic motor reflex (CMR)of rats, and to clarify the descending modulation of nucleus raphes magnus (NRM)in cardiac nociception and its pathway.Methods 34 male healthy SD rats were randomly divided into NRM electrical stimulation group (n=8 ), NRM stimulation combined with dorsolateral funiculus (DLF ) transection group (n= 8 ), NRM stimulation combined with antagonist of 5-hydroxytryptamine (5-HT)methysergide intrathecal administration group (n=18).The rat model of CMR was established through inj ecting capsaicin into the pericardial sac of the rats in various groups. The electromyogram (EMG) response of dorsal spinotrapezius muscle was used as detection index, and by placing the stimulation electrode in NRM and (or)intrathecal catheterization, the descending inhibitory modulation of NRM in CMR and the influence of DLF tansection or methysergide intrathecal administration in descending inhibitory modulation of NRM were observed.Results Compared with before stimulation,the EMG response was decreased after NRM electrical stimulation (75 μA) (P 0.05 ). In addition, after intrathecal administration of methysergide,the EMG response after NRM stimulation was significantly increased compared with before intrathecal treatment of methysergide (P<0.05),but it was still significantly smaller than that of its control (P<0.05). Conclusion Cardiac nociception evoked by capsaicin stimulation is subject to descending inhibitory modulation from NRM,and the descending inhibition from NRM is conveyed via the DLF and partially mediated by endogenous 5-HT system.%目的:观察大鼠心脏-躯体运动反射(CMR),阐明中缝大核(NRM)对大鼠心脏伤害性感受的下行抑制性调控作用及其调控通路。方法:34只雄性健康 SD大鼠随机分为 NRM电刺激组(n=8)、NRM电刺激联合脊髓背外侧束(DLF)横断组(n=8)和 NRM电刺激联合5-羟色胺(5-HT)受体拮抗剂鞘内微注射组(n=18

  5. Dermatomal sensory manifestations in lateral medullary infarction.

    Hongo, Hiroki; Tanaka, Yasutaka; Shimada, Yoshiaki; Tanaka, Ryota; Hattori, Nobutaka; Urabe, Takao


    A 61-year-old man who experienced a sudden onset of unstable gait followed by nuchal pain was admitted to our department. The neurologic examination revealed right-sided limb ataxia, right partial ptosis, and decreased sensation to 50% of the normal side to pinprick and temperature stimuli on the left side below the level of the T-6 dermatome. A lateral medullary infarction caused by spontaneous vertebral artery dissection was diagnosed by magnetic resonance imaging and computed tomography angiography. In conclusion, lateral medullary infarction is an important entity to consider in the differential diagnosis of dermatomal sensory manifestations.

  6. Metastatic medullary thyroid carcinoma: A case report

    Mitra Niafar


    Full Text Available Medullary thyroid carcinoma accounts for 4% of thyroid carcinoma and originates from parafollicular cells, secreting calcitonin and carcinoembryonic antigen (CEA. Conventional radiographic modalities such as Computerized Tomography (CT, Magnetic Resonance Imaging (MRI, and Ultrasonography (U/S, are used for detecting recurrences following total thyroidectomy. However, metastatic disease frequently escapes detection by the above modalities, even when its presence is suggested by persistently elevated serum calcitonin levels. In this paper, we report a case of medullary thyroid carcinoma in a 40 year-old woman who had whole body octreotide scintigraphy to evaluate and detect the origin of calcitonin and CEA secretion.

  7. NO-generating neurons in the medullary cardiovascular centers of rodents and carnivores.

    Maisky, Vladimir A; Datsenko, Vladimir V; Moibenko, Alexei A; Bugaychenko, Larisa A; Pilyavskii, Alexander I; Kostyukov, Alexander I; Kalezic, Ivana; Johansson, Håkan


    The aim of the study was to characterize the species-related differences in the distribution of nitric oxide synthase (NOS)-containing neurons in rodents and carnivores medullary cardiovascular centers that take part in regulation of the sympathetic or parasympathetic drives. The order of the mean number of NOS-containing neurons in the dorsomedial and ventrolateral medulla (per section) in different animals was as follows: dog>cat>rat. Although the density of the positive cells in the both regions was changed in the following sequence: rat=cat>dog. Within the dorsal motor nucleus of vagus significant exceeding of the mean number and density of positive cells (preganglionic vagal neurons) in dog were found. Differences in the distribution of NO-generating neurons in the medullary cardiovascular centers and the heterogeneity in the basal level of NO release may contribute to the distinctive alterations of the hemodynamic reactions in the studied species after administration of NOS inhibitors.

  8. Effect of electrolytic lesion of the dorsal raphe nucleus on water intake and sodium appetite

    E.L. Olivares


    Full Text Available The present study determined the effect of an electrolytic lesion of the dorsal raphe nucleus (DRN on water intake and sodium appetite. Male Wistar rats weighing 290-320 g with a lesion of the DRN (L-DRN, performed two days before experiments and confirmed by histology at the end of the experiments, presented increased sensitivity to the dehydration induced by fluid deprivation. The cumulative water intake of L-DRN rats reached 23.3 ± 1.9 ml (a 79% increase, N = 9 while sham-lesioned rats (SL-DRN did not exceed 13.0 ± 1.0 ml (N = 11, P < 0.0001 after 5 h. The L-DRN rats treated with isoproterenol (300 µg kg-1 ml-1, sc exhibited an increase in water intake that persisted throughout the experimental period (L-DRN, 15.7 ± 1.47 ml, N = 9 vs SL-DRN, 9.3 ± 1.8 ml, N = 11, P < 0.05. The L-DRN rats also showed an increased spontaneous sodium appetite during the entire period of assessment. The intake of 0.3 M NaCl after 12, 24, 36 and 72 h by the L-DRN rats was always higher than 20.2 ± 4.45 ml (N = 10, while the intake by SL-DRN was always lower than 2.45 ± 0.86 ml (N = 10, P < 0.00001. Sodium- and water-depleted L-DRN rats also exhibited an increased sodium appetite (13.9 ± 2.0 ml, N = 11 compared to SL-DRN (4.6 ± 0.64 ml, N = 11 after 120 min of observation (P < 0.02. The sodium preference of L-DRN rats in both conditions was always higher than that of SL-DRN rats. These results suggest that electrolytic lesion of the DRN overcomes a tonic inhibitory component of sodium appetite.

  9. Role of nitric oxide in nucleus raphe magnus in pain regulation and electroacupuncture analgesia in rats%大鼠中缝大核内一氧化氮在痛觉调制和针刺镇痛中的作用

    黄碧兰; 涂宗萍; 余良主


    BACKGROUND: L-arginine (L-Arg) is the precursor of endogenous nitric oxide (NO), which joins the pain regulation of peripheral myeloid level and above.OBJECTIVE: To study the role and mechanism of NO in nucleus raphe magnus (NRM) in pain regulation and electroacupuncture analgesia.DESIGN: A random control experiment on rats.SETTING: Physiology Department of Medical College of Xianning College.MATERIALS: The experiment was done during May 2002 to March 2003in the Physiology Department of Medical College of Xianning College. The 63 Wistar rats were randomized into 7 groups with 9 in each. ①. Five groups for the experiment of L-Arg dose-effect relationship: Normal saline group and L-Arg 1, 2, 4, 8 mmol groups. ②. Two groups for the experiment of relationship between L-Arg and electroacupuncture analgesia: Normal saline + electroacupuncture group and L-Arg + electroacupuncture group.METHODS: ①Experiment of L-Arg dose-effect relationship: Normal saline group was injected normal saline. L-Arg 1, 2, 4, 8 mmol groups were injected L-Arg 1, 2, 4, 8 mmol respectively. The volume was all 1.5 μL.Then, the hot water (50±0.5) ℃ was used to stimulate the tail once every 10 minutes to cause tail flick for testing the pain threshold. The observation was carried out continuously for 90 minutes. ②. Experiment of relationship between L-Arg and electroacupuncture analgesia: The two groups were injected normal saline and L-Arg 8 mmol respectively. The volume was all 1.5 μL. Ten minutes later, Zusanli (ST 36) of both posterior legs of rats were punctured with electric stimulation. The frequency was 4-16 Hz, and the intensity in an increasing order of 1, 2, 3V given 10 minutes of each. The electroacupuncture was totally 30 minutes, during which, testing the pain threshold 3 times. After needling, the pain threshold was still tested once every 10 minutes, till 90 minutes after injecting L-Arg.MAIN OUTCOME MEASURES: Pain threshold at different time points.RESULTS: The 63 rats

  10. Decreased adrenal medullary tyrosine hydroxylase mRNA in DMBA (7,12-dimethylbenz(a)anthracene)-induced mammary carcinoma

    Bunce, O.R.; Badary, O.A.; Abou El-Ela, S.; Hartle, D.K. (Univ. of Georgia, Athens (United States))


    Adrenal cortical hormones suppress initiation and promotion of DMBA-induced mammary tumorigenesis. The authors found a positive correlation between presence of DMBA-induced adrenal cortical necrosis and mammary tumor incidence. Because they find adrenal medullary as well as cortical lesions in tumor bearing (TB) DMBA-treated rats, they evaluated medullary function by quantitating hybridized cDNA- TH-S{sup 35} with in situ TH-mRNA u sing computer assisted quantitative autoradiographic technique. Virgin female Sprague-Dawley rats were given a 10 mg i.g. dose of DMBA. Three wks later, rats were placed on 20% polyunsaturated (PUFA) fat diets containing omega-6 and omega-3 fatty acids. All were killed 15 wks post-DMBA. TH-mRNA levels in adrenal medullae of TB animals were decreased compared to non-TB rats. Histopathology indicated a high incidence of medullary necrosis in TB rats, whereas, adrenal necrosis did not occur in non-TB animals. Adrenal necrosis correlated positively with tumor burden, but no correlation was found between incidence of adrenal lesions and type of PUFA in the diet. The authors suggest that DMBA adrenal necrosis may reduce TH-mRNA in the medulla, compromise its catecholamine synthetic capability, and thereby contribute to the overall metabolic stress condition of TB rats.

  11. Recurrent intramedullary epidermoid cyst of conus medullaris.

    Fleming, Christina


    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.

  12. Schwannosis induced medullary compression in VACTERL syndrome.

    Treacy, A


    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.

  13. Neuronal activation in the central nervous system of rats in the initial stage of chronic kidney disease-modulatory effects of losartan and moxonidine.

    Palkovits, Miklós; Šebeková, Katarína; Klenovics, Kristina Simon; Kebis, Anton; Fazeli, Gholamreza; Bahner, Udo; Heidland, August


    The effect of mild chronic renal failure (CRF) induced by 4/6-nephrectomy (4/6NX) on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos-immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus). Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons) and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow) did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain-related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances.

  14. Neuronal activation in the central nervous system of rats in the initial stage of chronic kidney disease-modulatory effects of losartan and moxonidine.

    Miklós Palkovits

    Full Text Available The effect of mild chronic renal failure (CRF induced by 4/6-nephrectomy (4/6NX on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos-immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus. Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain-related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances.

  15. Impaired Sacculocollic Reflex in Lateral Medullary Infarction

    Seonhye eKim; Hyo-Jung eKim; Ji Soo eKim


    Objective: The aim of this study was to determine saccular dysfunction by measuring cervical vestibular-evoked myogenic potentials (cVEMP) and to correlate abnormality of cVEMP with results of other vestibular function tests in lateral medullary infarction (LMI). Methods: We recorded cVEMP in 21 patients with LMI documented on MRI. cVEMP was induced by a short tone burst and was recorded in contracting sternocleidomastoid muscle while patients turned their heads forcefully to the contralatera...

  16. Advanced medullary thyroid cancer: pathophysiology and management

    Ferreira CV


    Full Text Available Carla Vaz Ferreira, Débora Rodrigues Siqueira, Lucieli Ceolin, Ana Luiza MaiaThyroid Section, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, BrazilAbstract: Medullary thyroid carcinoma (MTC is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3%–4% of thyroid gland neoplasias. MTC may occur sporadically or be inherited. Hereditary MTC appears as part of the multiple endocrine neoplasia syndrome type 2A or 2B, or familial medullary thyroid cancer. Germ-line mutations of the RET proto-oncogene cause hereditary forms of cancer, whereas somatic mutations can be present in sporadic forms of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration, and survival. Nowadays, early diagnosis of MTC followed by total thyroidectomy offers the only possibility of cure. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in an attempt to control metastatic disease. Of these, small-molecule tyrosine kinase inhibitors represent one of the most promising agents for MTC treatment, and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs and about the tyrosine kinase inhibitor-associated side effects will help in choosing the best therapeutic approach to enhance their benefits.Keywords: medullary thyroid carcinoma, proto-oncogene RET, tyrosine kinase inhibitors

  17. Dorsal Raphe Dopamine Neurons Represent the Experience of Social Isolation.

    Matthews, Gillian A; Nieh, Edward H; Vander Weele, Caitlin M; Halbert, Sarah A; Pradhan, Roma V; Yosafat, Ariella S; Glober, Gordon F; Izadmehr, Ehsan M; Thomas, Rain E; Lacy, Gabrielle D; Wildes, Craig P; Ungless, Mark A; Tye, Kay M


    The motivation to seek social contact may arise from either positive or negative emotional states, as social interaction can be rewarding and social isolation can be aversive. While ventral tegmental area (VTA) dopamine (DA) neurons may mediate social reward, a cellular substrate for the negative affective state of loneliness has remained elusive. Here, we identify a functional role for DA neurons in the dorsal raphe nucleus (DRN), in which we observe synaptic changes following acute social isolation. DRN DA neurons show increased activity upon social contact following isolation, revealed by in vivo calcium imaging. Optogenetic activation of DRN DA neurons increases social preference but causes place avoidance. Furthermore, these neurons are necessary for promoting rebound sociability following an acute period of isolation. Finally, the degree to which these neurons modulate behavior is predicted by social rank, together supporting a role for DRN dopamine neurons in mediating a loneliness-like state. PAPERCLIP.

  18. Tolerance to non-opioid analgesics is opioid-sensitive in nucleus raphe magnus

    Merab G Tsagareli


    Full Text Available Repeated injection of opioid analgesics can lead to a progressive loss of its effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs in the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM in the following four days result in progressively less antinociception, i.e. produce the development of tolerance to these drugs in mail rats. Special control experiments showed that post-treatment with μ-opioid antagonist naloxone in NRM significantly decreased antinociceptive effects of NSAIDs at the first day in behavioral tail flick reflex (TF and hot plate (HP latencies. At the second day, naloxone generally had trend effects in both TF and HP tests impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion on endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too.

  19. Cortical and medullary vascularity in renal allograft biopsies


    Aim: To evaluate the relation between cortical and medullary peritubular capillaries (PTCs) and scarring. There are presently no studies about medullary PTCs in renal allograft biopsies. Materials and methods: Nonprotocol allograft biopsies were evaluated and 41 with adequate medullary and cortical tissues were selected. Vascular structures were counted separately at the medulla and cortex on anti-CD34 stained sections. Other histopathological and clinical findings were retrieved from the p...

  20. Renal medullary ETB receptors produce diuresis and natriuresis via NOS1.

    Nakano, Daisuke; Pollock, Jennifer S; Pollock, David M


    Endothelin-1 (ET-1) plays an important role in the regulation of salt and water excretion in the kidney. Considerable in vitro evidence suggests that the renal medullary ET(B) receptor mediates ET-1-induced inhibition of electrolyte reabsorption by stimulating nitric oxide (NO) production. The present study was conducted to test the hypothesis that NO synthase 1 (NOS1) and protein kinase G (PKG) mediate the diuretic and natriuretic effects of ET(B) receptor stimulation in vivo. Infusion of the ET(B) receptor agonist sarafotoxin S6c (S6c: 0.45 microg x kg(-1) x h(-1)) in the renal medulla of anesthetized, male Sprague-Dawley rats markedly increased the urine flow (UV) and urinary sodium excretion (UNaV) by 67 and 120%, respectively. This was associated with an increase in medullary cGMP content but did not affect blood pressure. In addition, S6c-induced diuretic and natriuretic responses were absent in ET(B) receptor-deficient rats. Coinfusion of N(G)-propyl-l-arginine (10 microg x kg(-1) x h(-1)), a selective NOS1 inhibitor, suppressed S6c-induced increases in UV, UNaV, and medullary cGMP concentrations. Rp-8-Br-PET-cGMPS (10 microg x kg(-1) x h(-1)) or RQIKIWFQNRRMKWKK-LRK(5)H-amide (18 microg x kg(-1) x h(-1)), a PKG inhibitor, also inhibited S6c-induced increases in UV and UNaV. These results demonstrate that renal medullary ET(B) receptor activation induces diuretic and natriuretic responses through a NOS1, cGMP, and PKG pathway.

  1. Functional connectivity of the dorsal and median raphe nuclei at rest

    Beliveau, Vincent; Svarer, Claus; Frokjaer, Vibe G; Knudsen, Gitte M; Greve, Douglas N.; Fisher, Patrick M.


    Serotonin (5-HT) is a neurotransmitter critically involved in a broad range of brain functions and implicated in the pathophysiology of neuropsychiatric illnesses including major depression, anxiety and sleep disorders. Despite being widely distributed throughout the brain, there is limited knowledge on the contribution of 5-HT to intrinsic brain activity. The dorsal raphe (DR) and median raphe (MR) nuclei are the source of most serotonergic neurons projecting throughout the brain and thus pr...

  2. Chronic excitotoxic lesion of the dorsal raphe nucleus induces sodium appetite

    Cavalcante-Lima H.R.


    Full Text Available We determined if the dorsal raphe nucleus (DRN exerts tonic control of basal and stimulated sodium and water intake. Male Wistar rats weighing 300-350 g were microinjected with phosphate buffer (PB-DRN, N = 11 or 1 µg/0.2 µl, in a single dose, ibotenic acid (IBO-DRN, N = 9 to 10 through a guide cannula into the DRN and were observed for 21 days in order to measure basal sodium appetite and water intake and in the following situations: furosemide-induced sodium depletion (20 mg/kg, sc, 24 h before the experiment and a low dose of dietary captopril (1 mg/g chow. From the 6th day after ibotenic acid injection IBO-DRN rats showed an increase in sodium appetite (12.0 ± 2.3 to 22.3 ± 4.6 ml 0.3 M NaCl intake whereas PB-DRN did not exceed 2 ml (P < 0.001. Water intake was comparable in both groups. In addition to a higher dipsogenic response, sodium-depleted IBO-DRN animals displayed an increase of 0.3 M NaCl intake compared to PB-DRN (37.4 ± 3.8 vs 21.6 ± 3.9 ml 300 min after fluid offer, P < 0.001. Captopril added to chow caused an increase of 0.3 M NaCl intake during the first 2 days (IBO-DRN, 33.8 ± 4.3 and 32.5 ± 3.4 ml on day 1 and day 2, respectively, vs 20.2 ± 2.8 ml on day 0, P < 0.001. These data support the view that DRN, probably via ascending serotonergic system, tonically modulates sodium appetite under basal and sodium depletion conditions and/or after an increase in peripheral or brain angiotensin II.

  3. Intramedullary bronchogenic cyst of the conus medullaris.

    Yilmaz, Cem; Gulsen, Salih; Sonmez, Erkin; Ozger, Ozkan; Unlukaplan, Muge; Caner, Hakan


    Spinal bronchogenic cysts are rare congenital lesions. The authors describe their experience in the treatment of a 17-year-old boy who presented with back pain and paresthesia in both lower extremities. Lumbar MR imaging revealed the presence of an intramedullary cystic lesion at the conus medullaris and histopathological analysis revealed a bronchogenic cyst. To the best of the authors' knowledge, this is the first report of an intramedullary spinal bronchogenic cyst arising at the conus; all previously reported spinal bronchogenic cysts were either intradural extramedullary or not located at the conus.

  4. Intramedullary mature teratoma of the conus medullaris

    Kadir Oktay


    Full Text Available Teratoma is a tumor that derivatives from all three primitive germ layers and spinal intramedullary teratomas are very rare lesions. The primary treatment modality for these tumors is surgical resection, and total resection should be the aim. However, subtotal resection is a valid alternative to prevent traumatizing adjacent functional neural tissue. In this report, we presented a case of a 12-year-old male patient with spinal teratoma of the conus medullaris. We describe the presentation, evaluation, and treatment of this rare disease.

  5. Medullary trichomalacia in 6 German shepherd dogs.

    Tieghi, Chiara; Miller, William H; Scott, Danny W; Pasquinelli, Gianandrea


    Medullary trichomalacia is the name proposed for a hair shaft abnormality that was recognized in 6 German shepherd dogs. Affected dogs had multifocal areas of broken hairs, especially on the dorsolateral trunk. Microscopic examination of hair shafts revealed focal areas of loss of architecture, swelling, and apparent softening of the medulla, followed by longitudinal (length-wise) splitting and breakage of the hair shaft. No cause could be found. Affected dogs were otherwise healthy, and apparent spontaneous recovery was the usual outcome. Relapses may occur.

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

    Kuijf, Hugo J.; Bouvy, Willem H.; Zwanenburg, Jaco J M; Schultz, Tom B Razoux; Viergever, Max A.; Vincken, Koen L.; Biessels, Geert Jan


    Objectives: 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. Methods: Five participants were scanned

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

    Kuijf, Hugo J.; Bouvy, Willem H.; Zwanenburg, Jaco J M; Schultz, Tom B Razoux; Viergever, Max A.; Vincken, Koen L.; Biessels, Geert Jan


    Objectives: 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. Methods: Five participants were scanned twi




    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 di

  9. Divergent in vivo activity of non‐serotonergic and serotonergic VGluT3–neurones in the median raphe region

    Domonkos, Andor; Nikitidou Ledri, Litsa; Laszlovszky, Tamás; Cserép, Csaba; Borhegyi, Zsolt; Papp, Edit; Nyiri, Gábor; Freund, Tamás F.


    Key points The median raphe is a key subcortical modulatory centre involved in several brain functions, such as regulation of the sleep–wake cycle, emotions and memory storage.A large proportion of median raphe neurones are glutamatergic and implement a radically different mode of communication compared to serotonergic cells, although their in vivo activity is unknown.We provide the first description of the in vivo, brain state‐dependent firing properties of median raphe glutamatergic neurones identified by immunopositivity for the vesicular glutamate transporter type 3 (VGluT3) and serotonin (5‐HT). Glutamatergic populations (VGluT3+/5‐HT– and VGluT3+/5‐HT+) were compared with the purely serotonergic (VGluT3–/5‐HT+ and VGluT3–/5‐HT–) neurones.VGluT3+/5‐HT+ neurones fired similar to VGluT3–/5‐HT+ cells, whereas they significantly diverged from the VGluT3+/5‐HT– population. Activity of the latter subgroup resembled the spiking of VGluT3–/5‐HT– cells, except for their diverging response to sensory stimulation.The VGluT3+ population of the median raphe may broadcast rapidly varying signals on top of a state‐dependent, tonic modulation. Abstract Subcortical modulation is crucial for information processing in the cerebral cortex. Besides the canonical neuromodulators, glutamate has recently been identified as a key cotransmitter of numerous monoaminergic projections. In the median raphe, a pure glutamatergic neurone population projecting to limbic areas was also discovered with a possibly novel, yet undetermined function. In the present study, we report the first functional description of the vesicular glutamate transporter type 3 (VGluT3)‐expressing median raphe neurones. Because there is no appropriate genetic marker for the separation of serotonergic (5‐HT+) and non‐serotonergic (5‐HT–) VGluT3+ neurones, we utilized immunohistochemistry after recording and juxtacellular labelling in anaesthetized rats. VGluT3+/5

  10. Alterations in the Medullary Endocannabinoid System Contribute to Age-related Impairment of Baroreflex Sensitivity.

    Schaich, Chris L; Shaltout, Hossam A; Grabenauer, Megan; Thomas, Brian F; Gallagher, Patricia E; Howlett, Allyn C; Diz, Debra I


    As they age, Sprague-Dawley (SD) rats develop elevated systolic blood pressure associated with impaired baroreflex sensitivity (BRS) for control of heart rate. We previously demonstrated in young hypertensive (mRen2)27 rats that impaired BRS is restored by CB1 cannabinoid receptor blockade in the solitary tract nucleus (NTS), consistent with elevated content of the endocannabinoid 2-arachidonoylglycerol (2-AG) in dorsal medulla relative to normotensive SD rats. There is no effect of CB1 receptor blockade in young SD rats. We now report in older SD rats that dorsal medullary 2-AG levels are 2-fold higher at 70 versus 15 weeks of age (4.22 ± 0.61 vs. 1.93 ± 0.22 ng/mg tissue; P < 0.05). Furthermore, relative expression of CB1 receptor messenger RNA is significantly lower in aged rats, whereas CB2 receptor messenger RNA is significantly higher. In contrast to young adult SD rats, microinjection of the CB1 receptor antagonist SR141716A (36 pmole) into the NTS of older SD rats normalized BRS in animals exhibiting impaired baseline BRS (0.56 ± 0.06 baseline vs. 1.06 ± 0.05 ms/mm Hg after 60 minutes; P < 0.05). Therefore, this study provides evidence for alterations in the endocannabinoid system within the NTS of older SD rats that contribute to age-related impairment of BRS.

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

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


    . 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......Postnatal inhibition or deletion of angiotensin II (ANG II) AT1 receptors impairs renal medullary mircrovascular development through a mechanism that may include vascular endothelial growth factor (VEGF). The present study was designed to test if VEGF/VEGF receptor signaling is necessary...... mechanism....

  12. Effects of midbrain and medullary stimulation on spinomesencephalic tract cells in the cat.

    Yezierski, R P


    1. The effects of electrical stimulation at different rostrocaudal levels of the midbrain, and at sites in the rostral medulla ipsilateral and contralateral to spinal recording sites, were evaluated against the responses of 46 cells belonging to the cat spinomesencephalic tract (SMT). 2. Inhibitory and/or excitatory effects of brain stem stimulation were observed on SMT cells that responded best (26 cells) or exclusively (12 cells) to noxious mechanical or thermal stimuli, as well as on 7 cells responding only to tap and/or stimulation of deep tissues. Recording sites for 32 cells were located in laminae V-VIII (27 cells) and laminae I-III (5 cells). 3. Midbrain stimulation sites were located in the superior colliculus, central gray (CG), red nucleus, and the midbrain reticular formation. Both inhibitory-only and excitatory-only effects were observed, although the most common effect of midbrain stimulation was excitation followed by inhibition (mixed effects). The effects of stimulation at different midbrain levels were determined for each cell. Stimulation in the caudal, middle, or rostral midbrain was often found to exert different effects on the same SMT cell. 4. Stimulation in the rostral medulla at sites located in nucleus raphe magnus (NRM), nucleus reticularis gigantocellularis, and nucleus reticularis magnocellularis produced the same complement of effects observed with midbrain stimulation. Excitation followed by inhibition was the most common effect observed. 5. Stimulus intensities required to produce excitatory or inhibitory effects from midbrain were 114 +/- 85 (SD) microA and 210 +/- 91 microA, respectively. Stimulus currents required to produce excitatory or inhibitory effects from medullary stimulation sites were 124 +/- 56 microA and 70 +/- 60 microA, respectively. The mean currents required to produce mixed effects were 221 +/- 120 microA (midbrain) and 127 +/- 71 microA (medulla). Increasing the stimulus intensity used to evaluate brain stem

  13. Serotonergic neurons in the caudal raphe nuclei discharge in association with activity of masticatory muscles

    Ribeiro-do-Valle L.E.


    Full Text Available There is a dense serotonergic projection from nucleus raphe pallidus and nucleus raphe obscurus to the trigeminal motor nucleus and serotonin exerts a strong facilitatory action on the trigeminal motoneurons. Some serotonergic neurons in these caudal raphe nuclei increase their discharge during feeding. The objective of the present study was to investigate the possibility that the activity of these serotonergic neurons is related to activity of masticatory muscles. Cats were implanted with microelectrodes and gross electrodes. Caudal raphe single neuron activity, electrocorticographic activity, and splenius, digastric and masseter electromyographic activities were recorded during active behaviors (feeding and grooming, during quiet waking and during sleep. Seven presumed serotonergic neurons were identified. These neurons showed a long duration action potential (>2.0 ms, and discharged slowly (2-7 Hz and very regularly (interspike interval coefficient of variation <0.3 during quiet waking. The activity of these neurons decreased remarkably during fast wave sleep (78-100%. Six of these neurons showed tonic changes in their activity positively related to digastric and/or masseter muscle activity but not to splenius muscle activity during waking. These data are consistent with the hypothesis that serotonergic neurons in the caudal raphe nuclei play an important role in the control of jaw movements

  14. Sodium salicylate suppresses GABAergic inhibitory activity in neurons of rodent dorsal raphe nucleus.

    Yan Jin

    Full Text Available Sodium salicylate (NaSal, a tinnitus inducing agent, can activate serotonergic (5-HTergic neurons in the dorsal raphe nucleus (DRN and can increase serotonin (5-HT level in the inferior colliculus and the auditory cortex in rodents. To explore the underlying neural mechanisms, we first examined effects of NaSal on neuronal intrinsic properties and the inhibitory synaptic transmissions in DRN slices of rats by using whole-cell patch-clamp technique. We found that NaSal hyperpolarized the resting membrane potential, decreased the input resistance, and suppressed spontaneous and current-evoked firing in GABAergic neurons, but not in 5-HTergic neurons. In addition, NaSal reduced GABAergic spontaneous and miniature inhibitory postsynaptic currents in 5-HTergic neurons. We next examined whether the observed depression of GABAergic activity would cause an increase in the excitability of 5-HTergic neurons using optogenetic technique in DRN slices of the transgenic mouse with channelrhodopsin-2 expressed in GABAergic neurons. When the GABAergic inhibition was enhanced by optical stimulation to GABAergic neurons in mouse DRN, NaSal significantly depolarized the resting membrane potential, increased the input resistance and increased current-evoked firing of 5-HTergic neurons. However, NaSal would fail to increase the excitability of 5-HTergic neurons when the GABAergic synaptic transmission was blocked by picrotoxin, a GABA receptor antagonist. Our results indicate that NaSal suppresses the GABAergic activities to raise the excitability of local 5-HTergic neural circuits in the DRN, which may contribute to the elevated 5-HT level by NaSal in the brain.

  15. Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus.

    Tsagareli, Merab G; Nozadze, Ivliane; Tsiklauri, Nana; Gurtskaia, Gulnaz


    Repeated injection of opioid analgesics can lead to a progressive loss of effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) into the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac, and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM) in the following 4 days result in progressively less antinociception compare to the saline control, i.e., tolerance develops to these drugs in male rats. Special control experiments showed that post-treatment with the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive effects of NSAIDs on the first day of testing in the tail-flick (TF) reflex and hot plate (HP) latency tests. On the second day, naloxone generally had trend effects in both TF and HP tests and impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine, and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too.

  16. 中缝大核微量注射5-HT、IL-6及L-Arg对胃运动的调节作用%Effect of microinjecting 5-HT, IL-6 and L-Arg into nucleus raphe magnus on gastric motility in rat

    周梦鹤; 杨雪娟; 乔卉; 秦芳芳; 安书成


    为了研究中缝大核(Nucleus Raphe Magnus,NRM)对胃运动的调节作用及其机制,实验采用大鼠中缝大核给药,张力传感器记录胃收缩幅度及频率.结果显示:中缝大核微量注入五羟色胺(5-hydroxytryptamine,5-HT)能增强大鼠胃收缩幅度,纳洛酮能抑制5-HT的这一作用;中缝大核内白细胞介素-6(Interleukin-6,IL-6)可以增强胃收缩幅度;L-精氨酸(L-Arginine,L-Arg)可以减弱胃收缩幅度,消除5-HT的强胃效应,反转IL-6的强胃效应;利醅酮可以增强L-Arg效应,消除IL-6的强胃效应.研究表明,中缝大核内的5-HT对胃运动的调节与内源性阿片肽有关,并受一氧化氮(NO)的调制.同时,5-HT也通过2A受体调节NO的作用;NRM内IL-6也参与胃运动的调节,其作用也与NO和5-HT2A受体相关.IL-6、NO和5-HT在NRM组成了一个内部调节网络,相互协同调节胃运动.

  17. Cannabidiol inhibits the reward-facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus.

    Katsidoni, Vicky; Anagnostou, Ilektra; Panagis, George


    Cannabidiol is a non-psychotomimetic constituent of Cannabis sativa, which induces central effects in rodents. It has been shown that cannabidiol attenuates cue-induced reinstatement of heroin seeking. However, to the best of our knowledge, its effects on brain stimulation reward and the reward-facilitating effects of drugs of abuse have not yet been examined. Therefore, we investigated the effects of cannabidiol on brain reward function and on the reward-facilitating effect of morphine and cocaine using the intracranial self-stimulation (ICSS) paradigm. Rats were prepared with a stimulating electrode into the medial forebrain bundle (MFB), and a guide cannula into the dorsal raphe (microinjection experiments), and were trained to respond for electrical brain stimulation. A low dose of cannabidiol did not affect the reinforcing efficacy of brain stimulation, whereas higher doses significantly elevated the threshold frequency required for MFB ICSS. Both cocaine and morphine lowered ICSS thresholds. Cannabidiol inhibited the reward-facilitating effect of morphine, but not cocaine. This effect was reversed by pre-treatment with an intra-dorsal raphe injection of the selective 5-HT1A receptor antagonist WAY-100635. The present findings indicate that cannabidiol does not exhibit reinforcing properties in the ICSS paradigm at any of the doses tested, while it decreases the reward-facilitating effects of morphine. These effects were mediated by activation of 5-HT1A receptors in the dorsal raphe. Our results suggest that cannabidiol interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids, thus indicating that cannabidiol may be clinically useful in attenuating the rewarding effects of opioids.

  18. Schwannoma of the conus medullaris: a rare case

    Suat Canbay; Askin Esen Hasturk; Fatma Markoc; Sukru Caglar


    Intradural schwannoma of the conus medullaris is a rare form of spinal neoplasm,which commonly occurs in the lumbar region.Conus medullaris level is unusual for schwannomas.A 49-year-old woman presented with chronic sciatica,mild bladder dysfunction,and paresthesia in the buttocks.Magnetic resonance imaging of the spine showed a mass lesion in the conus medullaris region with nerve compression.The tumor was completely resected and diagnosed histologically as schwannoma.The patient recovered after surgery.Clinical and radiologic features of this rare tumor are reviewed and are accompanied by literature findings.

  19. Medullary sponge kidney and isolated hemihyperplasia

    P S Priyamvada


    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.

  20. [Dysphagia with lateral medullary infarction (Wallenberg's syndrome)].

    Oshima, Fumiko


    Dysphagia after lateral medullary infarction (LMI) is common. The dysphagia of LMI is dynamically characterized by a failure in triggering of the pharyngeal-phase swallowing movements, reduced output, and lack of coordination (swallowing pattern abnormality). Based on accurate evaluation, we can select suitable rehabilitative approaches for individual patients, including respiratory therapy, food modification, postural changes, and oral care. We focused on the absence of upper esophageal sphincter (UES) opening of the unaffected side of the medullae. The movement pattern was defined as failure of bolus passage through the intact side of the UES, occurring at least once during the videofluorographic evaluation of each individual. Three abnormal patterns of UES opening were classified. The passage pattern abnormality shows the failure of the stereotyped motor sequence. For severe cases, it is necessary to consider long-term treatment, including botulinum toxin injection or surgery to prevent aspiration and adequate nutritional management.

  1. Depressive-like profile induced by MCH microinjections into the dorsal raphe nucleus evaluated in the forced swim test.

    Lagos, Patricia; Urbanavicius, Jessika; Scorza, María Cecilia; Miraballes, Rodrigo; Torterolo, Pablo


    Antagonism of the melanin-concentrating hormone (MCH) receptor 1 (MCH-R1) has been recently shown to have antidepressant-like profile in rats. However, the mechanisms by which the MCHergic system participates in the modulation of emotional states are still to be determined. In the present study we confirmed the presence of MCHergic fibers within the dorsal raphe nucleus (DRN), a serotonergic nucleus involved in the physiopathology of major depression. We also assessed the effects of the administration of MCH and anti-MCH antibody (immunoneutralization) into the DRN using the forced swim test in rats, an animal model to screen antidepressant drugs. We found that a low dose of MCH (50 ng) evoked a depressive-like behavior indicated by a significant increase in the immobility time as well as a decrease in climbing behavior. Furthermore, the depressive-like response was prevented by pretreatment with fluoxetine. Consistent with these results, the immunoneutralization of MCH produced an antidepressant-like effect. By means of the open field test we discarded that these effects were related to unspecific changes in motor activity. Our results suggest that the MCHergic neurons are involved in the regulation of emotional behaviors through the modulation of the serotonergic neuronal activity within the DRN. In addition, the present results are in agreement with previous reports showing that antagonism of the MCHergic system may be a novel therapeutic strategy for the treatment of depressive disorders.

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

    D O Gazizova


    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.

  3. Reduction of noise in medullary renograms from dynamic MR images.

    Giele, E L; de Priester, J A; Blom, J A; den Boer, J A; van Engelshoven, J M; Hasman, A


    Dynamic magnetic resonance images of the kidney can be used to acquire separate renograms of the cortex and medulla. A high-quality cortical renogram can be determined directly from a region of interest (ROI) placed in the cortex. Due to partial volume effects, part of the signal from a ROI placed in the medulla is caused by cortical tissue. By subtracting a fraction of the cortical signal from the cortico-medullary signal, a purer medullary renogram can be obtained. A side effect of this subtraction is an increase in noise level. The noise level increases with larger partial volume fractions. Using a matched image filter, it is possible to exclude those areas from the ROI that have a high partial volume content, thus reducing the amount of cortical signal that has to be separated from the medullary signal. Noise reductions of up to 50% have been achieved in the medullary renogram, with an average reduction of 23%.

  4. Orthostatic hypotension associated with dorsal medullary cavernous angioma.

    Idiaquez, J; Araya, P; Benarroch, E


    Orthostatic hypotension (OH) is a rare manifestation of medulla oblongata lesions that may be because of interruption of descending sympathoexcitatory axons. To illustrate the location of a medullary lesion that produced OH following resection in relationship to the location of putative sympathoexcitatory pathways. A case with dorsal medullary cavernous angioma presenting with OH is described. The possible localization of lesion was compared with distribution of tyrosine hydroxylase (TH)-immunoreactive axons in a comparable section of the medulla of a control brain. The patient had marked OH after partial removal of the cavernous angioma. Biopsy confirmed the diagnosis. The magnetic resonance imaging location of the lesion overlapped that of TH-immunoreactive axons of the medullary transtegmental tract. A restricted lesion of medullary lesion interrupting the catecholaminergic transtegmental tract arising from the sympathoexcitatory C1 neurons of the rostral ventrolateral medulla could result in severe OH.

  5. Oral complications associated with idiopathic medullary aplasia: case report.

    Clercq, Marcel; Gagné-Tremblay, Mélanie


    This article describes a patient who experienced serious oral sequelae after severe oral hemorrhage associated with medullary aplasia. These complications required medical, surgical and prosthetic treatments necessitating dental expertise in the hospital setting.

  6. Introduction to European comments on "Medullary Thyroid Cancer

    Jarzab, Barbara; Feldt-Rasmussen, Ulla


    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....

  7. Vasopressin regulation of multisite phosphorylation of UT-A1 in the inner medullary collecting duct.

    Hoban, Carol A; Black, Lauren N; Ordas, Ronald J; Gumina, Diane L; Pulous, Fadi E; Sim, Jae H; Sands, Jeff M; Blount, Mitsi A


    Vasopressin signaling is critical for the regulation of urea transport in the inner medullary collecting duct (IMCD). Increased urea permeability is driven by a vasopressin-mediated elevation of cAMP that results in the direct phosphorylation of urea transporter (UT)-A1. The identification of cAMP-sensitive phosphorylation sites, Ser(486) and Ser(499), in the rat UT-A1 sequence was the first step in understanding the mechanism of vasopressin action on the phosphorylation-dependent modulation of urea transport. To investigate the significance of multisite phosphorylation of UT-A1 in response to elevated cAMP, we used highly specific and sensitive phosphosite antibodies to Ser(486) and Ser(499) to determine cAMP action at each phosphorylation site. We found that phosphorylation at both sites was rapid and sustained. Furthermore, the rate of phosphorylation of the two sites was similar in both mIMCD3 cells and rat inner medullary tissue. UT-A1 localized to the apical membrane in response to vasopressin was phosphorylated at Ser(486) and Ser(499). We confirmed that elevated cAMP resulted in increased phosphorylation of both sites by PKA but not through the vasopressin-sensitive exchange protein activated by cAMP pathway. These results elucidate the multisite phosphorylation of UT-A1 in response to cAMP, thus providing the beginning of understanding the intracellular factors underlying vasopressin stimulation of urea transport in the IMCD.

  8. Ciliated Median Raphe Cyst of Perineum Presenting as Perianal Polyp: A Case Report with Immunohistochemical Study, Review of Literature, and Pathogenesis

    Jayesh Sagar


    Full Text Available Median raphe cyst is a very rare, benign congenital lesion occurring mainly on the ventral aspect of the penis, but can develop anywhere in the midline between the external urethral meatus and anus. We report a case of median raphe cyst in the perineum presenting as a perianal polyp in a 65-year-old, English white male with exceptionally rare ciliated epithelium. According to our knowledge, this is the third such case of ciliated median raphe cyst in the English literature. This case, also the first case of ciliated median raphe cyst in the perineum location, focuses on pathogenesis of median raphe cyst.

  9. Functional analysis of a novel human serotonin transporter gene promoter in immortalized raphe cells

    Mortensen, O V; Thomassen, M; Larsen, M B


    were found to possess the additional 379 bp fragment. The integrity of the promoter was furthermore confirmed by genomic Southern blotting. The promoter activity was analyzed by reporter gene assays in neuronal and non-neuronal serotonergic cell lines. In immortalized serotonergic raphe neurons, RN46A...

  10. GATA-3 is involved in the development of serotonergic neurons in the caudal raphe nuclei

    J. van der Wees (Jacqueline); A. Karis (Alar); E. Goedknegt; M. Rutteman; F.G. Grosveld (Frank); J.H. van Doorninck (Hikke); C.I. de Zeeuw (Chris)


    textabstractAbstract The GATA-3 transcription factor shows a specific and restricted expression pattern in the developing and adult mouse brain. In the present study we investigated the role of GATA-3 in the caudal raphe system, which is known to operate as a modulator of motor activity. We demonst

  11. Dynamic examination of the femur in a rat model of osteoporosis after injection of CPC containing ABK and PLLA

    Tanaka, A.; Kusaka, T.; Sasaki, S.; Takano, I.; Tahara, Y.; Ishii, Y. [Kyorin Univ. School of Medicine, Tokyo (Japan). Dept. of Orthopaedic Surgery


    We developed calcium phosphate cement containing antibiotics and poly lactic acid, and examined the effects on bone strength by injecting the cement into the medullary space of the femur in model rats with osteoporosis. A good strength of bone was obtained over 6 months by injecting bone paste into the medullary space of the femur in model rats with bone formation. (orig.)

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

    Endo, K.; Koizumi, M.; Sakahara, H.; Nakashima, T.; Ohta, H.; Kasagi, K.; Konishi, J.; Miyauchi, A.; Kuma, K.; Torizuka, K.


    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.

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

    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)


    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.)

  14. 5-HT2A受体在尼可刹米增强新生大鼠延髓脑片呼吸放电中的作用%Role of 5-HT2A receptor in increase in respiratory-related rhythmic discharge activity by nikethamide in neonatal rat transverse medullary slices

    千智斌; 吴中海


    本文旨在探讨中枢呼吸兴奋剂尼可刹米对新生大鼠基本节律性呼吸的产生和调节的影响及5-HT2A受体在其中的作用.制作新生大鼠离体延髓脑片标本,含面神经后核内侧区(the medial region of the nucleus retrofacialis,mNRF)并保留舌下神经根,灌流改良Kreb'S液(modified Kreb'S solution,MKS),记录舌下神经根呼吸相关节律性放电活动(respiratory-re-lated rhythmic discharge activity,RRDA),观察不同浓度尼可刹米、5-HT2A受体特异激动剂2,5-二甲氧基-4-碘苯基丙烷[1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane,DOI]、5-HT2A受体特异拮抗剂酮舍林(ketanserine)以及联合使用尼可刹米和酮舍林对舌下神经根RRDA的影响.结果显示,尼可刹米在0.5~7μg/mL时对延髓脑片RRDA有兴奋作用,在5 μg/mL时对吸气时程(inspiratory time,TI)、放电积分幅度(integral amplitude,IA)、呼吸周期(respiratory cycle,Re)等呼吸指标综合效果最显著.DOI明显延长TI、增强IA、缩短RC,对RRDA有兴奋作用.酮舍林明显缩短TI、减弱IA、延长RC,对RRDA有抑制作用.联合使用DOI和酮舍林对RRDA无明显作用.酮舍林可完全阻断尼可刹米对RC的作用,部分阻断尼可刹米对IA的作用,对尼可刹米引起的TI变化无明显影响.结果提示,尼可刹米增强新生大鼠离体延髓脑片舌下神经根RRDA,5-HT2A受体可能足尼可刹米作用途径之一.%To investigate the effects of nikethamide on the generation and modulation of rhythmic respiration of neonatal rats and therole of 5-HT2A receptor in this course, experiments were performed on the transverse medullary slices of neonatal rats (both sexes, 1-3 d) in vitro. The slices containing the medial region of the nucleus retrofacialis (mNRF) with the hypoglossal nerve rootlets were preparedin which the respiratory-related rhythmic discharge activity (RRDA) was recorded from the hypoglossal nerve rootlets by suctionelectrode. The possible role of nikethamide

  15. Dorsal raphe nucleus acetylcholine-mediated neurotransmission modulates post-ictal antinociception: The role of muscarinic and nicotinic cholinergic receptors.

    de Oliveira, Rithiele Cristina; de Oliveira, Ricardo; Biagioni, Audrey Francisco; Falconi-Sobrinho, Luiz Luciano; Coimbra, Norberto Cysne


    The dorsal raphe nucleus (DRN) is a key structure of the endogenous pain inhibitory system. Although the DRN is rich in serotoninergic neurons, cholinergic neurons are also found in that nucleus. Both ictal and inter-ictal states are followed by post-ictal analgesia. The present study investigated the role of cholinergic mechanisms in postictal antinociceptive processes using microinjections of atropine and mecamylamine, muscarinic and nicotinic cholinergic receptor antagonists, respectively, in the DRN of rats. Intraperitoneal injection of pentylenetetrazole (PTZ) (at 64mg/kg) caused tonic and tonic-clonic seizures. The convulsive motor reactions were followed by an increase in pain thresholds, a phenomenon known as post-ictal analgesia. Pre-treatment of the DRN with atropine or mecamylamine at 1µg, 3µg and 5µg/0.2µL decreased the post-ictal antinociceptive phenomenon. The present results showed that the post-ictal analgesia was mediated by muscarinic and nicotinic cholinergic receptors in the DRN, a structure crucially involved in the neural network that organises post-ictal hypoalgesia.

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

    Natalia Daniela Escudero


    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.

  17. Mixed Medullary-follicular Thyroid Carcinoma: Report of a Case and Review of the Literature

    Xiangtao Ma; Liwei Yu; Jing Fu; Shan Wang; Ruyu Du; Zhirong Cui


    @@ Mixed medullary-follicular carcinomas (MMFCs) are tumors of the thyroid that display morphological and immunohistochemical features of both medullary and follicular neoplasms. These tumors are rare and less than 40 cases have been described in the literature since the early 1980s.[1] The term medullary-follicular thyroid carcinoma denotes a tumor which exhibits the features of a medullary carcinoma and shows positive expression of calcitonin on immunohistochemistry.

  18. Differential control of tryptophan hydroxylase expression in raphe and in pineal gland: evidence for a role of translation efficiency.

    Dumas, S; Darmon, M C; Delort, J; Mallet, J


    In a previous study, we characterized two tryptophan hydroxylase mRNAs (TPH mRNAs) in the pineal gland. However, we failed to detect these species in the raphe by Northern blot experiments. Here, we report by S1 nuclease analysis and in situ hybridization that these two TPH mRNAs, as well as a third species, are expressed both in pineal gland and in raphe. In both tissues, the three mRNAs are transcribed predominantly from the same promoter. Strikingly, from the results of S1 maping analysis, it was observed that the total level of TPH mRNA per tissue is at least 150 times lower in the raphe than in the pineal gland. In contrast, TPH antigen as quantified by immunoblot experiments is about threefold more abundant per raphe than per pineal gland. TPH mRNA from one raphe and one pineal gland yield in vitro about the same amount of TPH antigen, suggesting that the discrepancy in the ratios of TPH mRNA and TPH antigen between the raphe and the pineal gland results, at least in part, from a difference in the translation efficiency of TPH mRNAs in the two structures.

  19. Functional connectivity of the dorsal and median raphe nuclei at rest

    Beliveau, Vincent; Svarer, Claus; Frokjaer, Vibe G


    knowledge on the contribution of 5-HT to intrinsic brain activity. The dorsal raphe (DR) and median raphe (MR) nuclei are the source of most serotonergic neurons projecting throughout the brain and thus provide a compelling target for a seed-based probe of resting-state activity related to 5-HT. Here we...... implemented a novel multimodal neuroimaging approach for investigating resting-state functional connectivity (FC) between DR and MR and cortical, subcortical and cerebellar target areas. Using [(11)C]DASB positron emission tomography (PET) images of the brain serotonin transporter (5-HTT) combined...... with structural MRI from 49 healthy volunteers, we delineated DR and MR and performed a seed-based resting-state FC analysis. The DR and MR seeds produced largely similar FC maps: significant positive FC with brain regions involved in cognitive and emotion processing including anterior cingulate, amygdala, insula...

  20. Midline raphé, sternal cleft, and other midline abnormalities: a new dominant syndrome?

    Forzano, Francesca; Daubeney, Piers E F; White, Susan M


    Sternal fusion defects are malformations that often present as an isolated finding. An association with multiple malformations has been reported, in particular with midline raphe and craniofacial hemangiomas and as part of the pentalogy of Cantrell. Most syndromic cases were sporadic with a few families reported with recurrence in sibs. We describe a mother and two daughters with midline raphe and sternal defects. Affected members also had double central incisors, congenital heart defect, neck webbing, bicornuate uterus and minor anomalies including long face with hypotelorism. None of the three affected relatives had hemangiomas. The manifestations of these patients do not fit any previously described condition, and we propose they represent a new syndrome. This family is also important as it points to a possible genetic cause for at least some cases of this disorder of the ventral midline.

  1. Median raphe stimulation-induced motor inhibition concurrent with suppression of type 1 and type 2 hippocampal theta.

    Bland, Brian H; Bland, Cheryl E; MacIver, M Bruce


    This study investigated behavioral, anatomical and electrophysiological effects produced by electrical stimulation of posterior hypothalamic (PH) or median raphe (MR) nuclei, independently and during combined stimulation of both PH and MR. These three stimulation conditions were applied during spontaneous behavior in an open field and during PH stimulation-induced wheel running, while simultaneously recording hippocampal (HPC) field activity. An additional objective was to determine the effects of MR stimulation on Type 1 movement related theta and Type 2 sensory processing related theta. To achieve the latter, when behavioral studies were completed we studied the same rats under urethane anesthesia and then during urethane anesthesia with the addition of atropine sulfate (ATSO4). Here we demonstrated that electrical stimulation of a localized region of the MR nucleus resulted in a profound inhibition of both spontaneously occurring theta related motor behaviors and the theta related motor behaviors induced by electrical stimulation of the PH nucleus. Furthermore, this motor inhibition occurred concurrently with strong suppression of hippocampal theta field oscillations in the freely moving rat, a condition where the theta recorded is Type 2 sensory processing theta occurring coincidently with Type 1 movement related theta (Bland, 1986). Our results indicate that motor inhibition resulted from stimulation of neurons located in the mid central region of the MR, while stimulation in adjacent regions produced variable responses, including movements and theta activity. The present study provided evidence that the pharmacological basis of the suppression of Type 2 sensory processing HPC theta was cholinergic. However, MR inhibition of PH-induced wheel running was not affected by cholinergic blockade, which blocks Type 2 theta, indicating that MR stimulation-induced motor inhibition also requires the suppression of Type 1 theta.

  2. Estradiol increases α7 nicotinic receptor in serotonergic dorsal raphe and noradrenergic locus coeruleus neurons of macaques

    Centeno, Maria Luisa; Henderson, Jessica A.; Pau, K.-Y. Francis; Bethea, Cynthia L.


    Acetylcholine, acting on presynaptic nicotinic receptors (nAChRs) modulates the release of neurotransmitters in the brain. The rat dorsal raphe nucleus (DR) and the locus coeruleus (LC) receive cholinergic input and express the α7nAChR. In previous reports, we demonstrated that estradiol (E) administration stimulates DR serotonergic and LC noradrenergic function in the macaque. In addition, it has been reported that E induces the expression of the α7nAChR in rats. We questioned whether E increased the expression of the α7nAChR in the macaque DR and LC. We utilized double immunostaining to study the effect of a simulated preovulatory surge of E on the expression of the α7nAChR in the DR and the LC and to determine whether α7nAChR colocalizes with serotonin and tyrosine hydroxylase (TH) in macaques. There was no difference in the number of α7nAChR-positive neurons between ovariectomized (OVX) controls and OVX animals treated with a silastic capsule containing E (Ecap). However, supplemental infusion of E for 5–30 h to Ecap animals (Ecap+inf) significantly increased the number of α7nAChR-positive neurons in DR and LC. In addition, supplemental E infusion significantly increased the number of neurons in which α7nAChR colocalized with serotonin and TH. These results constitute an important antecedent to the study of the effects of nicotine and ovarian steroid hormones in the physiological functions regulated by the DR and the LC in woman. PMID:16736471

  3. Brainstem raphe and substantia nigra echogenicity in idiopathic REM sleep behavior disorder with comorbid depression.

    Vilas, Dolores; Iranzo, Alex; Pont-Sunyer, Claustre; Serradell, Mónica; Gaig, Carles; Santamaria, Joan; Tolosa, Eduardo


    In Parkinson disease (PD), REM sleep behavior disorder (RBD) and depression may occur before the onset of parkinsonism. Transcranial sonography (TCS) shows that hyperechogenicity of the substantia nigra (SN+) and hypoechogenicity of the brainstem raphe (BR+) are frequent in PD, particularly when depression is associated. Combined SN+ and BR+ identify PD subjects in whom depression antedates parkinsonism onset. It can be speculated that SN+ and BR+ may also identify idiopathic RBD (IRBD) subjects with comorbid depression, supporting the clinical diagnosis of this mood disorder. We aimed to study the brainstem raphe and substantia nigra echogenicity and their ability to predict comorbid depression in IRBD. Seventy-two IRBD patients and 71 age and sex-matched controls underwent TCS. Depression was diagnosed by means of DSM-IV criteria. Depression was more frequent in IRBD patients than in controls (44.4 vs. 18.3 %; p = 0.001). BR+ was more frequent in depressed than in nondepressed IRBD patients (32.0 vs. 11.4 %; p = 0.050). Sensitivity of BR+ to predict depression in IRBD was 32.0 %, specificity was 88.6 %, and relative risk was 1.88. Sensitivity of SN+ to predict depression in IRBD was 72.0 %, specificity was 44.1 %, and relative risk was 1.53. Sensitivity of combined BR+ and SN+ to predict depression in IRBD was 23.1 %, specificity 97.1 %, and relative risk was 2.31. Hypoechogenicity of the brainstem raphe, particularly when combined with hyperechogenicity of the substantia nigra, detects comorbid depression in IRBD. This finding suggests that dysfunction of the serotonergic dorsal raphe may be involved in the pathophysiology of depression in IRBD.

  4. Epac regulates UT-A1 to increase urea transport in inner medullary collecting ducts.

    Wang, Yanhua; Klein, Janet D; Blount, Mitsi A; Martin, Christopher F; Kent, Kimilia J; Pech, Vladimir; Wall, Susan M; Sands, Jeff M


    Urea plays a critical role in the concentration of urine, thereby regulating water balance. Vasopressin, acting through cAMP, stimulates urea transport across rat terminal inner medullary collecting ducts (IMCD) by increasing the phosphorylation and accumulation at the apical plasma membrane of UT-A1. In addition to acting through protein kinase A (PKA), cAMP also activates Epac (exchange protein activated by cAMP). In this study, we tested whether the regulation of urea transport and UT-A1 transporter activity involve Epac in rat IMCD. Functional analysis showed that an Epac activator significantly increased urea permeability in isolated, perfused rat terminal IMCD. Similarly, stimulating Epac by adding forskolin and an inhibitor of PKA significantly increased urea permeability. Incubation of rat IMCD suspensions with the Epac activator significantly increased UT-A1 phosphorylation and its accumulation in the plasma membrane. Furthermore, forskolin-stimulated cAMP significantly increased ERK 1/2 phosphorylation, which was not prevented by inhibiting PKA, indicating that Epac mediated this phosphorylation of ERK 1/2. Inhibition of MEK 1/2 phosphorylation decreased the forskolin-stimulated UT-A1 phosphorylation. Taken together, activation of Epac increases urea transport, accumulation of UT-A1 at the plasma membrane, and UT-A1 phosphorylation, the latter of which is mediated by the MEK-ERK pathway.

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

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


    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...

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

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


    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...

  7. Negative selection of murine medullary-type single positive thymocytes


    Negative selection depletes self-reactive T cells, thus ensuring self-tolerance. It is usually considered that negative selection imposed on double-positive (DP) thymocytes that reside at the cortico-medullary junction. Negative selection model was set up by injecting mice with anti-T cell receptor (TCR) monoclonal antibody (mAb) intraperitoneally in this work. As shown in phenotypic analysis of thymocytes, negative selection destroys not only cortical-type DP thymocytes, but also medullary-type CD3+TCRαβ+CD4SP and CD3+TCRαβ+CD8SP thymocytes. Negative selection of medullary-type single positive (SP) are more susceptible to apoptosis, while with development of the cells, their resistance to apoptosis increases. Therefore, negative selection does not operate on functionally mature thymocytes at the late stage. This result is a supplement to the traditional theory of negative selection. Negative selection of medullary-type thymocytes is probably to further deplete self-reactive T cells, thus producing precise TCR repertoire and inducing self-tolerance.

  8. [Is immediate prophylactic thyroidectomy indispensable in familiar medullary thyroid carcinoma?].

    Cañizo, A; Fanjul, M; Cerdá, J; Menárguez, J; Parente, A; Laín, A; Carrera, N; Rodríguez-Arnao, M D; Rodríguez-Sánchez, A; Polo, J R; Vázquez, J


    To emphasize the importance of genetic studies in family members and early prophylactic thyroidectomy in oncogene mutation carriers in the management of familiar medullary thyroid carcinoma. A retrospective review of families with familiar medullary thyroid carcinoma treated at our center in the last 7 years was performed. We identified a total of 7 families who has isolated prevalences with thyroid malignancies. Forty members of the 7 families were screened for gene RET mutations. Prophylactic total thyroidectomy was performed in every RET mutation gene carriers. In all families the index case were patients with medullary thyroid carcinoma presenting at a mean age of 37.25 years (range 23-42). The RET oncogen mutation was in codon 634 in exon 11 (multiple endocrine neoplasia type 2A) in all these patients. Fourteen gene carriers were identified with a mean age of 20 years (range 7-37), eleven of whom had medullary thyroid carcinoma at the time of surgery. Five of the gene carriers were children, with a mean age of 11 years (range 7-16), four of whom had microcarcinoma and one had metastatic carcinoma at the time of surgery. After surgery no hypoparathyroidism or recurrent nerve paralysis were documented. No pediatric patient has presented with phaeochromocytoma or hypoparathyroidism to date Four of the five children have normal calcitonin levels (< 2 pg/ml) and they are free of disease. The one who presented metastatic carcinoma has recurrent disease and is awaiting surgical treatment. Genetic studies of family members related to patients with familiar medullary thyroid carcinoma and RET mutations is indispensable. The RET mutation in codon 634 exon 11 was found to be the most frequent association. Prophylactic thyroidectomy is the only curative treatment and has minimal complications when performed by expert surgeons. Early thyroidectomy is recommended since distant metastatic spread can occur at early age.

  9. Corticotropin-releasing factor increases GABA synaptic activity and induces inward current in 5-hydroxytryptamine dorsal raphe neurons.

    Kirby, Lynn G; Freeman-Daniels, Emily; Lemos, Julia C; Nunan, John D; Lamy, Christophe; Akanwa, Adaure; Beck, Sheryl G


    Stress-related psychiatric disorders such as anxiety and depression involve dysfunction of the serotonin [5-hydroxytryptamine (5-HT)] system. Previous studies have found that the stress neurohormone corticotropin-releasing factor (CRF) inhibits 5-HT neurons in the dorsal raphe nucleus (DRN) in vivo. The goals of the present study were to characterize the CRF receptor subtypes (CRF-R1 and -R2) and cellular mechanisms underlying CRF-5-HT interactions. Visualized whole-cell patch-clamp recording techniques in brain slices were used to measure spontaneous or evoked GABA synaptic activity in DRN neurons of rats and CRF effects on these measures. CRF-R1 and -R2-selective agonists were bath applied alone or in combination with receptor-selective antagonists. CRF increased presynaptic GABA release selectively onto 5-HT neurons, an effect mediated by the CRF-R1 receptor. CRF increased postsynaptic GABA receptor sensitivity selectively in 5-HT neurons, an effect to which both receptor subtypes contributed. CRF also had direct effects on DRN neurons, eliciting an inward current in 5-HT neurons mediated by the CRF-R2 receptor and in non-5-HT neurons mediated by the CRF-R1 receptor. These results indicate that CRF has direct membrane effects on 5-HT DRN neurons as well as indirect effects on GABAergic synaptic transmission that are mediated by distinct receptor subtypes. The inhibition of 5-HT DRN neurons by CRF in vivo may therefore be primarily an indirect effect via stimulation of inhibitory GABA synaptic transmission. These results regarding the cellular mechanisms underlying the complex interaction between CRF, 5-HT, and GABA systems could contribute to the development of novel treatments for stress-related psychiatric disorders.

  10. Entanglement between thermoregulation and nociception in the rat: the case of morphine.

    El Bitar, Nabil; Pollin, Bernard; Karroum, Elias; Pincedé, Ivanne; Le Bars, Daniel


    In thermoneutral conditions, rats display cyclic variations of the vasomotion of the tail and paws, the most widely used target organs in current acute or chronic animal models of pain. Systemic morphine elicits their vasoconstriction followed by hyperthermia in a naloxone-reversible and dose-dependent fashion. The dose-response curves were steep with ED50 in the 0.5-1 mg/kg range. Given the pivotal functional role of the rostral ventromedial medulla (RVM) in nociception and the rostral medullary raphe (rMR) in thermoregulation, two largely overlapping brain regions, the RVM/rMR was blocked by muscimol: it suppressed the effects of morphine. "On-" and "off-" neurons recorded in the RVM/rMR are activated and inhibited by thermal nociceptive stimuli, respectively. They are also implicated in regulating the cyclic variations of the vasomotion of the tail and paws seen in thermoneutral conditions. Morphine elicited abrupt inhibition and activation of the firing of on- and off-cells recorded in the RVM/rMR. By using a model that takes into account the power of the radiant heat source, initial skin temperature, core body temperature, and peripheral nerve conduction distance, one can argue that the morphine-induced increase of reaction time is mainly related to the morphine-induced vasoconstriction. This statement was confirmed by analyzing in psychophysical terms the tail-flick response to random variations of noxious radiant heat. Although the increase of a reaction time to radiant heat is generally interpreted in terms of analgesia, the present data question the validity of using such an approach to build a pain index. Copyright © 2016 the American Physiological Society.

  11. Divergent projections of catecholaminergic neurons in the nucleus of the solitary tract to limbic forebrain and medullary autonomic brain regions.

    Reyes, Beverly A S; Van Bockstaele, Elisabeth J


    The nucleus of the solitary tract (NTS) is a critical structure involved in coordinating autonomic and visceral activities. Previous independent studies have demonstrated efferent projections from the NTS to the nucleus paragigantocellularis (PGi) and the central nucleus of the amygdala (CNA) in rat brain. To further characterize the neural circuitry originating from the NTS with postsynaptic targets in the amygdala and medullary autonomic targets, distinct green or red fluorescent latex microspheres were injected into the PGi and the CNA, respectively, of the same rat. Thirty-micron thick tissue sections through the lower brainstem and forebrain were collected. Every fourth section through the NTS region was processed for immunocytochemical detection of tyrosine hydroxylase (TH), a marker of catecholaminergic neurons. Retrogradely labeled neurons from the PGi or CNA were distributed throughout the rostro-caudal segments of the NTS. However, the majority of neurons containing both retrograde tracers were distributed within the caudal third of the NTS. Cell counts revealed that approximately 27% of neurons projecting to the CNA in the NTS sent collateralized projections to the PGi while approximately 16% of neurons projecting to the PGi sent collateralized projections to the CNA. Interestingly, more than half of the PGi and CNA-projecting neurons in the NTS expressed TH immunoreactivity. These data indicate that catecholaminergic neurons in the NTS are poised to simultaneously coordinate activities in limbic and medullary autonomic brain regions.

  12. Medullary Sponge Kidney and Testicular Dysgenesis Syndrome: A Rare Association

    Stefano Masciovecchio


    Full Text Available The medullary sponge kidney is also known as Lenarduzzi’s kidney or Cacchi and Ricci’s disease from the first Italian authors who described its main features. A review of the scientific literature underlines particular rarity of the association of MSK with developmental abnormalities of the lower urinary tract and genital tract such as hypospadias and bilateral cryptorchidism. The work presented is the only one in the scientific literature that shows the association between the medullary sponge kidney and the testicular dysgenesis syndrome. A question still remains unanswered: are the MSK and TDS completely independent malformation syndromes occurring, in this case, simultaneously for a rare event or are they different phenotypic expressions of a common malformative mechanism? In the future we hope that these questions will be clarified.

  13. Russell–Silver syndrome associated with low conus medullaris

    Gabor, Larisa; Canaz, Huseyin; Canaz, Gokhan; Kara, Nursu; Alatas, Ibrahim; Bozkus, Hakan


    Russell–Silver syndrome is a rare heterogeneous disorder mainly characterized by intrauterine and postnatal growth retardation, craniofacial disproportion, clinodactyly, variation in urogenital development, and skeletal asymmetry. It is rare to come across tethered cord-associated Russell–Silver syndrome. We report a rare case of Russell–Silver syndrome associated with low conus medullaris in a 2-year-old patient with demonstrative phenotype. Magnetic resonance imaging indicated a low conus medullaris at the inferior border of the L3 vertebral body. Urodynamic study revealed detrusor-sphincter dyssynergia and detrusor overactivity. A decision to follow-up the patient was made because of the suspicion of tethered cord syndrome. Even though tethered cord syndrome is not a common finding in Russell–Silver syndrome, it is important to consider tethered cord syndrome to avoid scoliosis and other long-term complications. PMID:28217167

  14. Acute Liver Failure Secondary to Metastatic Medullary Thyroid Cancer

    Emmanuel C. Gorospe


    Full Text Available Acute liver failure (ALF is a rare presentation of liver metastases. Although cases of ALF from metastatic disease have been reported, etiologies have been largely confined to lymphoma, metastatic breast, lung, and gastric cancers. ALF from medullary thyroid cancer (MTC has never been reported. We present a 59-year-old male with newly diagnosed MTC, who was admitted with ALF. He presented with jaundice, hepatic encephalopathy, and synthetic dysfunction. His clinical course was marked by rapid decompensation within 6 days from initial presentation of jaundice to development of hepatic coma. Although liver metastases from medullary thyroid cancer have been reported, to our knowledge, this is the first described case of MTC resulting in acute liver failure.

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

    Saurabh K Verma


    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.

  16. Russell-Silver syndrome associated with low conus medullaris.

    Gabor, Larisa; Canaz, Huseyin; Canaz, Gokhan; Kara, Nursu; Alatas, Ibrahim; Bozkus, Hakan


    Russell-Silver syndrome is a rare heterogeneous disorder mainly characterized by intrauterine and postnatal growth retardation, craniofacial disproportion, clinodactyly, variation in urogenital development, and skeletal asymmetry. It is rare to come across tethered cord-associated Russell-Silver syndrome. We report a rare case of Russell-Silver syndrome associated with low conus medullaris in a 2-year-old patient with demonstrative phenotype. Magnetic resonance imaging indicated a low conus medullaris at the inferior border of the L3 vertebral body. Urodynamic study revealed detrusor-sphincter dyssynergia and detrusor overactivity. A decision to follow-up the patient was made because of the suspicion of tethered cord syndrome. Even though tethered cord syndrome is not a common finding in Russell-Silver syndrome, it is important to consider tethered cord syndrome to avoid scoliosis and other long-term complications.

  17. Medial septal and median raphe innervation of vasoactive intestinal polypeptide-containing interneurons in the hippocampus.

    Papp, E C; Hajos, N; Acsády, L; Freund, T F


    Vasoactive intestinal polypeptide-immunoreactive interneurons are known to form three anatomically and neurochemically well-characterized neuron populations in the hippocampus. Two of these establish synaptic contacts selectively with other GABAergic cells (interneuron-selective cells), whereas the third type innervates pyramidal cell bodies and proximal dendrites like a conventional basket cell. Our aim was to examine which of the vasoactive intestinal polypeptide-containing interneuron populations are among the targets of GABAergic septohippocampal and serotonergic raphe-hippocampal pathways. Anterograde tracing with Phaseolus vulgaris leucoagglutinin combined with double immunocytochemistry for vasoactive intestinal polypeptide was used at the light and electron microscopic levels. Our results show that both interneuron-selective cells and vasoactive intestinal polypeptide-containing basket cells receive synaptic input from the medial septum and median raphe nucleus. The GABAergic component of the septohippocampal pathway establishes multiple contacts on both cell types. In the case of the raphe-hippocampal projection, single or double contacts were more frequent on vasoactive intestinal polypeptide-positive interneuron selective cells (76%), whereas multiple contacts predominated on basket cells (83%). The extrinsic GABAergic innervation of interneuron-selective cells in the hippocampus indicates a complex interaction among GABAergic systems, which might ensure the timing and rhythmic synchronization of inhibitory processes in the hippocampus. On the other hand, our results suggest that the serotonergic effect on perisomatic inhibition is exerted via vasoactive intestinal polypeptide-containing basket cells that are functionally distinct from their parvalbumin-positive relatives, which appear to escape control of serotonergic as well as local interneuron-selective cells.

  18. Medullary carcinomas of the thyroid: a monoclonal origin.

    Marques, A R; Catarino, A L; Moniz, S; Cavaco, B; Roque, L; Sobrinho, L; Leite, V


    We studied the clonality of medullary thyroid carcinomas (MTC) from 16 female patients by determining X chromosome inactivation by polymerase chain reaction (PCR) amplification of a CAG repeat in exon 1 of the human androgen-receptor gene. One patient with sporadic medullary thyroid carcinoma (MTC) was homozygous for this microsatellite and was not considered for the assessment of clonality. Sixteen tumor samples from the informative 15 patients were studied: 11 were from sporadic cases and 5 were from familial cases (3 cases of multiple endocrine neoplasia type 2A [MEN 2A]; 1 case of familial medullary thyroid carcinoma [FMTC]). Fourteen tumor samples (10/11 sporadic, 3/4 MEN 2A and 1/1 FMTC) were clearly monoclonal with allelic cleavage ratios between 2.5 and 49.1. Sixty-four percent of these cases (9/14) had the preferential amplification of the shorter allele while 36 percent (5/14) had the preferential amplification of the longer allele. Two frozen tumor samples (1 sporadic and 1 MEN 2A) were polyclonal. However, the corresponding tumor embedded in paraffin from the sporadic case was monoclonal. The other polyclonal tumor was found in the right thyroid lobe of a patient with MEN 2A who had a monoclonal tumor in the left lobe. Our results clearly demonstrate that MTC have a monoclonal origin in the majority of the cases.

  19. Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers.

    Sherman, Steven I


    Systemic chemotherapies for advanced or metastatic thyroid carcinomas have been of only limited effectiveness. For patients with differentiated or medullary carcinomas unresponsive to conventional treatments, novel therapies are needed to improve disease outcomes. The PubMed and Google Scholar search engines were used to identify publications and peer-reviewed meeting presentations addressing chemotherapy and targeted therapy for differentiated or medullary carcinoma. Multiple novel therapies primarily targeting angiogenesis have entered clinical trials for metastatic thyroid carcinoma. Partial response rates up to 30% have been reported in single agent studies, but prolonged disease stabilization is more commonly seen. The most successful agents target the vascular endothelial growth factor receptors, with potential targets including the mutant kinases associated with papillary and medullary oncogenesis. Two drugs approved for other malignancies, sorafenib and sunitinib, have had promising preliminary results reported, and are being used selectively for patients who do not qualify for clinical trials. Randomized trials for several agents are underway that may lead to eventual drug approval for thyroid cancer. Treatment for patients with metastatic or advanced thyroid carcinoma now emphasizes clinical trial opportunities for novel agents with considerable promise. Alternative options now exist for use of tyrosine kinase inhibitors that are well tolerated and may prove worthy of regulatory approval for this disease.

  20. EphrinA5 Signaling Is Required for the Distinctive Targeting of Raphe Serotonin Neurons in the Forebrain

    Muzerelle, Aude


    Serotonin (5-HT) neurotransmission in the brain relies on a widespread axon terminal network originating from the hindbrain raphe nuclei. These projections are topographically organized such that the dorsal (DR), and median raphe (MnR) nuclei have different brain targets. However, the guidance molecules involved in this selective targeting in development are unknown. Here, we show the implication of ephrinA5 signaling in this process. We find that the EphA5 gene is selectively expressed in a subset of 5-HT neurons during embryonic and postnatal development. Highest coexpression of EphA5 and the 5-HT marker Tph2 is found in the DR, with lower coexpression in the MnR, and hardly any colocalization of the caudal raphe in the medulla. Accordingly, ephrinA induced a dose-dependent collapse response of 5-HT growth cones cultured from rostral but not caudal raphe. Ectopic expression of ephrinA3, after in utero electroporation in the amygdala and piriform cortex, repelled 5-HT raphe fiber ingrowth. Conversely, misplaced DR 5-HT axons were found in ephrin A5 knockout mice in brain regions that are normally only targeted by MnR 5-HT axons. This causes an overall increase in the density of 5-HT innervation in the ventromedial hypothalamus, the suprachiasmatic nucleus, and the olfactory bulb. All these brain areas have high expression of ephrinAs at the time of 5-HT fiber ingrowth. Present results show for the first time the role of a guidance molecule for the region-specific targeting of raphe neurons. This has important implications to understand how functional parsing of central 5-HT neurons is established during development. PMID:28197551

  1. Lateral medullary infarction with ipsilateral hemiparesis, lemniscal sensation loss and hypoglossal nerve palsy.

    Li, Xiaodi; Wang, Yuzhou


    Here, we present a rare case of a lateral medullary infarction with ipsilateral hemiparesis, lemniscal sensation loss and hypoglossal nerve palsy. In this case, we proved Opalski's hypothesis by diffusion tensor tractography that ipsilateral hemiparesis in a medullary infarction is due to the involvement of the decussated corticospinal tract. We found that the clinical triad of ipsilateral hemiparesis, lemniscal sensation loss and hypoglossal nerve palsy, which had been regarded as a variant of medial medullary syndrome, turned out to be caused by lateral lower medullary infarction. Therefore, this clinical triad does not imply the involvement of the anteromedial part of medulla oblongata, when it is hard to distinguish a massive lateral medullary infarction from a hemimedullary infarction merely from MR images. At last, we suggest that hyperreflexia and Babinski's sign may not be indispensable to the diagnosis of Opalski's syndrome and we propose that "hemimedullary infarction with ipsilateral hemiparesis" is intrinsically a variant of lateral medullary infarction.

  2. Plasma levels of osteocalcin and retinol binding protein-4 in patients with medullary thyroid carcinoma

    Jabar Lotfi


    Conclusion: According to difference between plasma levels of osteocalcin and retinol binding protein-4 in patients suffered of medullary thyroid carcinoma comparison with normal subjects, it can be said that, probably medullary thyroid carcinoma has effect on bone and adipose tissue metabolism, so osteocalcin and retinol binding protein-4 hormones have potential to be used for confirmation of diagnosis or following treatment of medullary thyroid carcinoma.

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

    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)


    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

  4. Body sodium overload modulates the firing rate and fos immunoreactivity of serotonergic cells of dorsal raphe nucleus.

    Andrea Godino

    Full Text Available In order to determine whether serotonergic (5HT dorsal raphe nucleus (DRN cells are involved in body sodium status regulation, the effect of a s.c. infusion of either 2 M or 0.15 M NaCl on 5HT DRN neuron firing was studied using single unit extracellular recordings. In separate groups of 2 M and 0.15 M NaCl-infused rats, water intake, oxytocin (OT plasma concentration, urine and plasma sodium and protein concentrations were also measured. Also, to determine the involvement of particular brain nuclei and neurochemical systems in body sodium overload (SO, animals from both groups were perfused for brain immunohistochemical detection of Fos, Fos-OT and Fos-5HT expression. SO produced a significant increase in serotonergic DRN neuron firing rate compared to baseline and 0.15 M NaCl-infused rats. As expected, 2 M NaCl s.c. infusion also induced a significant increase of water intake, diuresis and natriuresis, plasma sodium concentration and osmolality, even though plasma volume did not increase as indicated by changes in plasma protein concentration. The distribution of neurons along the forebrain and brainstem expressing Fos after SO showed the participation of the lamina terminalis, extended amygdala, supraoptic and paraventricular hypothalamic nuclei in the neural network that controls osmoregulatory responses. Both Fos-OT immunoreactive and plasma OT concentration increased after s.c. hypertonic sodium infusion. Finally, matching the "in vivo" electrophysiological study, SO doubled the number of Fos-5HT immunolabeled cells within the DRN. In summary, the results characterize the behavioral, renal and endocrine responses after body sodium overload without volume expansion and specify the cerebral nuclei that participate at different CNS levels in the control of these responses. The electrophysiological approach also allows us to determine in an "in vivo" model that DRN 5HT neurons increase their firing frequency during an increase in systemic

  5. Caring about medullary anesthesia in Saimiri sciureus: the conus medullaris topography

    Ana R. Lima


    Full Text Available Saimiri sciureus is a New World non-human primate (NHP that inhabits Brazilian rain forests. Surgical interventions in wild NHPs can be considered common both for experimental studies procedures and corrective procedures for endangered species. Among various anesthetic procedures, the epidural anesthesia or blockades, depending on the surgical procedure, might be considered elective for wild monkeys, mostly based on its safeness, efficiency and non-time consuming characteristics. However its safeness would be limiting because of the spinal cord arrangement. Notwithstanding the available former studies on New World NHP anatomy, the description of the medullar cone of Saimiri sciureus is still scarce. Therefore, we believe that the better understanding the medullar cone of Saimiri sciureus would contribute to improve the applicability of epidural procedures in the species. Vertebrae architecture of Saimiri sciureus was composed by 9 lumbar, 3 sacral and 18 coccygeal vertebrae, and the medullar cone measured about 3.3 cm. We can conclude that the conus medullaris in Saimiri sciureus is situated more caudally in comparison to other species.Saimiri sciureus é um primata não humano do novo mundo (NHP que habita as florestas úmidas brasileiras. Intervenções cirúrgicas em NHP selvagens podem ser consideradas comuns em estudos experimentais ou procedimentos corretivos para espécies em perigo. Entre os vários procedimentos anestésicos, a anestesia ou bloqueio epidural depende do procedimento cirúrgico a ser realizado, podendo ser considerada eletiva para macacos selvagens baseada na segurança, eficiência e pouco tempo consumido, entretanto sua segurança pode estar limitada devido ao arranjo da medula espinhal. Apesar de existirem estudos anatômicos disponíveis de NHP a descrição do cone medular do Saimiri sciureus permanece escassa. Portanto, nós acreditamos que o melhor entendimento a respeito do cone medular do Saimiri sciureus pode

  6. Proteomic profiling of nuclear fractions from native renal inner medullary collecting duct cells.

    Pickering, Christina M; Grady, Cameron; Medvar, Barbara; Emamian, Milad; Sandoval, Pablo C; Zhao, Yue; Yang, Chin-Rang; Jung, Hyun Jun; Chou, Chung-Lin; Knepper, Mark A


    The control of renal water excretion occurs in part by regulation of transcription in response to vasopressin in cells of the collecting duct. A systems biology-based approach to understanding transcriptional control in renal collecting duct cells depends on knowledge of what transcription factors and other regulatory proteins are present in the cells' nuclei. The goal of this article is to report comprehensive proteomic profiling of cellular fractions enriched in nuclear proteins from native inner medullary collecting duct (IMCD) cells of the rat. Multidimensional separation procedures and state-of-the art protein mass spectrometry produced 18 GB of spectral data that allowed the high-stringency identification of 5,048 proteins in nuclear pellet (NP) and nuclear extract (NE) fractions of biochemically isolated rat IMCD cells (URL: The analysis identified 369 transcription factor proteins out of the 1,371 transcription factors coded by the rat genome. The analysis added 1,511 proteins to the recognized proteome of rat IMCD cells, now amounting to 8,290 unique proteins. Analysis of samples treated with the vasopressin analog dDAVP (1 nM for 30 min) or its vehicle revealed 99 proteins in the NP fraction and 88 proteins in the NE fraction with significant changes in spectral counts (Fisher exact test, P < 0.005). Among those altered by vasopressin were seven distinct histone proteins, all of which showed decreased abundance in the NP fraction, consistent with a possible effect of vasopressin to induce chromatin remodeling. The results provide a data resource for future studies of vasopressin-mediated transcriptional regulation in the renal collecting duct.

  7. Serotonergic projections from the raphe nuclei to the subthalamic nucleus; a retrograde- and anterograde neuronal tracing study

    Reznitsky, Martin; Plenge, Per; Hay-Schmidt, Anders


    the 5-HT1A and 5-HT2A not were present. Retrograde tracer FluoroGold or Choleratoxin subunit B were iontophoretically delivered in the STN and combined with immunohistochemistry for 5-HT in order to map the topographic organization in the dorsal raphe system. The study showed that approximately 320...

  8. Age-related deficit in behavioural extinction is counteracted by long-term ethanol consumption: correlation between 5-HIAA/5HT ratio in dorsal raphe nucleus and cognitive parameters.

    Oliveira-Silva, Ieda F; Pinto, Lucas; Pereira, Silvia R C; Ferraz, Vany P; Barbosa, Alfredo J A; Coelho, Vivian A A; Gualberto, Felipe F A S; Souza, Valeria F; Faleiro, Rosiane R M; Franco, Glaura C; Ribeiro, Angela M


    We investigated age-related changes in learning and memory performance and behavioural extinction in the water maze; and in endogenous levels of serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in the neocortex, hippocampus, thalamus and dorsal raphe nucleus of Wistar rats. Another aim was to assess the correlation between behavioural and biochemical parameters, which were measured in rodents of two different ages: 5 months (adults) and 16 months (middle-aged). The middle-aged subjects succeeded in learning the behavioural task, albeit with significantly worse performance when compared to adult animals. Aging also had significant main effects on memory and extinction. An age-dependent decrease in 5-HIAA levels was observed in both hippocampus and dorsal raphe nucleus (DRN). The decrease in DRN 5-HIAA was paralleled by a decrease in 5-HIAA/5-HT ratio in this brain area, which was significantly correlated to the animals' spatial memory performance and behavioural extinction. In addition, using middle-aged rats, a 2x2 factorial study was carried out to examine the effects of food restriction and chronic ethanol consumption on rat's performance in a spatial behavioural task and on central serotonergic parameters. None of these two treatments had a significant effect on the behavioural and biochemical parameters assessed, with the exception of extinction index, which was significantly affected by ethanol consumption. Long-term ethanol ameliorated the impairment in behavioural flexibility caused by aging. In conclusion, long-term ethanol consumption may have a role in protecting against age-related deficit in behavioural extinction. Moreover, the present results also indicate that DRN serotonergic system is involved in spatial memory and behavioural extinction.

  9. Projections from the raphe nuclei to the suprachiasmatic nucleus of the rat

    Hay-Schmidt, Anders; Vrang, N.; Larsen, P.J.


    Hypothalamus, Circadian rhythm, Serotonin, Nucleus, Neuronal connections, Phaseolus vulgaris-leucoagglutinin (PHA-L), Cholera toxin (ChB)......Hypothalamus, Circadian rhythm, Serotonin, Nucleus, Neuronal connections, Phaseolus vulgaris-leucoagglutinin (PHA-L), Cholera toxin (ChB)...

  10. Effects of creatine monohydrate supplementation and exercise on depression-like behaviors and raphe 5-HT neurons in mice

    Ahn, Nari; Leem, Yea Hyun; Kato, Morimasa; Chang, Hyukki


    [Purpose] The effects of creatine and exercise on chronic stress-induced depression are unclear. In the present study, we identified the effects of 4-week supplementation of creatine monohydrate and/or exercise on antidepressant behavior and raphe 5-HT expression in a chronic mild stress-induced depressed mouse model. [Methods] Seven-week-old male C57BL/6 mice (n=48) were divided randomly into 5 groups: (1) non-stress control (CON, n=10), (2) stress control (ST-CON, n=10), (3) stress and creatine intake (ST-Cr, n=10), (4) stress and exercise (ST-Ex, n=9), and (5) combined stress, exercise, and creatine intake (ST-Cr+Ex, n=9). After five weeks’ treatment, we investigated using both anti-behavior tests (the Tail Suspension Test (TST) and the Forced Swimming Test (FST)), and 5-HT expression in the raphe nuclei (the dorsal raphe (DR) and median raphe (MnR)). [Results] Stress for 4 weeks significantly increased depressive behaviors in the mice. Treatment with creatine supplementation combined with exercise significantly decreased depressive behaviors as compared with the CON-ST group in both the TST and FST tests. With stress, 5-HT expression in the raphe nuclei decreased significantly. With combined creatine and exercise, 5-HT positive cells increased significantly and had a synergic effect on both DR and MnR. [Conclusion] The present study found that even a single treatment of creatine or exercise has partial effects as an antidepressant in mice with chronic mild stress-induced depression. Furthermore, combined creatine and exercise has synergic effects and is a more effective prescription than a single treatment.

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

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


    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...

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

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


    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 ... in the mechanism of hypercalciuria and hypocitraturia in patients with medullary sponge kidney.(ABSTRACT TRUNCATED AT 250 WORDS)...

  13. Chemokine CCL2 up-regulated in the medullary dorsal horn astrocytes contributes to nocifensive behaviors induced by experimental tooth movement.

    Luo, Wei; Fu, Runqing; Tan, Yu; Fang, Bing; Yang, Zhi


    To test the hypothesis that the astrocytic chemokine (C-C motif) ligand 2 (CCL2) plays an important role in nocifensive behaviors after experimental tooth movement (ETM), the expression and cellular localization of CCL2 and astrocyte activation in the medullary dorsal horn (MDH) were determined by immunohistochemistry in rats. The dose-dependent effects of intrathecal C-C chemokine receptor type 2 (CCR2) antagonists on these changes in nocifensive behaviors were evaluated. Exogenous CCL2 was added to medullary dorsal horn slices to evaluate its contributory role in the induction of extracellular signal-regulated kinase (ERK) activation ex vivo. We found a significant increase in the expression of CCL2 and glial fibrillary acidic protein (GFAP), corresponding well to the nocifensive behaviors after ETM. In addition, application of recombinant CCL2 led to ERK activation, which could be attenuated effectively by pretreatment with CCL2-neutralizing antibody ex vivo. The magnitude of the nocifensive behavior could be reduced by medullary CCR2 antagonists in a dose-dependent manner. Therefore, the astrocytic CCL2 is actively involved in the development and maintenance of tooth-movement pain and thus may be a potential target for analgesics in orthodontic nocifensive responses control.

  14. Estrogen levels influence medullary bone quantity and density in female house finches and pine siskins.

    Squire, Maria E; Veglia, Megan K; Drucker, Kevin A; Brazeal, Kathleen R; Hahn, Thomas P; Watts, Heather E


    Medullary bone, a non-structural osseous tissue, serves as a temporary storage site for calcium that is needed for eggshell production in a number of avian species. Previous research focusing primarily on domesticated species belonging to the Anseriformes, Galliformes, and Columbiformes has indicated that rising estrogen levels are a key signal stimulating medullary bone formation; Passeriformes (which constitute over half of extant bird species and are generally small) have received little attention. In the current study, we examined the influence of estrogen on medullary bone and cortical bone in two species of Passeriformes: the Pine Siskin (Spinus pinus) and the House Finch (Haemorhous mexicanus). Females of these species received either an estradiol implant or were untreated as a control. After 4.5-5months, reproductive condition was assessed and leg (femora) and wing (humeri) bones were collected for analysis using high-resolution (10μm) micro-computed tomography scanning. We found that in both species estradiol-treated females had significantly greater medullary bone quantity in comparison to untreated females, but we found no differences in cortical bone quantity or microarchitecture. We were also able to examine medullary bone density in the pine siskins and found that estradiol treatment significantly increased medullary bone density. Furthermore, beyond the effect of the estradiol treatment, we observed a relationship between medullary bone quantity and ovarian condition that suggests that the timing of medullary bone formation may be related to the onset of yolk deposition in these species. Further research is needed to better understand the precise timing and endocrine regulation of medullary bone formation in Passerines and to determine the extent to which female Passerines rely on medullary bone calcium during the formation of calcified eggshells. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons.

    Qi, Jia; Zhang, Shiliang; Wang, Hui-Ling; Wang, Huikun; de Jesus Aceves Buendia, Jose; Hoffman, Alexander F; Lupica, Carl R; Seal, Rebecca P; Morales, Marisela


    Electrical stimulation of the dorsal raphe (DR) and ventral tegmental area (VTA) activates the fibres of the same reward pathway but the phenotype of this pathway and the direction of the reward-relevant fibres have not been determined. Here we report rewarding effects following activation of a DR-originating pathway consisting of vesicular glutamate transporter 3 (VGluT3) containing neurons that form asymmetric synapses onto VTA dopamine neurons that project to nucleus accumbens. Optogenetic VTA activation of this projection elicits AMPA-mediated synaptic excitatory currents in VTA mesoaccumbens dopaminergic neurons and causes dopamine release in nucleus accumbens. Activation also reinforces instrumental behaviour and establishes conditioned place preferences. These findings indicate that the DR-VGluT3 pathway to VTA utilizes glutamate as a neurotransmitter and is a substrate linking the DR-one of the most sensitive reward sites in the brain--to VTA dopaminergic neurons.

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

    Amir M. Torabi


    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.

  17. Characterisation of thyroid medullary carcinoma TT cell line.

    Zabel, M; Grzeszkowiak, J


    TT cell line is the best known stabilized cell line derived from the human medullary thyroid carcinoma. The ultrastructural characteristics of these cells include well developed rough endoplasmic reticulum, a prominent Golgi apparatus and a considerable number of secretory granules. Numerous hormones were immunocytochemically demonstrated in TT cells of which calcitonin and calcitonin gene-related peptide (CGRP) are the products of the same gene but an alternative RNA processing. TT cells were found to produce some other hormones as well, namely ACTH, neurotensin, enkephalin, PTHrP, gastrin-releasing peptide (GRP), serotonin but also functional proteins of the chromogranin group, synaptophysin, NSE, calbindin and tyrosine hydroxylase. Some marker proteins have been detected in the cytosol (CEA) and in the cytoskeleton (alpha-tubulin, cytokeratin). The influence of numerous factors on the secretory activity of these cells has been demonstrated so far, including effects of 1,25-dihydroxycholecalciferol, glucocorticoids, sex steroids, cAMP, gastrin-releasing peptide, sodium butyrate, phorbol esters, ionomycin and forskolin. The investigators performed on the TT cell line demonstrate that this is the most reliable model system for the human parafollicular cells developed so far, in comparison to other cell lines derived from the medullary carcinoma of the thyroid.

  18. Human renal medullary interstitial cells and analgesic nephropathy.

    Whiting, P H; Tisocki, K; Hawksworth, G M


    The aim of this study was to investigate the effects of known papillotoxins using cultures of human renal interstital medullary cells (hRMIC). The culture of hMIC was based on the primary culture of human renal medullary explants, selective detachment of interstitial cells and selective overgrowth of these cells in a serum-rich medium after dilution cloning. The homogeneous population of cells obtained exhibited the characteristic morphological and functional characteristics of Type I interstitial cells, viz. stellate-shaped cells demonstrating numerous lipid droplets, abundant endoplasmic reticulum and mitochondria, fine filaments underlying the cell membrane and the production of extracellular matrix. Cytotoxicity studies using hMIC and known papillotoxins clearly demonstrated a reduction in cell viability that varied with bath exposure time and type of agent tested. While only phenylbutazone and mefenamic acid produced significant cytotoxicity after a 24 h incubation period, cell viability assessed using the MTT assay was only profoundly reduced by aspirin and paracetamol following sub-chronic exposure for 7 days. The rank order of cytotoxicity observed in hMIC was phenylbutazone > mefenamic acid > aspirin > paracetamol. The results demonstrate the potential of hMIC for investigating and defining the early cellular events in the pathogenesis of analgesic nephropathy.

  19. Functional connectivity of the dorsal and median raphe nuclei at rest.

    Beliveau, Vincent; Svarer, Claus; Frokjaer, Vibe G; Knudsen, Gitte M; Greve, Douglas N; Fisher, Patrick M


    Serotonin (5-HT) is a neurotransmitter critically involved in a broad range of brain functions and implicated in the pathophysiology of neuropsychiatric illnesses including major depression, anxiety and sleep disorders. Despite being widely distributed throughout the brain, there is limited knowledge on the contribution of 5-HT to intrinsic brain activity. The dorsal raphe (DR) and median raphe (MR) nuclei are the source of most serotonergic neurons projecting throughout the brain and thus provide a compelling target for a seed-based probe of resting-state activity related to 5-HT. Here we implemented a novel multimodal neuroimaging approach for investigating resting-state functional connectivity (FC) between DR and MR and cortical, subcortical and cerebellar target areas. Using [(11)C]DASB positron emission tomography (PET) images of the brain serotonin transporter (5-HTT) combined with structural MRI from 49 healthy volunteers, we delineated DR and MR and performed a seed-based resting-state FC analysis. The DR and MR seeds produced largely similar FC maps: significant positive FC with brain regions involved in cognitive and emotion processing including anterior cingulate, amygdala, insula, hippocampus, thalamus, basal ganglia and cerebellum. Significant negative FC was observed within pre- and postcentral gyri for the DR but not for the MR seed. We observed a significant association between DR and MR FC and regional 5-HTT binding. Our results provide evidence for a resting-state network related to DR and MR and comprising regions receiving serotonergic innervation and centrally involved in 5-HT related behaviors including emotion, cognition and reward processing. These findings provide a novel advance in estimating resting-state FC related to 5-HT signaling, which can benefit our understanding of its role in behavior and neuropsychiatric illnesses.

  20. Tolerance effects of non-steroidal anti-inflammatory drugs microinjected into central amygdala, periaqueductal grey, and nucleus raphe Possible cellular mechanism

    Merab G. Tsagareli; Nana Tsiklauri; Ivliane Nozadze; Gulnaz Gurtskaia


    Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstay of medical pain therapy remains drugs that have been around for decades, like non-steroidal anti-inflammatory drugs (NSAIDs), or opiates. However, adverse effects of opiates, particularly tolerance, limit their clinical use. Several lines of investigations have shown that systemic (intraperitoneal) administration of NSAIDs induces antinociception with some effects of tolerance. In this review, we report that repeated microinjection of NSAIDs analgin, clodifen, ketorolac and xefocam into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus in the following 4 days result in progressively less antinociception compared to the saline control testing in the tail-flick reflex and hot plate latency tests. Hence, tolerance develops to these drugs and cross-tolerance to morphine in male rats. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, the periaqueductal grey-rostral ventro-medial part of medulla circuit should be viewed as a pain-modulation system. These data are important for human medicine. In particular, cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting.

  1. Somatosensory regulation of serotonin release in the central nucleus of the amygdala is mediated via corticotropin releasing factor and gamma-aminobutyric acid in the dorsal raphe nucleus.

    Tokunaga, Ryota; Shimoju, Rie; Shibata, Hideshi; Kurosawa, Mieko


    Noxious cutaneous stimulation increases, whereas innocuous cutaneous stimulation decreases serotonin (5-HT) release in the central nucleus of the amygdala (CeA) in anesthetized rats. In the present study, we investigated the contribution of corticotropin releasing factor (CRF) receptors and gamma-aminobutyric acid (GABA) receptors in the dorsal raphe nucleus (DRN) to those responses. Release of 5-HT in the CeA was monitored by microdialysis before and after 10-min stimulation by pinching or stroking. Increased 5-HT release in the CeA in response to pinching was abolished by CRF2 receptor antagonism in the DRN. Decreased 5-HT release in the CeA in response to stroking was abolished by either CRF1 receptor antagonism or GABAA receptor antagonism in the DRN. These results suggest that opposite responses of 5-HT release in the CeA to noxious versus innocuous stimulation of the skin are due to separate contributions of CRF2, CRF1 and GABAA receptors in the DRN.

  2. Combined treatment with subchronic lithium and acute intracerebral mirtazapine microinjection into the median raphe nucleus exerted an anxiolytic-like effect synergistically.

    An, Yan; Inoue, Takeshi; Kitaichi, Yuji; Chen, Chong; Nakagawa, Shin; Wang, Ce; Kusumi, Ichiro


    Although preclinical and clinical studies have established the efficacy of lithium augmentation of antidepressant drugs, the mechanism of action of lithium augmentation is not fully understood. Our previous study reported that subchronic lithium treatment enhanced the anxiolytic-like effect of systemic mirtazapine. In the present study, we examined the effect of subchronic lithium in combination with acute local intracerebral injection of mirtazapine on fear-related behaviors in a contextual fear conditioning test in rats to clarify the target brain region of lithium augmentation of mirtazapine. After conditioning by footshock, diet (food pellets) containing Li2CO3 at a concentration of 0.2% was administered for 7 days. Ten min before testing and 7 days after conditioning, mirtazapine (3μg/site) in a volume of 0.5µl was acutely injected into the median raphe nucleus (MRN), hippocampus or amygdala. The combination of subchronic lithium and acute mirtazapine microinjection into the MRN but not the hippocampus or the amygdala reduced fear expression synergistically. These results suggest that intra-MRN mirtazapine treatment with subchronic lithium exerts the anxiolytic-like effect through the facilitation of the MRN-5HT pathway.




    Extracellular concentrations of morphine from the dorsal spinal cord, the periaqueductal gray (FAG) including the dorsal raphe, and the lateral hypothalamus were measured by microdialysis in awake rats after intraperitoneal (i.p.) administration of 2.5, 5.0 and 10 mg/kg morphine. Morphine concentrat

  4. Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but is dispensable for medullary sublineage divergence.

    Craig S Nowell


    Full Text Available The forkhead transcription factor Foxn1 is indispensable for thymus development, but the mechanisms by which it mediates thymic epithelial cell (TEC development are poorly understood. To examine the cellular and molecular basis of Foxn1 function, we generated a novel and revertible hypomorphic allele of Foxn1. By varying levels of its expression, we identified a number of features of the Foxn1 system. Here we show that Foxn1 is a powerful regulator of TEC differentiation that is required at multiple intermediate stages of TE lineage development in the fetal and adult thymus. We find no evidence for a role for Foxn1 in TEC fate-choice. Rather, we show it is required for stable entry into both the cortical and medullary TEC differentiation programmes and subsequently is needed at increasing dosage for progression through successive differentiation states in both cortical and medullary TEC. We further demonstrate regulation by Foxn1 of a suite of genes with diverse roles in thymus development and/or function, suggesting it acts as a master regulator of the core thymic epithelial programme rather than regulating a particular aspect of TEC biology. Overall, our data establish a genetics-based model of cellular hierarchies in the TE lineage and provide mechanistic insight relating titration of a single transcription factor to control of lineage progression. Our novel revertible hypomorph system may be similarly applied to analyzing other regulators of development.

  5. Spinal projections from the lower brain stem in the cat as demonstrated by the horseradish peroxidase technique. II. Projections from the dorsolateral pontine tegmentum and raphe nuclei.

    Tohyama, M; Sakai, K; Touret, M; Salvert, D; Jouvet, M


    The descending projections to the spinal cord arising from the dorsolateral pontine tegmentum and brain stem raphe nuclei have been investigated by means of the horseradish peroxidase (HRP) technique. Particular attention was taken to clarify the cells of origin and the funicular trajectory of these spinal projections. After injections of HRP into the spinal cord, a significant of HRP labeled neurons were observed in the following dorsolateral pontine tegmental structures: (1) an area ventral to the nucleus cuneiformis; (2) principal locus coeruleus; (3) locus coeruleus a; (4) locuse subcoeruleus; (5) Kölliker-Fuse nucleus; and (6) nucleus parabrachialis lateralis. As a rule, the projections are ipsilateral and descendaphe-spinal projections, we have demonstrated that the nucleus raphe dorsalis also sends axons to the cervical segment of the spinal cord. Furthermore, in accord with previous reports, HRP labeled cells were also identified in the nucleus raphe magnus, pallidus and obscurus, but not in the nucleus raphe centralis superior and pontis. On the whole the present study further clarified the organization of spinal projections from the dorsolateral pons and raphe nuclei and provided some additional anatomical data for the physiology of the tegmentospinal and raphe-spinal projections.

  6. Simultaneous occurrence of medullary and papillary thyroid microcarcinomas: a case series and review of the literature

    Adnan Zaina


    Full Text Available Abstract Introduction Papillary thyroid microcarcinoma has been demonstrated to present in association with medullary thyroid carcinoma, however, medullary thyroid carcinoma and papillary thyroid carcinoma represent rare entities. In recent years this rarity has been increasingly observed. The pathogenesis is still controversial. Genetic analysis of RET proto-oncogenes in cases of simultaneous papillary thyroid carcinoma and medullary thyroid carcinoma has so far provided conflicting results; although it seems that germline mutations play a potential role in the development of both histological types. Case presentations This paper describes four rare cases of simultaneous medullary thyroid carcinoma and papillary thyroid microcarcinoma with unique features: Case one was a 43-year-old Jewish woman, born in Israel, daughter of a Latvian immigrant mother and a father born in Israel. Case two was a 44-year-old Arab woman born in Israel. Case three was a 45-year-old Jewish woman, born in Israel, daughter of Moroccan immigrant parents and is unique for the presence of lymph node metastatic medullary thyroid carcinoma, and one lymph node with metastatic papillary carcinoma found in the same side. Case four was a 77-year-old Jewish woman, born in Iraq. These cases are unique in their composition of thyroid carcinoma, consisting of histologic features of medullary thyroid carcinoma, papillary thyroid microcarcinoma, and follicular thyroid adenoma. The four cases represent different ethnicity groups that live in north Israel, and case four is notable for the advanced age of the patient (77 years. Conclusion These four cases add more data supporting the coincidental coexistence of papillary thyroid microcarcinoma and medullary thyroid carcinoma; our results may suggest that the simultaneous occurrence of medullary thyroid carcinoma and papillary thyroid microcarcinoma is generally a simple reflection of this coincidence. Endocrinologists and pathologists

  7. [Biomechanical analysis of the medullary bone nail and its locking].

    Teubner, E


    By mechanical definition an intramedullary nail is not a nail but rather a bendable feather, subject to longitudinal tension and to a lesser degree to transverse pressure. Reaming the medullary canal is necessary for centralization of the nail as well as to increase the area of contact with the bone. However, this procedure is detrimental to the bone metabolism and reduces its elasticity against torsional forces. The dynamic locking nail-system is more biologic than conventional nailing and it reduces rotatory instability with the help of additional components, such as transverse screws. Only static locking allows true static weight bearing with crutches, but not dynamic mobilisation. Nails with conventional strength and in leaf of trefoil formation are superior to other designs. However, an improved angle in the proximal locking is suggested, as this would allow for a three to four times greater weight bearing.

  8. Medullary Thyroid Carcinoma with Ectopic Adrenocorticotropic Hormone Syndrome

    Hong Seok Choi


    Full Text Available Ectopic adrenocorticotropic hormone (ACTH syndrome is caused most frequently by a bronchial carcinoid tumor or by small cell lung cancer. Medullary thyroid carcinoma (MTC is a rare etiology of ectopic ACTH syndrome. We describe a case of Cushing syndrome due to ectopic ACTH production from MTC in a 48-year-old male. He was diagnosed with MTC 14 years ago and underwent total thyroidectomy, cervical lymph node dissection and a series of metastasectomies. MTC was confirmed by the pathological examination of the thyroid and metastatic mediastinal lymph node tissues. Two years after his last surgery, he developed Cushingoid features, such as moon face and central obesity, accompanied by uncontrolled hypertension and new-onset diabetes. The laboratory results were compatible with ectopic ACTH syndrome. A bilateral adrenalectomy improved the clinical and laboratory findings that were associated with Cushing syndrome. This is the first confirmed case of ectopic ACTH syndrome caused by MTC in Korea.

  9. Pain and neuroma formation in Wallenberg's lateral medullary syndrome.

    Moffie, D; Hamburger, H L


    We report a patient with a Wallenberg's lateral medullary syndrome in which pain was a prominent feature. This led to substitution of the original and correct diagnosis by that of a thalamic syndrome for which a prefrontal leucotomy was performed. The patient died some years later from a myocardial infarction and autopsy was performed. In the dorsolateral part of the medulla oblongata a cavity was found in which aberrant nerve fibres with neuroma-like formations could be seen. These fibres coursed along blood vessels, and penetrated from the surface of the medulla oblongata. On the base of the clinico-pathological correlations, it is conjectured that destruction of the lateral reticular formation cannot be the sole cause of the severe pain.

  10. Medullary Sponge Kidney and Urinary Calculi Aeromedical Concerns

    Jones, Jeffrey A.; Cherian, Sebastian F.; Barr, Yael R.; Stocco, Amber


    Medullary Sponge Kidney (MSK) is a benign disorder associated with renal stones in 60% of patients. Patients frequently have episodic painless hematuria but are otherwise asymptomatic unless renal calculi or infections complicate the disease. Nephrolithiasis is a relative, but frequently enforced, contraindication to space or other high performance flight. Two case reports of asymptomatic NASA flight crew with MSK and three cases of military aviators diagnosed with MSK are reviewed, all cases resulted in waiver and return to flight status after treatment and a vigorous follow up and prophylaxis protocol. MSK in aviation and space flight necessitates a highly case-by-case dependent evaluation and treatment process to rule out other potential confounding factors that might also contribute to stone formation and in order to re-qualify the aviator for flight duties.

  11. Localization of metastases from medullary thyroid carcinoma using different methods

    Cabezas, R.C.; Berna, L.; Estorch, M.; Carrio, I.; Garcia-Ameijeiras, A.


    We analyzed the efficiency of three different noninvasive methods in the localization of recurrent medullary thyroid carcinoma (MTC). Nine patients (six females and three males) with biochemical evidence of disease after primary surgery were subjected to {sup 131}I anti-carcinoembryonic antigen (anti-CEA) antibody, {sup 131}I meta-iodo-benzylguanidine (MIBG), and computed tomography. Another female patient, in biochemical remission for six years after initial surgery, was also studied using the same methods. Three of the ten patients had negative results with all three methods (including the patient in remission). The other seven patients showed abnormal uptake of labeled anti-CEA antibody in various localizations; only two of these patients had a corresponding pathological image by computed tomography and only one by {sup 131}I MIBG. These preliminary results suggest that {sup 131}I anti-CEA scanning may be the most sensitive noninvasive method for the localization of MTC recurrences.

  12. Increased mRNA expression of cytochrome oxidase in dorsal raphe nucleus of depressive suicide victims

    A Sanchez-Bahillo


    Full Text Available A Sanchez-Bahillo1, V Bautista-Hernandez1, Carlos Barcia Gonzalez1, R Bañon2, A Luna2, EC Hirsch3, Maria-Trinidad Herrero11Clinical and Experimental Neuroscience, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED; 2Department of Legal Medicine, Department of Human Anatomy, School of Medicine, University of Murcia, Campus de Espinardo, Murcia 30100, Spain; 3INSERM U679 Hôpital de la Salpêtrière, Boulevard de l’Hôpital, Paris, FranceAbstract: Suicidal behavior is a problem with important social repercussions. Some groups of the population show a higher risk of suicide; for example, depression, alcoholism, psychosis or drug abuse frequently precedes suicidal behavior. However, the relationship between metabolic alterations in the brain and premorbid clinical symptoms of suicide remains uncertain. The serotonergic and noradrenergic systems have frequently been, implicated in suicidal behavior and the amount of serotonin in the brain and CSF of suicide victims has been found to be low compared with normal subjects. However, there are contradictory results regarding the role of noradrenergic neurons in the mediation of suicide attempts, possibly reflecting the heterogeneity of conditions that lead to a common outcome. In the present work we focus on the subgroup of suicide victims that share a common diagnosis of major depression. Based on post-mortem studies analyzing mRNA expression by in situ hybridization, serotonergic neurons from the dorsal raphe nucleus (DRN from depressive suicide victims are seen to over-express cytochrome oxidase mRNA. However, no corresponding changes were found in the expression of tyrosine hydroxylase (TH mRNA in the noradrenergic neurons of the Locus Coeruleus (LC. These results suggest that, despite of the low levels of serotonin described in suicide victims, the activity of DRN neurons could increase in the suicidally depressed, probably due to the over activation of

  13. Fenestration of the superior medullary velum as treatment for a trapped fourth ventricle: a feasibility study.

    Tubbs, R Shane; Wellons, John C; Salter, George; Oakes, W Jerry


    We developed a novel approach for fenestration of the trapped fourth ventricle utilizing the superior medullary velum (valve of Vieussens). Trapped fourth ventricles, which are seen often in the pediatric hydrocephalic population, are troublesome entities surgically. A right burr hole was carried out in 10 adult cadavers with no gross intracranial pathology and the superior medullary velum was fenestrated to the quadrigeminal cistern with the aid of an endoscope. This technique was carried out easily in all cadaveric specimens. With endoscopy, no vascular insult was appreciated either before or after fenestration of the superior medullary velum. These preliminary findings demonstrate that fenestration of the superior medullary velum may provide a good alternative to the present therapy of shunting trapped fourth ventricles, a therapy wrought with complications.

  14. Immunohistochemical analysis of medullary breast carcinoma autoantigens in different histological types of breast carcinomas

    Kostianets, Olga; Antoniuk, Stepan; Filonenko, Valeriy; Kiyamova, Ramziya


    ... and treatment of this disease. In current study we analyzed six previously identified medullary breast carcinoma autoantigens including LGALS3BP, RAD50, FAM50A, RBPJ, PABPC4, LRRFIP1 with cancer restricted serological profile...

  15. [An expert system for differential diagnosis of medullary and oxyphilic cell thyroid carcinoma].

    Kirillov, V A; Emel'ianova, O A; Gladyshev, A O


    To reveal the quantitative regularities of pathological changes in the nuclei and aggregates of C and B cells and to build an expert system on their basis for the differential diagnosis of medullary and oxyphilic cell thyroid carcinoma. Puncture smears with histologically verified medullary (C cell) carcinoma and oxyphilic cell (B cell) carcinoma were investigated. The nuclei and aggregates of C cells and B cells (Hürthle cells, oncocytes) were morphometrically examined with a computer color image analyzer on the basis of a light microscope and a digital photo camera. The quantitative regularities of the degree of C and B cell aggregation in medullary and oxyphilic cell thyroid carcinoma were found by morphometry. The threshold values for the aggregates in the comparison groups and their weight coefficients formed the basis for the expert system to differentially diagnose medullary and oxyphilic cell carcinoma at the initial stages of patient examination. The clinical trials showed the high efficiency of the developed expert system.

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

    McCarthy, Gerard


    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.

  17. [Development of the habenulointerpeduncular tract in rats].

    Klepukov, A A; Makarenko, I G


    Development of the habenulointerpeduncular tract has been carried out on fixed brain preparations obtained from 21 day rat embryos and from neonatal animals on the 0 and 9 days of postnatal development by diffusion oflipophilic fluorescent carbocyanine dye DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) through neuron membranes. The marker was introduced into the nuclei of the habenula, the interpeduncular nucleus, and into the area of raphe nuclei. Neurons and fibers that contained Dil were identified on vibratome sections by fluorescent and confocal microscopy. we have found that reciprocal links between the lateral habenula nucleus and raphe nuclei are formed in the prenatal period by stage E21. Raphe nuclei innervating neurons were located in dorso- and ventrocaudal parts of the lateral habenula nucleus. Projections of the medial habenula nucleus onto interpeduncular nucleus were found only in the postnatal P2 period. Neurons that provide a source of these projections form characteristic assemblies inside the medial habenula nucleus. Therefore, the present study for the first time describes heterogenic formation of different projection systems that are involved in the habenulointerpeduncular tract of rats at perinatal ontogenesis.

  18. Inhibiton of neurons in the amygdala by dorsal raphe stimulation: mediation through a direct serotonergic pathway.

    Wang, R Y; Aghajanian, G K


    This study presents data showing that the dorsal raphe nucleus (DRN) has a marked inhibitory influence upon neurons in the amygdala and that this inhibitory effect is mediated by a direct DRN-amygdala serotonergic pathway. The evidence may be briefly summarized as follows:(1) on the same amygdaloid cells, both iontophoresis of serotonin (5-HT) and electrical stimulation of the DRN markedly inhibited spontaneous single unit activities; (2) the latency of DRN-induced inhibition was relatively short and is compatible with the conduction velocities (which were determined by antidromic activation of the 5-HT pathway) of unmyelinated 5-HT fibers; (3) destruction of 5-HT projections by 5,7-dihydroxytryptamine (5,7-DHT) or pharmacological depletion of 5-HT by parachlorophenylalanine (PCPA) prevented the inhibitory responsed to DRN stimulation in the great majority of cells studied; (4) in PCPA-pretreated animals, injection of 5-hydroxytryptophan (5-HTP) reversed the PCPA effect, restoring the responses of amygdaloid cells to DRN stimulation. In the amygdala, the presumptive 5-HT antagonists which we tested did not block the inhibitory effects of 5-HT except that intravenously administered LSD blocked the inhibitory responses produced by submaximal DRN stimulation. The implications of these results for the possible functions of 5-HT in the amygdala is discussed.

  19. Neuropeptide FF receptors exhibit direct and anti-opioid effects on mice dorsal raphe nucleus neurons.

    Ding, Zhong; Zajac, Jean-Marie


    By using acutely dissociated dorsal raphe nucleus neurons (DRN) from young mice, direct and anti-opioid effects of Neuropeptide FF (NPFF) receptors were measured. The NPFF analog 1 DMe (10 µM) had no effect on resting Ca2+ channels but reduced the magnitude of Ca2+ transients induced by depolarization in 83.3% neurons tested, of which the inhibition rate is 45.4±2.9%. Pertussis toxin treatment reduced to 18.9% the number of responding neurons and attenuated by 47% the response of 1 DMe. In contrast, cholera toxin treatment had no significant effect. Eighteen minute perfusion with 1 DMe at a very low 10 nM concentration, that did not directly inhibit Ca2+ transients triggered by depolarization in every neuron, attenuated by 78% the inhibitory effect of Nociceptin/orphanin FQ (N/OFQ) on Ca2+ transients, but not that of by serotonin. These results demonstrated for the first time that NPFF receptors on mice DRN inhibit Ca2+ transients induced by depolarization via Gi/o protein and also exhibit a specific anti-opioid activity on nociceptin receptors, and that their specific anti-opioid activity is not a direct consequence of their activity on Ca2+ transients.

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

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


    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.

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

    S.I Gomez


    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.

  2. Raphe of the posterior neural tube in the chick embryo: its closure and reopening as studied in living embryos with a high definition light microscope.

    van Straaten, H W; Jaskoll, T; Rousseau, A M; Terwindt-Rouwenhorst, E A; Greenberg, G; Shankar, K; Melnick, M


    Chick embryos cultured on a curved substratum show a transient enlargement of the posterior neuropore (PN), mimicking the temporary delay of PN closure as seen in the curly tail (ct) mouse mutant (van Straaten et al. [1993] Development 117:1163-1172). In the present study the PN enlargement in the chick embryo was investigated further with a high definition light microscope (HDmic), allowing high resolution viewing of living embryos in vitro. The temporary PN enlargement appeared due to considerable reopening of the raphe of the posterior neural tube, which was followed by reclosure after several hours. The raphe was subsequently studied in detail. It appeared very irregular, with small zones of apposed, open and fused neural folds. During closure, these raphe features shifted posteriorly. A distinct fusion sequence between surface epithelium and neuroepithelium was not seen. During experimental reopening of the raphe in vitro, small bridges temporarily arose, broke and disappeared quickly; they likely represented the first adhesion sites between the neural folds. More prominent adhesion sites partly detached, resulting in bridging filopodia-like connections; they probably represented the first anteroposterior locations of neural fold fusion. Our observations in the living chick embryo in vitro thus show that the caudal neural tube has an irregular raphe with few adhesion sites, which can be readily reopened. As a result of the irregularity, the PN does not close zipper-like, but button-like by forming multiple closure sites.

  3. Subpopulations of PKCγ interneurons within the medullary dorsal horn revealed by electrophysiologic and morphologic approach.

    Alba-Delgado, Cristina; El Khoueiry, Corinne; Peirs, Cédric; Dallel, Radhouane; Artola, Alain; Antri, Myriam


    Mechanical allodynia, a cardinal symptom of persistent pain, is associated with the unmasking of usually blocked local circuits within the superficial spinal or medullary dorsal horn (MDH) through which low-threshold mechanical inputs can gain access to the lamina I nociceptive output neurons. Specific interneurons located within inner lamina II (IIi) and expressing the gamma isoform of protein kinase C (PKCγ⁺) have been shown to be key elements for such circuits. However, their morphologic and electrophysiologic features are still unknown. Using whole-cell patch-clamp recordings and immunohistochemical techniques in slices of adult rat MDH, we characterized such lamina IIi PKCγ⁺ interneurons and compared them with neighboring PKCγ⁻ interneurons. Our results reveal that PKCγ⁺ interneurons display very specific activity and response properties. Compared with PKCγ⁻ interneurons, they exhibit a smaller membrane input resistance and rheobase, leading to a lower threshold for action potentials. Consistently, more than half of PKCγ⁺ interneurons respond with tonic firing to step current. They also receive a weaker excitatory synaptic drive. Most PKCγ⁺ interneurons express Ih currents. The neurites of PKCγ⁺ interneurons arborize extensively within lamina IIi, can spread dorsally into lamina IIo, but never reach lamina I. In addition, at least 2 morphologically and functionally different subpopulations of PKCγ⁺ interneurons can be identified: central and radial PKCγ⁺ interneurons. The former exhibit a lower membrane input resistance, rheobase and, thus, action potential threshold, and less PKCγ⁺ immunoreactivity than the latter. These 2 subpopulations might thus differently contribute to the gating of dorsally directed circuits within the MDH underlying mechanical allodynia.

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

    Scott S Wildman


    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

  5. Targeted Therapy for Medullary Thyroid Cancer: A Review

    S. R. Priya


    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. Renal Medullary Cancer in a Patient with Sickle Cell Trait

    Narendrakumar Alappan


    Full Text Available Renal medullary cancer is a rare malignancy almost exclusively seen in young patients of African ethnicity. These patients often present with the cardinal symptoms of hematuria, flank pain, and an abdominal mass, and this malignancy has been associated with patients carrying sickle cell trait. It is estimated that 300 million people worldwide carry sickle cell trait, and the presence of hematuria in these patients should be treated as a harbinger of a possible malignancy. Notably, this tumor mostly develops on the right side of the body. Patients often present with it at an advanced stage and the prognosis is poor. Therefore, a high index of suspicion in a patient of African descent presenting with a right sided abdominal mass and hematuria may assist in an early diagnosis. Current chemotherapy options are very limited, and early detection may provide a chance for surgical resection. It may also provide a bigger time frame for the initiation of novel chemotherapy regimens in patients who fail current chemotherapy regimens.

  7. Renal medullary cancer in a patient with sickle cell trait.

    Alappan, Narendrakumar; Marak, Creticus P; Chopra, Amit; Joy, Parijat S; Dorokhova, Olena; Guddati, Achuta K


    Renal medullary cancer is a rare malignancy almost exclusively seen in young patients of African ethnicity. These patients often present with the cardinal symptoms of hematuria, flank pain, and an abdominal mass, and this malignancy has been associated with patients carrying sickle cell trait. It is estimated that 300 million people worldwide carry sickle cell trait, and the presence of hematuria in these patients should be treated as a harbinger of a possible malignancy. Notably, this tumor mostly develops on the right side of the body. Patients often present with it at an advanced stage and the prognosis is poor. Therefore, a high index of suspicion in a patient of African descent presenting with a right sided abdominal mass and hematuria may assist in an early diagnosis. Current chemotherapy options are very limited, and early detection may provide a chance for surgical resection. It may also provide a bigger time frame for the initiation of novel chemotherapy regimens in patients who fail current chemotherapy regimens.

  8. [Immuno-histochemical study of medullary thyroid carcinoma].

    Bessho, T


    Five peptide hormones including calcitonin (CT) and gastrin-releasing peptide (GRP), serotonin (5HT), CEA, nervous tissue specific proteins and monoclonal antibody Leu-7 were immuno-histochemically studied on 60 cases of medullary thyroid carcinoma (MTC). In addition, localization of varied products in the tumor cells and its relations with the clinical features in some cases were evaluated. MTC contains a variety of products in many cases, and CT and CEA were positive in all cases. In 50 of the 57 cases (87.7%), GRP was positive, which suggested that GRP could be a novel tumor marker for this tumor. Furthermore, in tumor cells and C-cell hyperplastic foci, identical cells were sometimes revealed to possess both CT and GRP. Existence of somatostatin (SS), substance-P (SP), beta-MSH, 5 HT, Leu-7 and NSE in the tumor cells were confirmed. NSE was positive in 32 of the 47 cases (61.8%) which could confirm that MTC possesses neuroendocrine nature. In two cases of autopsy in which the tumors were highly malignant in clinical course and undifferentiated in histology, most tumor cells showed poor stainability for peptide hormones, suggesting that specific qualities as neuroendocrine tumor had been lost. In familial cases, the tumor tended to contain multiple substances.

  9. Muscular metastasis heralding medullary carcinoma of the thyroid

    Rawdha Tekaya


    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.

  10. Hypervascularity is more frequent in medullary thyroid carcinoma

    Lai, Xingjian; Liu, Meijuan; Xia, Yu; Wang, Liang; Bi, Yalan; Li, Xiaoyi; Zhang, Bo; Yang, Meng; Dai, Qing; Jiang, Yuxin


    Abstract This study was designed to retrospectively compare the sonographic features of medullary thyroid carcinoma (MTC) and the features of papillary thyroid carcinoma (PTC). A total of 97 patients with 127 MTCs between January 2000 and January 2016 and 107 consecutive patients with 132 PTCs were included in this study. Two radiologists retrospectively determined the sonographic features and compared the findings of MTCs and PTCs. Compared with the patients with PTCs, the patients with MTCs were older (46.9 years vs 42.9 years, P = 0.016) and the male proportion was higher (53.6% vs 33.6%, P = 0.005). Most of the MTCs had an irregular shape (72.4%), a length/width ratio hypoechogenicity (96.9%), heterogeneous echotexture (76.4%), no cystic change (78.7%), calcification (63.8%), and hypervascularity (72.4%). There was no significant difference in the boundary, peripheral halo ring, echogenicity, and calcification between the MTCs and PTCs. However, compared with the PTCs, a larger size (2.2 vs 1.2 cm, P hypoechogenicity, the presence of microcalcifications, and increased intranodular vascularity. However, MTCs tend to possess these suspicious sonographic features less often than PTCs, with the exception of hypervascularity, which was more frequent in MTCs. PMID:27930537

  11. Simultaneous medullary and papillary thyroid cancer: two case reports

    Dionigi Gianlorenzo


    Full Text Available Abstract Background Papillary thyroid carcinoma (PTC and medullary thyroid carcinoma (MTC have always been considered different from each other; in their incidence, their cell origin and their histopathological features. Case presentation This paper describes two rare cases of the simultaneous occurrence of MTC and PTC in the thyroid gland. Case 1 is unique for different reasons: (a the patient was affected by both multicentric MTC and PTC; (b a "composite thyroid carcinoma" with mixed feautures of MTC and PTC carcinomas was found in the istmus of the gland; and (c these tumors were associated with diffuse lymphocytic-type thyroiditis (LT. Case 2 is notable for the long follow up: 16 years disease free. Conclusion There are only 16 reports in the English medical literature describing a total of 20 cases of concurrent occurrence of both PTC and MTC in the same thyroid gland. We discuss whether the finding of another cancer in these patients was coincidental or from possible activation of a common tumorigenic pathway for both follicular and parafollicular thyroid cells.

  12. Hormonal regulation of medullary bone metabolism in the laying hen

    Harrison, J.R.


    A new organ culture system for the study of bone formation has been developed using medullary bone, a non-structural, metabolically active form of bone which is found in the marrow cavities of egg-laying birds. In the presence of fetal calf serum, bone explants were viable in culture by morphological criteria, and retained large numbers of osteoblasts and osteoclasts. Incorporation of /sup 3/H-proline into collagenase-digestible protein (CDP) and non-collagen protein (NCP) was determined using purified bacterial collagenase. Collagen accounted for over 10% of the total protein labeled. The calcium-regulating hormones, parathyroid hormone and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), caused a dose-dependent inhibition of /sup 3/H-proline incorporation into CDP. The effective dose range of 1,25(OH)2D3 was 0.1 nM to 100 nM, while that of PTH was 1.0 nM to 100 nM. The effect of both hormones was specific for collagen, since /sup 3/H-proline incorporation into NCP was unaffected. Hydroxyproline analysis of bone explants and culture medium revealed that both hormones decreased the total hydroxyroline content of the cultures, suggesting that the inhibition of /sup 3/H-proline incorporation into DCP is due to inhibition of collagen synthesis.

  13. Are medullary breast cancers an indication for BRCA1 mutation screening? A mutation analysis of 42 cases of medullary breast cancer.

    Iau, P T C; Marafie, M; Ali, A; Sng, J H; Macmillan, R D; Pinder, S; Denley, H E; Ellis, I O; Wenzyck, P; Scott, N; Cross, G; Blamey, R W


    Recommended guidelines have limited breast cancer gene ( BRCA1 ) mutation testing to individuals with a personal or family history of early onset breast and/or ovarian cancer, and those with multiple affected close relatives. Such large breast cancer families are rare in the general population, limiting the clinical application of the BRCA1 discovery. Previous reports have suggested an association between medullary breast cancer and BRCA1 mutation carriers. To test the feasibility of using these rare histological subtypes as an alternative to epidemiological factors, 42 cases of medullary cancer unselected for family history were screened for BRCA1 point mutations and large exon rearrangements. The large majority (83%) of these patients did not have significant family of breast or ovarian cancer. Two deleterious mutations resulting in a premature stop codon, and one exon 13 duplication were found. All mutations were detected in patients with typical medullary cancer, who had family history of multiple breast and ovarian cancers. Our findings suggest that medullary breast cancers are not an indication for BRCA1 mutation screening in the absence of significant family risk factors.

  14. Unusual gastric mucosal infiltration by a medullary thyroid carcinoma: a case report.

    Karrasch, T; Doppl, W; Roller, F C; Schäffler, A; Schäffer, R; Gattenlöhner, S


    Medullary thyroid carcinoma accounts for approximately 1 to 2 % of all thyroid carcinoma cases. The most common route of dissemination is to locoregional lymph nodes. Distant metastases commonly affect bones, lungs, and liver. We present a case of a white woman with a 25-year history of medullary thyroid carcinoma on multiple medications including tyrosine kinase inhibitor therapy for the last 11 months, who exhibited unusual diffuse infiltration of advanced stage medullary thyroid carcinoma to her gastric mucosa. A 53-year-old white woman presented with increasing fatigue, loss of appetite, and severe epigastric pain radiating to her back. She had a history of medullary thyroid carcinoma (pT2pN1b), diagnosed 25 years ago and treated by complete thyroidectomy and repeated bilateral cervical lymph node dissection. Medical therapy included octreotide 20 mg every 4 weeks, which was switched to the tyrosine kinase inhibitor vandetanib 300 mg/day 11 months ago when computed tomography scanning revealed progressive mediastinal lymph node and diffuse and symptomatic pulmonary metastases. Of note, she demonstrated macroscopically stable pulmonary and mediastinal lymph node metastases; however, her calcitonin serum levels dramatically increased. Computed tomography scanning revealed a single new intrahepatic lesion (4 mm) as well as multiple (>10) new supraclavicular lesions suggestive of medullary thyroid carcinoma progress. As proven by gastric biopsy and immunohistochemical evaluation, her epigastric pain was explained by a diffuse infiltration of her gastric mucosa by metastatic medullary thyroid carcinoma. Subsequently, she rapidly deteriorated and died. The current case report shows for the first time an unusual metastatic infiltration of the gastric mucosa by medullary thyroid carcinoma. When treating these patients, it is important to include this differential diagnosis during follow-up.

  15. The role of the dorsal raphé nucleus in reward-seeking behavior

    Kae eNakamura


    Full Text Available Pharmacological experiments have shown that the modulation of brain serotonin levels has a strong impact on value-based decision making. Anatomical and physiological evidence also revealed that the dorsal raphé nucleus (DRN, a major source of serotonin, and the dopamine system receive common inputs from brain regions associated with appetitive and aversive information processing. The serotonin and dopamine systems also have reciprocal functional influences on each other. However, the specific mechanism by which serotonin affects value-based decision making is not clear.To understand the information carried by the DRN for reward-seeking behavior, we measured single neuron activity in the primate DRN during the performance of saccade tasks to obtain different amounts of a reward. We found that DRN neuronal activity was characterized by tonic modulation that was altered by the expected and received reward value. Consistent reward-dependent modulation across different task periods suggested that DRN activity kept track of the reward value throughout a trial. The DRN was also characterized by modulation of its activity in the opposite direction by different neuronal subgroups, one firing strongly for the prediction and receipt of large rewards, with the other firing strongly for small rewards. Conversely, putative dopamine neurons showed positive phasic responses to reward-indicating cues and the receipt of an unexpected reward amount, which supports the reward prediction error signal hypothesis of dopamine.I suggest that the tonic reward monitoring signal of the DRN, possibly together with its interaction with the dopamine system, reports a continuous level of motivation throughout the performance of a task. Such a signal may provide reward context information to the targets of DRN projections, where it may be integrated further with incoming motivationally salient information.

  16. Ovarian steroids increase PSD-95 expression and dendritic spines in the dorsal raphe of ovariectomized macaques.

    Rivera, Heidi M; Bethea, Cynthia L


    Estradiol (E) and progesterone (P) promote spinogenesis in several brain areas. Intracellular signaling cascades that promote spinogenesis involve RhoGTPases, glutamate signaling and synapse assembly. We found that in serotonin neurons, E ± P administration increases (a) gene and protein expression of RhoGTPases, (b) gene expression of glutamate receptors, and (c) gene expression of pivotal synapse assembly proteins. Therefore, in this study we determined whether structural changes in dendritic spines in the dorsal raphe follow the observed changes in gene and protein expression. Dendritic spines were examined with immunogold silver staining of a spine marker protein, postsynaptic density-95 (PSD-95) and with Golgi staining. In the PSD-95 study, adult Ovx monkeys received placebo, E, P, or E + P for 1 month (n = 3/group). Sections were immunostained for PSD-95 and the number of PSD-95-positive puncta was determined with stereology. E, P, and E + P treatment significantly increased the total number of PSD-95-positive puncta (ANOVA, P = 0.04). In the golgi study, adult Ovx monkeys received placebo, E or E + P for 1 month (n = 3-4) and the midbrain was golgi-stained. A total of 80 neurons were analyzed with Neurolucida software. There was a significant difference in spine density that depended on branch order (two-way ANOVA). E + P treatment significantly increased spine density in higher-order (3°-5°) dendritic branches relative to Ovx group (Bonferroni, P PSD-95, but not actual spines, suggests either a sampling or time lag issue. Increased spinogenesis on serotonin dendrites would facilitate excitatory glutamatergic input and, in turn, increase serotonin neurotransmission throughout the brain. Copyright © 2013 Wiley Periodicals, Inc.

  17. Impacts of brain serotonin deficiency following Tph2 inactivation on development and raphe neuron serotonergic specification.

    Lise Gutknecht

    Full Text Available Brain serotonin (5-HT is implicated in a wide range of functions from basic physiological mechanisms to complex behaviors, including neuropsychiatric conditions, as well as in developmental processes. Increasing evidence links 5-HT signaling alterations during development to emotional dysregulation and psychopathology in adult age. To further analyze the importance of brain 5-HT in somatic and brain development and function, and more specifically differentiation and specification of the serotonergic system itself, we generated a mouse model with brain-specific 5-HT deficiency resulting from a genetically driven constitutive inactivation of neuronal tryptophan hydroxylase-2 (Tph2. Tph2 inactivation (Tph2-/- resulted in brain 5-HT deficiency leading to growth retardation and persistent leanness, whereas a sex- and age-dependent increase in body weight was observed in Tph2+/- mice. The conserved expression pattern of the 5-HT neuron-specific markers (except Tph2 and 5-HT demonstrates that brain 5-HT synthesis is not a prerequisite for the proliferation, differentiation and survival of raphe neurons subjected to the developmental program of serotonergic specification. Furthermore, although these neurons are unable to synthesize 5-HT from the precursor tryptophan, they still display electrophysiological properties characteristic of 5-HT neurons. Moreover, 5-HT deficiency induces an up-regulation of 5-HT(1A and 5-HT(1B receptors across brain regions as well as a reduction of norepinephrine concentrations accompanied by a reduced number of noradrenergic neurons. Together, our results characterize developmental, neurochemical, neurobiological and electrophysiological consequences of brain-specific 5-HT deficiency, reveal a dual dose-dependent role of 5-HT in body weight regulation and show that differentiation of serotonergic neuron phenotype is independent from endogenous 5-HT synthesis.

  18. Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards.

    Miyazaki, Kayoko W; Miyazaki, Katsuhiko; Tanaka, Kenji F; Yamanaka, Akihiro; Takahashi, Aki; Tabuchi, Sawako; Doya, Kenji


    Serotonin is a neuromodulator that is involved extensively in behavioral, affective, and cognitive functions in the brain. Previous recording studies of the midbrain dorsal raphe nucleus (DRN) revealed that the activation of putative serotonin neurons correlates with the levels of behavioral arousal [1], rhythmic motor outputs [2], salient sensory stimuli [3-6], reward, and conditioned cues [5-8]. The classic theory on serotonin states that it opposes dopamine and inhibits behaviors when aversive events are predicted [9-14]. However, the therapeutic effects of serotonin signal-enhancing medications have been difficult to reconcile with this theory [15, 16]. In contrast, a more recent theory states that serotonin facilitates long-term optimal behaviors and suppresses impulsive behaviors [17-21]. To test these theories, we developed optogenetic mice that selectively express channelrhodopsin in serotonin neurons and tested how the activation of serotonergic neurons in the DRN affects animal behavior during a delayed reward task. The activation of serotonin neurons reduced the premature cessation of waiting for conditioned cues and food rewards. In reward omission trials, serotonin neuron stimulation prolonged the time animals spent waiting. This effect was observed specifically when the animal was engaged in deciding whether to keep waiting and was not due to motor inhibition. Control experiments showed that the prolonged waiting times observed with optogenetic stimulation were not due to behavioral inhibition or the reinforcing effects of serotonergic activation. These results show, for the first time, that the timed activation of serotonin neurons during waiting promotes animals' patience to wait for a delayed reward.

  19. The Alteration of Neonatal Raphe Neurons by Prenatal-Perinatal Nicotine. Meaning for Sudden Infant Death Syndrome.

    Cerpa, Verónica J; Aylwin, María de la Luz O; Beltrán-Castillo, Sebastián; Bravo, Eduardo U; Llona, Isabel R; Richerson, George B; Eugenín, Jaime L


    Nicotine may link maternal cigarette smoking with respiratory dysfunctions in sudden infant death syndrome (SIDS). Prenatal-perinatal nicotine exposure blunts ventilatory responses to hypercapnia and reduces central respiratory chemoreception in mouse neonates at Postnatal Days 0 (P0) to P3. This suggests that raphe neurons, which are altered in SIDS and contribute to central respiratory chemoreception, may be affected by nicotine. We therefore investigated whether prenatal-perinatal nicotine exposure affects the activity, electrical properties, and chemosensitivity of raphe obscurus (ROb) neurons in mouse neonates. Osmotic minipumps, implanted subcutaneously in 5- to 7-day-pregnant CF1 mice, delivered nicotine bitartrate (60 mg kg(-1) d(-1)) or saline (control) for up to 28 days. In neonates, ventilation was recorded by head-out plethysmography, c-Fos (neuronal activity marker), or serotonin autoreceptors (5HT1AR) were immunodetected using light microscopy, and patch-clamp recordings were made from raphe neurons in brainstem slices under normocarbia and hypercarbia. Prenatal-perinatal nicotine exposure decreased the hypercarbia-induced ventilatory responses at P1-P5, reduced both the number of c-Fos-positive ROb neurons during eucapnic normoxia at P1-P3 and their hypercapnia-induced recruitment at P3, increased 5HT1AR immunolabeling of ROb neurons at P3-P5, and reduced the spontaneous firing frequency of ROb neurons at P3 without affecting their CO2 sensitivity or their passive and active electrical properties. These findings reveal that prenatal-perinatal nicotine reduces the activity of neonatal ROb neurons, likely as a consequence of increased expression of 5HT1ARs. This hypoactivity may change the functional state of the respiratory neural network leading to breathing vulnerability and chemosensory failure as seen in SIDS.


    李辉; 吴乐; 李云庆


    CB(calbindin-D28k),CR(calretinin)和PV(parvalbumin)是最常见的3种钙结合蛋白(calcium-binding proteins,CaBPs).本研究首先观察了面口部给予伤害性刺激诱发大鼠延髓背角(又称三叉神经脊束核尾侧亚核)神经元表达FOS蛋白的状况;然后通过免疫荧光组织化学技术检测这些神经元内是否含有CaBPs(CB、CR和PV);最后通过免疫荧光和免疫电镜染色技术观察5-HT、GABA、甘氨酸转运体2(glycine transporter 2,GlvT2)、脑啡肽(enkephalin,ENK)或SP与CaBPs/FOS双标神经元间的联系.在光镜下可观察到:(1)FOS阳性神经元在延髓背角各层均有分布,以Ⅱ层最为密集;(2)大多数CB、CR或PV阳性神经元位于Ⅱ层,余者分布在Ⅰ层和Ⅲ层;(3)5-HT、GABA、GlyT2,ENK及SP阳性纤维和终末主要位于延髓背角浅层(4)部分FOS阳性神经元同时呈CB、CR或PV阳性;(5)5-HT、GABA、GlyT2或ENK阳性终末分别与FOS/CB、FOS/CR或FOS/PV双标神经元形成密切接触;(6)SP阳性终末与5-HT、GABA、GlyT2或ENK阳性终末同时与CB、CR或PV阳性神经元形成密切接触.在电镜下观察到5-HT、GABA、GlyT2或ENK阳性终末与CB、CR或PV阳性神经元主要形成对称型(抑制性)突触联系.这些结果提示在大鼠延髓背角,5-HT、GABA、甘氨酸或ENK可能通过抑制含钙结合蛋白的伤害性感受神经元来调节面口部伤害性信息的传递.%Calbindin-D28k (CB), calretinin (CR) and parvalbumin (PV) are the most common calcium-binding proteins (CaBPs). In the present study, FOS immunoreactivity was first induced in neurons of the medullary dorsal horn (MDH) of the rat by noxious orofacial stimulation; CaBPs (CB, CR and PV) in these neurons were then identified by imumunofluorescence histochemistry, and then, in addition, afferents to CaBPs/FOS double-labeled neurons were showed by immunofluorescence histochemical staining for the γ-aminobutyric acid (GABA) , glycine transporter 2 (GlyT2) , enkephalin (ENK) , serotonin

  1. New drugs for medullary thyroid cancer: new promises?

    Spitzweg, Christine; Morris, John C; Bible, Keith C


    Medullary thyroid cancer (MTC) is a rare tumor arising from the calcitonin-producing parafollicular C cells of the thyroid gland, occurring either sporadically or alternatively in a hereditary form based on germline RET mutations in approximately one-third of cases. Historically, patients with advanced, metastasized MTC have had a poor prognosis, partly due to limited response to conventional chemotherapy and radiation therapy. In the past decade, however, considerable progress has been made in identifying key genetic alterations and dysregulated signaling pathways paving the way for the evaluation of a series of multitargeted kinase inhibitors that have started to meaningfully impact clinical practice. Two drugs, vandetanib and cabozantinib, are now approved in the US and EU for use in advanced, progressive MTC, with additional targeted agents also showing promise or awaiting results from clinical trials. However, the potential for toxicities with significant reduction in quality of life and lack of curative outcomes has to be carefully weighed against potential for benefit. Despite significant PFS prolongation observed in randomized clinical trials, most patients even with metastatic disease enjoy indolent courses with slow progression observed over years, wherein watchful waiting is still the preferred strategy. As advanced, progressive MTC is a rare and complex disease, a multidisciplinary approach centered in specialized centers providing interdisciplinary expertise in the individualization of available therapeutic options is preferred. In this review, we summarize current concepts of the molecular pathogenesis of advanced MTC and discuss results from clinical trials of targeted agents and also cytotoxic chemotherapy in the context of clinical implications and future perspectives.

  2. Ultrasonographic features of medullary thyroid carcinoma and their diagnostic values

    CAI Sheng; JIANG Yu-xin; LIU He; LI Wen-bo; OUYANG Yun-shu; ZHANG Bo; LI Peng; WANG Xue-lian; ZHANG Xiao-yan; LI Jian-chu


    Background Medullary thyroid carcinoma (MTC) is a rare malignant tumour and usually difficult to diagnose with ultrasound. The aim of the study is to summarize the sonographic features of MTC and evaluate their diagnostic values.Methods We analyzed the sonographic features of 35 MTCs and 50 benign nodules with respect to nodular size,echogenecity, internal content, shape, height/width, border, peripheral halo, calcifications and colour flow pattern. The ratio of long to short axis, echogenecity, internal content and calcifications were also assessed in cervical lymph nodes.The differences in sonographic features between MTCs and benign nodules were analyzed with Chi square test. The diagnostic efficiency of each sonographic feature was determined.Results The main sonographic features of MTC were hypoechogenicity (including marked hypoechogenicity) (n=34,97%), internal solid content (n=29, 83%), taller than wide (n=34, 97%), well defined border (n=24, 69%),microcalcifications or macrocalcifications (n=23, 66%). The echogenicity, internal content, shape, peripheral halo and calcifications were significantly different between these two groups, while the tall/wide, border, and pednodular and intranodular vascularisation were not significantly different. Among all the individual sonographic features, irregular shape had the highest diagnostic efficiency with a sensitivity of 51% and specificity of 92%. The combination of marked hypoechogenicity, microcalcifications, and irregular shape yielded a sensitivity of 77% and specificity of 86%.Conclusions The typical sonographic features of MTC are hypoechogenicity, predominantly solid, irregularly shaped with intranodular micro- or macro-calcifications. The combination of multiple sonographic features is helpful, but not definitive, for the diagnosis of MTC.

  3. Pure ipsilateral central facial palsy and contralateral hemiparesis secondary to ventro-medial medullary stroke.

    Ahdab, R; Saade, H S; Kikano, R; Ferzli, J; Tarcha, W; Riachi, N


    Medullary infarcts are occasionally associated with facial palsy of the central type (C-FP). This finding can be explained by the course of the facial corticobulbar (F-CB) fibers. It is believed that fibers that project to the upper facial muscles decussate at the level of the facial nucleus, whereas those destined to the lower facial muscles decussate more caudally, at the level of the mid or upper medulla. It has been proposed that the lower F-CB fibers descend ventromedially near the corticospinal tract to the upper medulla where they cross midline and ascend dorsolaterally. Accordingly, ventromedial medullary infarcts are expected to result in contralateral facial and limb weakness. We report a patient with a medial medullary infarct restricted to the right pyramid and associated with ipsilateral C-FP and contralateral hemiparesis. The neurological findings are discussed in light of the hypothetical course of the F-CB fibers in the medulla.

  4. Effect of medullary cavity in cancellous bone on two-wave phenomenon

    Hachiken, Takuma; Nakanishi, Shoko; Matsukawa, Mami


    Osteoporotic patients have a larger medullary cavity in their cancellous bone than healthy people. In this study, the effect of the medullary cavity on the two-wave phenomenon was experimentally investigated using a cancellous bone model and a radius bone model. In the cancellous bone model, with the increase in hole (medullary cavity) diameter, the amplitudes of the fast waves became smaller, whereas the amplitudes of the slow waves became larger. In the radius bone model, the fast wave overlapped with the circumferential wave. The slow wave became larger with increasing hole diameter. The analysis of the slow wave thus seems to be useful for the in vivo diagnosis of the degree of osteoporosis.

  5. Raphe magnus and reticulospinal actions on primary afferent depolarization of group I muscle afferents in the cat.

    Quevedo, J; Eguibar, J R; Jiménez, I; Rudomin, P


    1. In the anaesthetized cat, electrical stimulation of the bulbar reticular formation produced a short latency (2.1 +/- 0.3 ms) positive potential in the cord dorsum. In contrast, stimulation of the nucleus raphe magnus with strengths below 50 microA evoked a slow negative potential with a mean latency of 5.5 +/- 0.6 ms that persisted after sectioning the contralateral pyramid and was abolished by sectioning the ipsilateral dorsolateral funiculus. 2. The field potentials evoked by stimulation of the bulbar reticular formation and of the nucleus raphe magnus had a different intraspinal distribution, suggesting activation of different sets of segmental interneurones. 3. Stimulation of these two supraspinal nuclei produced primary afferent depolarization (PAD) in single Ib fibres and inhibited the PAD elicited by group I volleys in single Ia fibres. The inhibition of the PAD of Ia fibres produced by reticulospinal and raphespinal inputs appears to be exerted on different interneurones along the PAD pathway. 4. It is concluded that, although reticulospinal and raphespinal pathways have similar inhibitory effects on PAD of Ia fibres, and similar excitatory effects on the PAD of Ib fibres, their actions are conveyed by partly independent pathways. This would allow their separate involvement in the control of posture and movement.

  6. Is Hashimoto's thyroiditis a risk factor for medullary thyroid carcinoma? Our experience and a literature review.

    Zayed, Ayman A; Ali, Moaath K Mustafa; Jaber, Omar I; Suleiman, Moh'd J; Ashhab, Ashraf A; Al Shweiat, Wajdi Mohammed; Momani, Munther Suliaman; Shomaf, Maha; AbuRuz, Salah Mohammed


    The etiology of medullary thyroid carcinoma remains unknown. The aim of this study was to determine whether there is a significant association between medullary thyroid carcinoma and Hashimoto's thyroiditis in the histopathologic material of thyroidectomized patients. Retrospective cross-sectional study. In this study, we reviewed the medical records of all patients who underwent total thyroidectomy for different thyroid-related complaints between January 2000 and January 2012 at Jordan University Hospital-Amman, Jordan. To highlight relevant previously published studies addressing this topic, a literature search was conducted for English language studies reporting "medullary thyroid carcinoma" or "C-cell hyperplasia" in patients with Hashimoto's thyroiditis. Of the 863 patients with a mean age of 47.2 ± 12.3 years who underwent total thyroidectomy during the study period, 78 (9.04 %) were diagnosed with Hashimoto's thyroiditis, and 15 (1.74 %) had medullary thyroid carcinoma, 3 (20 %) of whom had coexistent Hashimoto's thyroiditis. A total of 683 (79.1 %) patients had benign thyroid disease, 67 (9.8 %) of whom had Hashimoto's thyroiditis. The difference between these rates was not statistically significant (p = 0.19). When examined by gender, 9 females had medullary thyroid carcinoma, 3 (33.3 %) of whom had coexistent Hashimoto's thyroiditis; by contrast, of 560 females with benign thyroid disease, 62 (11.1 %) had Hashimoto's thyroiditis (p = 0.04). Although this study population represents a small and single-institution experience, our results suggest that there might be an association between Hashimoto's thyroiditis and medullary thyroid carcinoma only in female patients who undergo total thyroidectomy.

  7. Serum HSP27 is associated with medullary perfusion in kidney allografts

    Marquez, Eva; Sadowski, Elizabeth; Reese, Shannon; Vidyasagar, Aparna; Artz, Nathan; Fain, Sean; Jacobson, Lynn; Swain, William; Djamali, Arjang


    Background Heat shock protein 27 (HSP27) is a small HSP up-regulated in response to stress in the kidney. The relationship between HSP27 and intrarenal oxygenation in patients with native and transplant kidney disease is unknown. Methods We compared HSP27 levels, intrarenal oxygenation measured by blood oxygen-level dependent (BOLD) imaging using R2* values, and perfusion determined by arterial spin labeling (ASL) magnetic resonance imaging (MRI), between patients with native and transplant kidney disease (n=28). Results There were no statistical differences in mean age (53.9 vs. 47.1 years), kidney function (63.6 vs. 50.7 ml/min per 1.73 m2), mean arterial blood pressure (91.6 vs. 91.1 mm Hg), hematocrit (40.6% vs. 39.3%), diuretic or angiotensin-converting enzyme inhibitor use, serum or urine levels of hydrogen peroxide, nitric oxide, F2 isoprostanes and HSP27 between native and transplant kidneys. BOLD-MRI studies demonstrated comparable patterns in intrarenal oxygen bioavailability (medullary R2* 18.1 vs. 18.3/s and cortical R2* 12 vs. 11.7/s, respectively). However, medullary perfusion was significantly lower in transplant kidneys (36.4 vs. 78.7 ml/100 g per minute, p=0.0002). There was a linear relationship between serum HSP27 concentrations and medullary perfusion in kidney allografts (HSP27 concentration [ng/mL] = 0.78 + 0.09 medullary perfusion, R2=0.43, p=0.01). Conclusions Our study demonstrates that medullary perfusion is significantly lower in kidney allografts compared with native kidneys with comparable renal function. We further noted a direct association between serum HSP27 levels and medullary perfusion after transplantation. Additional studies are needed to examine the role of HSP27 as a biomarker of kidney disease progression. PMID:22383348

  8. Targeting medullary thyroid carcinomas with bispecific antibodies and bivalent haptens. Results and clinical perspectives.

    Rouvier, E; Gautherot, E; Meyer, P; Barbet, J


    The present article reviews the clinical trials that have been performed in recurrent medullary thyroid carcinoma patients with the Affinity Enhancement System. This technique uses bispecific antibodies to target radiolabelled bivalent haptens to tumour cells. Its sensitivity in the detection of known tumour sites is high (90%) and this technique also achieves good sensitivity (61%) in the detection of occult disease as revealed by abnormal thyrocalcitonin blood levels. Due to its high targeting capacity, this technique is now considered for use as a therapeutic agent in medullary thyroid carcinoma patients.

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

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


    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.

  10. Sporadic bilateral adrenal medullary hyperplasia: apparent false positive MIBG scan and expected MRI findings

    Yung, Babington C.K.; Loke, Tony K.L.; Tse, T.W.; Tsang, M.W.; Chan, James C.S. E-mail:


    Adrenal medullary hyperplasia is a rare cause of clinical symptoms and biochemical findings identical to pheochromocytoma occurring mostly in multiple endocrine neoplasia patients. The scenario of positive MIBG scan, but no focal lesion found on CT and MRI led to diagnostic and management difficulties. Like pheochromocytoma, surgical excision can lead to clinical and biochemical recovery. We report this unusual case of sporadic bilateral adrenal medullary hyperplasia, with hypertension and biochemical abnormalities alleviated after surgical adrenalectomy. Based on T2 values reported in literature, high signal focal lesions may not appear on T2-weighted MRI images until development of frank pheochromocytoma. MIBG scan remains the most sensitive imaging modality for this condition.

  11. Continuous ethanol administration influences rat brain 5-hyroxytrytamine synthesis non-umiformly: alpha-[14C]methyl-L-trytophan autoradiographic measurements.

    Yamane, Fumitaka; Tohyama, Yoshihiro; Diksic, Mirko


    The influence of alcohol on the brain serotonergic system has been studied for several decades with some discordant results. The effects of continuous and constant treatment with ethanol on the rates of serotonin [5-hydroxytryptamine (5-HT)] synthesis in discrete regions of the rat brain were studied. 5-HT synthesis rates were measured using the alpha-[(14)C]methyl-l-tryptophan autoradiographic method. The rats in the experimental group were treated with 50% ethyl alcohol and those in the control group received distilled water. The fluid was delivered subcutaneously by implanted osmotic mini-pumps for 14 days at the rate of 5 micro l/h or 0.12 ml/day (0.06 ml of alcohol per day). Chronic ethanol treatment, as delivered in the present experiment, induced a significant increase in the rate of 5-HT synthesis in descending serotonergic cell bodies (raphe pallidum, raphe obscurus, raphe magnus), nigrostriatal structures, the hippocampus and cortices. No significant changes were observed in the dorsal and median raphe nuclei or pineal body. The results suggest that there may be differences in the regulation of 5-HT synthesis in different brain structures after 14 days of continuous (subcutaneous) injection of 50% alcohol. Chronic ethanol treatments using osmotic mini-pumps induce non-uniform increases in 5-HT synthesis in the rat brain.

  12. Shear wave elastography in medullary thyroid carcinoma diagnostics

    Katarzyna Dobruch-Sobczak


    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

  13. Long-Term Follow-up in Medullary Thyroid Carcinoma.

    Raue, Friedhelm; Frank-Raue, Karin


    After surgery, patients with medullary thyroid carcinoma (MTC) should be assessed regarding the presence of residual disease, the localization of metastases, and the identification of progressive disease. Postoperatively, patients with MTC are staged to separate those at low risk from those at high risk of recurrence. The TNM staging system is based on tumor size, extra-thyroidal invasion, nodal metastasis, and distant spread of cancer. In addition, the number of lymph-node metastases, the number of compartments involved, and the postoperative calcitonin (CTN) and carcinoembryonic antigen (CEA) levels should be documented. The postoperative normalization of the serum CTN level is associated with a favorable outcome. When patients have basal serum CTN levels less than 150 pg/ml after a thyroidectomy, any persistent or recurrent disease is nearly always confined to lymph nodes in the neck. When the postoperative serum CTN level exceeds 150 pg/ml, patients should be evaluated with imaging procedures, including computed tomography (CT) of the neck and chest, contrast-enhanced magnetic resonance imaging (MRI) and ultrasound (US) of the liver, bone scintigraphy, MRI of the bone, and positron emission tomography (PET)/CT. One can estimate the growth rate of MTC metastases by quantifying increases in tumor size over time from sequential imaging studies analyzed with response evaluation criteria in solid tumors (RECIST), and by determining the tumor marker doubling time from sequential measures of serum CTN or CEA levels over multiple time points. One of the main challenges remains to find effective adjuvant and palliative options for patients with metastatic disease. Patients with persistent or recurrent MTC localized to the neck following thyroidectomy are candidates for neck operations, depending on the tumor extension. Once metastases appear, the clinician must decide which patients require therapy. This requires a balance between the (often) slow rate of tumor

  14. Motor recovery in a patient with an infarct in the medullary pyramid via the corticospinal tract passing through the small spared area within the infarcted medullary pyramid

    Hyeok Gyu Kwon; Sung Ho Jang


    The present study reported a 58-year-old male patient who exhibited complete paralysis of the right extremities at stroke onset.Brain MR images showed an infarct in the left medullary pyramid and a small spared area on the medial side of the infarct.He gained the ability to extend the affected fingers against gravity and to dorsiflex the affected ankle without gravity at 3 months after stroke onset.Diffusion tensor imaging results showed that at 6 months after stroke onset,the corticospinal tract of the affected (left) hemisphere descended through the small spared area of the infarcted medullary pyramid.No motor-evoked potential was elicited from the affected (left) hemisphere at 2 weeks after stroke onset;however,motor-evoked potential was elicited at 6 months as shown by transcranial magnetic stimulation results.The motor function of the affected side of this patient appears to have been recovered via the corticospinal tract that passed through the small spared area within the infarcted medullary pyramid.

  15. Brain SERT Expression of Male Rats Is Reduced by Aging and Increased by Testosterone Restitution

    José Jaime Herrera-Pérez


    Full Text Available In preclinical and clinical studies aging has been associated with a deteriorated response to antidepressant treatment. We hypothesize that such impairment is explained by an age-related decrease in brain serotonin transporter (SERT expression associated with low testosterone (T levels. The objectives of this study were to establish (1 if brain SERT expression is reduced by aging and (2 if the SERT expression in middle-aged rats is increased by T-restitution. Intact young rats (3–5 months and gonad-intact middle-aged rats with or without T-restitution were used. The identification of the brain SERT expression was done by immunofluorescence in prefrontal cortex, lateral septum, hippocampus, and raphe nuclei. An age-dependent reduction of SERT expression was observed in all brain regions examined, while T-restitution recovered the SERT expression only in the dorsal raphe of middle-aged rats. This last action seems relevant since dorsal raphe plays an important role in the antidepressant action of selective serotonin reuptake inhibitors. All data suggest that this mechanism accounts for the T-replacement usefulness to improve the response to antidepressants in the aged population.

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

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


    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

  17. Role of Pituitary Tumour Transforming Gene 1 in Medullary Thyroid Carcinoma

    Maria Chiara Zatelli


    Full Text Available Background: Pituitary tumour transforming gene 1 (PTTG1 is over-expressed in a variety of endocrine-related tumours. We aimed at evaluating PTTG1 expression and function in human neoplastic parafollicular C-cells, represented by medullary thyroid carcinoma (MTC and C-cell hyperplasia (CCH samples and by the TT cell line.

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

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


    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 ...... management of related adverse events (AEs) is vital to ensure patient compliance and maximize clinical benefit with vandetanib therapy....

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

    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

  20. The Effects of Four Different Tyrosine Kinase Inhibitors on Medullary and Papillary Thyroid Cancer Cells

    Verbeek, Hans H. G.; Alves, Maria M.; de Groot, Jan-Willem B.; Osinga, Jan; Plukker, John T. M.; Links, Thera P.; Hofstra, Robert M. W.

    Context: Medullary and papillary thyroid carcinoma (MTC and PTC) are two types of thyroid cancer that can originate from activating mutations or rearrangements in the RET gene. Therapeutic options are limited in recurrent disease, but because RET is a tyrosine kinase (TK) receptor involved in

  1. Diagnosis of medullary thyroid cancer and prognostic factors of disease aggressiveness

    D O Gazizova


    Full Text Available In the study were enrolled 137 patients with medullary thyroid cancer (MTC. Low 35%-sensitivity of FNAC and high accuracy of basal calcitonin in MTC diagnostics were found. Mutation analysis of the RET pro- tooncogene in familial and sporadic MTC, RAS -gene in sporadic MTC were done. The correlation between type of the mutation and disease aggressiveness was found.

  2. Progressive metastatic medullary thyroid carcinoma : first- and second-line strategies

    Links, Thera P.; Verbeek, Hans H. G.; Hofstra, Robert M. W.; Plukker, John Th M.


    The treatment for metastasised medullary thyroid cancer is still a topic of discussion. One of the main challenges remains to find effective adjuvant and palliative options for patients with metastatic disease. The diagnostic and treatment strategies for this tumour are discussed and possible new de

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

    T. Schepers (Tim); L.M.M. Vogels (Lucas)


    textabstractWe 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 jo

  4. E-cadherin and beta-catenin expression in breast medullary carcinomas.

    Charpin, C; Bonnier, P; Garcia, S; Andrac, L; Crebassa, B; Dorel, M; Lavaut, M N; Allasia, C


    The initial step of cancer invasion and metastasis is the escape of tumour cells from the primary site, involving disruption of normal cell-cell adhesion and E-cadherin (E-cad) and beta-catenin (beta-cat) down-regulation, as shown in various types of human malignancies including breast carcinomas. Medullary carcinomas are high grade and poorly differentiated tumours with syncytial typical pattern, and prognosis unexpectedly better than that in high grade breast carcinomas. In a series of 55 breast typical medullary carcinomas diagnosed according to the strict use of Ridolfi et al (Cancer 40: 1365-1385, 1977) criteria, E-cad and beta-cat were investigated using quantitative (SAMBA 2005 system) immunocytochemical assays on frozen sections. Results were compared to that obtained on paraffin sections and in a series (n=55) of grade 3 ductal carcinomas. It was shown that medullary carcinomas significantly (p<0.001) expressed more E-cad and beta-cat than grade 3 ductal carcinomas. E-cad and beta-cat correlated with high expression of P53, of c-erbB, and of Ki-67 antigens, and with lack of hormone receptors antigenic sites (p<0.001). It was concluded that favourable prognosis and syncytial pattern of typical breast medullary carcinomas likely results, at least partly, from a particular expression of cell-cell adhesion molecules, significantly limiting tumour growth and efficiently mastering the tumour cell dissemination, opposing to high proliferative activity (grade 3).

  5. Effect of an Outreach Programme on Vandetanib Safety in Medullary Thyroid Cancer

    Bastholt, Lars; Kreissl, Michael C; Führer, Dagmar


    III study, patients with locally advanced or metastatic medullary thyroid cancer were randomized to a patient outreach programme (outreach) or a standard AE monitoring schedule (vandetanib control) for 52 weeks. In addition to standard AE monitoring, patients in the outreach arm were contacted every 2...

  6. Radioactive iodine in the treatment of medullary thyroid carcinoma : a controlled multicenter study

    Meijer, J. A. A.; Bakker, L. E. H.; Valk, G. D.; de Herder, W. W.; de Wilt, J. H. W.; Netea-Maier, R. T.; Schaper, N.; Fliers, E.; Lips, P.; Plukker, J. T.; Links, T. P.; Smit, J. A.


    Objective: Radioactive iodine (RAI) therapy in medullary thyroid carcinoma (MTC) is applied in some centers, based on the assumption that cross-irradiation from thyroid follicular cells may be beneficial. However, no systematic studies on the effect of RAI treatment in MTC have been performed. The a

  7. Radioactive iodine in the treatment of medullary thyroid carcinoma: a controlled multicenter study

    Meijer, J.A.M.; Bakker, L.E.; Valk, G.D.; Herder, W.W. de; Wilt, J.H.W. de; Netea-Maier, R.T.; Schaper, N.; Fliers, E.; Lips, P.; Plukker, J.T.; Links, T.P.; Smit, Jan


    OBJECTIVE: Radioactive iodine (RAI) therapy in medullary thyroid carcinoma (MTC) is applied in some centers, based on the assumption that cross-irradiation from thyroid follicular cells may be beneficial. However, no systematic studies on the effect of RAI treatment in MTC have been performed. The a

  8. Radioactive iodine in the treatment of medullary thyroid carcinoma: A controlled multicenter study

    J.A.A. Meijer (J. A A); L.E.H. Bakker (Leontine); G.D. Valk (Gerlof); W.W. de Herder (Wouter); J.H.W. de Wilt (Johannes); R.T. Netea-Maier (Romana ); N. Schaper; E. Fliers (Eric); P. Lips (Paul); J.T. Plukker (John); T.P. Links (Thera); J.A. Smit (J.)


    textabstractObjective: Radioactive iodine (RAI) therapy in medullary thyroid carcinoma (MTC) is applied in some centers, based on the assumption that cross-irradiation from thyroid follicular cells may be beneficial. However, no systematic studies on the effect of RAI treatment in MTC have been perf

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

    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 gl

  10. Fewer cancer reoperations for medullary thyroid cancer after initial surgery according to ATA guidelines

    Verbeek, H.H.; Meijer, J.A.M.; Zandee, W.T.; Kramp, K.H.; Sluiter, W.J.; Smit, J.W.A.; Kievit, J.; Links, T.P.; Plukker, J.T.


    BACKGROUND: 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.

  11. 阴茎中线囊肿2例%Median raphe cyst of the penis:two cases report

    秦明珠; 闵仲生; 谭城


    We present 2 patients ( age 18 and age 25) with median raphe cyst of the penis. Two patients presented with an asymptomatic mass on the ventral aspect of the foreskin of the penis, for one and two years respectively. Biopsy showed a normal epidermis, cyst in dermis, pseudostratified epithelium of cyst wall.%报道2例阴茎中线囊肿。2例患者(18岁,25岁)分别于1年前及2年前发现阴茎包皮系带旁囊样肿物,无特殊不适,渐增大。病理检查示:表皮正常,真皮内见囊肿,囊壁为假复层上皮。

  12. The habenulo-raphe serotonergic circuit encodes an aversive expectation value essential for adaptive active avoidance of danger.

    Amo, Ryunosuke; Fredes, Felipe; Kinoshita, Masae; Aoki, Ryo; Aizawa, Hidenori; Agetsuma, Masakazu; Aoki, Tazu; Shiraki, Toshiyuki; Kakinuma, Hisaya; Matsuda, Masaru; Yamazaki, Masako; Takahoko, Mikako; Tsuboi, Takashi; Higashijima, Shin-ichi; Miyasaka, Nobuhiko; Koide, Tetsuya; Yabuki, Yoichi; Yoshihara, Yoshihiro; Fukai, Tomoki; Okamoto, Hitoshi


    Anticipation of danger at first elicits panic in animals, but later it helps them to avoid the real threat adaptively. In zebrafish, as fish experience more and more danger, neurons in the ventral habenula (vHb) showed tonic increase in the activity to the presented cue and activated serotonergic neurons in the median raphe (MR). This neuronal activity could represent the expectation of a dangerous outcome and be used for comparison with a real outcome when the fish is learning how to escape from a dangerous to a safer environment. Indeed, inhibiting synaptic transmission from vHb to MR impaired adaptive avoidance learning, while panic behavior induced by classical fear conditioning remained intact. Furthermore, artificially triggering this negative outcome expectation signal by optogenetic stimulation of vHb neurons evoked place avoidance behavior. Thus, vHb-MR circuit is essential for representing the level of expected danger and behavioral programming to adaptively avoid potential hazard.

  13. Toluene alters p75NTR expression in the rat brainstem.

    Pascual, Jesús; Morón, Lena; Zárate, Jon; Gutiérrez, Arantza; Churruca, Itziar; Echevarría, Enrique


    Toluene is a neurotoxic organic solvent widely used in industry. Acute toluene administration in rats induced a significant increase in the numbers of neural cells immunostained for p75NTR in several brainstem regions, such as the raphe magnus and the nucleus of the solitary tract, as well as in the lateral reticular, gigantocellular, vestibular and ventral cochlear nuclei, without any in the facial and spinal trigeminal nuclei and the dorsal horn of the spinal cord. These data suggest that p75NTR could be involved in toluene-induced neurotoxic efffects in the rat brainstem.

  14. Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresis.

    Garcia, Maria L; Priest, Birgit T; Alonso-Galicia, Magdalena; Zhou, Xiaoyan; Felix, John P; Brochu, Richard M; Bailey, Timothy; Thomas-Fowlkes, Brande; Liu, Jessica; Swensen, Andrew; Pai, Lee-Yuh; Xiao, Jianying; Hernandez, Melba; Hoagland, Kimberly; Owens, Karen; Tang, Haifeng; de Jesus, Reynalda K; Roy, Sophie; Kaczorowski, Gregory J; Pasternak, Alexander


    The renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human ROMK channel are associated with antenatal type II Bartter's syndrome, an autosomal recessive life-threatening salt-wasting disorder with mild hypokalemia. Similar observations have been reported from studies with ROMK knockout mice and rats. It is noteworthy that heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. Although selective ROMK inhibitors would be expected to represent a new class of diuretics, this hypothesis has not been pharmacologically tested. Compound A [5-(2-(4-(2-(4-(1H-tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one)], a potent ROMK inhibitor with appropriate selectivity and characteristics for in vivo testing, has been identified. Compound A accesses the channel through the cytoplasmic side and binds to residues lining the pore within the transmembrane region below the selectivity filter. In normotensive rats and dogs, short-term oral administration of compound A caused concentration-dependent diuresis and natriuresis that were comparable to hydrochlorothiazide. Unlike hydrochlorothiazide, however, compound A did not cause any significant urinary potassium losses or changes in plasma electrolyte levels. These data indicate that pharmacologic inhibition of ROMK has the potential for affording diuretic/natriuretic efficacy similar to that of clinically used diuretics but without the dose-limiting hypokalemia associated with the use of loop and thiazide-like diuretics.

  15. Activation of purinergic receptors (P2) in the renal medulla promotes endothelin-dependent natriuresis in male rats.

    Gohar, Eman Y; Speed, Joshua S; Kasztan, Malgorzata; Jin, Chunhua; Pollock, David M


    Renal endothelin-1 (ET-1) and purinergic signaling systems regulate Na(+) reabsorption in the renal medulla. A link between the renal ET-1 and purinergic systems was demonstrated in vitro, however, the in vivo interaction between these systems has not been defined. To test whether renal medullary activation of purinergic (P2) receptors promotes ET-dependent natriuresis, we determined the effect of increased medullary NaCl loading on Na(+) excretion and inner medullary ET-1 mRNA expression in anesthetized adult male Sprague-Dawley rats in the presence and absence of purinergic receptor antagonism. Isosmotic saline (NaCl; 284 mosmol/kgH2O) was infused into the medullary interstitium (500 μl/h) during a 30-min baseline urine collection period, followed by isosmotic or hyperosmotic saline (1,800 mosmol/kgH2O) for two further 30-min urine collection periods. Na(+) excretion was significantly increased during intramedullary infusion of hyperosmotic saline. Compared with isosmotic saline, hyperosmotic saline infused into the renal medulla caused significant increases in inner medullary ET-1 mRNA expression. Renal intramedullary infusion of the P2 receptor antagonist suramin inhibited the increase in Na(+) excretion and inner medullary ET-1 mRNA expression induced by NaCl loading in the renal medulla. Activation of medullary P2Y2/4 receptors by infusion of UTP increased urinary Na(+) excretion. Combined ETA and ETB receptor blockade abolished the natriuretic response to intramedullary infusion of UTP. These data demonstrate that activation of medullary P2 receptors promotes ET-dependent natriuresis in male rats, suggesting that the renal ET-1 and purinergic signaling systems interact to efficiently facilitate excretion of a NaCl load.


    储祥平; 李鹏; 徐宁善


    Extracellular single-unit discharges were obtained from 106 spontaneously active neurons in the region of the rostral ventrolateral medulla (RVLM) by glass microelectrode from 73 brain slices of Sprague-Dawley rats. Exogenous γ-aminobutyric acid (GABA, 0.1 ~ 3.0 mmol/L) inhibited the electrical activity of 84 out of 106 RVLM neurons dose-dependently. The inhibitory effect of GABA could be blocked by GABAA with BMI or PTX alone, the firing rates of most of the RVLM neurons were significantly increased. In 41 neurons responding to GABA, baclofen (0.1 ~ 3.0 μmol/L), a GABAB receptor selective agonist, inhibited the discharges of 33 of the neurons dose-dependently. GABAB receptor antagonist CGP35348 ( n = 13) blocked the inhibition due to baclofen ( n = 21). After perfused with CGP35348 alone, the firing rates of most of the RVLM neurons were significantly increased. Taken together, the inhibition of GABA on RVLM neurons is mediated through either GABAA or GABAB receptors and some intrinsic GABA neurons exert tonic inhibition activity.%在73张脑片上观察了γ-氨基丁酸(GABA)对106个延髓头端腹外侧区(RVLM)神经元单位放电的影响.外源性的GABA(0.1~3.0 mmol/L)抑制了106神经元中的84个神经元的电活动,这些抑制效应呈剂量-反应关系.GABA的抑制效应大部分可被GABAA受体选择性拮抗剂荷苞牡丹碱甲基碘化物(BMI)和Cl-通道阻断剂印防己毒素(PTX)所阻断,而单独灌流BMI和PTX对RVLM神经元主要起兴奋作用.在41个对GABA有抑制效应的RVLM神经元上,GABAB受体选择性激动剂苯氯丁氨酸(0.1~3.0 μmoL/L)抑制了其中33个神经元的单位放电,也呈剂量-反应关系.GABAB受体选择性拮抗剂CGP35348(n=13)可阻断苯氯丁氨酸的抑制效应(n=21),而单独灌流CGP35348对RVLM神经元主要起兴奋作用.上述结果提示:GABA对RVLM神经元的抑制效应,不仅可以通过GABAA受体,而且可以通过GABAB受体起作用;内源性的GABA参与了紧张性的抑制作用.

  17. Localization of prostaglandin E(2) EP2 and EP4 receptors in the rat kidney

    Jensen, B L; Stubbe, J; Hansen, P B


    -selective agonist, dose dependently raised cAMP levels in microdissected DTL and outer medullary vasa recta specimens but had no effect in EP2-negative outer medullary collecting duct segments. Dietary salt intake did not alter EP2 expression in the kidney medulla. These results suggest that PGE(2) may act......We investigated the localization of cAMP-coupled prostaglandin E(2) EP2 and EP4 receptor expression in the rat kidney. EP2 mRNA was restricted to the outer and inner medulla in rat kidney, as determined by RNase protection assay. RT-PCR analysis of microdissected resistance vessels and nephron...... segments showed EP2 expression in descending thin limb of Henle's loop (DTL) and in vasa recta of the outer medulla. The EP4 receptor was expressed in distal convoluted tubule (DCT) and cortical collecting duct (CCD) in preglomerular vessels, and in outer medullary vasa recta. Butaprost, an EP2 receptor...



    Objective To investigate the role of NRM in the antinociceptive effect of muscle spindle afferents, the influence of NRM lesion on the inhibitory effect of muscle spindle afferents on the nociceptive responses of wide dynamic range (WDR) neurons and the effects of the muscle spindle afferents on the NRM neuronal activities were observed. Methods The single units of WDR neurons in the spinal dorsal horn were recorded extracellularly, and the inhibitory effects of activating muscle spindle afferents by intravenous administration of succinyicholine (SCH) on the C-fibers evoked responses (C-responses) of WDR neurons were tested before and after lesion of NRM. The ef- fects of the muscle spindle afferents activated by administrating SCH on the single NRM neurons were also examined. Results ①lt was found that the C-responses of WDR neurons were significantly inhibited by intravenously adminis- tration of SCH, and the inhibitory effect was reduced after lesion of NRM ;②The activities of most of the NRM neu- rons could be changed significantly by administrating SCH. According to their responses, NRM neurons could be classified into three types:excitatory, inhibitory and non-responsive neurons, and the responses were dose-depen- dent. Conclusion These results suggest that the muscle spindle afferents evoked by SCH may activate the NRM neu- rons, which plays an important role in the antinociception of muscle spindle afferents.

  19. Rats

    Alexey Kondrashov


    Full Text Available We aimed to perform a chemical analysis of both Alibernet red wine and an alcohol-free Alibernet red wine extract (AWE and to investigate the effects of AWE on nitric oxide and reactive oxygen species production as well as blood pressure development in normotensive Wistar Kyoto (WKY and spontaneously hypertensive rats (SHRs. Total antioxidant capacity together with total phenolic and selected mineral content was measured in wine and AWE. Young 6-week-old male WKY and SHR were treated with AWE (24,2 mg/kg/day for 3 weeks. Total NOS and SOD activities, eNOS and SOD1 protein expressions, and superoxide production were determined in the tissues. Both antioxidant capacity and phenolic content were significantly higher in AWE compared to wine. The AWE increased NOS activity in the left ventricle, aorta, and kidney of SHR, while it did not change NOS activity in WKY rats. Similarly, increased SOD activity in the plasma and left ventricle was observed in SHR only. There were no changes in eNOS and SOD1 expressions. In conclusion, phenolics and minerals included in AWE may contribute directly to increased NOS and SOD activities of SHR. Nevertheless, 3 weeks of AWE treatment failed to affect blood pressure of SHR.

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

    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)


    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

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

    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.


    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

  2. Central Hypoventilation Syndrome Complicated with Lateral Medullary Infarction after Endovascular Treatment of the Vertebral Artery Dissecting Aneurysm: A Case Report

    TANAKA, Katsuhiro; Kanamaru, Hideki; Morikawa, Atsunori; Kawaguchi, Kenji


    Lateral medullary infarction rarely leads to central hypoventilation syndrome (CHS). CHS is a life-threatening disorder characterized by hypoventilation during sleep. We report the first case of CHS as a complication of lateral medullary infarction after endovascular treatment. A 65-year-old man presented twice with severe headache. Computed tomography revealed subarachnoid hemorrhage and cerebral angiography showed a right vertebral dissecting aneurysm involving the posterior inferior cerebe...

  3. A rare case of medullary carcinoma of the colon presenting as intussusception in an adult with rectal bleeding.

    Jain, Shilpa; Jain, Ankur; Onizuka, Neil; Boukhar, Sarag A


    Medullary carcinoma is a recently recognized rare subtype of colorectal cancer resembling both poorly differentiated adenocarcinoma and neuroendocrine tumors. Medullary carcinoma most commonly presents in the proximal colon and can be differentiated from other right-sided malignant lesions by histology and immunochemical markers. We present here a rare case of an adult patient with rectal bleeding who was found to have an intussusception due to underlying medullary carcinoma of the splenic flexure. A 72-year-old woman presented to our GI clinic with rectal bleeding. Colonoscopy revealed a necrotic mass of the sigmoid colon, later determined by CT to be a colo-colonic intussusception at the level of the splenic flexure. Patient underwent diagnostic laparoscopy with findings of a large splenic flexure mass, which was resected and found to be medullary carcinoma of the colon. The tumor was poorly differentiated and exhibited microsatellite instability but was discovered at an early stage and thus did not require any adjuvant chemotherapy. Unlike most previously reported cases of medullary carcinoma, our patient presented with a left sided tumor. To our knowledge, this is the first report of a medullary colon cancer presenting with intussusception.

  4. [Anterior and posterior medullary analgesic stimulation, using a percutaneous implantation technic].

    Lazorthes, Y; Verdie, J C; Arbus, L


    The technique of percutaneous implantation of a pain-relieving stimulator reduces the surgical procedure considerably. This advantage is, however, lessened by the absence of precision in placing epidural electrodes, and by the risk of their later displacement leading to inadequate stimulation. To reduce this disadvantage the authors suggest a technique that is a modification of the classical open procedure: it is particularly suitable for implantation at the cervico-dorsal junction. In 12 patients treated by percutaneous implantation, 5 received, from epidural electrodes, an anterior medullary electrical stimulation which caused analgesia without paraesthesiae in the painful ares. The results, however, do not justify a conclusion that anterior medullary stimulation is better than posterior column stimulation.

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

    Doerr, U.; Bihl, H. (Katharinenhospital, Stuttgart (Germany). Dept. of Nuclear Medicine); Frank-Raue, K.; Raue, F. (Heidelberg Univ. (Germany). Dept. of Internal Medicine); Sautter-Bihl, M.L.; Buhr, H.J. (Staedt. Klinikum, Karlsruhe (Germany). Dept. of Radiooncology and Nuclear Medicine); Guzman, G. (Katherinenhospital, Stuttgart (Germany). Dept. of Nuclear Medicine Inst. de Neurocirugia, Investigationes Cerebrales ' Dr Asenjo' Santiago (Chile). Dept. de Medicina Nuclear)


    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 [sup 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).

  6. Unusual histologic type of medullary carcinoma of thyroid: A case report

    Haery H


    Full Text Available In this paper we have reported and discussed an unusual histopathologic feature of medullary carcinoma which is one of the pitfalls in the diagnosis of this tumor. The patient was a 14 years old girl who complained of painless, gradually growing cervical mass from one year ago. She had no history of head and neck radiotherapy of familial history of thyroidal or other endocrine disease. In laboratory investigations a cold thyroid nodule was confirmed and FNA of it was reported as follicular lesion. The patient underwent lobectomy isthmectomy with frozen section wich was reported as Hurthle neoplasm and then the other lobe of patient's thyroid resected. In it's pathologic exam another nodule was observed which mostly composed of spindle cells; at last histochemically medullary carcinoma confirmed

  7. Sleep and dream suppression following a lateral medullary infarct: a first-person account.

    Allan Hobson, J


    Consciousness can be studied only if subjective experience is documented and quantified, yet first-person accounts of the effects of brain injury on conscious experience are as rare as they are potentially useful. This report documents the alterations in waking, sleeping, and dreaming caused by a lateral medullary infarct. Total insomnia and the initial suppression of dreaming was followed by the gradual recovery of both functions. A visual hallucinosis during waking that was associated with the initial period of sleep and dream suppression is described in detail. Since the changes in sleep and their recovery are comparable to results of animal experiments, it can be concluded that damage to the medullary brain stem causes extreme but short-lived alterations in conscious state and that substantial recovery occurs even though the damage to the brain stem endures.

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

    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.


    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

  9. Immunocytochemical localization and identification of prosomatostatin gene products in medullary carcinoma of human thyroid gland.

    Scopsi, L; Ferrari, C; Pilotti, S; Holst, J J; Rehfeld, J F; Fossati, G; Rilke, F


    Thirty-three cases of histologically proven calcitonin-positive medullary thyroid carcinoma were studied immunocytochemically for the occurrence of prosomatostatin-related peptides. Positive cells, identified with a panel of antisera raised against four different regions of the prosomatostatin molecule, were found in 100% of the tumors. Most but not all somatostatin-positive cells were also immunoreactive for calcitonin. Notably, seven patients harboring somatostatin-rich tumors revealed a more favorable clinical course. The results (1) indicate that somatostatin production is a universal concomitant of thyroid medullary carcinoma, (2) suggest that these cells are likely to produce a somatostatin precursor molecule similar to mammalian prosomatostatin, and (3) imply that somatostatin-reactive cells may have as yet unknown roles in these tumors, possibly in the realm of paracrine and autocrine regulation of cell growth.

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

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


    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.

  11. Cervico-medullary desmoplastic infantile ganglioglioma: an unusual case with diffuse leptomeningeal dissemination at diagnosis.

    Milanaccio, Claudia; Nozza, Paolo; Ravegnani, Marcello; Rossi, Andrea; Raso, Alessandro; Gambini, Claudio; Garrè, Maria Luisa; Pietsch, Torsten


    Desmoplastic infantile ganglioglioma (DIG) is a rare intracranial tumor affecting newborns and infants, and generally arising in the supratentorial region. We report a case of an unusual DIG, arising at the cervico-medullary junction, with diffuse leptomeningeal seeding at diagnosis that was treated with chemotherapy (CT) and delayed partial surgery. The case we describe demonstrates that DIG can occur in the subtentorial region and can show leptomeningeal dissemination like other low-grade gliomas.

  12. Renal Medullary Solute Depletion Resulting from Psychogenic Polydipsia in a Rhesus Monkey


    O ADH would normally indicate nerphrovenic served to have poivdipsia and an unthnftv diabetes insipidus . however, oae would expect the resulting in obesity. Four weeks before the onset of 1.000. On day 5. the specific gravity was 1.005. and polydipsia. the diet was restricted to 100...medullary solute depletion. One year after diagnosis tion for a rhesus monkey fed a commercial dry diet .’ and treatment, there was no evidence of




    Full Text Available The experiment was carried out on a batch formed by 10 laying hens, ISA Brown hybrid, at the first laying cycles, 50 weeks old, hold single in cages and fed with granulated forage. The hens were watched for 3 weeks in order to establish the moment of the oviposition and depending on that their slaughtering was set out so that the different stages of the egg formation could be observed. The hens were divided into 4 groups – I, II, III, IV- depending on the time elapsed from the last oviposition. Femur fragments have been drawn from the central zone of the diaphises and transformed in hematoxiline-eozine and alcian-blue stained preparations, the trichromic Mallory method and the Dorfmann-Epstein method for the emphasising of the alkaline phosphatasis. At the hens of the first group the presence of the medullary bone is shown and is characterised by an intense ossification process with compact bone structure, with well formed osseus trabeculae that occupy the medullar cavity. There is also present a rich content of acid mucopolyssacharide. The hens from the second group (II have a well formed medullary bone, with visible osseus trabeculae. From the histological point of view, the medullary bone of the hens from the third group (III is rarefied with large areolae, with collagen fibres that lack osein, having thus a characteristic aspect of massive decalcification. At the hens from the fourth group (IV the medullary bone shows synthesis processes and bone matrix forming, positive, intensive FAL activity, that proves the presence of active osteoblasts, i.e. bone remodelling processes.

  14. Immunohistochemical localisation of the voltage gated potassium ion channel subunit Kv3.3 in the rat medulla oblongata and thoracic spinal cord.

    Brooke, Ruth E; Atkinson, Lucy; Edwards, Ian; Parson, Simon H; Deuchars, Jim


    Voltage gated K+ channels (Kv) are a diverse group of channels important in determining neuronal excitability. The Kv superfamily is divided into 12 subfamilies (Kv1-12) and members of the Kv3 subfamily are highly abundant in the CNS, with each Kv3 gene (Kv3.1-Kv3.4) exhibiting a unique expression pattern. Since the localisation of Kv subunits is important in defining the roles they play in neuronal function, we have used immunohistochemistry to determine the distribution of the Kv3.3 subunit in the medulla oblongata and spinal cord of rats. Kv3.3 subunit immunoreactivity (Kv3.3-IR) was widespread but present only in specific cell populations where it could be detected in somata, dendrites and synaptic terminals. Labelled neurones were observed in the spinal cord in laminae IV and V, in the region of the central canal and in the ventral horn. In the medulla oblongata, labelled cell bodies were numerous in the spinal trigeminal, cuneate and gracilis nuclei whilst rarer in the lateral reticular nucleus, hypoglossal nucleus and raphe nucleus. Regions containing autonomic efferent neurones were predominantly devoid of labelling with only occasional labelled neurones being observed. Dual immunohistochemistry revealed that some Kv3.3-IR neurones in the ventral medullary reticular nucleus, spinal trigeminal nucleus, dorsal horn, ventral horn and central canal region were also immunoreactive for the Kv3.1b subunit. The presence of Kv3.3 subunits in terminals was confirmed by co-localisation of Kv3.3-IR with the synaptic vesicle protein SV2, the vesicular glutamate transporter VGluT2 and the glycine transporter GlyT2. Co-localisation of Kv3.3-IR was not observed with VGluT1, tyrosine hydroxylase, serotonin or choline acetyl transferase. Electron microscopy confirmed the presence of Kv3.3-IR in terminals and somatic membranes in ventral horn neurones, but not motoneurones. This study provides evidence supporting a role for Kv3.3 subunits in regulating neuronal excitability

  15. Medullary nephrocalcinosis, distal renal tubular acidosis and polycythaemia in a patient with nephrotic syndrome

    Karunarathne Suneth


    Full Text Available Abstract Background Medullary nephrocalcinosis and distal renal tubular acidosis are closely associated and each can lead to the other. These clinical entities are rare in patients with nephrotic syndrome and polycythaemia is an unusual finding in such patients. We describe the presence of medullary nephrocalcinosis, distal renal tubular acidosis and polycythaemia in a patient with nephrotic syndrome due to minimal change disease. Proposed mechanisms of polycythaemia in patients with nephrotic syndrome and distal renal tubular acidosis include, increased erythropoietin production and secretion of interleukin 8 which in turn stimulate erythropoiesis. Case presentation A 22 year old Sri Lankan Sinhala male with nephrotic syndrome due to minimal change disease was investigated for incidentally detected polycythaemia. Investigations revealed the presence of renal tubular acidosis type I and medullary nephrocalcinosis. Despite extensive investigation, a definite cause for polycythaemia was not found in this patient. Treatment with potassium and bicarbonate supplementation with potassium citrate led to correction of acidosis thereby avoiding the progression of nephrocalcinosis and harmful effects of chronic acidosis. Conclusion The constellation of clinical and biochemical findings in this patient is unique but the pathogenesis of erythrocytosis is not clearly explained. The proposed mechanisms for erythrocytosis in other patients with proteinuria include increased erythropoietin secretion due to renal hypoxia and increased secretion of interleukin 8 from the kidney. This case illustrates that there may exist hitherto unknown connections between tubular and glomerular dysfunction in patients with nephrotic syndrome.

  16. Depletion of putative chemosensitive respiratory neurons in the ventral medullary surface in multiple system atrophy.

    Benarroch, Eduardo E; Schmeichel, Ann M; Low, Phillip A; Parisi, Joseph E


    Multiple system atrophy (MSA) is a disorder that may manifest with reduced respiratory chemosensitivity and central sleep apnoea. Chemosensitive glutamatergic and serotonergic neurons located just beneath the ventral medullary surface, corresponding to the human arcuate nucleus (ArcN), have recently been implicated in control of automatic breathing in response to hypercapnia and hypoxia. We sought to determine whether these neurons were affected in MSA. Medullae were obtained at post-mortem from 11 patients (8 men, 3 women, age 64 +/- 3 years) with neuropathologically confirmed MSA and 11 control subjects (6 men and 5 women, age 66 +/- 4 years). Fifty micrometre sections obtained throughout the medulla were processed for vesicular glutamate transporter-2 (VGLUT-2), tryptophan-hydroxylase (TrOH), glial fibrillary acid protein (GFAP) and alpha-synuclein immunoreactivity. Cell counts, GFAP immunoreactivity and presence of glial cytoplasmic inclusions (GCIs) were assessed in the ArcN. In MSA, compared with controls, there was a marked depletion of ArcN neurons immunoreactive for either VGLUT-2 (74 +/- 21 versus 342 +/- 84 cells/section, P section, P medullary surface in all cases. Our results indicate that there is severe loss of putative chemosensitive glutamatergic and serotonergic neurons as well as marked astrocytic gliosis in the ventral medullary surface in MSA. This may provide a possible morphological basis for impaired respiratory chemosensitivity and central sleep apnoea in this disorder.

  17. Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain

    Andrea Forero


    Full Text Available Background: During early prenatal stages of brain development, serotonin (5-HT-specific neurons migrate through somal translocation to form the raphe nuclei and subsequently begin to project to their target regions. The rostral cluster of cells, comprising the median and dorsal raphe (DR, innervates anterior regions of the brain, including the prefrontal cortex. Differential analysis of the mouse 5-HT system transcriptome identified enrichment of cell adhesion molecules in 5-HT neurons of the DR. One of these molecules, cadherin-13 (Cdh13 has been shown to play a role in cell migration, axon pathfinding, and synaptogenesis. This study aimed to investigate the contribution of Cdh13 to the development of the murine brain 5-HT system.Methods: For detection of Cdh13 and components of the 5-HT system at different embryonic developmental stages of the mouse brain, we employed immunofluorescence protocols and imaging techniques, including epifluorescence, confocal and structured illumination microscopy. The consequence of CDH13 loss-of-function mutations on brain 5-HT system development was explored in a mouse model of Cdh13 deficiency.Results: Our data show that in murine embryonic brain Cdh13 is strongly expressed on 5-HT specific neurons of the DR and in radial glial cells (RGCs, which are critically involved in regulation of neuronal migration. We observed that 5-HT neurons are intertwined with these RGCs, suggesting that these neurons undergo RGC-guided migration. Cdh13 is present at points of intersection between these two cell types. Compared to wildtype controls, Cdh13-deficient mice display increased cell densities in the DR at embryonic stages E13.5, E17.5, and adulthood, and higher serotonergic innervation of the prefrontal cortex at E17.5.Conclusion: Our findings provide evidence for a role of CDH13 in the development of the serotonergic system in early embryonic stages. Specifically, we indicate that Cdh13 deficiency affects the cell

  18. Mesenchymal stem cells improve medullary inflammation and fibrosis after revascularization of swine atherosclerotic renal artery stenosis.

    Behzad Ebrahimi

    Full Text Available Atherosclerotic renal artery stenosis (ARAS raises blood pressure and can reduce kidney function. Revascularization of the stenotic renal artery alone does not restore renal medullary structure and function. This study tested the hypothesis that addition of mesenchymal stem cells (MSC to percutaneous transluminal renal angioplasty (PTRA can restore stenotic-kidney medullary tubular transport function and attenuate its remodeling. Twenty-seven swine were divided into three ARAS (high-cholesterol diet and renal artery stenosis and a normal control group. Six weeks after ARAS induction, two groups were treated with PTRA alone or PTRA supplemented with adipose-tissue-derived MSC (10 × 10(6 cells intra-renal. Multi-detector computed tomography and blood-oxygenation-level-dependent (BOLD MRI studies were performed 4 weeks later to assess kidney hemodynamics and function, and tissue collected a few days later for histology and micro-CT imaging. PTRA effectively decreased blood pressure, yet medullary vascular density remained low. Addition of MSC improved medullary vascularization in ARAS+PTRA+MSC and increased angiogenic signaling, including protein expression of vascular endothelial growth-factor, its receptor (FLK-1, and hypoxia-inducible factor-1α. ARAS+PTRA+MSC also showed attenuated inflammation, although oxidative-stress remained elevated. BOLD-MRI indicated that MSC normalized oxygen-dependent tubular response to furosemide (-4.3 ± 0.9, -0.1 ± 0.4, -1.6 ± 0.9 and -3.6 ± 1.0 s(-1 in Normal, ARAS, ARAS+PTRA and ARAS+PTRA+MSC, respectively, p<0.05, which correlated with a decrease in medullary tubular injury score (R(2 = 0.33, p = 0.02. Therefore, adjunctive MSC delivery in addition to PTRA reduces inflammation, fibrogenesis and vascular remodeling, and restores oxygen-dependent tubular function in the stenotic-kidney medulla, although additional interventions might be required to reduce oxidative-stress. This study supports development of

  19. Leptin receptor immunoreactivity is present in ascending serotonergic and catecholaminergic neurons of the rat

    Hay-Schmidt, Anders; Helboe, Lone; Larsen, Philip J.


    Obesity, tyrosine hydroxylase, arcuate nucleus, paracentricular nucleus, raphe nuclei, leptin, serotonin, catecholamines......Obesity, tyrosine hydroxylase, arcuate nucleus, paracentricular nucleus, raphe nuclei, leptin, serotonin, catecholamines...

  20. Neonatal citalopram exposure decreases serotonergic fiber density in the olfactory bulb of male but not female adult rats

    Junlin eZhang


    Full Text Available Manipulation of serotonin (5HT during early development has been shown to induce long-lasting morphological changes within the raphe nuclear complex and serotonergic circuitry throughout the brain. Recent studies have demonstrated altered raphe-derived 5HT transporter (SERT immunoreactive axonal expression in several cortical target sites after brief perinatal exposure to selective 5HT reuptake inhibitors such as citalopram (CTM. Since the serotonergic raphe nuclear complex projects to the olfactory bulb (OB and perinatal 5HT disruption has been shown to disrupt olfactory behaviors, the goal of this study was to further investigate such developmental effects in the OB of CTM exposed animals. Male and female rat pups were exposed to CTM from postnatal day 8-21. After animals reach adulthood (>90 days, OB tissue sections were processed immunohistochemically for SERT antiserum. Our data revealed that the density of the SERT immunoreactive fibers decreased ~40% in the OB of CTM exposed male rats, but not female rats. Our findings support a broad and long-lasting change throughout most of the 5HT system, including the OB, after early manipulation of 5HT. Because dysfunction of the early 5HT system has been implicated in the etiology of neurodevelopmental disorders such as autism spectrum disorders (ASDs, these new findings may offer insight into the abnormal olfactory perception often noted in patients with ASD.

  1. Chronic alcoholics without Wernicke-Korsakoff syndrome or cirrhosis do not lose serotonergic neurons in the dorsal raphe nucleus.

    Baker, K G; Halliday, G M; Kril, J J; Harper, C G


    Despite the considerable evidence that alcoholics have perturbation of serotonergic function, there is little pathological evidence for alcohol directly affecting the nervous system. The present study aims to assess neuronal loss that occurs as a consequence of alcohol neurotoxicity in the serotonergic dorsal raphe nucleus (DRN). To that end, the brains of eight alcoholics and eight age-matched control cases were carefully screened to eliminate serious liver disease, the sequela of thiamine deficiency, Wernicke-Korsakoff syndrome (WKS), and other pathological abnormalities. Brains were formalin-fixed for 2 weeks, cut, and then immunohistochemically stained using a monoclonal PH8 antibody specific for the rate-limiting enzyme of serotonin synthesis, tryptophan hydroxylase. The morphology of the serotonin-synthesizing neurons and their average size was similar in all cases. However, there was a reduction in the staining intensity of the reaction product in the DRN serotonergic neurons of most alcoholics. Neuronal counts on spaced serial sections revealed that there were an estimated average total of 106,100 +/- 19,500 serotonergic neurons in the DRN of alcoholics and 108,300 +/- 11,800 in the DRN of controls, indicating that in most alcoholics there is no reduction in the number of these neurons. Therefore, the effect of chronic alcohol consumption on the serotonergic system, in the absence of WKS or liver disease, seems to be functional rather than neuropathological.

  2. The hippocampus and dorsal raphe nucleus are key brain areas associated with the antidepressant effects of lithium augmentation of desipramine.

    Cussotto, Sofia; Cryan, John F; O'Leary, Olivia F


    Approximately 50% of depressed individuals fail to achieve remission with first-line antidepressant drugs and a third remain treatment-resistant. When first-line antidepressant treatment is unsuccessful, second-line strategies include dose optimisation, switching to another antidepressant, combination with another antidepressant, or augmentation with a non-antidepressant medication. Much of the evidence for the efficacy of augmentation strategies comes from studies using lithium to augment the effects of tricyclic antidepressants. The neural circuitry underlying the therapeutic effects of lithium augmentation is not yet fully understood. Recently, we reported that chronic treatment with a combination of lithium and the antidepressant desipramine, exerted antidepressant-like behavioural effects in a mouse strain (BALB/cOLaHsd) that did not exhibit an antidepressant-like behavioural response to either drug alone. In the present study, we used this model in combination with ΔFosB/FosB immunohistochemistry to identify brain regions chronically affected by lithium augmentation of desipramine when compared to either treatment alone. The data suggest that the dorsal raphe nucleus and the CA3 regions of the dorsal hippocampus are key nodes in the neural circuitry underlying antidepressant action of lithium augmentation of desipramine. These data give new insight into the neurobiology underlying the mechanism of lithium augmentation in the context of treatment-resistant depression.

  3. Role of the red nucleus in suppressing the jaw-opening reflex following stimulation of the raphe magnus nucleus.

    Satoh, Yoshihide; Ishizuka, Ken'Ichi; Iwasaki, Shin-ichi


    In a previous study, we found that electrical and chemical stimulation of the red nucleus (RN) suppressed the high-threshold afferent-evoked jaw-opening reflex (JOR). It has been reported that the RN receives bilaterally projection fibers from the raphe magnus nucleus (RMg), and that stimulation of the RMg inhibits the tooth pulp-evoked nociceptive JOR. These facts imply that RMg-induced inhibition of the JOR could be mediated via the RN. The present study first examines whether stimulation of the RMg suppresses the high-threshold afferent-evoked JOR. The JOR was evoked by electrical stimulation of the inferior alveolar nerve (IAN), and was recorded as the electromyographic response of the anterior belly of the digastric muscle. The stimulus intensity was 4.0 (high-threshold) times the threshold. Conditioning electrical stimulation of the RMg significantly suppressed the JOR. A further study then examined whether electrically induced lesions of the RN or microinjection of muscimol into the RN affects RMg-induced suppression of the JOR. Electrically induced lesions of the bilateral RN and microinjection of muscimol into the bilateral RN both reduced the RMg-induced suppression of the JOR. These results suggest that RMg-induced suppression of the high-threshold afferent-evoked JOR is mediated by a relay in the RN.

  4. Ribosomal DNA transcription in the dorsal raphe nucleus is increased in residual but not in paranoid schizophrenia.

    Krzyżanowska, Marta; Steiner, Johann; Brisch, Ralf; Mawrin, Christian; Busse, Stefan; Braun, Katharina; Jankowski, Zbigniew; Bernstein, Hans-Gert; Bogerts, Bernhard; Gos, Tomasz


    The central serotonergic system is implicated in the pathogenesis of schizophrenia, where the imbalance between dopamine, serotonin and glutamate plays a key pathophysiological role. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in schizophrenia patients. The study was carried out on paraffin-embedded brains from 17 (8 paranoid and 9 residual) schizophrenia patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver-staining method. An increased rDNA transcriptional activity was found in schizophrenia patients in the cumulative analysis of all DRN subnuclei (t test, P = 0.02). Further subgroup analysis revealed that it was an effect specific for residual schizophrenia versus paranoid schizophrenia or control groups (ANOVA, P = 0.002). This effect was confounded neither by suicide nor by antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in schizophrenia, particularly in residual patients. An activation of the rDNA transcription in DRN neurons may represent a compensatory mechanism to overcome the previously described prefrontal serotonergic hypofunction in this diagnostic subgroup.

  5. Ribosomal DNA transcription in dorsal raphe nucleus neurons is increased in residual schizophrenia compared to depressed patients with affective disorders.

    Krzyżanowska, Marta; Steiner, Johann; Brisch, Ralf; Mawrin, Christian; Busse, Stefan; Braun, Katharina; Jankowski, Zbigniew; Bernstein, Hans-Gert; Bogerts, Bernhard; Gos, Tomasz


    The central serotonergic system is implicated differentially in the pathogenesis of depression and schizophrenia. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in both disorders. The study was carried out on paraffin-embedded brains from 27 depressed (15 major depressive disorder, MDD and 12 bipolar disorder, BD) and 17 schizophrenia (9 residual and 8 paranoid) patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver staining method. A significant effect of diagnosis on rDNA activity was found in the cumulative analysis of all DRN subnuclei. Further analysis revealed an increase in this activity in residual (but not paranoid) schizophrenia compared to depressed (both MDD and BD) patients. The effect was most probably neither confounded by suicide nor related to antidepressant and antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in residual schizophrenia, related presumably to differentially disturbed inputs to the DRN and/or their local transformation compared with depressive episodes in patients with affective disorders.

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

    Sadat Alavi Mehr


    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.

  7. Evidence that adrenergic ventrolateral medullary cells are activated whereas precerebellar lateral reticular nucleus neurons are suppressed during REM sleep.

    Georg M Stettner

    Full Text Available Rapid eye movement sleep (REMS is generated in the brainstem by a distributed network of neurochemically distinct neurons. In the pons, the main subtypes are cholinergic and glutamatergic REMS-on cells and aminergic REMS-off cells. Pontine REMS-on cells send axons to the ventrolateral medulla (VLM, but little is known about REMS-related activity of VLM cells. In urethane-anesthetized rats, dorsomedial pontine injections of carbachol trigger REMS-like episodes that include cortical and hippocampal activation and suppression of motoneuronal activity; the episodes last 4-8 min and can be elicited repeatedly. We used this model to determine whether VLM catecholaminergic cells are silenced during REMS, as is typical of most aminergic neurons studied to date, and to investigate other REMS-related cells in this region. In 18 anesthetized, paralyzed and artificially ventilated rats, we obtained extracellular recordings from VLM cells when REMS-like episodes were elicited by pontine carbachol injections (10 mM, 10 nl. One major group were the cells that were activated during the episodes (n = 10. Their baseline firing rate of 3.7±2.1 (SD Hz increased to 9.7±2.1 Hz. Most were found in the adrenergic C1 region and at sites located less than 50 µm from dopamine β-hydroxylase-positive (DBH(+ neurons. Another major group were the silenced or suppressed cells (n = 35. Most were localized in the lateral reticular nucleus (LRN and distantly from any DBH(+ cells. Their baseline firing rates were 6.8±4.4 Hz and 15.8±7.1 Hz, respectively, with the activity of the latter reduced to 7.4±3.8 Hz. We conclude that, in contrast to the pontine noradrenergic cells that are silenced during REMS, medullary adrenergic C1 neurons, many of which drive the sympathetic output, are activated. Our data also show that afferent input transmitted to the cerebellum through the LRN is attenuated during REMS. This may distort the spatial representation of body position

  8. High frequency ultrasound features and pathological characteristics of medullary thyroid carcinoma.

    Wang, Hua; Liu, Mengmeng; Yang, Jianqiu; Song, Yimin


    To study high-frequency ultrasound features and pathological characteristics of medullary thyroid carcinoma (medullary thyroid carcinoma, MTC) with the purpose to improve the diagnostic accuracy of this disease. The clinical data of 20 cases of patients with MTC confirmed by the clinical surgery were retrospectively analyzed. And the high-frequency ultrasound features were analyzed and compared with the pathological characteristics. There were 16 cases with tumor invasion into one side of the thyroid gland; 17 cases with tumor in the middle-upper pole of the thyroid gland. And 8 cases were detected with uneven echo of high frequency ultrasound appearance and pathological manifestations of cystic degeneration to necrosis seen under the light microscope or normal thyroid tissue within part of the lump. 16 cases were tested with even echo of high frequency ultrasound appearance, and tumor cells were formed in the solid and block-like shape under the light microscope. And 18 cases were manifested with low echo, with proliferation of fibrous tissue within the intercellular substance under the light microscope. 18 cases could be seen the calcification points and often amyloid-like content deposited in the intercellular substance seen under the light microscope. In addition, the pathological manifestations of the 8 cases combined with lymph node metastasis were the "lash tumor" of the metastatic lymph nodes and primary tumor. MTC was commonly located in the middle-upper region of the thyroid gland and in one leaf of the thyroid gland, combined with lymph node metastasis. The high frequency ultrasound appearance was the even low-echo tumor in round or quasi-circular shape, with obscure boundary and often combined with rough calcification. High frequency ultrasound could be used as the prior physical diagnostic method for medullary thyroid carcinoma.

  9. Adrenal Medullary Hyperplasia Is a Precursor Lesion for Pheochromocytoma in MEN2 Syndrome

    Esther Korpershoek


    Full Text Available Adrenal medullary hyperplasias (AMHs are adrenal medullary proliferations with a size <1 cm, while larger lesions are considered as pheochromocytoma (PCC. This arbitrary distinction has been proposed decades ago, although the biological relationship between AMH and PCC has never been investigated. Both lesions are frequently diagnosed in multiple endocrine neoplasia type 2 (MEN2 patients in whom they are considered as two unrelated clinical entities. In this study, we investigated the molecular relationship between AMH and PCC in MEN2 patients. Molecular aberrations of 19 AMHs and 13 PCCs from 18 MEN2 patients were determined by rearranged during transfection (RET proto-oncogene mutation analysis and loss of heterozygosity (LOH analysis for chromosomal regions 1p13, 1p36, 3p, and 3q, genomic areas covering commonly altered regions in RET-related PCC. Identical molecular aberrations were found in all AMHs and PCCs, at similar frequencies. LOH was seen for chromosomes 1p13 in 8 of 18 (44%, 1p36 in 9 of 15 (60%, 3p12-13 in 12 of 18 (67%, and 3q23-24 in 10 of 16 (63% of AMHs, and for chromosome 1p13 in 13 of 13 (100%, 1p36 in 7 of 11 (64%, 3p12-13 in 4 of 11 (36%, and 3q23-24 in 11 of 12 (92% of PCCs. Our results indicate that AMHs are not hyperplasias and, in clinical practice, should be regarded as PCCs, which has an impact on diagnosis and treatment of MEN2 patients. We therefore propose to replace the term AMH by micro-PCC to indicate adrenal medullary proliferations of less than 1 cm.

  10. Adrenal Medullary Hyperplasia Is a Precursor Lesion for Pheochromocytoma in MEN2 Syndrome12

    Korpershoek, Esther; Petri, Bart-Jeroen; Post, Edward; van Eijck, Casper H.J.; Oldenburg, Rogier A.; Belt, Eric J.T.; de Herder, Wouter W.; de Krijger, Ronald R.; Dinjens, Winand N.M.


    Adrenal medullary hyperplasias (AMHs) are adrenal medullary proliferations with a size < 1 cm, while larger lesions are considered as pheochromocytoma (PCC). This arbitrary distinction has been proposed decades ago, although the biological relationship between AMH and PCC has never been investigated. Both lesions are frequently diagnosed in multiple endocrine neoplasia type 2 (MEN2) patients in whom they are considered as two unrelated clinical entities. In this study, we investigated the molecular relationship between AMH and PCC in MEN2 patients. Molecular aberrations of 19 AMHs and 13 PCCs from 18 MEN2 patients were determined by rearranged during transfection (RET) proto-oncogene mutation analysis and loss of heterozygosity (LOH) analysis for chromosomal regions 1p13, 1p36, 3p, and 3q, genomic areas covering commonly altered regions in RET-related PCC. Identical molecular aberrations were found in all AMHs and PCCs, at similar frequencies. LOH was seen for chromosomes 1p13 in 8 of 18 (44%), 1p36 in 9 of 15 (60%), 3p12-13 in 12 of 18 (67%), and 3q23-24 in 10 of 16 (63%) of AMHs, and for chromosome 1p13 in 13 of 13 (100%), 1p36 in 7 of 11 (64%), 3p12-13 in 4 of 11 (36%), and 3q23-24 in 11 of 12 (92%) of PCCs. Our results indicate that AMHs are not hyperplasias and, in clinical practice, should be regarded as PCCs, which has an impact on diagnosis and treatment of MEN2 patients. We therefore propose to replace the term AMH by micro-PCC to indicate adrenal medullary proliferations of less than 1 cm. PMID:25379023

  11. Ipsilateral hemiparesis in lateral medullary infarction: Clinical investigation of the lesion location on magnetic resonance imaging.

    Uemura, Masahiro; Naritomi, Hiroaki; Uno, Hisakazu; Umesaki, Arisa; Miyashita, Kotaro; Toyoda, Kazunori; Minematsu, Kazuo; Nagatsuka, Kazuyuki


    In 1946, Opalski reported two cases of Wallenberg syndrome with ipsilateral hemiparesis (IH). His hypothesis seems to be based on the view that IH is caused by post-decussating pyramidal tract damage. Afterwards, other researchers proposed a different hypothesis that ipsilateral sensory symptoms of limbs (ISSL) or ipsilateral limb ataxia (ILA) caused by lateral medullary infarction (LMI) might lead to ipsilateral motor weakness. The present study is aimed to clarify whether IH in LMI patients is attributable mainly to ISSL/ILA or disruption of ipsilateral post-decussating pyramidal tract. Thirty-two patients with acute LMI admitted during the last 13years were divided to IH Group (n=7) and Non-IH Group (n=25). Lesion location/distribution on MRI and neurological findings were compared between the two groups. LMI involved the lower medulla in all seven IH patients and 12 of 25 Non-IH patients. The lower medullary lesion extended to the cervico-medullary junction (CMJ) in four of seven IH patients and one of 12 Non-IH patients. Definitive extension to upper cervical cord (UCC) was confirmed in none of the patients. ISSL was found in two IH and three Non-IH patients all showing only superficial sensory impairments. ILA or hypotonia was observed in 57% of IH and 60% of Non-IH patients. IH in LMI appears to be due mainly to post-decussating pyramidal tract damage at the lower medulla instead of ILA or ISSL participation. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    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.

  13. Renal Medullary Carcinoma with an Aggressive Clinical Course: A Case Report and Review of the Literature

    Kalavar, Madhumati R.; Ali, Sami; Safarpour, Damoun; Kunnakkat, Saroj Davi


    Renal medullary carcinoma (RMC) is a rare, yet aggressive malignancy of the kidney that is found predominantly in young patients with African descent and sickle cell hemoglobinopathies and most specifically sickle cell trait. Due to its aggressive nature, most cases have metastasis or local invasion at the time of diagnosis. Prognosis is extremely poor with survival less than 1 year after diagnosis. Here we present a case of metastatic RMC in a 29-year-old African female. Despite chemotherapy with cisplatin, gemcitabine, and paclitaxel, and initial shrinkage of the tumor, the patient died 5 months after diagnosis. PMID:28203160

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

    Chaudhary Kshitij


    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.

  15. Response to Radiation in Renal Medullary Carcinoma: a Case Report and Review of the Literature

    Alexandra M. Walsh


    Full Text Available Renal Medullary Carcinoma (RMC is a rare and highly aggressive malignancy arising from the renal medulla and found mostly in patients with sickle cell trait. RMC usually presents with widely metastatic disease. We describe a young man diagnosed with RMC who sustained a complete response to systemic chemotherapy but developed brain metastases with leptomeningeal involvement who had a partial response to brain irradiation. We discuss the use of radiation in RMC and propose upfront craniospinal irradiation as a reasonable addition to chemotherapy in order to give patients with metastatic RMC a chance at cure.

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

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


    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.

  17. Medullary carcinoma of the thyroid metastatic to the breast: a case report and literature review

    Sebastião Nunes Martins Filho


    Full Text Available Breast malignancies, apart from skin cancer, are the leading cause of cancer from cancer among the female population. Unlike the high prevalence of primary mammary malignancies, metastases to the breast are uncommon, and account for only 0.2-2.7% of all malignancies affecting this organ. We report the case of a 35-year-old woman who sought medical care because of a breast lump. A mammogram suggested a breast tumor, which was biopsied. The histopathological workup resulted in the diagnosis of a metastasis from a medullary thyroid cancer. The authors review the most useful clinical, radiological, histological, and immunohistochemical features concerning extramammary malignancy to the breast.

  18. Fracture of the femoral shaft in children: advantages of the descending medullary nailing.

    Bourdelat, D


    In a 7-year period, 70 children aged 5-15 years (mean 9.2 years) were treated for a fracture of the femoral shaft (73 fractures: 71 closed and 2 open) by flexible medullary nailing, either ascending (12 cases) or descending (61 cases). Although the classic treatment is use of the ascending route described by the Nancy team, the subtrochanteric descending route was preferred for its simplicity. Noninvolvement of the knee by the insertion of the nail allows earlier autonomy in children. Results were satisfactory and no complications related to the method were observed. Biomechanical principles are also respected by such treatment.

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

    Nicholas S. Mastronikolis


    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.

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

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


    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

  1. Chronic vasodilation increases renal medullary PDE5A and α-ENaC through independent renin-angiotensin-aldosterone system pathways.

    West, Crystal A; Shaw, Stefan; Sasser, Jennifer M; Fekete, Andrea; Alexander, Tyler; Cunningham, Mark W; Masilamani, Shyama M E; Baylis, Chris


    We have previously observed that many of the renal and hemodynamic adaptations seen in normal pregnancy can be induced in virgin female rats by chronic systemic vasodilation. Fourteen-day vasodilation with sodium nitrite or nifedipine (NIF) produced plasma volume expansion (PVE), hemodilution, and increased renal medullary phosphodiesterase 5A (PDE5A) protein. The present study examined the role of the renin-angiotensin-aldosterone system (RAAS) in this mechanism. Virgin females were treated for 14 days with NIF (10 mg·kg(-1)·day(-1) via diet), NIF with spironolactone [SPR; mineralocorticoid receptor (MR) blocker, 200-300 mg·kg(-1)·day(-1) via diet], NIF with losartan [LOS; angiotensin type 1 (AT1) receptor blocker, 20 mg·kg(-1)·day(-1) via diet], enalapril (ENAL; angiotensin-converting enzyme inhibitor, 62.5 mg/l via water), or vehicle (CON). Mean arterial pressure (MAP) was reduced 7.4 ± 0.5% with NIF, 6.33 ± 0.5% with NIF + SPR, 13.3 ± 0.9% with NIF + LOS, and 12.0 ± 0.4% with ENAL vs. baseline MAP. Compared with CON (3.6 ± 0.3%), plasma volume factored for body weight was increased by NIF (5.2 ± 0.4%) treatment but not by NIF + SPR (4.3 ± 0.3%), NIF + LOS (3.6 ± 0.1%), or ENAL (4.0 ± 0.3%). NIF increased PDE5A protein abundance in the renal inner medulla, and SPR did not prevent this increase (188 ± 16 and 204 ± 22% of CON, respectively). NIF increased the α-subunit of the epithelial sodium channel (α-ENaC) protein in renal outer (365 ± 44%) and inner (526 ± 83%) medulla, and SPR prevented these changes. There was no change in either PDE5A or α-ENaC abundance vs. CON in rats treated with NIF + LOS or ENAL. These data indicate that the PVE and renal medullary adaptations in response to chronic vasodilation result from RAAS signaling, with increases in PDE5A mediated through AT1 receptor and α-ENaC through the MR.

  2. Multiple endocrine neoplasia similar to human subtype 2A in a dog: Medullary thyroid carcinoma, bilateral pheochromocytoma and parathyroid adenoma

    Arias, E.A. Soler; Castillo, V.A.; Trigo, R.H.; Caneda Aristarain, M.E.


    Human multiple endocrine neoplasia subtype 2A (MEN 2A) is characterized by medullary thyroid carcinoma, pheochromocytoma and parathyroid hyperplasia or adenoma in the same individual. In this report, a case of a female Rottweiler with medullary thyroid carcinoma, bilateral pheochromocytoma and parathyroid adenoma was described. Clinical manifestations of muscle weakness, polydipsia, polyuria, diarrhea and weight loss were observed. Two adrenal neoplasms were identified incidentally by ultrasonography, and tumor in the left thyroid lobe was identified by palpation. Primary hyperparathyroidism was diagnosed by biochemical testing. Histopathology report was consistent with diagnosis of bilateral pheochromocytoma and parathyroid adenoma. Immunohistochemical staining was positive for calcitonin and synaptophysin, and negative for thyroglobulin, which confirmed medullary thyroid carcinoma. This case in a dog is presenting neoplastic characteristics similar to human MEN 2A and emphasizing the importance of using immunohistochemistry for confirmation. PMID:27822452

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

    Amit Tyagi


    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.

  4. Central Hypoventilation Syndrome Complicated with Lateral Medullary Infarction after Endovascular Treatment of the Vertebral Artery Dissecting Aneurysm: A Case Report.

    Tanaka, Katsuhiro; Kanamaru, Hideki; Morikawa, Atsunori; Kawaguchi, Kenji


    Lateral medullary infarction rarely leads to central hypoventilation syndrome (CHS). CHS is a life-threatening disorder characterized by hypoventilation during sleep. We report the first case of CHS as a complication of lateral medullary infarction after endovascular treatment. A 65-year-old man presented twice with severe headache. Computed tomography revealed subarachnoid hemorrhage and cerebral angiography showed a right vertebral dissecting aneurysm involving the posterior inferior cerebellar artery. After emergent endovascular patent artery occlusion, he developed Wallenberg syndrome and experienced apnea and a conscious disturbance episode due to CHS on postoperative days 6 and 16. Intensive respiratory care including intubation, tracheostomy, mechanical ventilation, and rehabilitation prevented subsequent recurrence of apnea and the CHS resolved completely. CHS after unilateral medullary infarction involving respiratory centers tends to occur in the acute and subacute phase and may be lethal without careful respiratory management.

  5. Optogenetic modulation of descending prefrontocortical inputs to the dorsal raphe bidirectionally bias socioaffective choices after social defeat

    Collin eChallis


    Full Text Available It has been well established that modulating serotonin (5-HT levels in humans and animals affects perception and response to social threats, however the circuit mechanisms that control 5-HT output during social interaction are not well understood. A better understanding of these systems could provide groundwork for more precise and efficient therapeutic interventions. Here we examined the organization and plasticity of microcircuits implicated in top-down control of 5-HT neurons in the dorsal raphe nucleus (DRN by excitatory inputs from the ventromedial prefrontal cortex (vmPFC and their role in social approach-avoidance decisions. We did this in the context of a social defeat model that induces a long lasting form of social aversion that is reversible by antidepressants. We first used viral tracing and Cre-dependent genetic identification of vmPFC glutamatergic synapses in the DRN to determine their topographic distribution in relation to 5-HT and GABAergic subregions and found that excitatory vmPFC projections primarily localized to GABA-rich areas of the DRN. We then used optogenetics in combination with cFos mapping and slice electrophysiology to establish the functional effects of repeatedly driving vmPFC inputs in DRN. We provide the first direct evidence that vmPFC axons drive synaptic activity and immediate early gene expression in genetically identified DRN GABA neurons through an AMPA receptor-dependent mechanism. In contrast, we did not detect vmPFC-driven synaptic activity in 5-HT neurons and cFos induction in 5-HT neurons was limited. Finally we show that optogenetically increasing or decreasing excitatory vmPFC input to the DRN during sensory exposure to an aggressor’s cues enhances or diminishes avoidance bias, respectively. These results clarify the functional organization of vmPFC-DRN pathways and identify GABAergic neurons as a key cellular element filtering top-down vmPFC influences on affect-regulating 5-HT output.

  6. Role of opioidergic and GABAergic neurotransmission of the nucleus raphe magnus in the modulation of tonic immobility in guinea pigs.

    da Silva, Luis Felipe Souza; Menescal-de-Oliveira, Leda


    Tonic immobility (TI) is an inborn defensive behavior characterized by a temporary state of profound and reversible motor inhibition elicited by some forms of physical restraint. Previous results from our laboratory have demonstrated that nucleus raphe magnus (NRM) is also a structure involved in the modulation of TI behavior, as chemical stimulation through carbachol decreases the duration of TI in guinea pigs. In view of the fact that GABAergic and opioidergic circuits participate in the regulation of neuronal activity in the NRM and since these neurotransmitters are also involved in the modulation of TI, the objective of the present study was to evaluate the role of these circuits of the NRM in the modulation of the behavioral TI response. Microinjection of morphine (4.4 nmol/0.2 microl) or bicuculline (0.4 nmol/0.2 microl) into the NRM increased the duration of TI episodes while muscimol (0.5 nmol/0.2 microl) decreased it. The effect of morphine injection into the NRM was blocked by previous microinjection of naloxone (2.7 nmol/0.2 microl). Muscimol at 0.25 nmol did not produce any change in TI duration; however, it blocked the increased response induced by morphine. Our results indicate a facilitatory role of opioidergic neurotransmission in the modulation of the TI response within the NRM, whereas GABAergic activity plays an inhibitory role. In addition, in the present study the modulation of TI in the NRM possibly occurred via an interaction between opioidergic and GABAergic systems, where the opioidergic effect might be due to inhibition of tonically active GABAergic interneurons.

  7. Mu Opioid Receptor Modulation of Dopamine Neurons in the Periaqueductal Gray/Dorsal Raphe: A Role in Regulation of Pain.

    Li, Chia; Sugam, Jonathan A; Lowery-Gionta, Emily G; McElligott, Zoe A; McCall, Nora M; Lopez, Alberto J; McKlveen, Jessica M; Pleil, Kristen E; Kash, Thomas L


    The periaqueductal gray (PAG) is a brain region involved in nociception modulation, and an important relay center for the descending nociceptive pathway through the rostral ventral lateral medulla. Given the dense expression of mu opioid receptors and the role of dopamine in pain, the recently characterized dopamine neurons in the ventral PAG (vPAG)/dorsal raphe (DR) region are a potentially critical site for the antinociceptive actions of opioids. The objectives of this study were to (1) evaluate synaptic modulation of the vPAG/DR dopamine neurons by mu opioid receptors and to (2) dissect the anatomy and neurochemistry of these neurons, in order to assess the downstream loci and functions of their activation. Using a mouse line that expresses eGFP under control of the tyrosine hydroxylase (TH) promoter, we found that mu opioid receptor activation led to a decrease in inhibitory inputs onto the vPAG/DR dopamine neurons. Furthermore, combining immunohistochemistry, optogenetics, electrophysiology, and fast-scan cyclic voltammetry in a TH-cre mouse line, we demonstrated that these neurons also express the vesicular glutamate type 2 transporter and co-release dopamine and glutamate in a major downstream projection structure-the bed nucleus of the stria terminalis. Finally, activation of TH-positive neurons in the vPAG/DR using Gq designer receptors exclusively activated by designer drugs displayed a supraspinal, but not spinal, antinociceptive effect. These results indicate that vPAG/DR dopamine neurons likely play a key role in opiate antinociception, potentially via the activation of downstream structures through dopamine and glutamate release.

  8. Extramedullary plasmacytoma of thyroid - a mimicker of medullary carcinoma at fine needle aspiration cytology: A case report

    Vidya Bhat


    Full Text Available A rare case of extra medullary plasmacytoma (EMP of thyroid gland in a 60 year old male, occurring against a background of Hashimoto′s thyroiditis is reported. The fine needle aspiration cytology (FNAC initially done as an outpatient procedure, showed atypical epithelial cells on a background of amyloid. Considering these findings we gave a diagnosis of medullary carcinoma. Histology of the total thyroidectomy specimen showed an extensive infiltration of neoplastic plasma cells against a background of Hashimoto′s thyroiditis, with a bizarre Hurthle cell change. Immunohistochemistry on the histology sections confirmed the diagnosis of solitary plasmacytoma of thyroid against a background of Hashimoto′s thyroiditis.

  9. Microvascular patterns in human medullary tegmentum at the level of the area postrema.

    Porzionato, Andrea; Macchi, Veronica; Morsut, Leonardo; Parenti, Anna; De Caro, Raffaele


    Abstract The aim of the present study was to evaluate the regional differences in microvessel density (MVD) of the human medullary tegmentum in adults and newborns/infants. Transverse serial sections of formalin-fixed, paraffin-embedded brainstems, taken from 16 adult and eight newborn/infant subjects, were stained with anti-von Willebrand factor (vWF) polyclonal antibodies. The boundaries of the area postrema (AP), dorsal motor vagal nucleus (DMVN), solitary tract nucleus (STN), solitary tract (ST) and hypoglossal nucleus (XII) were defined, all vessels were counted and the values were divided by the areas. In adult cases, statistically significant heterogeneity in MVD was found among the nuclei studied (P sections of the medulla of adult subjects stained with anti-vWF, all vessels showed an intense reaction of endothelial cells whereas in the DMVN, XII, STN and ST of newborns/infants, only rare, isolated vessels showed anti-vWF reactivity and in the AP, 41 +/- 21% of vessels expressed vWF. Differences in MVD among the nuclei may be related to their different functions and metabolic demands. Light and heterogeneous expression of vWF in endothelial cells of newborns/infants indicates that differentiation of microvasculature in the human medullary tegmentum extends beyond fetal stages.

  10. Metastatic medullary thyroid cancer: a dramatic response to a systemic chemotherapy (temozolomide and capecitabine regimen

    Lacin S


    Full Text Available Sahin Lacin, Ece Esin, Yusuf Karakas, Suayib Yalcin Department of Medical Oncology, Institute of Cancer, Hacettepe University, Ankara, Turkey Abstract: A 40-year-old male patient presented with increasing serum levels of calcitonin and CEA. He underwent potential curative surgery for medullary thyroid carcinoma, 3 years ago and then 7 months later he had metastasectomy and cervical lymph node dissection for recurrent disease. On admission he had multiple metastatic skin nodules on the chest wall and positron emission tomography–computed tomography revealed multiple visceral metastases as well. The patient had not received any systemic treatment up to that time; therefore, we considered systemic treatment with the new tyrosine kinase inhibitors (vandetanib, cabozantinib, etc. However, since these drugs are only available after cytotoxic chemotherapy, we started temozolomide and capecitabine chemotherapy. After two courses of the treatment all skin nodules disappeared and CEA and calcitonin levels normalized, radiological imaging showed a good partial response. Keywords: medullary thyroid cancer, capecitabine, temozolomide, chemotherapy

  11. Cortico-medullary continuity in bizarre parosteal osteochondromatous proliferation mimicking osteochondroma on imaging

    Rybak, Leon D. [NYU Hospital for Joint Diseases, Department of Radiology, New York, NY (United States); Abramovici, Luigia; Steiner, German C. [NYU Hospital for Joint Diseases, Department of Pathology and Laboratory Medicine, New York, NY (United States); Kenan, Samuel [NYU Hospital for Joint Diseases, Oncology Service, Department of Orthopedics, New York, NY (United States); Posner, Martin A. [NYU Hospital for Joint Diseases, Hand Service, Department of Orthopedics, New York, NY, 10128 (United States); Bonar, Fiona [Douglass Hanly Moir Pathology, North Ryde, NSW (Australia)


    Bizarre parosteal osteochondromatous proliferation (BPOP), or Nora's lesion, is an unusual surface-based lesion of bone found most commonly in the hands and feet. In the original description of the lesion and in all publications that followed, one of the key imaging characteristics used to define this entity was the lack of cortico-medullary continuity with the underlying bone. The authors present 4 unique cases of pathologically proven BPOP in which cortico-medullary continuity with the underlying bone was demonstrated on imaging. It is believed that florid reactive periostitis, BPOP and turret osteochondroma may reflect points along the same continuum with trauma the likely inciting event. The authors suggest that, given this continuum, it may be possible to have BPOP lesions demonstrating overlapping imaging features with osteochondroma. If this is the case, strict adherence to the standard imaging criterion of lack of continuity between the lesion and the underlying bone may lead to misdiagnosis of these unusual cases of BPOP as osteochondromas. (orig.)

  12. Medullary metastasis of a malignant peripheral nerve sheath tumor: A case report

    Hagi, Tomohito; Nakamura, Tomoki; Yokoji, Ayumu; Matsumine, Akihiko; Sudo, Akihiro


    The present study reports a case of medullary metastasis without lung metastasis that occurred as a result of a malignant peripheral nerve sheath tumor (MPNST). An 81-year-old woman presented with a MPNST in the left brachial plexus, arising from the cervical nerve root. The patient underwent carbon ion radiotherapy; however, tumor recurrence was identified in the left shoulder. Subsequently, the patient underwent wide excision. Three weeks subsequent to surgery, imbalance and dysarthria developed suddenly. Dysphagia emerged and left upper limb pain disappeared on the day after symptom development. Magnetic resonance imaging (MRI) revealed that this was due to metastasis to the medulla. Five days subsequent to the onset of dysarthria, the patient succumbed due to respiratory failure. To the best of our knowledge, no previous cases of medullary metastasis arising from a MPNST in the absence of lung metastasis have been reported. MRI is a useful examination tool for the identification of brain metastases; however, the high cost of MRI as a routine examination must be considered due to the rarity of brain metastases. Therefore, methods to detect brain metastasis warrant further investigation. PMID:27588138

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

    Khan, Ali E-mail:; Thomas, Nigel; Costello, Brandon; Jobling, Louis; Kretser, Dan de; Broadfield, Emma; O' Shea, Sarah


    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.

  14. Ultrasonographic Findings of Medullary Thyroid Carcinoma: a Comparison with Papillary Thyroid Carcinoma

    Kim, Sung Hun; Kim, Bum Soo; Jung, So Lyung [The Catholic University of Korea, Seoul (Korea, Republic of)] (and others)


    This study was designed to evaluate the ultrasonographic (US) findings of medullary thyroid carcinoma (MTC) as compared to findings for papillary thyroid carcinoma (PTC). The study included 21 cases of MTC that were surgically diagnosed between 2002 and 2007 and 114 cases of PTC that were diagnosed in 2007. Two radiologists reached a consensus in the evaluation of the US findings. The US findings were classified as recommended by the Thyroid Study Group of the Korean Society of Neuroradiology and Head and Neck Radiology (KSNHNR) and each nodule was identified as suspicious malignant, indeterminate or probably benign. The findings of medullary and papillary carcinomas were compared with use of the chi-squared test. The common US findings for MTCs were solid internal content (91%), an ovoid to round shape (57%), marked hypoechogenicity (52%) and calcifications (52%). Among the 21 cases of MTC nodules, 17 (81%) were classified as suspicious malignant nodules. The mean size (longest diameter) of MTC nodules was 19 {+-}13.9 mm and the mean size (longest diameter) of PTC nodules was 11 {+-} 7.4 mm; this difference was statistically significant (p < 0.05). An ovoid to round shape was more prevalent for MTC lesions than for PTC lesions (p < 0.05). The US criteria for suspicious malignant nodules as recommended by the Thyroid Study Group of the KSNHNR correspond to most MTC cases. The US findings for MTC are not greatly different from PTC except for the prevalence of an ovoid to round shape.

  15. Adrenal medullary transplantation to the caudate nucleus in Parkinson's disease. Initial clinical results in 18 patients.

    Allen, G S; Burns, R S; Tulipan, N B; Parker, R A


    Results from a pilot study of adrenal medullary autotransplantation for Parkinson's disease are presented. Eighteen patients were studied; 12 were followed up for 1 year, and 6 were followed up for 6 months. Four of 12 patients showed distinct improvement in the signs and symptoms of their disease, as assessed using the Columbia Rating Scale, at 1 year; none showed distinct deterioration. The 6 patients who were followed up for only 6 months were an average of 20 years older and generally more severely affected. None distinctly improved. Morbidity was considered to be minor and transient among the first 12 patients, while 4 of the last 6 patients experienced alteration in mental status lasting as long as several months. This problem has led us to conclude that older patients with preexisting cognitive impairment should not be included in future studies until the benefits are more clearly established. However, we believe that the distinct and persistent improvement seen in some of the younger patients warrants the initiation of a well-designed, randomized, and controlled trial of adrenal medullary autotransplantation for the purpose of confirming these results and assessing the effect of the procedure on the natural progression of Parkinson's disease.

  16. Changes in renal cortical and medullary perfusion in a patient with renal vein thrombosis

    Al-Said Jafar


    Full Text Available Dynamic renal perfusion computerized tomographic (CT scan was performed to test the cortical and medullary perfusion in a patient with unilateral renal vein thrombosis secondary to idiopathic focal and segmental glomerulosclerosis (FSGS. Forty mL of Iohexol was injected intra-venously. Multiple fixed repeated axial renal CT scan cuts at specific intervals, over the mid pole, were recorded over 400 seconds. Radio density was measured over the aorta, cortex and medulla during that period. Graphs for the radio contrast density against time were plotted. Aortic, cortical and medullary perfusions were calculated by estimating the slopes of the curves. Based on the CT scan findings, perfusion of different parts of the kidney was measured. The reduction in kidney function with renal vein thrombosis seems to be secondary to hypoperfusion of renal cortex and medulla. Further studies are required to confirm this observation. The blood flow to the kidney im-proved within four days after therapy with anticoagulation and pulse steroids. The sequences of events that take place need further studies for validation.

  17. Anti-tumor effects of shikonin derivatives on human medullary thyroid carcinoma cells

    Carina Hasenoehrl


    Full Text Available New treatment options are needed for medullary thyroid carcinoma (MTC, a highly metastasizing neuroendocrine tumor that is resistant to standard radiotherapy and chemotherapy. We show that the following shikonin derivatives inhibit cell proliferation and cell viability of the MTC cell line TT: acetylshikonin, β,β-dimethylacrylshikonin, shikonin and a petroleum ether extract of the roots of Onosma paniculata containing several shikonin derivatives. The unsubstituted shikonin derivative was found to be the most effective compound with an IC50 of 1.1 μM. The cell viability of normal human skin fibroblasts, however, was not affected by the tested substances, indicating that shikonin derivatives might be selectively toxic for cancer cells. We further report that migration and invasion of TT cells were inhibited at non-toxic concentrations. Finally, shikonin was tested in vivo using the chick chorioallantoic membrane assay, where it significantly reduced tumor growth by inhibiting cell proliferation and inducing apoptosis. In summary, our results suggest that shikonin derivatives have the potential for the treatment of medullary thyroid carcinomas.

  18. Clinical utility of vandetanib in the treatment of patients with advanced medullary thyroid cancer

    Deshpande H


    Full Text Available Hari Deshpande1,3, Vicky Marler3, Julie Ann Sosa2,31Department of Medicine, 2Department of Surgery, Yale University School of Medicine, 3Yale Cancer Center, New Haven, CT, USAAbstract: Vandetanib (ZD6474 became the first systemic agent to be approved for the treatment of metastatic or locally advanced medullary thyroid cancer. It was a proof of principle, because it is an orally bioavailable medication that targets the growth factors felt to be important in the pathogenesis of this disease, ie, the rearranged during transfection proto-oncogene and vascular endothelial growth factor receptor. It was tested initially in two Phase II studies at doses of 100 mg and 300 mg daily. Although activity was seen at both doses, the higher dose was chosen for a randomized, placebo-controlled Phase II study. This trial, which accrued more than 300 patients, showed a statistically significant benefit for the group taking vandetanib compared with those taking placebo medication. Progression-free survival for the vandetanib arm has not been reached, compared with 19 months for the placebo arm. The main toxicity appears to be diarrhea, although some patients experienced significant side effects, including torsades de pointes and sudden cardiac death. Therefore, it is now necessary for practitioners to enroll in a Risk Evaluation Mitigation Strategy before being allowed to prescribe this medication, to reduce the risk of serious side effects occurring.Keywords: ZD6474, medullary thyroid cancer, vandetanib

  19. Tissue injury after lithium treatment in human and rat postnatal kidney involves glycogen synthase kinase 3β-positive epithelium

    Kjaersgaard, Gitte; Madsen, Kirsten; Marcussen, Niels


    concentration capacity and diminished outer medullary volume. Histological sections of nephrectomy samples and a biopsy from 3 long-term lithium-treated patients showed multiple cortical microcysts that originated from normally appearing tubules. Microcysts were lined by a cuboidal PCNA-, GSK-3β- and pGSK-3β...... plasma lithium concentration of 1.0 mmol/L. Kidneys from lithium-treated rat pups exhibited dilated distal nephron segments with microcysts. Stereological analysis showed reduced cortex and outer medullary volumes. Lithium increased pGSK-3β and the proliferation marker PCNA protein abundances in cortex...

  20. Selective estrogen receptor-beta (SERM-beta) compounds modulate raphe nuclei tryptophan hydroxylase-1 (TPH-1) mRNA expression and cause antidepressant-like effects in the forced swim test.

    Clark, J A; Alves, S; Gundlah, C; Rocha, B; Birzin, E T; Cai, S-J; Flick, R; Hayes, E; Ho, K; Warrier, S; Pai, L; Yudkovitz, J; Fleischer, R; Colwell, L; Li, S; Wilkinson, H; Schaeffer, J; Wilkening, R; Mattingly, E; Hammond, M; Rohrer, S P


    Estrogen acts through two molecularly distinct receptors termed estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) which bind estradiol with similar affinities and mediate the effects of estrogen throughout the body. ERα plays a major role in reproductive physiology and behavior, and mediates classic estrogen signaling in such tissues as the uterus, mammary gland, and skeleton. ERβ, however, modulates estrogen signaling in the ovary, the immune system, prostate, gastrointestinal tract, and hypothalamus, and there is some evidence that ERβ can regulate ERα activity. Moreover, ERβ knockout studies and receptor distribution analyses in the CNS suggest that this receptor may play a role in the modulation of mood and cognition. In recent years several ERβ-specific compounds (selective estrogen receptor beta modulators; SERM-beta) have become available, and research suggests potential utility of these compounds in menopausal symptom relief, breast cancer prevention, diseases that have an inflammatory component, osteoporosis, cardiovascular disease, and inflammatory bowel disease, as well as modulation of mood, and anxiety. Here we demonstrate an antidepressant-like effect obtained using two SERM-beta compounds, SERM-beta1 and SERM-beta2. These compounds exhibit full agonist activity at ERβ in a cell based estrogen response element (ERE) transactivation assay. SERM-beta1 and 2 are non-proliferative with respect to breast as determined using the MCF-7 breast cancer cell-based assay and non-proliferative in the uterus as determined by assessing the effects of SERM-beta compounds on immature rat uterine weight and murine uterine weight. In vivo SERM-beta1 and 2 are brain penetrant and display dose dependent efficacy in the murine dorsal raphe assays for induction of tryptophan hydroxylase mRNA and progesterone receptor protein. These compounds show activity in the murine forced swim test and promote hippocampal neurogenesis acutely in rats. Taken

  1. Differential regulation of serotonin-1A receptor-stimulated [35S]GTP gamma S binding in the dorsal raphe nucleus by citalopram and escitalopram.

    Rossi, Dania V; Burke, Teresa F; Hensler, Julie G


    The effect of chronic citalopram or escitalopram administration on 5-HT1A receptor function in the dorsal raphe nucleus was determined by measuring [35S]GTP gamma S binding stimulated by the 5-HT1A receptor agonist (R)-(+)-8-OH-DPAT (1nM-10 microM). Although chronic administration of citalopram or escitalopram has been shown to desensitize somatodendritic 5-HT1A autoreceptors, we found that escitalopram treatment decreased the efficacy of 5-HT1A receptors to activate G proteins, whereas citalopram treatment did not. The binding of [3H]8-OH-DPAT to the coupled, high affinity agonist state of the receptor was not altered by either treatment. Interestingly, escitalopram administration resulted in greater occupancy of serotonin transporter sites as measured by the inhibition of [3H]cyanoimipramine binding. As the binding and action of escitalopram is limited by the inactive enantiomer R-citalopram present in racemic citalopram, we propose that the regulation of 5-HT1A receptor function in the dorsal raphe nucleus at the level of receptor-G protein interaction may be a result of greater inhibition of the serotonin transporter by escitalopram.

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

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


    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

  3. Mixed medullary-papillary carcinoma of the thyroid: report of two cases and review of the literature.

    Gurkan, Eren; Gurbuz, Yesim; Tarkun, Ilhan; Canturk, Zeynep; Cetinarslan, Berrin


    Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are two distinct types of thyroid carcinoma with considerable difference in terms of cellular origin, histopathological appearance, clinical course and prevalence. The histogenetic origin and possible molecular mechanisms responsible for the development of mixed medullary-papillary carcinoma of the thyroid are still unclear. The most widely accepted hypotheses considering co-occurrence of MTC and PTC are stem cell theory, collision effect theory and hostage theory. Herein we describe two rare cases of mixed medullary-papillary thyroid carcinoma with co-occurrence of MTC and PTC which developed with concomitant MEN 2A and different sites of lymph node metastasis in the first patient, while with atypical clinical presentation in the second patient. In conclusion, co-expression of thyroglobulin, synaptophysin and chromogranin by the papillary component of mixed tumor seems to support stem cell theory in our first case, whereas positive staining for calcitonin but not for thyroglobulin in the medullary component of the tumor along with separation of these two tumors from each other by a normal thyroid tissue seem to indicates the likelihood of collision effect theory in our second case.

  4. Distinguishing medullary carcinoma of the breast from high-grade hormone receptor-negative invasive ductal carcinoma: an immunohistochemical approach.

    Flucke, U.E.; Flucke, M.T.; Hoy, L.; Breuer, E.; Goebbels, R.; Rhiem, K.; Schmutzler, R.; Winzenried, H.; Braun, M.; Steiner, S.; Buettner, R.; Gevensleben, H.


    AIMS: Medullary carcinomas (MCs) represent a rare breast cancer subtype associated with a rather favourable prognosis compared with invasive ductal carcinomas (IDCs). Due to histopathological overlap, MCs are frequently misclassified as high-grade IDCs, potentially leading to overtreatment of MCs. O

  5. Histological features of medullary carcinoma and prognosis in triple-negative basal-like carcinomas of the breast.

    Marginean, Felicia; Rakha, Emad A; Ho, Bernard C; Ellis, Ian O; Lee, Andrew H S


    Medullary carcinomas have a better prognosis than other grade 3 mammary carcinomas, but they typically show basal-like biological features, which are associated with a poor prognosis. In this study we examined the associations and prognostic relevance of medullary histological features in a series of 165 invasive carcinomas with a basal-like phenotype: triple-negative (oestrogen receptor, progesterone receptor, HER2) and expressing at least one basal marker (CK5/6, CK14, CK17 or EGFR). The following histological features were associated with each other: prominent inflammation, anastomosing sheets, absence of fibrosis, absence of infiltrative margin and absence of gland formation. Prominent inflammation and anastomosing sheets in at least 30% of the tumour were associated with a better prognosis on univariate analysis. The combination of these two features (a simplified definition of medullary-like type) was present in 17% of tumours and was an independent prognostic factor on multivariate analysis. This simplified definition had good inter-observer reproducibility (κ=0.61) and is worthy of more detailed assessment in an unselected group of mammary carcinomas. A fibrotic focus was present in 36% of carcinomas. Only 3% of tumours with a fibrotic focus had features of medullary-like carcinomas. Fibrotic focus of greater than 30% of the tumour was associated with a poor prognosis. This study emphasizes the heterogeneity of morphology and behaviour of triple-negative basal-like carcinomas.

  6. Association of urothelial carcinoma of the renal pelvis with papillary and medullary thyroid carcinomas. A new sporadic neoplastic syndrome?

    Albores-Saavedra, Jorge; Dorantes-Heredia, Rita; Chablé-Montero, Fredy; Córdova-Ramón, Juan Carlos; Henson, Donald E


    We describe 2 adult women (72 and 54 years), 1 with a low-grade noninvasive papillary urothelial carcinoma of the renal pelvis, who 14 years later developed a papillary carcinoma in 1 thyroid lobe and a medullary carcinoma in the contralateral lobe. Both neoplasms were similar in size and appeared symmetrical. Despite its small size, the medullary carcinoma metastasized in multiple cervical lymph nodes. The second patient had a high-grade invasive papillary urothelial carcinoma of the renal pelvis that infiltrated the renal parenchyma and metastasized in one of the lungs. Five months later, a papillary carcinoma was discovered in the thyroid gland. The 2 papillary thyroid carcinomas were of the follicular variant. Adjacent to 1 papillary carcinoma, there was a dominant nodule of a colloid and adenomatous goiter. The medullary carcinoma contained stromal amyloid and was immunoreactive for calcitonin and carcinoembryonic antigen. There was no C-cell hyperplasia (medullary carcinoma in situ). The 2 patients are alive, 1 is living with pulmonary metastasis from the high-grade urothelial carcinoma. Twelve cases of this neoplastic association were registered in the Survey, Epidemiology, and End Results Program from 1980 to 2009. We believe that the combination of these unusual neoplasms in the same patient may represent a new sporadic neoplastic syndrome.

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

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


    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 analog

  8. MicroPET imaging of 5-HT{sub 1A} receptors in rat brain: a test-retest [{sup 18}F]MPPF study

    Aznavour, Nicolas [McGill University, Department of Psychiatry, Montreal, QC (Canada)]|[Laboratory of Neuroenergetics and Cellular Dynamics, EPFL, SV, BMI, Lausanne (Switzerland); Benkelfat, Chawki; Gravel, Paul [McGill University, Department of Psychiatry, Montreal, QC (Canada)]|[McGill University, Department of Neurology and Neurosurgery, Montreal, QC (Canada); Aliaga, Antonio [McGill University, Department of Small Animal Imaging Laboratory, Montreal, QC (Canada); Rosa-Neto, Pedro [Douglas Hospital, Molecular NeuroImaging Laboratory, Montreal, QC (Canada); Bedell, Barry [McGill University, Department of Neurology and Neurosurgery, Montreal, QC (Canada)]|[McGill University, Department of Small Animal Imaging Laboratory, Montreal, QC (Canada); Zimmer, Luc [CERMEP, ANIMAGE Department, Lyon (France)]|[Universite Lyon 1 and CNRS, Lyon (France); Descarries, Laurent [Universite de Montreal, Department of Pathology and Cell Biology, Montreal, QC (Canada)]|[Universite de Montreal, Department of Physiology, Montreal, QC (Canada)]|[Universite de Montreal, GRSNC, Montreal, QC (Canada)


    Earlier studies have shown that positron emission tomography (PET) imaging with the radioligand [{sup 18}F]MPPF allows for measuring the binding potential of serotonin 5-hydroxytryptamine{sub 1A} (5-HT{sub 1A}) receptors in different regions of animal and human brain, including that of 5-HT{sub 1A} autoreceptors in the raphe nuclei. In the present study, we sought to determine if such data could be obtained in rat, with a microPET (R4, Concorde Microsystems). Scans from isoflurane-anaesthetised rats (n = 18, including six test-retest) were co-registered with magnetic resonance imaging data, and binding potential, blood to plasma ratio and radiotracer efflux were estimated according to a simplified reference tissue model. Values of binding potential for hippocampus (1.2), entorhinal cortex (1.1), septum (1.1), medial prefrontal cortex (1.0), amygdala (0.8), raphe nuclei (0.6), paraventricular hypothalamic nucleus (0.5) and raphe obscurus (0.5) were comparable to those previously measured with PET in cats, non-human primates or humans. Test-retest variability was in the order of 10% in the larger brain regions (hippocampus, medial prefrontal and entorhinal cortex) and less than 20% in small nuclei such as the septum and the paraventricular hypothalamic, basolateral amygdaloid and raphe nuclei. MicroPET brain imaging of 5-HT{sub 1A} receptors with [{sup 18}F]MPPF thus represents a promising avenue for investigating 5-HT{sub 1A} receptor function in rat. (orig.)

  9. The cholinergic agonist carbachol increases the frequency of spontaneous GABAergic synaptic currents in dorsal raphe serotonergic neurons in the mouse.

    Yang, C; Brown, R E


    Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons play an important role in feeding, mood control and stress responses. One important feature of their activity across the sleep-wake cycle is their reduced firing during rapid-eye-movement (REM) sleep which stands in stark contrast to the wake/REM-on discharge pattern of brainstem cholinergic neurons. A prominent model of REM sleep control posits a reciprocal interaction between these cell groups. 5-HT inhibits cholinergic neurons, and activation of nicotinic receptors can excite DRN 5-HT neurons but the cholinergic effect on inhibitory inputs is incompletely understood. Here, in vitro, in DRN brain slices prepared from GAD67-GFP knock-in mice, a brief (3 min) bath application of carbachol (50 μM) increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in GFP-negative, putative 5-HT neurons but did not affect miniature (tetrodotoxin-insensitive) IPSCs. Carbachol had no direct postsynaptic effect. Thus, carbachol likely increases the activity of local GABAergic neurons which synapse on 5-HT neurons. Removal of dorsal regions of the slice including the ventrolateral periaqueductal gray (vlPAG) region where GABAergic neurons projecting to the DRN have been identified, abolished the effect of carbachol on sIPSCs whereas the removal of ventral regions containing the oral region of the pontine reticular nucleus (PnO) did not. In addition, carbachol directly excited GFP-positive, GABAergic vlPAG neurons. Antagonism of both muscarinic and nicotinic receptors completely abolished the effects of carbachol. We suggest cholinergic neurons inhibit DRN 5-HT neurons when acetylcholine levels are lower i.e. during quiet wakefulness and the beginning of REM sleep periods, in part via excitation of muscarinic and nicotinic receptors located on local vlPAG and DRN GABAergic neurons. Higher firing rates or burst firing of cholinergic neurons associated with attentive wakefulness or phasic REM sleep periods

  10. Association of vitamin D levels and receptor gene polymorphisms with medullary thyroid cancer

    Mehrnoosh Ramezani


    Full Text Available Background: Thyroid cancer is the most common endocrine malignancy. Accounting for approximately 1-2% of all cancers. Thyroid cancers have been divided into four main types: papillary, follicular, medullary and anaplastic. The active form of vitamin D (1,25- (OH 2-vitamin D3 by binding to its receptor, using genomic and non-genomic mechanisms inhibits the proliferative effect of TSH on thyroid cells. Therefore, vitamin D may have a role in regulating of thyroid gland cell proliferation. Many studies have shown anti-cancer effects of vitamin D in cancers. Polymorphisms of Vitamin D receptor can influence the prevalence to various cancers. In the present study, serum level of vitamin D and FokI, BsmI and Tru9I polymorphism of vitamin D receptor was investigated. Methods: This case-control study was performed in the summer of 2015 in Endocrinology and Metabolism Center of Shahid Beheshti University of Medical Sciences, Tehran, Iran. Forty medullary thyroid cancer patients and 40 healthy controls were investigated. Genomic DNA of subjects was extracted with saturated salt/proteinase K and polymorphisms of vitamin D receptor gene investigated by polymerase chain reaction-sequencing. Serum level of vitamin D evaluated by ELISA technique. The results were analyzed by SPSS, ver. 20 (Chicago, IL, USA and GraphPad Prism, ver. 5 (GraphPad, Inc., CA, USA softwares. Results: Genotypic and allelic abundance of FokI and BsmI polymorphisms between test and control groups have not shown significant different. In Tru9I polymorphism, Tt genotype abundance in test group were 45 percent and in control group were 17.5 percent and t allelic abundance in test group were 25 percent and in control group were 8.7 percent which this different were significant. Average serum level of vitamin D in test group was 23.32 ng/ml and in control group was 18.95 ng/ml which was statistically significant. Conclusion: Unexpectedly, serum levels of vitamin D in test group were higher

  11. Brain-gut interactions between central vagal activation and abdominal surgery to influence gastric myenteric ganglia Fos expression in rats


    We previously showed that medullary thyrotropin-releasing hormone (TRH) or the stable TRH agonist, RX-77368 administered intracisternally induces vagal-dependent activation of gastric myenteric neurons and prevents post surgery-induced delayed gastric emptying in rats. We investigated whether abdominal surgery alters intracisternal (ic) RX-77368 (50 ng)-induced gastric myenteric neuron activation. Under 10 min enflurane anesthesia, rats underwent an ic injection of saline or RX-77368 followed...

  12. The alpha(1G)-subunit of a voltage-dependent Ca(2+) channel is localized in rat distal nephron and collecting duct

    Andreasen, D; Jensen, B L; Hansen, P B


    +CCD), and inner medullary collecting duct (IMCD). alpha(1G) mRNA was expressed in the IMCD cell line mIMCD-3. Single- and double-labeling immunohistochemistry and confocal laser microscopy on semithin paraffin sections of rat kidneys by using an anti-alpha(1G) antibody demonstrated a distinct labeling...

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

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


    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 ....32 +/- 1.45 mmol) compared to patients with normal urinary acidification (3.83 +/- 0.12 mmol) (p normal urinary acidification (23.8 +/- 0.8) and healthy women (22.7 +/- 0.......6) (p urinary excretion of citrate (0.93 +/- 0.25 mmol) compared to patients with normal urinary acidification (3.58 +/- 0.51) and healthy women (2.78 +/- 0.49) (p

  14. Multiple endocrine neoplasias type 2A and thyroid medullary carcinoma: an interdisciplinary challenge.

    Haecker, Frank-Martin; Oertli, Daniel; Gissler, Stefanie; Zumsteg, Urs; Avoledo, Pierino; von Schweinitz, Dietrich


    The diagnosis and treatment of multiple endocrine neoplasias type 2A (MEN 2A) requires interdisciplinary management. The association of RET proto-oncogene mutations and medullary thyroid carcinoma (MTC) in children is well-known, but the optimal timing for elective surgery is controversial. Besides the risk of MTC, associated anomalies like hyperparathyroidism have to be considered. We report the results of molecular genetic investigations, the pentagastrin stimulation test, pre- and postoperative staging, and histologic examinations of four children who had a positive family history for MEN 2A. Histologic specimens of the removed thyroid glands showed MTC in all four cases. The patients had an uneventful postoperative clinical course. In view of the recent literature and our patients' results, we suggest a concept for diagnostic strategy and timing of the elective thyroidectomy.

  15. Conus medullaris hematomyelia associated with an intradural-extramedullary cavernous angioma.

    Mastronardi, L; Frondizi, D; Guiducci, A; Nardi, M; Maira, G


    A unique case of a 50-year-old woman with a conus medullaris hematomyelia associated with a low thoracic intradural-extramedullary cavernous angioma localized 2 cm above is reported. The patient had a 2-month history of progressive paraparesis, hypoesthesia of legs, and bowel and bladder disturbances. The symptoms worsened acutely during the last days before admission. A thoraco-lumbar MRI showed a space-occupying lesion at T10-T11 (vertebral interspace associated with a hematomyelia localized about 2 cm below. A T10-L1 laminectomy was performed and complete removal of both lesions was obtained with microsurgical technique. A non-traumatic hematomyelia should always prompt the suspicion of a spinal AVM or, more rarely, of a cavernous angioma. The possible anatomical and clinical correlations of this unusual association are discussed.

  16. Pentagastrin, calcium and whisky stimulated serum calcitonin in medullary carcinoma of the thyroid.

    Emmertsen, K K; Nielsen, H E; Mosekilde, L; Hansen, H H


    The efficiency of pentagastrin, calcium and whisky in raising serum immunoreactive calcitonin (S-iCT) concentrations was analysed in 6 patients with medullary carcinoma of the thyroid and in 8 healthy controls. All 6 patients responded to pentagastrin with a significant increase in S-iCT, 5 responded to calcium and only 3 to whisky. In the 8 controls no or only a modest increase in S-iCT occurred following pentagastrin, calcium and whisky with no difference between the three. It is concluded that pentagastrin is the most useful stimulative agent for ICT secretion in patients with C-cell neoplasms. In selected cases the additional use of calcium could be advantageous.

  17. An Unusual presentation Of Lateral Medullary Syndrome With Ipsilateral UMN Facial Palsy - An Anatomical Postulate

    Srinivasan M


    Full Text Available The clinical features of lateral medullary syndrome include ipsilateral decreased pain and temperature sensation over face, Horner′s syndrome, gait ataxia, vertigo with nausea and vomiting and reduction of pain and temperature of contra lateral half of body (6. At times, there is also an ipsilateral facial weakness due to ischemia of the caudal part of the 7the nerve nucleus just rostral to the nucleus ambiguus (11. Rarely an ipsilateral upper motor neuron (UMN facial weakness may be present and the same may be explained by the interruption of the hypothetical looping supranuclear corticofacial fibres which are said to ascend up in the dorsolateral medulla to reach the 7th nerve nucleus from below (8, 9, 10. A single case report is presented here in support of the above neuroanatomical postulate.

  18. [A case of Avellis' syndrome with ipsilateral central facial palsy due to a small medullary infarction].

    Takahashi, K; Kitani, M; Fukuda, H


    We report a 51-year-old man with mild left central facial palsy and left Avellis' syndrome due to a small medullary infarction. On admission, neurological examination revealed hoarseness, dysphasia, absent left gag reflex, palsies of the left vocal cord and left soft palate, and hypalgesia and thermohypesthesia on the right side of the trunk and extremities. In addition, he had a mild left central facial palsy. He had no nausea, vomiting, vertigo, hiccups, nystagmus, Horner's sign, facial numbness, or paresis or ataxia of the limbs. A T2 weighted MRI showed a small, high signal intensity area in the left dorsal region of the medulla and this lesion was presumed to involve the nucleus ambiguus and a part of the spinothalamic tract. These findings suggest that an aberrant supranuclear pathway, looping around the nucleus ambiguus to the facial nucleus exists in our patient.

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


    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.

  20. The rhythmic, transverse medullary slice preparation in respiratory neurobiology: contributions and caveats.

    Funk, Gregory D; Greer, John J


    Our understanding of the sites and mechanisms underlying rhythmic breathing as well as the neuromodulatory control of respiratory rhythm, pattern, and respiratory motoneuron excitability during perinatal development has advanced significantly over the last 20 years. A major catalyst was the development in 1991 of the rhythmically-active medullary slice preparation, which provided precise mechanical and chemical control over the network as well as enhanced physical and optical access to key brainstem regions. Insights obtained in vitro have informed multiple mechanistic hypotheses. In vivo tests of these hypotheses, performed under conditions of reduced control and precision but more obvious physiological relevance, have clearly established the significance for respiratory neurobiology of the rhythmic slice preparation. We review the contributions of this preparation to current understanding/concepts in respiratory control, and outline the limitations of this approach in the context of studying rhythm and pattern generation, homeostatic control mechanisms and murine models of human genetic disorders that feature prominent breathing disturbances.

  1. Vandetanib successfully controls medullary thyroid cancer-related Cushing syndrome in an adolescent patient.

    Nella, A A; Lodish, M B; Fox, E; Balis, F M; Quezado, M M; Whitcomb, P O; Derdak, J; Kebebew, E; Widemann, B C; Stratakis, C A


    Ectopic Cushing syndrome due to ACTH secretion from metastatic medullary thyroid cancer (MTC) is associated with significant morbidity and mortality. The aim of the study was to describe the first case of Cushing syndrome associated with MTC in a pediatric patient and the successful reversal of Cushing syndrome with tyrosine kinase inhibitor (vandetanib) therapy. A 17-year-old Brazilian adolescent presented with metastatic MTC and associated ACTH-dependent ectopic Cushing syndrome in the context of multiple endocrine neoplasia type 2B. When the patient was treated with the tyrosine kinase inhibitor vandetanib, rapid decrease in serum cortisol and improvement of clinical symptoms were observed. We describe the first pediatric case of clinical and biochemical improvement of paraneoplastic MTC-related Cushing syndrome after treatment with vandetanib. Vandetanib and possibly other tyrosine kinase inhibitors may be a novel beneficial option in patients with neuroendocrine tumor-related ectopic Cushing syndrome.

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

    D M Mahesh


    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.

  3. Juvenile nephropathy in a Boxer dog resembling the human nephronophthisis-medullary cystic kidney disease complex.

    Basile, Angelo; Onetti-Muda, Andrea; Giannakakis, Konstantinos; Faraggiana, Tullio; Aresu, Luca


    A juvenile nephropathy in a 4-year-old male Boxer dog, closely resembling the Nephronophthisis (NPHP)-Medullary Cystic Kidney Disease Complex (MCKD) in humans is described. Gross examination of the kidneys revealed several multiple cysts at the corticomedullary junction and in the medulla. Histological examination was characterized by a widespread tubular atrophy and dilatation, with a marked thickening of the tubular basement membrane, interstitial lymphocytic infiltration and fibrosis. Ultrastructural studies revealed dilated tubules with irregular basement membrane thickening and splitting. Lectin histochemistry investigation revealed that the cysts originated in the distal convoluted tubule and collecting duct. Having excluded all other known cystic diseases of the kidney, and based on the lectin histochemistry results, the macroscopic and histological findings of our case are highly compatible with a diagnosis of the NPHP-MCKD complex. To our knowledge, this is the first report describing this particular lesion.

  4. Population pharmacokinetic/pharmacodynamic modeling of tumor growth kinetics in medullary thyroid cancer patients receiving cabozantinib.

    Miles, Dale R; Wada, David R; Jumbe, Nelson L; Lacy, Steven A; Nguyen, Linh T


    Nonlinear mixed effects models were developed to describe the relationship between cabozantinib exposure and target lesion tumor size in a phase III study of patients with progressive metastatic medullary thyroid cancer. These models used cabozantinib exposure estimates from a previously published population pharmacokinetic model for cabozantinib in cancer patients that was updated with data from healthy-volunteer studies. Semi-mechanistic models predict well for tumors with static, increasing, or decreasing growth over time, but they were not considered adequate for predicting tumor sizes in medullary thyroid cancer patients, among whom an early reduction in tumor size was followed by a late stabilization phase in those receiving cabozantinib. A semi-empirical tumor model adequately predicted tumor profiles that were assumed to have a net growth rate constant that was piecewise continuous in the regions of 0-110 and 110-280 days. Emax models relating average concentration to average change in tumor size predicted that an average concentration of 79 and 58 ng/ml, respectively, would yield 50% of the maximum possible tumor reduction during the first 110 days of dosing and during the subsequent 110-280 days of dosing. Simulations of tumor responses showed that daily doses of 60 mg or greater are expected to provide a similar tumor reduction. Both model evaluation of observed data and simulation results suggested that the two protocol-defined cabozantinib dose reductions from 140 to 100 mg/day and from 100 to 60 mg/day are not projected to result in a marked reduction in target lesion regrowth.

  5. RET gene mutations and polymorphisms in medullary thyroid carcinomas in Indian patients

    B P Sharma; D Saranath


    Germline mutations of RET gene are pathognomonic of multiple endocrine neoplasia (MEN; MEN 2A/MEN 2B) and familial medullary thyroid carcinoma (FMTC), constituting 25% of medullary thyroid carcinomas (MTCs). We investigated RET gene mutations and polymorphisms at exons 10, 11, 13, 14, 15 and 16 in 140 samples, comprising 51 clinically diagnosed MTC patients, 39 family members of patients and 50 normal individuals. The method of choice was PCR and direct nucleotide sequencing of the PCR products. RET gene mutations were detected in 15 (29.4%) patients, with MEN 2A/FMTC in 13 patients and MEN 2B in 2 patients. Further, 39 family members of seven index cases were analysed, wherein four of the seven index cases showed identical mutations, in 13 of 25 family members. We also examined single nucleotide polymorphisms (SNPs) in RET gene exons in 101 unrelated samples. Significant differences in the allelic frequencies of SNPs at codons 691, 769, 836 and 904 between patient and control groups were not observed. However, SNP frequencies were significantly different in the Indian group as compared with other European groups. We identified two novel, rare and unique SNPs separately in single patients. Our study demonstrated presence of MEN 2A/MEN 2B/FMTC-associated mutations in accordance with the reported literature. Thus, RET gene mutations in exons 10, 11, 13, 14, 15 and 16 constitute a rapid test to confirm diagnosis and assess risk of the disease in familial MEN 2A/MEN 2B/FMTC.

  6. Determinations of renal cortical and medullary oxygenation using BOLD Magnetic Resonance Imaging and selective diuretics

    Warner, Lizette; Glockner, James F.; Woollard, John; Textor, Stephen C.; Romero, Juan C.; Lerman, Lilach O.


    Objective This study was undertaken to test the hypothesis that blood O2 level dependent magnetic resonance imaging (BOLD MRI) can detect changes in cortical proximal tubule (PT) and medullary thick ascending limb of Henle (TAL) oxygenation consequent to successive administration of furosemide and acetazolamide (Az). Assessment of PT and TAL function could be useful to monitor renal disease states in vivo. Therefore, the adjunct use of diuretics that inhibit Na+ reabsorption selectively in PT and TAL, Az and furosemide, respectively, may help discern tubular function by using BOLD MRI to detect changes in tissue oxygenation. Material and Methods BOLD MRI signal R2* (inversely related to oxygenation) and tissue oxygenation with intrarenal O2 probes were measured in pigs that received either furosemide (0.5mg/kg) or Az (15mg/kg) alone, Az sequentially after furosemide (n=6 each, 15-minute intervals), or only saline vehicle (n=3). Results R2* decreased in the cortex of Az-treated and medulla of furosemide-treated kidneys, corresponding to an increase in their tissue O2 assessed with probes. However, BOLD MRI also showed decreased cortical R2* following furosemide that was additive to the Az-induced decrease. Az administration, both alone and after furosemide, also decreased renal blood flow (−26±3.5 and −29.2±3%, respectively, p<0.01). Conclusion These results suggest that an increase in medullary and cortical tissue O2 elicited by selective diuretics is detectable by BOLD MRI, but may be complicated by hemodynamic effects of the drugs. Therefore, the BOLD MRI signal may reflect functional changes additional to oxygenation, and needs to be interpreted cautiously. PMID:20856128

  7. Fine needle aspiration cytology stained with Rius method in quicker diagnosis of medullary thyroid carcinoma.

    Hsieh, Min-Huang; Hsiao, Yung-Lien; Chang, Tien-Chun


    The cytologic features of medullary thyroid carcinoma (MTC) have been described and documented in the literature. Most of the studies were related to the Papanicolaou stain or the May-Grnwald-Giemsa stain. The aim of the present study was to analyze detailed cytologic characteristics of MTC diagnosed by fine-needle aspiration cytology (FNAC) stained with a quick method, Rius stain. We collected the FNAC slides of 38 cases with MTC that were proven by surgical pathology. The cytologic findings were reviewed under a light microscope. The median age at diagnosis was 46.5 years, ranging from 13 to 83 years; 20 were women and 18 were men. Among them, seven cases were familial forms and the others were sporadic. The majority of these cases showed moderate to abundant cellularity. Small round cells, spindle-shaped cells and large oval to polygonal cells formed the usual components. Twenty-seven cases were categorized as pleomorphic cell type and 11 cases as monomorphic type. Except in one case, cohesive and clustered small round cells predominated in all cases, alone or coupled with cohesive spindle cells and/or scattered large oval to polygonal cells. The diagnosis of mixed medullary-follicular thyroid carcinoma was made in the case composed solely of grouped polygonal cells. Cytoplasmic granularities were noted in 14 cases and vacuolations were seen in eight. Binucleated and multinucleated cells were not uncommon, while intranuclear cytoplasmic inclusions were less frequent. The diagnostic sensitivity for MTC by FNAC was 89%. The distinctive cytopathologic characteristics of MTC by Rius stain allowed us to make the diagnosis in aspiration biopsies accurately and quickly.

  8. The diagnostic role of gadolinium enhanced MRI in distinguishing between acute medullary bone infarct and osteomyelitis.

    Umans, H; Haramati, N; Flusser, G


    The objective of the study was to evaluate the diagnostic utility of contrast enhanced magnetic resonance imaging (MRI) for distinguishing between acute medullary bone infarct and osteomyelitis. There were 11 patients (age 6-34 years) presented to our institution between December 1994 and February 1998 with a clinical differential diagnosis of acute bone infarct versus osteomyelitis and inconclusive radiographs were imaged using MRI. All but one received i.v. gadolinium. Nine of the patients had homozygous Sickle Cell disease (SCD) and two had Systemic Lupus Erythematosus (SLE), the latter requiring chronic methylprednisolone. Osteomyelitis was confirmed either by biopsy alone or by the combination of Gallium(67) scan in conjunction with positive blood cultures and clinical resolution following antibiotics. Infarcts without osteomyelitis were confirmed either by biopsy or resolution of symptoms without antibiotic therapy. All patients had at least six months clinical follow-up. The results found that seven of nine patients with SCD had acute infarct only. One patient with SCD had osteomyelitis only. Three patients (two SLE and one SCD) had both acute-on-chronic infarcts and superimposed osteomyelitis, one with an adjacent soft tissue abscess. Accurate distinction between infarct and osteomyelitis was impossible for one patient with SLE who did not receive contrast. All other cases were correctly diagnosed prospectively based on distinct patterns of MRI contrast enhancement. In all adult patients, acute infarcts demonstrated thin, linear rim enhancement on MRI while osteomyelitis revealed more geographic and irregular marrow enhancement. Two of four cases of osteomyelitis also demonstrated subtle cortical defects with abnormal signal traversing marrow and soft tissue. The single pediatric patient demonstrated elongated, serpiginous central medullary enhancement with periostitis. We concluded that the pattern of MR contrast enhancement may allow accurate distinction

  9. The Fos expression in rat brain following electrical stimulation of dura mater surrounding the superior sagittal sinus changed with the pre-treatment of rizatriptan benzoate.

    Wang, Xiaolin; Yu, Shengyuan; Dong, Zhao; Jiang, Lei


    Fos expression in the brain was systematically investigated by means of immunohistochemical staining after electrical stimulation of the dura mater surrounding the superior sagittal sinus in conscious rats. Fos-like immunoreactive neurons are distributed mainly in the upper cervical spinal cord, spinal trigeminal nucleus caudal part, raphe magnus nucleus, periaqueductal gray, ventromedial hypothalamic nucleus, and mediodorsal thalamus nucleus. With the pre-treatment of intraperitoneal injection of rizatriptan benzoate, the number of Fos-like immunoreactive neurons decreased in the spinal trigeminal nucleus caudal part and raphe magnus nucleus, increased in the periaqueductal gray, and remained unchanged in the ventromedial hypothalamic nucleus and mediodorsal thalamus nucleus. These results provide morphological evidence that the nuclei described above are involved in the development and maintenance of the trigeminovascular headache.

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

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


    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.

  11. Peripheral type facial palsy in a patient with dorsolateral medullary infarction with infranuclear involvement of the caudal pons.

    Park, Jong-Ho; Yoo, Han-Uk; Shin, Hyung-Woo


    The corticobulbar tract fibers descend near the corticospinal tract, mostly to the upper medulla, where they decussate and ascend in the dorsolateral medulla to connect with the contralateral facial nucleus. Therefore, central type facial palsy can be present in patients with ipsilateral dorsolateral upper medullar lesion. We describe a 71-year-old man with lateral medullary infarction who showed ipsilateral peripheral type facial palsy. Brain diffusion-weighted image showed hyperintensities on the left dorsolateral portion of upper medulla and adjacent inferomedial tegmentum of the lower pons. Transfemoral cerebral angiography depicted prominence of ipsilateral posterior inferior cerebellar artery with focal stenosis. Left posterior inferior cerebellar artery might supply the inferolateral tegmentum of the lower pons, which is usually supplied from anterior inferior cerebellar artery. The peripheral type facial palsy in our patient may have resulted from facial infranuclear involvement of the caudal pons extended from dorsolateral upper medullary lesion in ascending pathway of corticobulbar tract fibers.

  12. Synchronous sporadic medullary carcinoma of the thyroid and small-cell carcinoma of lung: A rare entity

    Manigreeva Krishnatreya


    Full Text Available Synchronous medullary carcinoma of the thyroid and small-cell carcinoma of the lung is a rare phenomenon and both these tumors are characterized by poor treatment outcome and prognosis. A 45-year-old woman presented with a progressive swelling in front and side of the neck of 3-month duration without any pulmonary symptoms. The tumor of the lung was an incidental finding on routine chest radiological examination. The diagnosis of synchronous primary cancers of the thyroid and the lung were made after cytopathological examination of both the lesions. We report here a case of loco-regional sporadic medullary carcinoma of the thyroid associated with limited stage small-cell carcinoma of the lung and its therapeutic challenges.

  13. Detection of medullary carcinoma of thyroid, with liver metastasis, using 99mTc DMSA(V scintigraphy.

    Shikare S


    Full Text Available A sixty year old female referred for thyroid and liver scintigraphy had a clinical history of progressive swelling in the neck with hepatomegaly. A large cold area was detected in the right thyroid lobe using 99mTc pertechnetate and in the right lobe of liver using 99mTc phytate. Subsequent whole body scan with 99mTC DMSA(V showed avid tracer uptake in right lobe of thyroid and liver. Aspiration cytology of thyroid and liver showed medullary carcinoma of thyroid with its metastasis in liver. Histopathology following thyroidectomy confirmed the diagnosis. Thus 99mTc pentavalent DMSA contributes specificity to diagnose medullary carcinoma of thyroid and metastatic lesions.

  14. Aneurysm of the posterior meningeal artery embedded within a dorsal exophytic medullary hemangioblastoma: surgical management and review of literature.

    Raygor, Kunal P; Rowland, Nathan C; Cooke, Daniel L; Solomon, David A; Huang, Michael C


    Hemangioblastomas are World Health Organization (WHO) Grade I neoplasms of the hindbrain and spinal cord, whose management can be complicated by preoperative hemorrhage. We report on a case of a young female in extremis with posterior fossa hemorrhage following rupture of a fusiform posterior meningeal artery aneurysm embedded within a medullary hemangioblastoma. We discuss management options, including operative staging and embolization, and review similar cases of hemangioblastoma associated with aneurysm.

  15. Selective Mitochondrial Uptake of MKT-077 Can Suppress Medullary Thyroid Carcinoma Cell Survival In Vitro and In Vivo

    Starenki, Dmytro; Park, Jong-In


    Background Medullary 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 xenogr...

  16. Adenosine A{sub 1} receptors in contrast media-induced renal dysfunction in the normal rat

    Liss, Per; Palm, Fredrik [Department of Diagnostic Radiology, University Hospital, 75185, Uppsala (Sweden); Department of Medical Cell Biology, University Hospital, 75185, Uppsala (Sweden); Carlsson, Per-Ola [Department of Medical Cell Biology, University Hospital, 75185, Uppsala (Sweden); Department of Medical Sciences, University Hospital, 75185, Uppsala (Sweden); Hansell, Peter [Department of Medical Cell Biology, University Hospital, 75185, Uppsala (Sweden)


    Renal vasoconstriction with resultant tissue hypoxia, especially in the renal medulla, has been suggested to play a role in contrast media (CM)-induced nephropathy. In this study we investigated the effects of injection of the non-ionic low-osmolar CM iopromide with and without pretreatment with the selective adenosine A{sub 1}-receptor antagonist DPCPX. The effects were evaluated on regional renal blood flow, outer medullary oxygen tension (PO{sub 2}) and urine output in normal anaesthetised rats. A laser-Doppler technique was used for recording haemodynamic changes while oxygen microelectrodes were used for oxygen measurements. The A{sub 1}-receptor antagonist per se elevated glomerular filtration rate (+44%), cortical blood flow (+15%) and urine output (threefold) while reducing outer medullary PO{sub 2} (-24%). Administration of CM reduced outer medullary blood flow (OMBF; -26%) and PO{sub 2} (-80%) but did not affect cortical blood flow. Urine output increased 28-fold by CM while arterial blood pressure was reduced. The CM-mediated effect on haemodynamics, PO{sub 2}, urine output and blood pressure was unaffected by the A{sub 1}-receptor antagonist. Adenosine A{sub 1}-receptors are not important mediators of the depression of outer medullary blood flow and PO{sub 2} caused by the CM iopromide in the normal rat; however, A{sub 1}-receptors are tonically active to regulate renal haemodynamics, PO{sub 2} and urine production during normal physiological conditions. (orig.)

  17. Activation of medullary dorsal horn γ isoform of protein kinase C interneurons is essential to the development of both static and dynamic facial mechanical allodynia.

    Pham-Dang, Nathalie; Descheemaeker, Amélie; Dallel, Radhouane; Artola, Alain


    The γ isoform of protein kinase C (PKCγ), which is concentrated in a specific class of interneurons within inner lamina II (IIi ) of the spinal dorsal horn and medullary dorsal horn (MDH), is known to be involved in the development of mechanical allodynia, a widespread and intractable symptom of inflammatory or neuropathic pain. However, although genetic and pharmacological impairment of PKCγ were shown to prevent mechanical allodynia in animal models of pain, after nerve injury or reduced inhibition, the functional consequences of PKCγ activation alone on mechanical sensitivity are still unknown. Using behavioural and anatomical approaches in the rat MDH, we tested whether PKCγ activation in naive animals is sufficient for the establishment of mechanical allodynia. Intracisternal injection of the phorbol ester, 12,13-dibutyrate concomitantly induced static as well as dynamic facial mechanical allodynia. Monitoring neuronal activity within the MDH with phospho-extracellular signal-regulated kinases 1 and 2 immunoreactivity revealed that activation of both lamina I-outer lamina II and IIi -outer lamina III neurons, including lamina IIi PKCγ-expressing interneurons, was associated with the manifestation of mechanical allodynia. Phorbol ester, 12,13-dibutyrate-induced mechanical allodynia and associated neuronal activations were all prevented by inhibiting selectively segmental PKCγ with KIG31-1. Our findings suggest that PKCγ activation, without any other experimental manipulation, is sufficient for the development of static and dynamic mechanical allodynia. Lamina IIi PKCγ interneurons have been shown to be directly activated by low-threshold mechanical inputs carried by myelinated afferents. Thus, the level of PKCγ activation within PKCγ interneurons might gate the transmission of innocuous mechanical inputs to lamina I, nociceptive output neurons, thus turning touch into pain.

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

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


    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.

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

    Meghan Murphy


    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.

  20. Management of medullary thyroid carcinoma and MEN2 syndromes in childhood.

    Waguespack, Steven G; Rich, Thereasa A; Perrier, Nancy D; Jimenez, Camilo; Cote, Gilbert J


    Medullary thyroid carcinoma (MTC) and the multiple endocrine neoplasia (MEN) type 2 syndromes are rare but important endocrine diseases that are increasingly managed by pediatric providers. MTC is generally associated with a favorable prognosis when diagnosed during childhood, where it frequently occurs secondary to activating mutations in the RET proto-oncogene and arises from pre-existing C-cell hyperplasia. MEN2A accounts for 90-95% of childhood MTC cases and is most commonly due to mutations in codon 634 of RET. MEN2B is associated with the most aggressive clinical presentation of MTC and is almost always due to the Met918Thr mutation of RET. Surgery is the primary treatment and only chance of cure, although the advent of targeted therapies seems to be improving progression-free survival in advanced cases. Since the discovery of the role of RET in MEN2A, considerable advances in the management of this syndrome have occurred, and most of the children with MEN2A who have undergone early thyroidectomy will now lead full, productive lives. Strong genotype-phenotype correlations have facilitated the development of guidelines for interventions. Contemporary approaches for deciding the appropriate age at which surgery should take place incorporate data from ultrasonography and calcitonin measurements in addition to the results of genotyping. To optimize care and to facilitate ongoing research, children with MTC and the MEN2 syndromes are optimally treated at tertiary centers with multidisciplinary expertise.

  1. Silent neurenteric cyst with split cord malformation at conus medullaris: Case report and literature review

    Hanuma Srinivas


    Full Text Available Split cord malformations (SCM are a common pediatric abnormality where children present with features of tethering and backache along with varying neurological deficits. Multiple neural tube defects may co-exist in children having defects of primary and/or secondary neurulation. Co-existent neurenteric cysts along with type 1 SCM have been described very rarely in the literature. We report a case of silent neurenteric cyst at conus medullaris with SCM type 1 where the cyst was missed in the preoperative imaging. Until date, only 8 such cases of neurenteric cysts with SCM at lumbar region have been reported. We review the literature regarding co-existing dual pathologies of neurenteric cysts and type 1 SCMs in light of limited capacity of imaging modalities to detect small neurenteric cysts in presence of co-existent neural tube defects. Multiple spinal neural tube defects in children need more attention and precise microneurosurgical skills as management differs in each of them. Co-existence of such pathologies detected intra-operatively may need modifications in preoperative planning to achieve the best possible outcomes.

  2. Molecular Basis of Medullary Thyroid Carcinoma: The Role of RET Polymorphisms

    Ana Luiza Maia


    Full Text Available Medullary thyroid carcinoma is a rare malignant tumor originating in parafollicular C cells. It accounts for 5 to 8% of all thyroid cancers. MTC develops in either sporadic (75% or hereditary form (25%. Genetic and molecular studies have demonstrated the involvement of the RET proto-oncogene in hereditary MTC and, less often, in its sporadic form. Although a strong genotype-phenotype correlation has been described, wide clinical heterogeneity is observed among families with the same RET mutation or even in carriers of the same kindred. In recent years, several single nucleotide polymorphisms of the RET gene have been described in the general population as well as in patients with MTC. Some studies have reported associations between the presence of polymorphisms and development or progression of MTC. Nonetheless, other studies failed to demonstrate any effect of the RET variants. Differences in the genetic background of distinct populations or methodological approaches have been suggested as potential reasons for the conflicting results. Here, we review current knowledge concerning the molecular pathogenesis of sporadic and hereditary MTC. In particular, we analyze the role of RET polymorphisms in the clinical presentation and prognosis of MTC based on the current literature.

  3. Inhomogeneous response of expiratory muscle activity to cold block of the ventral medullary surface.

    Chonan, T; Okabe, S; Hida, W; Izumiyama, T; Kikuchi, Y; Takishima, T


    We assessed the effects of cooling the ventral medullary surface (VMS) on the activity of chest wall and abdominal expiratory muscles in eight anesthetized artificially ventilated dogs after vagotomy and denervation of the carotid sinus nerves. Electromyograms (EMGs) of the triangularis sterni, internal intercostal, abdominal external oblique, abdominal internal oblique, and transversus abdominis muscles were measured with EMG of the diaphragm as an index of inspiratory activity. Bilateral localized cooling (2 x 2 mm) in the thermosensitive intermediate part of the VMS produced temperature-dependent reduction in the EMG of diaphragm and abdominal muscles. The rib cage expiratory EMGs were little affected at 25 degrees C; their amplitudes decreased at lower VMS temperatures (less than 20 degrees C) but by significantly fewer degrees than the diaphragmatic and abdominal expiratory EMGs at a constant VMS temperature. With moderate to severe cooling (less than 20 degrees C) diaphragmatic EMG disappeared, but rib cage expiratory EMGs became tonic and resumed a phasic pattern shortly before the recovery of diaphragmatic EMG during rewarming of the VMS. These results indicate that the effects of cooling the VMS differ between the activity of rib cage and abdominal expiratory muscles. This variability may be due to inhomogeneous inputs from the VMS to expiratory motoneurons or to a different responsiveness of various expiratory motoneurons to the same input either from the VMS or the inspiratory neurons.

  4. False positive results using calcitonin as a screening method for medullary thyroid carcinoma

    Rafael Loch Batista


    Full Text Available The role of serum calcitonin as part of the evaluation of thyroid nodules has been widely discussed in literature. However there still is no consensus of measurement of calcitonin in the initial evaluation of a patient with thyroid nodule. Problems concerning cost-benefit, lab methods, false positive and low prevalence of medullary thyroid carcinoma (MTC are factors that limit this approach. We have illustrated two cases where serum calcitonin was used in the evaluation of thyroid nodule and rates proved to be high. A stimulation test was performed, using calcium as secretagogue, and calcitonin hyper-stimulation was confirmed, but anatomopathologic examination did not evidence medullar neoplasia. Anatomopathologic diagnosis detected Hashimoto thyroiditis in one case and adenomatous goiter plus an occult papillary thyroid carcinoma in the other one. Recommendation for routine use of serum calcitonin in the initial diagnostic evaluation of a thyroid nodule, followed by a confirming stimulation test if basal serum calcitonin is showed to be high, is the most currently recommended approach, but questions concerning cost-benefit and possibility of diagnosis error make the validity of this recommendation discussible.

  5. Cytologic aspects of an interesting case of medullary thyroid carcinoma coexisting with Hashimoto′s thyroiditis

    Bidish K Patel


    Full Text Available Among primary thyroid neoplasms, papillary thyroid carcinoma (PTC and primary thyroid lymphoma (PTL are known to coexist and are pathogenetically linked with Hashimoto′s thyroiditis (HT. However, HT occurring in association with medullary thyroid carcinoma (MTC is rarely documented. We report here an interesting case. A 34-year-old female with a solitary thyroid nodule underwent fine needle aspiration cytology (FNAC that was interpreted as "MTC with admixed reactive lymphoid cells, derived possibly from a pretracheal lymph node." Total thyroidectomy specimen showed "MTC with coexisting HT." At a later stage, a follow-up FNAC from the recurrent thyroid swelling showed features consistent with HT. As an academic exercise, the initial smears on which a diagnosis of MTC was offered were reviewed to look for evidence of coexisting HT that showed scanty and patchy aggregates of reactive lymphoid cells without Hόrthle cells. Our case highlights an unusual instance of MTC in concurrence with HT that can create a tricky situation for cytopathologists.

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

    Rahul Mannan


    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.

  7. Radioiodinated meta-iodobenzylguanidine uptake in medullary thyroid cancer. A French cooperative study

    Baulieu, J.L.; Guilloteau, D.; Delisle, M.J.; Perdrisot, R.; Gardet, P.; Delepine, N.; Baulieu, F.; Dupont, J.L.; Talbot, J.N.; Coutris, G.


    Fifty meta-iodobenzylguanidine (MIBG) scintiscans were performed in three groups of medullary thyroid cancer (MTC) patients. Group 1 (n = 11) included treated patients with normal calcitonin levels; Group 2 (n = 24) included patients with elevated calcitonin levels due to sporadic and isolated MTC; Group 3 (n = 15) included patients with elevated calcitonin levels due to familial MTC or multiple endocrine neoplasia Type IIA syndrome (MEN). In Group 1 three pheochromocytoma were depicted by MIBG scintiscan. In Group 2 MTC was seen in a small number of patients (3 of 24). In Group 3, besides adrenal hyperplasia and pheochromocytoma four patients, MIBG scintigraphy showed where MTC had localized and spread in almost half of patients (7 of 15). MIBG uptake occurred in patients with relatively high calcitonin level (greater than 0.6 nmol/l). These data indicate that in patients with familial MTC or MEN syndrome, MIBG scintiscan can be useful not only in detecting associated pheochromocytoma, but also in showing MTC.

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

    Serena Giunti


    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.

  9. Overview and Management of Dermatologic Events Associated with Targeted Therapies for Medullary Thyroid Cancer

    Ciccolini, Kathryn; Kloos, Richard T.; Agulnik, Mark


    Background: Treatment options for patients with advanced or metastatic medullary thyroid cancer (MTC) have, in recent years, expanded with the approval of two tyrosine kinase inhibitors (TKIs): vandetanib and cabozantinib. Other agents, including TKIs, are under clinical investigation for MTC. Although patients treated with TKIs are at risk of developing dermatologic adverse events (AE), these untoward events may be mitigated through AE-driven algorithms. Summary: AE-driven algorithms combine effective nonpharmaceutical and pharmaceutical treatment modalities implemented by a multidisciplinary effort that incorporates nursing interventions, patient education, and referrals to pain-management specialists, podiatrists, and dermatologists, as appropriate. Effective AE prevention and management reduce the need for dose interruptions and modifications, allowing patients the opportunity to derive the maximal benefit from TKI therapy, while maintaining quality of life. Conclusions: Optimal use of targeted therapies in the treatment of MTC depends on careful patient selection, interdisciplinary communication, and patient education and encouragement to enhance compliance and safety, optimize consistent dosing, and maximize the use of effective therapies. PMID:24902006

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

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


    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

  11. Familial clustering of medullary sponge kidney is autosomal dominant with reduced penetrance and variable expressivity.

    Fabris, Antonia; Lupo, Antonio; Ferraro, Pietro M; Anglani, Franca; Pei, York; Danza, Francesco M; Gambaro, Giovanni


    Medullary sponge kidney (MSK) is a renal malformation typically associated with nephrocalcinosis and recurrent calcium nephrolithiasis. Approximately 12% of recurrent stone formers have MSK, which is generally considered a sporadic disorder. Since its discovery, three pedigrees have been described in which an apparently autosomal dominant inheritance was suggested. Here, family members of 50 patients with MSK were systematically investigated by means of interviews, renal imaging, and biochemical studies in an effort to establish whether MSK is an inheritable disorder. Twenty-seven MSK probands had 59 first- and second-degree relatives of both genders with MSK in all generations. There were progressively lower mean levels of serum calcium, urinary sodium, pH, and volume, combined with higher serum phosphate and potassium from probands to relatives with bilateral, to those with unilateral, and to those unaffected by MSK. This suggests that most affected relatives have a milder form of MSK than the probands, which would explain why they had not been so diagnosed. Thus, our study provides strong evidence that familial clustering of MSK is common, and has an autosomal dominant inheritance, a reduced penetrance, and variable expressivity.

  12. Ondine's curse with accompanying trigeminal and glossopharyngeal neuralgia secondary to medullary telangiectasia.

    Kapnadak, Siddhartha G; Mikolaenko, Ivan; Enfield, Kyle; Gress, Daryl R; Nathan, Barnett R


    Central hypoventilation syndrome ("Ondine's Curse") is an infrequent disorder that can lead to serious acute or chronic health consequences. This syndrome, especially in adults, is rare, and even less frequent in the absence of clear pathogenic lesions on MRI. In addition, we are not aware of any previously reported cases with associated cranial nerve neuralgias. We describe a patient with baseline trigeminal and glossopharyngeal neuralgia, admitted with episodes of severe hypoventilatory failure of central origin, consistent with "Ondine's Curse". After evaluation, she was found to have a medullary capillary telangiectasia, thought to be the causative lesion, and which could explain her complete neurologic and hypoventilatory syndrome. The patient was treated with placement of a diaphragmatic pacing system, which has been effective thus far. This case illustrates the need for investigation of centrally mediated apnea, especially when co-occurring cranial nerve neuralgia is present and cardiopulmonary evaluation is negative. It provides an example of capillary telangiectasia as the causative lesion, one that to our knowledge has not been reported before. Placement of a diaphragmatic pacing system was warranted and became lifesaving as the patient was deemed to be severely incapacitated by chronic ventilatory insufficiency.

  13. Neural plasticity occurs in the adrenal medulla of asthmatic rats

    FENG Jun-tao; LI Xiao-zhao; HU Cheng-ping; WANG Jun; NIE Hua-ping


    Background Airway symptoms in asthma are related to decrease of epinephrine secretion, which may be ascribed to elevated nerve growth factor (NGF) in the organism.The aim of this study was to monitor the neuroendocrine alteration in the adrenal medulla of asthmatic rats.Methods Sixteen rats were randomly divided into two groups (n=8), control group and asthma group, and the asthmatic rats were sensitized and challenged with ovalbumin (OVA).The levels of NGF, epinephrine and norepinephrine in serum were detected by enzyme linked immunosorbent assay (ELISA), the NGF expression in adrenal medulla was detected by immunohistochemistry, and the changes in the ultrastructure of the adrenal medulla was observed by electron microscopy.Results The NGF expression was increased in asthmatic rats compared with control rats.Compared with control rats,the results indicated that the epinephrine level was decreased in asthmatic rats, but no significant difference was found in norepinephrine levels.We found more ganglion cells in the adrenal medulla of asthmatic rats than in control rats, with NGF immunostaining mainly located in these ganglion cells.Electron microscopic images showed the density of chromaffin granula decreased and there was shrunken nucleolemma in the adrenal medullary cells of asthmatic rats.Conclusion The innervation of the adrenal medulla is changed in asthmatic rats, and it may contribute to the epinephrine decrease in asthma.

  14. Lymphotoxin signals from positively selected thymocytes regulate the terminal differentiation of medullary thymic epithelial cells.

    White, Andrea J; Nakamura, Kyoko; Jenkinson, William E; Saini, Manoj; Sinclair, Charles; Seddon, Benedict; Narendran, Parth; Pfeffer, Klaus; Nitta, Takeshi; Takahama, Yousuke; Caamano, Jorge H; Lane, Peter J L; Jenkinson, Eric J; Anderson, Graham


    The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) provide a spectrum of tissue-restricted Ags that, through both direct presentation and cross-presentation by dendritic cells, purge the developing T cell repertoire of autoimmune specificities. Despite this role, the mechanisms of Aire(+) mTEC development remain unclear, particularly those stages that occur post-Aire expression and represent mTEC terminal differentiation. In this study, in mouse thymus, we analyze late-stage mTEC development in relation to the timing and requirements for Aire and involucrin expression, the latter a marker of terminally differentiated epithelium including Hassall's corpuscles. We show that Aire expression and terminal differentiation within the mTEC lineage are temporally separable events that are controlled by distinct mechanisms. We find that whereas mature thymocytes are not essential for Aire(+) mTEC development, use of an inducible ZAP70 transgenic mouse line--in which positive selection can be temporally controlled--demonstrates that the emergence of involucrin(+) mTECs critically depends upon the presence of mature single positive thymocytes. Finally, although initial formation of Aire(+) mTECs depends upon RANK signaling, continued mTEC development to the involucrin(+) stage maps to activation of the LTα-LTβR axis by mature thymocytes. Collectively, our results reveal further complexity in the mechanisms regulating thymus medulla development and highlight the role of distinct TNFRs in initial and terminal differentiation stages in mTECs.

  15. Effect of an Outreach Programme on Vandetanib Safety in Medullary Thyroid Cancer

    Bastholt, Lars; Kreissl, Michael C.; Führer, Dagmar; Maia, Ana L.; Locati, Laura D.; Maciel, Léa; Wu, Yi; Heller, Kevin N.; Webster, Alan; Elisei, Rossella


    Objectives Effective management of adverse events (AEs) following vandetanib treatment is important to maximize clinical benefits. We examined whether more frequent contact with vandetanib-treated patients reduced AEs of CTCAE grade 2 or higher. Study Design In this open-label, multicentre, phase III study, patients with locally advanced or metastatic medullary thyroid cancer were randomized to a patient outreach programme (outreach) or a standard AE monitoring schedule (vandetanib control) for 52 weeks. In addition to standard AE monitoring, patients in the outreach arm were contacted every 2 weeks by telephone/during their clinic visit for specific AE questioning related to diarrhoea, nausea, vomiting, fatigue, headache and rash. Patients received vandetanib at 200 or 300 mg/day, depending on the creatinine levels at screening. Results Altogether, 205 patients were randomized (outreach, n = 103; vandetanib control, n = 102). This study did not meet its primary objective; the mean percentage of time patients experienced at least one AE of grade 2 or higher was higher for the outreach group (51.65%) than for the vandetanib control group (45.19%); the difference was not statistically significant (t statistic: 1.29; 95% CI −3.44 to 16.37%; p = 0.199). The most frequently reported AEs were diarrhoea (56.9% for the outreach group vs. 46.6% for the vandetanib controls), hypertension (36.3 vs. 31.1%), rash (25.5 vs. 24.3%) and nausea (25.5% vs. 18.4%), and the most frequently reported AEs of grade 2 or higher were hypertension (33.3 vs. 23.3%), diarrhoea (26.5 vs. 24.3%) and dermatitis acneiform (11.8 vs. 9.7%). Conclusions Additional outreach to patients treated with vandetanib had no impact on the rate or severity of AEs compared to the standard AE monitoring schedule. AEs were consistent with the known safety profile of vandetanib. PMID:27843809

  16. Medullary Carcinoma of the Penis: A Distinctive HPV-related Neoplasm: A Report of 12 Cases.

    Cañete-Portillo, Sofía; Clavero, Omar; Sanchez, Diego F; Silvero, Arturo; Abed, Francisco; Rodriguez, Ingrid M; Ayala, Gustavo; Alemany, Laia; Munoz, Nubia; de Sanjose, Silvia; Quint, Wim; Bosch, Francesc X; Cubilla, Antonio L


    A third to half of penile invasive squamous cell carcinomas are human papillomavirus (HPV) related. Warty (condylomatous), warty-basaloid, and basaloid carcinomas are the most common subtypes associated with HPV. Less frequent are clear cell and lymphoepithelioma-like carcinomas. Here we report a novel penile tumor associated with HPV. Twelve cases were selected from 1010 penile carcinomas, part of an international HPV detection study conducted at the Institut Català d'Oncologia, Barcelona, Spain. Immunostaining with p16 was performed on all cases, and HPV-mRNA detection was also performed. En bloc full tumor staining was the utilized criteria for positivity of p16. For HPV-DNA detection, whole-tissue section polymerase chain reaction analysis was performed by SPF10-DEIA-LiPA25 (version 1). The patients' ages ranged from 42 to 92 years (average, 71 y). The tumor was most commonly located in the glans. A characteristic microscopic finding was the presence of a moderate to dense tumor-associated inflammatory cell infiltrate composed of neutrophils, lymphocytes, plasma cells, or eosinophils. Tumors grew in large solid sheets, nests, or had a trabecular pattern. Cells were large and poorly differentiated or anaplastic. Keratinization was minimal or absent. Nuclei were large with prominent nucleoli. Mitoses were numerous. Tumor necrosis was common. Deep invasion of the corpora cavernosa was frequent. p16 and HPV-DNA were positive in all cases, whereas mRNA detection was positive in 9 cases only. The prevalent genotype was HPV16 (9 cases, 75%). Other genotypes were HPVs 58, 33, and 66. Medullary carcinomas of the penis are morphologically distinctive HPV-related high-grade neoplasms affecting older individuals. More studies are necessary to delineate the epidemiological, clinical, and molecular features of this unusual penile neoplasm.

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

    Berna, L.; Catafau, A.; Mari, C.; Flotats, A.; Martin, J.C.; Estorch, M.; Carrio, I. [Department of Nuclear Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona (Spain); Chico, A.; Mato, E. [Department of Endocrinology, Hospital de la Santa Creu i Sant Pau, Barcelona (Spain); Matias-Guiu, X. [Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona (Spain); Alonso, C. [Department of Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona (Spain); Mora, J.; Rodriguez-Espinosa, J. [Department of Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona (Spain); Mauricio, D. [Department of Endocrinology, Hospital Parc Tauli, Sabadell (Spain)


    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. {sup 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 {sup 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 {sup 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 {sup 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.) With 4 figs., 3 tabs., 29 refs.

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

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


    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.

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

    Dmytro Starenki


    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.

  20. Selective optogenetic activation of rostral ventrolateral medullary catecholaminergic neurons produces cardiorespiratory stimulation in conscious mice.

    Abbott, Stephen B G; DePuy, Seth D; Nguyen, Thanh; Coates, Melissa B; Stornetta, Ruth L; Guyenet, Patrice G


    Activation of rostral ventrolateral medullary catecholaminergic (RVLM-CA) neurons e.g., by hypoxia is thought to increase sympathetic outflow thereby raising blood pressure (BP). Here we test whether these neurons also regulate breathing and cardiovascular variables other than BP. Selective expression of ChR2-mCherry by RVLM-CA neurons was achieved by injecting Cre-dependent vector AAV2-EF1α-DIO-ChR2-mCherry unilaterally into the brainstem of dopamine-β-hydroxylase(Cre/0) mice. Photostimulation of RVLM-CA neurons increased breathing in anesthetized and conscious mice. In conscious mice, photostimulation primarily increased breathing frequency and this effect was fully occluded by hypoxia (10% O(2)). In contrast, the effects of photostimulation were largely unaffected by hypercapnia (3 and 6% CO(2)). The associated cardiovascular effects were complex (slight bradycardia and hypotension) and, using selective autonomic blockers, could be explained by coactivation of the sympathetic and cardiovagal outflows. ChR2-positive RVLM-CA neurons expressed VGLUT2 and their projections were mapped. Their complex cardiorespiratory effects are presumably mediated by their extensive projections to supraspinal sites such as the ventrolateral medulla, the dorsal vagal complex, the dorsolateral pons, and selected hypothalamic nuclei (dorsomedial, lateral, and paraventricular nuclei). In sum, selective optogenetic activation of RVLM-CA neurons in conscious mice revealed two important novel functions of these neurons, namely breathing stimulation and cardiovagal outflow control, effects that are attenuated or absent under anesthesia and are presumably mediated by the numerous supraspinal projections of these neurons. The results also suggest that RVLM-CA neurons may underlie some of the acute respiratory response elicited by carotid body stimulation but contribute little to the central respiratory chemoreflex.

  1. Synergistic antitumour activity of RAF265 and ZSTK474 on human TT medullary thyroid cancer cells

    Bertazza, Loris; Barollo, Susi; Radu, Claudia Maria; Cavedon, Elisabetta; Simioni, Paolo; Faggian, Diego; Plebani, Mario; Pelizzo, Maria Rosa; Rubin, Beatrice; Boscaro, Marco; Pezzani, Raffaele; Mian, Caterina


    Medullary thyroid cancer (MTC) is an aggressive malignancy responsible for up to 14% of all thyroid cancer-related deaths. It is characterized by point mutations in the rearranged during transfection (RET) proto-oncogene. The activated RET kinase is known to signal via extracellular signal regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), leading to enhanced proliferation and resistance to apoptosis. In the present work, we have investigated the effect of two serine/threonine-protein kinase B-Raf (BRAF) inhibitors (RAF265 and SB590885), and a PI3K inhibitor (ZSTK474), on RET-mediated signalling and proliferation in a MTC cell line (TT cells) harbouring the RETC634W activating mutation. The effects of the inhibitors on VEGFR2, PI3K/Akt and mitogen-activated protein kinases signalling pathways, cell cycle, apoptosis and calcitonin production were also investigated. Only the RAF265+ ZSTK474 combination synergistically reduced the viability of treated cells. We observed a strong decrease in phosphorylated VEGFR2 for RAF265+ ZSTK474 and a signal reduction in activated Akt for ZSTK474. The activated ERK signal also decreased after RAF265 and RAF265+ ZSTK474 treatments. Alone and in combination with ZSTK474, RAF265 induced a sustained increase in necrosis. Only RAF265, alone and combined with ZSTK474, prompted a significant drop in calcitonin production. Combination therapy using RAF265 and ZSTK47 proved effective in MTC, demonstrating a cytotoxic effect. As the two inhibitors have been successfully tested individually in clinical trials on other human cancers, our preclinical data support the feasibility of their combined use in aggressive MTC. PMID:26081844

  2. Metformin inhibits growth and decreases resistance to anoikis in medullary thyroid cancer cells.

    Klubo-Gwiezdzinska, Joanna; Jensen, Kirk; Costello, John; Patel, Aneeta; Hoperia, Victoria; Bauer, Andrew; Burman, Kenneth D; Wartofsky, Leonard; Vasko, Vasyl


    Medullary thyroid cancer (MTC) is associated with activation of mammalian target of rapamycin (mTOR) signaling pathways. Recent studies showed that the antidiabetic agent metformin decreases proliferation of cancer cells through 5'-AMP-activated protein kinase (AMPK)-dependent inhibition of mTOR. In the current study, we assessed the effect of metformin on MTC cells. For this purpose, we determined growth, viability, migration, and resistance to anoikis assays using two MTC-derived cell lines (TT and MZ-CRC-1). Expressions of molecular targets of metformin were examined in MTC cell lines and in 14 human MTC tissue samples. We found that metformin inhibited growth and decreased expression of cyclin D1 in MTC cells. Treatment with metformin was associated with inhibition of mTOR/p70S6K/pS6 signaling and downregulation of pERK in both TT and MZ-CRC-1 cells. Metformin had no significant effects on pAKT in the cell lines examined. Metformin-inducible AMPK activation was noted only in TT cells. Treatment with AMPK inhibitor (compound C) or AMPK silencing did not prevent growth inhibitory effects of metformin in TT cells. Metformin had no effect on MTC cell migration but reduced the ability of cells to form multicellular spheroids in nonadherent conditions. Immunostaining of human MTC showed over-expression of cyclin D1 in all tumors compared with corresponding normal tissue. Activation of mTOR/p70S6K was detected in 8/14 (57.1%) examined tumors. Together, these findings indicate that growth inhibitory effects in MTC cells are associated with downregulation of both mTOR/6SK and pERK signaling pathways. Expression of metformin's molecular targets in human MTC cells suggests its potential utility for the treatment of MTC in patients.

  3. A rare case of concomitant sicca keratopathy and ipsilateral central facial palsy in Wallenberg’s dorsolateral medullary syndrome

    De Bruyn, Deborah; Van Aken, Elisabeth; Herman, Kristien


    Objective: To describe a patient with a right-sided supranuclear facial palsy and concomitant sicca keratopathy of the right eye following right-sided dorsolateral medullary infarction. Methods: Our patient underwent a complete ophthalmologic and neurologic examination including biomicroscopy, fundus examination, cranial nerve examination, Shirmer I test, and magnetic resonance imaging of the brain. Results: A 61-year-old woman presented in emergency with a central facial nerve palsy on the right side and truncal ataxia. Neurologic assessment revealed a concurrent dysphagia, dysarthria, hypoesthesia of the right face, and weakness of the right upper limb. Magnetic resonance imaging of the brain showed an old left-sided cerebellar infarction, but a recent ischemic infarction at the level of the right dorsolateral medulla oblongata was the cause of our patient’s current problems. One month after diagnosis of the right-sided dorsolateral medullary syndrome, there were complaints of ocular irritation and a diminished visual acuity in the right eye. Biomicroscopy showed a sicca keratopathy with nearly complete absence of tear secretion on the Shirmer I test, but with normal eye closure and preserved corneal reflexes and sensitivity. Conclusion: A dorsolateral medullary syndrome can have a variable expression in symptomatology. Our case is special because of the combination of an ipsilateral supranuclear facial palsy with normal upper facial muscle function together with an ipsilateral sicca keratopathy as a result of a nearly absent tear secretion. We hypothesized that the mechanism underlying the patient’s sicca keratopathy ipsilateral to the supranuclear facial palsy involved the superior salivatory nucleus, which is situated in the caudal pons inferiorly of the motor facial nucleus and is most probably affected by a superior extension of the infarcted area in the right medulla oblongata. PMID:28293537

  4. A rare case of concomitant sicca keratopathy and ipsilateral central facial palsy in Wallenberg’s dorsolateral medullary syndrome

    De Bruyn, Deborah


    Full Text Available Objective: To describe a patient with a right-sided supranuclear facial palsy and concomitant sicca keratopathy of the right eye following right-sided dorsolateral medullary infarction. Methods: Our patient underwent a complete ophthalmologic and neurologic examination including biomicroscopy, fundus examination, cranial nerve examination, Shirmer I test, and magnetic resonance imaging of the brain.Results: A 61-year-old woman presented in emergency with a central facial nerve palsy on the right side and truncal ataxia. Neurologic assessment revealed a concurrent dysphagia, dysarthria, hypoesthesia of the right face, and weakness of the right upper limb. Magnetic resonance imaging of the brain showed an old left-sided cerebellar infarction, but a recent ischemic infarction at the level of the right dorsolateral medulla oblongata was the cause of our patient’s current problems. One month after diagnosis of the right-sided dorsolateral medullary syndrome, there were complaints of ocular irritation and a diminished visual acuity in the right eye. Biomicroscopy showed a sicca keratopathy with nearly complete absence of tear secretion on the Shirmer I test, but with normal eye closure and preserved corneal reflexes and sensitivity.Conclusion: A dorsolateral medullary syndrome can have a variable expression in symptomatology. Our case is special because of the combination of an ipsilateral supranuclear facial palsy with normal upper facial muscle function together with an ipsilateral sicca keratopathy as a result of a nearly absent tear secretion. We hypothesized that the mechanism underlying the patient’s sicca keratopathy ipsilateral to the supranuclear facial palsy involved the superior salivatory nucleus, which is situated in the caudal pons inferiorly of the motor facial nucleus and is most probably affected by a superior extension of the infarcted area in the right medulla oblongata.

  5. Effects and mechanisms of auricular electroacupuncture on visceral pain induced by colorectal distension in conscious rats.

    Li, Han; Hu, Shasha; Zhang, Jianbin; Zhou, Jingzhu; Ran, Hongxing; Tang, Yichun; Chen, Jiande; Wang, Yinping


    To investigate the effects and mechanisms of action of auricular electroacupuncture (AEA) on visceral pain induced by colorectal distension (CRD). Twenty-nine female Sprague-Dawley rats were randomly divided into four groups: control; untreated CRD; CRD+AEA; and CRD+sham electroacupuncture (SEA). An electromyogram (EMG) was recorded for 120 min in the conscious state. After a 30 min baseline recording, CRD was performed in untreated CRD, AEA and SEA groups and lasted for 90 min. AEA and SEA were started at 30 min and lasted for 30 min. The EMG was recorded and analysed to evaluate the severity of visceral pain, indicated by the magnitude of the vasomotor response (VMR). mRNA expression of the 5-hydroxytryptamine 1a (5-HT1a) receptor was measured separately in the colon and raphe nuclei using real-time fluorescent quantitative PCR. No differences were seen in the baseline EMG among the four groups (p>0.05). During pre-stimulation, VMR magnitude in the CRD, AEA and SEA groups increased compared with that in the control group (pvisceral pain in rats, and increase mRNA expression of the 5-HT1a receptor peripherally (in the colon) and centrally (in the raphe nuclei), suggesting a serotonergic mechanism of action. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

  6. Primary Primitive Neuroectodermal Tumor of the Conus Medullaris in an Elderly Patient: A Case Report and Review of the Literature

    H. Shimosawa


    Full Text Available Primary spinal primitive neuroectodermal tumors (PNETs are very rare conditions. Most of these tumors occur in children and young adults. A 63-year-old man with a primary spinal PNET in the conus medullaris from the L1 to L2 level is presented in this report. The optimal treatment of primary spinal PNETs is yet unknown. Surgical resection, radiation therapy, and chemotherapy have been advocated for the treatment of spinal PNET based on PNETs at other sites. However, the outcome is very poor. There are a few reports of cases with long-term survival and no recurrence. In these patients, en bloc resections were performed.

  7. Acute coronary syndrome:a rare case of multiple endocrine neoplasia syndromes with pheochromocytoma and medullary thyroid carcinoma

    Alessadro Maloberti; Paola Loli; Cristina Giannattasio; Paolo Meani; Roberto Pirola; Marisa Varrenti; Marco Boniardi; Anna Maria De Biase; Paola Vallerio; Edgardo Bonacina; Giuseppe Mancia


    Pheochromocytoma is a tumor arising from neuroectodermal chromaffin tissues in the adrenal gland or extra-adrenal paraganglia (paragangliomas). hTe 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 ifnal diagnosis of multiple endocrine neoplasia with pheochromocytoma and medullary thyroid carcinoma (MTC).

  8. Sonographic Findings of Medullary Thyroid Carcinoma Leading to Diagnosis of Multiple Endocrine Neoplasia Type 2a during Pregnancy

    David M. Sherer


    Full Text Available Multiple endocrine neoplasia (MEN type 2a (Sipple's syndrome is characterized by medullary thyroid carcinoma and pheochromocytoma, and in a smaller percentage of cases, multiglandular parathyroid hyperplasia. This autosomal-dominant syndrome is due to a mutation in the rearranged during transfection (RET proto-oncogene located on chromosome 10cen–10q11.2 and rarely complicates pregnancy. We present an unusual case in a patient with an enlarged thyroid with sonographic findings characteristic of thyroid cancer, which led to diagnosis and subsequent management of RET proto-oncogene-positive MEN type 2a complicating pregnancy.

  9. Surgical and clinical strategies in the management of thyroid medullary carcinoma in children with and without ret proto-oncogene mutations.

    Boybeyi-Türer, Özlem; Vurallı, Doğuş; Karnak, İbrahim; Gönç, Nazlı; Yalçın, Emel Şule; Orhan, Diclehan; Kandemir, Nurgün; Tanyel, Feridun Cahit


    Medullary thyroid carcinoma (MTC) may arise sporadically or in familial manner. We presented sporadic and familial cases with MTC in order to raise awareness on management of such patients. Three medullary thyroid carcinoma (MTC) cases were presented. Case 1 had RET634 mutation; managed with total thyroidectomy (TT) and cervical lymph node dissection (CLND). Case 2 had RET804 mutation; managed with prophylactic TT. Case 3 had thyroid nodule; managed with TT and CLND. Case 1 had micro-carcinomatosis foci, Case 2 had normal thyroid tissue in histopathological examination and Case 3 had medullary thyroid carcinoma with tumor negative surgical borders. Case 1 was re-operated for persisting focus of disease. Follow-up of cases were uneventful. Clinicians and surgeons should be aware of critical timing for surgery and various surgical and clinical strategies in the management of MTC in children.

  10. 大鼠中枢内源性镇痛系统内GABAB受体的分布%Localization of GABAB receptor in the centr al endogenous pain control system of rats

    闫励; 赵华; 李云庆


    目的观察α-氨基丁酸B受体(GABABR)在大鼠中枢内源性镇痛系统内的定位分布. 方法 GABABR特异性抗体的免疫组织化学染色方法. 结果 GABABR样阳性胞体较密集地分布于中缝核簇的核团,如中缝背核、中缝正中核、中缝桥核、中缝大核、中缝苍白核、中缝隐核. 此外,中脑导水管周围灰质和巨细胞网状核α部内也有GABABR样阳性胞体. 上述核团内亦可见GABABR样阳性纤维和终末. 结论中枢内源性镇痛系统内有GABABR样阳性胞体、纤维及终末,这些阳性结构可能与对该系统的调控有关.%AIM To examine the distribution of gamma-aminob utyric acid B receptor (GABABR) in the central endogenous pain control system of the rat. METHODS Immunohistochemical staining technique was used with specific antibody agains t GABABR. [ WTHZ〗RESULTS Densely stained GABABR-like immunoreactive neuronal ce ll bodies were observed in the dorsal raphe nucleus (DR), median raphe nucleus (MnR), pontine raphe nucleus (PnR), nuc leus raphe magnus (NRM), nucleus raphe obscurus (ROb) and nucleus raphe pallidus (RPa). Add itionally, GABABR-like immunoreactive neuronal cell bodies were also found in the midbra in periaqueductal gray (PAG) and gigantocellular reticular nucleus pars α (GiA). G ABABR-like immunoreactive fibers and terminals were encountered in those nuclei as well. [ WTHZ〗CONCLUSION Present results indicate that GABABR-like immunorea ctive neuronal cell bodies, fibers and terminals are located in the central endogenous pain control system. They might be involved in the regulatory effects upon this system.

  11. Role of dorsal raphe nucleus 5-HT(1A) and 5-HT(2) receptors in tonic immobility modulation in guinea pigs.

    Ferreira, Mateus Dalbem; Menescal-de-Oliveira, Leda


    Tonic immobility (TI) is an innate defensive behavior characterized by a state of physical inactivity and diminished responsiveness to environmental stimuli. Behavioral adaptations to changes in the external and internal milieu involve complex neuronal network activity and a large number of chemical neurotransmitters. The TI response is thought to be influenced by serotonin (5-HT) activity in the central nervous system (CNS) of vertebrates, but the neuronal groups involved in the mechanisms underlying this behavior are poorly understood. Owing to its extensive afferents and efferents, the dorsal raphe nucleus (DRN) has been implicated in a great variety of physiological and behavioral functions. In the current study, we investigated the influence of serotonergic 5-HT(1A) and 5-HT(2) receptor activity within the DRN on the modulation of TI behavior in the guinea pig. Microinjection of a 5-HT(1A) receptor agonist (8-OH-DPAT, 0.01 and 0.1 microg) decreased TI behavior, an effect blocked by pretreatment with WAY-100635 (0.033 microg), a 5-HT(1A) antagonist. In contrast, activation of 5-HT(2) receptors within the DRN (alpha-methyl-5-HT, 0.5 microg) increased the TI duration, and this effect could be reversed by pretreatment with an ineffective dose (0.01 microg) of ketanserine. Since the 5-HT(1A) and 5-HT(2) agonists decreased and increased, respectively, the duration of TI, different serotonin receptor subtypes may play distinct roles in the modulation of TI in the guinea pig.

  12. Chronic alcoholism in the absence of Wernicke-Korsakoff syndrome and cirrhosis does not result in the loss of serotonergic neurons from the median raphe nucleus.

    Baker, K G; Halliday, G M; Kril, J J; Harper, C G


    Previous studies have identified alcohol, thiamine deficiency and liver disease as contributing to the neuropathology of alcohol-related brain damage. In order to examine the effects of alcohol toxicity and thiamine deficiency on serotonergic neurons in the median raphe nucleus (MnR), alcoholic and previously published Wernicke-Korsakoff syndrome (WKS) cases without liver disease, were compared with age-matched non-alcoholic controls. While there was no difference between the estimated number of serotonergic neurons in either controls or alcoholics without WKS (means of 63,010 +/- 8,900 and 59,560 +/- 8,010 respectively), a substantial loss of serotonergic neurons was previously found in WKS cases (mean of 19,050 +/- 13,140). Further analysis revealed a significant difference in the maximum daily alcohol consumption between these groups. However, analysis of covariance showed that the number or serotonergic neurons in the MnR did not correlate with the amount of alcohol consumed. Therefore, our results suggest that cell loss in the MnR can be attributed to thiamine deficiency rather than alcohol per se.

  13. Morphological findings relating to the problem of cortex and medulla in the pineal glands of rat and hamster.

    Heidbüchel, U; Vollrath, L.


    Because, in previous investigations on the rat pineal gland, karyometric studies of pinealocytes from cortical and medullary regions had yielded contradictory results, experiments were carried out to resolve this problem. In immersion-fixed, paraffin-embedded pineal glands, nuclear size of cortical regions was invariably larger than that in the medulla, the nuclear size clearly depending on the plane of sectioning. The differences between cortex and medulla were abolished in (a) pineal glands...

  14. Autoimmune regulator (Aire) controls the expression of microRNAs in medullary thymic epithelial cells.

    Macedo, Claudia; Evangelista, Adriane F; Marques, Márcia M; Octacílio-Silva, Shirlei; Donadi, Eduardo A; Sakamoto-Hojo, Elza T; Passos, Geraldo A


    The autoimmune regulator (Aire) is a transcription factor that controls the ectopic expression of a large set of peripheral tissue antigen (PTA) genes in medullary thymic epithelial cells (mTECs). Recent evidence has demonstrated that Aire releases stalled RNA polymerase II (RNA Pol II) from blockage at the promoter region of its target genes. Given that, in addition to messenger RNAs (mRNA), RNA Pol II also transcribes microRNAs (miRNAs), we raised the hypothesis that Aire might play a role as an upstream controller of miRNA transcription. To test this, we initially analyzed the expression profiles of 662 miRNAs in control and Aire-silenced (siRNA) murine mTEC 3.10 cells using microarrays. The bioinformatics programs SAM and Cluster-TreeView were then used to identify the differentially expressed miRNAs and their profiles, respectively. Thirty Aire-dependent miRNAs were identified in the Aire-silenced mTECs, of which 18 were up- and 12 were down-regulated. The down-regulated miR-376 family was the focus of this study because its members (miR-376a, miR-376b and miR-376c) are located in the genome within the Gm2922 open-reading frame (ORF) gene segment on the chromosome 12F1. The T-boxes (TTATTA) and G-boxes (GATTGG), which represent putative RNA Pol II promoter motifs, were located in a portion spanning 10 kb upstream of the ATG codon of Gm2922. Moreover, we found that Gm2922 encodes an mRNA, which was also down-regulated in Aire-silenced mTECs. These results represent the first evidence that Aire can play a role as a controller of transcription of miRNAs located within genomic regions encompassing ORF and/or mRNA genes. Copyright © 2012 Elsevier GmbH. All rights reserved.

  15. DNA methylation profile of Aire-deficient mouse medullary thymic epithelial cells.

    Wu, Guoying; Hirabayashi, Keiji; Sato, Shinya; Akiyama, Nobuko; Akiyama, Taishin; Shiota, Kunio; Yagi, Shintaro


    Medullary thymic epithelial cells (mTECs) are characterized by ectopic expression of self-antigens during the establishment of central tolerance. The autoimmune regulator (Aire), which is specifically expressed in mTECs, is responsible for the expression of a large repertoire of tissue-restricted antigens (TRAs) and plays a role in the development of mTECs. However, Aire-deficient mTECs still express TRAs. Moreover, a subset of mTECs, which are considered to be at a stage of terminal differentiation, exists in the Aire-deficient thymus. The phenotype of a specific cell type in a multicellular organism is governed by the epigenetic regulation system. DNA methylation modification is an important component of this system. Every cell or tissue type displays a DNA methylation profile, consisting of tissue-dependent and differentially methylated regions (T-DMRs), and this profile is involved in cell-type-specific genome usage. The aim of this study was to examine the DNA methylation profile of mTECs by using Aire-deficient mTECs as a model. We identified the T-DMRs of mTECs (mTEC-T-DMRs) via genome-wide DNA methylation analysis of Aire(-/-) mTECs by comparison with the liver, brain, thymus, and embryonic stem cells. The hypomethylated mTEC-T-DMRs in Aire(-/-) mTECs were associated with mTEC-specific genes, including Aire, CD80, and Trp63, as well as other genes involved in the RANK signaling pathway. While these mTEC-T-DMRs were also hypomethylated in Aire(+/+) mTECs, they were hypermethylated in control thymic stromal cells. We compared the pattern of DNA methylation levels at a total of 55 mTEC-T-DMRs and adjacent regions and found that the DNA methylation status was similar for Aire(+/+) and Aire(-/-) mTECs but distinct from that of athymic cells and tissues. These results indicate a unique DNA methylation profile that is independent of Aire in mTECs. This profile is distinct from other cell types in the thymic microenvironment and is indicated to be involved in the

  16. mTOR activation in medullary thyroid carcinoma with RAS mutation.

    Lyra, Joana; Vinagre, João; Batista, Rui; Pinto, Vasco; Prazeres, Hugo; Rodrigues, Fernando; Eloy, Catarina; Sobrinho-Simões, Manuel; Soares, Paula


    Rearranged during transfection (RET) mutations are well-known genetic events in sporadic and familial medullary thyroid carcinoma (FMTC). The presence of RAS mutations in sporadic cases, challenging the RET paradigm in these tumors, has been recently reported. We intend to evaluate mTOR pathway activation in RET- and RAS-mutated MTC. In this study, we analysed the presence of RET, H-RAS, and K-RAS mutations in a series of 87 MTCs (82 apparently sporadic and five FMTCs; five apparently sporadic MTCs were eventually found to be familial). We also evaluated mTOR activation--using the expression of its downstream effector phospho-S6 ribosomal protein (p-S6) and the expression of the mTOR inhibitor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN)--by immunohistochemistry. Our results revealed that RET mutations were present in 52.9% of the cases (46/87) and RAS mutations in 12.6% (11/87) of the whole series of MTCs and 14.3% of the 77 sporadic MTCs. The presence of RET and RAS mutations was mutually exclusive. RAS mutations were significantly associated with higher intensity of p-S6 expression (P=0.007), suggesting that the mTOR pathway is activated in such MTCs. We observed also an increased expression of p-S6 in invasive tumors (P=0.042) and in MTCs with lymph node metastases (P=0.046). Cytoplasmic PTEN expression was detected in 58.8% of the cases; cases WT for RAS showed a significantly lower expression of PTEN (P=0.045). We confirmed the presence of RAS mutation in 14.3% of sporadic MTCs and report, for the first time, an association between such mutations and the activation of the mTOR pathway. The evaluation of the mTOR activation by pS6 expression may serve as an indicator of invasive MTC. © 2014 European Society of Endocrinology.

  17. Role of the medial medullary reticular formation in relaying vestibular signals to the diaphragm and abdominal muscles

    Mori, R. L.; Bergsman, A. E.; Holmes, M. J.; Yates, B. J.


    Changes in posture can affect the resting length of respiratory muscles, requiring alterations in the activity of these muscles if ventilation is to be unaffected. Recent studies have shown that the vestibular system contributes to altering respiratory muscle activity during movement and changes in posture. Furthermore, anatomical studies have demonstrated that many bulbospinal neurons in the medial medullary reticular formation (MRF) provide inputs to phrenic and abdominal motoneurons; because this region of the reticular formation receives substantial vestibular and other movement-related input, it seems likely that medial medullary reticulospinal neurons could adjust the activity of respiratory motoneurons during postural alterations. The objective of the present study was to determine whether functional lesions of the MRF affect inspiratory and expiratory muscle responses to activation of the vestibular system. Lidocaine or muscimol injections into the MRF produced a large increase in diaphragm and abdominal muscle responses to vestibular stimulation. These vestibulo-respiratory responses were eliminated following subsequent chemical blockade of descending pathways in the lateral medulla. However, inactivation of pathways coursing through the lateral medulla eliminated excitatory, but not inhibitory, components of vestibulo-respiratory responses. The simplest explanation for these data is that MRF neurons that receive input from the vestibular nuclei make inhibitory connections with diaphragm and abdominal motoneurons, whereas a pathway that courses laterally in the caudal medulla provides excitatory vestibular inputs to these motoneurons.

  18. Medullary thyroid carcinoma in a patient with Hashimoto's thyroiditis diagnosed by calcitonin washout from a thyroid nodule.

    Mousa, Umut; Gursoy, Alptekin; Ozdemir, Handan; Moray, Gokhan


    Serum calcitonin is a tumor marker used in the diagnosis and follow-up of medullary thyroid carcinoma. Calcitonin washout evaluation is a new method used for suspicious thyroid nodules and lymph nodes. Limited clinical data are present about the efficacy of this method. A 61-year-old female patient with known Hashimoto's thyroditis and an 8-mm hypoechoic nodule was presented with one previously benign fine-needle aspiration cytology (FNAC). On referral to our department, she had a moderately high-serum calcitonin level, and we repeated the FNAC that was reported as nondiagnostic. We performed FNAC for the third time together with calcitonin washout evaluation from the thyroid nodule. The FNAC was again nondiagnostic, but the calcitonin washout level from the thyroid nodule was 152.569 pg/mL. Total thyroidectomy was performed, and the diagnosis was confirmed as medullary thyroid carcinoma. Calcitonin washout evaluation may be a useful method in the differential diagnosis of patients with thyroid nodules having moderately high-serum calcitonin levels.

  19. Behavior study of the doped castor bean polymer rod with bioactive glass and hidroxyapatite in mice femur medullary canal.

    Santos, Viviani Teixeira Dos; Facco, Gilberto Gonçalves; Ortiz, Hudman Cunha; Silva, Iandara Schettert da


    Purpose To evaluate the polymer doped rods behavior with bioactive glass and hydroxyapatite for possible application as a fracture fixing method. Methods Twenty eight Rattus norvegicus Wistar underwent bone defect for access to the femoral medullary canal and distributed into three experimental groups: group A - doped castor bean polymer with bioactive glass; group B - castor bean polymer and; group C - castor bean polymer doped with bioactive glass and hydroxyapatite. After 15 and 60 evaluation days, the femurs were removed and sent for histology and scanning electron microscopy. Results Initially mild and moderate inflammatory infiltrate is observed that decreases as time goes by, and the presence of connective tissue capsule around the graft in all groups. Regarding the biomaterials resorption little was observed. The implanted rods did not favor the osteoconductive process in the femoral medullary canal which was observed only in the C15 group. Conclusions The association of castor bean polymer, bioactive glass and hydroxyapatite was biocompatible and osteointegrable. The osteoconductive only occurred in the presence of hydroxyapatite and bioactive glass (C15 Group) and little biodegradation was observed.

  20. Fully automatic segmentation of femurs with medullary canal definition in high and in low resolution CT scans.

    Almeida, Diogo F; Ruben, Rui B; Folgado, João; Fernandes, Paulo R; Audenaert, Emmanuel; Verhegghe, Benedict; De Beule, Matthieu


    Femur segmentation can be an important tool in orthopedic surgical planning. However, in order to overcome the need of an experienced user with extensive knowledge on the techniques, segmentation should be fully automatic. In this paper a new fully automatic femur segmentation method for CT images is presented. This method is also able to define automatically the medullary canal and performs well even in low resolution CT scans. Fully automatic femoral segmentation was performed adapting a template mesh of the femoral volume to medical images. In order to achieve this, an adaptation of the active shape model (ASM) technique based on the statistical shape model (SSM) and local appearance model (LAM) of the femur with a novel initialization method was used, to drive the template mesh deformation in order to fit the in-image femoral shape in a time effective approach. With the proposed method a 98% convergence rate was achieved. For high resolution CT images group the average error is less than 1mm. For the low resolution image group the results are also accurate and the average error is less than 1.5mm. The proposed segmentation pipeline is accurate, robust and completely user free. The method is robust to patient orientation, image artifacts and poorly defined edges. The results excelled even in CT images with a significant slice thickness, i.e., above 5mm. Medullary canal segmentation increases the geometric information that can be used in orthopedic surgical planning or in finite element analysis.

  1. Successful surgical removal of occult metastases of medullary thyroid carcinoma recurrences with the help of immunoscintigraphy and radioimmunoguided surgery.

    de Labriolle-Vaylet, C; Cattan, P; Sarfati, E; Wioland, M; Billotey, C; Brochériou, C; Rouvier, E; de Roquancourt, A; Rostène, W; Askienazy, S; Barbet, J; Milhaud, G; Gruaz-Guyon, A


    Patients with recurrent or metastatic medullary thyroid carcinoma (MTC) were referred for pretargeted immunoscintigraphy (Affinity Enhancement System; AES) and radioimmunoguided surgery (RIGS). Data collected from 13 patients establish that whole-body AES immunoscintigraphy revealed metastases < 360 mg and RIGS detected micrometastases (5-15 mg). All tissue samples removed by the surgeon were diagnosed by histology and immunohistochemistry of calcitonin to check the accuracy of IS and RIGS results. AES immunoscintigraphy is very sensitive. Of 34 metastases or recurrences detected, 22 had escaped physical examination or conventional imaging. The accuracy of RIGS was 86%, its sensitivity 75%, and its specificity was 90% (n = 208). IS and RIGS detected occult tumors that would have escaped surgery, clearly demonstrating clinical benefit. Serum calcitonin (normal, 10 pg/ml) and carcinoembryonic antigen (normal, 5 ng/ml) of two patients were restored to normal. In patients whose tumors were discovered, progression of their disease was slowed, as evidenced by the large decrease in serum calcitonin and carcinoembryonic antigen, an important prognostic factor. Surgery was canceled in one case where IS detected distant metastases out of surgical reach. Thus, AES immunoscintigraphy and RIGS might be of valuable help for the surgical management of medullary thyroid carcinoma.

  2. Methylation of the BRCA1 promoter in peripheral blood DNA is associated with triple-negative and medullary breast cancer.

    Gupta, Satish; Jaworska-Bieniek, Katarzyna; Narod, Steven A; Lubinski, Jan; Wojdacz, Tomasz K; Jakubowska, Anna


    It has been proposed that methylation signatures in blood-derived DNA may correlate with cancer risk. In this study, we evaluated whether methylation of the promoter region of the BRCA1 gene detectable in DNA from peripheral blood cells is a risk factor for breast cancer, in particular for tumors with pathologic features characteristic for cancers with BRCA1 gene mutations. We conducted a case-control study of 66 breast cancer cases and 36 unaffected controls. Cases were triple-negative or of medullary histology, or both; 30 carried a constitutional BRCA1 mutation and 36 did not carry a mutation. Blood for DNA methylation analysis was taken within three months of diagnosis. Methylation of the promoter of the BRCA1 gene was measured in cases and controls using methylation-sensitive high-resolution melting (MS-HRM). A sample with any detectable level of methylation was considered to be positive. Methylation of the BRCA1 promoter was detected in 15 of 66 cases and in 2 of 36 controls (OR 5.0, p = 0.03). Methylation was present in 15 of 36 women with breast cancer and without germline BRCA1 mutation, but in none of 30 women with breast cancer and a germline mutation (p blood DNA may be a marker of increased susceptibility to triple-negative or medullary breast cancer.

  3. Cyclooxygenase-2-dependent phosphorylation of the pro-apoptotic protein Bad inhibits tonicity-induced apoptosis in renal medullary cells.

    Küper, Christoph; Bartels, Helmut; Beck, Franz-X; Neuhofer, Wolfgang


    During antidiuresis, cell survival in the renal medulla requires cyclooxygenase-2 (COX-2) activity. We have recently found that prostaglandin E2 (PGE2) promotes cell survival by phosphorylation and, hence, inactivation of the pro-apoptotic protein Bad during hypertonic stress in Madin-Darby canine kidney (MDCK) cells in vitro. Here we determine the role of COX-2-derived PGE(2) on phosphorylation of Bad and medullary apoptosis in vivo using COX-2-deficient mice. Both wild-type and COX-2-knockout mice constitutively expressed Bad in tubular epithelial cells of the renal medulla. Dehydration caused a robust increase in papillary COX-2 expression, PGE2 excretion, and Bad phosphorylation in wild-type, but not in the knockout mice. The abundance of cleaved caspase-3, a marker of apoptosis, was significantly higher in papillary homogenates, especially in tubular epithelial cells of the knockout mice. Knockdown of Bad in MDCK cells decreased tonicity-induced caspase-3 activation. Furthermore, the addition of PGE2 to cells with knockdown of Bad had no effect on caspase-3 activation; however, PGE2 caused phosphorylation of Bad and substantially improved cell survival in mock-transfected cells. Thus, tonicity-induced COX-2 expression and PGE2 synthesis in the renal medulla entails phosphorylation and inactivation of the pro-apoptotic protein Bad, thereby counteracting apoptosis in renal medullary epithelial cells.

  4. Biopsy proven medullary sponge kidney: clinical findings, histopathology, and role of osteogenesis in stone and plaque formation.

    Evan, Andrew P; Worcester, Elaine M; Williams, James C; Sommer, Andre J; Lingeman, James E; Phillips, Carrie L; Coe, Fredric L


    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.

  5. Intermediate expression of CCRL1 reveals novel subpopulations of medullary thymic epithelial cells that emerge in the postnatal thymus.

    Ribeiro, Ana R; Meireles, Catarina; Rodrigues, Pedro M; Alves, Nuno L


    Cortical and medullary thymic epithelial cells (cTECs and mTECs, respectively) provide inductive microenvironments for T-cell development and selection. The differentiation pathway of cTEC/mTEC lineages downstream of common bipotent progenitors at discrete stages of development remains unresolved. Using IL-7/CCRL1 dual reporter mice that identify specialized TEC subsets, we show that the stepwise acquisition of chemokine (C-C motif) receptor-like 1 (CCRL1) is a late determinant of cTEC differentiation. Although cTECs expressing high CCRL1 levels (CCRL1(hi) ) develop normally in immunocompetent and Rag2(-/-) thymi, their differentiation is partially blocked in Rag2(-/-) Il2rg(-/-) counterparts. These results unravel a novel checkpoint in cTEC maturation that is regulated by the cross-talk between TECs and immature thymocytes. Additionally, we identify new Ulex europaeus agglutinin 1 (UEA)(+) mTEC subtypes expressing intermediate CCRL1 levels (CCRL1(int) ) that conspicuously emerge in the postnatal thymus and differentially express Tnfrsf11a, Ccl21, and Aire. While rare in fetal and in Rag2(-/-) thymi, CCRL1(int) mTECs are restored in Rag2(-/-) Marilyn TCR-Tg mice, indicating that the appearance of postnatal-restricted mTECs is closely linked with T-cell selection. Our findings suggest that alternative temporally restricted routes of new mTEC differentiation contribute to the establishment of the medullary niche in the postnatal thymus.

  6. Effect of novel atypical antipsychotic, blonanserin, on extracellular neurotransmitter level in rat prefrontal cortex.

    Ohoyama, Keiko; Yamamura, Satoshi; Hamaguchi, Tatsuya; Nakagawa, Masanori; Motomura, Eishi; Shiroyama, Takashi; Tanii, Hisashi; Okada, Motohiro


    To clarify the mechanisms of action of blonanserin, an atypical antipsychotic drug, we studied the effects of systemic administration of blonanserin and risperidone on extracellular levels of norepinephrine, dopamine, serotonin, GABA and glutamate in the medial prefrontal cortex using microdialysis, and neuronal firing in the ventral tegmental area, locus coeruleus, dorsal raphe nucleus and mediodorsal thalamic nucleus using radiotelemetry. The binding affinities of blonanserin to D(2) and 5-HT(2A) receptors in the rat brain were confirmed and found to be similar. Blonanserin transiently increased neuronal firing in locus coeruleus and ventral tegmental area but not in dorsal raphe nucleus or mediodorsal thalamic nucleus, whereas risperidone increased the firing in locus coeruleus, ventral tegmental area and dorsal raphe nucleus but not in mediodorsal thalamic nucleus. Blonanserin persistently increased frontal extracellular levels of norepinephrine and dopamine but not serotonin, GABA or glutamate, whereas risperidone persistently increased those of norepinephrine, dopamine and serotonin but not GABA or glutamate. These results suggest a pharmacological correlation between the stimulatory effects of these antipsychotics on frontal monoamine release and neuronal activity in monoaminergic nuclei. Inhibition of the α(2) adrenoceptor increased extracellular monoamine levels and enhanced blonanserin-induced increase in extracellular serotonin level. These results indicated that the combination of antagonism of D(2) and 5-HT(2A) receptors contribute to the rise in extracellular levels of norepinephrine and dopamine, and that α(2) adrenoceptors play important roles in frontal serotonin release. They also suggest that blonanserin-induced activation of monoaminergic transmission could be, at least partially, involved in atypical antipsychotic properties of blonanserin. Copyright © 2010 Elsevier B.V. All rights reserved.

  7. 5-Hydroxytryptamine2A/2C receptors of nucleus raphe magnus and gigantocellularis/paragigantocellularis pars α reticular nuclei modulate the unconditioned fear-induced antinociception evoked by electrical stimulation of deep layers of the superior colliculus and dorsal periaqueductal grey matter.

    de Oliveira, Ricardo; de Oliveira, Rithiele Cristina; Falconi-Sobrinho, Luiz Luciano; da Silva Soares, Raimundo; Coimbra, Norberto Cysne


    The electrical stimulation of the dorsolateral columns of the periaquedutal grey matter (dlPAG) or deep layers of the superior colliculus (dlSC) evokes defensive behaviours followed by an antinociceptive response. Monoaminergic brainstem reticular nuclei are suggested to comprise the endogenous pain modulatory system. The aim of the present work was to investigate the role played by 5-HT2 subfamily of serotonergic receptors of the nucleus raphe magnus (NRM) and the gigantocellularis/paragigantocellularis pars α reticular nuclei (Gi/PGiα) in the elaboration of instinctive fear-induced antinociception elicited by electrical stimulation of dlPAG or of dlSC. The nociceptive thresholds were measured by the tail-flick test in Wistar rats. The 5-HT2A/2C-serotonergic receptors antagonist ritanserin was microinjected at different concentrations (0.05, 0.5 and 5.0μg/0.2μL) either in Gi/PGiα or in NRM. The blockade of 5-HT2 receptors in both Gi/PGiα and NRM decreased the innate fear-induced antinociception elicited by electrical stimulation of the dlSC or the dlPAG. These findings indicate that serotonin is involved in the hypo-algesia induced by unconditioned fear-induced behavioural responses and the 5-HT2A/2C-serotonergic receptor subfamily in neurons situated in the Gi/PGiα complex and NRM are critically recruited in pain modulation during the panic-like emotional behaviour.

  8. Functional reorganization of motor and limbic circuits after exercise training in a rat model of bilateral parkinsonism.

    Zhuo Wang

    Full Text Available Exercise training is widely used for neurorehabilitation of Parkinson's disease (PD. However, little is known about the functional reorganization of the injured brain after long-term aerobic exercise. We examined the effects of 4 weeks of forced running wheel exercise in a rat model of dopaminergic deafferentation (bilateral, dorsal striatal 6-hydroxydopamine lesions. One week after training, cerebral perfusion was mapped during treadmill walking or at rest using [(14C]-iodoantipyrine autoradiography. Regional cerebral blood flow-related tissue radioactivity (rCBF was analyzed in three-dimensionally reconstructed brains by statistical parametric mapping. In non-exercised rats, lesions resulted in persistent motor deficits. Compared to sham-lesioned rats, lesioned rats showed altered functional brain activation during walking, including: 1. hypoactivation of the striatum and motor cortex; 2. hyperactivation of non-lesioned areas in the basal ganglia-thalamocortical circuit; 3. functional recruitment of the red nucleus, superior colliculus and somatosensory cortex; 4. hyperactivation of the ventrolateral thalamus, cerebellar vermis and deep nuclei, suggesting recruitment of the cerebellar-thalamocortical circuit; 5. hyperactivation of limbic areas (amygdala, hippocampus, ventral striatum, septum, raphe, insula. These findings show remarkable similarities to imaging findings reported in PD patients. Exercise progressively improved motor deficits in lesioned rats, while increasing activation in dorsal striatum and rostral secondary motor cortex, attenuating a hyperemia of the zona incerta and eliciting a functional reorganization of regions participating in the cerebellar-thalamocortical circuit. Both lesions and exercise increased activation in mesolimbic areas (amygdala, hippocampus, ventral striatum, laterodorsal tegmental n., ventral pallidum, as well as in related paralimbic regions (septum, raphe, insula. Exercise, but not lesioning, resulted

  9. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer

    Schlumberger, Martin J; Elisei, Rossella; Bastholt, Lars


    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 A...

  10. Ectopic Cushing syndrome secondary to metastatic medullary thyroid cancer in a child with multiple endocrine neoplasia syndrome type 2B: clues to early diagnosis of the paraneoplastic syndromes.

    Singer, Kanakadurga; Heiniger, Nicholas; Thomas, Inas; Worden, Francis P; Menon, Ram K; Chen, Ming


    We describe a 13-year-old male with multiple endocrine neoplasia syndrome type 2B with medullary thyroid carcinoma who was diagnosed with ectopic adrenocorticotropin-dependent Cushing syndrome. This report highlights the importance of monitoring for paraneoplastic syndrome in MEN and clues to the diagnosis of this complication provided by growth patterns.

  11. Fine Needle Aspiration and Medullary Thyroid Carcinoma: The Risk of Inadequate Preoperative Evaluation and Initial Surgery When Relying Upon FNAB Cytology Alone

    Essig, G.F.; Porter, K.; Schneider, D.; Debora, A.; Lindsey, S.C.; Busonero, G.; Fineberg, D.; Fruci, B.; Boelaert, K.; Smit, J.W.A.; Meijer, J.A.M.; Duntas, L.; Sharma, N.; Costante, G.; Filetti, S.; Sippel, R.S.; Biondi, B.; Topliss, D.J.; Pacini, F.; Maciel, R.M.; Walz, P.C.; Kloos, R.T.


    Objectives: To evaluate the diagnostic accuracy of fine-needle aspiration biopsy (FNAB) to preoperatively diagnose medullary thyroid cancer (MTC) among multiple international centers and evaluate how the cytological diagnosis alone could impact patient management.Methods: We performed a retrospectiv

  12. Results and summary of voting among the audience during presentation and discussion of Medullary Thyroid Carcinoma clinical guidelines prepared by American Thyroid Association

    Feldt-Rasmussen, Ulla; Soderstrom, Folke


    , related to the specific aspect, were presented to the audience. The responses from the audience were collected by an AudioResponseSystem (ARS voting system). The results of the voting showed in summary that European expert opinion leaders and an audience of specialists in treatment of Medullary Carcinoma...

  13. [Role of CT/111In-octreotide SPECT digital fusion imaging in the localization of loco-regional recurrence of medullary thyroid carcinoma

    Fiore, D.; Rubello, D.; Casara, D.; Pelizzo, M.R.; Franchi, A.; Muzzio, P.C.


    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 pati

  14. Immunohistochemical localization of glutamate transporter EAAC1 in the brainstem of adult rat

    ZHANG Fu-xing; LIU Tao; ZHAO Jing-wei; LI Jin-lian; DONG Yu-lin; LI Ji-shuo


    Objective: To observe the distribution of EAAC1, a subtype of glutamate transporters, in the brainstem of adult rat. Methods: Immunocytochemical staining with avidin-biotin complex (ABC) method was employed. Results:EAAC1 was widely distributed throughout the brainstem. In many regions, the EAAC1-like immunoreactivity was primarily distributed in the neuropil. Cell body staining was observed in the prepositus hypoglossal nucleus, external cortex of the inferior colliculus, red nucleus, substantia nigra, mesencephalic raphe nuclei, ventral tegmental nucleus, superior olivary complex, nucleus of the trapezoid body, cochlear nucleus, sensory trigeminal complex, Barrington's nucleus,trigeminal motor nucleus, parabrachial nuclei, dorsal nucleus of vagus, hypoglossal nucleus, locus coeruleus, lateral and superior vestibular nuclei, lateral paragigantocellular nucleus and dorsal paragigantocellular nucleus. Conclusion: Glutamate transporter EAAC 1 is widely distributed throughout the brainstem of adult rat, which may play an important role in excitatory activities of the neurons induced by glutamate.

  15. Morphological and Functional Changes in Rat Brain under Total Sleep Deprivation

    Babak ABUSHOV


    Full Text Available In this article the effect of 36 h total sleep deprivation (TSD on behavioural reactions of rats (rearing, grooming and sexual activity and on ultrastructure of brain neurons have been studied. A group of somnogenic structures (III-V layers of the frontal limbic cortex, CA1 area of the dorsal hippocampus, reticular formation of pons varolli, nucleus raphe dorsalis and locus coeruleus of the brain of 6 month-old Wistar rats has been analized in this study. It has been revealed that dystrophic changes (chromatolysis of cytoplasm and vacuolization enveloping a group of medium-sized neurons (20-30 (μ micron in diameter are accompanied by decrease of numbers of rearing, grooming and sexual activity. It is supposed that dystrophic changes revealed in medium-sized neurons result in partial disturbances of integrative and behavioral reactions of animals.

  16. Calcitonin receptors in the rat mesencephalon mediate its analgesic actions: autoradiographic and behavioral analyses

    Fabbri, A.; Pert, C.B.; Pert, A.; Fraioli, F.


    Autoradiographic analyses of salmon calcitonin (sCT) binding in the rat mesencephalon revealed an exceptionally high concentration of receptors in the ventral and ventrolateral segments of the periaqueductal gray matter (PAG) extending along the entire rostralcaudal axis. Relatively heavy labeling was also seen along a band extending ventrolaterally through the mesencephalic reticular formation. Other receptor-rich areas include the nucleus linearis, pars compacta and lateralis of the substantia nigra, locus coeruleus, parabrachial nuclei and nucleus raphe pontis of the pontine reticular formation. The biological effects are consistent with the potencies of both peptides in displacing SVI-sCT from slide-mounted sections of rat PAG. Naloxone failed to antagonize sCT-induced analgesia, suggesting an opiate independent mechanism for this peptide in elicting analgesia. (Auth.). 60 refs.; 9 figs.

  17. Serotonergic neural links from the dorsal raphe nucleus modulate defensive behaviours organised by the dorsomedial hypothalamus and the elaboration of fear-induced antinociception via locus coeruleus pathways.

    Biagioni, Audrey Francisco; de Freitas, Renato Leonardo; da Silva, Juliana Almeida; de Oliveira, Rithiele Cristina; de Oliveira, Ricardo; Alves, Vani Maria; Coimbra, Norberto Cysne


    Decrease of γ-aminobutyric acid (GABA)-mediated neurotransmission in the dorsomedial hypothalamus (DMH) evokes instinctive fear-like responses. The aim of the present study was to investigate the involvement of the serotonin (5-HT)- and norepinephrine-mediated pathways of the endogenous pain inhibitory system, including the dorsal raphe nucleus (DRN) and the locus coeruleus (LC), in the defensive responses and antinociceptive processes triggered by the blockade of GABAergic receptors in the DMH. The intra-hypothalamic microinjection of the GABA(A) receptor antagonist bicuculline (40 ng/200 nL) elicited elaborate defensive behaviours interspersed with exploratory responses. This escape behaviour was followed by significantly increased pain thresholds, a phenomenon known as fear-induced antinociception. Furthermore, at 5 and 14 days after DRN serotonin-containing neurons were damaged using the selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), the frequency and duration of alertness and escape behaviour evoked by the GABA(A) receptor blockade in the DMH decreased, as well as fear-induced antinociception. Pre-treatment with the non-selective 5-HT receptor antagonist methysergide, the 5-HT(2A/2C) receptor antagonist ketanserin and the 5-HT(2A) receptor selective antagonist R-96544 in the LC also decreased fear-induced antinociception, without significant changes in the expression of defensive behaviours. These data suggest that the serotonergic neurons of the DRN are directly involved in the organisation of defensive responses as well as in the elaboration of the innate fear-induced antinociception. However, serotonin-mediated inputs from the NDR to the LC modulate only fear-induced antinociception and not the defensive behaviours evoked by GABA(A) receptor blockade in the DMH.

  18. 5-Hydroxytryptamine 1A receptors in the dorsomedial hypothalamus connected to dorsal raphe nucleus inputs modulate defensive behaviours and mediate innate fear-induced antinociception.

    Biagioni, Audrey Franceschi; de Oliveira, Rithiele Cristina; de Oliveira, Ricardo; da Silva, Juliana Almeida; dos Anjos-Garcia, Tayllon; Roncon, Camila Marroni; Corrado, Alexandre Pinto; Zangrossi, Hélio; Coimbra, Norberto Cysne


    The dorsal raphe nucleus (DRN) is an important brainstem source of 5-hydroxytryptamine (5-HT), and 5-HT plays a key role in the regulation of panic attacks. The aim of the present study was to determine whether 5-HT1A receptor-containing neurons in the medial hypothalamus (MH) receive neural projections from DRN and to then determine the role of this neural substrate in defensive responses. The neurotracer biotinylated dextran amine (BDA) was iontophoretically microinjected into the DRN, and immunohistochemical approaches were then used to identify 5HT1A receptor-labelled neurons in the MH. Moreover, the effects of pre-treatment of the dorsomedial hypothalamus (DMH) with 8-OH-DPAT and WAY-100635, a 5-HT1A receptor agonist and antagonist, respectively, followed by local microinjections of bicuculline, a GABAA receptor antagonist, were investigated. We found that there are many projections from the DRN to the perifornical lateral hypothalamus (PeFLH) but also to DMH and ventromedial (VMH) nuclei, reaching 5HT1A receptor-labelled perikarya. DMH GABAA receptor blockade elicited defensive responses that were followed by antinociception. DMH treatment with 8-OH-DPAT decreased escape responses, which strongly suggests that the 5-HT1A receptor modulates the defensive responses. However, DMH treatment with WAY-100635 failed to alter bicuculline-induced defensive responses, suggesting that 5-HT exerts a phasic influence on 5-HT1A DMH neurons. The activation of the inhibitory 5-HT1A receptor had no effect on antinociception. However, blockade of the 5-HT1A receptor decreased fear-induced antinociception. The present data suggest that the ascending pathways from the DRN to the DMH modulate panic-like defensive behaviours and mediate antinociceptive phenomenon by recruiting 5-HT1A receptor in the MH.

  19. Treadmill exercise during pregnancy ameliorates post‑traumatic stress disorder‑induced anxiety‑like responses in maternal rats.

    Seo, Jin-Hee; Kim, Tae-Woon; Kim, Chang-Ju; Sung, Yun-Hee; Lee, Sam-Jun


    Post‑traumatic stress disorder (PTSD) is an anxiety disorder triggered by life‑threatening events that cause intense fear. Exercise is known to have protective effects on neuropsychiatric diseases. The present study investigated whether treadmill exercise during pregnancy reduced or alleviated symptoms of PTSD in maternal rats. To induce predator stress in pregnant rats, rats were exposed to a hunting dog in an enclosed room. Exposure time was three 10‑min daily sessions separated by 1 h, starting at week 1 of pregnancy until delivery. Pregnant rats in the exercise group were forced to run on a treadmill for 30 min once a day, starting one week following pregnancy until delivery. Rats receiving predator stress during pregnancy exhibited PTSD anxiety‑like behaviors following delivery. Expression of 5‑hydroxytryptamine (5‑HT) and its synthesizing enzyme tryptophan hydroxylase (TPH) in the dorsal raphe was increased compared with unstressed rats. Expression of c‑Fos and neuronal nitric oxide synthases (nNOS) in the hypothalamus and locus coeruleus were higher in the rats receiving stress during pregnancy compared with unstressed rats. By contrast, treadmill exercise during pregnancy ameliorated anxiety‑like behaviors and reduced the expression of 5‑HT, TPH, c‑Fos and nNOS in the PTSD maternal rats. The results of the present study indicate that exercise during pregnancy is suitable for use as a therapeutic strategy to reduce anxiety‑related disorders, including PTSD.

  20. Rethinking the Current American Joint Committee on Cancer TNM Staging System for Medullary Thyroid Cancer.

    Adam, Mohamed Abdelgadir; Thomas, Samantha; Roman, Sanziana A; Hyslop, Terry; Sosa, Julie A


    Controversy exists around the American Joint Committee on Cancer (AJCC) TNM staging system for medullary thyroid cancer (MTC). Because of the rarity of the disease and limited available data, the staging system for MTC has been largely extrapolated from staging for differentiated thyroid cancer. To evaluate how well the current (seventh and eighth editions) AJCC TNM staging system correlates with survival for patients with MTC and to suggest a possible revision. This population-based retrospective cohort analysis used the National Cancer Database to select patients aged 18 years or older diagnosed with MTC in the United States between 1998 and 2012. Patient demographic and tumor characteristics were assessed, and pathologic tumor stages were provided as T, N, and M categories. Recursive partitioning with bootstrapping was used to divide patients by TNM stages into groups with similar survival. The newly identified groupings were validated in a Surveillance, Epidemiology, and End Results (SEER) cohort. Data analysis was conducted between July 17, 2016, and November 11, 2016. Overall survival and disease-specific survival. Of the 3315 patients with MTC included in the analysis, 1941 (58.6%) were women. The median (interquartile range) age was 54 (42-65) years, and 2839 (85.6%) self-reported their race/ethnicity as white. The current AJCC TNM staging system classified 941 of these patients (28.4%) as stage I, 907 (27.4%) as stage II, 424 (12.9%) as stage III, and 1043 (31.5%) as stage IV. Recursive partitioning analysis yielded 4 TNM groups: stage I (T1N0-1aM0, T2N0M0), stage II (T1N1bM0, T2N1a-bM0, and T3N0M0), stage III (T3N1a-bM0, T4N0-1bM0), and stage IV (T1-4N0-1bM1). Based on these proposed TNM groupings, 1797 of the 3315 patients (54.2%) were classified as stage I, 684 (20.6%) as stage II, 669 (20.2%) as stage III, and 165 (5.0%) as stage IV. Under the proposed TNM groupings, survival differences across TNM groups were more distinct than under the current AJCC

  1. Facial sensory symptoms in medullary infarcts Sintomas sensitivos na face em infartos medulares

    Adriana Bastos Conforto


    Full Text Available OBJECTIVE: To investigate the correlation between facial sensory abnormalities and lesional topography in eight patients with lateral medullary infarcts (LMIs. METHOD: We reviewed eight sequential cases of LMIs admitted to the Neurology Division of Hospital das Clínicas/ São Paulo University between July, 2001 and August, 2002 except for one patient who had admitted in 1996 and was still followed in 2002. All patients were submitted to conventional brain MRI including axial T1-, T2-weighted and Fluid attenuated inversion-recovery (FLAIR sequences. MRIs were evaluated blindly to clinical features to determine extension of the infarct to presumed topographies of the ventral trigeminothalamic (VTT, lateral spinothalamic, spinal trigeminal tracts and spinal trigeminal nucleus. RESULTS: Sensory symptoms or signs were ipsilateral to the bulbar infarct in 3 patients, contralateral in 4 and bilateral in 1. In all of our cases with exclusive contralateral facial sensory symptoms, infarcts had medial extensions that included the VTT topography. In cases with exclusive ipsilateral facial sensory abnormalities, infarcts affected lateral and posterior bulbar portions, with slight or no medial extension. The only patient who presented bilateral facial symptoms had an infarct that covered both medial and lateral, in addition to the posterior region of the medulla. CONLUSION: Our results show a correlation between medial extension of LMIs and presence of contralateral facial sensory symptoms.OBJETIVO: Investigar a correlação entre alterações de sensibilidade na face e topografia lesional em oito pacientes com infartos bulbares laterais (IBLs. MÉTODO: Revisamos oito casos seqüenciais de IBLs admitidos na Divisão de Clínica Neurológica do Hospital das Clínicas da Universidade de São Paulo entre julho de 2001 e agosto de 2002, exceto por um caso que havia sido admitido em 1996 e estava sendo seguido em 2002. Todos os pacientes foram submetidos a

  2. Mycophenolate mofetil prevents high-fat diet-induced hypertension and renal glomerular injury in Dahl SS rats.

    Spradley, Frank T; De Miguel, Carmen; Hobbs, Janet; Pollock, David M; Pollock, Jennifer S


    We designed experiments to test the hypothesis that Dahl salt-sensitive (SS) rats are sensitive to high-fat diet (HFD)-induced hypertension and renal injury via an inflammatory mechanism. Twelve-week-old Dahl SS rats were maintained on a normal diet (ND; 14% fat), HFD (59% fat), or HFD supplemented with the lymphocyte immunosuppressive agent, mycophenolate mofetil (HFD + MMF; 30 mg/kg/day orally in diet), for a period of 4 weeks. Mean arterial pressure (MAP), metabolic parameters, T lymphocyte (CD3(+)) localization, and renal structural damage were assessed during the studies. Four weeks of HFD significantly elevated MAP and visceral adiposity without changing circulating levels of lipids or adipokines. Immunohistochemical analysis demonstrated that SS rats on HFD had significantly greater numbers of CD3(+) cells in renal glomerular and medullary areas compared to ND SS rats. Additionally, HFD led to increased glomerular injury, but did not alter renal medullary injury. Chronic MMF treatment in HFD-fed Dahl SS rats reduced MAP, visceral adiposity, infiltration of CD3(+) cells in the glomerulus, as well as glomerular injury. However, MMF treatment did not alter HFD-induced infiltration of CD3(+) cells in the renal medulla. In conclusion, Dahl SS rats are sensitized to HFD-induced hypertension and renal glomerular injury via infiltration of T lymphocytes.

  3. Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats.

    O'Neill, Julie; Fasching, Angelica; Pihl, Liselotte; Patinha, Daniela; Franzén, Stephanie; Palm, Fredrik


    Early stage diabetic nephropathy is characterized by glomerular hyperfiltration and reduced renal tissue Po2. Recent observations have indicated that increased tubular Na(+)-glucose linked transport (SGLT) plays a role in the development of diabetes-induced hyperfiltration. The aim of the present study was to determine how inhibition of SLGT impacts upon Po2 in the diabetic rat kidney. Diabetes was induced by streptozotocin in Sprague-Dawley rats 2 wk before experimentation. Renal hemodynamics, excretory function, and renal O2 homeostasis were measured in anesthetized control and diabetic rats during baseline and after acute SGLT inhibition using phlorizin (200 mg/kg ip). Baseline arterial pressure was similar in both groups and unaffected by SGLT inhibition. Diabetic animals displayed reduced baseline Po2 in both the cortex and medulla. SGLT inhibition improved cortical Po2 in the diabetic kidney, whereas it reduced medullary Po2 in both groups. SGLT inhibition reduced Na(+) transport efficiency [tubular Na(+) transport (TNa)/renal O2 consumption (Qo2)] in the control kidney, whereas the already reduced TNa/Qo2 in the diabetic kidney was unaffected by SGLT inhibition. In conclusion, these data demonstrate that when SGLT is inhibited, renal cortex Po2 in the diabetic rat kidney is normalized, which implies that increased proximal tubule transport contributes to the development of hypoxia in the diabetic kidney. The reduction in medullary Po2 in both control and diabetic kidneys during the inhibition of proximal Na(+) reabsorption suggests the redistribution of active Na(+) transport to less efficient nephron segments, such as the medullary thick ascending limb, which results in medullary hypoxia.

  4. Central angiotensin-(1-7) improves vagal function independent of blood pressure in hypertensive (mRen2)27 rats.

    Nautiyal, Manisha; Shaltout, Hossam A; de Lima, Daniel C; do Nascimento, Kenia; Chappell, Mark C; Diz, Debra I


    Hypertensive transgenic (mRen2)27 rats with overexpression of the mRen2 gene have impaired baroreflex sensitivity for heart rate control and high nicotinamide adenine dinucleotide phosphate oxidase and kinase-to-phosphatase signaling activity in medullary tissue compared with normotensive Hannover Sprague-Dawley control rats. They also exhibit insulin resistance at a young age. To determine whether blocking angiotensin II actions, supplementing angiotensin-(1-7), or scavenging reactive oxygen species in brain differentially alters mean arterial pressure, baroreflex sensitivity, or metabolic function, while altering medullary signaling pathways in these animals, we compared intracerebroventricular infusions of the angiotensin II type 1 receptor antagonist candesartan (4 μg/5 μL/h), angiotensin-(1-7) (0.1 μg/5 μL/h), a reactive oxygen species scavenger tempol (25 μg/5 μL/h), or artificial cerebrospinal fluid (5 μL/h) for 2 weeks. Mean arterial pressure was reduced in candesartan-treated rats without significantly improving the vagal components of baroreflex function or heart rate variability. In contrast, angiotensin-(1-7) treatment significantly improved the vagal components of baroreflex function and heart rate variability at a dose that did not significantly lower mean arterial pressure. Tempol significantly reduced nicotinamide adenine dinucleotide phosphate oxidase activity in brain dorsal medullary tissue but had no effect on mean arterial pressure or autonomic function. Candesartan tended to reduce fat mass, but none of the treatments significantly altered indices of metabolic function or mitogen-activated protein kinase signaling pathways in dorsal medulla. Although additional dose response studies are necessary to determine the potential maximal effectiveness of each treatment, the current findings demonstrate that blood pressure and baroreflex function can be essentially normalized independently of medullary nicotinamide adenine dinucleotide

  5. CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth.

    Strock, Christopher J; Park, Jong-In; Rosen, Mark; Dionne, Craig; Ruggeri, Bruce; Jones-Bolin, Susan; Denmeade, Samuel R; Ball, Douglas W; Nelkin, Barry D


    All of the cases of medullary thyroid carcinoma (MTC) express the RET receptor tyrosine kinase. In essentially all of the hereditary cases and approximately 40% of the sporadic cases of MTC, the RET kinase is constitutively activated by mutation. This suggests that RET may be an effective therapeutic target for treatment of MTC. We show that the indolocarbazole derivatives, CEP-701 and CEP-751, inhibit RET in MTC cells. These compounds effectively inhibit RET phosphorylation in a dose-dependent manner at concentrations <100 nM in 0.5% serum and at somewhat higher concentrations in the presence of 16% serum. They also blocked the growth of these MTC cells in culture. CEP-751 and its prodrug, CEP-2563, also inhibited tumor growth in MTC cell xenografts. These results show that inhibiting RET can block the growth of MTC cells and may have a therapeutic benefit in MTC.

  6. Identification of genes with altered expression in medullary breast cancer vs. ductal breast cancer and normal breast epithelia

    Gjerstorff, Morten; Benoit, Vivian; Laenkholm, Anne-Vibeke


    to both immunological and endogenous cellular factors, although little is known about the distinct biology of MCB that may contribute to the improved outcome of MCB patients. To identify candidate genes, we performed gene array expression analysis of cell lines of MCB, ductal breast cancer and normal......Medullary breast cancer (MCB) is a morphologically and biologically distinct subtype that, despite cytologically highly malignant characteristics, has a favorable prognosis compared to the more common infiltrating ductal breast carcinoma. MCB metastasizes less frequently, which has been attributed......) gene families, Vav1, monoglyceride lipase and NADP+-dependent malic enzyme, exhibited altered expression in MCB vs. ductal breast cancer, and the differences for some of these genes were confirmed on an extended panel of cell lines by quantitative PCR. Immunohistochemical analysis further established...

  7. Identification of genes with altered expression in medullary breast cancer vs. ductal breast cancer and normal breast epithelia

    Gjerstorff, Morten F; Benoit, Vivian M; Laenkholm, Anne-Vibeke;


    Medullary breast cancer (MCB) is a morphologically and biologically distinct subtype that, despite cytologically highly malignant characteristics, has a favorable prognosis compared to the more common infiltrating ductal breast carcinoma. MCB metastasizes less frequently, which has been attributed...... to both immunological and endogenous cellular factors, although little is known about the distinct biology of MCB that may contribute to the improved outcome of MCB patients. To identify candidate genes, we performed gene array expression analysis of cell lines of MCB, ductal breast cancer and normal......) gene families, Vav1, monoglyceride lipase and NADP+-dependent malic enzyme, exhibited altered expression in MCB vs. ductal breast cancer, and the differences for some of these genes were confirmed on an extended panel of cell lines by quantitative PCR. Immunohistochemical analysis further established...

  8. Identification of genes with altered expression in medullary breast cancer vs. ductal breast cancer and normal breast epithelia

    Gjerstorff, Morten; Benoit, Vivian; Laenkholm, Anne-Vibeke


    Medullary breast cancer (MCB) is a morphologically and biologically distinct subtype that, despite cytologically highly malignant characteristics, has a favorable prognosis compared to the more common infiltrating ductal breast carcinoma. MCB metastasizes less frequently, which has been attributed...... to both immunological and endogenous cellular factors, although little is known about the distinct biology of MCB that may contribute to the improved outcome of MCB patients. To identify candidate genes, we performed gene array expression analysis of cell lines of MCB, ductal breast cancer and normal......) gene families, Vav1, monoglyceride lipase and NADP+-dependent malic enzyme, exhibited altered expression in MCB vs. ductal breast cancer, and the differences for some of these genes were confirmed on an extended panel of cell lines by quantitative PCR. Immunohistochemical analysis further established...

  9. The rare intracellular RET mutation p.S891A in a Chinese Han family with familial medullary thyroid carcinoma

    Xiao-Ping Qi; Rong-Xin Zhang; Jin-Lin Cao; Zhen-Guang Chen; Hang-Yang Jin; Ren-Rong Yang


    We report intracellular RET mutation in a Han Chinese pedigree with familial medullary thyroid carcinoma (FMTC). Direct sequencing of RET proto-oncogene identified a missense c.2671T > G (p.S891A) mutation in 6 of 14 family members. The single nucleotide polymorphisms c. 135A > G (p.A45A), IVS4+48A >G, c. 1296A > G (p.A432A), c. 2071G > A (p.G691S), c. 2307T > G (p.L769L) and a variant c. 833C > A (p.T278N) were also found in 6 carriers. Among 5 of the 6 carriers presented medullary thyroid carcinoma (MTC) as an isolated clinical phenotype, with elevated basal serum calcitonin (Ct). Two underwent non-normative thyroidectomy either two or four times without physician awareness or diagnosis of this disease at initial treatment, but with elevated Ct. One with elevated pre-Ct accepted total thyroidectomy (TT) with modified bilateral neck dissection (MBiND), and whose seventh posterior rib MTC metastases was confirmed 5 months after surgery. Moreover, results of two affected individuals with elevated Ct were reduced to normal after TT with MBiND or prophylactic VI compartmental dissection. However, only another carrier with the variant p.T278N had slightly elevated Ct rejected surgery and was strictly monitored. Given these case results, we suggest that screening of RET and pre-surgical Ct levels in the management of MTC patients is essential for earlier diagnosis and more normative initial treatment, that FMTC patients with cervical lymph nodes metastases may be cured by TT with MBiND, and that prophylactic VI compartmental dissection should be avoided when Ct levels are low.


    Winn, Brody; Tavares, Rosemarie; Fanion, Jacqueline; Noble, Lelia; Gao, John; Sabo, Edmond; Resnick, Murray B.


    Undifferentiated or medullary carcinoma (MC) is characterized by its distinct histologic appearance and relatively better prognosis compared to poorly differentiated colonic carcinoma (PDC). These two entities may be difficult to differentiate by light microscopy alone. Only limited immunohistochemical studies investigating MC have been reported. These studies suggest a loss of intestinal differentiation, exemplified by a high percentage of CDX2 negativity. Our aim was to further characterize the immunohistochemical profile of MC, with particular emphasis on intestinal markers. Paraffin blocks from 16 cases of MC and 33 cases of PDC were retrieved and tissue microarrays were constructed and stained with an immunohistochemical panel including, CDX2, CK7, CK20, p53, intestinal trefoil factor 3 (TFF3), chromogranin, synaptophysin, MLH-1, MUC-1, MUC-2 and calretinin. A significantly higher proportion of MC, as opposed to PDC showed loss of staining for MLH-1 and for the intestinal transcription factor CDX2, in accordance with previous studies. MLH-1 staining was present in only 21% of MC cases compared with 60% of the PDC cases (p=0.02), whereas CDX2 was positive in 19% of MCs and 55% of PDCs (p=0.03). Interestingly, calretinin staining was strongly positive in 73% of MCs compared to only 12% of PDCs (p<0.0001). Evidence of intestinal differentiation by MUC-1, MUC-2 and TFF-3 staining was seen in 67, 60 and 53% of the MCs respectively. These three markers were frequently positive in many of the CDX2 negative MC cases. Medullary carcinoma of the colon retains a significant degree of intestinal differentiation as evidenced by its high percentage of staining for MUC-1, MUC-2, and TFF-3. Calretinin, MLH-1 and CDX2 may help to differentiate MC from PDC of the colon. PMID:18992917

  11. Application value of multi-mode ultrasound imaging technique of observing conus medullaris in diagnosis of fetal spina bifida occulta%多模式超声成像技术观察脊髓圆锥在胎儿隐性脊柱裂诊断的应用价值

    刘桃; 李金英; 王抒雁


    Objective To analyze two-dimensional ultrasonography and three-dimensional ultrasound with skeletal pattern and VCI pattern in the observation of position of conus medullaris as well as diagnostic value of their shapes on fetal spina bifida occulta.Methods 51 896 gravidas who underwent prenatal screening during January,2013 to December,2015 were selected,and multi-mode ultrasound imaging technique was used to analyze changes of the position and morphology of conus medullaris in 6 cases of fetal spina bifida occulta which showed by prenatal ultrasound,and they were confirmed by high fre-quency ultrasonography or MRI after delivery.Results Prenatal ultrasound showed that position of conus medullaris of the 6 cases of fetal spina bifida occulta were all significantly lower than pelvis level,losing the normal form of“rat tail”,and one cases was complicated with soft palate cleft(missed prenatal diagnosis).The position and morphology of the conus medullaris could be showed by prenatal ultrasound in 100%.Conclusion Prenatal multi-mode ultrasound imaging is the first choice for the observation of the position and the shape of the conus medullaris,it can provide valuable information.%目的:探讨运用超声检查的二维模式结合三维成像的骨骼模式、VCI 模式观察胎儿脊髓圆锥的位置及其形态对胎儿隐性脊柱裂的诊断价值。方法选取2013年1月至2015年12月行产前系统筛查孕妇51896例,运用多模式超声成像技术分析产前超声提示隐性脊柱裂胎儿6例的脊髓圆锥位置及其形态的变化声像图,且经产后高频超声检查或出生后 MRI 证实。结果6例隐性脊柱裂胎儿中产前超声均发现其脊髓圆锥位置明显低于肾盂水平,失去正常的“鼠尾状”形态,其中1例合并软腭裂(产前漏诊)。产前超声胎儿脊髓圆锥位置及其形态100%可以显示。结论产前多模式超声成像技术是观察胎儿脊髓圆锥位置及其形态的首选

  12. Benefits of hormone therapy estrogens depend on estrogen type: 17β-estradiol and conjugated equine estrogens have differential effects on cognitive, anxiety-like, and depressive-like behaviors and increase tryptophan hydroxylase-2 mRNA levels in dorsal raphe nucleus subregions

    Ryoko Hiroi


    Full Text Available Decreased serotonin (5-HT function is associated with numerous cognitive and affective disorders. Women are more vulnerable to these disorders and have a lower rate of 5-HT synthesis than men. Serotonergic neurons in the dorsal raphe nucleus (DRN are a major source of 5-HT in the forebrain and play a critical role in regulation of stress-related disorders. In particular, polymorphisms of tryptophan hydroxylase-2 (TpH2, the brain-specific, rate-limiting enzyme for 5-HT biosynthesis are implicated in cognitive and affective disorders. Administration of 17β-estradiol (E2, the most potent naturally circulating estrogen in women and rats, can have beneficial effects on cognitive, anxiety-like, and depressive-like behaviors. Moreover, E2 increases TpH2 mRNA in specific subdivisions of the DRN. Although conjugated equine estrogens (CEE are a commonly prescribed estrogen component of hormone therapy in menopausal women, there is a marked gap in knowledge regarding how CEE affects these behaviors and the brain 5-HT system. Therefore, we compared the effects of E2 and CEE treatments on TpH2 mRNA and on behavior. Female Sprague-Dawley rats were ovariectomized, administered either vehicle, E2, or CEE, and tested on a battery of cognitive, anxiety-like, and depressive-like behaviors. The brains of these animals were subsequently analyzed for TpH2 mRNA. E2 increased TpH2 mRNA in the caudal and mid DRN, corroborating previous findings. However, CEE increased TpH2 mRNA in the caudal and rostral, but not the mid DRN, suggesting that distinct estrogens can have subregion-specific effects on TpH2 gene expression. We also found differential correlations between the level of TpH2 mRNA in specific DRN subregions and behavior, depending on the type of behavior. These distinct associations imply that cognition, anxiety-like, and depressive-like behaviors are modulated by unique serotonergic neurocircuitry, opening the possibility of novel avenues of targeted treatment

  13. Postnatal adrenalectomy impairs urinary concentrating ability by increased COX-2 and leads to renal medullary injury

    Stubbe, Jane; Madsen, Kirsten; Nielsen, Finn T


    at postnatal day 10. Adrenalectomized rats were divided into no steroid substitution (ADX), corticosterone replacement (ADX-C), and corticosterone and DOCA substitution (ADX-CD) groups that received subcutaneous pellets with steroids. Without replacement, pups failed to thrive and exhibited impaired urinary...... deprivation, parecoxib attenuated weight loss and the increase in plasma Na+ concentration and osmolality. It is concluded that mineralocorticoid is required for normal postnatal development of the renal medulla. COX-2 contributes to impaired urine-concentrating ability, NaCl loss, and extracellular volume...

  14. Protective effect of sulfated chitosan of C3 sulfation on glycerol-induced acute renal failure in rat kidney.

    Xing, Ronge; Liu, Song; Yu, Huahua; Qin, Yukun; Chen, Xiaolin; Li, Kecheng; Li, Pengcheng


    The purpose of this study was to investigate the protective effects of sulfated chitosan of C3 sulfation (TCTS) on the glycerol-induced acute renal failure. Compared with the normal group, rats from model group exhibited collecting duct and medullary ascending limb dilation and casts by glycerol treating. TCTS, which was injected to pretreat rats by glycerol, exerted a protective effect. The results showed that serum creatinine and blood urea nitrogen were markedly increased in glycerol-treated rats. It is proved that TCTS reduced their levels significantly. Ions level in plasma and urine were significantly changed in glycerol-treated rats, whereas TCTS almost recovered their levels back to normal. For female rats, administration of TCTS reduced their mortality. This study showed a noticeable renal morphologic and functional protection by TCTS in glycerol-induced acute renal failure.

  15. A description of the lumbar interfascial triangle and its relation with the lateral raphe: anatomical constituents of load transfer through the lateral margin of the thoracolumbar fascia.

    Schuenke, M D; Vleeming, A; Van Hoof, T; Willard, F H


    rib to the iliac crest. This triangle results in the unification of different fascial sheaths along the lateral border of the TLF, creating a ridged-union of dense connective tissue that has been termed the lateral raphe (Spine, 9,1984, 163). This triangle may function in the distribution of laterally mediated tension to balance different viscoelastic moduli, along either the middle or posterior layers of the TLF. © 2012 The Authors. Journal of Anatomy © 2012 Anatomical Society.

  16. A description of the lumbar interfascial triangle and its relation with the lateral raphe: anatomical constituents of load transfer through the lateral margin of the thoracolumbar fascia

    Schuenke, M D; Vleeming, A; Van Hoof, T; Willard, F H


    rib to the iliac crest. This triangle results in the unification of different fascial sheaths along the lateral border of the TLF, creating a ridged-union of dense connective tissue that has been termed the lateral raphe (Spine, 9,1984, 163). This triangle may function in the distribution of laterally mediated tension to balance different viscoelastic moduli, along either the middle or posterior layers of the TLF. PMID:22582887

  17. Differential behavioral sensitivity to carbon dioxide (CO2) inhalation in rats.

    Winter, Andrew; Ahlbrand, Rebecca; Naik, Devanshi; Sah, Renu


    Inhalation of carbon dioxide (CO2) is frequently employed as a biological challenge to evoke intense fear and anxiety. In individuals with panic disorder, CO2 reliably evokes panic attacks. Sensitivity to CO2 is highly heterogeneous among individuals, and although a genetic component is implicated, underlying mechanisms are not clear. Preclinical models that can simulate differential responsivity to CO2 are therefore relevant. In the current study we investigated CO2-evoked behavioral responses in four different rat strains: Sprague-Dawley (SD), Wistar (W), Long Evans (LE) and Wistar-Kyoto, (WK) rats. We also assessed tryptophan hydroxylase 2 (TPH-2)-positive serotonergic neurons in anxiety/panic regulatory subdivisions of the dorsal raphe nucleus (DR), as well as dopamine β hydroxylase (DβH)-positive noradrenergic neurons in the locus coeruleus, implicated in central CO2-chemosensitivity. Behavioral responsivity to CO2 inhalation varied between strains. CO2-evoked immobility was significantly higher in LE and WK rats as compared with W and SD cohorts. Differences were also observed in CO2-evoked rearing and grooming behaviors. Exposure to CO2 did not produce conditioned behavioral responses upon re-exposure to CO2 context in any strain. Reduced TPH-2-positive cell counts were observed specifically in the panic-regulatory dorsal raphe ventrolateral (DRVL)-ventrolateral periaqueductal gray (VLPAG) subdivision in CO2-sensitive strains. Conversely, DβH-positive cell counts within the LC were significantly higher in CO2-sensitive strains. Collectively, our data provide evidence for strain dependent, differential CO2-sensitivity and potential differences in monoaminergic systems regulating panic and anxiety. Comparative studies between CO2-vulnerable and resistant strains may facilitate the mechanistic understanding of differential CO2-sensitivity in the development of panic and anxiety disorders.

  18. Behavioral and neurochemical effects of repeated MDMA administration during late adolescence in the rat.

    Cox, Brittney M; Shah, Mrudang M; Cichon, Teri; Tancer, Manuel E; Galloway, Matthew P; Thomas, David M; Perrine, Shane A


    Adolescents and young adults disproportionately abuse 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy'); however, since most MDMA research has concentrated on adults, the effects of MDMA on the developing brain remain obscure. Therefore, we evaluated place conditioning to MDMA (or saline) during late adolescence and assessed anxiety-like behavior and monoamine levels during abstinence. Rats were conditioned to associate 5 or 10mg/kg MDMA or saline with contextual cues over 4 twice-daily sessions. Five days after conditioning, anxiety-like behavior was examined with the open field test and brain tissue was collected to assess serotonin (5-hydroxytryptamine, 5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the dorsal raphe, amygdala, and hippocampus by high-pressure liquid chromatography (HPLC). In a separate group of rats, anxiety-like and avoidant behaviors were measured using the light-dark box test under similar experimental conditions. MDMA conditioning caused a place aversion at 10, but not at 5, mg/kg, as well as increased anxiety-like behavior in the open field and avoidant behavior in light-dark box test at the same dose. Additionally, 10mg/kg MDMA decreased 5-HT in the dorsal raphe, increased 5-HT and 5-HIAA in the amygdala, and did not alter levels in the hippocampus. Overall, we show that repeated high (10mg/kg), but not low (5mg/kg), dose MDMA during late adolescence in rats increases anxiety-like and avoidant behaviors, accompanied by region-specific alterations in 5-HT levels during abstinence. These results suggest that MDMA causes a region-specific dysregulation of the serotonin system during adolescence that may contribute to maladaptive behavior.

  19. Behavioral impairments in rats with chronic epilepsy suggest comorbidity between epilepsy and attention deficit/hyperactivity disorder.

    Pineda, Eduardo; Jentsch, J David; Shin, Don; Griesbach, Grace; Sankar, Raman; Mazarati, Andrey


    Attention deficit/hyperactivity disorder (ADHD) is encountered among patients with epilepsy at a significantly higher rate than in the general population. Mechanisms of epilepsy-ADHD comorbidity remain largely unknown. We investigated whether a model of chronic epilepsy in rats produces signs of ADHD, and thus, whether it can be used for studying mechanisms of this comorbidity. Epilepsy was induced in male Wistar rats via pilocarpine status epilepticus. Half of the animals exhibited chronic ADHD-like abnormalities, particularly increased impulsivity and diminished attention in the lateralized reaction-time task. These impairments correlated with the suppressed noradrenergic transmission in locus coeruleus outputs. The other half of animals exhibited depressive behavior in the forced swimming test congruently with the diminished serotonergic transmission in raphe nucleus outputs. Attention deficit/hyperactivity disorder and depressive behavior appeared mutually exclusive. Therefore, the pilocarpine model of epilepsy affords a system for reproducing and studying mechanisms of comorbidity between epilepsy and both ADHD and/or depression.

  20. Medullary thyroid carcinoma in a 2-month-old male with multiple endocrine neoplasia 2B and symptoms of pseudo-Hirschsprung disease: a case report.

    Unruh, Annika; Fitze, Guido; Jänig, Ute; Bielack, Stefan; Lochbühler, Helmut; Coerdt, Wiltrud


    A 5-week-old male patient was seen for symptoms suggestive of Hirschsprung disease (abdominal distension, failure to thrive, and explosive defecation). Rectum biopsies revealed an intestinal ganglioneuromatosis, which is usually associated with multiple endocrine neoplasia (MEN) syndrome type 2B. The ensuing molecular genetic analysis revealed a M918T mutation of the RET protooncogene, which is associated with early-onset medullary thyroid carcinoma (MTC). Therefore, total thyroidectomy and central lymphadenectomy were performed at the age of 9 weeks. Histology showed a medullary microcarcinoma. This report of MTC occurrence within the first weeks of life underlines the importance of early diagnosis and thyroidectomy in patients with MEN 2B syndrome. Because many patients with MEN 2A and B show gastrointestinal symptoms before the development of MTC, the possibility of MEN 2 should be recognized, and genetic testing for the presence of RET mutations should be included in the explorative diagnosis for megacolon.