Science.gov

Sample records for newborn mice restore

  1. Safety study of Ciprofloxacin in newborn mice.

    PubMed

    Bourgeois, Thomas; Delezoide, Anne-Lise; Zhao, Wei; Guimiot, Fabien; Adle-Biassette, Homa; Durand, Estelle; Ringot, Maud; Gallego, Jorge; Storme, Thomas; Le Guellec, Chantal; Kassaï, Behrouz; Turner, Mark A; Jacqz-Aigrain, Evelyne; Matrot, Boris

    2016-02-01

    Ciprofloxacin, a broad-spectrum antimicrobial agent belonging to the fluoroquinolone family, is prescribed off-label in infants less than one year of age. Ciprofloxacin is included in the European Medicines Agency priority list of off-patent medicinal products requiring evaluation in neonates. This evaluation is undergoing within the TINN (Treat Infections in Neonates) FP7 EU project. As part of the TINN project, the present preclinical study was designed to assess the potential adverse effects of Ciprofloxacin on neurodevelopment, liver and joints in mice. Newborn mice received subcutaneous Ciprofloxacin at 10, 30 and 100 mg/kg/day from 2 to 12 postnatal days. Peak plasma levels of Ciprofloxacin were in the range of levels measured in human neonates. We examined vital functions in vivo, including cardiorespiratory parameters and temperature, psychomotor development, exploratory behavior, arthro-, nephro- and hepato-toxic effects. We found no effect of Ciprofloxacin at 10 and 30 mg/kg/day. In contrast, administration at 100 mg/kg/day delayed weight gain, impaired cardiorespiratory and psychomotor development, caused inflammatory infiltrates in the connective tissues surrounding the knee joint, and moderately increased extramedullary hematopoiesis. The present study pleads for careful watching of cardiorespiratory and motor development in neonates treated with Ciprofloxacin, in addition to the standard surveillance of arthrotoxicity.

  2. Hyperoxia exposure alters hepatic eicosanoid metabolism in newborn mice.

    PubMed

    Rogers, Lynette K; Tipple, Trent E; Britt, Rodney D; Welty, Stephen E

    2010-02-01

    Prematurely born infants are often treated with supraphysiologic amounts of oxygen, which is associated with lung injury and the development of diseases such as bronchopulmonary dysplasia. Complimentary responses between the lung and liver during the course of hyperoxic lung injury have been studied in adult animals, but little is known about this relationship in neonates. These studies tested the hypothesis that oxidant stress occurs in the livers of newborn mice in response to continuous hyperoxia exposure. Greater levels of glutathione disulfide and nitrotyrosine were detected in lung tissues but not liver tissues from newborn mice exposed to hyperoxia than in room air-exposed controls. However, early increases in 5-lipoxygenase and cyclooxygenases-2 protein levels and increases in total hydroxyeicosatetraenoic acid and prostaglandin levels were observed in the liver tissues of hyperoxia-exposed pups. These studies indicate that free radical oxidation occurs in the lungs of newborn pups exposed to hyperoxia, and alterations in lipid metabolism could be a primary response in the liver tissues. The findings of this study identify possible new mechanisms associated with hyperoxic lung injury in a newborn model of bronchopulmonary dysplasia and thus open opportunities for research.

  3. Melatonin prevents learning disorders in brain-lesioned newborn mice.

    PubMed

    Bouslama, M; Renaud, J; Olivier, P; Fontaine, R H; Matrot, B; Gressens, P; Gallego, J

    2007-12-12

    Perinatal brain injuries often result in irreversible learning disabilities, which manifest in early childhood. These injuries are chiefly ascribable to marked susceptibility of the immature brain to glutamate-induced excitotoxicity. No treatments are available. One well-characterized model of perinatal brain injuries consists in injecting the glutamate analog ibotenate into the brain of 5-day-old mice. The resulting excitotoxic lesions resemble the hypoxic-ischemic gray-matter lesions seen in full-term and near-term newborns, as well as the white-matter lesions of preterm newborns. We previously reported that these lesions disrupted odor preference conditioning in newborn mice. The aim of this study was to assess the effectiveness of the neuroprotector melatonin in preventing learning disabilities in newborn mice with ibotenate-induced brain injury. In postnatal day (P) 6-P7 pups, we tested psychomotor reflexes, spontaneous preference for maternal odors as an index of memory, ultrasonic vocalization responses to stroking as an index of sensitivity to tactile stimuli, and conditioned preference for an odor previously paired with stroking as an index of learning abilities. Without melatonin, conditioning was abolished, whereas spontaneous odor preference, psychomotor reflexes, and sensitivity to tactile stimuli were normal. Thus, abolition of conditioning was not associated with sensorimotor impairments. Histological analysis confirmed the efficacy of melatonin in reducing white-matter lesions induced by ibotenate. Furthermore, treatment with melatonin protected the ability to develop conditioning. Thus, melatonin, which easily crosses the blood-brain barrier and has been proven safe in children, may be effective in preventing learning disabilities caused by perinatal brain injuries in human preterm infants.

  4. Cold stimulates the behavioral response to hypoxia in newborn mice.

    PubMed

    Bollen, Bieke; Bouslama, Myriam; Matrot, Boris; Rotrou, Yann; Vardon, Guy; Lofaso, Frédéric; Van den Bergh, Omer; D'Hooge, Rudi; Gallego, Jorge

    2009-05-01

    In newborns, hypoxia elicits increased ventilation, arousal followed by defensive movements, and cries. Cold is known to affect the ventilatory response to hypoxia, but whether it affects the arousal response remains unknown. The aim of the present study was to assess the effects of cold on the ventilatory and arousal responses to hypoxia in newborn mice. We designed an original platform measuring noninvasively and simultaneously the breathing pattern by whole body plethysmography, body temperature by infrared thermography, as well as motor and ultrasonic vocal (USV) responses. Six-day-old mice were exposed twice to 10% O(2) for 3 min at either cold temperature (26 degrees C) or thermoneutrality (33 degrees C). At 33 degrees C, hypoxia elicited a marked increase in ventilation followed by a small ventilatory decline, small motor response, and almost no USVs. Body temperature was not influenced by hypoxia, and oxygen consumption (Vo(2)) displayed minimal changes. At 26 degrees C, hypoxia elicited a slight increase in ventilation with a large ventilatory decline and a large drop of Vo(2). This response was accompanied by marked USV and motor responses. Hypoxia elicited a small decrease in temperature after the return to normoxia, thus precluding any causal influence on the motor and USV responses to hypoxia. In conclusion, cold stimulated arousal and stress responses to hypoxia, while depressing hypoxic hyperpnea. Arousal is an important defense mechanism against sleep-disordered breathing. The dissociation between ventilatory and behavioral responses to hypoxia suggests that deficits in the arousal response associated with sleep breathing disorders cannot be attributed to a depressed hypoxic response.

  5. Laser speckle contrast imaging of cerebral blood flow of newborn mice at optical clearing

    NASA Astrophysics Data System (ADS)

    Timoshina, Polina A.; Zinchenko, Ekaterina M.; Tuchina, Daria K.; Sagatova, Madina M.; Semyachkina-Glushkovskaya, Oxana V.; Tuchin, Valery V.

    2017-03-01

    In this work, we consider the use of optical clearing agents to improve imaging quality of the cerebral blood flow of newborn mice. Aqueous 60%-glycerol solution, aqueous 70%-OmnipaqueTM(300) solution and OmnipaqueTM (300) solution in water/DMSO(25%/5%) were selected as the optical clearing agents. Laser speckle contrast imaging (LSCI) was used for imaging of cerebral blood flow in newborn mice brain during topical optical clearing of tissuesin the area of the fontanelle. These results demonstrate the effectiveness of glycerol and Omnipaque solutions as optical clearing agents for investigation of cerebral blood flow in newborn mice without scalp removing and skull thinning.

  6. Gene Therapy Restores Hair Cell Stereocilia Morphology in Inner Ears of Deaf Whirler Mice.

    PubMed

    Chien, Wade W; Isgrig, Kevin; Roy, Soumen; Belyantseva, Inna A; Drummond, Meghan C; May, Lindsey A; Fitzgerald, Tracy S; Friedman, Thomas B; Cunningham, Lisa L

    2016-02-01

    Hereditary deafness is one of the most common disabilities affecting newborns. Many forms of hereditary deafness are caused by morphological defects of the stereocilia bundles on the apical surfaces of inner ear hair cells, which are responsible for sound detection. We explored the effectiveness of gene therapy in restoring the hair cell stereocilia architecture in the whirlin mouse model of human deafness, which is deaf due to dysmorphic, short stereocilia. Wild-type whirlin cDNA was delivered via adeno-associated virus (AAV8) by injection through the round window of the cochleas in neonatal whirler mice. Subsequently, whirlin expression was detected in infected hair cells (IHCs), and normal stereocilia length and bundle architecture were restored. Whirlin gene therapy also increased inner hair cell survival in the treated ears compared to the contralateral nontreated ears. These results indicate that a form of inherited deafness due to structural defects in cochlear hair cells is amenable to restoration through gene therapy.

  7. Gene Therapy Restores Hair Cell Stereocilia Morphology in Inner Ears of Deaf Whirler Mice

    PubMed Central

    Chien, Wade W; Isgrig, Kevin; Roy, Soumen; Belyantseva, Inna A; Drummond, Meghan C; May, Lindsey A; Fitzgerald, Tracy S; Friedman, Thomas B; Cunningham, Lisa L

    2016-01-01

    Hereditary deafness is one of the most common disabilities affecting newborns. Many forms of hereditary deafness are caused by morphological defects of the stereocilia bundles on the apical surfaces of inner ear hair cells, which are responsible for sound detection. We explored the effectiveness of gene therapy in restoring the hair cell stereocilia architecture in the whirlin mouse model of human deafness, which is deaf due to dysmorphic, short stereocilia. Wild-type whirlin cDNA was delivered via adeno-associated virus (AAV8) by injection through the round window of the cochleas in neonatal whirler mice. Subsequently, whirlin expression was detected in infected hair cells (IHCs), and normal stereocilia length and bundle architecture were restored. Whirlin gene therapy also increased inner hair cell survival in the treated ears compared to the contralateral nontreated ears. These results indicate that a form of inherited deafness due to structural defects in cochlear hair cells is amenable to restoration through gene therapy. PMID:26307667

  8. Self-organization process in newborn skin organoid formation inspires strategy to restore hair regeneration of adult cells.

    PubMed

    Lei, Mingxing; Schumacher, Linus J; Lai, Yung-Chih; Juan, Wen-Tau; Yeh, Chao-Yuan; Wu, Ping; Jiang, Ting-Xin; Baker, Ruth E; Widelitz, Randall Bruce; Yang, Li; Chuong, Cheng-Ming

    2017-08-22

    Organoids made from dissociated progenitor cells undergo tissue-like organization. This in vitro self-organization process is not identical to embryonic organ formation, but it achieves a similar phenotype in vivo. This implies genetic codes do not specify morphology directly; instead, complex tissue architectures may be achieved through several intermediate layers of cross talk between genetic information and biophysical processes. Here we use newborn and adult skin organoids for analyses. Dissociated cells from newborn mouse skin form hair primordia-bearing organoids that grow hairs robustly in vivo after transplantation to nude mice. Detailed time-lapse imaging of 3D cultures revealed unexpected morphological transitions between six distinct phases: dissociated cells, cell aggregates, polarized cysts, cyst coalescence, planar skin, and hair-bearing skin. Transcriptome profiling reveals the sequential expression of adhesion molecules, growth factors, Wnts, and matrix metalloproteinases (MMPs). Functional perturbations at different times discern their roles in regulating the switch from one phase to another. In contrast, adult cells form small aggregates, but then development stalls in vitro. Comparative transcriptome analyses suggest suppressing epidermal differentiation in adult cells is critical. These results inspire a strategy that can restore morphological transitions and rescue the hair-forming ability of adult organoids: (i) continuous PKC inhibition and (ii) timely supply of growth factors (IGF, VEGF), Wnts, and MMPs. This comprehensive study demonstrates that alternating molecular events and physical processes are in action during organoid morphogenesis and that the self-organizing processes can be restored via environmental reprogramming. This tissue-level phase transition could drive self-organization behavior in organoid morphogenies beyond the skin.

  9. Physical Exercise Restores the Generation of Newborn Neurons in an Animal Model of Chronic Epilepsy

    PubMed Central

    Mendonça, Fabricio N.; Santos, Luiz E. C.; Rodrigues, Antônio M.; Gomes da Silva, Sérgio; Arida, Ricardo M.; da Silveira, Gilcélio A.; Scorza, Fulvio A.; Almeida, Antônio-Carlos G.

    2017-01-01

    Neurogenesis impairment is associated with the chronic phase of the epilepsy in humans and also observed in animal models. Recent studies with animal models have shown that physical exercise is capable of improving neurogenesis in adult subjects, alleviating cognitive impairment and depression. Here, we show that there is a reduction in the generation of newborn granule cells in the dentate gyrus of adult rats subjected to a chronic model of epilepsy during the postnatal period of brain development. We also show that the physical exercise was capable to restore the number of newborn granule cells in this animals to the level observed in the control group. Notably, a larger number of newborn granule cells exhibiting morphological characteristics indicative of correct targeting into the hippocampal circuitry and the absence of basal dendrite projections was also observed in the epileptic animals subjected to physical exercise compared to the epileptic animals. The results described here could represent a positive interference of the physical exercise on the neurogenesis process in subjects with chronic epilepsy. The results may also help to reinterpret the benefits of the physical exercise in alleviating symptoms of depression and cognitive dysfunction. PMID:28298884

  10. Physical Exercise Restores the Generation of Newborn Neurons in an Animal Model of Chronic Epilepsy.

    PubMed

    Mendonça, Fabricio N; Santos, Luiz E C; Rodrigues, Antônio M; Gomes da Silva, Sérgio; Arida, Ricardo M; da Silveira, Gilcélio A; Scorza, Fulvio A; Almeida, Antônio-Carlos G

    2017-01-01

    Neurogenesis impairment is associated with the chronic phase of the epilepsy in humans and also observed in animal models. Recent studies with animal models have shown that physical exercise is capable of improving neurogenesis in adult subjects, alleviating cognitive impairment and depression. Here, we show that there is a reduction in the generation of newborn granule cells in the dentate gyrus of adult rats subjected to a chronic model of epilepsy during the postnatal period of brain development. We also show that the physical exercise was capable to restore the number of newborn granule cells in this animals to the level observed in the control group. Notably, a larger number of newborn granule cells exhibiting morphological characteristics indicative of correct targeting into the hippocampal circuitry and the absence of basal dendrite projections was also observed in the epileptic animals subjected to physical exercise compared to the epileptic animals. The results described here could represent a positive interference of the physical exercise on the neurogenesis process in subjects with chronic epilepsy. The results may also help to reinterpret the benefits of the physical exercise in alleviating symptoms of depression and cognitive dysfunction.

  11. Maternal immunity partially protects newborn mice against a Chlamydia trachomatis intranasal challenge

    PubMed Central

    Pal, Sukumar; Tatarenkova, Olga; de la Maza, Luis M.

    2010-01-01

    To determine the role of maternal immunity in protecting newborn mice against a C. trachomatis infection female BALB/c mice were immunized intranasally (i.n.) with 104 inclusion forming units (IFU) of the C. trachomatis mouse pneumonitis biovar (MoPn). As a control, another group of female mice was sham-immunized i.n. with HeLa cell extracts. Immunized animals mounted strong immune responses as evidenced by high Chlamydia-specific antibody titers in serum and milk. Newborn mice born from immunized and sham-immunized dams were challenged i.n. with 103 IFU of MoPn at 2-post natal days (PND). Following inoculation, newborn mice were euthanized at 7-PND and 18-PND and the lungs, spleen and intestine were cultured for Chlamydia. Overall, no significant differences were observed between the mice born from and fed by immunized dams and mice born from and fed by sham-immunized dams. Of the mice born from immunized dams, 75% and 25% had positive lung cultures at 7-PND and 18-PND, respectively. Of the mice born from sham-immunized dams, 82% and 50% had positive lung cultures for those same days. When the number of IFU recovered from the lungs and spleens were compared between the two groups no significant differences were observed. However, when the number of IFU recovered from the small intestine were compared, significant differences were observed between the two groups of newborn mice (2×105 versus 32×106 at 7-PND and 9.2×106 versus 85×106 at 18-PND). In conclusion, maternal immunity plays a limited role in protecting newborn mice against a Chlamydia infection. PMID:20554327

  12. Functional Deficiency of Aryl Hydrocarbon Receptor Augments Oxygen Toxicity-Induced Alveolar Simplification in Newborn Mice

    PubMed Central

    Shivanna, Binoy; Zhang, Wenyan; Jiang, Weiwu; Welty, Stephen E.; Couroucli, Xanthi I.; Wang, Lihua; Moorthy, Bhagavatula

    2013-01-01

    Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. New BPD is characterized as having alveolar simplification. We reported previously that aryl hydrocarbon receptor (AhR) deficiency increased susceptibility to hyperoxic lung injury in adult mice, and this was associated with decreased expression of cytochrome P450 1A enzymes and increased lung inflammation. Whether AhR protects newborn mice against hyperoxia-induced alveolar simplification is unknown. Thus, we tested the hypothesis that decreased activation of the pulmonary AhR augments hyperoxia-induced alveolar simplification and lung inflammation in newborn mice. Experimental groups included one-day old wild type (WT) and AhR dysfunctional (AhRd) mice exposed to 21% O2 (air) or 85% O2 (hyperoxia) for 14 d. Exposure of newborn WT mice to hyperoxia resulted in increased protein, enzyme and mRNA expression of the AhR-regulated lung cytochrome P450 1A1, NAD(P)H quinone oxidoreductase-1, and microsomal glutathione S-transferase 1 enzymes, suggesting that hyperoxia increases activation of the pulmonary AhR. On the other hand, in the AhRd mice, hyperoxia induced the AhR-regulated enzymes to a lesser extent probably due to the dysfunctional AhR in these mice. Alveolar simplification and lung inflammation was increased in mice exposed to hyperoxia compared to those exposed to air, and AhRd mice were more susceptible to hyperoxia-induced alveolar simplification and lung inflammation compared to WT mice. These findings suggest that decreased activation of the pulmonary AhR in newborn AhRd mice augments hyperoxia-induced alveolar simplification and lung inflammation in these mice. PMID:23337360

  13. Mechanism of T-cell mediated protection in newborn mice against a Chlamydia infection.

    PubMed

    Pal, Sukumar; de la Maza, Luis M

    2013-01-01

    To determine the immune components needed for protection of newborn mice against Chlamydia muridarum, animals born to Chlamydia-immunized and to sham-immunized dams were infected intranasally with C. muridarum at 2 post-natal days. T-cells isolated from immunized or sham-immunized adult mice were adoptively transferred to newborn mice at the time of infection. Also, to establish what cytokines are involved in protection, IFN-γ, TNF-α, IL-10, and IL-12 were passively transferred to newborn mice. To assess the Chlamydia burden in the lungs mice were euthanized at 12 post-natal days. When T-cells from immunized adult mice were transferred, mice born to and fed by immunized dams were significantly protected as evidenced by the reduced number of Chlamydia isolated from the lungs compared to mice born to and fed by sham-immunized dams. Transfer of IFN-γ and TNF-α also significantly reduced the number of Chlamydia in the lungs of mice born to immunized dams. Transfer of IL-10 or IL-12 did not result in a significant reduction of Chlamydia. In vitro T-cell proliferation data suggest that neonatal antigen presenting cells can present Chlamydia antigens to adult T-cells. In conclusion, maternal antibodies and Chlamydia specific T-cells or Th1 cytokines are required for protection of neonates against this pathogen.

  14. MTBVAC vaccine is safe, immunogenic and confers protective efficacy against Mycobacterium tuberculosis in newborn mice.

    PubMed

    Aguilo, Nacho; Uranga, Santiago; Marinova, Dessislava; Monzon, Marta; Badiola, Juan; Martin, Carlos

    2016-01-01

    Development of novel more efficient preventive vaccines against tuberculosis (TB) is crucial to achieve TB eradication by 2050, one of the Millennium Development Goals (MDG) for the current century. MTBVAC is the first and only live attenuated vaccine based on a human isolate of Mycobacterium tuberculosis developed as BCG-replacement strategy in newborns that has entered first-in-human adult clinical trials. In this work, we characterize the safety, immunogenicity and protective efficacy of MTBVAC in a model of newborn C57/BL6 mice. Our data clearly indicate that MTBVAC is safe for newborn mice, and does not affect animal growth or organ development. In addition, MTBVAC-vaccinated mice at birth showed enhanced immunogenicity and better protection against M. tuberculosis challenge in comparison with BCG. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. MTBVAC vaccine is safe, immunogenic and confers protective efficacy against Mycobacterium tuberculosis in newborn mice

    PubMed Central

    Aguilo, Nacho; Uranga, Santiago; Marinova, Dessislava; Monzon, Marta; Badiola, Juan; Martin, Carlos

    2016-01-01

    Summary Development of novel more efficient preventive vaccines against tuberculosis (TB) is crucial to achieve TB eradication by 2050, one of the Millennium Development Goals (MDG) for the current century. MTBVAC is the first and only live attenuated vaccine based on a human isolate of Mycobacterium tuberculosis developed as BCG-replacement strategy in newborns that has entered first-in-human adult clinical trials. In this work, we characterize the safety, immunogenicity and protective efficacy of MTBVAC in a model of newborn C57/BL6 mice. Our data clearly indicate that MTBVAC is safe for newborn mice, and does not affect animal growth or organ development. In addition, MTBVAC-vaccinated mice at birth showed enhanced immunogenicity and better protection against M. tuberculosis challenge in comparison with BCG. PMID:26786657

  16. Arsenic speciation transported through the placenta from mother mice to their newborn pups.

    PubMed

    Jin, Yaping; Xi, Shuhua; Li, Xin; Lu, Chunwei; Li, Gexin; Xu, Yuanyuan; Qu, Chunqing; Niu, Yuhong; Sun, Guifan

    2006-07-01

    The primary goal of the present study was to confirm the arsenic species that can be transferred from the mother to the bodies of newborn pups through the placenta and the speciated arsenic distribution in the liver and brain of newborn mice after gestational maternal exposure to inorganic arsenic (iAs). Mother mice were exposed to iAsIII and iAsV in drinking water during gestation. The livers and brains of the mother mice and their newborn pups were taken. Contents of iAs, monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), and trimethylarsenic (TMA) compound were detected using the HG-AAS method. Contents of iAs, MMA, and DMA in the liver of mother mice increased with the concentration of arsenite or arsenate in their drinking water. However, only DMA increased with the concentration of arsenate or arsenite in the drinking water in the brain of mother mice. On the other hand, contents of both iAs and DMA in the liver and brain of newborn mice increased with the concentration of arsenate or arsenite administered to their mother orally. Contents of arsenic species in the liver and brain of both mother mice and their newborn pups were significantly lower in the 10 ppm iAsV group than in the 10 ppm iAsIII group. Ratios of iAs or DMA levels between the brain and the liver of newborn mice were larger than 1, whereas those in mother mice were much smaller than 1. iAs taken from drinking water was distributed and metabolized mainly in the liver of mother mice. iAsIII in low levels may be taken up and metabolized easily in the liver compared to iAsV. Both iAs and DMA are transferred from the mother through the placenta and cross the immature blood-brain barrier (BBB) easily. Compared to that in the liver of newborn mice, DMA as an organic metabolite is prevalent in brain, a lipidic organ, if the BBB is not matured enough to prevent it from entering the brain.

  17. Methylphenidate restores novel object recognition in DARPP-32 knockout mice.

    PubMed

    Heyser, Charles J; McNaughton, Caitlyn H; Vishnevetsky, Donna; Fienberg, Allen A

    2013-09-15

    Previously, we have shown that Dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32) knockout mice required significantly more trials to reach criterion than wild-type mice in an operant reversal-learning task. The present study was conducted to examine adult male and female DARPP-32 knockout mice and wild-type controls in a novel object recognition test. Wild-type and knockout mice exhibited comparable behavior during the initial exploration trials. As expected, wild-type mice exhibited preferential exploration of the novel object during the substitution test, demonstrating recognition memory. In contrast, knockout mice did not show preferential exploration of the novel object, instead exhibiting an increase in exploration of all objects during the test trial. Given that the removal of DARPP-32 is an intracellular manipulation, it seemed possible to pharmacologically restore some cellular activity and behavior by stimulating dopamine receptors. Therefore, a second experiment was conducted examining the effect of methylphenidate. The results show that methylphenidate increased horizontal activity in both wild-type and knockout mice, though this increase was blunted in knockout mice. Pretreatment with methylphenidate significantly impaired novel object recognition in wild-type mice. In contrast, pretreatment with methylphenidate restored the behavior of DARPP-32 knockout mice to that observed in wild-type mice given saline. These results provide additional evidence for a functional role of DARPP-32 in the mediation of processes underlying learning and memory. These results also indicate that the behavioral deficits in DARPP-32 knockout mice may be restored by the administration of methylphenidate.

  18. EFFECT OF HYPOXIA ON THE RATE OF OXYGEN CONSUMPTION OF NEWBORN, YOUNG, AND ADULT MICE AT VARIOUS ENVIRONMENTAL TEMPERATURES,

    DTIC Science & Technology

    Critical Po2 that is, Po2 below the point at which oxygen consumption is reduced - was measured in newborn, 5-day-old, and adult mice. At...thermoneutral environmental temperatures, the critical Po2 of newborn was 85 mm. Hg; that of 5-day-old mice was 100 mm. Hg; and that of adults was 70 mm. Hg

  19. Toltrazuril treatment of congenitally acquired Neospora caninum infection in newborn mice.

    PubMed

    Strohbusch, M; Müller, N; Hemphill, A; Krebber, R; Greif, G; Gottstein, B

    2009-06-01

    C57BL/6 mice were infected with Neospora caninum tachyzoites during pregnancy, yielding a transplacental infection of developing fetuses. Subsequently, congenitally infected newborn mice were treated either once or three times with toltrazuril (or placebo) at a concentration of 31.25 mg compound per kg body weight. Both toltrazuril and placebo treatment had no negative effect on newborns, as noninfected treated pups developed normally without differences in mortality and morbidity to matching nontreated control animals. Already one application of toltrazuril was significantly (p < 0.01) able to delay the outbreak of neosporosis in newborn mice, when compared to placebo-treated infected controls. We found significantly higher proportion of surviving newborns in one-time-toltrazuril-treated and three-time-toltrazuril-treated groups (34% and 54%, respectively) when compared to one-time-placebo-treated and three-time-placebo-treated groups (14% and 30%, respectively). There was no significant difference (p = 0.2) in the proportion of surviving pups between one-time-toltrazuril and three-time-toltrazuril treatment. However, the number of diseased and Neospora-positive pups (46% and 47%, respectively) was markedly reduced after three-time-toltrazuril treatment compared to all other groups. Three-time-treatment also resulted in the highest antibody (IgG, IgG2a) response. Pharmacokinetic analyses using individual serum samples revealed that, although toltrazuril was absorbed and metabolized to toltrazuril sulfone by newborn mice, medicated animals exhibited an unexpected rapid turn-over (half-life time) of the compound. Toltrazuril and the metabolite were also found in brain tissues, indicating that passage of the blood-brain barrier occurred. In conclusion, we could show that three times treatment with toltrazuril had a high impact on the course of infection in congenitally N. caninum-infected newborn mice.

  20. Enzyme replacement therapy in newborn mucopolysaccharidosis IVA mice: early treatment rescues bone lesions?

    PubMed

    Tomatsu, Shunji; Montaño, Adriana M; Oikawa, Hirotaka; Dung, Vu Chi; Hashimoto, Amiko; Oguma, Toshihiro; Gutiérrez, Monica L; Takahashi, Tatsuo; Shimada, Tsutomu; Orii, Tadao; Sly, William S

    2015-02-01

    We treated mucopolysaccharidosis IVA (MPS IVA) mice to assess the effects of long-term enzyme replacement therapy (ERT) initiated at birth, since adult mice treated by ERT showed little improvement in bone pathology [1]. To conduct ERT in newborn mice, we used recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produced in a CHO cell line. First, to observe the tissue distribution pattern, a dose of 250units/g body weight was administered intravenously in MPS IVA mice at day 2 or 3. The infused enzyme was primarily recovered in the liver and spleen, with detectable activity in the bone and brain. Second, newborn ERT was conducted after a tissue distribution study. The first injection of newborn ERT was performed intravenously, the second to fourth weekly injections were intraperitoneal, and the remaining injections from 5th to 14th weeks were intravenous into the tail vein. MPS IVA mice treated with GALNS showed clearance of lysosomal storage in the liver and spleen, and sinus lining cells in bone marrow. The column structure of the growth plate was organized better than that in adult mice treated with ERT; however, hyaline and fibrous cartilage cells in the femur, spine, ligaments, discs, synovium, and periosteum still had storage materials to some extent. Heart valves were refractory to the treatment. Levels of serum keratan sulfate were kept normal in newborn ERT mice. In conclusion, the enzyme, which enters the cartilage before the cartilage cell layer becomes mature, prevents disorganization of column structure. Early treatment from birth leads to partial remission of bone pathology in MPS IVA mice. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice.

    PubMed

    Garcia, Stéphanie; Dirat, Béatrice; Tognacci, Thomas; Rochet, Nathalie; Mouska, Xavier; Bonnafous, Stéphanie; Patouraux, Stéphanie; Tran, Albert; Gual, Philippe; Le Marchand-Brustel, Yannick; Gennero, Isabelle; Gouze, Elvire

    2013-09-18

    Achondroplasia is a rare genetic disease characterized by abnormal bone development, resulting in short stature. It is caused by a single point mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3), which leads to prolonged activation upon ligand binding. To prevent excessive intracellular signaling and rescue the symptoms of achondroplasia, we have developed a recombinant protein therapeutic approach using a soluble form of human FGFR3 (sFGFR3), which acts as a decoy receptor and prevents FGF from binding to mutant FGFR3. sFGFR3 was injected subcutaneously to newborn Fgfr3(ach/+) mice-the mouse model of achondroplasia-twice per week throughout the growth period during 3 weeks. Effective maturation of growth plate chondrocytes was restored in bones of treated mice, with a dose-dependent enhancement of skeletal growth in Fgfr3(ach/+) mice. This resulted in normal stature and a significant decrease in mortality and associated complications, without any evidence of toxicity. These results describe a new approach for restoring bone growth and suggest that sFGFR3 could be a potential therapy for children with achondroplasia and related disorders.

  2. Effects of plum extract on skeletal system of fetal and newborn mice.

    PubMed

    Monsefi, Malihezaman; Parvin, Fatemeh; Farzaneh, Maryam

    2013-01-01

    To evaluate the effects of Prunus domestica L. extracts on fetuses and neonatal skeletal systems. A total of 32 pregnant mice (Mus musculus) received vehicle and plum hydroalcoholic extract at gestational days 1-18 and during the entire gestational period as well as 10 days postpartum, respectively. A total of 30 nonpregnant mice were fed plum hydroalcoholic extract and plum juice extract for 30 days. Bone calcium content and serum concentrations of calcium, magnesium and alkaline phosphatase were measured. The skeletal systems of their fetuses and neonates were stained with Alcian blue and alizarin red S and the length of femur, tibia, and their ossification center were measured. Crown-rump length of the newborn mice from mothers treated with plum extract (4.61 ± 0.25 mm) was higher compared to the control group (4.48 ± 0.31 mm, p = 0.001), and the femur osteogenesis index of newborn mice from mothers treated with plum extract was also higher (0.87 ± 0.09) compared to the control group (0.81 ± 0.06, p = 0.007). The findings showed that pregnant mice treated with plum extract had fetuses and newborn mice with higher osteogenesis index than those of the controls. Copyright © 2013 S. Karger AG, Basel.

  3. Enzyme replacement therapy in newborn mucopolysaccharidosis IVA mice: early treatment rescues bone lesions?

    PubMed Central

    Tomatsu, Shunji; Montaño, Adriana M.; Oikawa, Hirotaka; Dung, Vu Chi; Hashimoto, Amiko; Oguma, Toshihiro; Takahashi, Tatsuo; Shimada, Tsutomu; Orii, Tadao; Sly, William S.

    2014-01-01

    We treated mucopolysaccharidosis IVA (MPS IVA) mice to assess the effects of long-term enzyme replacement therapy (ERT) initiated at birth, since adult mice treated by ERT showed little improvement in bone pathology (1). To conduct ERT in newborn mice, we used recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produced in a CHO cell line. First, to observe the tissue distribution pattern, a dose of 250 units/g body weight was administered intravenously in MPS IVA mice at day 2 or 3. The infused enzyme was primarily recovered in liver and spleen, with detectable activity in bone and brain. Second, newborn ERT was conducted after tissue distribution study. The first injection of newborn ERT was performed intravenously, the second to fourth weekly injections were intraperitoneal, and the remaining injections from 5th to 14th week were intravenous into the tail vein. MPS IVA mice treated with GALNS showed clearance of lysosomal storage in liver, spleen, and sinus lining cells in bone marrow. The column structure of the growth plate was organized better than adult mice treated with ERT; however, hyaline and fibrous cartilage cells in femur, spine, ligaments, discs, synovium, and periosteum still had storage materials to some extent. Heart valves were refractory to the treatment. Levels of serum keratan sulfate were kept normal in newborn ERT mice. In conclusion, the enzyme, which enters the cartilage before the cartilage cell layer becomes mature, prevents disorganization of column structure. Early treatment from birth leads to partial remission of bone pathology in MPS IVA mouse. PMID:24953405

  4. ApoE gene delivery inhibits severe hypercholesterolemia in newborn ApoE-KO mice.

    PubMed

    Signori, Emanuela; Rinaldi, Monica; Fioretti, Daniela; Iurescia, Sandra; Seripa, Davide; Perrone, Giuseppe; Norata, Giuseppe Danilo; Catapano, Alberico Luigi; Fazio, Vito Michele

    2007-09-21

    Apolipoprotein E, a key regulator in cholesterol-rich lipoprotein metabolism, is considered a strong candidate for treating hypercholesterolemia and cardiovascular disease. Inherited deficiency of this protein results in type III hyperlipoproteinemia in humans. ApoE-knockout mice, which develop spontaneous hypercholesterolemia, are an excellent model of human atherosclerosis. Here we investigated the therapeutic effects of a plasmid vector encoding human APOE3 sequence intramuscularly injected in hypercholesterolemic newborn mice at the ages of 5 and 14 days. We further explored the possibility of inducing tolerance in newborns when injected early. Our data show that direct i.m. naked DNA injection reduces severe hypercholesterolemia in newborn mice. Moreover, when naked DNA is administrated early, no immune response is generated against the human APOE, allowing repeated administrations. Neonatal therapies are important for the treatment of many genetic childhood diseases where early administration is required to prevent developmental damage. We propose the use of direct i.m. naked gene transfer in newborns to prevent long-term damages arising from hypercholesterolemic conditions.

  5. Induction of Protective CTL Responses in Newborn Mice by a Murine Retrovirus

    NASA Astrophysics Data System (ADS)

    Sarzotti, Marcella; Robbins, Deanna S.; Hoffman, Paul M.

    1996-03-01

    The susceptibility of neonates to virus-induced disease is thought to reflect, in part, the immaturity of their immune systems. However, inoculation of newborn mice with low doses of Cas-Br-M murine leukemia virus induced a protective cytotoxic T lymphocyte (CTL) response. The inability of neonates to develop a CTL response to high doses of virus was not the result of immunological immaturity but correlated with the induction of a nonprotective type 2 cytokine response. Thus, the initial viral dose is critical in the development of protective immunity in newborns.

  6. Differences between Newborn and Adult Mice in Their Response to Immune Thrombocytopenia

    PubMed Central

    Hu, Zhongbo; Slayton, William B.; Rimsza, Lisa M.; Bailey, Matthew; Sallmon, Hannes; Sola-Visner, Martha C.

    2010-01-01

    Background Sick neonates frequently develop severe thrombocytopenia. Objective and Methods: In order to test the ability of fetal mice to increase their megakaryocyte size and ploidy in response to thrombocytopenia, we injected an antiplatelet antibody (MWReg30) into pregnant mice daily for 7 days, and into nonpregnant adult mice to serve as controls. After that time, platelet counts were obtained and megakaryocytes in the bone marrow, liver, and spleen were stained with anti-von Willebrand factor antibody, individually measured, and quantified. Results Our study demonstrated that megakaryocytopoiesis in newborn mice shares many features of human fetal/neonatal megakaryocytopoiesis, including the small size of megakaryocytes. In response to thrombocytopenia, adult mice increased megakaryocyte volume and concentration, primarily in the spleen. Newborn mice, in contrast, increased the megakaryocyte concentration in the spleen, but exhibited no increase in megakaryocyte volume in any of the organs studied. In fact, the megakaryocyte mass was significantly lower in the bone marrow of thrombocytopenic neonates than in age-matched controls. Conclusions We concluded that fetuses have a limited ability to increase their megakaryocyte mass in response to consumptive thrombocytopenia, compared to adult mice. These observations provide further evidence for the existence of biological differences between fetal/neonatal and adult megakaryocytopoiesis. PMID:20134184

  7. Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice.

    PubMed

    Hilgendorff, Anne; Parai, Kakoli; Ertsey, Robert; Navarro, Edwin; Jain, Noopur; Carandang, Francis; Peterson, Joanna; Mokres, Lucia; Milla, Carlos; Preuss, Stefanie; Alcazar, Miguel Alejandre; Khan, Suleman; Masumi, Juliet; Ferreira-Tojais, Nancy; Mujahid, Sana; Starcher, Barry; Rabinovitch, Marlene; Bland, Richard

    2015-03-01

    Elastin plays a pivotal role in lung development. We therefore queried if elastin haploinsufficient newborn mice (Eln(+/-)) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. Because mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haploinsufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5-day-old wild-type (Eln(+/+)) and Eln(+/-) littermates at baseline and after MV with air for 8-24 h. Lungs of unventilated Eln(+/-) mice contained ∼50% less elastin and ∼100% more collagen-1 and lysyl oxidase compared with Eln(+/+) pups. Eln(+/-) lungs contained fewer capillaries than Eln(+/+) lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln(+/+) neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln(+/-) mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln(+/-) than in Eln(+/+) pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln(+/-) compared with Eln(+/+) mice, was similar in both groups after MV. These results suggest that elastin haploinsufficiency adversely impacts pulmonary angiogenesis and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln(+/+) and Eln(+/-) mice. Paucity of lung capillaries in Eln(+/-) newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln(+/-) mice.

  8. Photochemical restoration of visual responses in blind mice

    PubMed Central

    Polosukhina, Aleksandra; Litt, Jeffrey; Tochitsky, Ivan; Nemargut, Joseph; Sychev, Yivgeny; De Kouchkovsky, Ivan; Huang, Tracy; Borges, Katharine; Trauner, Dirk; Van Gelder, Russell N.; Kramer, Richard H.

    2012-01-01

    Summary Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are degenerative blinding diseases caused by the death of rods and cones, leaving the remainder of the visual system intact but largely unable to respond to light. Here we show that, AAQ, a synthetic small molecule photoswitch, can restore light sensitivity to the retina and behavioral responses in vivo in mouse models of RP without exogenous gene delivery. Brief application of AAQ bestows prolonged light sensitivity on multiple types of retinal neurons, resulting in synaptically amplified responses and center-surround antagonism in arrays of retinal ganglion cells (RGCs). Intraocular injection of AAQ restores the pupillary light reflex and locomotory light avoidance responses in mice lacking retinal photoreceptors, indicating reconstitution of light signaling to brain circuits. AAQ and related photoswitch molecules present a new drug strategy for restoring retinal function in degenerative blinding diseases. PMID:22841312

  9. Photochemical restoration of visual responses in blind mice.

    PubMed

    Polosukhina, Aleksandra; Litt, Jeffrey; Tochitsky, Ivan; Nemargut, Joseph; Sychev, Yivgeny; De Kouchkovsky, Ivan; Huang, Tracy; Borges, Katharine; Trauner, Dirk; Van Gelder, Russell N; Kramer, Richard H

    2012-07-26

    Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are degenerative blinding diseases caused by the death of rods and cones, leaving the remainder of the visual system intact but largely unable to respond to light. Here, we show that AAQ, a synthetic small molecule photoswitch, can restore light sensitivity to the retina and behavioral responses in vivo in mouse models of RP, without exogenous gene delivery. Brief application of AAQ bestows prolonged light sensitivity on multiple types of retinal neurons, resulting in synaptically amplified responses and center-surround antagonism in arrays of retinal ganglion cells (RGCs). Intraocular injection of AAQ restores the pupillary light reflex and locomotory light avoidance behavior in mice lacking retinal photoreceptors, indicating reconstitution of light signaling to brain circuits. AAQ and related photoswitch molecules present a potential drug strategy for restoring retinal function in degenerative blinding diseases.

  10. Insulin treatment restores islet microvascular vasomotion function in diabetic mice.

    PubMed

    Liu, Mingming; Zhang, Xiaoyan; Li, Ailing; Zhang, Xu; Wang, Bing; Li, Bingwei; Liu, Shuying; Li, Hongwei; Xiu, Ruijuan

    2017-10-01

    The microcirculation plays an important role in the pathogenesis of diabetes and its complications. We hypothesized that pancreatic islet microvascular (PIM) vasomotion, as a parameter of pancreatic islet microcirculation function, is abnormal in diabetic mice and that insulin treatment may reverse this dysfunction. Mice were randomly assigned to non-diabetic control, untreated diabetic, and insulin-treated diabetic groups (n = 6 in each group). Separate groups of streptozotocin (STZ)-induced diabetic and high-fat diet-fed mice were used as a model of hyperglycemia. Insulin-treated diabetic mice were treated with 1-1.5 IU/day insulin for 1 week. Laser Doppler monitors were used to evaluate PIM vasomotion. Morphological and ultrastructural changes in islet endothelial cells were determined by immunohistochemistry and transmission electron microscopy. Glucagon, insulin, vascular endothelial growth factor (VEGF)-A, and platelet endothelial cell adhesion molecule (PECAM-1) expression was determined by immunohistochemistry and Western blotting. In both untreated diabetic groups, the pancreatic islet microcirculation was unable to regulate PIM vasomotion. The rhythm of vasomotion was irregular, and the average blood perfusion, amplitude, frequency, and relative velocity of vasomotion were significantly lower than in non-diabetic controls. Insulin treatment restored the functional status of PIM vasomotion. In islet endothelial cells from both untreated diabetic groups, the mitochondria were swollen with disarrangement of the cristae, and the distribution of PECAM-1 was discontinuous. Insulin treatment significantly increased the reduced expression of PECAM-1 in both untreated diabetic groups and VEGF-A expression in untreated STZ-diabetic mice. The results suggest that the functional status of PIM vasomotion is impaired in diabetic mice but can be restored by insulin. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons

  11. Tmc gene therapy restores auditory function in deaf mice.

    PubMed

    Askew, Charles; Rochat, Cylia; Pan, Bifeng; Asai, Yukako; Ahmed, Hena; Child, Erin; Schneider, Bernard L; Aebischer, Patrick; Holt, Jeffrey R

    2015-07-08

    Genetic hearing loss accounts for up to 50% of prelingual deafness worldwide, yet there are no biologic treatments currently available. To investigate gene therapy as a potential biologic strategy for restoration of auditory function in patients with genetic hearing loss, we tested a gene augmentation approach in mouse models of genetic deafness. We focused on DFNB7/11 and DFNA36, which are autosomal recessive and dominant deafnesses, respectively, caused by mutations in transmembrane channel-like 1 (TMC1). Mice that carry targeted deletion of Tmc1 or a dominant Tmc1 point mutation, known as Beethoven, are good models for human DFNB7/11 and DFNA36. We screened several adeno-associated viral (AAV) serotypes and promoters and identified AAV2/1 and the chicken β-actin (Cba) promoter as an efficient combination for driving the expression of exogenous Tmc1 in inner hair cells in vivo. Exogenous Tmc1 or its closely related ortholog, Tmc2, were capable of restoring sensory transduction, auditory brainstem responses, and acoustic startle reflexes in otherwise deaf mice, suggesting that gene augmentation with Tmc1 or Tmc2 is well suited for further development as a strategy for restoration of auditory function in deaf patients who carry TMC1 mutations.

  12. Chronic alcohol exposure is associated with decreased neurogenesis, aberrant integration of newborn neurons, and cognitive dysfunction in female mice

    PubMed Central

    Golub, Haleigh M.; Zhou, Qi-Gang; Zucker, Hannah; McMullen, Megan R.; Kokiko-Cochran, Olga Nicole; Ro, Eun Jeoung; Nagy, Laura E.; Suh, Hoonkyo

    2015-01-01

    Background Neurological deficits of alcohol use disorder (AUD) have been attributed to dysfunctions of specific brain structures. Studies of alcoholic patients and chronic alcohol exposure animal models consistently identify reduced hippocampal mass and cogntive dysfunctions as a key alcohol-induced brain adaptation. However, the precise substrate of chronic alcohol exposure that leads to structural and functional impairments of the hippocampus is largely unknown. Methods Using a calorie-matched alcohol feeding method, we tested whether chronic alcohol exposure targets neural stem cells and neurogenesis in the adult hippocampus. The effect of alcohol on proliferation of neural stem cells as well as cell fate determination and survival of newborn cells was evaluated via BrdU pulse and chase methods. A retrovirus-mediated single-cell labeling method was used to determine the effect of alcohol on the morphological development and circuitry incorporation of individual hippocampal newborn neurons. Finally, Novel Object Recognition and Y-maze tests were performed to examine whether disrupted neurogenesis is associated with hippocampus-dependent functional deficits in alcohol-fed mice. Results Chronic alcohol exposure reduced proliferation of neural stem cells and survival rate of newborn neurons; however, the fate determination of newborn cells remained unaltered. Moreover, the dendritic spine density of newborn neurons significantly decreased in alcohol-fed mice. Impaired spine formation indicates that alcohol interfered the synaptic connectivity of newborn neurons with excitatory neurons originating from a various areas of the brain. In the Novel Object Recognition test, alcohol-fed mice displayed deficits in the ability to discriminate the novel object. Conclusions Our study revealed that chronic alcohol exposure disrupted multiple steps of neurogenesis, including the production and development of newborn neurons. In addition, chronic alcohol exposure altered

  13. Carcinogenic Activity of Some Benz(a)Anthracene Derivatives in Newborn Mice

    PubMed Central

    Roe, F. J. C.; Dipple, A.; Mitchley, B. C. V.

    1972-01-01

    Equimolar doses of 7-methylbenz(a)anthracene and 3 of its derivatives were given to newborn male and female Swiss mice. All 4 substances tested increased the risk of tumour development compared with that seen in control mice given the vehicle, arachis oil, only. 7-Methylbenz(a)anthracene itself was the most actively tumorigenic of the compounds studied, giving rise to subcutaneous sarcomata at the site of injection, and multiple lung tumours and liver tumours. 7-Bromomethyl-12-methylbenz(a)-anthracene was similarly active in the lung and liver but evoked fewer subcutaneous sarcomata. 7-Bromomethylbenz(a)anthracene was seemingly slightly less active than either 7-methylbenz(a)anthracene or 7-bromomethyl-12-methylbenz(a)anthracene. 4-Chloro-7-bromomethylbenz(a)anthracene exhibited only marginal activity in that it slightly increased the risk of liver tumour development in male mice. PMID:4647396

  14. Protective Cellular Immunity Against Influenza Virus Induced by Plasmid Inoculation of Newborn Mice

    PubMed Central

    Bot, Adrian; Bot, Simona; García-Sastre, Adolfo

    1998-01-01

    Neonate organisms display an intrinsic disability to mount effective immune responses to infectious agents or conventional vaccines. Whereas low. doses of antigens trigger a suboptimal response, higher doses are frequently associated with tolerance induction. We investigated the ability of a plasmid-expressing nucleoprotein of influenza virus to prime a specific cellular immune response when administered to newborn mice. We found that persistent exposure to antigen following plasmid inoculation of neonates leads to a vigorous priming of specific CTLs rather than tolerance induction. The CTLs were cross-reactive against multiple strains of type A influenza viruses and produced IFNγ but no IL-4. The immunity triggered by plasmid inoculation of neonates was protective in terms of pulmonary virus clearance as well as survival rate following lethal challenge with influenza virus. Whereas the persistence of the plasmid at the site of injection was readily demonstrable in adult mice at 3 months after inoculation, mice immunized as newborns displayed no plasmid at 3 months and very little at 1 month after injection. Thus, DNA-based immunization of neonates may prove an effective and safe vaccination strategy for induction of cellular immunity against microbes that cause serious infectious diseases in the early period of life. PMID:9851359

  15. Pathology of Murine Cytomegalovirus Infection in Newborn Mice. Muscle, Heart and Brown Fat Lesions

    PubMed Central

    Lussier, G.

    1974-01-01

    Newborn mice were inoculated intracerebrally with murine cytomegalovirus and studies were made of the pathological changes in the striate and cardiac muscle and brown fat. Widespread necrosis was seen in muscle and brown fat in the early stages of the infection. Necrotic lesions became calcified. By 56 days lesions were not resolved in the heart and brown fat but were completely resolved in skeletal muscle. ImagesFig. 1.Fig. 2.Fig. 3.Fig. 4.Fig. 5.Fig. 6.Fig. 7.Fig. 8.Fig. 9. PMID:4363374

  16. Omeprazole Attenuates Pulmonary Aryl Hydrocarbon Receptor Activation and Potentiates Hyperoxia-Induced Developmental Lung Injury in Newborn Mice

    PubMed Central

    Shivanna, Binoy; Zhang, Shaojie; Patel, Ananddeep; Jiang, Weiwu; Wang, Lihua; Welty, Stephen E.; Moorthy, Bhagavatula

    2015-01-01

    Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in human preterm infants and a similar lung phenotype characterized by alveolar simplification in newborn mice. Omeprazole (OM) is a proton pump inhibitor that is used to treat humans with gastric acid related disorders. OM-mediated aryl hydrocarbon receptor (AhR) activation attenuates acute hyperoxic lung injury (HLI) in adult mice. Whether OM activates pulmonary AhR and protects C57BL/6J newborn mice against hyperoxia-induced developmental lung (alveolar and pulmonary vascular simplification, inflammation, and oxidative stress) injury (HDLI) is unknown. Therefore, we tested the hypothesis that OM will activate pulmonary AhR and mitigate HDLI in newborn mice. Newborn mice were treated daily with i.p. injections of OM at doses of 10 (OM10) or 25 (OM25) mg/kg while being exposed to air or hyperoxia (FiO2 of 85%) for 14 days, following which their lungs were harvested to determine alveolarization, pulmonary vascularization, inflammation, oxidative stress, vascular injury, and AhR activation. To our surprise, hyperoxia-induced alveolar and pulmonary vascular simplification, inflammation, oxidative stress, and vascular injury were augmented in OM25-treated animals. These findings were associated with attenuated pulmonary vascular endothelial growth factor receptor 2 expression and decreased pulmonary AhR activation in the OM25 group. We conclude that contrary to our hypothesis, OM decreases functional activation of pulmonary AhR and potentiates HDLI in newborn mice. These observations are consistent with our previous findings, which suggest that AhR activation plays a protective role in HDLI in newborn mice. PMID:26272953

  17. Myeloid depression follows infection of susceptible newborn mice with the parvovirus minute virus of mice (strain i).

    PubMed

    Segovia, J C; Bueren, J A; Almendral, J M

    1995-05-01

    The in vivo myelosuppressive capacity of strain i of the parovirus minute virus of mice (MVMi) was investigated in newborn BALB/c mice inoculated with a lethal intranasal dose. MVMi infection reached maximum levels of DNA synthesis and infectious titers in lymphohemopoietic organs at 4 to 6 days postinoculation and was restricted by an early neutralizing humoral immune response. After viral control (by 10 days postinoculation), a significant decrease in femoral and splenic cellularity, as well as in granulocyte-macrophage colony-forming unit and erythroid burst-forming unit hemopoietic progenitors, was observed in most inoculated animals. This delayed myeloid depression, although it may be not a major cause of the lethality of the infection, implies indirect pathogenic mechanisms induced by MVMi infection in a susceptible host.

  18. Myeloid depression follows infection of susceptible newborn mice with the parvovirus minute virus of mice (strain i).

    PubMed Central

    Segovia, J C; Bueren, J A; Almendral, J M

    1995-01-01

    The in vivo myelosuppressive capacity of strain i of the parovirus minute virus of mice (MVMi) was investigated in newborn BALB/c mice inoculated with a lethal intranasal dose. MVMi infection reached maximum levels of DNA synthesis and infectious titers in lymphohemopoietic organs at 4 to 6 days postinoculation and was restricted by an early neutralizing humoral immune response. After viral control (by 10 days postinoculation), a significant decrease in femoral and splenic cellularity, as well as in granulocyte-macrophage colony-forming unit and erythroid burst-forming unit hemopoietic progenitors, was observed in most inoculated animals. This delayed myeloid depression, although it may be not a major cause of the lethality of the infection, implies indirect pathogenic mechanisms induced by MVMi infection in a susceptible host. PMID:7707557

  19. Newborn resuscitation.

    PubMed

    Rahm, Stephen J

    2002-07-01

    Assessment and management of the newborn is a very rapid sequence of events. Unlike adult resuscitation, where the goal is to "restore" the breathing and perfusion that they once had, the goal of resuscitating a newborn is to "initiate" effective breathing and perfusion. It is of paramount importance for prehospital care providers to be prepared to handle these critical cases in an expedient manner. The vast majority of newborns breathe spontaneously at delivery or very shortly thereafter, with little intervention required by EMS; however, EMS providers should always be mentally and physically prepared to assist a struggling newborn.

  20. VARA attenuates hyperoxia-induced impaired alveolar development and lung function in newborn mice

    PubMed Central

    James, Masheika L.; Ross, A. Catharine; Nicola, Teodora; Steele, Chad

    2013-01-01

    We have recently shown that a combination of vitamin A (VA) and retinoic acid (RA) in a 10:1 molar ratio (VARA) synergistically increases lung retinoid content in newborn rodents, more than either VA or RA alone in equimolar amounts. We hypothesized that the increase in lung retinoids would reduce oxidative stress and proinflammatory cytokines, resulting in attenuation of alveolar simplification and abnormal lung function in hyperoxia-exposed newborn mice. Newborn C57BL/6 mice were exposed to 85% O2 (hyperoxia) or air (normoxia) for 7 or 14 days from birth and given vehicle or VARA every other day. Lung retinol content was measured by HPLC, function was assessed by flexiVent, and development was evaluated by radial alveolar counts, mean linear intercept, and secondary septal crest density. Mediators of oxidative stress, inflammation, and alveolar development were evaluated in lung homogenates. We observed that VARA increased lung retinol stores and attenuated hyperoxia-induced alveolar simplification while increasing lung compliance and lowering resistance. VARA attenuated hyperoxia-induced increases in DNA damage and protein oxidation accompanied with a reduction in nuclear factor (erythroid-derived 2)-like 2 protein but did not alter malondialdehyde adducts, nitrotyrosine, or myeloperoxidase concentrations. Interferon-γ and macrophage inflammatory protein-2α mRNA and protein increased with hyperoxia, and this increase was attenuated by VARA. Our study suggests that the VARA combination may be a potential therapeutic strategy in conditions characterized by VA deficiency and hyperoxia-induced lung injury during lung development, such as bronchopulmonary dysplasia in preterm infants. PMID:23585226

  1. Experimental Zika virus infection induces spinal cord injury and encephalitis in newborn Swiss mice.

    PubMed

    Fernandes, Natália C C A; Nogueira, Juliana S; Réssio, Rodrigo A; Cirqueira, Cinthya S; Kimura, Lidia M; Fernandes, Karolina R; Cunha, Mariana S; Souza, Renato P; Guerra, Juliana M

    2017-02-01

    A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America, with neurological symptons including meningoencephalitis and Guillain-Barré syndrome in adults, besides an apparent increased incidence of microcephaly in infants born to infected mothers. It is becoming a necessity to have a trustworthy animal model to better understand ZIKV infection. In this study we used newborn white Swiss mice as a model to investigate the ZIKV strain recently isolated in Brazil. ZIKV was inoculated via intracerebral and subcutaneous routes and analysed through gross histopathology and immunohistochemistry. Here we demonstrated first that the intracerebral group (ICG) displayed severe cerebral lesions, with neuronal death, presence of apoptotic bodies, white matter degeneration and neutrophil perivascular cuffing. In the subcutaneous group (SCG), we observed moderate cerebral lesions, morphologically similar to that found in ICG and additional myelopathy, with architectural loss, marked by neuronal death and apoptotic bodies. Interestingly, we found an intense astrogliosis in brain of both groups, with increased immunoexpression of GFAP (glial fibrillary acidic protein) and presence of hypertrophic astrocytes. The spinal cord of subcutaneous group (SCG) exhibited reduction of astrocytes, but those positive for GFAP were hypertrophic and presented prolonged cellular processes. Finally significant lesions in the central nervous system (CNS) were present in newborn mice inoculated by both routes, but SCG method led to an important neurological manifestations (including myelopathy), during a longer period of time and appears for us to be a better model for ZIKV infection.

  2. Restoration of Regenerative Osteoblastogenesis in Aged Mice: Modulation of TNF

    PubMed Central

    Wahl, Elizabeth C; Aronson, James; Liu, Lichu; Fowlkes, John L; Thrailkill, Kathryn M; Bunn, Robert C; Skinner, Robert A; Miller, Mike J; Cockrell, Gael E; Clark, Lindsey M; Ou, Yang; Isales, Carlos M; Badger, Thomas M; Ronis, Martin J; Sims, John; Lumpkin, Charles K

    2010-01-01

    Skeletal changes accompanying aging are associated with both increased risk of fractures and impaired fracture healing, which, in turn, is due to compromised bone regeneration potential. These changes are associated with increased serum levels of selected proinflammatory cytokines, e.g., tumor necrosis factor α (TNF-α). We have used a unique model of bone regeneration to demonstrate (1) that aged-related deficits in direct bone formation can be restored to young mice by treatment with TNF blockers and (2) that the cyclin-dependent kinase inhibitor p21 is a candidate for mediation of the osteoinhibitory effects of TNF. It has been hypothesized recently that TNF antagonists may represent novel anabolic agents, and we believe that the data presented here represent a successful test of this hypothesis. © 2010 American Society for Bone and Mineral Research PMID:19580462

  3. Immunotherapy with Aducanumab Restores Calcium Homeostasis in Tg2576 Mice

    PubMed Central

    Bussiere, Thierry; Shakerdge, Naomi; Qian, Fang; Weinreb, Paul H.; Rhodes, Ken

    2016-01-01

    Calcium homeostasis plays a major role in maintaining neuronal function under physiological conditions. Amyloid-β (Aβ) initiates pathological processes that include disruption in intracellular calcium levels, so amelioration of the calcium alteration could serve as an indirect functional indicator of treatment efficacy. Therefore, calcium dynamics were used as a measure of functional outcome. We evaluated the effects of the anti-Aβ antibody aducanumab on calcium homeostasis and plaque clearance in aged Tg2576 mice with in vivo multiphoton imaging. Acute topical application of aducanumab to the brain resulted in clearance of amyloid plaques. Although chronic systemic administration of aducanumab in 22-month-old mice did not clear existing plaques, calcium overload was ameliorated over time. Therefore, this antibody likely restores neuronal network function that possibly underlies cognitive deficits, indicating promise as a clinical treatment. In addition, functional readouts such as calcium overload may be a more useful outcome measure to monitor treatment efficacy in models of Alzheimer's disease compared with amyloid burden alone. SIGNIFICANCE STATEMENT Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is currently without a cure. Aducanumab is an anti-amyloid-β antibody being developed for the treatment of AD. Interim analyses of a phase 1b clinical trial have suggested potential beneficial effects on amyloid pathology and cognitive status in patients treated with aducanumab (Sevigny et al., 2016). Here, we show that a murine analog of aducanumab clears amyloid plaques in an acute setting and restores calcium homeostasis disrupted in a mouse model of AD upon chronic treatment. Therefore, we demonstrate that aducanumab reverses a functional outcome measure reflective of neural network activity. PMID:27810931

  4. Hyperoxia-induced immature brain injury through the TLR4 signaling pathway in newborn mice.

    PubMed

    Liu, Yang; Jiang, Pu; Du, Min; Chen, Kun; Chen, Amber; Wang, Yang; Cao, Fei; Deng, Shixiong; Xu, Ying

    2015-06-12

    hyperoxia-induced immune responses in the immature brain and 2) the loss of TLR4 activation may abrogate the neuronal apoptosis and cognitive deficits following hyperoxia exposure in newborn mice.

  5. GABA Regulates Corticotropin Releasing Hormone Levels in the Paraventricular Nucleus of the Hypothalamus in Newborn Mice

    PubMed Central

    Stratton, Matthew S.; Searcy, Brian T.; Tobet, Stuart A.

    2011-01-01

    The paraventricular nucleus of the hypothalamus (PVN) is a major regulator of stress responses via release of Corticotropin Releasing Hormone (CRH) to the pituitary gland. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is characteristic of individuals with Major Depressive Disorder (MDD). Postmortem data from individuals diagnosed with MDD show increased levels of CRH mRNA and CRH immunoreactive neurons in the PVN. In the current study, an immunohistochemical (IHC) analysis revealed increased levels of CRH in the PVN of newborn mice lacking functional GABAB receptors. There was no difference in the total number of CRH immunoreactive cells. By contrast, there was a significant increase in the amount of CRH immunoreactivity per cell. Interestingly, this increase in CRH levels in the GABAB receptor R1 subunit knockout was limited to the rostral PVN. While GABAergic regulation of the HPA axis has been previously reported in adult animals, this study provides evidence of region-specific GABA modulation of immunoreactive CRH in newborns. PMID:21236282

  6. Orientation of newborn mice to lactating females: identifying biological substrates of semiochemical interest.

    PubMed

    Al Aïn, Syrina; Chraïti, Amal; Schaal, Benoist; Patris, Bruno

    2013-03-01

    Among mammals, odor-based communication between females and infants is decisive for neonatal survival. So far, the nature of odor substrates involved in the localization of the mother and their nipples is unknown in mice. The present study aims: (1) to evaluate the specific attractive value of lactating females to newborn mice, (2) to localize the abdominal region that is most attractive to pups, and (3) to identify odor substrates that support such attraction. Results showed that 5-6-day-old mice roam preferentially over the abdomen of lactating females than the abdomen of non-lactating females. In lactating females, pups are more attracted to abdominal areas comprising nipples. The blend of odor substrates from nipples, as well as separate sources presumed to compose it, viz. milk, maternal saliva and pup saliva, were detectable and equivalently attractive to pups. The equivalent attraction of these different odor substrates may derive either from overlap in chemical constituents, or from associative learning during nursing. Copyright © 2011 Wiley Periodicals, Inc.

  7. A simple method for short-term controlled anesthesia in newborn mice.

    PubMed

    Drobac, Estelle; Durand, Estelle; Laudenbach, Vincent; Mantz, Jean; Gallego, Jorge

    2004-09-15

    In this study, we describe a simple and inexpensive method for inducing short-term anesthesia and rapid recovery in newborn mice. Litters of Swiss mice pups were randomly allocated to testing on postnatal days 2, 5, and 8. Anesthesia was induced by placing the pup in a syringe and adding a volume of isoflurane-saturated gas that produced an estimated level of 32% isoflurane. Exposure to isoflurane lasted 30 s. All the pups survived the anesthesia. At all study ages, this method abolished the nociceptive response to tail clamp without inducing mortality, thus showing effective anesthesia. Recovery from anesthesia was assessed immediately after isoflurane exposure, based on two nonnoxious behavioral tests: the defensive response to a drop of water (10 tests, 1 min apart) and 10 min later the righting reflex, i.e., the time to recovery of the prone position (five tests, 10 min apart). The water drop test scores increased during the recovery phase toward the control values in all age groups. Treatment and time had no significant effect on righting reflex scores. The initial volume in the syringe, the volume of added isoflurane-saturated gas, and the duration of exposure may be adjusted according to postnatal age and specific strains or species (e.g., rats). This method is well suited to behavioral or physiological phenotype studies in developing mice, in which noxious procedures must precede functional testing, making rapid recovery from anesthesia a key requirement.

  8. Uptake of mercury by the hair of methylmercury-treated newborn mice

    SciTech Connect

    Shi, Chenyang; Lane, A.T.; Clarkson, T.W. )

    1990-04-01

    Human hair has unique advantages in monitoring environmental exposures to methyl-mercury. Using newborn Balb/c mice as a model system, the incorporation of methylmercury into the hair was studied and compared with methylmercury distributions in other tissues. Newborn mice were given intraperitoneal injections of {sup 203}Hg-labeled methylmercury at designated times according to hair growth stages of the mouse. Animals were sacrificed 2 days after dosing. Distribution of mercury in pelt and other tissues was measured. The level of mercury in pelt was found to correlate with hair growth. The amount of mercury in pelt peaked when hair growth was most rapid and the total amount of mercury in pelt was significantly higher than that in other tissues, constituting 40% of the whole body burden. However, when the hair ceased growing, the amount of mercury in pelt dramatically dropped to 4% of whole body burden and mercury concentrations in other tissues except brain were elevated. Autoradiographic studies with tritium-labeled methylmercury demonstrated that methylmercury concentrated in hair follicles in the skin. Within hair follicles and hairs, methylmercury accumulated in regions that are rich in high-sulfur proteins. The uptake of inorganic mercury (administered as HgCl{sub 2}) by pelt was also compared with that of methylmercury. The amount of inorganic mercury found in pelt was less than one-half that of methylmercury in animals with growing hair. Cessation of hair growth did not decrease the inorganic mercury level in pelt to the same extent as in the case of methylmercury.

  9. Glucocortiocoid Treatment of MCMV Infected Newborn Mice Attenuates CNS Inflammation and Limits Deficits in Cerebellar Development

    PubMed Central

    Kosmac, Kate; Bantug, Glenn R.; Pugel, Ester P.; Cekinovic, Djurdjica; Jonjic, Stipan; Britt, William J.

    2013-01-01

    Infection of the developing fetus with human cytomegalovirus (HCMV) is a major cause of central nervous system disease in infants and children; however, mechanism(s) of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV) results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC) proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ) in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV. PMID:23505367

  10. Cerebral cortex hyperthyroidism of newborn mct8-deficient mice transiently suppressed by lat2 inactivation.

    PubMed

    Núñez, Bárbara; Martínez de Mena, Raquel; Obregon, Maria Jesus; Font-Llitjós, Mariona; Nunes, Virginia; Palacín, Manuel; Dumitrescu, Alexandra M; Morte, Beatriz; Bernal, Juan

    2014-01-01

    Thyroid hormone entry into cells is facilitated by transmembrane transporters. Mutations of the specific thyroid hormone transporter, MCT8 (Monocarboxylate Transporter 8, SLC16A2) cause an X-linked syndrome of profound neurological impairment and altered thyroid function known as the Allan-Herndon-Dudley syndrome. MCT8 deficiency presumably results in failure of thyroid hormone to reach the neural target cells in adequate amounts to sustain normal brain development. However during the perinatal period the absence of Mct8 in mice induces a state of cerebral cortex hyperthyroidism, indicating increased brain access and/or retention of thyroid hormone. The contribution of other transporters to thyroid hormone metabolism and action, especially in the context of MCT8 deficiency is not clear. We have analyzed the role of the heterodimeric aminoacid transporter Lat2 (Slc7a8), in the presence or absence of Mct8, on thyroid hormone concentrations and on expression of thyroid hormone-dependent cerebral cortex genes. To this end we generated Lat2-/-, and Mct8-/yLat2-/- mice, to compare with wild type and Mct8-/y mice during postnatal development. As described previously the single Mct8 KO neonates had a transient increase of 3,5,3'-triiodothyronine concentration and expression of thyroid hormone target genes in the cerebral cortex. Strikingly the absence of Lat2 in the double Mct8Lat2 KO prevented the effect of Mct8 inactivation in newborns. The Lat2 effect was not observed from postnatal day 5 onwards. On postnatal day 21 the Mct8 KO displayed the typical pattern of thyroid hormone concentrations in plasma, decreased cortex 3,5,3'-triiodothyronine concentration and Hr expression, and concomitant Lat2 inactivation produced little to no modifications. As Lat2 is expressed in neurons and in the choroid plexus, the results support a role for Lat2 in the supply of thyroid hormone to the cerebral cortex during early postnatal development.

  11. Restoration of cardiopulmonary function with 21% versus 100% oxygen after hypoxaemia in newborn pigs

    PubMed Central

    Fugelseth, D; Borke, W; Lenes, K; Matthews, I; Saugstad, O; Thaulow, E

    2005-01-01

    Objective: To assess the consequences of hypoxaemia and resuscitation with room air versus 100% O2 on cardiac troponin I (cTnI), cardiac output (CO), and pulmonary artery pressure (PAP) in newborn pigs. Design: Twenty anaesthetised pigs (12–36 hours; 1.7–2.7 kg) were subjected to hypoxaemia by ventilation with 8% O2. When mean arterial blood pressure fell to 15 mm Hg, or arterial base excess was ⩽ –20 mmol/l, resuscitation was performed with 21% (n = 10) or 100% (n = 10) O2 for 30 minutes, then ventilation with 21% O2 for 120 minutes. Blood was analysed for cTnI. Ultrasound examinations of CO and PAP (estimated from tricuspid regurgitation velocity (TR-Vmax)) were performed at baseline, during hypoxia, and at the start of and during reoxygenation. Results: cTnI increased from baseline to the end point (p<0.001), confirming a serious myocardial injury, with no differences between the 21% and 100% O2 group (p = 0.12). TR-Vmax increased during the insult and returned towards baseline values during reoxygenation, with no differences between the groups (p = 0.11) or between cTnI concentrations (p = 0.31). An inverse relation was found between increasing age and TR-Vmax during hypoxaemia (p = 0.034). CO per kg body weight increased during the early phase of hypoxaemia (p<0.001), then decreased. Changes in CO per kg were mainly due to changes in heart rate, with no differences between the groups during reoxygenation (p = 0.298). Conclusion: Hypoxaemia affects the myocardium and PAP. During this limited period of observation, reoxygenation with 100% O2 showed no benefits compared with 21% O2 in normalising myocardial function and PAP. The important issue may be resuscitation and reoxygenation without hyperoxygenation. PMID:15846013

  12. Genetic Restoration of Plasma ApoE Improves Cognition and Partially Restores Synaptic Defects in ApoE-Deficient Mice.

    PubMed

    Lane-Donovan, Courtney; Wong, Wen Mai; Durakoglugil, Murat S; Wasser, Catherine R; Jiang, Shan; Xian, Xunde; Herz, Joachim

    2016-09-28

    Alzheimer's disease (AD) is the most common form of dementia in individuals over the age of 65 years. The most prevalent genetic risk factor for AD is the ε4 allele of apolipoprotein E (ApoE4), and novel AD treatments that target ApoE are being considered. One unresolved question in ApoE biology is whether ApoE is necessary for healthy brain function. ApoE knock-out (KO) mice have synaptic loss and cognitive dysfunction; however, these findings are complicated by the fact that ApoE knock-out mice have highly elevated plasma lipid levels, which may independently affect brain function. To bypass the effect of ApoE loss on plasma lipids, we generated a novel mouse model that expresses ApoE normally in peripheral tissues, but has severely reduced ApoE in the brain, allowing us to study brain ApoE loss in the context of a normal plasma lipid profile. We found that these brain ApoE knock-out (bEKO) mice had synaptic loss and dysfunction similar to that of ApoE KO mice; however, the bEKO mice did not have the learning and memory impairment observed in ApoE KO mice. Moreover, we found that the memory deficit in the ApoE KO mice was specific to female mice and was fully rescued in female bEKO mice. Furthermore, while the AMPA/NMDA ratio was reduced in ApoE KO mice, it was unchanged in bEKO mice compared with controls. These findings suggest that plasma lipid levels can influence cognition and synaptic function independent of ApoE expression in the brain. One proposed treatment strategy for Alzheimer's disease (AD) is the reduction of ApoE, whose ε4 isoform is the most common genetic risk factor for the disease. A major concern of this strategy is that an animal model of ApoE deficiency, the ApoE knock-out (KO) mouse, has reduced synapses and cognitive impairment; however, these mice also develop dyslipidemia and severe atherosclerosis. Here, we have shown that genetic restoration of plasma ApoE to wild-type levels normalizes plasma lipids in ApoE KO mice. While this does

  13. Epidermal growth factor inhibits radioiodine uptake but stimulates deoxyribonucleic acid synthesis in newborn rat thyroids grown in nude mice

    SciTech Connect

    Ozawa, S.; Spaulding, S.W. )

    1990-08-01

    We have studied the effect of altering the level of circulating epidermal growth factor (EGF) on the function and growth of newborn rat thyroids transplanted into nude mice. Preliminary studies confirmed that sialoadenectomy reduced circulating EGF levels in nude mice (from 0.17 +/- 0.02 to 0.09 +/- 0.02 ng/ml), and that ip injection of 5 micrograms EGF raised EGF levels (the peak level of 91.7 +/- 3.3 ng/ml was achieved at 30 min, with a subsequent half-life of about 1 h). The radioiodine uptake by newborn rat thyroid transplants in the sialoadenectomized and sham-operated animals correlated inversely with the circulating EGF levels determined when the mice were killed (r = -0.99). Low-dose TSH treatment (0.1 microU/day) generally stimulated the radioiodine uptake, but high-dose TSH groups (100 microU/day) were not significantly different from the control group. The 5-day nuclear (3H)thymidine labeling index was 6.8 +/- 0.5% IN newborn rat thyroid transplants grown in sialoadenectomized animals, 13.1 +/- 0.3% in sham-operated animals, and 16.8 +/- 0.5% in nude mice receiving 5 micrograms EGF ip daily. In general, both low-dose and high-dose TSH promoted DNA synthesis under low EGF conditions but were ineffective in the presence of higher levels of EGF. Adult rat thyroid transplants showed no significant responses. Although sialoadenectomy may alter other factors besides EGF, it appears that changes in the levels of circulating EGF within the physiological range affect the function and growth of newborn rat thyroid transplants. Circulating EGF may play a role in thyroid maturation and may also be involved in the regulation of thyroid function throughout life.

  14. Fluorescent Labeling of Newborn Dentate Granule Cells in GAD67-GFP Transgenic Mice: A Genetic Tool for the Study of Adult Neurogenesis

    PubMed Central

    Zhao, Shengli; Zhou, Yang; Gross, Jimmy; Miao, Pei; Qiu, Li; Wang, Dongqing; Chen, Qian; Feng, Guoping

    2010-01-01

    Neurogenesis in the adult hippocampus is an important form of structural plasticity in the brain. Here we report a line of BAC transgenic mice (GAD67-GFP mice) that selectively and transitorily express GFP in newborn dentate granule cells of the adult hippocampus. These GFP+ cells show a high degree of colocalization with BrdU-labeled nuclei one week after BrdU injection and express the newborn neuron marker doublecortin and PSA-NCAM. Compared to mature dentate granule cells, these newborn neurons show immature morphological features: dendritic beading, fewer dendritic branches and spines. These GFP+ newborn neurons also show immature electrophysiological properties: higher input resistance, more depolarized resting membrane potentials, small and non-typical action potentials. The bright labeling of newborn neurons with GFP makes it possible to visualize the details of dendrites, which reach the outer edge of the molecular layer, and their axon (mossy fiber) terminals, which project to the CA3 region where they form synaptic boutons. GFP expression covers the whole developmental stage of newborn neurons, beginning within the first week of cell division and disappearing as newborn neurons mature, about 4 weeks postmitotic. Thus, the GAD67-GFP transgenic mice provide a useful genetic tool for studying the development and regulation of newborn dentate granule cells. PMID:20824075

  15. A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice

    PubMed Central

    Yang, Yang; Wang, Lili; Bell, Peter; McMenamin, Deirdre; He, Zhenning; White, John; Yu, Hongwei; Xu, Chenyu; Morizono, Hiroki; Musunuru, Kiran; Batshaw, Mark L.; Wilson, James M.

    2016-01-01

    Many genetic liver diseases present in newborns with repeated, often lethal, metabolic crises. Gene therapy using non-integrating viruses such as AAV is not optimal in this setting because the non-integrating genome is lost as developing hepatocytes proliferate1,2. We reasoned that newborn liver may be an ideal setting for AAV-mediated gene correction using CRISPR/Cas9. Here we intravenously infuse two AAVs, one expressing Cas9 and the other expressing a guide RNA and the donor DNA, into newborn mice with a partial deficiency in the urea cycle disorder enzyme, ornithine transcarbamylase (OTC). This resulted in reversion of the mutation in 10% (6.7% – 20.1%) of hepatocytes and increased survival in mice challenged with a high-protein diet, which exacerbates disease. Gene correction in adult OTC-deficient mice was lower and accompanied by larger deletions that ablated residual expression from the endogenous OTC gene, leading to diminished protein tolerance and lethal hyperammonemia on a chow diet. PMID:26829317

  16. Hypergravity exposure during gestation modifies the TCRβ repertoire of newborn mice

    PubMed Central

    Ghislin, Stéphanie; Ouzren-Zarhloul, Nassima; Kaminski, Sandra; Frippiat, Jean-Pol

    2015-01-01

    During spaceflight, organisms are subjected to mechanical force changes (gravity (G) changes) that affect the immune system. However, gravitational effects on lymphopoiesis have rarely been studied. Consequently, we investigated whether the TCRβ repertoire, created by V(D)J recombination during T lymphopoiesis, is affected by hypergravity exposure during murine development. To address this question, C57BL/6j mice were mated in a centrifuge so that embryonic development, birth and TCRβ rearrangements occurred at 2G. Pups were sacrificed at birth, and their thymus used to quantify transcripts coding for factors required for V(D)J recombination and T lymphopoiesis. We also created cDNA mini-libraries of TCRβ transcripts to study the impact of hypergravity on TCRβ diversity. Our data show that hypergravity exposure increases the transcription of TCRβ chains, and of genes whose products are involved in TCR signaling, and affects the V(D)J recombination process. We also observed that ~85% of the TCRβ repertoire is different between hypergravity and control pups. These data indicate that changing a mechanical force (the gravity) during ontogeny will likely affect host immunity because properties of loops constituting TCR antigen-binding sites are modified in hypergravity newborns. The spectrum of peptides recognized by TCR will therefore likely be different. PMID:25792033

  17. An Intrastriatal Brain-Derived Neurotrophic Factor Infusion Restores Striatal Gene Expression in Bdnf Heterozygous Mice

    PubMed Central

    Saylor, Alicia J.; McGinty, Jacqueline F.

    2011-01-01

    Reduction in the amount of brain-derived neurotrophic factor (BDNF) in corticostriatal afferents is thought to contribute to the vulnerability of medium spiny striatal neurons in Huntington’s disease. In young Bdnf heterozygous (+/−) mice, striatal medium spiny neurons express less preprodynorphin, preproenkephalin, and D3 receptor mRNA than wildtype mice. Further, in aged Bdnf+/− mice, opioid, trkB receptor, and glutamic acid decarboxylase gene expression, and the number of dendritic spines on medium spiny neurons are more affected than in wildtype or younger Bdnf+/− mice. In this study, the possibility that intrastriatal infusions of BDNF would elevate gene expression in the striatum of Bdnf+/− mice was investigated. Wildtype and Bdnf+/− mice received a single, bilateral microinjection of BDNF or PBS into the dorsal striatum. Mice were sacrificed 24 hours later and semi-quantitative in situ hybridization histochemical analysis confirmed that preprodynorphin, preproenkephalin and D3 receptor mRNA was less in the caudate-putamen and nucleus accumbens core of Bdnf+/− mice than in wildtype mice. A BDNF infusion increased preprodynorphin mRNA in the caudate-putamen and NAc core of wildtype mice and restored preprodynorphin mRNA levels in the nucleus accumbens core of Bdnf+/− mice. BDNF also restored the gene expression of preproenkephalin in the caudate-putamen of Bdnf+/− mice to wildtype levels; however, preproenkephalin mRNA in the nucleus accumbens did not differ among groups. Furthermore, BDNF increased D3 receptor mRNA in the nucleus accumbens core of wildtype and Bdnf+/− mice. These results demonstrate that exogenous BDNF restores striatal opioid and D3R gene expression in mice with genetically reduced levels of endogenous BDNF. PMID:20938680

  18. Inhibiting Inducible Nitric Oxide Synthase in Enteric Glia Restores Electrogenic Ion Transport in Mice With Colitis.

    PubMed

    MacEachern, Sarah J; Patel, Bhavik A; Keenan, Catherine M; Dicay, Michael; Chapman, Kevin; McCafferty, Donna-Marie; Savidge, Tor C; Beck, Paul L; MacNaughton, Wallace K; Sharkey, Keith A

    2015-08-01

    Disturbances in the control of ion transport lead to epithelial barrier dysfunction in patients with colitis. Enteric glia regulate intestinal barrier function and colonic ion transport. However, it is not clear whether enteric glia are involved in epithelial hyporesponsiveness. We investigated enteric glial regulation of ion transport in mice with trinitrobenzene sulfonic acid- or dextran sodium sulfate-induced colitis and in Il10(-/-) mice. Electrically evoked ion transport was measured in full-thickness segments of colon from CD1 and Il10(-/-) mice with or without colitis in Ussing chambers. Nitric oxide (NO) production was assessed using amperometry. Bacterial translocation was investigated in the liver, spleen, and blood of mice. Electrical stimulation of the colon evoked a tetrodotoxin-sensitive chloride secretion. In mice with colitis, ion transport almost completely disappeared. Inhibiting inducible NO synthase (NOS2), but not neuronal NOS (NOS1), partially restored the evoked secretory response. Blocking glial function with fluoroacetate, which is not a NOS2 inhibitor, also partially restored ion transport. Combined NOS2 inhibition and fluoroacetate administration fully restored secretion. Epithelial responsiveness to vasoactive intestinal peptide was increased after enteric glial function was blocked in mice with colitis. In colons of mice without colitis, NO was produced in the myenteric plexus almost completely via NOS1. NO production was increased in mice with colitis, compared with mice without colitis; a substantial proportion of NOS2 was blocked by fluoroacetate administration. Inhibition of enteric glial function in vivo reduced the severity of trinitrobenzene sulfonic acid-induced colitis and associated bacterial translocation. Increased production of NOS2 in enteric glia contributes to the dysregulation of intestinal ion transport in mice with colitis. Blocking enteric glial function in these mice restores epithelial barrier function and reduces

  19. Inhibiting Inducible Nitric Oxide Synthase in Enteric Glia Restores Electrogenic Ion Transport in Mice with Colitis

    PubMed Central

    MacEachern, Sarah J.; Patel, Bhavik A.; Keenan, Catherine M.; Dicay, Michael; Chapman, Kevin; McCafferty, Donna-Marie; Savidge, Tor C.; Beck, Paul L.; MacNaughton, Wallace K.; Sharkey, Keith A.

    2015-01-01

    Background & Aims Disturbances in the control of ion transport lead to epithelial barrier dysfunction in patients with colitis. Enteric glia regulate intestinal barrier function and colonic ion transport. However, it is not clear whether enteric glia are involved in the epithelial hypo-responsiveness. We investigated enteric glial regulation of ion transport in mice with trinitrobenzene sulphonic acid- or dextran sodium sulfate-induced colitis and in Il10−/− mice. Methods Electrically-evoked ion transport was measured in full-thickness segments of colon from CD1 and Il10−/− mice with or without colitis in Ussing chambers. Nitric oxide (NO) production was assessed using amperometry. Bacterial translocation was investigated in the liver, spleen and blood of mice. Results Electrical stimulation of the colon evoked a tetrodotoxin-sensitive chloride secretion. In mice with colitis, ion transport almost completely disappeared. Inhibiting inducible NO synthase (NOS2), but not neuronal NOS (NOS1), partially restored the evoked secretory response. Blocking glial function with fluoroacetate, which is not a NOS2 inhibitor, also partially restored ion transport. Combined NOS2 inhibition and fluoroacetate administration fully restored secretion. Epithelial responsiveness to vasoactive intestinal peptide was increased after enteric glial function was blocked in mice with colitis. In colons of mice without colitis, NO was produced in the myenteric plexus almost completely via NOS1. NO production was increased in mice with colitis, compared to mice without colitis; a substantial proportion of NOS2 was blocked by fluoroacetate administration. Inhibition of enteric glial function in vivo reduced the severity of trinitrobenzene sulphonic acid -induced colitis and associated bacterial translocation. Conclusions Increased production of NOS2 in enteric glia contributes to the dysregulation of intestinal ion transport in mice with colitis. Blocking enteric glial function in these

  20. Cerebral Cortex Hyperthyroidism of Newborn Mct8-Deficient Mice Transiently Suppressed by Lat2 Inactivation

    PubMed Central

    Núñez, Bárbara; Martínez de Mena, Raquel; Obregon, Maria Jesus; Font-Llitjós, Mariona; Nunes, Virginia; Palacín, Manuel; Dumitrescu, Alexandra M.; Morte, Beatriz; Bernal, Juan

    2014-01-01

    Thyroid hormone entry into cells is facilitated by transmembrane transporters. Mutations of the specific thyroid hormone transporter, MCT8 (Monocarboxylate Transporter 8, SLC16A2) cause an X-linked syndrome of profound neurological impairment and altered thyroid function known as the Allan-Herndon-Dudley syndrome. MCT8 deficiency presumably results in failure of thyroid hormone to reach the neural target cells in adequate amounts to sustain normal brain development. However during the perinatal period the absence of Mct8 in mice induces a state of cerebral cortex hyperthyroidism, indicating increased brain access and/or retention of thyroid hormone. The contribution of other transporters to thyroid hormone metabolism and action, especially in the context of MCT8 deficiency is not clear. We have analyzed the role of the heterodimeric aminoacid transporter Lat2 (Slc7a8), in the presence or absence of Mct8, on thyroid hormone concentrations and on expression of thyroid hormone-dependent cerebral cortex genes. To this end we generated Lat2-/-, and Mct8-/yLat2-/- mice, to compare with wild type and Mct8-/y mice during postnatal development. As described previously the single Mct8 KO neonates had a transient increase of 3,5,3′-triiodothyronine concentration and expression of thyroid hormone target genes in the cerebral cortex. Strikingly the absence of Lat2 in the double Mct8Lat2 KO prevented the effect of Mct8 inactivation in newborns. The Lat2 effect was not observed from postnatal day 5 onwards. On postnatal day 21 the Mct8 KO displayed the typical pattern of thyroid hormone concentrations in plasma, decreased cortex 3,5,3′-triiodothyronine concentration and Hr expression, and concomitant Lat2 inactivation produced little to no modifications. As Lat2 is expressed in neurons and in the choroid plexus, the results support a role for Lat2 in the supply of thyroid hormone to the cerebral cortex during early postnatal development. PMID:24819605

  1. Facilitated Diagnosis of Pneumothoraces in Newborn Mice Using X-ray Dark-Field Radiography.

    PubMed

    Hellbach, Katharina; Yaroshenko, Andre; Willer, Konstantin; Pritzke, Tina; Baumann, Alena; Hesse, Nina; Auweter, Sigrid; Reiser, Maximilian F; Eickelberg, Oliver; Pfeiffer, Franz; Hilgendorff, Anne; Meinel, Felix G

    2016-10-01

    The aim of this study was to evaluate the diagnostic value of x-ray dark-field imaging in projection radiography-based depiction of pneumothoraces in the neonatal murine lung, a potentially life-threatening medical condition that requires a timely and correct diagnosis. By the use of a unique preclinical model, 7-day-old C57Bl/6N mice received mechanical ventilation for 2 or 8 hours with oxygen-rich gas (FIO2 = 0.4; n = 24). Unventilated mice either spontaneously breathed oxygen-rich gas (FIO2 = 0.4) for 2 or 8 hours or room air (n = 22). At the end of the experiment, lungs were inflated with a standardized volume of air after a lethal dose of pentobarbital was administered to the pups. All lungs were imaged with a prototype grating-based small-animal scanner to acquire x-ray transmission and dark-field radiographs. Image contrast between the air-filled pleural space and lung tissue was quantified for both transmission and dark-field radiograms. After the independent expert's assessment, 2 blinded readers evaluated all dark-field and transmission images for the presence or absence of pneumothoraces. Contrast ratios, diagnostic accuracy, as well as reader's confidence and interreader agreement were recorded for both imaging modalities. Evaluation of both x-ray transmission and dark-field radiographs by independent experts revealed the development of a total of 10 pneumothoraces in 8 mice. Here, the contrast ratio between the air-filled pleural space of the pneumothoraces and the lung tissue was significantly higher in the dark field (8.4 ± 3.5) when compared with the transmission images (5.1 ± 2.8; P < 0.05). Accordingly, the readers' diagnostic confidence for the diagnosis of pneumothoraces was significantly higher for dark-field compared with transmission images (P = 0.001). Interreader agreement improved from moderate for the analysis of transmission images alone (κ = 0.41) to very good when analyzing dark-field images alone (κ = 0.90) or in combination with

  2. Transient restoration of gene rearrangement at multiple T cell receptor loci in gamma-irradiated scid mice

    PubMed Central

    1996-01-01

    The developmental arrest of thymocytes from scid mice, deficient in variable, (diversity), and joining, or V(D)J recombination, can be overcome by sublethal gamma-irradiation. Since previous studies focused on restoration of rearrangement of the T cell receptor (TCR) beta locus, productive rearrangement of which is selected for, we sought to examine to what extent locus specificity and cellular selection contributed to the observed effects. We report here that irradiation of newborn scid mice induces normal V-D-J rearrangements of the TCR delta locus, which like TCR beta, is also actively rearranged in CD(4-)CD(8-) (double negative) thymocytes. In contrast, no complete V-J alpha rearrangements were detected. Instead, we detected substantial levels of hairpin-terminated coding ends at the 5' end of the J alpha locus, demonstrating that TCR alpha rearrangements manifest the effects of the scid mutation. Irradiation, therefore, transiently compensates for the effects of the scid mutation in a locus-nonspecific manner in thymocytes, resulting in a burst of normal TCR beta and delta rearrangements. Irradiation also allows the development of cells that can initiate but fail to complete V(D)J recombination events at the TCR alpha locus, which is normally inaccessible in scid thymocytes. PMID:8760795

  3. Dehydroepiandrosterone and metyrapone partially restore the adaptive humoral and cellular immune response in endotoxin immunosuppressed mice.

    PubMed

    Rearte, Bárbara; Maglioco, Andrea; Machuca, Damián; Greco, Daiana Martire; Landoni, Verónica I; Rodriguez-Rodrigues, Nahuel; Meiss, Roberto; Fernández, Gabriela C; Isturiz, Martín A

    2014-08-01

    Prior exposure to endotoxins renders the host temporarily refractory to subsequent endotoxin challenge (endotoxin tolerance). Clinically, this state has also been pointed out as the initial cause of the non-specific humoral and cellular immunosuppression described in these patients. We recently demonstrated the restoration of immune response with mifepristone (RU486), a receptor antagonist of glucocorticoids. Here we report the treatment with other modulators of glucocorticoids, i.e. dehydroepiandrosterone (DHEA), a hormone with anti-glucocorticoid properties, or metyrapone (MET) an inhibitor of corticosterone synthesis. These drugs were able to partially, but significantly, restore the humoral immune response in immunosuppressed mice. A significant recovery of proliferative responsiveness was also observed when splenocytes were obtained from DHEA- or MET-treated immunosuppressed mice. In addition, these treatments restored the hypersensitivity response in immunosuppressed mice. Finally, although neither DHEA nor MET improved the reduced CD4 lymphocyte count in spleen from immunosuppressed mice, both treatments promoted spleen architecture reorganization, partially restoring the distinct cellular components and their localization in the spleen. The results from this study indicate that DHEA and MET could play an important role in the restoration of both adaptive humoral and cellular immune response in LPS-immunosuppressed mice, reinforcing the concept of a central involvement of endogenous glucocorticoids on this phenomenon. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  4. Failure-to-Thrive Syndrome Associated with Tumor Formation by Madin–Darby Canine Kidney Cells in Newborn Nude Mice

    PubMed Central

    Brinster, Lauren R; Omeir, Romelda L; Foseh, Gideon S; Macauley, Juliete N; Snoy, Philip J; Beren, Joel J; Teferedegne, Belete; Peden, Keith; Lewis, Andrew M

    2013-01-01

    Tumors that formed in newborn nude mice that were inoculated with 107 Madin–Darby canine kidney (MDCK) cells were associated with a failure-to-thrive (FTT) syndrome consisting of growth retardation, lethargy, weakness, and dehydration. Scoliosis developed in 41% of affected pups. Pups were symptomatic by week 2; severely affected pups became moribund and required euthanasia within 3 to 4 wk. Mice with FTT were classified into categories of mild, moderate, and severe disease by comparing their weight with that of age-matched normal nude mice. The MDCK-induced tumors were adenocarcinomas that invaded adjacent muscle, connective tissue, and bone; 6 of the 26 pups examined had lung metastases. The induction of FTT did not correlate with cell-line aggressiveness as estimated by histopathology or the efficiency of tumor formation (tumor-forming dose 50% endpoint range = 102.8 to 107.5); however, tumor invasion of the paravertebral muscles likely contributed to the scoliosis noted. In contrast to the effect of MDCK cells, tumor formation observed in newborn mice inoculated with highly tumorigenic, human-tumor–derived cell lines was not associated with FTT development. We suggest that tumor formation and FTT are characteristics of these MDCK cell inocula and that FTT represents a new syndrome that may be similar to the cachexia that develops in humans with cancer or other diseases. PMID:24209967

  5. Maternal docosahexaenoic acid supplementation decreases lung inflammation in hyperoxia-exposed newborn mice.

    PubMed

    Rogers, Lynette K; Valentine, Christina J; Pennell, Michael; Velten, Markus; Britt, Rodney D; Dingess, Kelly; Zhao, Xuilan; Welty, Stephen E; Tipple, Trent E

    2011-02-01

    DHA is a long-chain fatty acid that has potent antiinflammatory properties. Whereas maternal DHA dietary supplementation has been shown to improve cognitive development in infants fed DHA-supplemented milk, the antiinflammatory effects of maternal DHA supplementation on the developing fetus and neonate have not been extensively explored. Pregnant C3H/HeN dams were fed purified control or DHA-supplemented diets (~0.25% of total fat) at embryonic d 16 and consumed these diets throughout the study. At birth, the nursing mouse pups were placed in room air (RA; 21% O(2)) or >95% O(2) (hyperoxia) for up to 7 d. These studies tested the hypothesis that maternal DHA supplementation would decrease inflammation and improve alveolarization in the lungs of newborn mouse pups exposed to hyperoxia. Survival, inflammatory responses, and lung growth were compared among control diet/RA, DHA/RA, control/O(2), and DHA/O(2) pups. There were fewer neutrophils and macrophages in lung tissues from pups nursed by DHA-supplemented dams than in those nursed by dams fed the control diet at 7 d of hyperoxia exposure (P < 0.015). Although differences due to hyperoxia exposure were observed, maternal diet did not affect keratinocyte-derived chemokine, macrophage inflammatory protein-2, IL-1β, or TNFα mRNA levels in pup tissues. Hyperoxia also induced NF-κB activity, but maternal diet did not affect NF-κB or PPARγ activities. In mice, DHA supplementation decreases leukocyte infiltration in the offspring exposed to hyperoxia, suggesting a potential role for DHA supplementation as a therapy to reduce inflammation in preterm infants.

  6. Clone-forming activity of embryonal stem hemopoietic cells after transplantation to newborn or adult sublethally irradiated mice.

    PubMed

    Drize, N I; Chertkov, I L

    2000-07-01

    Hemopoietic activity of stem hemopoietic cells from the liver of embryos was studied at different terms of intrauterine development. The fate of individual clones of hemopoietic cells marked by human adenosine deaminase gene was followed up in sublethally irradiated or newborn recipients. The efficiency of marker gene incorporation in primitive stem hemopoietic cells from the liver of 12-, 13-, and 17-day embryos was not high. Gene transfer was performed without cell prestimulation to division, and hence, these data show that primitive stem cells proliferate even in 17-day embryos. Cells from embryonal liver in all terms maintain hemopoiesis both in newborn and adult microenvironment, hemopoiesis being realized according to the clonal succession model, i. e. in the some way after transplantation of the bone marrow from adult mice.

  7. Brief dark exposure restored ocular dominance plasticity in aging mice and after a cortical stroke.

    PubMed

    Stodieck, Sophia Katharina; Greifzu, Franziska; Goetze, Bianka; Schmidt, Karl-Friedrich; Löwel, Siegrid

    2014-12-01

    In the primary visual cortex (V1), monocular deprivation (MD) induces a shift in the ocular dominance (OD) of binocular neurons towards the open eye (Wiesel and Hubel, 1963; Gordon and Stryker, 1996). In V1 of C57Bl/6J mice, this OD-plasticity is maximal in juveniles, declines in adults and is absent beyond postnatal day (PD) 110 (Lehmann and Löwel, 2008) if mice are raised in standard cages. Since it was recently shown that brief dark exposure (DE) restored OD-plasticity in young adult rats (PD70-100) (He et al., 2006), we wondered whether DE would restore OD-plasticity also in adult and old mice and after a cortical stroke. To this end, we raised mice in standard cages until adulthood and transferred them to a darkroom for 10-14 days. Using intrinsic signal optical imaging we demonstrate that short-term DE can restore OD-plasticity after MD in both adult (PD138) and old mice (PD535), and that OD-shifts were mediated by an increase of open eye responses in V1. Interestingly, restored OD-plasticity after DE was accompanied by a reduction of both parvalbumin expressing cells and perineuronal nets and was prevented by increasing intracortical inhibition with diazepam. DE also maintained OD-plasticity in adult mice (PD150) after a stroke in the primary somatosensory cortex. In contrast, short-term DE did not affect basic visual parameters as measured by optomotry. In conclusion, short-term DE was able to restore OD-plasticity in both adult and aging mice and even preserved plasticity after a cortical stroke, most likely mediated by reducing intracortical inhibition.

  8. Transplantation of Young Ovaries Restored Cardioprotective Influence in Postreproductive-Aged Mice

    PubMed Central

    Mason, Jeffrey B.; Cargill, Shelley L.; Griffey, Stephen M.; Reader, J. Rachel; Anderson, Gary B.; Carey, James R.

    2011-01-01

    Summary The female cardioprotective advantage, present in mammals of a reproductively-competent age, is lost during the transition to a postreproductive state. The role of reproductive hormones in this transition is most evident in women with premature ovarian failure, where reduced estrogen production has been associated with an increased incidence of early death from cardiovascular disease. Previously, we reported that postreproductive-aged mice that received young ovaries displayed an increased life span. Subsequent histopathological analysis suggested the presence of a cardioprotective effect associated with the restoration of ovarian influence. This restoration in postreproductive-aged mice produced a sharp decrease in evidence of significant cardiomyopathy at death, compared with sham-transplanted mice (36.0% vs. 73.3%, respectively). Within the intact transplant group, evidence of cardiomyopathy at death was decreased in mice that were reproductively cycling at the time of transplant, compared with acyclic mice (26.7% vs. 50.0%, respectively). This observation reflects the importance of timing in restoration of ovarian influence in this study. Transplantation of young ovaries to intact, postreproductive-aged female mice provided significant, long-term restoration of a cardioprotective benefit, similar to that previously present during a reproductively-competent age. In these mice, restoration of ovarian influence through ovarian transplantation may, in effect, have postponed the advance of age-associated cardiomyopathy to a point where the disease did not reach a clinically-relevant threshold during the lifetime of the recipients. These results offer support for previous clinical observations suggesting that hormone replacement therapy can produce divergent results if initiated during the perimenopausal period compared with the postmenopausal ages. PMID:21385306

  9. Blockade of advanced glycation end-product formation restores ischemia-induced angiogenesis in diabetic mice

    PubMed Central

    Tamarat, Radia; Silvestre, Jean-Sébastien; Huijberts, Maya; Benessiano, Joelle; Ebrahimian, Teni G.; Duriez, Micheline; Wautier, Marie-Paule; Wautier, Jean Luc; Lévy, Bernard I.

    2003-01-01

    We hypothesized that formation of advanced glycation end products (AGEs) associated with diabetes reduces matrix degradation by metalloproteinases (MMPs) and contributes to the impairment of ischemia-induced angiogenesis. Mice were treated or not with streptozotocin (40 mg/kg) and streptozotocin plus aminoguanidine (AGEs formation blocker, 50 mg/kg). After 8 weeks of treatment, hindlimb ischemia was induced by right femoral artery ligature. Plasma AGE levels were strongly elevated in diabetic mice when compared with control mice (579 ± 21 versus 47 ± 4 pmol/ml, respectively; P < 0.01). Treatment with aminoguanidine reduced AGE plasma levels when compared with untreated diabetic mice (P < 0.001). After 28 days of ischemia, ischemic/nonischemic leg angiographic score, capillary density, and laser Doppler skin-perfusion ratios were 1.4-, 1.5-, and 1.4-fold decreased in diabetic mice in reference to controls (P < 0.01). Treatment with aminoguanidine completely normalized ischemia-induced angiogenesis in diabetic mice. We next analyzed the role of proteolysis in AGE formation-induced hampered neovascularization process. After 3 days of ischemia, MMP-2 activity and MMP-3 and MMP-13 protein levels were increased in untreated and aminoguanidine-treated diabetic mice when compared with controls (P < 0.05). Despite this activation of the MMP pathway, collagenolysis was decreased in untreated diabetic mice. Conversely, treatment of diabetic mice with aminoguanidine restored collagenolysis toward levels found in control mice. In conclusion, blockade of AGE formation by aminoguanidine normalizes impaired ischemia-induced angiogenesis in diabetic mice. This effect is probably mediated by restoration of matrix degradation processes that are disturbed as a result of AGE accumulation. PMID:12805564

  10. Blockade of advanced glycation end-product formation restores ischemia-induced angiogenesis in diabetic mice.

    PubMed

    Tamarat, Radia; Silvestre, Jean-Sébastien; Huijberts, Maya; Benessiano, Joelle; Ebrahimian, Teni G; Duriez, Micheline; Wautier, Marie-Paule; Wautier, Jean Luc; Lévy, Bernard I

    2003-07-08

    We hypothesized that formation of advanced glycation end products (AGEs) associated with diabetes reduces matrix degradation by metalloproteinases (MMPs) and contributes to the impairment of ischemia-induced angiogenesis. Mice were treated or not with streptozotocin (40 mg/kg) and streptozotocin plus aminoguanidine (AGEs formation blocker, 50 mg/kg). After 8 weeks of treatment, hindlimb ischemia was induced by right femoral artery ligature. Plasma AGE levels were strongly elevated in diabetic mice when compared with control mice (579 +/- 21 versus 47 +/- 4 pmol/ml, respectively; P < 0.01). Treatment with aminoguanidine reduced AGE plasma levels when compared with untreated diabetic mice (P < 0.001). After 28 days of ischemia, ischemic/nonischemic leg angiographic score, capillary density, and laser Doppler skin-perfusion ratios were 1.4-, 1.5-, and 1.4-fold decreased in diabetic mice in reference to controls (P < 0.01). Treatment with aminoguanidine completely normalized ischemia-induced angiogenesis in diabetic mice. We next analyzed the role of proteolysis in AGE formation-induced hampered neovascularization process. After 3 days of ischemia, MMP-2 activity and MMP-3 and MMP-13 protein levels were increased in untreated and aminoguanidine-treated diabetic mice when compared with controls (P < 0.05). Despite this activation of the MMP pathway, collagenolysis was decreased in untreated diabetic mice. Conversely, treatment of diabetic mice with aminoguanidine restored collagenolysis toward levels found in control mice. In conclusion, blockade of AGE formation by aminoguanidine normalizes impaired ischemia-induced angiogenesis in diabetic mice. This effect is probably mediated by restoration of matrix degradation processes that are disturbed as a result of AGE accumulation.

  11. Immunogenicity and protective efficacy of an EV71 virus-like particle vaccine against lethal challenge in newborn mice.

    PubMed

    Sun, Shiyang; Gao, Fan; Mao, Qunying; Shao, Jie; Jiang, Liping; Liu, Dawei; Wang, Yiping; Yao, Xin; Wu, Xing; Sun, Bo; Zhao, Dandan; Ma, Youlei; Lu, Jingcai; Kong, Wei; Jiang, Chunlai; Liang, Zhenglun

    2015-01-01

    Enterovirus 71(EV71) has caused severe epidemics of hand, foot and mouth disease (HFMD) in the Asia Pacific in recent years, particularly in infants and pre-school children. It has become a serious public health threat, as currently there are no approved vaccines or antiviral drugs for EV71 infection. Many EV71 vaccines have been under development worldwide, however the main focus is inactivated EV71 vaccines. For example, the inactivated EV71 vaccine has recently finished phase III clinical trial in Mainland China. There have been very few studies on EV71 virus like particles (VLPs). In this study, the immunogenicity and protective potency of the EV71 VLPs produced in insect cells were evaluated in mice with different dosages. Our results showed that EV71 VLPs could elicit high titers of neutralizing antibodies (NTAbs) in a dose-dependent manner and NTAbs were sustained after the second injection with an average GMT (geometric mean titer) level from 19 to 2960 in immunized mice. Survival rates were 100%, 100%, 85%, and 40% after challenge with 15 LD50 (median lethal dose) of EV71 in these newborn mice, respectively. ED50 (50% effective dose) of VLPs was 0.20 μg/dose in newborn mice, while NTAb titer under this dosage was about 50. Passive protection was determined with 2 methods and demonstrated that the survival rates were positively correlated with NTAb titers, which at 24 and 54 induced 50% survival rates in experimental animals. The ED50 of VLP vaccines and the passive NTAb titers were also analyzed. The maternal NTAb titer was similar as the passive NTAb titer in the mouse model challenged with our lethal mouse EV71 strain. Hence, our work has provided preliminary data on the protection potency of VLPs as a vaccine candidate and would facilitate future VLP vaccine development.

  12. CHIP enhances angiogenesis and restores cardiac function after infarction in transgenic mice.

    PubMed

    Xu, Cheng-Wei; Zhang, Tian-Peng; Wang, Hong-Xia; Yang, Hui; Li, Hui-Hua

    2013-01-01

    Carboxyl terminus of Hsp70-interacting protein (CHIP) is a chaperone/ubiquitin ligase that plays an important role in stress-induced apoptosis. However, the effect of CHIP on angiogenesis, cardiac function and survival 4 weeks after myocardial infarction (MI) remain to be explored. Wild-type (WT) and transgenic mice (TG) with cardiac-specific overexpression of CHIP were used for coronary artery ligation. The cardiac function, cardiomyocyte apoptosis, inflammation and angiogenesis were examined by echocardiography, histological analysis, real-time PCR and Western blot analysis. At 4 weeks of after coronary artery ligation, echocardiography demonstrated that cardiac remodeling and dysfunction were prevented in TG mice compared with WT mice. The infarct size, cardiomyocyte apoptosis and inflammation were significantly reduced in TG mice than in WT mice. The survival rate after MI in TG mice was higher than that of WT mice. Furthermore, the levels of p53 protein was markedly decreased, but the expression of HIF-1α and VEGF, and the formation of capillary and arteriole after MI were significantly enhanced in TG mice compared with WT mice. We report the first in vivo evidence that CHIP enhances angiogenesis, inhibits inflammation, restores cardiac function, and improves survival at 4 weeks after MI. The present study expands on previous results and defines a novel mechanism. Thus, increased CHIP level may provide a novel therapeutic approach for left ventricular dysfunction after MI. Copyright © 2013 S. Karger AG, Basel.

  13. Restoring vision in mice with retinal degeneration using multicharacteristic opsin.

    PubMed

    Wright, Weldon; Gajjeraman, Sivakumar; Batabyal, Subrata; Pradhan, Sanjay; Bhattacharya, Sulagna; Mahapatra, Vasu; Tripathy, Ashutosh; Mohanty, Samarendra

    2017-10-01

    Retinal degenerative diseases, such as retinitis pigmentosa (RP) and dry age-related macular degeneration, have led to loss of vision in millions of individuals. Currently, no surgical or medical treatment is available, although optogenetic therapies are in clinical development. We demonstrate vision restoration using multicharacteristics opsin (MCO1) in animal models with degenerated retina. MCO1 is reliably delivered to specific retinal cells via intravitreal injection of adeno-associated virus (vMCO1), leading to significant improvement in visually guided behavior conducted using a radial arm water maze. The time to reach the platform and the number of error arms decreased significantly after delivery of MCO1. Notably, the improvement in visually guided behavior was observed even at light intensity levels orders of magnitude lower than that required for channelrhodopsin-2 opsin. Viability of vMCO1-treated retina is not compromised by chronic light exposure. Safe virus-mediated MCO1 delivery has potential for effective gene therapy of diverse retinal degenerations in patients.

  14. Hormonal suppression restores fertility in irradiated mice from both endogenous and donor-derived stem spermatogonia.

    PubMed

    Wang, Gensheng; Shao, Shan H; Weng, Connie C Y; Wei, Caimiao; Meistrich, Marvin L

    2010-09-01

    Irradiation interrupts spermatogenesis and causes prolonged sterility in male mammals. Hormonal suppression treatment with gonadotropin-releasing hormone (GnRH) analogues has restored spermatogenesis in irradiated rats, but similar attempts were unsuccessful in irradiated mice, monkeys, and humans. In this study, we tested a stronger hormonal suppression regimen (the GnRH antagonist, acyline, and plus flutamide) for efficacy both in restoring endogenous spermatogenesis and in enhancing colonization of transplanted stem spermatogonia in mouse testes irradiated with a total doses between 10.5 and 13.5 Gy. A 4-week hormonal suppression treatment, given immediately after irradiation, increased endogenous spermatogenic recovery 1.5-fold, and 11-week hormonal suppression produced twofold increases compared with sham-treated irradiated controls. Furthermore, 10-week hormonal suppression restored fertility from endogenous surviving spermatogonial stem cells in 90% of 10.5-Gy irradiated mice, whereas only 10% were fertile without hormonal suppression. Four- and 11-week hormonal suppression also enhanced spermatogenic development from transplanted stem spermatogonia in irradiated recipient mice, by 3.1- and 4.8-fold, respectively, compared with those not given hormonal treatment. Moreover, the 10-week hormonal suppression regimen, but not a sham treatment, restored fertility of some 13.5-Gy irradiated recipient mice from donor-derived spermatogonial stem cells. This is the first report of hormonal suppression inducing recovery of endogenous spermatogenesis and fertility in a mouse model treated with anticancer agents. The combination of spermatogonial transplantation with hormonal suppression should be investigated as a treatment to restore fertility in young men after cytotoxic cancer therapy.

  15. GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet.

    PubMed

    Clemmensen, Christoffer; Chabenne, Joseph; Finan, Brian; Sullivan, Lorraine; Fischer, Katrin; Küchler, Daniela; Sehrer, Laura; Ograjsek, Teja; Hofmann, Susanna M; Schriever, Sonja C; Pfluger, Paul T; Pinkstaff, Jason; Tschöp, Matthias H; Dimarchi, Richard; Müller, Timo D

    2014-04-01

    We recently reported restoration of leptin responsiveness in diet-induced obese (DIO) mice using a pharmacologically optimized, polyethylene-glycolated (PEG)-leptin analog in combination with exendin-4 or FGF21. However, the return of leptin action required discontinuation of high-fat diet (HFD) exposure. Here we assess whether a single peptide possessing balanced coagonism at the glucagon-like peptide 1 (GLP-1) and glucagon receptors can restore leptin responsiveness in DIO mice maintained on a HFD. DIO mice were treated with PEG-GLP-1/glucagon (30 nmol/kg every fourth day) to induce an ∼15% body weight loss, upon which they were randomized to continue PEG-GLP-1/glucagon therapy or reassigned to receive supplemental daily PEG-leptin (185 nmol/kg/day). The addition of PEG-leptin to PEG-GLP-1/glucagon resulted in an ∼18% greater weight loss as compared with PEG-GLP-1/glucagon alone and was accompanied by further decreases in food intake and improved glucose and lipid metabolism. The beneficial effect of PEG-leptin supplementation occurred after an initial body weight loss similar to what we previously reported following reduced dietary fat along with PEG-leptin and exendin-4 or FGF21 cotreatment. In summary, we report that GLP-1/glucagon coagonism restores leptin responsiveness in mice maintained on a HFD, thus emphasizing the translational value of this polypharmacotherapy for the treatment of obesity and diabetes.

  16. Boosting the coagulation restores haemostasis in ticagrelor-treated mice.

    PubMed

    Pehrsson, Susanne; Hansson, Kenny; Nelander, Karin; Nylander, Sven

    2016-12-01

    Antiplatelet therapy is given to patients with acute coronary syndrome to reduce the risk for thrombotic events, but may increase the risk for bleeding. Ticagrelor was administered intravenously to mice. Cumulative blood loss and bleeding time were measured after cutting 5 mm of the tail, 20 min after the start of ticagrelor infusion. The tail was placed in a hemoglobin-sensitive device measuring light absorbance (abs) over time for 35 min. Activated recombinant human factor VII (rhFVIIa; NovoSeven; NovoNordisk A/S, Bagsvaerd, Denmark) 1 mg/kg (study 1); recombinant human prothrombin (rhFII, MEDI8111) 10 mg/kg (study 2); or vehicle was given intravenously once bleeding had commenced, within 90s after tail cut. Ticagrelor resulted in more than 98% inhibition of ex-vivo ADP-induced platelet aggregation. In study 1, the median blood loss in the ticagrelor, vehicle, and rhFVIIa groups were 909, 122, and 397 abs*s, respectively (P < 0.05 for both comparisons, including the ticagrelor group). Similar pattern was seen for bleeding time. The median bleeding time in the ticagrelor, vehicle, and rhFVIIa groups were 2003, 449, and 884s, respectively (P < 0.05 for both comparisons, including the ticagrelor group). In study 2, the median blood loss and bleeding time in the ticagrelor group were 362 abs*s and 1847s. The corresponding numbers for the vehicle and rhFII groups were 71 abs*s and 613s, and 178 abs*s and 701s, respectively (P < 0.05 for comparisons between ticagrelor and vehicle for both blood loss and bleeding time). In mice dosed to complete P2Y12 inhibition, boosting coagulation by administration of rhFVIIa or rhFII within 90s after bleeding initiation can partly reverse ticagrelor-enhanced bleeding.

  17. Genetic Deletion of the NOS3 Gene in CAV1-/- Mice Restores Aqueous Humor Outflow Function.

    PubMed

    Song, Maomao; Wu, Jihong; Lei, Yuan; Sun, Xinghuai

    2017-10-01

    The purpose of this study was to investigate the impact of genetic deletion of NOS3 in CAV1-/- mice on aqueous humor outflow function using a mouse genetic double knockout model (DKO, NOS3-/- CAV1-/-). IOP was measured in DKO, NOS3 KO, CAV1 KO, and wild-type (WT) mice by rebound tonometry. Outflow facility was measured by perfusing enucleated mouse eyes at multiple pressure steps. Sodium nitroprusside (SNP) and L-NG-nitroarginine methyl ester (L-NAME) was administered topically, whereas the contralateral eyes served as vehicle controls. IOP was measured in both eyes before drug treatment and 1 hour after the last drug treatment. Mock aqueous humor ± the nitric oxide (NO) donor SNP or NOS inhibitor L-NAME was perfused into enucleated eyes. IOP was 11 ± 0.23 mm Hg in DKO mice, which was similar to WT mice and significantly lower than CAV1 KO mice (n = 18, P > 0.05). NOS3 deletion in CAV1-/- mice resulted in a 1.9-fold increase in conventional outflow facility (Ccon) compared with CAV1 KO mice (n = 7, P < 0.05). Topical application of NO donor SNP did not significantly change IOP (n = 18, P > 0.05) or Ccon in DKO mice (SNP, n = 20; vehicle, n = 11, P > 0.05). Topical application of L-NAME significantly increased IOP in WT, DKO, and CAV1 mice by reducing Ccon. Nitrotyrosine and PKG levels of DKO mice were similar to, whereas sGC was lower than, WT mice (P < 0.05). Genetic deletion of NOS3 in CAV1-deficient mice restored IOP and conventional aqueous humor drainage to WT level. NOS3 and CAV1 interaction is important to IOP regulation.

  18. [Implantation of newborn mice skin cells with chamber method to construct a model of hair follicle development].

    PubMed

    Xiao, Shun-e; Hu, Zhi-qi; Feng, Chuan-bo; Liu, Ge; Miao, Yong

    2012-05-01

    To construct a convenient, reliable and visual model of hair follicle development to test the hair-inductive potential of follicular cells and investigate the molecular mechanism regulating hair follicle morphogenesis and cycling. An open chamber was transplanted into the nude mice dorsal skin, dermal and epidermal cells isolated from newborn C57BL/6 mice skin were mixed at a specific ratio and then injected into the chamber together, 1 week after transplantation, the chamber was removed, and then, hair formation and regeneration after hair plucking was observed. 1 week after cells implantation, the wound was moist without apparent contraction and among that pink and translucent tissue was formed. 2 weeks after implantation, the wound healed completely. 3 weeks after implantation, black hair grew from the skin was observed. 4 weeks after implantation, thick and black hair grew from the skin vertically. Completely developed structure of hair follicle was observed with paraffin section and HE staining. 1 week after plucking, new hair had regrown. The ratio of cell component was varied, whereas the other component was fixed at 1 x 10(7) cells. When the number of epidermal cells was reduced to 1 x 10(6) cells, the efficiency of hair follicle reconstitution was mostly unchanged. On the other hand, the density of newly formed hair was diminished considerably by reducing the number of dermal cells to 5 x 10(6) cells or lower. Neither epidermal cells nor dermal cells transplanted alone formed hair follicle. Newborn mice skin cells transplanted by chamber method can construct a complete model of hair follicle development, which can be used to test the hair-inductive potential of follicular cells and investigate the molecular mechanism regulating hair follicle morphogenesis and cycling.

  19. Respiratory syncytial virus infection of newborn CX3CR1-deficent mice induces a pathogenic pulmonary innate immune response.

    PubMed

    Das, Sudipta; Raundhal, Mahesh; Chen, Jie; Oriss, Timothy B; Huff, Rachael; Williams, John V; Ray, Anuradha; Ray, Prabir

    2017-09-07

    Respiratory syncytial virus (RSV) infects almost all infants by 2 years of age, and severe bronchiolitis resulting from RSV infection is the primary cause of hospitalization in the first year of life. Among infants hospitalized due to RSV-induced bronchiolitis, those with a specific mutation in the chemokine receptor CX3CR1, which severely compromises binding of its ligand CX3CL1, were at a higher risk for more severe viral bronchiolitis than those without the mutation. Here, we show that RSV infection of newborn mice deficient in CX3CR1 leads to significantly greater neutrophilic inflammation in the lungs, accompanied by an increase in mucus production compared with that induced in WT mice. Analysis of innate and adaptive immune responses revealed an early increase in the number of IL-17+ γδ T cells in CX3CR1-deficient mice that outnumbered IFN-γ+ γδ T cells as well as IFN-γ+ NK cells, IFN-γ being host protective in the context of RSV infection. This bias toward IL-17+ γδ T cells persisted at a later time. The lungs of CX3CR1-deficient mice expressed higher levels of IL-1β mRNA and protein, and blockade of IL-1β signaling using IL-1 receptor antagonist significantly reduced the number of IL-17+ γδ T cells in the lungs of infected mice. Blockade of IL-17RC abolished RSV-induced lung pathology in infected CX3CR1-deficient mice. We propose that, in infants harboring mutant CX3CR1, targeting the IL-17R may minimize disease severity and hospitalization in early life.

  20. Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration

    PubMed Central

    Arnold, W. David; Duque, Sandra; Iyer, Chitra C.; Zaworski, Phillip; McGovern, Vicki L.; Taylor, Shannon J.; von Herrmann, Katharine M.; Kobayashi, Dione T.; Chen, Karen S.; Kolb, Stephen J.; Paushkin, Sergey V.; Burghes, Arthur H. M.

    2016-01-01

    Introduction and Objective Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder. SMA is caused by homozygous loss of the SMN1 gene and retention of the SMN2 gene resulting in reduced levels of full length SMN protein that are insufficient for motor neuron function. Various treatments that restore levels of SMN are currently in clinical trials and biomarkers are needed to determine the response to treatment. Here, we sought to investigate in SMA mice a set of plasma analytes, previously identified in patients with SMA to correlate with motor function. The goal was to determine whether levels of plasma markers were altered in the SMNΔ7 mouse model of SMA and whether postnatal SMN restoration resulted in normalization of the biomarkers. Methods SMNΔ7 and control mice were treated with antisense oligonucleotides (ASO) targeting ISS-N1 to increase SMN protein from SMN2 or scramble ASO (sham treatment) via intracerebroventricular injection on postnatal day 1 (P1). Brain, spinal cord, quadriceps muscle, and liver were analyzed for SMN protein levels at P12 and P90. Ten plasma biomarkers (a subset of biomarkers in the SMA-MAP panel available for analysis in mice) were analyzed in plasma obtained at P12, P30, and P90. Results Of the eight plasma biomarkers assessed, 5 were significantly changed in sham treated SMNΔ7 mice compared to control mice and were normalized in SMNΔ7 mice treated with ASO. Conclusion This study defines a subset of the SMA-MAP plasma biomarker panel that is abnormal in the most commonly used mouse model of SMA. Furthermore, some of these markers are responsive to postnatal SMN restoration. These findings support continued clinical development of these potential prognostic and pharmacodynamic biomarkers. PMID:27907033

  1. Prophylactic versus Therapeutic Fingolimod: Restoration of Presynaptic Defects in Mice Suffering from Experimental Autoimmune Encephalomyelitis.

    PubMed

    Bonfiglio, Tommaso; Olivero, Guendalina; Merega, Elisa; Di Prisco, Silvia; Padolecchia, Cristina; Grilli, Massimo; Milanese, Marco; Di Cesare Mannelli, Lorenzo; Ghelardini, Carla; Bonanno, Giambattista; Marchi, Mario; Pittaluga, Anna

    2017-01-01

    Fingolimod, the first oral, disease-modifying therapy for MS, has been recently proposed to modulate glutamate transmission in the central nervous system (CNS) of mice suffering from Experimental Autoimmune Encephalomyelitis (EAE) and in MS patients. Our study aims at investigating whether oral fingolimod recovers presynaptic defects that occur at different stages of disease in the CNS of EAE mice. In vivo prophylactic (0.3 mg/kg for 14 days, from the 7th day post immunization, d.p.i, the drug dissolved in the drinking water) fingolimod significantly reduced the clinical symptoms and the anxiety-related behaviour in EAE mice. Spinal cord inflammation, demyelination and glial cell activation are markers of EAE progression. These signs were ameliorated following oral fingolimod administration. Glutamate exocytosis was shown to be impaired in cortical and spinal cord terminals isolated from EAE mice at 21 ± 1 d.p.i., while GABA alteration emerged only at the spinal cord level. Prophylactic fingolimod recovered these presynaptic defects, restoring altered glutamate and GABA release efficiency. The beneficial effect occurred in a dose-dependent, region-specific manner, since lower (0.1-0.03 mg/kg) doses restored, although to a different extent, synaptic defects in cortical but not spinal cord terminals. A delayed reduction of glutamate, but not of GABA, exocytosis was observed in hippocampal terminals of EAE mice at 35 d.p.i. Therapeutic (0.3 mg/kg, from 21 d.p.i. for 14 days) fingolimod restored glutamate exocytosis in the cortex and in the hippocampus of EAE mice at 35 ± 1 d.p.i. but not in the spinal cord, where also GABAergic defects remained unmodified. These results improve our knowledge of the molecular events accounting for the beneficial effects elicited by fingolimod in demyelinating disorders.

  2. Orexin Gene Therapy Restores the Timing and Maintenance of Wakefulness in Narcoleptic Mice

    PubMed Central

    Kantor, Sandor; Mochizuki, Takatoshi; Lops, Stefan N.; Ko, Brian; Clain, Elizabeth; Clark, Erika; Yamamoto, Mihoko; Scammell, Thomas E.

    2013-01-01

    Study Objectives: Narcolepsy is caused by selective loss of the orexin/hypocretin-producing neurons of the hypothalamus. For patients with narcolepsy, chronic sleepiness is often the most disabling symptom, but current therapies rarely normalize alertness and do not address the underlying orexin deficiency. We hypothesized that the sleepiness of narcolepsy would substantially improve if orexin signaling were restored in specific brain regions at appropriate times of day. Design: We used gene therapy to restore orexin signaling in a mouse model of narcolepsy. In these Atx mice, expression of a toxic protein (ataxin-3) selectively kills the orexin neurons. Interventions: To induce ectopic expression of the orexin neuropeptides, we microinjected an adeno-associated viral vector coding for prepro-orexin plus a red fluorescence protein (AAV-orexin) into the mediobasal hypothalamus of Atx and wild-type mice. Control mice received an AAV coding only for red fluorescence protein. Two weeks later, we recorded sleep/wake behavior, locomotor activity, and body temperature and examined the patterns of orexin expression. Measurements and Results: Atx mice rescued with AAV-orexin produced long bouts of wakefulness and had a normal diurnal pattern of arousal, with the longest bouts of wake and the highest amounts of locomotor activity in the first hours of the night. In addition, AAV-orexin improved the timing of rapid eye movement sleep and the consolidation of nonrapid eye movement sleep in Atx mice. Conclusions: These substantial improvements in sleepiness and other symptoms of narcolepsy demonstrate the effectiveness of orexin gene therapy in a mouse model of narcolepsy. Additional work is needed to optimize this approach, but in time, AAV-orexin could become a useful therapeutic option for patients with narcolepsy. Citation: Kantor S; Mochizuki T; Lops SN; Ko B; Clain E; Clark E; Yamamoto M; Scammell TE. Orexin gene therapy restores the timing and maintenance of wakefulness

  3. Prophylactic versus Therapeutic Fingolimod: Restoration of Presynaptic Defects in Mice Suffering from Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Merega, Elisa; Di Prisco, Silvia; Padolecchia, Cristina; Grilli, Massimo; Milanese, Marco; Di Cesare Mannelli, Lorenzo; Ghelardini, Carla; Bonanno, Giambattista; Marchi, Mario

    2017-01-01

    Fingolimod, the first oral, disease-modifying therapy for MS, has been recently proposed to modulate glutamate transmission in the central nervous system (CNS) of mice suffering from Experimental Autoimmune Encephalomyelitis (EAE) and in MS patients. Our study aims at investigating whether oral fingolimod recovers presynaptic defects that occur at different stages of disease in the CNS of EAE mice. In vivo prophylactic (0.3 mg/kg for 14 days, from the 7th day post immunization, d.p.i, the drug dissolved in the drinking water) fingolimod significantly reduced the clinical symptoms and the anxiety-related behaviour in EAE mice. Spinal cord inflammation, demyelination and glial cell activation are markers of EAE progression. These signs were ameliorated following oral fingolimod administration. Glutamate exocytosis was shown to be impaired in cortical and spinal cord terminals isolated from EAE mice at 21 ± 1 d.p.i., while GABA alteration emerged only at the spinal cord level. Prophylactic fingolimod recovered these presynaptic defects, restoring altered glutamate and GABA release efficiency. The beneficial effect occurred in a dose-dependent, region-specific manner, since lower (0.1–0.03 mg/kg) doses restored, although to a different extent, synaptic defects in cortical but not spinal cord terminals. A delayed reduction of glutamate, but not of GABA, exocytosis was observed in hippocampal terminals of EAE mice at 35 d.p.i. Therapeutic (0.3 mg/kg, from 21 d.p.i. for 14 days) fingolimod restored glutamate exocytosis in the cortex and in the hippocampus of EAE mice at 35 ± 1 d.p.i. but not in the spinal cord, where also GABAergic defects remained unmodified. These results improve our knowledge of the molecular events accounting for the beneficial effects elicited by fingolimod in demyelinating disorders. PMID:28125677

  4. Modified Aloe Polysaccharide Restores Chronic Stress-Induced Immunosuppression in Mice.

    PubMed

    Lee, Youngjoo; Im, Sun-A; Kim, Jiyeon; Lee, Sungwon; Kwon, Junghak; Lee, Heetae; Kong, Hyunseok; Song, Youngcheon; Shin, Eunju; Do, Seon-Gil; Lee, Chong-Kil; Kim, Kyungjae

    2016-09-30

    Chronic stress generally experienced in our daily lives; is known to augment disease vulnerability by suppressing the host immune system. In the present study; the effect of modified Aloe polysaccharide (MAP) on chronic stress-induced immunosuppression was studied; this Aloe compound was characterized in our earlier study. Mice were orally administered with MAP for 24 days and exposed to electric foot shock (EFS; duration; 3 min; interval; 10 s; intensity; 2 mA) for 17 days. The stress-related immunosuppression and restorative effect of MAP were then analyzed by measuring various immunological parameters. MAP treatment alleviated lymphoid atrophy and body weight loss. The numbers of lymphocyte subsets were significantly normalized in MAP-treated mice. Oral administration of MAP also restored the proliferative activities of lymphocytes; ovalbumin (OVA)-specific T cell proliferation; antibody production; and the cell killing activity of cytotoxic T lymphocytes. In summary; oral administration of MAP ameliorated chronic EFS stress-induced immunosuppression.

  5. Modified Aloe Polysaccharide Restores Chronic Stress-Induced Immunosuppression in Mice

    PubMed Central

    Lee, Youngjoo; Im, Sun-A; Kim, Jiyeon; Lee, Sungwon; Kwon, Junghak; Lee, Heetae; Kong, Hyunseok; Song, Youngcheon; Shin, Eunju; Do, Seon-Gil; Lee, Chong-Kil; Kim, Kyungjae

    2016-01-01

    Chronic stress generally experienced in our daily lives; is known to augment disease vulnerability by suppressing the host immune system. In the present study; the effect of modified Aloe polysaccharide (MAP) on chronic stress-induced immunosuppression was studied; this Aloe compound was characterized in our earlier study. Mice were orally administered with MAP for 24 days and exposed to electric foot shock (EFS; duration; 3 min; interval; 10 s; intensity; 2 mA) for 17 days. The stress-related immunosuppression and restorative effect of MAP were then analyzed by measuring various immunological parameters. MAP treatment alleviated lymphoid atrophy and body weight loss. The numbers of lymphocyte subsets were significantly normalized in MAP-treated mice. Oral administration of MAP also restored the proliferative activities of lymphocytes; ovalbumin (OVA)-specific T cell proliferation; antibody production; and the cell killing activity of cytotoxic T lymphocytes. In summary; oral administration of MAP ameliorated chronic EFS stress-induced immunosuppression. PMID:27706024

  6. Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice

    PubMed Central

    Proulx, Steven T.; Dillard, Miriam E.; Johnson, Nicole; Detmar, Michael

    2016-01-01

    Prox1 heterozygous mice have a defective lymphatic vasculature and develop late-onset obesity. Chyle abnormally leaks from those vessels, accumulates in the surrounding tissues, and causes an increase in adipose tissue. We characterized the lymphatics of Prox1+/– mice to determine whether the extent of obesity correlated with the severity of lymphatic defects. The lymphatic vasculature in Prox1+/– mice exhibited reduced tracer clearance from the ear skin, dysfunctional perfusion of the lower legs, and reduced tracer uptake into the deep lymphatic collectors during mechanostimulation prior to the onset of obesity. Ear lymphatic vessels and leg collectors in Prox1+/– mice were disorganized and irregular, further confirming that defective lymphatic vessels are associated with obesity in Prox1+/– mice. We now provide conclusive in vivo evidence that demonstrates that leaky lymphatics mediate obesity in Prox1+/– mice, as restoration of lymphatic vasculature function was sufficient to rescue the obesity features in Prox1+/– mice. Finally, depth-lipomic profiling of lymph contents showed that free fatty acids induce adipogenesis in vitro. PMID:26973883

  7. Sources, sinks, and spatial ecology of cotton mice in longleaf pine stands undergoing restoration

    USGS Publications Warehouse

    Sharp, N.W.; Mitchell, M.S.; Grand, J.B.

    2009-01-01

    The Fire and Fire Surrogate studya replicated, manipulative experimentsought the most economically and ecologically efficient way to restore the nation's fire-maintained ecosystems. As part of this study, we conducted a 3-year markrecapture study, comprising 105,000 trap-nights, to assess demographic responses of cotton mice (Peromyscus gossypinus) to Fire and Fire Surrogate treatments at the Gulf Coastal Plain site, where longleaf pine was the ecosystem to be restored. We compared competing models to evaluate restoration effects on variation in apparent survival and recruitment over time, space, and treatment, and incorporated measures of available source habitat for cotton mice with reverse-time modeling to infer immigration from outside the study area. The top-ranked survival model contained only variation over time, but the closely ranked 2nd and 3rd models included variation over space and treatment, respectively. The top 4 recruitment models all included effects for availability of source habitat and treatments. Burning appeared to degrade habitat quality for cotton mice, showing demographic characteristics of a sink, but treatments combining fire with thinning of trees or application of herbicide to the understory appeared to improve habitat quality, possibly creating sources. Bottomland hardwoods outside the study also acted as sources by providing immigrants to experimental units. Models suggested that population dynamics operated over multiple spatial scales. Treatments applied to 15-ha stands probably only caused local variation in vital rates within the larger population. ?? 2009 American Society of Mammalogists.

  8. Inoculation of newborn SWR/J females with an ecotropic murine leukemia virus can produce transgenic mice.

    PubMed

    Panthier, J J; Condamine, H; Jacob, F

    1988-02-01

    Endogenous ecotropic murine leukemia proviruses that were not present in the parental stock are acquired by the progeny of some SWR/J X RF/J hybrid females. We have made a stock of an ecotropic murine leukemia virus produced by such a hybrid female and inoculated newborn SWR/J females with it. We show that upon crossing of the inoculated females to SWR/J males, some of their progeny acquire ecotropic proviruses. Although most of these proviruses appear to be distributed in somatic tissues in a mosaic way, some are transmitted through the germ line. Thus an exogenous infection is able to mimic the phenomenon observed in SWR/J X RF/J hybrid mice. Available evidence suggests that this infection occurs during oogenesis in the recipient female. Our results document the conversion of an exogenous infectious ecotropic murine leukemia virus to an endogenous provirus without any manipulation of either eggs or embryos.

  9. Vitamin C prevents cigarette smoke-induced pulmonary emphysema in mice and provides pulmonary restoration.

    PubMed

    Koike, Kengo; Ishigami, Akihito; Sato, Yasunori; Hirai, Toyohiro; Yuan, Yiming; Kobayashi, Etsuko; Tobino, Kazunori; Sato, Tadashi; Sekiya, Mitsuaki; Takahashi, Kazuhisa; Fukuchi, Yoshinosuke; Maruyama, Naoki; Seyama, Kuniaki

    2014-02-01

    Vitamin C (VC) is a potent antioxidant and is essential for collagen synthesis. We investigated whether VC treatment prevents and cures smoke-induced emphysema in senescence marker protein-30 knockout (SMP30-KO) mice, which cannot synthesize VC. Two smoke-exposure experiments using SMP30-KO mice were conducted. In the first one (a preventive study), 4-month-old mice received minimal VC (0.0375 g/l) [VC(L)] or physiologically sufficient VC (1.5 g/l) [VC(S)] and exposed to cigarette smoke or smoke-free air for 2 months. Pulmonary evaluations followed when the mice were 6 months of age. The second study began after the establishment of smoke-induced emphysema (a treatment study). These mice no longer underwent smoke exposure but received VC(S) or VC(L) treatment for 2 months. Morphometric analysis was performed, and measurements of oxidative stress, collagen synthesis, and vascular endothelial growth factor in the lungs were evaluated. Chronic smoke exposure caused emphysema (29.6% increases of mean linear intercepts [MLI] and 106.5% increases of destructive index compared with the air-only group) in 6-month-old SMP30-KO mice, and this emphysema closely resembled human chronic obstructive pulmonary disease. Smoke-induced emphysema persisted in the VC(L) group after smoking cessation, whereas VC treatment provided pulmonary restoration (18.5% decrease of MLI and 41.3% decrease of destructive index compared with VC(L) group). VC treatment diminished oxidative stress, increased collagen synthesis, and improved vascular endothelial growth factor levels in the lungs. Our results suggest that VC not only prevents smoke-induced emphysema in SMP30-KO mice but also restores emphysematous lungs. Therefore, VC may provide a new therapeutic strategy for treating chronic obstructive pulmonary disease in humans.

  10. Adipose-Derived Mesenchymal Stem Cells Restore Impaired Mucosal Immune Responses in Aged Mice

    PubMed Central

    Aso, Kazuyoshi; Tsuruhara, Akitoshi; Takagaki, Kentaro; Oki, Katsuyuki; Ota, Megumi; Nose, Yasuhiro; Tanemura, Hideki; Urushihata, Naoki; Sasanuma, Jinichi; Sano, Masayuki; Hirano, Atsuyuki; Aso, Rio; McGhee, Jerry R.; Fujihashi, Kohtaro

    2016-01-01

    It has been shown that adipose-derived mesenchymal stem cells (AMSCs) can differentiate into adipocytes, chondrocytes and osteoblasts. Several clinical trials have shown the ability of AMSCs to regenerate these differentiated cell types. Age-associated dysregulation of the gastrointestinal (GI) immune system has been well documented. Our previous studies showed that impaired mucosal immunity in the GI tract occurs earlier during agingthan is seen in the systemic compartment. In this study, we examined the potential of AMSCs to restore the GI mucosal immune system in aged mice. Aged (>18 mo old) mice were adoptively transferred with AMSCs. Two weeks later, mice were orally immunized with ovalbumin (OVA) plus cholera toxin (CT) three times at weekly intervals. Seven days after the final immunization, when fecal extract samples and plasma were subjected to OVA- and CT-B-specific ELISA, elevated levels of mucosal secretory IgA (SIgA) and plasma IgG antibody (Ab) responses were noted in aged mouse recipients. Similar results were also seen aged mice which received AMSCs at one year of age. When cytokine production was examined, OVA-stimulated Peyer’s patch CD4+ T cells produced increased levels of IL-4. Further, CD4+ T cells from the lamina propria revealed elevated levels of IL-4 and IFN-γ production. In contrast, aged mice without AMSC transfer showed essentially no OVA- or CT-B-specific mucosal SIgA or plasma IgG Ab or cytokine responses. Of importance, fecal extracts from AMSC transferred aged mice showed neutralization activity to CT intoxication. These results suggest that AMSCs can restore impaired mucosal immunity in the GI tract of aged mice. PMID:26840058

  11. Voltage-activated Ca2+ channels and their role in the endocrine function of the pituitary gland in newborn and adult mice

    PubMed Central

    Sedej, Simon; Tsujimoto, Tetsuhiro; Zorec, Robert; Rupnik, Marjan

    2004-01-01

    We have prepared fresh pituitary gland slices from adult and, for the first time, from newborn mice to assess modulation of secretory activity via voltage-activated Ca2+ channels (VACCs). Currents through VACCs and membrane capacitance have been measured with the whole-cell patch-clamp technique. Melanotrophs in newborns were significantly larger than in adults. In both newborn and adult melanotrophs activation of VACCs triggered exocytosis. All pharmacologically isolated VACC types contributed equally to the secretory activity. However, the relative proportion of VACCs differed between newborns and adults. In newborn cells L-type channels dominated and, in addition, an exclusive expression of a toxin-resistant R-type-like current was found. The expression of L-type VACCs was up-regulated by the increased oestrogen levels observed in females, and was even more emphasized in the cells of pregnant females and oestrogen-treated adult male mice. We suggest a general mechanism modulating endocrine secretion in the presence of oestrogen and particularly higher sensitivity to treatments with L-type channel blockers during high oestrogen physiological states. PMID:14724188

  12. Photopharmacological control of bipolar cells restores visual function in blind mice

    PubMed Central

    Tochitsky, Ivan; Kaur, Kuldeep; Stein, Marco; Barber, David M.; Schön, Christian; Biel, Martin; Kramer, Richard H.; Sumser, Martin P.; Trauner, Dirk; Van Gelder, Russell N.

    2017-01-01

    Photopharmacological control of neuronal activity using synthetic photochromic ligands, or photoswitches, is a promising approach for restoring visual function in patients suffering from degenerative retinal diseases. Azobenzene photoswitches, such as AAQ and DENAQ, have been shown to restore the responses of retinal ganglion cells to light in mouse models of retinal degeneration but do not recapitulate native retinal signal processing. Here, we describe diethylamino-azo-diethylamino (DAD), a third-generation photoswitch that is capable of restoring retinal ganglion cell light responses to blue or white light. In acute brain slices of murine layer 2/3 cortical neurons, we determined that the photoswitch quickly relaxes to its inactive form in the dark. DAD is not permanently charged, and the uncharged form enables the photoswitch to rapidly and effectively cross biological barriers and thereby access and photosensitize retinal neurons. Intravitreal injection of DAD restored retinal light responses and light-driven behavior to blind mice. Unlike DENAQ, DAD acts upstream of retinal ganglion cells, primarily conferring light sensitivity to bipolar cells. Moreover, DAD was capable of generating ON and OFF visual responses in the blind retina by utilizing intrinsic retinal circuitry, which may be advantageous for restoring visual function. PMID:28581442

  13. Newborn Screening

    MedlinePlus

    ... Laboratory Sciences Office of Public Health Genomics Publications & Articles Newborn Screening Lab Bulletin Laboratory Partners Multimedia Tools Newborn Screening Program – Role of Laboratories Meet the Scientist Newborn Screening: Family Stories Newborn Screening: Public Health ...

  14. Restoration of skeletal muscle ischemia-reperfusion injury in humanized immunodeficient mice.

    PubMed

    Sheu, Eric G; Oakes, Sean M; Ahmadi-Yazdi, Cyrus; Afnan, Jalil; Carroll, Michael C; Moore, Francis D

    2009-08-01

    Ischemia and reperfusion (I/R) of tissue provokes an inflammatory process that is highly dependent on circulating natural immunoglobulin M (IgM) and the complement cascade. In mice, a single IgM specificity produced by peritoneal B cells can initiate reperfusion injury. It is unknown whether humans express natural IgM with a similar specificity. It is also unknown whether pathogenic IgM is produced solely from peritoneal B cells or can also be made by circulating B cells. Immunodeficient mice lacking endogenous immunoglobulin were used. Mice were reconstituted with 0.9% normal saline, human serum, or xenografted human peripheral blood lymphocytes (PBLs) and then subjected to tourniquet-induced hindlimb I/R. Serum human IgM and immunoglobulin G (IgG) were measured by enzyme-linked immunosorbent (ELISA) assay. Skeletal muscle was harvested for injury assessment by histology and for immunohistochemistry. Immunodeficient mice were protected from skeletal muscle injury after hindlimb I/R. Transfer of human serum restored skeletal muscle damage. Rag2/gammaR-/- mice that were engrafted with human PBL (huPBL-SCID) had high levels of human IgM. huPBL-SCID mice developed significantly more skeletal muscle injury than control saline-treated mice (P < or = .01) and human serum-reconstituted Rag2/gammaR-/- mice (P < or = 0.01). Sham-treated huPBL-SCID mice had no muscle injury, demonstrating that human lymphocyte engraftment did not cause injury in the absence of ischemia. Deposition of human IgM was observed on injured but not sham-injured muscle. Human serum can initiate murine skeletal muscle I/R injury. Circulating human PBL may be a source of pathogenic IgM. The huPBL-SCID mouse may be a useful model to define the specificity of pathogenic human IgM and to test therapeutics for I/R injury.

  15. Ajoene restored behavioral patterns and liver glutathione level in morphine treated C57BL6 mice.

    PubMed

    Yun, Jaesuk; Oliynyk, Sergiy; Lee, Yeonju; Kim, Jieun; Yun, Kyunghwa; Jeon, Raok; Ryu, Jae-Ha; Oh, Seikwan

    2017-01-01

    Oxidative stress exacerbates drug dependence induced by administration of opiate analgesics such as morphine-induced tolerance and physical dependence associated with the reduction in hepatic glutathione (GSH) level. Ajoene obtained from garlic (Allium sativum L.) has been reported for anti-tumorigenic, anti-oxidative and neuroprotective properties, however, little is known about its effect on morphine-induced dependence. Therefore, this study aimed at the effect of ajoene on physical and/or psychological dependence and liver GSH content in morphine-treated mice. Conditioned place preference (CPP) test and measurement of morphine withdrawal syndrome were performed in C57BL6 mice for behavioral experiments. Thereafter, mice were sacrificed for measurement of serum and liver GSH levels. Ajoene restored CPP and naloxone-precipitated jumping behavior in mice exposed to morphine. Moreover, the reduced level of liver GSH content in morphine treated mice was back to normal after ajoene administration. Taken together, ajoene improved behavioral patterns in mice exposed to morphine suggesting its potential therapeutic benefit against morphine-induced dependence.

  16. PD-1 deletion restores susceptibility to experimental autoimmune encephalomyelitis in miR-155-deficient mice.

    PubMed

    Zhang, Jinyu; Braun, Michel Y

    2014-07-01

    MiR-155 (-/-) mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), while Pdcd1 (-/-) mice develop a more severe form of the disease. To determine the conflicting roles of these two molecules in the disease, we generated miR-155 (-/-) Pdcd1 (-/-) double knockout (DKO) mice. We found that ablation of programmed cell death protein 1 (PD-1) expression in miR-155-deficient mice restored the susceptibility to EAE. The increased severity of the disease in DKO mice was accompanied by an enhanced T-cell infiltration into the brain as well as an increased production of pro-inflammatory cytokines IFN-γ and IL-17. Furthermore, the major contribution of the DKO to EAE was T-cell intrinsic since adoptive transfer of CD4(+) T cells from DKO donors promoted the disease in lymphopenic recipients. These results define PD-1 deficiency in miR-155 (-/-) mice as a promoting factor of autoimmune inflammation by increasing antigen-driven T-cell expansion and infiltration.

  17. Restoration of the immune functions in aged mice by supplementation with a new herbal composition, HemoHIM.

    PubMed

    Park, Hae-Ran; Jo, Sung-Kee; Jung, Uhee; Yee, Sung-Tae

    2008-01-01

    The effect of a new herbal composition, HemoHIM, on immune functions was examined in aged mice, in which various immune responses had been impaired. The composition HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of three edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Supplementation to the aged mice with HemoHIM restored the proliferative response and cytokine production of splenocytes with a response to ConA. Also, HemoHIM recovered the NK cell activity which had been impaired in the aged mice. Meanwhile aging is known to reduce the Th1-like function, but not the Th2-like function, resulting in a Th1/Th2 imbalance. HemoHIM restored the Th1/Th2 balance in the aged mice through enhanced IFN-gamma and IgG2a production, and conversely a reduced IL-4 and IgG1 production. It was found that one factor for the Th1/Th2 imbalance in the aged mice was a lower production of IL-12p70. However, HemoHIM restored the IL-12p70 production in the aged mice. These results suggested that HemoHIM was effective for the restoration of impaired immune functions of the aged mice and therefore could be a good recommendation for immune restoration in elderly humans. Copyright (c) 2007 John Wiley & Sons, Ltd.

  18. Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology

    PubMed Central

    Yang, Sujeong; Cacquevel, Matthias; Saksida, Lisa M.; Bussey, Timothy J.; Schneider, Bernard L.; Aebischer, Patrick; Melani, Riccardo; Pizzorusso, Tommaso; Fawcett, James W.; Spillantini, Maria Grazia

    2015-01-01

    Alzheimer's disease is the most prevalent tauopathy and cause of dementia. We investigate the hypothesis that reactivation of plasticity can restore function in the presence of neuronal damage resulting from tauopathy. We investigated two models with tau hyperphosphorylation, aggregation and neurodegeneration: a transgenic mouse model in which the mutant P301S tau is expressed in neurons (Tg P301S), and a model in which an adeno-associated virus expressing P301S tau (AAV-P301S) was injected in the perirhinal cortex, a region critical for object recognition (OR) memory. Both models show profound loss of OR memory despite only 15% neuronal loss in the Tg P301S and 26% in AAV-P301S-injected mice. Recordings from perirhinal cortex slices of 3 month-old P301S transgenic mice showed a diminution in synaptic transmission following temporal stimulation. Chondroitinase ABC (ChABC) can reactivate plasticity and affect memory through actions on perineuronal nets. ChABC was injected into the perirhinal cortex and animals were tested for OR memory 1 week later, demonstrating restoration of OR memory to normal levels. Synaptic transmission indicated by fEPSP amplitude was restored to control levels following ChABC treatment. ChABC did not affect the progression of neurodegenerative tauopathy. These findings suggest that increasing plasticity by manipulation of perineuronal nets offers a novel therapeutic approach to the treatment of memory loss in neurodegenerative disorders. PMID:25483398

  19. Restoration of skeletal muscle ischemia-reperfusion injury in humanized immunodeficient mice

    PubMed Central

    Sheu, Eric G.; Oakes, Sean M.; Ahmadi-Yazdi, Cyrus; Afnan, Jalil; Carroll, Michael C.; Moore, Francis D.

    2009-01-01

    Background Ischemia and reperfusion (I/R) of tissue provokes an inflammatory process that is highly dependent on circulating natural immunoglobulin M (IgM) and the complement cascade. In mice, a single IgM specificity produced by peritoneal B cells can initiate reperfusion injury. It is unknown whether humans express natural IgM with a similar specificity. It is also unknown whether pathogenic IgM is produced solely from peritoneal B cells or can also be made by circulating B cells. Methods Immunodeficient mice lacking endogenous immunoglobulin were used. Mice were reconstituted with normal saline, human serum, or xenografted human peripheral blood lymphocytes (PBLs) and then subjected to tourniquet induced hindlimb ischemia and reperfusion. Serum human IgM and IgG were measured by ELISA. Skeletal muscle was harvested for injury assessment by histology and for immunohistochemistry. Results Immunodeficient mice are protected from skeletal muscle injury following hindlimb I/R. Transfer of human serum restores skeletal muscle damage. Rag2/γR -/- mice engrafted with human PBL (huPBL-SCID) have high levels of human IgM. huPBL-SCID mice develop significantly more skeletal muscle injury than control saline treated (p ≤ 0.01) and human serum reconstituted Rag2/γR -/- mice (p ≤ 0.01). Sham treated huPBL-SCID mice have no muscle injury, demonstrating that human lymphocyte engraftment does not cause injury in the absence of ischemia. Deposition of human IgM is seen on injured but not sham injured muscle. Conclusions Human serum can initiate murine skeletal muscle ischemia reperfusion injury. Circulating human PBL may be a source of pathogenic IgM. The huPBL-SCID mouse may be a useful model to define the specificity of pathogenic human IgM and to test therapeutics for ischemia-reperfusion injury. PMID:19628094

  20. Modafinil improves methamphetamine-induced object recognition deficits and restores prefrontal cortex ERK signaling in mice

    PubMed Central

    Gonzalez, Betina; Raineri, Mariana; Cadet, Jean Lud; García-Rill, Edgar; Urbano, Francisco J.; Bisagno, Veronica

    2016-01-01

    Chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and in animal models. Modafinil is a wake-promoting compound approved for the treatment of sleeping disorders. It is also prescribed off label to treat METH dependence. In the present study, we investigated whether modafinil could improve cognitive deficits induced by sub-chronic METH treatment in mice by measuring visual retention in a Novel Object Recognition (NOR) task. After sub-chronic METH treatment (1 mg/Kg, once a day for 7 days), mice performed the NOR task, which consisted of habituation to the object recognition arena (5 min a day, 3 consecutive days), training session (2 equal objects, 10 min, day 4), and a retention session (1 novel object, 5 min, day 5). One hour before the training session, mice were given a single dose of modafinil (30 or 90 mg/Kg). METH-treated mice showed impairments in visual memory retention, evidenced by equal preference of familiar and novel objects during the retention session. The lower dose of modafinil (30 mg/Kg) had no effect on visual retention scores in METH-treated mice, while the higher dose (90 mg/Kg) rescued visual memory retention to control values. We also measured ERK phosphorylation in medial prefrontal cortex (mPFC), hippocampus, and nucleus accumbens (NAc) of METH- and vehicle-treated mice that received modafinil 1 hr before exposure to novel objects in the training session, compared to mice placed in the arena without objects. Elevated Extracellular signal-regulated kinase (ERK) phosphorylation was found in the mPFC of vehicle-treated mice, but not in METH-treated mice, exposed to objects (p<0.05). The lower dose of modafinil had no effect on ERK phosphorylation in METH-treated mice, while 90 mg/Kg modafinil treatment restored the ERK phosphorylation induced by novelty in METH-treated mice to values comparable to controls (p<0.05). We found neither a novelty nor treatment effect on ERK phosphorylation in hippocampus or

  1. Modafinil improves methamphetamine-induced object recognition deficits and restores prefrontal cortex ERK signaling in mice.

    PubMed

    González, Betina; Raineri, Mariana; Cadet, Jean Lud; García-Rill, Edgar; Urbano, Francisco J; Bisagno, Veronica

    2014-12-01

    Chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and in animal models. Modafinil is a wake-promoting compound approved for the treatment of sleeping disorders. It is also prescribed off label to treat METH dependence. In the present study, we investigated whether modafinil could improve cognitive deficits induced by sub-chronic METH treatment in mice by measuring visual retention in a Novel Object Recognition (NOR) task. After sub-chronic METH treatment (1 mg/kg, once a day for 7 days), mice performed the NOR task, which consisted of habituation to the object recognition arena (5 min a day, 3 consecutive days), training session (2 equal objects, 10 min, day 4), and a retention session (1 novel object, 5 min, day 5). One hour before the training session, mice were given a single dose of modafinil (30 or 90 mg/kg). METH-treated mice showed impairments in visual memory retention, evidenced by equal preference of familiar and novel objects during the retention session. The lower dose of modafinil (30 mg/kg) had no effect on visual retention scores in METH-treated mice, while the higher dose (90 mg/kg) rescued visual memory retention to control values. We also measured extracellular signal-regulated kinase (ERK) phosphorylation in medial prefrontal cortex (mPFC), hippocampus, and nucleus accumbens (NAc) of METH- and vehicle-treated mice that received modafinil 1 h before exposure to novel objects in the training session, compared to mice placed in the arena without objects. Elevated ERK phosphorylation was found in the mPFC of vehicle-treated mice, but not in METH-treated mice, exposed to objects. The lower dose of modafinil had no effect on ERK phosphorylation in METH-treated mice, while 90 mg/kg modafinil treatment restored the ERK phosphorylation induced by novelty in METH-treated mice to values comparable to controls. We found neither a novelty nor treatment effect on ERK phosphorylation in hippocampus or NAc of vehicle

  2. Carcinogenicity study of outdoor airborne particulate matter in newborn male NMRI mice.

    PubMed

    Heussen, G A; van den Berg, J H; Dreef-van der Meulen, H C; Alink, G M

    1996-11-01

    An organic extract of airborne particulate matter (APM) was tested for carcinogenicity at two dose levels in the newborn mouse bioassay. The samples used were taken under specific polluted conditions. The doses tested corresponded with 0.75 and 1.5 times the amount of air man inhales during lifetime. Benzo(a)pyrene, which was used as a positive control, significantly increased the lung tumor incidence. No evidence was found for a carcinogenic activity of the organic extract of APM. Considering the high dose of APM applied in this animal model and the much lower actual cumulative dose to which man is exposed to in many areas, the conclusion can be drawn that exposure to APM alone probably does not represent an important cancer risk for man.

  3. Physical Exercise Preserves Adult Visual Plasticity in Mice and Restores it after a Stroke in the Somatosensory Cortex.

    PubMed

    Kalogeraki, Evgenia; Pielecka-Fortuna, Justyna; Hüppe, Janika M; Löwel, Siegrid

    2016-01-01

    The primary visual cortex (V1) is widely used to study brain plasticity, which is not only crucial for normal brain function, such as learning and memory, but also for recovery after brain injuries such as stroke. In standard cage (SC) raised mice, experience-dependent ocular dominance (OD) plasticity in V1 declines with age and is compromised by a lesion in adjacent and distant cortical regions. In contrast, mice raised in an enriched environment (EE), exhibit lifelong OD plasticity and are protected from losing OD plasticity after a stroke-lesion in the somatosensory cortex. Since SC mice with an access to a running wheel (RW) displayed preserved OD plasticity during aging, we investigated whether physical exercise might also provide a plasticity promoting effect after a cortical stroke. To this end, we tested if adult RW-raised mice preserved OD plasticity after stroke and also if short-term running after stroke restored OD plasticity to SC mice. Indeed, unlike mice without a RW, adult RW mice continued to show OD plasticity even after stroke, and a 2 weeks RW experience after stroke already restored lost OD plasticity. Additionally, the experience-enabled increase of the spatial frequency and contrast threshold of the optomotor reflex of the open eye, normally lost after a stroke, was restored in both groups of RW mice. Our data suggest that physical exercise alone can not only preserve visual plasticity into old age, but also restore it after a cortical stroke.

  4. Physical Exercise Preserves Adult Visual Plasticity in Mice and Restores it after a Stroke in the Somatosensory Cortex

    PubMed Central

    Kalogeraki, Evgenia; Pielecka-Fortuna, Justyna; Hüppe, Janika M.; Löwel, Siegrid

    2016-01-01

    The primary visual cortex (V1) is widely used to study brain plasticity, which is not only crucial for normal brain function, such as learning and memory, but also for recovery after brain injuries such as stroke. In standard cage (SC) raised mice, experience-dependent ocular dominance (OD) plasticity in V1 declines with age and is compromised by a lesion in adjacent and distant cortical regions. In contrast, mice raised in an enriched environment (EE), exhibit lifelong OD plasticity and are protected from losing OD plasticity after a stroke-lesion in the somatosensory cortex. Since SC mice with an access to a running wheel (RW) displayed preserved OD plasticity during aging, we investigated whether physical exercise might also provide a plasticity promoting effect after a cortical stroke. To this end, we tested if adult RW-raised mice preserved OD plasticity after stroke and also if short-term running after stroke restored OD plasticity to SC mice. Indeed, unlike mice without a RW, adult RW mice continued to show OD plasticity even after stroke, and a 2 weeks RW experience after stroke already restored lost OD plasticity. Additionally, the experience-enabled increase of the spatial frequency and contrast threshold of the optomotor reflex of the open eye, normally lost after a stroke, was restored in both groups of RW mice. Our data suggest that physical exercise alone can not only preserve visual plasticity into old age, but also restore it after a cortical stroke. PMID:27708575

  5. Gene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179.

    PubMed

    Nishiguchi, Koji M; Carvalho, Livia S; Rizzi, Matteo; Powell, Kate; Holthaus, Sophia-Martha kleine; Azam, Selina A; Duran, Yanai; Ribeiro, Joana; Luhmann, Ulrich F O; Bainbridge, James W B; Smith, Alexander J; Ali, Robin R

    2015-01-23

    The rd1 mouse with a mutation in the Pde6b gene was the first strain of mice identified with a retinal degeneration. However, AAV-mediated gene supplementation of rd1 mice only results in structural preservation of photoreceptors, and restoration of the photoreceptor-mediated a-wave, but not in restoration of the bipolar cell-mediated b-wave. Here we show that a mutation in Gpr179 prevents the full restoration of vision in rd1 mice. Backcrossing rd1 with C57BL6 mice reveals the complete lack of b-wave in a subset of mice, consistent with an autosomal recessive Mendelian inheritance pattern. We identify a mutation in the Gpr179 gene, which encodes for a G-protein coupled receptor localized to the dendrites of ON-bipolar cells. Gene replacement in rd1 mice that are devoid of the mutation in Gpr179 successfully restores the function of both photoreceptors and bipolar cells, which is maintained for up to 13 months. Our discovery may explain the failure of previous gene therapy attempts in rd1 mice, and we propose that Grp179 mutation status should be taken into account in future studies involving rd1 mice.

  6. Gene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179

    PubMed Central

    Nishiguchi, Koji M.; Carvalho, Livia S.; Rizzi, Matteo; Powell, Kate; Holthaus, Sophia-Martha kleine; Azam, Selina A.; Duran, Yanai; Ribeiro, Joana; Luhmann, Ulrich F. O.; Bainbridge, James W. B.; Smith, Alexander J.; Ali, Robin R.

    2015-01-01

    The rd1 mouse with a mutation in the Pde6b gene was the first strain of mice identified with a retinal degeneration. However, AAV-mediated gene supplementation of rd1 mice only results in structural preservation of photoreceptors, and restoration of the photoreceptor-mediated a-wave, but not in restoration of the bipolar cell-mediated b-wave. Here we show that a mutation in Gpr179 prevents the full restoration of vision in rd1 mice. Backcrossing rd1 with C57BL6 mice reveals the complete lack of b-wave in a subset of mice, consistent with an autosomal recessive Mendelian inheritance pattern. We identify a mutation in the Gpr179 gene, which encodes for a G-protein coupled receptor localized to the dendrites of ON-bipolar cells. Gene replacement in rd1 mice that are devoid of the mutation in Gpr179 successfully restores the function of both photoreceptors and bipolar cells, which is maintained for up to 13 months. Our discovery may explain the failure of previous gene therapy attempts in rd1 mice, and we propose that Grp179 mutation status should be taken into account in future studies involving rd1 mice. PMID:25613321

  7. Ornithine restores ureagenesis capacity and mitigates hyperammonemia in Otc(spf-ash) mice.

    PubMed

    Marini, Juan C; Lee, Brendan; Garlick, Peter J

    2006-07-01

    We showed that Otc(spf-ash) mice, a model of ornithine transcarbamylase deficiency, were able to sustain ureagenesis at the same rate as control mice, despite reduced enzyme activity, when a complete mixture of amino acids was provided. An unbalanced amino acid mixture, however, resulted in reduced ureagenesis and hyperammonemia. To study the effect of ornithine supplementation [316 micromol/(kg.h)] on urea and glutamine kinetics in conscious Otc(spf-ash) mice under a glycine-alanine load [6.06 mmol/(kg.h)], a multiple tracer infusion protocol ([(13)C(18)O]urea, [5-(15)N]glutamine, [2,3,3,4,4 D(5)]glutamine and [ring-D(5)] phenylalanine) was conducted. Ornithine supplementation increased ureagenesis [3.18 +/- 0.88 vs. 4.56 +/- 0.51 mmol/(kg.h), P < 0.001], reduced plasma ammonia concentration (1125 +/- 621 vs. 193 +/- 94 micromol/L, P < 0.001), and prevented acute hepatic enlargement (P < 0.006) in Otc(spf-ash) mice. Ornithine supplementation also increased [96 +/- 20 vs. 120 +/- 16 micromol/(kg.h), P < 0.001] the transfer of (15)N from glutamine to urea, to values observed in the control mice [123 +/- 17 micromol/(kg.h)]. De novo amido-N glutamine flux was higher [1.57 +/- 0.37 vs. 3.04 +/- 0.86 mmol/(kg.h); P < 0.001] in Otc(spf-ash) mice, but ornithine supplementation had no effect (P < 0.56). The flux of glutamine carbon skeleton was affected by both genotype (P < 0.0001) and by ornithine (P 0. 036). In conclusion, ornithine supplementation restored ureagenesis, mitigated hyperammonemia, prevented liver enlargement, and normalized the transfer of (15)N from glutamine to urea. These data strongly suggest that ornithine has the potential for the biochemical correction of OTCD in Otc(spf-ash) mice.

  8. Tumor-promoting activities of hydroquinone and 1,1-dimethylhydrazine after initiation of newborn mice with 1-methyl-1-nitrosourea.

    PubMed

    Tamura, T; Shibutani, M; Toyoda, K; Shoda, T; Takada, K; Uneyama, C; Takahashi, M; Hirose, M

    1999-08-23

    To clarify the suitability of a newborn-mouse carcinogenesis assay to detect tumor-promoting activities of carcinogens, the non-genotoxic hydroquinone (HQ) and genotoxic 1,1-dimethylhydrazine (UDMH) were administered to mice during the promotion stage after treatment with 1-methyl-1-nitrosourea (MNU) (20 mg/kg body wt, single intraperitoneal injection) at day 9 after birth. Initiated males and females thus received either HQ at 0.8% in basal diet, or UDMH, at 20 mg/kg body wt once weekly by subcutaneous injection, from day 14 until the end of the experiment at 30 weeks of age. Uninitiated newborn mice, given an injection of the vehicle (0.01 M citrate buffer (pH 5.5), 20 mg/kg body wt), also received HQ or UDMH in the same way. Histopathologically, focal proliferative lesions were found in the livers of male mice and in the lungs of both male and female mice in the MNU-treated groups. HQ significantly increased the incidence and multiplicity of altered hepatocellular foci, the combined incidence of hepatocellular adenomas and carcinomas in males and the incidence and multiplicity of lung adenomas and the combined incidence of lung adenomas and carcinomas in female mice. In addition, four out of eleven MNU + HQ-treated male mice developed lung carcinomas, showing a significant elevation in multiplicity. UDMH also exhibited a tendency to increase the incidence and multiplicity of lung adenomas in female mice. Thus tumor-promoting effects of HQ or UDMH were apparently exerted in the target organs and the MNU-initiated two-stage newborn-mouse carcinogenesis assay may be useful for detection of genotoxic or non-genotoxic carcinogenicity.

  9. Engraftment of human HSCs in nonirradiated newborn NOD-scid IL2rγnull mice is enhanced by transgenic expression of membrane-bound human SCF

    PubMed Central

    Racki, Waldemar J.; Leif, Jean; Burzenski, Lisa; Hosur, Vishnu; Wetmore, Amber; Gott, Bruce; Herlihy, Mary; Ignotz, Ronald; Dunn, Raymond; Shultz, Leonard D.; Greiner, Dale L.

    2012-01-01

    Immunodeficient mice engrafted with human HSCs support multidisciplinary translational experimentation, including the study of human hematopoiesis. Heightened levels of human HSC engraftment are observed in immunodeficient mice expressing mutations in the IL2-receptor common γ chain (IL2rg) gene, including NOD-scid IL2rγnull (NSG) mice. Engraftment of human HSC requires preconditioning of immunodeficient recipients, usually with irradiation. Such preconditioning increases the expression of stem cell factor (SCF), which is critical for HSC engraftment, proliferation, and survival. We hypothesized that transgenic expression of human membrane-bound stem cell factor Tg(hu-mSCF)] would increase levels of human HSC engraftment in nonirradiated NSG mice and eliminate complications associated with irradiation. Surprisingly, detectable levels of human CD45+ cell chimerism were observed after transplantation of cord blood–derived human HSCs into nonirradiated adult as well as newborn NSG mice. However, transgenic expression of human mSCF enabled heightened levels of human hematopoietic cell chimerism in the absence of irradiation. Moreover, nonirradiated NSG-Tg(hu-mSCF) mice engrafted as newborns with human HSCs rejected human skin grafts from a histoincompatible donor, indicating the development of a functional human immune system. These data provide a new immunodeficient mouse model that does not require irradiation preconditioning for human HSC engraftment and immune system development. PMID:22246028

  10. Beta Cell Mass Restoration in Alloxan-Diabetic Mice Treated with EGF and Gastrin.

    PubMed

    Song, Imane; Patel, Oelfah; Himpe, Eddy; Muller, Christo J F; Bouwens, Luc

    2015-01-01

    One week of treatment with EGF and gastrin (EGF/G) was shown to restore normoglycemia and to induce islet regeneration in mice treated with the diabetogenic agent alloxan. The mechanisms underlying this regeneration are not fully understood. We performed genetic lineage tracing experiments to evaluate the contribution of beta cell neogenesis in this model. One day after alloxan administration, mice received EGF/G treatment for one week. The treatment could not prevent the initial alloxan-induced beta cell mass destruction, however it did reverse glycemia to control levels within one day, suggesting improved peripheral glucose uptake. In vitro experiments with C2C12 cell line showed that EGF could stimulate glucose uptake with an efficacy comparable to that of insulin. Subsequently, EGF/G treatment stimulated a 3-fold increase in beta cell mass, which was partially driven by neogenesis and beta cell proliferation as assessed by beta cell lineage tracing and BrdU-labeling experiments, respectively. Acinar cell lineage tracing failed to show an important contribution of acinar cells to the newly formed beta cells. No appearance of transitional cells co-expressing insulin and glucagon, a hallmark for alpha-to-beta cell conversion, was found, suggesting that alpha cells did not significantly contribute to the regeneration. An important fraction of the beta cells significantly lost insulin positivity after alloxan administration, which was restored to normal after one week of EGF/G treatment. Alloxan-only mice showed more pronounced beta cell neogenesis and proliferation, even though beta cell mass remained significantly depleted, suggesting ongoing beta cell death in that group. After one week, macrophage infiltration was significantly reduced in EGF/G-treated group compared to the alloxan-only group. Our results suggest that EGF/G-induced beta cell regeneration in alloxan-diabetic mice is driven by beta cell neogenesis, proliferation and recovery of insulin. The

  11. Overstimulation of newborn mice leads to behavioral differences and deficits in cognitive performance

    PubMed Central

    Christakis, D. A.; Ramirez, J. S. B.; Ramirez, J. M.

    2012-01-01

    Observational studies in humans have found associations between overstimulation in infancy via excessive television viewing and subsequent deficits in cognition and attention. We developed and tested a mouse model of overstimulation whereby p10 mice were subjected to audio (70 db) and visual stimulation (flashing lights) for six hours per day for a total of 42 days. 10 days later cognition and behavior were tested using the following tests: Light Dark Latency, Elevated Plus Maze, Novel Object Recognition, and Barnes Maze. In all tests, overstimulated mice performed significantly worse compared to controls suggesting increased activity and risk taking, diminished short term memory, and decreased cognitive function. These findings suggest that excessive non-normative stimulation during critical periods of brain development can have demonstrable untoward effects on subsequent neurocognitive function. PMID:22855702

  12. Neurodevelopmental Consequences of Sub-Clinical Carbon Monoxide Exposure in Newborn Mice

    PubMed Central

    Cheng, Ying; Thomas, Adia; Mardini, Feras; Bianchi, Shannon L.; Tang, Junxia X.; Peng, Jun; Wei, Huafeng; Eckenhoff, Maryellen F.; Eckenhoff, Roderic G.; Levy, Richard J.

    2012-01-01

    Carbon monoxide (CO) exposure at high concentrations results in overt neurotoxicity. Exposure to low CO concentrations occurs commonly yet is usually sub-clinical. Infants are uniquely vulnerable to a variety of toxins, however, the effects of postnatal sub-clinical CO exposure on the developing brain are unknown. Apoptosis occurs normally within the brain during development and is critical for synaptogenesis. Here we demonstrate that brief, postnatal sub-clinical CO exposure inhibits developmental neuroapoptosis resulting in impaired learning, memory, and social behavior. Three hour exposure to 5 ppm or 100 ppm CO impaired cytochrome c release, caspase-3 activation, and apoptosis in neocortex and hippocampus of 10 day old CD-1 mice. CO increased NeuN protein, neuronal numbers, and resulted in megalencephaly. CO-exposed mice demonstrated impaired memory and learning and reduced socialization following exposure. Thus, CO-mediated inhibition of neuroapoptosis might represent an important etiology of acquired neurocognitive impairment and behavioral disorders in children. PMID:22348142

  13. Protective Effect of Parsley Juice (Petroselinum crispum, Apiaceae) against Cadmium Deleterious Changes in the Developed Albino Mice Newborns (Mus musculus) Brain

    PubMed Central

    Allam, Ahmed A.; Maodaa, Salah N.; Abo-Eleneen, Rasha; Ajarem, Jamaan

    2016-01-01

    Parsley was used as a probe of the current experiment to prevent the behavioral, morphological and biochemical changes in the newborn brain following the administration of cadmium (Cd) to the pregnant mice. The nonanesthetized pregnant mice were given daily parsley juice (Petroselinum crispum) at doses of 20 mg/kg and 10 mg/kg. Pregnant mothers were given Cd at a dose of 30 mg/kg divided into 3 equal times. The newborns have been divided into 6 groups: Group A, mothers did not take treatment; Groups B and C, mothers were treated with low and high dose of parsley, respectively; Group D, mothers were treated only with Cd (perinatal intoxication); Groups E and F, mothers were treated with Cd doses and protected by low and high doses of parsley, respectively. Light microscopy showed that Cd-induced neuronal degeneration by chromatolysis and pyknosis in the brain regions. The low dose of parsley 10 g/kg/day exhibited significant effects in neutralizing and reducing the deleterious changes due to Cd exposure during pregnancy on the behavioral activities, neurotransmitters, oxidative stress, and brain neurons morphology of the mice newborns. PMID:26966507

  14. Protective Effect of Parsley Juice (Petroselinum crispum, Apiaceae) against Cadmium Deleterious Changes in the Developed Albino Mice Newborns (Mus musculus) Brain.

    PubMed

    Allam, Ahmed A; Maodaa, Salah N; Abo-Eleneen, Rasha; Ajarem, Jamaan

    2016-01-01

    Parsley was used as a probe of the current experiment to prevent the behavioral, morphological and biochemical changes in the newborn brain following the administration of cadmium (Cd) to the pregnant mice. The nonanesthetized pregnant mice were given daily parsley juice (Petroselinum crispum) at doses of 20 mg/kg and 10 mg/kg. Pregnant mothers were given Cd at a dose of 30 mg/kg divided into 3 equal times. The newborns have been divided into 6 groups: Group A, mothers did not take treatment; Groups B and C, mothers were treated with low and high dose of parsley, respectively; Group D, mothers were treated only with Cd (perinatal intoxication); Groups E and F, mothers were treated with Cd doses and protected by low and high doses of parsley, respectively. Light microscopy showed that Cd-induced neuronal degeneration by chromatolysis and pyknosis in the brain regions. The low dose of parsley 10 g/kg/day exhibited significant effects in neutralizing and reducing the deleterious changes due to Cd exposure during pregnancy on the behavioral activities, neurotransmitters, oxidative stress, and brain neurons morphology of the mice newborns.

  15. Morphological restoration of gonadotrope population by thymulin gene therapy in nude mice

    PubMed Central

    Reggiani, Paula; Martines, Eliana; Ferese, Celia; Goya, Rodolfo; Cónsole, Gloria

    2009-01-01

    Summary The integrity of the thymus during the first week of life is necessary for a proper maturation of the pituitary-gonadal axis as revealed by the significantly reduced levels of circulating gonadotropins in congenitally athymic (nude) mice. In the present work we studied the impact of athymia and the effect of neonatal thymulin gene therapy on the pituitaries of adult nude mice. Also circulating thymulin and gonadotropin levels were evaluated. We used an adenoviral vector expressing a synthetic gene for the thymic peptide thymulin (metFTS) termed RAd-FTS. On postnatal day 1, each experimental heterozygous (nu/+) and homozygous (nu/nu) pup of both sexes received a single bilateral i.m. injection of RAd-FTS or RAd-GFP/TK, a control vector expressing green fluorescent protein. On postnatal days 51-52, mice were bled and sacrificed, their pituitaries were immediately dissected, fixed and immunostained. Morphometry was performed by means of an image analysis system. The following parameters were calculated: volume density (VD: cell area/reference area), cell density (CD: number of cells/reference area), and cell size (expressed in μm2). Serum thymulin levels were measured by a bioassay and gonadotropin levels were assayed by RIA. It was observed that neonatal thymulin gene therapy in the athymic mice restored their serum thymulin levels and prevented the reduction in circulating gonadotropin levels. The histometrical analysis revealed that the treatment prevented the reduction in gonadotrope CD and the VD in athymic mice. Our data suggest that thymulin gene therapy may be an effective strategy to approach reproductive deficits associated with endocrine thymus dysfunction. PMID:19337971

  16. Bifidobacterium pseudocatenulatum CECT 7765 supplementation restores altered vascular function in an experimental model of obese mice

    PubMed Central

    Mauricio, María D.; Serna, Eva; Fernández-Murga, María Leonor; Portero, Jesica; Aldasoro, Martín; Valles, Soraya L.; Sanz, Yolanda; Vila, José M.

    2017-01-01

    Aims. Bifidobacterium pseudocatenulatum CECT 7765 improves metabolic and immunological altered functions in high fat fed mice, however little is known about the effects of potential probiotics on vascular reactivity. The aim of the present study was to investigate the effects of a potential probiotic strain, Bifidobacterium pseudocatenulatum CECT 7765, on vascular response in obese mice. Methods. Aorta samples were obtained from mice, which were divided into three groups: a control group, receiving a standard diet; an obese group, receiving a high-fat diet; and an obese group receiving high-fat diet and a daily dose of B. pseudocatenulatum CECT 7765 by oral gavage. Aortic rings were suspended in organ baths for isometric recording of tension. mRNA expression of eNOS was evaluated by real-time polymerase chain reaction. Results. Contractions induced by KCl, noradrenaline and thromboxane analogue were 33%, 30% and 45% lower respectively in aortic rings from obese mice. Bifidobacteria administration reversed this effect. eNOS inhibition increased the response to noradrenaline in the three groups with a significant lower magnitude in aortic rings from obese mice receiving bifidobacteria supplement. Acetylcholine caused a greater vasodilation in aorta from obese group (46±3% for control and 69±4% for obese group; p<0.05) and bifidobacteria reversed it (57±5%). Response to sodium nitroprusside was displaced 2.9 times to the left in a parallel manner in obese group. Relaxation to sodium nitroprusside remained unchanged in the bifidobacteria fed group. There was about five-fold decreased mRNA expression of eNOS in aortic segments from the group receiving bifidobacteria. Conclusion. Bifidobacterium pseudocatenulatum CECT 7765 restores the obesity-induced altered vascular function mainly by reducing nitric oxide release. PMID:28539820

  17. Neuroprotective effects of NAP against excitotoxic brain damage in the newborn mice: implications for cerebral palsy.

    PubMed

    Sokolowska, P; Passemard, S; Mok, A; Schwendimann, L; Gozes, I; Gressens, P

    2011-01-26

    Activity-dependent neuroprotective protein (ADNP) was shown to be essential for embryogenesis and brain development while NAP, an active motif of ADNP, is neuroprotective in a broad range of neurodegenerative disorders. In the present study, we examined the protective potential of ADNP/NAP in a mouse model of excitotoxic brain lesion mimicking brain damage associated with cerebral palsy. We demonstrated that NAP had a potent neuroprotective effect against ibotenate-induced excitotoxic damage in the cortical plate and the white matter of P5 mice, and moderate against brain lesions of P0 mice. In contrast, endogenous ADNP appears not to be involved in the response to excitotoxic challenge in the studied model. Our findings further show that NAP reduced the number of apoptotic neurons through activation of PI-3K/Akt pathway in the cortical plate or both PI-3K/Akt and MAPK/MEK1 kinases in the white matter. In addition, NAP prevented ibotenate-induced loss of pre-oligodendrocytes without affecting the number of astrocytes or activated microglia around the site of injection. These findings indicate that protective actions of NAP are mediated by triggering transduction pathways that are crucial for neuronal and oligodendroglial survival, thus, NAP might be a promising therapeutic agent for treating developing brain damage.

  18. Cre recombinase-mediated restoration of nigrostriatal dopamine in dopamine-deficient mice reverses hypophagia and bradykinesia.

    PubMed

    Hnasko, Thomas S; Perez, Francisco A; Scouras, Alex D; Stoll, Elizabeth A; Gale, Samuel D; Luquet, Serge; Phillips, Paul E M; Kremer, Eric J; Palmiter, Richard D

    2006-06-06

    A line of dopamine-deficient (DD) mice was generated to allow selective restoration of normal dopamine signaling to specific brain regions. These DD floxed stop (DDfs) mice have a nonfunctional Tyrosine hydroxylase (Th) gene because of insertion of a NeoR gene flanked by lox P sites targeted to the first intron of the Th gene. DDfs mice have trace brain dopamine content, severe hypoactivity, and aphagia, and they die without intervention. However, they can be maintained by daily treatment with l-3,4-dihydroxyphenylalanine (L-dopa). Injection of a canine adenovirus (CAV-2) engineered to express Cre recombinase into the central caudate putamen restores normal Th gene expression to the midbrain dopamine neurons that project there because CAV-2 efficiently transduces axon terminals and is retrogradely transported to neuronal cell bodies. Bilateral injection of Cre recombinase into the central caudate putamen restores feeding and normalizes locomotion in DDfs mice. Analysis of feeding behavior by using lickometer cages revealed that virally rescued DDfs mice are hyperphagic and have modified meal structures compared with control mice. The virally rescued DDfs mice are also hyperactive at night, have reduced motor coordination, and are thigmotactic compared with controls. These results highlight the critical role for dopamine signaling in the dorsal striatum for most dopamine-dependent behaviors but suggest that dopamine signaling in other brain regions is important to fine-tune these behaviors. This approach offers numerous advantages compared with previous models aimed at examining dopamine signaling in discrete dopaminergic circuits.

  19. Alteration of protein prenylation promotes spermatogonial differentiation and exhausts spermatogonial stem cells in newborn mice

    PubMed Central

    Diao, Fan; Jiang, Chen; Wang, Xiu-Xing; Zhu, Rui-Lou; Wang, Qiang; Yao, Bing; Li, Chao-Jun

    2016-01-01

    Spermatogenesis in adulthood depends on the successful neonatal establishment of the spermatogonial stem cell (SSC) pool and gradual differentiation during puberty. The stage-dependent changes in protein prenylation in the seminiferous epithelium might be important during the first round of spermatogenesis before sexual maturation, but the mechanisms are unclear. We have previous found that altered prenylation in Sertoli cells induced spermatogonial apoptosis in the neonatal testis, resulting in adult infertility. Now we further explored the role of protein prenylation in germ cells, using a conditional deletion of geranylgeranyl diphosphate synthase (Ggpps) in embryonic stage and postmeiotic stage respectively. We observed infertility of Ggpps−/− Ddx4-Cre mice that displayed a Sertoli-cell-only syndrome phenotype, which resulted from abnormal spermatogonial differentiation and SSC depletion during the prepubertal stage. Analysis of morphological characteristics and cell-specific markers revealed that spermatogonial differentiation was enhanced from as early as the 7th postnatal day in the first round of spermatogenesis. Studies of the molecular mechanisms indicated that Ggpps deletion enhanced Rheb farnesylation, which subsequently activated mTORC1 and facilitated spermatogonial differentiation. In conclusion, the prenylation balance in germ cells is crucial for spermatogonial differentiation fate decision during the prepubertal stage, and the disruption of this process results in primary infertility. PMID:27374985

  20. A bioprosthetic ovary created using 3D printed microporous scaffolds restores ovarian function in sterilized mice

    PubMed Central

    Laronda, Monica M.; Rutz, Alexandra L.; Xiao, Shuo; Whelan, Kelly A.; Duncan, Francesca E.; Roth, Eric W.; Woodruff, Teresa K.; Shah, Ramille N.

    2017-01-01

    Emerging additive manufacturing techniques enable investigation of the effects of pore geometry on cell behavior and function. Here, we 3D print microporous hydrogel scaffolds to test how varying pore geometry, accomplished by manipulating the advancing angle between printed layers, affects the survival of ovarian follicles. 30° and 60° scaffolds provide corners that surround follicles on multiple sides while 90° scaffolds have an open porosity that limits follicle–scaffold interaction. As the amount of scaffold interaction increases, follicle spreading is limited and survival increases. Follicle-seeded scaffolds become highly vascularized and ovarian function is fully restored when implanted in surgically sterilized mice. Moreover, pups are born through natural mating and thrive through maternal lactation. These findings present an in vivo functional ovarian implant designed with 3D printing, and indicate that scaffold pore architecture is a critical variable in additively manufactured scaffold design for functional tissue engineering. PMID:28509899

  1. Population calcium imaging of spontaneous respiratory and novel motor activity in the facial nucleus and ventral brainstem in newborn mice

    PubMed Central

    Persson, Karin; Rekling, Jens C

    2011-01-01

    Abstract The brainstem contains rhythm and pattern forming circuits, which drive cranial and spinal motor pools to produce respiratory and other motor patterns. Here we used calcium imaging combined with nerve recordings in newborn mice to reveal spontaneous population activity in the ventral brainstem and in the facial nucleus. In Fluo-8 AM loaded brainstem–spinal cord preparations, respiratory activity on cervical nerves was synchronized with calcium signals at the ventrolateral brainstem surface. Individual ventrolateral neurons at the level of the parafacial respiratory group showed perfect or partial synchrony with respiratory nerve bursts. In brainstem–spinal cord preparations, cut at the level of the mid-facial nucleus, calcium signals were recorded in the dorsal, lateral and medial facial subnuclei during respiratory activity. Strong activity initiated in the dorsal subnucleus, followed by activity in lateral and medial subnuclei. Whole-cell recordings from facial motoneurons showed weak respiratory drives, and electrical field potential recordings confirmed respiratory drive to particularly the dorsal and lateral subnuclei. Putative facial premotoneurons showed respiratory-related calcium signals, and were predominantly located dorsomedial to the facial nucleus. A novel motor activity on facial, cervical and thoracic nerves was synchronized with calcium signals at the ventromedial brainstem extending from the level of the facial nucleus to the medulla–spinal cord border. Cervical dorsal root stimulation induced similar ventromedial activity. The medial facial subnucleus showed calcium signals synchronized with this novel motor activity on cervical nerves, and cervical dorsal root stimulation induced similar medial facial subnucleus activity. In conclusion, the dorsal and lateral facial subnuclei are strongly respiratory-modulated, and the brainstem contains a novel pattern forming circuit that drives the medial facial subnucleus and cervical motor

  2. Relationship between age of allogeneic thymus donor and immunological restoration of athymic ('nude") mice.

    PubMed

    Radov, L A; Sussdorf, D H; McCann, R L

    1975-12-01

    In nude mice back-crossed a minimum of five times to BALB/c, solid thymus grafts from C57Bl donors 3 days of age or younger restored both the humoral immune response against sheep erythrocytes and cellular immunity as tested by rejection of CBA skin grafts. Donor thymus placed under the renal capsule at a dose of 0-5 mg/g of recipient resulted in normal humoral immunity, while a minimum dose of 1-5 mg/g was required to reconstitute cellular competence. None of the various amounts of allogeneic thymus tissue transplanted affected the immunological status of nude recipients when grafts were obtained from donors 4 days of age or older. Histological findings correlated with the humoral and cellular responses observed. In nudes grafted with neonatal tissue, the thymus implant proliferated and developed normal architecture. The density of lymphocytes in thymus-dependent regions of peripheral lymphoid organs was near normal. On the other hand, most grafts from older (3-week-old) donors were resorbed by 90 days after implantation. In a number of cases, however, Russell bodies and numerous blast and plasma cells were seen in the graft site. Our observations suggest a possible cytotoxic rejection of implants from older allogeneic donors, while the survival and restorative capacity of transplants from 3-day-old or younger donors may have been due to a tolerogenic effect of the graft on the nude recipient.

  3. Relationship between age of allogeneic thymus donor and immunological restoration of athymic ('nude") mice.

    PubMed Central

    Radov, L A; Sussdorf, D H; McCann, R L

    1975-01-01

    In nude mice back-crossed a minimum of five times to BALB/c, solid thymus grafts from C57Bl donors 3 days of age or younger restored both the humoral immune response against sheep erythrocytes and cellular immunity as tested by rejection of CBA skin grafts. Donor thymus placed under the renal capsule at a dose of 0-5 mg/g of recipient resulted in normal humoral immunity, while a minimum dose of 1-5 mg/g was required to reconstitute cellular competence. None of the various amounts of allogeneic thymus tissue transplanted affected the immunological status of nude recipients when grafts were obtained from donors 4 days of age or older. Histological findings correlated with the humoral and cellular responses observed. In nudes grafted with neonatal tissue, the thymus implant proliferated and developed normal architecture. The density of lymphocytes in thymus-dependent regions of peripheral lymphoid organs was near normal. On the other hand, most grafts from older (3-week-old) donors were resorbed by 90 days after implantation. In a number of cases, however, Russell bodies and numerous blast and plasma cells were seen in the graft site. Our observations suggest a possible cytotoxic rejection of implants from older allogeneic donors, while the survival and restorative capacity of transplants from 3-day-old or younger donors may have been due to a tolerogenic effect of the graft on the nude recipient. PMID:1193689

  4. Partial Restoration of CFTR Function in cftr-Null Mice following Targeted Cell Replacement Therapy.

    PubMed

    Duchesneau, Pascal; Besla, Rickvinder; Derouet, Mathieu F; Guo, Li; Karoubi, Golnaz; Silberberg, Amanda; Wong, Amy P; Waddell, Thomas K

    2017-03-01

    Cystic fibrosis (CF) is a fatal recessive genetic disorder caused by a mutation in the gene encoding CF transmembrane conductance regulator (CFTR) protein. Alteration in CFTR leads to thick airway mucus and bacterial infection. Cell therapy has been proposed for CFTR restoration, but efficacy has been limited by low engraftment levels. In our previous studies, we have shown that using a pre-conditioning regimen in combination with optimization of cell number and time of delivery, we could obtain greater bone marrow cell (BMC) retention in the lung. Here, we found that optimized delivery of wild-type (WT) BMC contributed to apical CFTR expression in airway epithelium and restoration of select ceramide species and fatty acids in CFTR(-/-) mice. Importantly, WT BMC delivery delayed Pseudomonas aeruginosa lung infection and increased survival of CFTR(-/-) recipients. Only WT BMCs had a beneficial effect beyond 6 months, suggesting a dual mechanism of BMC benefit: a non-specific effect early after cell delivery, possibly due to the recruitment of macrophages and neutrophils, and a late beneficial effect dependent on long-term CFTR expression. Taken together, our results suggest that BMC can improve overall lung function and may have potential therapeutic benefit for the treatment of CF.

  5. Dosimetry of a set-up for the exposure of newborn mice to 2.45-GHZ WiFi frequencies.

    PubMed

    Pinto, R; Lopresto, V; Galloni, P; Marino, C; Mancini, S; Lodato, R; Pioli, C; Lovisolo, G A

    2010-08-01

    This work describes the dosimetry of a two waveguide cell system designed to expose newborn mice to electromagnetic fields associated with wireless fidelity signals in the frequency band of 2.45 GHz. The dosimetric characterisation of the exposure system was performed both numerically and experimentally. Specific measures were adopted with regard to the increase in both weight and size of the biological target during the exposure period. The specific absorption rate (SAR, W kg(-1)) for 1 W of input power vs. weight curve was assessed. The curve evidenced an SAR pattern varying from <1 W kg(-1) to >6 W kg(-1) during the first 5 weeks of the life of mice, with a peak resonance phenomenon at a weight around 5 g. This curve was used to set the appropriate level of input power during experimental sessions to expose the growing mice to a defined and constant dose.

  6. CRISPR-mediated Genome Editing Restores Dystrophin Expression and Function in mdx Mice.

    PubMed

    Xu, Li; Park, Ki Ho; Zhao, Lixia; Xu, Jing; El Refaey, Mona; Gao, Yandi; Zhu, Hua; Ma, Jianjie; Han, Renzhi

    2016-03-01

    Duchenne muscular dystrophy (DMD) is a degenerative muscle disease caused by genetic mutations that lead to the disruption of dystrophin in muscle fibers. There is no curative treatment for this devastating disease. Clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) has emerged as a powerful tool for genetic manipulation and potential therapy. Here we demonstrate that CRIPSR-mediated genome editing efficiently excised a 23-kb genomic region on the X-chromosome covering the mutant exon 23 in a mouse model of DMD, and restored dystrophin expression and the dystrophin-glycoprotein complex at the sarcolemma of skeletal muscles in live mdx mice. Electroporation-mediated transfection of the Cas9/gRNA constructs in the skeletal muscles of mdx mice normalized the calcium sparks in response to osmotic shock. Adenovirus-mediated transduction of Cas9/gRNA greatly reduced the Evans blue dye uptake of skeletal muscles at rest and after downhill treadmill running. This study provides proof evidence for permanent gene correction in DMD.

  7. Dietary Nitrite Restores NO Homeostasis and is Cardioprotective in eNOS Deficient Mice

    PubMed Central

    Bryan, Nathan S.; Calvert, John W.; Gundewar, Susheel; Lefer, David J.

    2008-01-01

    Endothelial production of nitric oxide (NO) is critical for vascular homeostasis. Nitrite and nitrate are formed endogenously by the step wise oxidation of NO and have for years been regarded as inactive degradation products. As a result both anions are routinely used as surrogate markers of NO production with nitrite as a more sensitive marker. However, both nitrite and nitrate are derived from dietary sources. We sought to determine how exogenous nitrite affects steady state concentrations of NO metabolites thought to originate from NOS derived NO as well as blood pressure and myocardial ischemia-reperfusion (I/R) injury. Mice deficient in endothelial nitric oxide synthase (eNOS−/−) demonstrated decreased blood and tissue nitrite, nitrate and nitroso which were further reduced by low nitrite (NOx) diet for 1 week. Nitrite supplementation (50mg/L) in the drinking water for 1 week restored NO homeostasis in eNOS−/− mice and protected against I/R injury. Nitrite failed to alter heart rate or mean arterial blood pressure at the protective dose. These data demonstrate the significant influence of dietary nitrite intake on the maintenance of steady-state NO levels. Dietary nitrite and nitrate may serve as essentials nutrient for optimal cardiovascular health and may provide a novel prevention/treatment modality for disease associated with NO insufficiency. PMID:18501719

  8. CRISPR-mediated Genome Editing Restores Dystrophin Expression and Function in mdx Mice

    PubMed Central

    Xu, Li; Park, Ki Ho; Zhao, Lixia; Xu, Jing; El Refaey, Mona; Gao, Yandi; Zhu, Hua; Ma, Jianjie; Han, Renzhi

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a degenerative muscle disease caused by genetic mutations that lead to the disruption of dystrophin in muscle fibers. There is no curative treatment for this devastating disease. Clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) has emerged as a powerful tool for genetic manipulation and potential therapy. Here we demonstrate that CRIPSR-mediated genome editing efficiently excised a 23-kb genomic region on the X-chromosome covering the mutant exon 23 in a mouse model of DMD, and restored dystrophin expression and the dystrophin-glycoprotein complex at the sarcolemma of skeletal muscles in live mdx mice. Electroporation-mediated transfection of the Cas9/gRNA constructs in the skeletal muscles of mdx mice normalized the calcium sparks in response to osmotic shock. Adenovirus-mediated transduction of Cas9/gRNA greatly reduced the Evans blue dye uptake of skeletal muscles at rest and after downhill treadmill running. This study provides proof evidence for permanent gene correction in DMD. PMID:26449883

  9. Developmental cell death in the liver and newborn lethality of Ku86 deficient mice suppressed by antioxidant N-acetyl-cysteine.

    PubMed

    Reliene, Ramune; Goad, Marry E P; Schiestl, Robert H

    2006-11-08

    Repair of DNA double-strand breaks (DSBs) is essential for genome integrity and cell survival. Ku86 is involved in the repair of DNA DSBs by non-homologous end joining (NHEJ). Mice deficient in Ku86 show growth retardation, dwarfism, premature aging, and immunodeficiency. In this study, we observed severely compromised survival of Ku86(-/-) mice, such that most Ku86(-/-) mice died within the first postnatal weeks and only 1.5% of the expected 25% from heterozygous crosses survived for 1 month. Since post-mortem analysis was not possible due to parental cannibalism, histopathological examination was performed on Ku86(-/-) fetuses to assess possible causes of newborn death. Eighty percent and 75% of Ku86(-/-) fetuses exhibited apoptosis and necrosis in the liver, while only 20% and 10% of Ku86(+/+) littermates had apoptosis and necrosis, respectively. In addition, the severity of liver damage was significantly higher in Ku86(-/-) fetuses. Developmental liver damage may have led to postnatal lethality because the fetal liver with pre-existing injury may not be able to undergo transformation from a lymphohematopoietic to an indispensable metabolic organ. Free radicals can cause chromosomal breaks and lead to cell death. We postulated that endogenous oxidative stress might be involved in the resulting liver damage and animal lethality in Ku86(-/-) mice deficient in DNA DSB repair. This hypothesis was tested by treating Ku86(-/-) mice with the well known free radical scavenger, thiol antioxidant N-acetyl-cysteine (NAC), during embryonic development. We found that a significantly higher percentage, 7.7% of NAC treated Ku86(-/-) offspring versus 1.5% untreated Ku86(-/-) mice were alive at 1 month of age. In addition, the incidence of liver necrosis decreased by 21% and the severity of necrosis significantly reduced. Thus, Ku86 deficiency results in severe developmental liver damage and newborn lethality associated with oxidative stress.

  10. Pharmacological concentrations of recombinant factor VIIa restore hemostasis independent of tissue factor in antibody-induced hemophilia mice.

    PubMed

    Keshava, S; Sundaram, J; Rajulapati, A; Pendurthi, U R; Rao, L V M

    2016-03-01

    ESSENTIALS: The role of tissue factor (TF) in recombinant factor VIIa (rFVIIa) therapy in hemophilia is unclear. An acquired mouse hemophilia model with very low or normal levels of human TF was used in the study. rFVIIa is equally effective in correcting the bleeding in mice expressing low or normal levels of TF. Pharmacological doses of rFVIIa restore hemostasis in hemophilia independent of TF. Recombinant factor VIIa (rFVIIa) has been used widely for treating hemophilia patients with inhibitory autoantibodies against factor VIII or IX. Its mechanism of action is not entirely known. A majority of in vitro studies suggested that pharmacological concentrations of rFVIIa restore hemostasis in hemophilia in a phospholipid-dependent manner, independent of tissue factor (TF). However, a few studies suggested that a TF-dependent mechanism has a primary role in correction of bleeding by rFVIIa in hemophilia patients. Here, we investigated the potential contribution of TF in rFVIIa-induced hemostasis in hemophilia employing a model system of FVIII antibody-induced hemophilia in TF transgenic mice. Mice expressing low levels of human TF (LTF mice), mice expressing relatively high levels of human TF (HTF mice) and wild-type mice (WT mice) had neutralizing anti-FVIII antibodies administered in order to induce hemophilia in these mice. The mice were then treated with varying concentrations of rFVIIa. rFVIIa-induced hemostasis was evaluated with the saphenous vein bleeding model. Administration of FVIII inhibitory antibodies induced the hemophilic bleeding phenotype in all three genotypes. rFVIIa administration rescued the bleeding phenotype in all three genotypes. No significant differences were observed in rFVIIa-induced correction of bleeding between LTF and HTF mice that had FVIII antibodies administered. Our results provide strong evidence supporting the suggestion that the hemostatic effect of pharmacological doses of rFVIIa stems from a TF-independent mechanism. © 2016

  11. EEA1 restores homeostatic synaptic plasticity in hippocampal neurons from Rett syndrome mice.

    PubMed

    Xu, Xin; Pozzo-Miller, Lucas

    2017-08-15

    Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Mecp2 deletion in mice results in an imbalance of excitation and inhibition in hippocampal neurons, which affects 'Hebbian' synaptic plasticity. We show that Mecp2-deficient neurons also lack homeostatic synaptic plasticity, likely due to reduced levels of EEA1, a protein involved in AMPA receptor endocytosis. Expression of EEA1 restored homeostatic synaptic plasticity in Mecp2-deficient neurons, providing novel targets of intervention in Rett syndrome. Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Deletion of Mecp2 in mice results in an imbalance of synaptic excitation and inhibition in hippocampal pyramidal neurons, which affects 'Hebbian' long-term synaptic plasticity. Since the excitatory-inhibitory balance is maintained by homeostatic mechanisms, we examined the role of MeCP2 in homeostatic synaptic plasticity (HSP) at excitatory synapses. Negative feedback HSP, also known as synaptic scaling, maintains the global synaptic strength of individual neurons in response to sustained alterations in neuronal activity. Hippocampal neurons from Mecp2 knockout (KO) mice do not show the characteristic homeostatic scaling up of the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and of synaptic levels of the GluA1 subunit of AMPA-type glutamate receptors after 48 h silencing with the Na(+) channel blocker tetrodotoxin. This deficit in HSP is bidirectional because Mecp2 KO neurons also failed to scale down mEPSC amplitudes and GluA1 synaptic levels after 48 h blockade of type A GABA receptor (GABAA R)-mediated inhibition with bicuculline. Consistent with the role of synaptic trafficking of AMPA-type of glutamate receptors in HSP, Mecp2 KO neurons

  12. REPLACEMENT WITH GABAERGIC STEROID PRECURSORS RESTORES THE ACUTE ETHANOL WITHDRAWAL PROFILE IN ADX/GDX MICE

    PubMed Central

    Kaufman, KR; Tanchuck, MA; Strong, MN; Finn, DA

    2010-01-01

    The neurosteroid allopregnanolone (ALLO) is a progesterone metabolite that is one of a family of neuroactive steroids (NAS) that are potent positive allosteric modulators of γ-aminobutyric acidA (GABAA) receptors. These GABAergic NAS are produced peripherally (in the adrenals and gonads) and centrally in the brain. Peripherally produced NAS modulate some effects of ethanol intoxication (e.g., anxiolytic, antidepressant, and anticonvulsant effects) in rodents. We have found that NAS also may be involved in the rebound neural hyperexcitability following a high ethanol dose. Removal of the adrenals and gonads (ADX/GDX) increased withdrawal severity following 4 g/kg ethanol, as measured by handling-induced convulsions (HICs) in male and female DBA/2J mice. NAS are produced through the metabolism of progesterone (PROG), deoxycorticosterone (DOC), or testosterone, which can be blocked with the administration of finasteride (FIN), a 5α-reductase enzyme inhibitor. The current investigation was undertaken to clarify the step(s) in the biosynthetic NAS pathway that were sufficient to restore the acute ethanol withdrawal profile in ADX/GDX mice to that seen in intact animals. Male and female DBA/2J mice underwent ADX/GDX or SHAM surgery. After recovery, separate groups of animals were administered PROG, DOC, PROG+FIN, DOC+FIN, FIN, ALLO, ganaxalone (a synthetic ALLO derivative), corticosterone, or vehicle. Animals were then administered a 4 g/kg ethanol dose and allowed to undergo withdrawal. HICs were measured for 12 hours and again at 24 hours. The results indicate that replacement with PROG and DOC restored the withdrawal profile in ADX/GDX animals to SHAM levels, and that this effect was blocked with co-administration of FIN. Administration of FIN alone increased the withdrawal profile in both SHAM and ADX/GDX males. These findings indicate that the increase in acute withdrawal severity after ADX/GDX may be due to the loss of GABAergic NAS, providing insight into the

  13. Prenatal administration of the cytochrome P4501A inducer, {Beta}-naphthoflavone (BNF), attenuates hyperoxic lung injury in newborn mice: Implications for bronchopulmonary dysplasia (BPD) in premature infants

    SciTech Connect

    Couroucli, Xanthi I.; Liang Yanhong Wei; Jiang Weiwu; Wang Lihua; Barrios, Roberto; Yang Peiying; Moorthy, Bhagavatula

    2011-10-15

    Supplemental oxygen contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. In this investigation, we tested the hypothesis that prenatal treatment of pregnant mice (C57BL/6J) with the cytochrome P450 (CYP)1A1 inducer, ss-napthoflavone (BNF), will lead to attenuation of lung injury in newborns (delivered from these dams) exposed to hyperoxia by mechanisms entailing transplacental induction of hepatic and pulmonary CYP1A enzymes. Pregnant mice were administered the vehicle corn oil (CO) or BNF (40 mg/kg), i.p., once daily for 3 days on gestational days (17-19), and newborns delivered from the mothers were either maintained in room air or exposed to hyperoxia (> 95% O{sub 2}) for 1-5 days. After 3-5 days of hyperoxia, the lungs of CO-treated mice showed neutrophil infiltration, pulmonary edema, and perivascular inflammation. On the other hand, BNF-pretreated neonatal mice showed decreased susceptibility to hyperoxic lung injury. These mice displayed marked induction of ethoxyresorufin O-deethylase (EROD) (CYP1A1) and methoxyresorufin O-demethylase (MROD) (CYP1A2) activities, and levels of the corresponding apoproteins and mRNA levels until PND 3 in liver, while CYP1A1 expression alone was augmented in the lung. Prenatal BNF did not significantly alter gene expression of pulmonary NAD(P)H quinone reductase (NQO1). Hyperoxia for 24-72 h resulted in increased pulmonary levels of the F{sub 2}-isoprostane 8-iso-PGF{sub 2{alpha}}, whose levels were decreased in mice prenatally exposed to BNF. In conclusion, our results suggest that prenatal BNF protects newborns against hyperoxic lung injury, presumably by detoxification of lipid hydroperoxides by CYP1A enzymes, a phenomenon that has implications for prevention of BPD in infants. - Highlights: > Supplemental oxygen is routinely administered to premature infants. > Hyperoxia causes lung injury in experimental animals. > Prenatal treatment of mice with beta-naphthoflavone attenuates oxygen

  14. The effects of cytotoxic necrotizing factor 1 expression in the uptake of Escherichia coli K1 by macrophages and the onset of meningitis in newborn mice.

    PubMed

    Chang, Alexander C; Krishnan, Subramanian; Prasadarao, Nemani V

    2016-10-02

    Macrophages are a permissive niche for E. coli K1 multiplication for which the interaction of the bacterial outer membrane protein A and its cognate receptor CD64 are critical. Using in vitro immunofluorescence and live microscopy with ex vivo macrophage cultures from RFP-Lifeact mice, we show that cytotoxic necrotizing factor 1 (CNF1) secreted by E. coli K1 sequesters cellular actin toward microspike formation, thereby limiting actin availability for OmpA-mediated bacterial invasion. Surprisingly, the observed effects of CNF1 occur despite the absence of 67-kDa laminin receptor in macrophages. Concomitantly, the CNF1 deletion mutant of E. coli K1 (Δcnf1) invades macrophages and the brains of newborn mice in greater numbers compared to wild-type. However, the Δcnf1 strain induces less severe pathology in the brain. These results suggest a novel role for CNF1 in limiting E. coli K1 entry into macrophages while exacerbating disease severity in the brains of newborn mice.

  15. Human melanopsin-AAV2/8 transfection to retina transiently restores visual function in rd1 mice

    PubMed Central

    Liu, Ming-Ming; Dai, Jia-Man; Liu, Wen-Yi; Zhao, Cong-Jian; Lin, Bin; Yin, Zheng-Qin

    2016-01-01

    AIM To explore whether ectopic expression of human melanopsin can effectively and safely restore visual function in rd1 mice. METHODS Hematoxylin-eosin staining of retinal sections from rd1 mice was used to detect the thickness of the outer nuclear layer to determine the timing of surgery. We constructed a human melanopsin-AAV2/8 viral vector and injected it into the subretinal space of rd1 mice. The Phoenix Micron IV system was used to exclude the aborted injections, and immunohistochemistry was used to validate the ectopic expression of human melanopsin. Furthermore, visual electrophysiology and behavioral tests were used to detect visual function 30 and 45d after the injection. The structure of the retina was compared between the human melanopsin-injected group and phosphate buffer saline (PBS)-injected group. RESULTS Retinas of rd1 mice lost almost all of their photoreceptors on postnatal day 28 (P28). We therefore injected the human melanopsin-adeno-associated virus (AAV) 2/8 viral vector into P30 rd1 mice. After excluding aborted injections, we used immunohistochemistry of the whole mount retina to confirm the ectopic expression of human melanopsin by co-expression of human melanopsin and YFP that was carried by a viral vector. At 30d post-injection, visual electrophysiology and the behavioral test significantly improved. However, restoration of vision disappeared 45d after human melanopsin injection. Notably, human melanopsin-injected mice did not show any structural differences in their retinas compared with PBS-injected mice. CONCLUSION Ectopic expression of human melanopsin effectively and safely restores visual function in rd1 mice. PMID:27275417

  16. Quantitative evaluation of ontogenetic change in heart rate and its autonomic regulation in newborn mice with the use of a noninvasive piezoelectric sensor.

    PubMed

    Sato, Shinichi

    2008-04-01

    A reliable basal heart rate (HR) measurement in freely moving newborn mice was accomplished for the first time by using a novel noninvasive piezoelectric transducer (PZT) sensor. The basal HR was approximately 320 beats/min at postnatal day (P)0 and increased with age to approximately 690 beats/min at P14. Contribution of autonomic control to HR was then assessed. Sympathetic blockade with metoprolol significantly reduced basal HR at both P6 (-236 +/- 23 beats/min; mean +/- SE) and P12 (-105 +/- 8 beats/min), but atropine was without effect, indicating the predominant tonic adrenergic stimulation and absence of vagal control for basal HR in newborn mice. In contrast to stable basal HR during 5-min recording, HR measured by ECG (ECG-HR) was markedly decreased because of the restraint stress of attaching ECG electrodes, with accompanying freezing behavior. ECG-HR lowered and further decreased gradually during 5 min (slow cardiodeceleration) at P0-P3 and rapidly decreased and gradually recovered within 5 min (transient bradycardia) at P9-P14. The response was not uniform in P4-P8 mice: they showed either of these two patterns or sustained bradycardia (9-29%), and the number of mice that showed transient bradycardia increased with age (30-100%) during the period. Studies with autonomic blockade suggest that the slow cardiodeceleration and transient bradycardia are mediated mainly by withdrawal of adrenergic stimulation and phasic vagal activation, respectively, and the autonomic control of HR response to restraint stress is likely to change from the withdrawal of adrenergic stimulation to the phasic vagal activation at different stages during P4-P8 in individual mice. The PZT sensor may offer excellent opportunities to monitor basal HR of small animals noninvasively.

  17. Hyaluronic acid-bound letrozole nanoparticles restore sensitivity to letrozole-resistant xenograft tumors in mice.

    PubMed

    Nair, Hareesh B; Huffman, Steven; Veerapaneni, Poornachand; Kirma, Nameer B; Binkley, Peter; Perla, Rao P; Evans, Dean B; Tekmal, Rajeshwar R

    2011-05-01

    Letrozole is a potent aromatase inhibitor and superior to other defined selective estrogen receptor modulators such as tamoxifen in treating hormone-responsive postmenopausal breast cancer patients. Patients who receive this drug may become insensitive to the effects of estrogen deprivation induced by letrozole. Letrozole has known side effects on bone metabolism due to systemic ablation of estrogen production. The purpose of this study was to examine the therapeutic efficacy of hyaluronic acid-bound letrozole nanoparticles (HA-Letr-NPs) in restoring sensitivity to letrozole-resistant (LTLT-Ca) cells. To target letrozole to LTLT-Ca cells, hyaluronic acid-bound letrozole nanoparticles were prepared by nanoprecipitation using biodegradable PLGA-PEG co-polymer. Binding specificity of HA to CD44 on the cell surface was analyzed in vitro using FITC-CD44 Ab and CD44 siRNA by flow cytometry. Effects on in vitro cytotoxicity and aromatase enzymatic activity of HA-Letr-NPs were performed in MCF-7 breast cancer cells, MCF-7 cells over-expressing aromatase (MCF-7/Aro), and LTLT-Ca cells resistant to letrozole. Preclinical efficacy of HA-Letr-NPs was examined in mice using LTLT-Ca xenograft tumors. HA-Letr-NPs were restricted to a maximum size of 100 nm. The in vitro drug release assay showed that the highest released concentration of letrozole occurred after 23 hours at 37 degrees C in phosphate-buffered saline. HA-Letr-NPs on MCF-7/Aro and LTLT-Ca cells showed an IC50 of 2 microM and 5 microM, respectively. HA-Letr-NPs were more efficacious in inhibiting tumor growth, reducing in vitro cellular and in vivo tumor aromatase enzyme activity more than the corresponding Letr-NPs or letrozole. HA-Letr-NPs restored and maintained a prolonged sensitivity and targeted delivery of letrozole in letrozole-resistant tumors in vivo.

  18. Influences of DTC and zinc supplementation on the cellular response restoration in restrained mice.

    PubMed

    Obminska-Mrukowicz, Bozena; Szczypka, Marianna

    2005-03-01

    The studies were conducted on Balb/c mice exposed to restraint stress twice for 12 h at 24 h intervals. Prior to restraint stress the mice were treated with sodium diethyldithiocarbamate (DTC) i.p. at a dose of 20 mg/kg five times at 48 h intervals. DTC was used per se or with zinc ions interaction, by adding zinc sulfate to drinking water at a dose of 72 microgram/mouse daily. The results obtained in the study show that restraint stress causes involution of lymphatic organs, decreased the percentage of immature (CD4+CD8+) and, mature (CD4+) thymocytes and CD4+), CD8+ and CD19+ splenocytes and proliferative response of thymocytes stimulated in vitro with concanavalin A (Con A) and phytohemagglutinin (PHA). The restraint stress decreased also interleukin-1 (IL-1) production by murine intraperitoneal macrophages stimulated in vitro with lipopolysaccharide (LPS) from E. coli. Pretreatment with DTC counteracted restraint stress-induced immunosuppression, which is expressed as partial normalisation of the total number of thymocytes, splenocytes and IL-1 production, accelerated regeneration of thymus and spleen, shorter suppressive action of restraint stress on the percentage of CD4+CD8+thymocytes and in total normalisation of the CD4+thymocytes and splenocytes. DTC administered prior to restraint stress augmented the proliferative response of thymocytes to two mitogens. The immunocorrecting action of DTC is enhanced by zinc supplementation, expressed in the increased percentage of CD4+thymocytes and splenocytes, CD19+splenocytes, proliferative activity of thymocytes stimulated with PHA and IL-1 production. The obtained results show that DTC administration can be supplemented with zinc in order to restore the immune system impaired by stress.

  19. Newborn jaundice

    MedlinePlus

    Jaundice of the newborn; Neonatal hyperbilirubinemia; Bili lights - jaundice; Infant - yellow skin; Newborn - yellow skin ... lasts 1 to 2 days. Sometimes special blue lights are used on infants whose levels are very ...

  20. Restoration of nerve growth factor in organs of mice injected with cobra venom followed by specific treatment and reversal period.

    PubMed

    Lipps, Binie V

    2002-05-01

    Research from this laboratory reported the decreased levels of endogenously present nerve growth factor (NGF) in organs of mice as a consequence of sub-lethal injection of Naja kaouthia venom. This research reports that the decreased levels of NGF in organs of mice were prevented by (1) specific treatment and (2) restored to normal by a prolonged period. Adult female Balb/c mice were injected intramuscularly (IM) with a sub-lethal dose of cobra venom. The injected mice were divided into five groups. Mice in group I were injected with PBS, group II with anti-cobra venom, and group III with lethal toxin neutralizing factor (LTNF). Mice in group IV were treated IM with synthetic LTNF (LT-10), and mice in group V were treated orally with LT-10. After 24 hr. mice were sacrificed and NGF levels in organ homogenates were assayed and compared with control mice not injected with venom. It was observed that the organs from group I treated with PBS showed a tremendous drop in NGF level in comparison to the organs of the control mice. It was further revealed that the decreased levels of NGF in organs of injected mice were prevented by treatment with anti-cobra venom, LTNF and LT-10 by IM, or oral routes. In the second series of experiments, mice injected with sub-lethal dose of cobra venom were sacrificed after 1, 3, 7, and 10 days, and the organs were assayed for NGF levels. It was observed that the recovery period for normal homeostasis of NGF was between 7 and 10 days in the brain, heart, liver, salivary glands, and ovaries.

  1. Eicosapentaenoic acid ameliorates hyperglycemia in high-fat diet-sensitive diabetes mice in conjunction with restoration of hypoadiponectinemia

    PubMed Central

    Morimoto, M; Lee, E-Y; Zhang, X; Inaba, Y; Inoue, H; Ogawa, M; Shirasawa, T; Yokosuka, O; Miki, T

    2016-01-01

    Background/Objective: Eicosapentaenoic acid (EPA) exerts pleiotropic effects on metabolic disorders such as atherosclerosis and dyslipidemia, but its effectiveness in the treatment of type 2 diabetes mellitus remains controversial. Methods: We examined the antidiabetic effect of EPA in insulin receptor mutant (InsrP1195L/+) mice that exhibit high-fat diet (HFD)-dependent hyperglycemia. Results: EPA supplementation was found to alleviate hyperglycemia of InsrP1195L/+ mice fed HFD (InsrP1195L/+/HFD mice), which was accompanied by amelioration of increased gluconeogenesis and impaired insulin signaling, as assessed by glucose-6-phosphatase (G6pc) expression on refeeding and insulin-induced phosphorylation of Akt in the liver, respectively. We found that serum levels of adiponectin, the antidiabetic adipokine, were decreased by HFD along with the body weight gain in InsrP1195L/+ mice but not in wild-type mice, suggesting that InsrP1195L/+ mice are prone to hypoadiponectinemia in response to obesity. Interestingly, the blood glucose levels of InsrP1195L/+ mice were in reverse proportion to their serum adiponectin levels and EPA supplementation ameliorated their hyperglycemia in conjunction with the restoration of hypoadiponectinemia. Conclusions: EPA exerts an antidiabetic effect in InsrP1195L/+/HFD mice, an HFD-sensitive, insulin-resistant animal model, possibly through its action against hypoadiponectinemia. PMID:27348201

  2. Role of gammaENaC subunit in lung liquid clearance and electrolyte balance in newborn mice. Insights into perinatal adaptation and pseudohypoaldosteronism.

    PubMed Central

    Barker, P M; Nguyen, M S; Gatzy, J T; Grubb, B; Norman, H; Hummler, E; Rossier, B; Boucher, R C; Koller, B

    1998-01-01

    Genetic evidence supports a critical role for the epithelial sodium channel (ENaC) in both clearance of fetal lung liquid at birth and total body electrolyte homeostasis. Evidence from heterologous expression systems suggests that expression of the alphaENaC subunit is essential for channel function, whereas residual channel function can be measured in the absence of beta or gamma subunits. We generated mice without gammaENaC (gammaENaC -/-) to test the role of this subunit in neonatal lung liquid clearance and total body electrolyte balance. Relative to controls, gammaENaC (-/-) pups showed low urinary [K+] and high urinary [Na+] and died between 24 and 36 h, probably from hyperkalemia (gammaENaC -/- 18.3 mEq/l, control littermates 9.7 mEq/l). Newborn gammaENaC (-/-) mice cleared lung liquid more slowly than control littermates, but lung water at 12 h (wet/dry = 5.5) was nearly normal (wet/dry = 5.3). This study suggests that gammaENaC facilitates neonatal lung liquid clearance and is critical for renal Na+ and K+ transport, and that low level Na+ transport may be sufficient for perinatal lung liquid absorption but insufficient to maintain electrolyte balance by the distal nephron. The gammaENaC (-/-) newborn exhibits a phenotype that resembles the clinical manifestations of human neonatal PHA1. PMID:9788978

  3. Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice.

    PubMed

    Bland, Richard D; Mokres, Lucia M; Ertsey, Robert; Jacobson, Berit E; Jiang, Shu; Rabinovitch, Marlene; Xu, Liwen; Shinwell, Eric S; Zhang, Feijie; Beasley, Matthew A

    2007-11-01

    Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice. Am J Physiol Lung Cell Mol Physiol 293: , 2007. First published August 17, 2007; - Mechanical ventilation (MV) with O(2)-rich gas offers life-saving treatment for extremely premature infants with respiratory failure but often leads to neonatal chronic lung disease (CLD), characterized by defective formation of alveoli and blood vessels in the developing lung. We discovered that MV of 2- to 4-day-old mice with 40% O(2) for 8 h, compared with unventilated control pups, reduced lung expression of genes that regulate lung septation and angiogenesis (VEGF-A and its receptor, VEGF-R2; PDGF-A; and tenascin-C). MV with air for 8 h yielded similar results for PDGF-A and tenascin-C but did not alter lung mRNA expression of VEGF or VEGF-R2. MV of 4- to 6-day-old mice with 40% O(2) for 24 h reduced lung protein abundance of VEGF-A, VEGF-R2, PDGF-A, and tenascin-C and resulted in lung structural abnormalities consistent with evolving CLD. After MV with 40% O(2) for 24 h, lung volume was similar to unventilated controls, whereas distal air space size, assessed morphometrically, was greater in lungs of ventilated pups, indicative of impaired septation. Immunostaining for vimentin, which is expressed in myofibroblasts, was reduced in distal lung after 24 h of MV with 40% O(2). These molecular, cellular, and structural changes occurred without detectable lung inflammation as evaluated by histology and assays for proinflammatory cytokines, myeloperoxidase activity, and water content in lung. Thus lengthy MV of newborn mice with O(2)-rich gas reduces lung expression of genes and proteins that are critical for normal lung growth and development. These changes yielded lung structural defects similar to those observed in evolving CLD.

  4. Red-shifted channelrhodopsin stimulation restores light responses in blind mice, macaque retina, and human retina.

    PubMed

    Sengupta, Abhishek; Chaffiol, Antoine; Macé, Emilie; Caplette, Romain; Desrosiers, Mélissa; Lampič, Maruša; Forster, Valérie; Marre, Olivier; Lin, John Y; Sahel, José-Alain; Picaud, Serge; Dalkara, Deniz; Duebel, Jens

    2016-11-01

    Targeting the photosensitive ion channel channelrhodopsin-2 (ChR2) to the retinal circuitry downstream of photoreceptors holds promise in treating vision loss caused by retinal degeneration. However, the high intensity of blue light necessary to activate channelrhodopsin-2 exceeds the safety threshold of retinal illumination because of its strong potential to induce photochemical damage. In contrast, the damage potential of red-shifted light is vastly lower than that of blue light. Here, we show that a red-shifted channelrhodopsin (ReaChR), delivered by AAV injections in blind rd1 mice, enables restoration of light responses at the retinal, cortical, and behavioral levels, using orange light at intensities below the safety threshold for the human retina. We further show that postmortem macaque retinae infected with AAV-ReaChR can respond with spike trains to orange light at safe intensities. Finally, to directly address the question of translatability to human subjects, we demonstrate for the first time, AAV- and lentivirus-mediated optogenetic spike responses in ganglion cells of the postmortem human retina. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  5. Acceleration of Biliary Cholesterol Secretion Restores Glycemic Control and Alleviates Hypertriglyceridemia in Obese db/db Mice

    PubMed Central

    Su, Kai; Sabeva, Nadezhda S.; Wang, Yuhuan; Liu, Xiaoxi; Lester, Joshua D.; Liu, Jingjing; Liang, Shuang; Graf, Gregory A.

    2014-01-01

    Objective Recent studies support a role for cholesterol in the development of obesity and nonalcoholic fatty liver disease. Mice lacking the ABCG5 ABCG8 (G5G8) sterol transporter have reduced biliary cholesterol secretion and are more susceptible to steatosis, hepatic insulin resistance, and loss of glycemic control when challenged with a high-fat diet. We hypothesized that accelerating G5G8-mediated biliary cholesterol secretion would correct these phenotypes in obese mice. Approach and Results Obese (db/db) male and their lean littermates were administered a cocktail of control adenovirus or adenoviral vectors encoding ABCG5 and ABCG8 (AdG5G8). Three days after viral administration, measures of lipid and glucose homeostasis were determined, and tissues were collected for biochemical analyses. AdG5G8 increased biliary cholesterol and fecal sterol elimination. Fasting glucose and triglycerides declined, and glucose tolerance improved in obese mice expressing G5G8 compared with mice receiving control adenovirus. These changes were associated with a reduction in phosphorylated eukaryotic initiation factor 2α and c-Jun N-terminal kinase in liver, suggesting alleviation of endoplasmic reticulum stress. Phosphorylated insulin receptor and protein kinase B were increased, indicating restored hepatic insulin signaling. However, there was no reduction in hepatic triglycerides after the 3-day treatment period. Conclusions Accelerating biliary cholesterol secretion restores glycemic control and reduces plasma triglycerides in obese db/db mice. PMID:24202306

  6. Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese db/db mice.

    PubMed

    Su, Kai; Sabeva, Nadezhda S; Wang, Yuhuan; Liu, Xiaoxi; Lester, Joshua D; Liu, Jingjing; Liang, Shuang; Graf, Gregory A

    2014-01-01

    Recent studies support a role for cholesterol in the development of obesity and nonalcoholic fatty liver disease. Mice lacking the ABCG5 ABCG8 (G5G8) sterol transporter have reduced biliary cholesterol secretion and are more susceptible to steatosis, hepatic insulin resistance, and loss of glycemic control when challenged with a high-fat diet. We hypothesized that accelerating G5G8-mediated biliary cholesterol secretion would correct these phenotypes in obese mice. Obese (db/db) male and their lean littermates were administered a cocktail of control adenovirus or adenoviral vectors encoding ABCG5 and ABCG8 (AdG5G8). Three days after viral administration, measures of lipid and glucose homeostasis were determined, and tissues were collected for biochemical analyses. AdG5G8 increased biliary cholesterol and fecal sterol elimination. Fasting glucose and triglycerides declined, and glucose tolerance improved in obese mice expressing G5G8 compared with mice receiving control adenovirus. These changes were associated with a reduction in phosphorylated eukaryotic initiation factor 2α and c-Jun N-terminal kinase in liver, suggesting alleviation of endoplasmic reticulum stress. Phosphorylated insulin receptor and protein kinase B were increased, indicating restored hepatic insulin signaling. However, there was no reduction in hepatic triglycerides after the 3-day treatment period. Accelerating biliary cholesterol secretion restores glycemic control and reduces plasma triglycerides in obese db/db mice.

  7. Ectopic norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice.

    PubMed

    Ohlmann, Andreas; Scholz, Michael; Goldwich, Andreas; Chauhan, Bharesh K; Hudl, Kristiane; Ohlmann, Anne V; Zrenner, Eberhart; Berger, Wolfgang; Cvekl, Ales; Seeliger, Mathias W; Tamm, Ernst R

    2005-02-16

    Norrie disease is an X-linked retinal dysplasia that presents with congenital blindness, sensorineural deafness, and mental retardation. Norrin, the protein product of the Norrie disease gene (NDP), is a secreted protein of unknown biochemical function. Norrie disease (Ndp(y/-)) mutant mice that are deficient in norrin develop blindness, show a distinct failure in retinal angiogenesis, and completely lack the deep capillary layers of the retina. We show here that the transgenic expression of ectopic norrin under control of a lens-specific promoter restores the formation of a normal retinal vascular network in Ndp(y/-) mutant mice. The improvement in structure correlates with restoration of neuronal function in the retina. In addition, lenses of transgenic mice with ectopic expression of norrin show significantly more capillaries in the hyaloid vasculature that surrounds the lens during development. In vitro, lenses of transgenic mice in coculture with microvascular endothelial cells induce proliferation of the cells. Transgenic mice with ectopic expression of norrin show more bromodeoxyuridine-labeled retinal progenitor cells at embryonic day 14.5 and thicker retinas at postnatal life than wild-type littermates, indicating a putative direct neurotrophic effect of norrin. These data provide direct evidence that norrin induces growth of ocular capillaries and that pharmacologic modulation of norrin might be used for treatment of the vascular abnormalities associated with Norrie disease or other vascular disorders of the retina.

  8. Treatment with garlic restores membrane thiol content and ameliorates lead induced early death of erythrocytes in mice.

    PubMed

    Sarkar, Avik; Sengupta, Dipanwita; Mandal, Samir; Sen, Gargi; Dutta Chowdhury, Kaustav; Chandra Sadhukhan, Gobinda

    2015-04-01

    Sequelae of chronic lead (Pb(2+) ) toxicity includes anemia that is partially due to early death of erythrocytes characterized by excess accumulation of ROS and downregulation of antioxidant system causing oxidative stress and externalization of phosphatidylserine. In this study, pathophysiological based therapeutic application of garlic was evaluated against erythrocyte death. Results suggest that garlic administration prevents oxidative stress, restored the antioxidant balance in erythrocytes of Pb(2+) exposed mice. Moreover, in vitro studies revealed that activity of both scramblase and aminophospholipid translocase could be changed by modifying the critical sulfhydryl groups in presence of dithiothreitol during Pb(2+) exposure. Data also indicated that garlic treatment in Pb(2+) exposed mice exhibited sharp decline in PS exposure and increase in erythrocyte membrane thiol group followed by increase in aminophospholipid translocase activity and decline in scramblase activity. Findings indicated that garlic has the ability to restore the lifespan of erythrocytes during Pb(2+) exposure. Copyright © 2013 Wiley Periodicals, Inc.

  9. Exercise restores bioavailability of hydrogen sulfide and promotes autophagy influx in livers of mice fed with high-fat diet.

    PubMed

    Wang, Bing; Zeng, Jing; Gu, Qi

    2017-06-01

    In the gold standard treatment for nonalcoholic fatty liver disease (NAFLD), exercise training has been shown to effectively improve nonalcoholic steatohepatitis (NASH). However, limited data are available about the underlying mechanisms involved. This work was undertaken to investigate the mechanisms underlying the beneficial effect of exercise training on high-fat diet (HFD)-induced NAFLD in mice. Male mice were fed with HFD and given moderate-intensity exercise for 24 weeks. Exercise training lowered mass gain, attenuated systemic insulin resistance and glucose intolerance, and mitigated hepatic steatosis and fibrosis in mice fed with HFD. Exercise training improved mitochondrial function and enhanced mitochondrial β-oxidation in livers of HFD-fed mice. Exercise training enhanced hydrogen sulfide (H2S) levels in plasma and livers, and mRNA expression of cystathionine β-synthase (CBS), cystathionine γ-lyase (CES), and 3-mercaptopyruvate sulfurtransferase (3-MST) in livers of HFD-fed mice. Exercise training had no significant effect on the ratio of LC3-II/LC3-I, but decreased p62 protein expression in livers of HFD-fed mice. Additionally, exercise training reduced formation of malondialdehyde, enhanced ratio of GSH/GSSG, and down-regulated expression of TNF-α and IL-6 in livers of HFD-fed mice. Exercise training restored bioavailability of H2S and promoted autophagy influx in livers, which might contribute to its benefit on HFD-induced NAFLD.

  10. Physiological and functional changes in the stratum corneum restored by oestrogen in an ovariectomized mice model of climacterium.

    PubMed

    Chen, Yue; Yokozeki, Hiroo; Katagiri, Kazumoto

    2017-05-01

    Significant decreases in hormonal levels at menopause induce physiological and functional discomfort in the skin. Representative changes at menopause are based on so-called dry skin. However, there is no evidence to explain the mechanism, even though hydration of the stratum corneum (SC) in women at menopause is comparable with that at premenopause but is enhanced by hormone replacement therapy. This study objective was to evaluate structural and functional changes in the SC in ovariectomized mice model of menopause. Hydration of the SC, recovery of the permeability barrier function, integrity and cohesion of the SC, and irritant dermatitis were analysed in mice that underwent ovariectomy with or without replacement of 17ß-estradiol. In ovariectomized mice, hydration of the SC was reduced, recovery of permeability barrier function after acute disruption was impaired, and integrity of the SC was weakened and was associated with increased cohesion and increased levels of irritant dermatitis. Oestrogen replacement treatment restored all changes. Immunohistochemistry revealed reduced levels of expression of desmoglein-1 and differentiation markers of epidermis in ovariectomized mice compared with control mice and mice with oestrogen replacement treatment. These changes might be directly associated with weakened integrity and impaired permeability barrier function of the SC in ovariectomized mice. This study results reveal that so-called dry skin at menopause is caused by not only lower hydration of the SC but also complicated structural and functional changes in the SC and skin. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. NCAM-deficient mice show prominent abnormalities in serotonergic and BDNF systems in brain - Restoration by chronic amitriptyline.

    PubMed

    Aonurm-Helm, Anu; Anier, Kaili; Zharkovsky, Tamara; Castrén, Eero; Rantamäki, Tomi; Stepanov, Vladimir; Järv, Jaak; Zharkovsky, Alexander

    2015-12-01

    Mood disorders are associated with alterations in serotonergic system, deficient BDNF (brain-derived neurotrophic factor) signaling and abnormal synaptic plasticity. Increased degradation and reduced functions of NCAM (neural cell adhesion molecule) have recently been associated with depression and NCAM deficient mice show depression-related behavior and impaired learning. The aim of the present study was to investigate potential changes in serotonergic and BDNF systems in NCAM knock-out mice. Serotonergic nerve fiber density and SERT (serotonin transporter) protein levels were robustly reduced in the hippocampus, prefrontal cortex and basolateral amygdala of adult NCAM(-)(/-) mice. This SERT reduction was already evident during early postnatal development. [(3)H]MADAM binding experiments further demonstrated reduced availability of SERT in cell membranes of NCAM(-)(/-) mice. Moreover, the levels of serotonin and its major metabolite 5-HIAA were down regulated in the brains of NCAM(-)(/-) mice. NCAM(-)(/-) mice also showed a dramatic reduction in the BDNF protein levels in the hippocampus and prefrontal cortex. This BDNF deficiency was associated with reduced phosphorylation of its receptor TrkB. Importantly, chronic administration of antidepressant amitriptyline partially or completely restored these changes in serotonergic and BDNF systems, respectively. In conclusion, NCAM deficiency lead to prominent and persistent abnormalities in brain serotonergic and BDNF systems, which likely contributes to the behavioral and neurobiological phenotype of NCAM(-/-) mice.

  12. Carnitine deficiency in OCTN2-/- newborn mice leads to a severe gut and immune phenotype with widespread atrophy, apoptosis and a pro-inflammatory response.

    PubMed

    Sonne, Srinivas; Shekhawat, Prem S; Matern, Dietrich; Ganapathy, Vadivel; Ignatowicz, Leszek

    2012-01-01

    We have investigated the gross, microscopic and molecular effects of carnitine deficiency in the neonatal gut using a mouse model with a loss-of-function mutation in the OCTN2 (SLC22A5) carnitine transporter. The tissue carnitine content of neonatal homozygous (OCTN2(-/-)) mouse small intestine was markedly reduced; the intestine displayed signs of stunted villous growth, early signs of inflammation, lymphocytic and macrophage infiltration and villous structure breakdown. Mitochondrial β-oxidation was active throughout the GI tract in wild type newborn mice as seen by expression of 6 key enzymes involved in β-oxidation of fatty acids and genes for these 6 enzymes were up-regulated in OCTN2(-/-) mice. There was increased apoptosis in gut samples from OCTN2(-/-) mice. OCTN2(-/-) mice developed a severe immune phenotype, where the thymus, spleen and lymph nodes became atrophied secondary to increased apoptosis. Carnitine deficiency led to increased expression of CD45-B220(+) lymphocytes with increased production of basal and anti-CD3-stimulated pro-inflammatory cytokines in immune cells. Real-time PCR array analysis in OCTN2(-/-) mouse gut epithelium demonstrated down-regulation of TGF-β/BMP pathway genes. We conclude that carnitine plays a major role in neonatal OCTN2(-/-) mouse gut development and differentiation, and that severe carnitine deficiency leads to increased apoptosis of enterocytes, villous atrophy, inflammation and gut injury.

  13. Carnitine Deficiency in OCTN2−/− Newborn Mice Leads to a Severe Gut and Immune Phenotype with Widespread Atrophy, Apoptosis and a Pro-Inflammatory Response

    PubMed Central

    Sonne, Srinivas; Shekhawat, Prem S.; Matern, Dietrich; Ganapathy, Vadivel; Ignatowicz, Leszek

    2012-01-01

    We have investigated the gross, microscopic and molecular effects of carnitine deficiency in the neonatal gut using a mouse model with a loss-of-function mutation in the OCTN2 (SLC22A5) carnitine transporter. The tissue carnitine content of neonatal homozygous (OCTN2−/−) mouse small intestine was markedly reduced; the intestine displayed signs of stunted villous growth, early signs of inflammation, lymphocytic and macrophage infiltration and villous structure breakdown. Mitochondrial β-oxidation was active throughout the GI tract in wild type newborn mice as seen by expression of 6 key enzymes involved in β-oxidation of fatty acids and genes for these 6 enzymes were up-regulated in OCTN2−/− mice. There was increased apoptosis in gut samples from OCTN2−/− mice. OCTN2−/− mice developed a severe immune phenotype, where the thymus, spleen and lymph nodes became atrophied secondary to increased apoptosis. Carnitine deficiency led to increased expression of CD45-B220+ lymphocytes with increased production of basal and anti-CD3-stimulated pro-inflammatory cytokines in immune cells. Real-time PCR array analysis in OCTN2−/− mouse gut epithelium demonstrated down-regulation of TGF-β/BMP pathway genes. We conclude that carnitine plays a major role in neonatal OCTN2−/− mouse gut development and differentiation, and that severe carnitine deficiency leads to increased apoptosis of enterocytes, villous atrophy, inflammation and gut injury. PMID:23112839

  14. Mifepristone (RU486) restores humoral and T cell-mediated immune response in endotoxin immunosuppressed mice

    PubMed Central

    Rearte, B; Maglioco, A; Balboa, L; Bruzzo, J; Landoni, V I; Laborde, E A; Chiarella, P; Ruggiero, R A; Fernández, G C; Isturiz, M A

    2010-01-01

    Sepsis and septic shock can be caused by Gram-positive and -negative bacteria and other microorganisms. In the case of Gram-negative bacteria, endotoxin, a normal constituent of the bacterial wall, also known as lipopolysaccharide (LPS), has been considered as one of the principal agents causing the undesirable effects in this critical illness. The response to LPS involves a rapid secretion of proinflammatory cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, interferon (IFN)-γ and the concomitant induction of anti-inflammatory mediators such as IL-10, transforming growth factor (TGF)-β or glucocorticoids, which render the host temporarily refractory to subsequent lethal doses of LPS challenge in a process known as LPS or endotoxin tolerance. Although protective from the development of sepsis or systemic inflammation, endotoxin tolerance has also been pointed out as the main cause of the non-specific humoral and cellular immunosuppression described in these patients. In this report we demonstrate, using a mouse model, that mifepristone (RU486), a known glucocorticoid receptor antagonist, could play an important role in the restoration of both adaptive humoral and cellular immune response in LPS immunosuppressed mice, suggesting the involvement of endogenous glucocorticoids in this phenomenon. On the other hand, using cyclophosphamide and gemcitabine, we demonstrated that regulatory/suppressor CD4+CD25+forkhead boxP3+ and GR-1+CD11b+ cells do not play a major role in the establishment or the maintenance of endotoxin tolerance, a central mechanism for inducing an immunosuppression state. PMID:20964639

  15. Prolonged therapy with the soluble guanylyl cyclase activator BAY 60-2770 restores the erectile function in obese mice.

    PubMed

    Silva, Fábio H; Leiria, Luiz O; Alexandre, Eduardo C; Davel, Ana Paula C; Mónica, Fabíola Z; De Nucci, Gilberto; Antunes, Edson

    2014-11-01

    Cardiovascular and endocrine-metabolic diseases associated with increased oxidative stress such as obesity lead to erectile dysfunction (ED). Activators of soluble guanylyl cyclase (sGC) such as BAY 60-2770 reactivate the heme-oxidized sGC in vascular diseases. This study aimed to evaluate the effects of 2-week oral intake with BAY 60-2270 on a murine model of obesity-associated ED. C57BL/6 male mice were fed for 12 weeks with standard chow or high-fat diet. Lean and obese mice were treated with BAY 60-2770 (1 mg/kg/day, 2 weeks). Measurements of intracavernosal pressure (ICP), along with acetylcholine (10(-9) to 10(-5)  M) and electrical field stimulation (EFS; 4-10 Hz)-induced corpus cavernosum relaxations in vitro, were obtained. Levels of cyclic guanosine monophosphate (cGMP), reactive oxygen species (ROS), and sGC protein expressions in cavernosal tissues were measured. Cavernous nerve stimulation caused frequency-dependent ICP increases, which were significantly lower in obese compared with lean mice (P < 0.05). Two-week therapy with BAY 60-2770 fully reversed the decreased ICP in obese group. Acetylcholine-induced cavernosal relaxations were 45% lower (P < 0.001) in obese mice, which were fully restored by BAY 60-2770 treatment. Likewise, the EFS-induced relaxations in obese mice were restored by BAY 60-2770. Basal cGMP content in erectile tissue was 68% lower (P < 0.05) in obese mice, an effect normalized by BAY 60-2770. Levels of ROS were 52% higher (P < 0.05) whereas protein expression of α1 sGC subunit was reduced in cavernosal tissue of obese mice, both of which were normalized by BAY 60-2770. In lean group, BAY 60-2770 did not significantly affect any functional, biochemical, or molecular parameter analyzed. Two-week therapy with BAY 60-2770 restores the erectile function in obese mice that is associated with reduced ROS levels, up-regulation of α1 sGC subunit, and increased cGMP levels in the erectile tissue. © 2014

  16. Pharmacological concentrations of rFVIIa restore hemostasis independent of tissue factor in antibody-induced hemophilia mice

    PubMed Central

    KESHAVA, S.; SUNDARAM, J.; RAJULAPATI, A.; PENDURTHI, U.R.; RAO, L.V.M.

    2016-01-01

    Summary Background Recombinant factor VIIa (rFVIIa) has been used widely for treating hemophilia patients with inhibitory autoantibodies against factor VIII or IX. Its mechanism of action is not entirely known. A majority of in vitro studies suggested that pharmacological concentrations of rFVIIa restore hemostasis in hemophilia in a phospholipid-dependent mechanism, independent of tissue factor (TF). However, a few studies suggested that a TF-dependent mechanism plays a primary role in rFVIIa correction of bleeding in hemophilia patients. Here, we investigated the potential contribution of TF in rFVIIa-induced hemostasis in hemophilia employing a model system of FVIII antibody-induced hemophilia in TF transgenic mice. Methods Mice expressing low levels of human TF (LTF mice), relatively high levels of human TF (HTF mice) or wild-type mice (WT mice) were administered with neutralizing anti-FVIII antibodies to induce hemophilia in these mice. The mice were then treated with varying concentrations of rFVIIa. rFVIIa-induced hemostasis was evaluated with the saphenous vein bleeding model. Results Administration of FVIII inhibitory antibodies induced the hemophilic bleeding phenotype in all three genotypes. rFVIIa administration rescued the bleeding phenotype in all three genotypes. No significant differences were observed in rFVIIa-induced correction in the bleeding of LTF and HTF mice administered with FVIII antibodies. Conclusions Our results provide strong evidence supporting that the hemostatic effect of pharmacological doses of rFVIIa stems from a TF-independent mechanism. PMID:26727350

  17. MPTP Impairs Dopamine D1 Receptor-Mediated Survival of Newborn Neurons in Ventral Hippocampus to Cause Depressive-Like Behaviors in Adult Mice

    PubMed Central

    Zhang, Tingting; Hong, Juan; Di, Tingting; Chen, Ling

    2016-01-01

    Parkinson’s disease (PD) is characterized by motor symptoms with depression. We evaluated the influence of dopaminergic depletion on hippocampal neurogenesis process to explore mechanisms of depression production. Five consecutive days of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection in mice (MPTP-mice) reduced dopaminergic fibers in hippocampal dentate gyrus (DG). MPTP-mice exhibited depressive-like behaviors later for 2–3 weeks. BrdU was injected 4 h after last-injection of MPTP. BrdU-positive (BrdU+) cells in dorsal (d-DG) and ventral (v-DG) DG were examined on day 1 (D1), 7 (D7), 14 (D14) and 21 (D21) after BrdU injection. Fewer D7-, D14- and D21-BrdU+ cells or BrdU+/NeuN+ cells, but not D1-BrdU+ cells, were found in v-DG of MPTP-mice than in controls. However, the number of BrdU+ cells in d-DG did not differ between the both. Loss of doublecortin-positive (DCX+) cells was observed in v-DG of MPTP-mice. Protein kinase A (PKA) and Ca2+/cAMP-response element binding protein (CREB) phosphorylation were reduced in v-DG of MPTP-mice, which were reversed by D1-like receptor (D1R) agonist SKF38393, but not D2R agonist quinpirole. The treatment of MPTP-mice with SKF38393 on days 2–7 after BrdU-injection reduced the loss of D7- and D21-BrdU+ cells in v-DG and improved the depressive-like behaviors; these changes were sensitive to PKA inhibitor H89. Moreover, the v-DG injection of SKF38393 in MPTP-mice could reduce the loss of D21-BrdU+ cells and relieve the depressive-like behaviors. In control mice, the blockade of D1R by SCH23390 caused the reduction of D21-BrdU+ cells in v-DG and the depressive-like behaviors. Our results indicate that MPTP-reduced dopaminergic depletion impairs the D1R-mediated early survival of newborn neurons in v-DG, producing depressive-like behaviors. PMID:27790091

  18. Hyperviscosity - newborn

    MedlinePlus

    ... Seizures Strokes Alternative Names Neonatal polycythemia; Hyperviscosity - newborn Images Blood cells References Mathews DC, Glader B. Erythrocyte disorders of infancy. In: Gleason CA, Devaskar SU, ...

  19. AAV-encoded OTC activity persisting to adulthood following delivery to newborn spf(ash) mice is insufficient to prevent shRNA-induced hyperammonaemia.

    PubMed

    Cunningham, S C; Kok, C Y; Spinoulas, A; Carpenter, K H; Alexander, I E

    2013-12-01

    Urea cycle defects presenting in the neonatal period with hyperammonaemia are associated with high morbidity and mortality, and necessitate liver transplantation for long-term management. Gene therapy is therefore an attractive possibility, with vectors based on adeno-associated virus (rAAV) currently showing exciting promise in liver-targeted clinical trials in adults. Successful use of rAAV vectors in infants, however, is more challenging as episomal rAAV genomes will be lost from proliferating hepatocytes during liver growth, leaving stable transgene expression dependent on the subset of vector genomes that undergo genomic integration. To explore this challenge, we exploited the partially ornithine transcarbamylase (OTC)-deficient spf(ash) mouse model and small hairpin RNA-mediated knockdown of residual endogenous OTC enzyme activity in adult mice that had received neonatal treatment with an OTC-encoding rAAV. This leaves mice reliant on vector-encoded OTC activity that has persisted from the newborn period. Despite stable transduction in approximately 8% of hepatocytes and residual vector-encoded OTC activity of up to 33% of wild-type, well above endogenous spf(ash) levels (5-7%), mice were not protected from hyperammonaemia. These data show that the distribution of OTC activity within the liver is critical and that rAAV vector re-delivery after early neonatal treatment is likely to be necessary for stable control of hyperammonaemia into adulthood.

  20. Ovarian-Cell-Like Cells from Skin Stem Cells Restored Estradiol Production and Estrus Cycling in Ovariectomized Mice

    PubMed Central

    Park, Bong-Wook; Pan, Bo; Toms, Derek; Huynh, Evanna; Byun, June-Ho; Lee, Yeon-Mi; Shen, Wei

    2014-01-01

    Reduction of estradiol production and high serum concentrations of follicular stimulating hormone (FSH) are endocrine disorders associated with premature ovarian failure. Here, we report that transplantation of ovarian-like cells differentiated from stem cells restored endogenous serum estradiol levels. Stem cells were isolated from postnatal mouse skin and differentiated into ovarian-cell-like cells that are consistent with female germ, and ovarian follicle somatic cells. The ovarian-cell-like cells were transplanted into ovariectomized mice (Cell Trans), whereas control mice were subjected to bilateral ovariectomies without cell transplantation (OVX). Using vaginal cytology analysis, it was revealed that in 13 out of 19 Cell Trans mice, estrus cycles were restored around 8 weeks after cell transplantation and were maintained until 16 weeks post-transplantation, whereas in the OVX group, all mice were arrested at metestrus/diestrus of the estrus cycle. The uterine weight in the Cell Trans group was similar to sham operation mice (Sham OP), while severe uterine atrophy and a decreased uterine weight were observed in the OVX group. Histologically, ectopic follicle-like structures and blood vessels were found within and around the transplants. At 12–14 weeks after cell transplantation, mean serum estradiol level in Cell Trans mice (178.0±35 pg/mL) was comparable to that of the Sham OP group (188.9±29 pg/mL), whereas it was lower in the OVX group (59.0±4 pg/mL). Serum FSH concentration increased in the OVX group (1.62±0.32 ng/mL) compared with the Sham OP group (0.39±0.34 ng/mL). Cell Trans mice had a similar FSH level (0.94±0.23 ng/mL; P<0.05) to Sham OP mice. Our results suggest that ovarian somatic cells differentiated from stem cells are functional in vivo. In addition to providing insights into the function of ovarian somatic cells derived from stem cells, our study may offer potential therapeutic means for patients with hypo-estradiol levels

  1. Senses and Your Newborn

    MedlinePlus

    ... may startle at the unexpected bark of a dog nearby or seem soothed by the gentle whirring ... Newborns Your Child's Checkup: Newborn Pregnancy & Newborn Center Feeding Your Newborn Learning, Play, and Your Newborn Your ...

  2. Epigallocatechin-3-gallate Prevents Triptolide-Induced Hepatic Injury by Restoring the Th17/Treg Balance in Mice.

    PubMed

    Yu, Shu-Jing; Jiang, Rong; Mazzu, Ying Z; Wei, Cai-Bing; Sun, Zong-Liang; Zhang, Yu-Zhen; Zhou, Lian-Di; Zhang, Qi-Hui

    2016-01-01

    Drug-induced liver injury (DILI) is the most common cause of acute liver failure. Disruption of the Th17/Treg balance can lead to hepatic inflammation, which causes the main symptoms of DILI. Here we investigate the protective mechanisms of (-)-Epigallocatechin-3-gallate (EGCG) on triptolide (TP)-induced DILI that shows the Th17/Treg imbalance. Pretreatment with EGCG (5[Formula: see text]mg/kg) for 10 days before TP (0.5[Formula: see text]mg/kg) administration in mice significantly reduced the increased alanine aminotransferase (ALT) level ([Formula: see text]) induced by TP treatment. The hepatic histology analysis further proved that EGCG protected mice from TP-induced liver injury. The imbalance of Th17/Treg was induced by TP treatment, as shown by the upregulation of TLR4 and downregulation of Tim3 expression. EGCG pretreatment can maintain the expression of TLR4 and Tim3 at normal levels to restore the Th17/Treg imbalance. In addition, EGCG can block the TP-induced expression of the downstream targets of TLR4, including MyD88, NF[Formula: see text]B, and retinoid related orphan receptor (ROR-[Formula: see text]t), while EGCG can restore the TP inhibition of forkhead/winged-helix family transcriptional repressor p3 (FoxP3) that is the downstream target of Tim3. Consequently, EGCG pretreatment can effectively inhibit the Th17-related pro-inflammatory cytokine (e.g. IL-17 and IL-6) upregulation induced by TP treatment. However, TP inhibition of Treg-related anti-inflammatory cytokine IL-10 production was restored by EGCG pretreatment. Taken together, these results suggest that EGCG possesses significant protective properties against TP-induced hepatic inflammatory injury, and that these properties are carried out via the restoration of the Th17/Treg imbalance by the inhibition of the TLR4 signaling pathway and the enhanced activation of the Tim3 signaling pathway.

  3. Immune function in cyclophosphamide-treated mice is restored by the T-cell-tropic isoxazole derivative R-13.

    PubMed

    Zimecki, Michał; Artym, Jolanta; Kocięba, Maja; Obmińska-Mrukowicz, Bożena; Mączyński, Marcin; Ryng, Stanisław

    2015-01-01

    Reconstitution of the immune function in chemotherapy patients will lead to decreases in post-operative complications. A preliminary investigation showed that an isoxazole derivative R-13 (3,5-dimethyl-isoxazole[5,4-e]8H-triazepin-4-one) hydrochloride, given in a single oral dose to normal mice, induced significant increases in the content of CD4(+) cells in the spleens and lymph nodes. That observation prompted the authors to assess the immune reconstituting effects of R-13 in mice pre-treated with cyclophosphamide (CP). Mice were given intraperitoneally (IP) a sublethal dose of CP (200 mg/kg) and then R-13 (as 20 µg IP doses, every 3 days post-CP treatment). Control mice, not treated with CP, received R-13 or the vehicle (DMSO in appropriate dilution). Blood leukocyte and splenocyte numbers, blood cell type levels, splenocyte spontaneous and ConA-induced proliferation, and delayed-type hypersensitivity (DTH) to ovalbumin (OVA) were investigated on day 15 post-CP treatment and five R-13 doses. The humoral immune response (antibody-forming cell development to sheep erythrocytes) was measured 30 days post-CP treatment and 10 R-13 doses. In CP-treated mice, five dosings with R-13 led to increases in numbers of splenocytes and blood leukocytes, as well as in spontaneous and ConA-induced splenocyte proliferation, relative to levels in mice that received only CP 15 days earlier. Blood analysis revealed decreases in neutrophil and eosinophil contents and an increased appearance of lymphocyte immature forms in all mice that received the R-13. Both cell-mediated responses to OVA and humoral immune response to sheep erythrocytes in CP-treated hosts were restored. Based on the data here, it is concluded that R-13 may be of potential value for reconstitution of the immune function of chemotherapy patients.

  4. The effect of Coriandrum sativum seed extract on the learning of newborn mice by electric shock: interaction with caffeine and diazepam.

    PubMed

    Zargar-Nattaj, Seyed Sadegh; Tayyebi, Pooya; Zangoori, Vahid; Moghadamnia, Yasaman; Roodgari, Hasan; Jorsaraei, Seyed Gholamali; Moghadamnia, Ali Akbar

    2011-01-01

    Coriander has been recommended for the relief of pain, anxiety, flatulence, and loss of appetite. In traditional medicine, it is believed that coriander can induce some degree of amnesia in a child when his/her mother uses coriander during the pregnancy. We evaluated the effect of Coriandrum sativum seed extract on learning in second-generation mice. Ethanolic extract (2%) of coriander (100 mg/kg intraperitoneal) was dissolved in sunflower oil (oil) as a vehicle and injected into the control group mother mice during breastfeeding for 25 days at 5-day intervals. After feeding the newborn mice, their learning was evaluated using a step-through passive avoidance task with 0.4 mA electric shock for 2 or 4 seconds. While coriander extract showed a negative effect in the short term (1 hour) after the training session, it potentiated the mice's learning in later assessments (24 hours post-training [P = 0.022] and 1 week post-training [P = 0.002] by a 4-second shock). Low-dose caffeine (25 mg/kg ip after training) improved the learning after 1 hour (P = 0.024); while diazepam (1 mg/kg ip) suppressed learning at all time points after the 4-second shock training (1 hour, P = 0.022; 24 hours, P = 0.002; and 1 week, P = 0.008). No modification in the pain threshold was elicited by electric stimuli both in coriander and control groups. In conclusion, coriander does not improve learning within a short period of time after training; however, learning after coriander administration can be improved in the long term.

  5. Consumption of probiotic Lactobacillus rhamnosus (MTCC: 5897) containing fermented milk plays a key role in development of the immune system in newborn mice during the suckling-weaning transition.

    PubMed

    Saliganti, Vamshi; Kapila, Rajeev; Kapila, Suman

    2016-04-01

    Early infancy, the period when offspring rely not only on their own immunity to combat food-borne antigens but also acquire immunity through maternal sources (via transplacental routes and breast milk), is critical for immune system development Hence the present study was designed to evaluate the effect on offspring of administration of probiotic-containing fermented milk (PFM) either to mothers during the suckling period or to their offspring after weaning either separately or sequentially. PFM-fed mice showed enhanced leukocyte functionality in offspring as evidenced by significantly (P < 0.05) increased release of lysosomal enzymes (β-galactosidase, β-glucuronidase) in peritoneal fluid and nitric oxide production in culture supernatants of activated macrophages. Further, remarkably reduced levels (P < 0.01) of inflammatory markers (TNF-α, monocyte chemotactic protein-1) and allergic antibodies (total and milk specific IgE) were observed in offspring where PFM was fed either to them or to their mothers. However, considerably increased levels (P < 0.05) of SIgA were found in the guts of control and experimental groups animals irrespective of their exposure to PFM. Restoration of Th1/Th2 homeostasis further confirmed the useful effects of PFM supplementation by shifting the cytokine profile (IL-4, IFN-γ and IL-10) with increased IFN-γ/IL-4 and reduced IgE/Ig2Ga ratios. Hence, it is logical to conclude that administration of Lactobacillus rhamnosus-containing (MTCC:5897) fermented milk to mothers during the suckling period and to their offspring after weaning has beneficial effects on the development of newborns immune systems; this effect appears to be more pronounced when mothers are fed with it. © 2015 The Societies and John Wiley & Sons Australia, Ltd.

  6. Developmental restoration of LTP deficits in heterozygous CaMKIIα KO mice.

    PubMed

    Goodell, Dayton J; Benke, Tim A; Bayer, K Ulrich

    2016-11-01

    The Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a major mediator of long-term potentiation (LTP) and depression (LTD), two opposing forms of synaptic plasticity underlying learning, memory and cognition. The heterozygous CaMKIIα isoform KO (CaMKIIα(+/-)) mice have a schizophrenia-related phenotype, including impaired working memory. Here, we examined synaptic strength and plasticity in two brain areas implicated in working memory, hippocampus CA1 and medial prefrontal cortex (mPFC). Young CaMKIIα(+/-) mice (postnatal days 12-16; corresponding to a developmental stage well before schizophrenia manifestation in humans) showed impaired hippocampal CA1 LTP. However, this LTP impairment normalized over development and was no longer detected in older CaMKIIα(+/-) mice (postnatal weeks 9-11; corresponding to young adults). By contrast, the CaMKIIα(+/-) mice failed to show the developmental increase of basal synaptic transmission in the CA1 seen in wild-type (WT) mice, resulting in impaired basal synaptic transmission in the older CaMKIIα(+/-) mice. Other electrophysiological parameters were normal, including mPFC basal transmission, LTP, and paired-pulse facilitation, as well as CA1 LTD, depotentiation, and paired-pulse facilitation at either age tested. Hippocampal CaMKIIα levels were ∼60% of WT in both the older CaMKIIα(+/-) mice and in the younger WT mice, resulting in ∼30% of adult WT expression in the younger CaMKIIα(+/-) mice; levels in frontal cortex were the same as in hippocampus. Thus, in young mice, ∼30% of adult CaMKIIα expression is sufficient for normal LTD and depotentiation, while normal LTP requires higher levels, with ∼60% of CaMKIIα expression sufficient for normal LTP in adult mice.

  7. FNDC5 Alleviates Hepatosteatosis by Restoring AMPK/mTOR-Mediated Autophagy, Fatty Acid Oxidation, and Lipogenesis in Mice.

    PubMed

    Liu, Tong-Yan; Xiong, Xiao-Qing; Ren, Xing-Sheng; Zhao, Ming-Xia; Shi, Chang-Xiang; Wang, Jue-Jin; Zhou, Ye-Bo; Zhang, Feng; Han, Ying; Gao, Xing-Ya; Chen, Qi; Li, Yue-Hua; Kang, Yu-Ming; Zhu, Guo-Qing

    2016-11-01

    Fibronectin type III domain-containing 5 (FNDC5) protein induces browning of subcutaneous fat and mediates the beneficial effects of exercise on metabolism. However, whether FNDC5 is associated with hepatic steatosis, autophagy, fatty acid oxidation (FAO), and lipogenesis remains unknown. Herein, we show the roles and mechanisms of FNDC5 in hepatic steatosis, autophagy, and lipid metabolism. Fasted FNDC5(-/-) mice exhibited severe steatosis, reduced autophagy, and FAO, and enhanced lipogenesis in the liver compared with wild-type mice. Energy deprivation-induced autophagy, FAO, and AMPK activity were attenuated in FNDC5(-/-) hepatocytes, which were restored by activating AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Inhibition of mammalian target of rapamycin (mTOR) complex 1 with rapamycin enhanced autophagy and FAO and attenuated lipogenesis and steatosis in FNDC5(-/-) livers. FNDC5 deficiency exacerbated hyperlipemia, hepatic FAO and autophagy impairment, hepatic lipogenesis, and lipid accumulation in obese mice. Exogenous FNDC5 stimulated autophagy and FAO gene expression in hepatocytes and repaired the attenuated autophagy and palmitate-induced steatosis in FNDC5(-/-) hepatocytes. FNDC5 overexpression prevented hyperlipemia, hepatic FAO and autophagy impairment, hepatic lipogenesis, and lipid accumulation in obese mice. These results indicate that FNDC5 deficiency impairs autophagy and FAO and enhances lipogenesis via the AMPK/mTOR pathway. FNDC5 deficiency aggravates whereas FNDC5 overexpression prevents the HFD-induced hyperlipemia, hepatic lipid accumulation, and impaired FAO and autophagy in the liver.

  8. Virally expressed connexin26 restores gap junction function in the cochlea of conditional Gjb2 knockout mice.

    PubMed

    Yu, Q; Wang, Y; Chang, Q; Wang, J; Gong, S; Li, H; Lin, X

    2014-01-01

    Mutations in GJB2, which codes for the gap junction (GJ) protein connexin26 (Cx26), are the most common causes of human nonsyndromic hereditary deafness. We inoculated modified adeno-associated viral (AAV) vectors into the scala media of early postnatal conditional Gjb2 knockout mice to drive exogenous Cx26 expression. We found extensive virally expressed Cx26 in cells lining the scala media, and intercellular GJ network was re-established in the organ of Corti of mutant mouse cochlea. Widespread ectopic Cx26 expression neither formed ectopic GJs nor affected normal hearing thresholds in wild-type (WT) mice, suggesting that autonomous cellular mechanisms regulate proper membrane trafficking of exogenously expressed Cx26 and govern the functional manifestation of them. Functional recovery of GJ-mediated coupling among the supporting cells was observed. We found that both cell death in the organ of Corti and degeneration of spiral ganglion neurons in the cochlea of mutant mice were substantially reduced, although auditory brainstem responses did not show significant hearing improvement. This is the first report demonstrating that virally mediated gene therapy restored extensive GJ intercellular network among cochlear non-sensory cells in vivo. Such a treatment performed at early postnatal stages resulted in a partial rescue of disease phenotypes in the cochlea of the mutant mice.

  9. Targeted Restoration of the Intestinal Microbiota with a Simple, Defined Bacteriotherapy Resolves Relapsing Clostridium difficile Disease in Mice

    PubMed Central

    Lawley, Trevor D.; Stares, Mark D.; Connor, Thomas R.; Raisen, Claire; Goulding, David; Rad, Roland; Schreiber, Fernanda; Brandt, Cordelia; Deakin, Laura J.; Pickard, Derek J.; Duncan, Sylvia H.; Flint, Harry J.; Clark, Taane G.; Parkhill, Julian; Dougan, Gordon

    2012-01-01

    Relapsing C. difficile disease in humans is linked to a pathological imbalance within the intestinal microbiota, termed dysbiosis, which remains poorly understood. We show that mice infected with epidemic C. difficile (genotype 027/BI) develop highly contagious, chronic intestinal disease and persistent dysbiosis characterized by a distinct, simplified microbiota containing opportunistic pathogens and altered metabolite production. Chronic C. difficile 027/BI infection was refractory to vancomycin treatment leading to relapsing disease. In contrast, treatment of C. difficile 027/BI infected mice with feces from healthy mice rapidly restored a diverse, healthy microbiota and resolved C. difficile disease and contagiousness. We used this model to identify a simple mixture of six phylogenetically diverse intestinal bacteria, including novel species, which can re-establish a health-associated microbiota and clear C. difficile 027/BI infection from mice. Thus, targeting a dysbiotic microbiota with a defined mixture of phylogenetically diverse bacteria can trigger major shifts in the microbial community structure that displaces C. difficile and, as a result, resolves disease and contagiousness. Further, we demonstrate a rational approach to harness the therapeutic potential of health-associated microbial communities to treat C. difficile disease and potentially other forms of intestinal dysbiosis. PMID:23133377

  10. Comparative Hair Restorer Efficacy of Medicinal Herb on Nude (Foxn1nu) Mice

    PubMed Central

    Begum, Shahnaz; Lee, Mi Ra; Gu, Li Juan; Hossain, Md. Jamil; Kim, Hyun Kyoung; Sung, Chang Keun

    2014-01-01

    Eclipta alba (L.) Hassk, Asiasarum sieboldii (Miq.) F. Maek (Asiasari radix), and Panax ginseng C. A. Mey (red ginseng) are traditionally acclaimed for therapeutic properties of various human ailments. Synergistic effect of each standardized plant extract was investigated for hair growth potential on nude mice, as these mutant mice genetically lack hair due to abnormal keratinization. Dried plant samples were ground and extracted by methanol. Topical application was performed on the back of nude mice daily up to completion of two hair growth generations. The hair density and length of Eclipta alba treated mice were increased significantly (P > 0.001) than control mice. Hair growth area was also distinctly visible in Eclipta alba treated mice. On the other hand, Asiasari radix and Panax ginseng treated mice developing hair loss were recognized from the abortive boundaries of hair coverage. Histomorphometric observation of nude mice skin samples revealed an increase in number of hair follicles (HFs). The presence of follicular keratinocytes was confirmed by BrdU labeling, S-phase cells in HFs. Therefore, Eclipta alba extract and/or phytochemicals strongly displayed incomparability of hair growth promotion activity than others. Thus, the standardized Eclipta alba extract can be used as an effective, alternative, and complementary treatment against hair loss. PMID:25478567

  11. Comparative hair restorer efficacy of medicinal herb on nude (Foxn1nu) mice.

    PubMed

    Begum, Shahnaz; Lee, Mi Ra; Gu, Li Juan; Hossain, Md Jamil; Kim, Hyun Kyoung; Sung, Chang Keun

    2014-01-01

    Eclipta alba (L.) Hassk, Asiasarum sieboldii (Miq.) F. Maek (Asiasari radix), and Panax ginseng C. A. Mey (red ginseng) are traditionally acclaimed for therapeutic properties of various human ailments. Synergistic effect of each standardized plant extract was investigated for hair growth potential on nude mice, as these mutant mice genetically lack hair due to abnormal keratinization. Dried plant samples were ground and extracted by methanol. Topical application was performed on the back of nude mice daily up to completion of two hair growth generations. The hair density and length of Eclipta alba treated mice were increased significantly (P>0.001) than control mice. Hair growth area was also distinctly visible in Eclipta alba treated mice. On the other hand, Asiasari radix and Panax ginseng treated mice developing hair loss were recognized from the abortive boundaries of hair coverage. Histomorphometric observation of nude mice skin samples revealed an increase in number of hair follicles (HFs). The presence of follicular keratinocytes was confirmed by BrdU labeling, S-phase cells in HFs. Therefore, Eclipta alba extract and/or phytochemicals strongly displayed incomparability of hair growth promotion activity than others. Thus, the standardized Eclipta alba extract can be used as an effective, alternative, and complementary treatment against hair loss.

  12. Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation

    PubMed Central

    Wang, Yongxing; Suh, Young-Ah; Fuller, Maren Y.; Jackson, James G.; Xiong, Shunbin; Terzian, Tamara; Quintás-Cardama, Alfonso; Bankson, James A.; El-Naggar, Adel K.; Lozano, Guillermina

    2011-01-01

    The transcription factor p53 is a tumor suppressor. As such, the P53 gene is frequently altered in human cancers. However, over 80% of the P53 mutations found in human cancers are missense mutations that lead to expression of mutant proteins that not only lack p53 transcriptional activity but exhibit new functions as well. Recent studies show that restoration of p53 expression leads to tumor regression in mice carrying p53 deletions. However, the therapeutic efficacy of restoring p53 expression in tumors containing p53 missense mutations has not been evaluated. Here we demonstrate that restoring wild-type p53 expression halted tumor growth in mice inheriting a p53R172H missense mutation that is equivalent to a P53 missense mutation detected in approximately 6% of human cancers. However, it did not lead to tumor regression, as was observed in mice lacking p53. We further showed that the dominant-negative effect of the mutant p53 encoded by p53R172H dampened the activity of the restored wild-type p53. We therefore conclude that in a mutant p53 background, p53 restoration has the therapeutic potential to suppress tumor progression. Our findings support using p53 restoration as a strategy to treat human cancers with P53 missense mutations and provide direction for optimizing p53 restoration in cancer therapy. PMID:21285512

  13. Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation.

    PubMed

    Wang, Yongxing; Suh, Young-Ah; Fuller, Maren Y; Jackson, James G; Xiong, Shunbin; Terzian, Tamara; Quintás-Cardama, Alfonso; Bankson, James A; El-Naggar, Adel K; Lozano, Guillermina

    2011-03-01

    The transcription factor p53 is a tumor suppressor. As such, the P53 gene is frequently altered in human cancers. However, over 80% of the P53 mutations found in human cancers are missense mutations that lead to expression of mutant proteins that not only lack p53 transcriptional activity but exhibit new functions as well. Recent studies show that restoration of p53 expression leads to tumor regression in mice carrying p53 deletions. However, the therapeutic efficacy of restoring p53 expression in tumors containing p53 missense mutations has not been evaluated. Here we demonstrate that restoring wild-type p53 expression halted tumor growth in mice inheriting a p53(R172H) missense mutation that is equivalent to a P53 missense mutation detected in approximately 6% of human cancers. However, it did not lead to tumor regression, as was observed in mice lacking p53. We further showed that the dominant-negative effect of the mutant p53 encoded by p53(R172H) dampened the activity of the restored wild-type p53. We therefore conclude that in a mutant p53 background, p53 restoration has the therapeutic potential to suppress tumor progression. Our findings support using p53 restoration as a strategy to treat human cancers with P53 missense mutations and provide direction for optimizing p53 restoration in cancer therapy.

  14. The Type I Interferon Response Determines Differences in Choroid Plexus Susceptibility between Newborns and Adults in Herpes Simplex Virus Encephalitis.

    PubMed

    Wilcox, Douglas R; Folmsbee, Stephen S; Muller, William J; Longnecker, Richard

    2016-04-12

    Newborns are significantly more susceptible to severe viral encephalitis than adults, with differences in the host response to infection implicated as a major factor. However, the specific host signaling pathways responsible for differences in susceptibility and neurologic morbidity have remained unknown. In a murine model of HSV encephalitis, we demonstrated that the choroid plexus (CP) is susceptible to herpes simplex virus 1 (HSV-1) early in infection of the newborn but not the adult brain. We confirmed susceptibility of the CP to HSV infection in a human case of newborn HSV encephalitis. We investigated components of the type I interferon (IFN) response in the murine brain that might account for differences in cell susceptibility and found that newborns have a dampened interferon response and significantly lower basal levels of the alpha/beta interferon (IFN-α/β) receptor (IFNAR) than do adults. To test the contribution of IFNAR to restricting infection from the CP, we infected IFNAR knockout (KO) adult mice, which showed restored CP susceptibility to HSV-1 infection in the adult. Furthermore, reduced IFNAR levels did not account for differences we found in the basal levels of several other innate signaling proteins in the wild-type newborn and the adult, including protein kinase R (PKR), that suggested specific regulation of innate immunity in the developing brain. Viral targeting of the CP, a region of the brain that plays a critical role in neurodevelopment, provides a link between newborn susceptibility to HSV and long-term neurologic morbidity among survivors of newborn HSV encephalitis. Compared to adults, newborns are significantly more susceptible to severe disease following HSV infection. Over half of newborn HSV infections result in disseminated disease or encephalitis, with long-term neurologic morbidity in 2/3 of encephalitis survivors. We investigated differences in host cell susceptibility between newborns and adults that contribute to severe

  15. Failure to remove autoreactive Vβ6+ T cells in Mls-1a newborn mice attributed to the delayed development of B cells in the thymus

    PubMed Central

    Touma, M; Mori, K J; Hosono, M

    2000-01-01

    Clonal deletion of autoreactive T cells in the thymus is one of the major mechanisms for establishing tolerance to self-antigens, and self-reactive T cells bearing Vβ6 T-cell receptors are usually deleted before their maturation in Mls-1a mice. However, these T cells develop transiently in the neonatal thymus, and migrate to the periphery. In order to understand the mechanisms which permit these potentially auto-toxic T cells to generate, we investigated in vivo the physiological or functional properties of the elements involved, such as neonatal T cells, antigens and antigen-presenting cells (APC). Confirming the previous findings that each of these elements per se is already completed in function in neonates, we investigated the possibility of the absence or immaturity of particular APC with Mls antigens of their own products in the neonatal thymus. In the search for the cellular and histological changes occurring in the newborn thymus, we found that the elimination of Vβ6+ T cells progressed in parallel with the development of thymic B cells. Involvement of B cells in purging the autoreactive T cells from the newborn thymus was shown by prevention of the deletion of Vβ6+ T cells after the removal of B cells by the treatment of neonates with anti-immunoglobulin M antibodies. The restricted and stable expression of CD5 on the thymic B cells, but not on the splenic cells, suggests that these B cells are not postnatal immigrants from the periphery. Finally, it is concluded that the deficiency in the deletion of self-reactive T cells in the thymus of Mls-1a neonates is due to the delayed development of B cells. PMID:10929068

  16. Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice

    PubMed Central

    Besnard, Valérie; Matsuzaki, Yohei; Clark, Jean; Xu, Yan; Wert, Susan E.; Ikegami, Machiko; Stahlman, Mildred T.; Weaver, Timothy E.; Hunt, Alan N.; Postle, Anthony D.

    2010-01-01

    ATP-binding cassette A3 (ABCA3) is a lipid transport protein required for synthesis and storage of pulmonary surfactant in type II cells in the alveoli. Abca3 was conditionally deleted in respiratory epithelial cells (Abca3Δ/Δ) in vivo. The majority of mice in which Abca3 was deleted in alveolar type II cells died shortly after birth from respiratory distress related to surfactant deficiency. Approximately 30% of the Abca3Δ/Δ mice survived after birth. Surviving Abca3Δ/Δ mice developed emphysema in the absence of significant pulmonary inflammation. Staining of lung tissue and mRNA isolated from alveolar type II cells demonstrated that ∼50% of alveolar type II cells lacked ABCA3. Phospholipid content and composition were altered in lung tissue, lamellar bodies, and bronchoalveolar lavage fluid from adult Abca3Δ/Δ mice. In adult Abca3Δ/Δ mice, cells lacking ABCA3 had decreased expression of mRNAs associated with lipid synthesis and transport. FOXA2 and CCAAT enhancer-binding protein-α, transcription factors known to regulate genes regulating lung lipid metabolism, were markedly decreased in cells lacking ABCA3. Deletion of Abca3 disrupted surfactant lipid synthesis in a cell-autonomous manner. Compensatory surfactant synthesis was initiated in ABCA3-sufficient type II cells, indicating that surfactant homeostasis is a highly regulated process that includes sensing and coregulation among alveolar type II cells. PMID:20190032

  17. Effect of resveratrol on restoring spermatogenesis in experimental cryptorchid mice and analysis of related differentially expressed proteins.

    PubMed

    Li, Enzhong; Guo, Yuping; Wang, Gailing; Chen, Fujia; Li, Qingwang

    2015-06-01

    The present study aimed to evaluate the effect of trans-Resveratrol on spermatogenesis. Male Kunming suckling mice (10 days old) were surgically rendered cryptorchid and subcutaneously injected with trans-Resveratrol at doses of 5, 10, 20, and 40 µg/g/day as groups I, II, III, and IV, respectively, for 35 days. Animals in the control group received 10 µL/mouse/day of olive oil. Serum estradiol, testosterone, FSH, and LH levels were measured on day 45. Tissue analysis and sperm morphological abnormalities analysis were done. Results showed that in the control group and group I only spermatogonia and primary spermatocytes were present, whereas spermatogenesis was totally restored in groups II, III, and IV. Sperm counts in groups III and IV were remarkably higher than the control group (P<0.05). The morphological abnormalities in resveratrol-treated groups were higher than the mature mice. Serum estradiol levels in the resveratrol-treated groups were not significantly different from the control group, but were lower than the mature mice (P<0.05). There was no significant difference in serum testosterone levels between the resveratrol-treated groups and mature mice, but the levels in the resveratrol-treated groups was significantly lower than the control group (P<0.05). No significant influence of trans-Resveratrol was observed on serum FSH levels in all cryptorchid mice. Serum LH levels in groups I, II, and III were higher than the control group. These results indicate that trans-Resveratrol restores spermatogenesis in cryptorchid mice. In addition, proteomic analysis between the 20 μg/g/day resveratrol-treated group and the control group was carried out, and five kinds of proteins (BAF250, ZFP261, CHD1L, RBBP9, and SOHLH2) were identified. The expression of SOHLH2 increased, while that of BAF250, ZFP261, CHD1L, and RBBP9 decreased in the 20 µg/g/day resveratrol-treated group, indicating that SOHLH2 may contribute to testicular germ cell differentiation.

  18. The effect of Coriandrum sativum seed extract on the learning of newborn mice by electric shock: interaction with caffeine and diazepam

    PubMed Central

    Zargar-Nattaj, Seyed Sadegh; Tayyebi, Pooya; Zangoori, Vahid; Moghadamnia, Yasaman; Roodgari, Hasan; Jorsaraei, Seyed Gholamali; Moghadamnia, Ali Akbar

    2011-01-01

    Coriander has been recommended for the relief of pain, anxiety, flatulence, and loss of appetite. In traditional medicine, it is believed that coriander can induce some degree of amnesia in a child when his/her mother uses coriander during the pregnancy. We evaluated the effect of Coriandrum sativum seed extract on learning in second-generation mice. Ethanolic extract (2%) of coriander (100 mg/kg intraperitoneal) was dissolved in sunflower oil (oil) as a vehicle and injected into the control group mother mice during breastfeeding for 25 days at 5-day intervals. After feeding the newborn mice, their learning was evaluated using a step-through passive avoidance task with 0.4 mA electric shock for 2 or 4 seconds. While coriander extract showed a negative effect in the short term (1 hour) after the training session, it potentiated the mice’s learning in later assessments (24 hours post-training [P = 0.022] and 1 week post-training [P = 0.002] by a 4-second shock). Low-dose caffeine (25 mg/kg ip after training) improved the learning after 1 hour (P = 0.024); while diazepam (1 mg/kg ip) suppressed learning at all time points after the 4-second shock training (1 hour, P = 0.022; 24 hours, P = 0.002; and 1 week, P = 0.008). No modification in the pain threshold was elicited by electric stimuli both in coriander and control groups. In conclusion, coriander does not improve learning within a short period of time after training; however, learning after coriander administration can be improved in the long term. PMID:22114531

  19. An mRNA Vaccine Encoding Rabies Virus Glycoprotein Induces Protection against Lethal Infection in Mice and Correlates of Protection in Adult and Newborn Pigs.

    PubMed

    Schnee, Margit; Vogel, Annette B; Voss, Daniel; Petsch, Benjamin; Baumhof, Patrick; Kramps, Thomas; Stitz, Lothar

    2016-06-01

    Rabies is a zoonotic infectious disease of the central nervous system (CNS). In unvaccinated or untreated subjects, rabies virus infection causes severe neurological symptoms and is invariably fatal. Despite the long-standing existence of effective vaccines, vaccine availability remains insufficient, with high numbers of fatal infections mostly in developing countries. Nucleic acid based vaccines have proven convincingly as a new technology for the fast development of vaccines against newly emerging pathogens, diseases where no vaccine exists or for replacing already existing vaccines. We used an optimized non-replicating rabies virus glycoprotein (RABV-G) encoding messenger RNA (mRNA) to induce potent neutralizing antibodies (VN titers) in mice and domestic pigs. Functional antibody titers were followed in mice for up to one year and titers remained stable for the entire observation period in all dose groups. T cell analysis revealed the induction of both, specific CD4+ as well as CD8+ T cells by RABV-G mRNA, with the induced CD4+ T cells being higher than those induced by a licensed vaccine. Notably, RABV-G mRNA vaccinated mice were protected against lethal intracerebral challenge infection. Inhibition of viral replication by vaccination was verified by qRT-PCR. Furthermore, we demonstrate that CD4+ T cells are crucial for the generation of neutralizing antibodies. In domestic pigs we were able to induce VN titers that correlate with protection in adult and newborn pigs. This study demonstrates the feasibility of a non-replicating mRNA rabies vaccine in small and large animals and highlights the promises of mRNA vaccines for the prevention of infectious diseases.

  20. An mRNA Vaccine Encoding Rabies Virus Glycoprotein Induces Protection against Lethal Infection in Mice and Correlates of Protection in Adult and Newborn Pigs

    PubMed Central

    Voss, Daniel; Petsch, Benjamin; Baumhof, Patrick; Kramps, Thomas; Stitz, Lothar

    2016-01-01

    Rabies is a zoonotic infectious disease of the central nervous system (CNS). In unvaccinated or untreated subjects, rabies virus infection causes severe neurological symptoms and is invariably fatal. Despite the long-standing existence of effective vaccines, vaccine availability remains insufficient, with high numbers of fatal infections mostly in developing countries. Nucleic acid based vaccines have proven convincingly as a new technology for the fast development of vaccines against newly emerging pathogens, diseases where no vaccine exists or for replacing already existing vaccines. We used an optimized non-replicating rabies virus glycoprotein (RABV-G) encoding messenger RNA (mRNA) to induce potent neutralizing antibodies (VN titers) in mice and domestic pigs. Functional antibody titers were followed in mice for up to one year and titers remained stable for the entire observation period in all dose groups. T cell analysis revealed the induction of both, specific CD4+ as well as CD8+ T cells by RABV-G mRNA, with the induced CD4+ T cells being higher than those induced by a licensed vaccine. Notably, RABV-G mRNA vaccinated mice were protected against lethal intracerebral challenge infection. Inhibition of viral replication by vaccination was verified by qRT-PCR. Furthermore, we demonstrate that CD4+ T cells are crucial for the generation of neutralizing antibodies. In domestic pigs we were able to induce VN titers that correlate with protection in adult and newborn pigs. This study demonstrates the feasibility of a non-replicating mRNA rabies vaccine in small and large animals and highlights the promises of mRNA vaccines for the prevention of infectious diseases. PMID:27336830

  1. Ovarian wedge resection restores fertility in estrogen receptor beta knockout (ERbeta-/-) mice.

    PubMed

    Inzunza, José; Morani, Andrea; Cheng, Guojun; Warner, Margaret; Hreinsson, Julius; Gustafsson, Jan-Ake; Hovatta, Outi

    2007-01-09

    Ovulation rarely occurs in mice in which the estrogen receptor beta (ERbeta) gene has been inactivated (ERbeta-/- mice). Here, we investigated whether this subfertility is due to a defect in the ovary itself or to more general endocrine changes in ERbeta-/- mice. We transplanted ERbeta-/- ovaries into WT mice and WT ovaries into ERbeta-/- mice. Upon mating with ERbeta-/- males, fertility increased from 20% in control intact ERbeta-/- group to 40% in the WT recipients with ERbeta-/- ovaries. The transplantation procedure was not efficient, and when WT ovaries were transplanted into WT mice, fertility was only 36%. Surgical ovarian wedge resection, a procedure which induces ovulation in anovulatory women with polycystic ovarian syndrome, resulted in 100% fertility of ERbeta-/- mice. In ERbeta-/- mice, as the follicles enlarged, the thecal layer remained very compact (revealed by H&E and collagen staining), and there was no increase in vascularization (measured as smooth muscle actin). In addition, there was an increase in PDGF receptor alpha (PDGFRalpha) and a decrease in PDGFbeta expression in the granulosa cells, similar to what has been found in follitropin receptor knockout mice. After wedge resection, expression of both smooth muscle actin and PDGFRs was normalized. During normal follicular development, increased vascularization of the thecal layer is a prerequisite for further follicular growth. We suggest that the defect in ERbeta-/- mouse ovaries is a failure of communication between the granulosa and thecal layers. The follicles do not mature because of insufficient blood supply. This problem is overcome by stimulating neovascularization by simple wedge resection of the ovaries.

  2. Ovarian wedge resection restores fertility in estrogen receptor β knockout (ERβ−/−) mice

    PubMed Central

    Inzunza, José; Morani, Andrea; Cheng, Guojun; Warner, Margaret; Hreinsson, Julius; Gustafsson, Jan-Åke; Hovatta, Outi

    2007-01-01

    Ovulation rarely occurs in mice in which the estrogen receptor β (ERβ) gene has been inactivated (ERβ−/− mice). Here, we investigated whether this subfertility is due to a defect in the ovary itself or to more general endocrine changes in ERβ−/− mice. We transplanted ERβ−/− ovaries into WT mice and WT ovaries into ERβ−/− mice. Upon mating with ERβ−/− males, fertility increased from 20% in control intact ERβ−/− group to 40% in the WT recipients with ERβ−/− ovaries. The transplantation procedure was not efficient, and when WT ovaries were transplanted into WT mice, fertility was only 36%. Surgical ovarian wedge resection, a procedure which induces ovulation in anovulatory women with polycystic ovarian syndrome, resulted in 100% fertility of ERβ−/− mice. In ERβ−/− mice, as the follicles enlarged, the thecal layer remained very compact (revealed by H&E and collagen staining), and there was no increase in vascularization (measured as smooth muscle actin). In addition, there was an increase in PDGF receptor α (PDGFRα) and a decrease in PDGFβ expression in the granulosa cells, similar to what has been found in follitropin receptor knockout mice. After wedge resection, expression of both smooth muscle actin and PDGFRs was normalized. During normal follicular development, increased vascularization of the thecal layer is a prerequisite for further follicular growth. We suggest that the defect in ERβ−/− mouse ovaries is a failure of communication between the granulosa and thecal layers. The follicles do not mature because of insufficient blood supply. This problem is overcome by stimulating neovascularization by simple wedge resection of the ovaries. PMID:17197418

  3. Nutritional Intervention Restores Muscle but Not Kidney Phenotypes in Adult Calcineurin Aα Null Mice

    PubMed Central

    Madsen, Kirsten; Reddy, Ramesh N.; Price, S. Russ; Williams, Clintoria R.; Gooch, Jennifer L.

    2013-01-01

    Mice lacking the α isoform of the catalytic subunit of calcineurin (CnAα) were first reported in 1996 and have been an important model to understand the role of calcineurin in the brain, immune system, bones, muscle, and kidney. Research using the mice has been limited, however, by failure to thrive and early lethality of most null pups. Work in our laboratory led to the rescue of CnAα−/− mice by supplemental feeding to compensate for a defect in salivary enzyme secretion. The data revealed that, without intervention, knockout mice suffer from severe caloric restriction. Since nutritional deprivation is known to significantly alter development, it is imperative that previous conclusions based on CnAα−/− mice are revisited to determine which aspects of the phenotype were attributable to caloric restriction versus a direct role for CnAα. In this study, we find that defects in renal development and function persist in adult CnAα−/− mice including a significant decrease in glomerular filtration rate and an increase in blood urea nitrogen levels. These data indicate that impaired renal development we previously reported was not due to caloric restriction but rather a specific role for CnAα in renal development and function. In contrast, we find that rather than being hypoglycemic, rescued mice are mildly hyperglycemic and insulin resistant. Examination of muscle fiber types shows that previously reported reductions in type I muscle fibers are no longer evident in rescued null mice. Rather, loss of CnAα likely alters insulin response due to a reduction in insulin receptor substrate-2 (IRS2) expression and signaling in muscle. This study illustrates the importance of re-examining the phenotypes of CnAα−/− mice and the advances that are now possible with the use of adult, rescued knockout animals. PMID:23638102

  4. Restoration of cocaine stimulation and reward by reintroducing wild type dopamine transporter in adult knock-in mice with a cocaine-insensitive dopamine transporter.

    PubMed

    Wu, Haiyin; O'Neill, Brian; Han, Dawn D; Thirtamara-Rajamani, Keerthi; Wang, Yanlin; Gu, Howard H

    2014-11-01

    In previous studies, we generated knock-in mice with a cocaine-insensitive dopamine transporter (DAT-CI mice) and found cocaine does not stimulate locomotion or produce reward in these mice, indicating DAT inhibition is necessary for cocaine stimulation and reward. However, DAT uptake is reduced in DAT-CI mice and thus the lack of cocaine responses could be due to adaptive changes. To test this, we used adeno-associated virus (AAV) to reintroduce the cocaine-sensitive wild type DAT (AAV-DATwt) back into adult DAT-CI mice, which restores cocaine inhibition of DAT in affected brain regions but does not reverse the adaptive changes. In an earlier study we showed that AAV-DATwt injections in regions covering the lateral nucleus accumbens (NAc) and lateral caudate-putamen (CPu) restored cocaine stimulation but not cocaine reward. In the current study, we expanded the AAV-DATwt infected areas to cover the olfactory tubercle (Tu) and the ventral midbrain (vMB) containing the ventral tegmental area (VTA) and substantia nigra (SN) in addition to CPu and NAc with multiple injections. These mice displayed the restoration of both locomotor stimulation and cocaine reward. We further found that AAV-DATwt injection in the vMB alone was sufficient to restore both cocaine stimulation and reward in DAT-CI mice. AAV injected in the VTA and SN resulted in DATwt expression and distribution to the DA terminal regions. In summary, cocaine induced locomotion and reward can be restored in fully developed DAT-CI mice, and cocaine inhibition of DAT expressed in dopaminergic neurons originated from the ventral midbrain mediates cocaine reward and stimulation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Optogenetic stimulation of dentate gyrus engrams restores memory in Alzheimer's disease mice.

    PubMed

    Perusini, Jennifer N; Cajigas, Stephanie A; Cohensedgh, Omid; Lim, Sean C; Pavlova, Ina P; Donaldson, Zoe R; Denny, Christine A

    2017-10-01

    Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. APPswe/PS1dE9 (APP/PS1) mice have been developed as an AD model and are characterized by plaque formation at 4-6 months of age. Here, we sought to better understand AD-related cognitive decline by characterizing various types of memory. In order to better understand how memory declines with AD, APP/PS1 mice were bred with ArcCreER(T2) mice. In this line, neural ensembles activated during memory encoding can be indelibly tagged and directly compared with neural ensembles activated during memory retrieval (i.e., memory traces/engrams). We first administered a battery of tests examining depressive- and anxiety-like behaviors, as well as spatial, social, and cognitive memory to APP/PS1 × ArcCreER(T2) × channelrhodopsin (ChR2)-enhanced yellow fluorescent protein (EYFP) mice. Dentate gyrus (DG) neural ensembles were then optogenetically stimulated in these mice to improve memory impairment. AD mice had the most extensive differences in fear memory, as assessed by contextual fear conditioning (CFC), which was accompanied by impaired DG memory traces. Optogenetic stimulation of DG neural ensembles representing a CFC memory increased memory retrieval in the appropriate context in AD mice when compared with control (Ctrl) mice. Moreover, optogenetic stimulation facilitated reactivation of the neural ensembles that were previously activated during memory encoding. These data suggest that activating previously learned DG memory traces can rescue cognitive impairments and point to DG manipulation as a potential target to treat memory loss commonly seen in AD. © 2017 Wiley Periodicals, Inc.

  6. Restoration of Retarded Influenza Virus-specific Immunoglobulin Class Switch in Aged Mice

    PubMed Central

    Zhang, Yongxin; Wang, Ying; Zhang, Monica; Liu, Lin; Mbawuike, Innocent N

    2016-01-01

    Objective The declined immune response to infection causes significant higher morbidity and mortality in aging in spite of the coexisted hyperimmunoglobulinemia (HIG). This study is to reveal the cellular basis of HIG and mechanism of weakened HA-specific IgG response in aged mice and to test cell therapy in the treatment of age-related IgG antibody production deficiency with immunocyte adoptive transfer. Methods BALB/c mice was immunized with Influenza A/Taiwan vaccine and challenged with the same strain of virus. ELISA was used to assess the levels of total immunoglobulins and antigen specific antibody response. The flow cytometry and ELISPOT were used to evaluate the frequencies of total immunoglobulin- and specific antibody-producing and secreting B lymphocytes. In vitro expanded mononuclear cells, CD4+ T lymphocytes and CD20+ B lymphocytes from old and young mice were adoptively transferred into influenza virus-challenged aged mice, and HA-specific IgG responses were observed. Results It is found that old mice exhibited higher levels of total serum IgG, IgM and IgA, higher frequencies of IgG+, IgM+ and IgA+ cells, and greater antigen-specific IgM and IgA responses to influenza infection, in comparison to young mice. However, influenza antigen- specific IgG and its subclass responses in old mice were significantly lower. Conclusion The retarded specific IgG response could be attributed to an insufficiency of immunoglobulin class switch in aging. Correlation analysis indicated that HIG and deficient specific IgG production in aged mice could be independent to each other in their pathogenesis. Correction of deficient specific IgG production by adoptive transfer of in vitro expanded and unexpanded CD4+ cells from immunized young mice suggests the CD4+ cell dysfunction contributes to the insufficiency of immunoglobulin class switch in aged mice. The transfusion of in vitro expanded lymphocytes could be a potential effective therapy for the age

  7. Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice

    PubMed Central

    Takiishi, Tatiana; Korf, Hannelie; Van Belle, Tom L.; Robert, Sofie; Grieco, Fabio A.; Caluwaerts, Silvia; Galleri, Letizia; Spagnuolo, Isabella; Steidler, Lothar; Van Huynegem, Karolien; Demetter, Pieter; Wasserfall, Clive; Atkinson, Mark A.; Dotta, Francesco; Rottiers, Pieter; Gysemans, Conny; Mathieu, Chantal

    2012-01-01

    Current interventions for arresting autoimmune diabetes have yet to strike the balance between sufficient efficacy, minimal side effects, and lack of generalized immunosuppression. Introduction of antigen via the gut represents an appealing method for induction of antigen-specific tolerance. Here, we developed a strategy for tolerance restoration using mucosal delivery in mice of biologically contained Lactococcus lactis genetically modified to secrete the whole proinsulin autoantigen along with the immunomodulatory cytokine IL-10. We show that combination therapy with low-dose systemic anti-CD3 stably reverted diabetes in NOD mice and increased frequencies of local Tregs, which not only accumulated in the pancreatic islets, but also suppressed immune response in an autoantigen-specific way. Cured mice remained responsive to disease-unrelated antigens, which argues against excessive immunosuppression. Application of this therapeutic tool achieved gut mucosal delivery of a diabetes-relevant autoantigen and a biologically active immunomodulatory cytokine, IL-10, and, when combined with a low dose of systemic anti-CD3, was well tolerated and induced autoantigen-specific long-term tolerance, allowing reversal of established autoimmune diabetes. Therefore, we believe this method could be an effective treatment strategy for type 1 diabetes in humans. PMID:22484814

  8. Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice.

    PubMed

    Takiishi, Tatiana; Korf, Hannelie; Van Belle, Tom L; Robert, Sofie; Grieco, Fabio A; Caluwaerts, Silvia; Galleri, Letizia; Spagnuolo, Isabella; Steidler, Lothar; Van Huynegem, Karolien; Demetter, Pieter; Wasserfall, Clive; Atkinson, Mark A; Dotta, Francesco; Rottiers, Pieter; Gysemans, Conny; Mathieu, Chantal

    2012-05-01

    Current interventions for arresting autoimmune diabetes have yet to strike the balance between sufficient efficacy, minimal side effects, and lack of generalized immunosuppression. Introduction of antigen via the gut represents an appealing method for induction of antigen-specific tolerance. Here, we developed a strategy for tolerance restoration using mucosal delivery in mice of biologically contained Lactococcus lactis genetically modified to secrete the whole proinsulin autoantigen along with the immunomodulatory cytokine IL-10. We show that combination therapy with low-dose systemic anti-CD3 stably reverted diabetes in NOD mice and increased frequencies of local Tregs, which not only accumulated in the pancreatic islets, but also suppressed immune response in an autoantigen-specific way. Cured mice remained responsive to disease-unrelated antigens, which argues against excessive immunosuppression. Application of this therapeutic tool achieved gut mucosal delivery of a diabetes-relevant autoantigen and a biologically active immunomodulatory cytokine, IL-10, and, when combined with a low dose of systemic anti-CD3, was well tolerated and induced autoantigen-specific long-term tolerance, allowing reversal of established autoimmune diabetes. Therefore, we believe this method could be an effective treatment strategy for type 1 diabetes in humans.

  9. Aquaporin deletion in mice reduces corneal water permeability and delays restoration of transparency after swelling.

    PubMed

    Thiagarajah, Jay R; Verkman, A S

    2002-05-24

    Two aquaporin (AQP)-type water channels are expressed in mammalian cornea, AQP1 in endothelial cells and AQP5 in epithelial cells. To test whether these aquaporins are involved in corneal fluid transport and transparency, we compared corneal thickness, water permeability, and response to experimental swelling in wild type mice and transgenic null mice lacking AQP1 and AQP5. Corneal thickness in fixed sections was remarkably reduced in AQP1 null mice and increased in AQP5 null mice. By z-scanning confocal microscopy, corneal thickness in vivo was (in microm, mean +/- S.E., n = 5 mice) 123 +/- 1 (wild type), 101 +/- 2 (AQP1 null), and 144 +/- 2 (AQP5 null). After exposure of the external corneal surface to hypotonic saline (100 mosm), the rate of corneal swelling (5.0 +/- 0.3 microm/min, wild type) was reduced by AQP5 deletion (2.7 +/- 0.1 microm/min). After exposure of the endothelial surface to hypotonic saline by anterior chamber perfusion, the rate of corneal swelling (7.1 +/- 1.0 microm/min, wild type) was reduced by AQP1 deletion (1.6 +/- 0.4 microm/min). Base-line corneal transparency was not impaired by AQP1 or AQP5 deletion. However, the recovery of corneal transparency and thickness after hypotonic swelling (10-min exposure of corneal surface to hypotonic saline) was remarkably delayed in AQP1 null mice with approximately 75% recovery at 7 min in wild type mice compared with 5% recovery in AQP1 null mice. Our data indicate that AQP1 and AQP5 provide the principal routes for corneal water transport across the endothelial and epithelial barriers, respectively. The impaired recovery of corneal transparency in AQP1 null mice provides evidence for the involvement of AQP1 in active extrusion of fluid from the corneal stroma across the corneal endothelium. The up-regulation of AQP1 expression and/or function in corneal endothelium may reduce corneal swelling and opacification following injury.

  10. Pyridostigmine restores cardiac autonomic balance after small myocardial infarction in mice.

    PubMed

    Durand, Marina T; Becari, Christiane; de Oliveira, Mauro; do Carmo, Jussara M; Silva, Carlos Alberto Aguiar; Prado, Cibele M; Fazan, Rubens; Salgado, Helio C

    2014-01-01

    The effect of pyridostigmine (PYR)--an acetylcholinesterase inhibitor--on hemodynamics and cardiac autonomic control, was never studied in conscious myocardial infarcted mice. Telemetry transmitters were implanted into the carotid artery under isoflurane anesthesia. Seven to ten days after recovery from the surgery, basal arterial pressure and heart rate were recorded, while parasympathetic and sympathetic tone (ΔHR) was evaluated by means of methyl atropine and propranolol. After the basal hemodynamic recording the mice were subjected to left coronary artery ligation for producing myocardial infarction (MI), or sham operation, and implantation of minipumps filled with PYR or saline. Separate groups of anesthetized (isoflurane) mice previously (4 weeks) subjected to MI, or sham coronary artery ligation, were submitted to cardiac function examination. The mice exhibited an infarct length of approximately 12%, no change in arterial pressure and increased heart rate only in the 1st week after MI. Vagal tone decreased in the 1st week, while the sympathetic tone was increased in the 1st and 4th week after MI. PYR prevented the increase in heart rate but did not affect the arterial pressure. Moreover, PYR prevented the increase in sympathetic tone throughout the 4 weeks. Concerning the parasympathetic tone, PYR not only impaired its attenuation in the 1st week, but enhanced it in the 4th week. MI decreased ejection fraction and increased diastolic and systolic volume. Therefore, the pharmacological increase of peripheral acetylcholine availability by means of PYR prevented tachycardia, increased parasympathetic and decreased sympathetic tone after MI in mice.

  11. Pyridostigmine Restores Cardiac Autonomic Balance after Small Myocardial Infarction in Mice

    PubMed Central

    Durand, Marina T.; Becari, Christiane; de Oliveira, Mauro; do Carmo, Jussara M.; Aguiar Silva, Carlos Alberto; Prado, Cibele M.; Fazan, Rubens; Salgado, Helio C.

    2014-01-01

    The effect of pyridostigmine (PYR) - an acetylcholinesterase inhibitor - on hemodynamics and cardiac autonomic control, was never studied in conscious myocardial infarcted mice. Telemetry transmitters were implanted into the carotid artery under isoflurane anesthesia. Seven to ten days after recovery from the surgery, basal arterial pressure and heart rate were recorded, while parasympathetic and sympathetic tone (ΔHR) was evaluated by means of methyl atropine and propranolol. After the basal hemodynamic recording the mice were subjected to left coronary artery ligation for producing myocardial infarction (MI), or sham operation, and implantation of minipumps filled with PYR or saline. Separate groups of anesthetized (isoflurane) mice previously (4 weeks) subjected to MI, or sham coronary artery ligation, were submitted to cardiac function examination. The mice exhibited an infarct length of approximately 12%, no change in arterial pressure and increased heart rate only in the 1st week after MI. Vagal tone decreased in the 1st week, while the sympathetic tone was increased in the 1st and 4th week after MI. PYR prevented the increase in heart rate but did not affect the arterial pressure. Moreover, PYR prevented the increase in sympathetic tone throughout the 4 weeks. Concerning the parasympathetic tone, PYR not only impaired its attenuation in the 1st week, but enhanced it in the 4th week. MI decreased ejection fraction and increased diastolic and systolic volume. Therefore, the pharmacological increase of peripheral acetylcholine availability by means of PYR prevented tachycardia, increased parasympathetic and decreased sympathetic tone after MI in mice. PMID:25133392

  12. Ectopic Expression of a Microbial-Type Rhodopsin Restores Visual Responses in Mice with Photoreceptor Degeneration

    PubMed Central

    Bi, Anding; Cui, Jinjuan; Ma, Yu-Ping; Olshevskaya, Elena; Pu, Mingliang; Dizhoor, Alexander M.; Pan, Zhuo-Hua

    2006-01-01

    Summary The death of photoreceptor cells caused by retinal degenerative diseases often results in a complete loss of retinal responses to light. We explore the feasibility of converting inner retinal neurons to photosensitive cells as a possible strategy for imparting light sensitivity to retinas lacking rods and cones. Using delivery by an adeno-associated viral vector, here, we show that long-term expression of a microbial-type rhodopsin, channelrhodopsin-2 (ChR2), can be achieved in rodent inner retinal neurons in vivo. Furthermore, we demonstrate that expression of ChR2 in surviving inner retinal neurons of a mouse with photoreceptor degeneration can restore the ability of the retina to encode light signals and transmit the light signals to the visual cortex. Thus, expression of microbial-type channelrhodopsins, such as ChR2, in surviving inner retinal neurons is a potential strategy for the restoration of vision after rod and cone degeneration. PMID:16600853

  13. Bone marrow transplantation helps restore the intestinal mucosal barrier after total body irradiation in mice.

    PubMed

    Garg, Sarita; Wang, Wenze; Prabath, Biju G; Boerma, Marjan; Wang, Junru; Zhou, Daohong; Hauer-Jensen, Martin

    2014-03-01

    Bone marrow transplantation (BMT) substantially improves 10-day survival after total body irradiation (TBI), consistent with an effect on intestinal radiation death. Total body irradiation, in addition to injuring the intestinal epithelium, also perturbs the mucosal immune system, the largest immune system in the body. This study focused on how transplanted bone marrow cells (BMCs) help restore mucosal immune cell populations after sublethal TBI (8.0 Gy). We further evaluated whether transplanted BMCs: (a) home to sites of radiation injury using green fluorescent protein labeled bone marrow; and (b) contribute to restoring the mucosal barrier in vivo. As expected, BMT accelerated recovery of peripheral blood (PB) cells. In the intestine, BMT was associated with significant early recovery of mucosal granulocytes (P = 0.005). Bone marrow transplantation did not affect mucosal macrophages or lymphocyte populations at early time points, but enhanced the recovery of these cells from day 14 onward (P = 0.03). Bone marrow transplantation also attenuated radiation-induced increase of intestinal CXCL1 and restored IL-10 levels (P = 0.001). Most importantly, BMT inhibited the post-radiation increase in intestinal permeability after 10 Gy TBI (P = 0.02) and modulated the expression of tight junction proteins (P = 0.01-0.05). Green fluorescent protein-positive leukocytes were observed both in intestinal tissue and in PB. These findings strongly suggest that BMT, in addition to enhancing general hematopoietic and immune system recovery, helps restore the intestinal immune system and enhances intestinal mucosal barrier function. These findings may be important in the development and understanding of strategies to alleviate or treat intestinal radiation toxicity.

  14. Post-Training Reward Partially Restores Chronic Stress Induced Effects in Mice

    PubMed Central

    Dalm, Sergiu; de Kloet, E. Ron; Oitzl, Melly S.

    2012-01-01

    Reduced responsiveness to positive stimuli is a core symptom of depression, known as anhedonia. In the present study, we assessed the expression of anhedonia in our chronic stress mouse model using a subset of read-out parameters. In line with this, we investigated in how far chronic stress would affect the facilitating effect of post-training self-administration of sugar, as we previously observed in naïve mice. Male C57BL/6J mice were repeatedly and at unpredictable times exposed to rats (no physical contact) over the course of two weeks. Following novelty exploration, (non-) spatial learning and memory processes with and without post-training sugar acting as reinforcer, emotionality, reward sensitivity and corticosterone levels were determined. We found that (1) the effects of chronic stress persisted beyond the period of the actual rat exposure. (2) Post-training self-administration of sugar as reinforcer improved spatial performance in naïve mice, whereas (3) in stressed mice sugar partially “normalized” the impaired performance to the level of controls without sugar. Chronic stress (4) increased behavioral inhibition in response to novelty; (5) induced dynamic changes in the pattern of circadian corticosterone secretion during the first week after rat stress and (6) increased the intake of sucrose and water. (7) Chronic stress and sugar consumed during spatial training facilitated the memory for the location of the sucrose bottle weeks later. Concluding, our chronic stress paradigm induces the expression of anhedonia in mice, at different levels of behavior. The behavioral inhibition appears to be long lasting in stressed mice. Interestingly, sugar consumed in close context with spatial learning partially rescued the stress-induced emotional and cognitive impairments. This suggests that reward can ameliorate part of the negative consequences of chronic stress on memory. PMID:22745700

  15. Post-training reward partially restores chronic stress induced effects in mice.

    PubMed

    Dalm, Sergiu; de Kloet, E Ron; Oitzl, Melly S

    2012-01-01

    Reduced responsiveness to positive stimuli is a core symptom of depression, known as anhedonia. In the present study, we assessed the expression of anhedonia in our chronic stress mouse model using a subset of read-out parameters. In line with this, we investigated in how far chronic stress would affect the facilitating effect of post-training self-administration of sugar, as we previously observed in naïve mice. Male C57BL/6J mice were repeatedly and at unpredictable times exposed to rats (no physical contact) over the course of two weeks. Following novelty exploration, (non-) spatial learning and memory processes with and without post-training sugar acting as reinforcer, emotionality, reward sensitivity and corticosterone levels were determined. We found that (1) the effects of chronic stress persisted beyond the period of the actual rat exposure. (2) Post-training self-administration of sugar as reinforcer improved spatial performance in naïve mice, whereas (3) in stressed mice sugar partially "normalized" the impaired performance to the level of controls without sugar. Chronic stress (4) increased behavioral inhibition in response to novelty; (5) induced dynamic changes in the pattern of circadian corticosterone secretion during the first week after rat stress and (6) increased the intake of sucrose and water. (7) Chronic stress and sugar consumed during spatial training facilitated the memory for the location of the sucrose bottle weeks later. Concluding, our chronic stress paradigm induces the expression of anhedonia in mice, at different levels of behavior. The behavioral inhibition appears to be long lasting in stressed mice. Interestingly, sugar consumed in close context with spatial learning partially rescued the stress-induced emotional and cognitive impairments. This suggests that reward can ameliorate part of the negative consequences of chronic stress on memory.

  16. Survival of Cajal-Retzius cells after cortical lesions in newborn mice: a possible role for Cajal-Retzius cells in brain repair.

    PubMed

    Supèr, H; Pérez Sust, P; Soriano, E

    1997-01-02

    Transient Cajal-Retzius (CR) cells in layer I of the mammalian cerebral cortex are the first postmitotic neurons and they are believed to play a role in neuronal migration and lamination during cortical development. Freezing insults to the cortex of newborn mice produce cortical malformations similar to those observed in human brain disorders. Here we have used calretinin immunostaining to investigate the response of CR cells to freezing lesions of the cortical surface. Shortly after injury, CR cells disappeared from the lesioned zone. Moreover, CR cells located near the lesioned area adopted extremely fusiform shapes. At later postnatal stages (P12), CR cells were still abundant in layer I of the lesioned zone, in contrast to their almost complete loss in control animals. These results show that CR cells survive for longer developmental periods following cortical injury. Furthermore, the initial loss and later re-appearance of CR cells suggest that these neurons might migrate tangentially from the cortical areas surrounding the lesioned zone. These findings imply a role for CR cells in brain repair after cortical injury during development.

  17. Attenuated methamphetamine-induced locomotor sensitization in serotonin transporter knockout mice is restored by serotonin 1B receptor antagonist treatment.

    PubMed

    Igari, Moe; Shen, Hao-Wei; Hagino, Yoko; Fukushima, Setsu; Kasahara, Yoshiyuki; Lesch, Klaus-Peter; Murphy, Dennis L; Hall, Frank Scott; Uhl, George R; Ikeda, Kazutaka; Yaegashi, Nobuo; Sora, Ichiro

    2015-02-01

    Repeated administration of methamphetamine (METH) enhances acute locomotor responses to METH administered in the same context, a phenomenon termed as 'locomotor sensitization'. Although many of the acute effects of METH are mediated by its influences on the compartmentalization of dopamine, serotonin systems have also been suggested to influence the behavioral effects of METH in ways that are not fully understood. The present experiments examined serotonergic roles in METH-induced locomotor sensitization by assessing: (a) the effect of serotonin transporter (SERT; Slc6A4) knockout (KO) on METH-induced locomotor sensitization; (b) extracellular monoamine levels in METH-treated animals as determined by in-vivo microdialysis; and (c) effects of serotonin (5-HT) receptor antagonists on METH-induced behavioral sensitization, with focus on effects of the 5-HT1B receptor antagonist SB 216641 and a comparison with the 5-HT2 receptor antagonist ketanserin. Repeated METH administration failed to induce behavioral sensitization in homozygous SERT KO (SERT-/-) mice under conditions that produced substantial sensitization in wild-type or heterozygous SERT KO (SERT+/-) mice. The selective 5-HT1B antagonist receptor SB 216641 restored METH-induced locomotor sensitization in SERT-/- mice, whereas ketanserin was ineffective. METH-induced increases in extracellular 5-HT (5-HTex) levels were substantially reduced in SERT-/- mice, although SERT genotype had no effect on METH-induced increases in extracellular dopamine. These experiments demonstrate that 5-HT actions, including those at 5-HT1B receptors, contribute to METH-induced locomotor sensitization. Modulation of 5-HT1B receptors might aid therapeutic approaches to the sequelae of chronic METH use.

  18. Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

    PubMed Central

    Di Pardo, Alba; Maglione, Vittorio; Alpaugh, Melanie; Horkey, Melanie; Atwal, Randy S.; Sassone, Jenny; Ciammola, Andrea; Steffan, Joan S.; Fouad, Karim; Truant, Ray; Sipione, Simonetta

    2012-01-01

    Huntington disease (HD) is a progressive neurodegenerative monogenic disorder caused by expansion of a polyglutamine stretch in the huntingtin (Htt) protein. Mutant huntingtin triggers neural dysfunction and death, mainly in the corpus striatum and cerebral cortex, resulting in pathognomonic motor symptoms, as well as cognitive and psychiatric decline. Currently, there is no effective treatment for HD. We report that intraventricular infusion of ganglioside GM1 induces phosphorylation of mutant huntingtin at specific serine amino acid residues that attenuate huntingtin toxicity, and restores normal motor function in already symptomatic HD mice. Thus, our studies have identified a potential therapy for HD that targets a posttranslational modification of mutant huntingtin with critical effects on disease pathogenesis. PMID:22331905

  19. Treatment with Salvianolic Acid B restores endothelial function in angiotensin II-induced hypertensive mice.

    PubMed

    Ling, Wei Chih; Liu, Jian; Lau, Chi Wai; Murugan, Dharmani Devi; Mustafa, Mohd Rais; Huang, Yu

    2017-04-07

    Salvianolic acid B (Sal B) is one of the most abundant phenolic acids derived from the root of Danshen with potent anti-oxidative properties. The present study examined the vasoprotective effect of Sal B in hypertensive mice induced by angiotensin II (Ang II). Sal B (25 mg/kg/day) was administered via oral gavage for 11 days to Ang II (1.2 mg/kg/day)-infused C57BL/6J mice (8-10 weeks old). The vascular reactivity (both endothelium-dependent relaxations and contractions) in mouse arteries was examined by wire myography. The production of reactive oxygen species (ROS), protein level and localization of angiotensin AT1 receptors and the proteins involved in ROS formation were evaluated using dihydroethidium (DHE) fluorescence, lucigenin-enhanced chemiluminescence, immunohistochemistry and Western blotting, respectively. The changes of ROS generating proteins were also assessed in vitro in human umbilical vein endothelial cells (HUVECs) exposed to Ang II with and without co-treatment with Sal B (0.1 - 10 nM). Oral administration of Sal B reversed the Ang II-induced elevation of arterial systolic blood pressure in mice, augmented the impaired endothelium-dependent relaxations and attenuated the exaggerated endothelium-dependent contractions in both aortas and renal arteries of Ang II-infused mice. In addition, Sal B treatment normalized the elevated levels of AT1 receptors, NADPH oxidase subunits (NOx-2 and NOx-4) and nitrotyrosine in arteries of Ang II-infused mice or in Ang II-treated HUVECs. In summary, the present study provided additional evidence demonstrating that Sal B treatment for 11 days reverses the impaired endothelial function and with a marked inhibition of AT1 receptor-dependent vascular oxidative stress. This vasoprotective and anti-oxidative action of Sal B most likely contributes to the anti-hypertensive action of the plant-derived compound.

  20. Melatonin reduces obesity and restores adipokine patterns and metabolism in obese (ob/ob) mice.

    PubMed

    Favero, Gaia; Stacchiotti, Alessandra; Castrezzati, Stefania; Bonomini, Francesca; Albanese, Massimo; Rezzani, Rita; Rodella, Luigi Fabrizio

    2015-10-01

    The increasing incidence of obesity, leading to metabolic complications, is now recognized as a major public health problem. The adipocytes are not merely energy-storing cells, but they play crucial roles in the development of the so-called metabolic syndrome due to the adipocyte-derived bioactive factors such as adipokines, cytokines, and growth factors. The dysregulated production and secretion of adipokines seen in obesity is linked to the pathogenesis of the metabolic disease processes. In this study, we hypothesized that dietary melatonin administration would support an anti-inflammatory response and play an important role in energy metabolism in subcutaneous and visceral adipose tissues of obese mice and so may counteract some of the disruptive effects of obesity. Lean and obese mice (ob/ob) received melatonin or vehicle in drinking water for 8 weeks. Thereafter, they were evaluated for morphologic alteration, inflammatory cell infiltration, and the adipokine patterns in visceral and subcutaneous white fat depots. In obese mice treated with vehicle, we observed a significant increase in fat depots, inflammation, and a dysregulation of the adipokine network. In particular, we measured a significant reduction of adiponectin and an increase of tumor necrosis factor α, resistin, and visfatin in adipose tissue deposits. These changes were partially reversed when melatonin was supplemented to obese mice. Melatonin supplementation by regulating inflammatory infiltration ameliorates obesity-induced adipokine alteration, whereas melatonin administration in lean mice was unaffected. Thus, it is likely that melatonin would be provided in supplement form to control some of the disruptive effects on the basis of obesity pathogenic process.

  1. Vertical sleeve gastrectomy restores glucose homeostasis in apolipoprotein A-IV KO mice.

    PubMed

    Pressler, Josh W; Haller, April; Sorrell, Joyce; Wang, Fei; Seeley, Randy J; Tso, Patrick; Sandoval, Darleen A

    2015-02-01

    Bariatric surgery is the most successful strategy for treating obesity, yet the mechanisms for this success are not clearly understood. Clinical literature suggests that plasma levels of apolipoprotein A-IV (apoA-IV) rise with Roux-en-Y gastric bypass (RYGB). apoA-IV is secreted from the intestine postprandially and has demonstrated benefits for both glucose and lipid homeostasis. Because of the parallels in the metabolic improvements seen with surgery and the rise in apoA-IV levels, we hypothesized that apoA-IV was necessary for obtaining the metabolic benefits of bariatric surgery. To test this hypothesis, we performed vertical sleeve gastrectomy (VSG), a surgery with clinical efficacy very similar to that for RYGB, in whole-body apoA-IV knockout (KO) mice. We found that VSG reduced body mass and improved both glucose and lipid homeostasis similarly in wild-type mice compared with apoA-IV KO mice. In fact, VSG normalized the impairment in glucose tolerance and caused a significantly greater improvement in hepatic triglyceride storage in the apoA-IV KO mice. Last, independent of surgery, apoA-IV KO mice had a significantly reduced preference for a high-fat diet. Altogether, these data suggest that apoA-IV is not necessary for the metabolic improvements shown with VSG, but also suggest an interesting role for apoA-IV in regulating macronutrient preference and hepatic triglyceride levels. Future studies are necessary to determine whether this is the case for RYGB as well.

  2. Bifidobacterium animalis ssp. lactis CNCM-I2494 Restores Gut Barrier Permeability in Chronically Low-Grade Inflamed Mice.

    PubMed

    Martín, Rebeca; Laval, Laure; Chain, Florian; Miquel, Sylvie; Natividad, Jane; Cherbuy, Claire; Sokol, Harry; Verdu, Elena F; van Hylckama Vlieg, Johan; Bermudez-Humaran, Luis G; Smokvina, Tamara; Langella, Philippe

    2016-01-01

    Growing evidence supports the efficacy of many probiotic strains in the management of gastrointestinal disorders associated with deregulated intestinal barrier function and/or structure. In particular, bifidobacteria have been studied for their efficacy to both prevent and treat a broad spectrum of animal and/or human gut disorders. The aim of the current work was thus to evaluate effects on intestinal barrier function of Bifidobacterium animalis ssp. lactis CNCM-I2494, a strain used in fermented dairy products. A chronic dinitrobenzene sulfonic acid (DNBS)-induced low-grade inflammation model causing gut dysfunction in mice was used in order to study markers of inflammation, intestinal permeability, and immune function in the presence of the bacterial strain. In this chronic low-grade inflammation mice model several parameters pointed out the absence of an over active inflammation process. However, gut permeability, lymphocyte populations, and colonic cytokines were found to be altered. B. animalis ssp. lactis CNCM-I2494 was able to protect barrier functions by restoring intestinal permeability, colonic goblet cell populations, and cytokine levels. Furthermore, tight junction (TJ) proteins levels were also measured by qRT-PCR showing the ability of this strain to specifically normalize the level of several TJ proteins, in particular for claudin-4. Finally, B. lactis strain counterbalanced CD4(+) lymphocyte alterations in both spleen and mesenteric lymphoid nodes. It restores the Th1/Th2 ratio altered by the DNBS challenge (which locally augments CD4(+) Th1 cells) by increasing the Th2 response as measured by the increase in the production of major representative Th2 cytokines (IL-4, IL-5, and IL-10). Altogether, these data suggest that B. animalis ssp. lactis CNCM-I2494 may efficiently prevent disorders associated with increased barrier permeability.

  3. Bifidobacterium animalis ssp. lactis CNCM-I2494 Restores Gut Barrier Permeability in Chronically Low-Grade Inflamed Mice

    PubMed Central

    Martín, Rebeca; Laval, Laure; Chain, Florian; Miquel, Sylvie; Natividad, Jane; Cherbuy, Claire; Sokol, Harry; Verdu, Elena F.; van Hylckama Vlieg, Johan; Bermudez-Humaran, Luis G.; Smokvina, Tamara; Langella, Philippe

    2016-01-01

    Growing evidence supports the efficacy of many probiotic strains in the management of gastrointestinal disorders associated with deregulated intestinal barrier function and/or structure. In particular, bifidobacteria have been studied for their efficacy to both prevent and treat a broad spectrum of animal and/or human gut disorders. The aim of the current work was thus to evaluate effects on intestinal barrier function of Bifidobacterium animalis ssp. lactis CNCM-I2494, a strain used in fermented dairy products. A chronic dinitrobenzene sulfonic acid (DNBS)-induced low-grade inflammation model causing gut dysfunction in mice was used in order to study markers of inflammation, intestinal permeability, and immune function in the presence of the bacterial strain. In this chronic low-grade inflammation mice model several parameters pointed out the absence of an over active inflammation process. However, gut permeability, lymphocyte populations, and colonic cytokines were found to be altered. B. animalis ssp. lactis CNCM-I2494 was able to protect barrier functions by restoring intestinal permeability, colonic goblet cell populations, and cytokine levels. Furthermore, tight junction (TJ) proteins levels were also measured by qRT-PCR showing the ability of this strain to specifically normalize the level of several TJ proteins, in particular for claudin-4. Finally, B. lactis strain counterbalanced CD4+ lymphocyte alterations in both spleen and mesenteric lymphoid nodes. It restores the Th1/Th2 ratio altered by the DNBS challenge (which locally augments CD4+ Th1 cells) by increasing the Th2 response as measured by the increase in the production of major representative Th2 cytokines (IL-4, IL-5, and IL-10). Altogether, these data suggest that B. animalis ssp. lactis CNCM-I2494 may efficiently prevent disorders associated with increased barrier permeability. PMID:27199937

  4. Restoring auditory cortex plasticity in adult mice by restricting thalamic adenosine signaling

    DOE PAGES

    Blundon, Jay A.; Roy, Noah C.; Teubner, Brett J. W.; ...

    2017-06-30

    Circuits in the auditory cortex are highly susceptible to acoustic influences during an early postnatal critical period. The auditory cortex selectively expands neural representations of enriched acoustic stimuli, a process important for human language acquisition. Adults lack this plasticity. We show in the murine auditory cortex that juvenile plasticity can be reestablished in adulthood if acoustic stimuli are paired with disruption of ecto-5'-nucleotidase–dependent adenosine production or A1–adenosine receptor signaling in the auditory thalamus. This plasticity occurs at the level of cortical maps and individual neurons in the auditory cortex of awake adult mice and is associated with long-term improvement ofmore » tone-discrimination abilities. We determined that, in adult mice, disrupting adenosine signaling in the thalamus rejuvenates plasticity in the auditory cortex and improves auditory perception.« less

  5. TLR7/TLR8 Activation Restores Defective Cytokine Secretion by Myeloid Dendritic Cells but Not by Plasmacytoid Dendritic Cells in HIV-Infected Pregnant Women and Newborns

    PubMed Central

    Cardoso, Elaine Cristina; Pereira, Nátalli Zanete; Mitsunari, Gabrielle Eimi; Oliveira, Luanda Mara da Silva; Ruocco, Rosa Maria S. A.; Francisco, Rossana Pulcineli Vieira; Zugaib, Marcelo; da Silva Duarte, Alberto José; Sato, Maria Notomi

    2013-01-01

    Mother-to-child transmission (MTCT) of HIV-1 has been significantly reduced with the use of antiretroviral therapies, resulting in an increased number of HIV-exposed uninfected infants. The consequences of HIV infection on the innate immune system of both mother-newborn are not well understood. In this study, we analyzed peripheral blood and umbilical cord blood (CB) collected from HIV-1-infected and uninfected pregnant women. We measured TNF-α, IL-10 and IFN-α secretion after the stimulation of the cells with agonists of both extracellular Toll-like receptors (TLRs) (TLR2, TLR4 and TLR5) and intracellular TLRs (TLR7, TLR7/8 and TLR9). Moreover, as an indicator of the innate immune response, we evaluated the responsiveness of myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) to TLRs that are associated with the antiviral response. Our results showed that peripheral blood mononuclear cells (PBMCs) from HIV-1-infected mothers and CB were defective in TNF-α production after activation by TLR2, TLR5, TLR3 and TLR7. However, the TNF-α response was preserved after TLR7/8 (CL097) stimulation, mainly in the neonatal cells. Furthermore, only CL097 activation was able to induce IL-10 and IFN-α secretion in both maternal and CB cells in the infected group. An increase in IFN-α secretion was observed in CL097-treated CB from HIV-infected mothers compared with control mothers. The effectiveness of CL097 stimulation was confirmed by observation of similar mRNA levels of interferon regulatory factor-7 (IRF-7), IFN-α and TNF-α in PBMCs of both groups. The function of both mDCs and pDCs was markedly compromised in the HIV-infected group, and although TLR7/TLR8 activation overcame the impairment in TNF-α secretion by mDCs, such stimulation was unable to reverse the dysfunctional type I IFN response by pDCs in the HIV-infected samples. Our findings highlight the dysfunction of innate immunity in HIV-infected mother-newborn pairs. The activation of the TLR7/8 pathway

  6. Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice.

    PubMed

    Seleme, Maria C; Kosmac, Kate; Jonjic, Stipan; Britt, William J

    2017-04-15

    Congenital human cytomegalovirus (HCMV) infection is a significant cause of abnormal neurodevelopment and long-term neurological sequelae in infants and children. Resident cell populations of the developing brain have been suggested to be more susceptible to virus-induced cytopathology, a pathway thought to contribute to the clinical outcomes following intrauterine HCMV infection. However, recent findings in a newborn mouse model of the infection in the developing brain have indicated that elevated levels of proinflammatory mediators leading to mononuclear cell activation and recruitment could underlie the abnormal neurodevelopment. In this study, we demonstrate that treatment with tumor necrosis factor alpha (TNF-α)-neutralizing antibodies decreased the frequency of CD45(+) Ly6C(hi) CD11b(+) CCR2(+) activated myeloid mononuclear cells (MMCs) and the levels of proinflammatory cytokines in the blood and the brains of murine CMV-infected mice. This treatment also normalized neurodevelopment in infected mice without significantly impacting the level of virus replication. These results indicate that TNF-α is a major component of the inflammatory response associated with altered neurodevelopment that follows murine CMV infection of the developing brain and that a subset of peripheral blood myeloid mononuclear cells represent a key effector cell population in this model of virus-induced inflammatory disease of the developing brain.IMPORTANCE Congenital human cytomegalovirus (HCMV) infection is the most common viral infection of the developing human fetus and can result in neurodevelopmental sequelae. Mechanisms of disease leading to neurodevelopmental deficits in infected infants remain undefined, but postulated pathways include loss of neuronal progenitor cells, damage to the developing vascular system of the brain, and altered cellular positioning. Direct virus-mediated cytopathic effects cannot explain the phenotypes of brain damage in most infected infants. Using a

  7. Bryostatin-1 restores hippocampal synapses and spatial learning and memory in adult fragile x mice.

    PubMed

    Sun, Miao-Kun; Hongpaisan, Jarin; Lim, Chol Seung; Alkon, Daniel L

    2014-06-01

    Fragile X syndrome (FXS) is caused by transcriptional silencing in neurons of the FMR1 gene product, fragile X mental retardation protein (FMRP), a repressor of dendritic mRNA translation. The lack of FMRP leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, a disorder that currently has no effective therapeutics. Fragile X mice were treated with chronic bryostatin-1, a relatively selective protein kinase ε activator with pharmacological profiles of rapid mGluR desensitization, synaptogenesis, and synaptic maturation/repairing. Differences in the major FXS phenotypes, synapses, and cognitive functions were evaluated and compared among the age-matched groups. Long-term treatment with bryostatin-1 rescues adult fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in hippocampal brain-derived neurotrophic factor expression and secretion, postsynaptic density-95 levels, glycogen synthase kinase-3β phosphorylation, transformation of immature dendritic spines to mature synapses, densities of the presynaptic and postsynaptic membranes, and spatial learning and memory. Our results show that synaptic and cognitive function of adult FXS mice can be normalized through pharmacologic treatment and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation even after postpartum brain development has largely completed.

  8. Characterization of Minaçu virus (Reoviridae: Orbivirus) and pathological changes in experimentally infected newborn mice

    PubMed Central

    Martins, Lívia C; Diniz, José A P; Silva, Eliana V P; Barros, Vera L R S; Monteiro, Hamilton A O; Azevedo, Raimunda S S; Quaresma, Juarez A S; Vasconcelos, Pedro F C

    2007-01-01

    Minaçu virus was isolated from Ochlerotatus scapularis (Diptera: Culicidae) in Minaçu, Goiás State, Brazil, in 1996. In attempting characterization of virus serological (hemagluttination inhibition, HI; indirect immunofluorescence assay, IFA), physicochemical [test for deoxycholate acid (DCA) sensitivity; polyacrylamide gel electrophoresis (PAGE)] tests and ultrastructural studies were made. Virus was also assayed in suckling mice after intracerebral inoculation of 0.02 ml and in VERO and C6/36 cells with 0.1 ml of viral suspension containing 105 LD50/ml. Inoculated and control systems were observed daily. Every 24 h, one control and two inoculated animals were killed for tissue testing, including histopathological changes by haematoxylin and eosin (HE)-stained sections, which were semi-quantified. Research into viral antigen in the tissues of mice [central nervous system (CNS), liver, heart, lungs, spleen and kidneys] was carried out by the immunohistochemical technique using the peroxidase system. The virus only replicated in VERO cells, with antigen positive by IFA. Positive complement fixation tests were only obtained using antiserum of Minaçu virus. Minaçu virus is DCA resistant; haemagglutinating activity was negative. By electronic microscopy non-enveloped virus particles were 75 nm in diameter. PAGE analysis showed Minaçu virus genome profile with 10 RNA segments. Infected, non-killed animals died 7 days after inoculation. Tissue lesions were observed in all organs, except the lungs. Intense lesions were observed in the CNS and the heart, where neurone and cardiocyte necroses, respectively, were noted. The liver, spleen and kidneys had moderate tissue changes. Viral antigens were more abundant in the CNS and the heart, and absent in the lungs. In conclusion, Minaçu virus belongs to the family Reoviridae, genus Orbivirus. PMID:17244340

  9. Enhanced dihydropyridine receptor calcium channel activity restores muscle strength in JP45/CASQ1 double knockout mice

    PubMed Central

    Mosca, Barbara; Delbono, Osvaldo; Messi, Maria Laura; Bergamelli, Leda; Wang, Zhong-Min; Vukcevic, Mirko; Lopez, Ruben; Treves, Susan; Nishi, Miyuki; Takeshima, Hiroshi; Paolini, Cecilia; Martini, Marta; Rispoli, Giorgio; Protasi, Feliciano; Zorzato, Francesco

    2016-01-01

    Muscle strength declines with age in part due to a decline of Ca2+ release from sarcoplasmic reticulum calcium stores. Skeletal muscle dihydropyridine receptors (Cav1.1) initiate muscle contraction by activating ryanodine receptors in the sarcoplasmic reticulum. Cav1.1 channel activity is enhanced by a retrograde stimulatory signal delivered by the ryanodine receptor. JP45 is a membrane protein interacting with Cav1.1 and the sarcoplasmic reticulum Ca2+ storage protein calsequestrin (CASQ1). Here we show that JP45 and CASQ1 strengthen skeletal muscle contraction by modulating Cav1.1 channel activity. Using muscle fibres from JP45 and CASQ1 double knockout mice, we demonstrate that Ca2+ transients evoked by tetanic stimulation are the result of massive Ca2+ influx due to enhanced Cav1.1 channel activity, which restores muscle strength in JP45/CASQ1 double knockout mice. We envision that JP45 and CASQ1 may be candidate targets for the development of new therapeutic strategies against decay of skeletal muscle strength caused by a decrease in sarcoplasmic reticulum Ca2+ content. PMID:23443569

  10. Restoration of virulence of escape mutants of H5 and H9 influenza viruses by their readaptation to mice.

    PubMed

    Rudneva, Irina A; Ilyushina, Natalia A; Timofeeva, Tatiana A; Webster, Robert G; Kaverin, Nikolai V

    2005-10-01

    Antigenic mapping of the haemagglutinin (HA) molecule of H5 and H9 influenza viruses by selecting escape mutants with monoclonal anti-HA antibodies and subjecting the selected viruses to immunological analysis and sequencing has previously been performed. The viruses used as wild-type strains were mouse-adapted variants of the original H5 and H9 isolates. Phenotypic characterization of the escape mutants revealed that the amino acid change in HA that conferred resistance to a monoclonal antibody was sometimes associated with additional effects, including decreased virulence for mice. In the present study, the low-virulence H5 and H9 escape mutants were readapted to mice. Analysis of the readapted variants revealed that the reacquisition of virulence was not necessarily achieved by reacquisition of the wild-type HA gene sequence, but was also associated either with the removal of a glycosylation site (the one acquired previously by the escape mutant) without the exact restoration of the initial wild-type amino acid sequence, or, for an H5 escape mutant that had no newly acquired glycosylation sites, with an additional amino acid change in a remote part of the HA molecule. The data suggest that such 'compensating' mutations, removing the damaging effects of antibody-selected amino acid changes, may be important in the course of influenza virus evolution.

  11. L-DOPA treatment selectively restores spine density in dopamine receptor D2-expressing projection neurons in dyskinetic mice.

    PubMed

    Suárez, Luz M; Solís, Oscar; Caramés, Jose M; Taravini, Irene R; Solís, Jose M; Murer, Mario G; Moratalla, Rosario

    2014-05-01

    L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia is an incapacitating complication of L-DOPA therapy that affects most patients with Parkinson's disease. Previous work indicating that molecular sensitization to dopamine receptor D1 (D1R) stimulation is involved in dyskinesias prompted us to perform electrophysiological recordings of striatal projection "medium spiny neurons" (MSN). Moreover, because enhanced D1R signaling in drug abuse induces changes in spine density in striatum, we investigated whether the dyskinesia is related to morphological changes in MSNs. Wild-type and bacterial artificial chromosome transgenic mice (D1R-tomato and D2R-green fluorescent protein) mice were lesioned with 6-hydroxydopamine and subsequently treated with L-DOPA to induce dyskinesia. Functional, molecular, and structural changes were assessed in corticostriatal slices. Individual MSNs injected with Lucifer-Yellow were detected by immunohistochemistry for three-dimensional reconstructions with Neurolucida software. Intracellular current-clamp recordings with high-resistance micropipettes were used to characterize electrophysiological parameters. Both D1R-MSNs and D2R-MSNs showed diminished spine density in totally denervated striatal regions in parkinsonian mice. Chronic L-DOPA treatment, which induced dyskinesia and aberrant FosB expression, restored spine density in D2R-MSNs but not in D1R-MSNs. In basal conditions, MSNs are more excitable in parkinsonian than in sham mice, and excitability decreases toward normal values after L-DOPA treatment. Despite this normalization of basal excitability, in dyskinetic mice, the selective D1R agonist SKF38393 increased the number of evoked action potentials in MSNs, compared with sham animals. Chronic L-DOPA induces abnormal spine re-growth exclusively in D2R-MSNs and robust supersensitization to D1R-activated excitability in denervated striatal MSNs. These changes might constitute the anatomical and electrophysiological substrates

  12. A plant polyphenol-rich extract restores the suppressed functions of phagocytes in influenza virus-infected mice.

    PubMed

    Ivanova, Emilia; Toshkova, Reneta; Serkedjieva, Julia

    2005-03-01

    Influenza infection was induced in white ICR mice by intranasal (i.n.) inoculation of the virus A/Aichi/2/68 (H3N2). The number, migration and phagocyte indices of alveolar and peritoneal macrophages (pMØ) and of blood polymorphonuclear leukocytes (PMNs), as well as the inhibition of the PMN adherence in the presence of a specific antigen were followed for 9 days after infection. The effect of the i.n. application of a polyphenol-rich extract, designated as polyphenolic complex (PC), isolated from the medicinal plant Geranium sanguineum L., on the inspected immune parameters was studied in parallel with the virological parameters of the infection, e.g. rate of mortality, mean survival time (MST), infectious lung virus titre and consolidation of the lungs. It was found that the application of PC induced a continuous 2- to 2.5-fold rise in the number of both peritoneal and alveolar macrophages (aMØ) in the infected and healthy controls. The migration of both peritoneal and aMØ increased 1.5- to 2-fold in the group of infected PC-treated animals and four to fivefold in the control group, the maximum being on day 9. PC stimulated phagocyte activities of blood PMNs in both infected and healthy mice. The leukocyte adherence inhibition (LAI) index decreased in the infected and PC-treated animals. The restoration of the suppressed functions of phagocytes in influenza virus-infected mice (VIM) was consistent with a prolongation of MST and reduction in mortality rate, infectious virus titre and lung consolidation. The immunoenhancing properties of PC apparently contribute to the overall protective effect of the plant preparation in the lethal murine experimental influenza A/Aichi infection.

  13. TREM-1 inhibition restores impaired autophagy activity and reduces colitis in mice.

    PubMed

    Kökten, Tunay; Gibot, Sébastien; Lepage, Patricia; D'Alessio, Silvia; Hablot, Julie; Ndiaye, Ndeye-Coumba; Busby-Venner, Hélène; Monot, Céline; Garnier, Benjamin; Moulin, David; Jouzeau, Jean-Yves; Hansmannel, Franck; Danese, Silvio; Guéant, Jean-Louis; Muller, Sylviane; Peyrin-Biroulet, Laurent

    2017-09-16

    Triggering receptor expressed on myeloid cells-1 [TREM-1] is known to amplify inflammation in several diseases. Autophagy and endoplasmic reticulum [ER] stress, which activates the unfolded protein response [UPR] are closely linked and defects in these pathways contribute to the pathogenesis of inflammatory bowel disease [IBD]. Both autophagy and UPR are deeply involved in host-microbiota interactions for the clearance of intracellular pathogens thus contributing to dysbiosis. We investigated whether inhibition of TREM-1 would prevent aberrant inflammation by modulating autophagy, ER stress and preventing dysbiosis. Experimental mouse model of colitis was caused by dextran sulfate sodium treatment. TREM-1 was inhibited, either pharmacologically by LR12 peptide or genetically with Trem-1 knock-out [KO] mice. Colon tissues and fecal pellets of control and colitic mice were used. Levels of macroautophagy, chaperone-mediated autophagy [CMA], and UPR proteins were evaluated by western blotting. The composition of the intestinal microbiota was assessed by MiSeq sequencing in both LR12-treated and KO animals. We confirmed that inhibition of TREM-1 attenuates the severity of colitis at clinically, endoscopically and histologically levels. We observed an increase in macroautophagy [ATG1/ULK-1, ATG13, ATG5, ATG16L1, and MAP1LC3-I/II] and in CMA [HSPA8 and HSP90AA1] while there was a decrease in the UPR [PERK, IRE-1α and ATF-6α] protein expression levels in TREM-1 inhibited colitic mice. TREM-1 inhibition prevented dysbiosis. TREM-1 may represent a novel drug target for the treatment of IBD by modulating autophagy activity and ER stress.

  14. Normocaloric Diet Restores Weight Gain and Insulin Sensitivity in Obese Mice

    PubMed Central

    Lombardo, Giovanni Enrico; Arcidiacono, Biagio; De Rose, Roberta Francesca; Lepore, Saverio Massimo; Costa, Nicola; Montalcini, Tiziana; Brunetti, Antonio; Russo, Diego; De Sarro, Giovambattista; Celano, Marilena

    2016-01-01

    An increased incidence of obesity is registered worldwide, and its association with insulin resistance and type 2 diabetes is closely related with increased morbidity and mortality for cardiovascular diseases. A major clinical problem in the management of obesity is the non-adherence or low adherence of patients to a hypocaloric dietetic restriction. In this study, we evaluated in obese mice the effects of shifting from high-calorie foods to normal diet on insulin sensitivity. Male C57BL/6JOlaHsd mice (n = 20) were fed with high fat diet (HFD) for a 24-week period. Afterward, body weight, energy, and food intake were measured in all animals, together with parameters of insulin sensitivity by homeostatic model assessment of insulin resistance and plasma glucose levels in response to insulin administration. Moreover, in half of these mice, Glut4 mRNA levels were measured in muscle at the end of the high fat treatment, whereas the rest of the animals (n = 10) were shifted to normocaloric diet (NCD) for 10 weeks, after which the same analyses were carried out. A significant reduction of body weight was found after the transition from high to normal fat diet, and this decrease correlated well with an improvement in insulin sensitivity. In fact, we found a reduction in serum insulin levels and the recovery of insulin responsiveness in terms of glucose disposal measured by insulin tolerance test and Glut4 mRNA and protein expression. These results indicate that obesity-related insulin resistance may be rescued by shifting from HFD to NCD. PMID:27303363

  15. Transgenerational inheritance of enhanced susceptibility to radiation-induced medulloblastoma in newborn Ptch1+/− mice after paternal irradiation

    PubMed Central

    Tanno, Barbara; Meschini, Roberta; Cordelli, Eugenia; Benassi, Barbara; Longobardi, Maria Grazia; Izzotti, Alberto; Pulliero, Alessandra; Mancuso, Mariateresa; Pacchierotti, Francesca

    2015-01-01

    The hypothesis of transgenerational induction of increased cancer susceptibility after paternal radiation exposure has long been controversial because of inconsistent results and the lack of a mechanistic interpretation. Here, exploiting Ptch1 heterozygous knockout mice, susceptible to spontaneous and radiation-induced medulloblastoma, we show that exposure of paternal germ cells to 1 Gy X-rays, at the spermatogonial stage, increased by a considerable 1.4-fold the offspring susceptibility to medulloblastoma induced by neonatal irradiation. This effect gained further biological significance thanks to a number of supporting data on the immunohistochemical characterization of the target tissue and preneoplastic lesions (PNLs). These results altogether pointed to increased proliferation of cerebellar granule cell precursors and PNLs cells, which favoured the development of frank tumours. The LOH analysis of tumor DNA showed Ptch1 biallelic loss in all tumor samples, suggesting that mechanisms other than interstitial deletions, typical of radiation-induced medulloblastoma, did not account for the observed increased cancer risk. This data was supported by comet analysis showing no differences in DNA damage induction and repair in cerebellar cells as a function of paternal irradiation. Finally, we provide biological plausibility to our results offering evidence of a possible epigenetic mechanism of inheritance based on radiation-induced changes of the microRNA profile of paternal sperm. PMID:26452034

  16. Restoration of Declined Immune Responses and Hyperlipidemia by Rubus occidenalis in Diet-Induced Obese Mice

    PubMed Central

    Lee, Youngjoo; Kim, Jiyeon; An, Jinho; Lee, Sungwon; Lee, Heetae; Kong, Hyunseok; Song, Youngcheon; Choi, Hye Ran; Kwon, Ji-Wung; Shin, Daekeun; Lee, Chong-Kil; Kim, Kyungjae

    2017-01-01

    Hyperlipidemia, which is closely associated with a fatty diet and aging, is commonly observed in the western and aged society. Therefore, a novel therapeutic approach for this disease is critical, and an immunological view has been suggested as a novel strategy, because hyperlipidemia is closely associated with inflammation and immune dysfunction. In this study, the effects of an aqueous extract of Rubus occidentalis (RO) in obese mice were investigated using immunological indexes. The mice were fed a high-fat diet (HFD) to induce hyperlipidemia, which was confirmed by biochemical analysis and examination of the mouse physiology. Two different doses of RO and rosuvastatin, a cholesterol synthesis inhibitor used as a control, were orally administered. Disturbances in immune cellularity as well as lymphocyte proliferation and cytokine production were significantly normalized by oral administration of RO, which also decreased the elevated serum tumor necrosis factor (TNF)-α level and total cholesterol. The specific immune-related actions of RO comprised considerable improvement in cytotoxic T cell killing functions and regulation of antibody production to within the normal range. The immunological evidence confirms the significant cholesterol-lowering effect of RO, suggesting its potential as a novel therapeutic agent for hyperlipidemia and associated immune decline. PMID:27737523

  17. Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice

    PubMed Central

    Musner, Nicolò; Scapin, Cristina; Ungaro, Daniela; Del Carro, Ubaldo; Ron, David; Feltri, M. Laura

    2013-01-01

    P0 glycoprotein is an abundant product of terminal differentiation in myelinating Schwann cells. The mutant P0S63del causes Charcot-Marie-Tooth 1B neuropathy in humans, and a very similar demyelinating neuropathy in transgenic mice. P0S63del is retained in the endoplasmic reticulum of Schwann cells, where it promotes unfolded protein stress and elicits an unfolded protein response (UPR) associated with translational attenuation. Ablation of Chop, a UPR mediator, from S63del mice completely rescues their motor deficit and reduces active demyelination by half. Here, we show that Gadd34 is a detrimental effector of CHOP that reactivates translation too aggressively in myelinating Schwann cells. Genetic or pharmacological limitation of Gadd34 function moderates translational reactivation, improves myelination in S63del nerves, and reduces accumulation of P0S63del in the ER. Resetting translational homeostasis may provide a therapeutic strategy in tissues impaired by misfolded proteins that are synthesized during terminal differentiation. PMID:23547100

  18. Killer Treg restore immune homeostasis and suppress autoimmune diabetes in prediabetic NOD mice.

    PubMed

    Kaminitz, Ayelet; Yolcu, Esma S; Stein, Jerry; Yaniv, Isaac; Shirwan, Haval; Askenasy, Nadir

    2011-08-01

    We hypothesized that regulatory T cells (Treg) effectively target diabetogenic cells, and reinforcing their killing capacity will attenuate the course of disease. For proof of concept, Fas-ligand (FasL) protein was conjugated to CD25(+) Treg (killer Treg) to simulate the physiological mechanism of activation-induced cell death. Cytotoxic and suppressive activity of killer Treg was superior to naïve Treg in vitro. Administration of 3-4 × 10(6) Treg prevented hyperglycemia in 65% prediabetic NOD females, however only killer Treg postponed disease onset by 14 weeks. CD25(+) Treg homed to the pancreas and regional lymph nodes of prediabetic NOD females, proliferated and ectopic FasL protein induced apoptosis in CD25(-) T cells in situ. This mechanism of pathogenic cell debulking is specific to killer Treg, as FasL-coated splenocytes have no immunomodulatory effect, and only killer Treg prevent the disease in 80% of NOD.SCID recipients of effector:suppressor T cells (10:1 ratio). All immunomodulated mice displayed increased fractional expression of FoxP3 in the pancreas and draining lymph nodes, which was accompanied by CD25 only in recipients of killer Treg. A therapeutic intervention that uses the affinity of Treg to reduce the pathogenic load has long-term consequences: arrest of destructive insulitis in mice with established disease prior to β-cell extinction.

  19. Direct endothelial junction restoration results in significant tumor vascular normalization and metastasis inhibition in mice

    PubMed Central

    Agrawal, Vijayendra; Maharjan, Sony; Kim, Kyeojin; Kim, Nam-Jung; Son, Jimin; Lee, Keunho; Choi, Hyun-Jung; Rho, Seung-Sik; Ahn, Sunjoo; Won, Moo-Ho; Ha, Sang-Jun; Koh, Gou Young; Kim, Young-Myeong; Suh, Young-Ger; Kwon, Young-Guen

    2014-01-01

    Tumor blood vessels are leaky and immature, which causes inadequate blood supply to tumor tissues resulting in hypoxic microenvironment and promotes metastasis. Here we have explored tumor vessel modulating activity of Sac-1004, a recently developed molecule in our lab, which directly potentiates VE-cadherin-mediated endothelial cell junction. Sac-1004 could enhance vascular junction integrity in tumor vessels and thereby inhibit vascular leakage and enhance vascular perfusion. Improved perfusion enabled Sac-1004 to have synergistic anti-tumor effect on cisplatin-mediated apoptosis of tumor cells. Interestingly, characteristics of normalized blood vessels namely reduced hypoxia, improved pericyte coverage and decreased basement membrane thickness were readily observed in tumors treated with Sac-1004. Remarkably, Sac-1004 was also able to inhibit lung and lymph node metastasis in MMTV and B16BL6 tumor models. This was in correlation with a reduction in epithelial-to-mesenchymal transition of tumor cells with considerable diminution in expression of related transcription factors. Moreover, cancer stem cell population dropped substantially in Sac-1004 treated tumor tissues. Taken together, our results showed that direct restoration of vascular junction could be a significant strategy to induce normalization of tumor blood vessels and reduce metastasis. PMID:24811731

  20. Podophyllum hexandrum-Mediated Survival Protection and Restoration of Other Cellular Injuries in Lethally Irradiated Mice

    PubMed Central

    Sankhwar, Sanghmitra; Gupta, Manju Lata; Gupta, Vanita; Verma, Savita; Suri, Krishna Avtar; Devi, Memita; Sharma, Punita; Khan, Ehsan Ahmed; Alam, M. Sarwar

    2011-01-01

    This study aims at the development of a safe and effective formulation to counter the effects of lethal irradiation. The sub-fraction (G-001M), prepared from Podophyllum hexandrum has rendered high degree of survival (>90%) at a dose of 6 mg kg−1 body weight (intramuscular) in lethally irradiated mice. Therapeutic dose of G-001M, at about 20 times lower concentration than its LD100, has revealed a DRF of 1.62. Comet assay studies in peripheral blood leukocytes have reflected that, treatment of G-001M before irradiation has significantly reduced DNA tail length (P < .001) and DNA damage score (P < .001), as compared to radiation-only group. Spleen cell counts in irradiated animals had declined drastically at the very first day of exposure, and the fall continued till the 5th day (P < .001). In the treated irradiated groups, there was a steep reduction in the counts initially, but this phase did not prolong. More than 60% decline in thymocytes of irradiated group animals was registered at 5 h of irradiation when compared with controls, and the fall progressed further downwards with the similar pace till 5th day of exposure (P < .001). At later intervals, thymus was found fully regressed. In G-001M pre-treated irradiated groups also, thymocytes decreased till the 5th day but thereafter rejuvenated and within 30 days of treatment the values were close to normal. Current studies have explicitly indicated that, G-001M in very small doses has not only rendered high survivability in lethally irradiated mice, but also protected their cellular DNA, besides supporting fast replenishment of the immune system. PMID:19553386

  1. Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(-/-) mice.

    PubMed

    Campbell, Elizabeth J; Vissers, Margreet C M; Bozonet, Stephanie; Dyer, Arron; Robinson, Bridget A; Dachs, Gabi U

    2015-02-01

    Hypoxia-inducible factor-1 (HIF-1) governs cellular adaption to the hypoxic microenvironment and is associated with a proliferative, metastatic, and treatment-resistant tumor phenotype. HIF-1 levels and transcriptional activity are regulated by proline and asparagine hydroxylases, which require ascorbate as cofactor. Ascorbate supplementation reduced HIF-1 activation in vitro, but only limited data are available in relevant animal models. There is no information of the effect of physiological levels of ascorbate on HIF activity and tumor growth, which was measured in this study. C57BL/6 Gulo(-/-) mice (a model of the human ascorbate dependency condition) were supplemented with 3300 mg/L, 330 mg/L, or 33 mg/L of ascorbate in their drinking water before and during subcutaneous tumor growth of B16-F10 melanoma or Lewis lung carcinoma (LL/2). Ascorbate levels in tumors increased significantly with elevated ascorbate intake and restoration of wild-type ascorbate levels led to a reduction in growth of B16-F10 (log phase P < 0.001) and LL/2 tumors (lag growth P < 0.001, log phase P < 0.05). Levels of HIF-1α protein in tumors decreased as dietary ascorbate supplementation increased for both tumor models (P < 0.001). Similarly, tumor ascorbate was inversely correlated with levels of the HIF-1 target proteins CA-IX, GLUT-1, and VEGF in both B16-F10 and LL/2 tumors (P < 0.05). The extent of necrosis was similar between ascorbate groups but varied between models (30% for B16-F10 and 21% for LL/2), indicating that ascorbate did not affect tumor hypoxia. Our data support the hypothesis that restoration of optimal intracellular ascorbate levels reduces tumor growth via moderation of HIF-1 pathway activity.

  2. Broadly impaired NK cell function in non-obese diabetic mice is partially restored by NK cell activation in vivo and by IL-12/IL-18 in vitro.

    PubMed

    Johansson, Sofia E; Hall, Håkan; Björklund, Jens; Höglund, Petter

    2004-01-01

    NK cells represent a link between innate and adaptive immunity, and may play a role in regulating autoimmune disorders. We have characterized the NK cell population in non-obese diabetic (NOD) mice. The percentage and absolute numbers of NK cells were similar in NOD and control MHC-matched B6.g7 mice. However, the capacity of NOD NK cells to mediate natural cytotoxicity as well as FcR- and Ly49D-mediated killing was compromised in vitro, suggesting a defect affecting multiple activation pathways. The defect was neither linked to the NK gene complex nor to the MHC, as determined by comparison with mice congenic for these regions. Introducing the beta(2)-microglobulin mutation on the NOD background further impaired NK cell function, showing that the compromised cytotoxic capacity in these two strains arises from two independent mechanisms. In vivo rejection responses against tumor cells and against MHC class I-deficient spleen cells were decreased in naive NOD recipients, but restored in mice pre-activated with tilorone, a potent activator of NK cells. In addition, killing of some tumor targets was restored in vitro after activation of NK cells with IL-12 plus IL-18 or with IFN-alpha/beta, but not with IL-2. Interestingly, natural killing of RMA-S targets by NOD NK cells could not be restored in vitro, indicating that restoration of killing capacity was only partial. Our data suggest a severe, but partially restorable, killing defect in NOD NK cells, affecting activation through several pathways.

  3. Propionate Protects against Lipopolysaccharide-Induced Mastitis in Mice by Restoring Blood-Milk Barrier Disruption and Suppressing Inflammatory Response.

    PubMed

    Wang, Jingjing; Wei, Zhengkai; Zhang, Xu; Wang, Yanan; Yang, Zhengtao; Fu, Yunhe

    2017-01-01

    Mastitis, an inflammation of the mammary glands, is a major disease affecting dairy animal worldwide. Propionate is one of the main short-chain fatty acid that can exert multiple effects on the inflammatory process. The purpose of this study is to investigate the mechanisms underlying the protective effects of sodium propionate against lipopolysaccharide (LPS)-induced mastitis model in mice. The data mainly confirm that inflammation and blood-milk barrier breakdown contribute to progression of the disease in this model. In mice with LPS, sodium propionate attenuates the LPS-induced histopathological changes, inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) production, myeloperoxidase activity in mammary tissues. Given their importance in the blood-milk barrier, tight junction proteins occludin and claudin-3 are further investigated. Our results show that sodium propionate strikingly increases the expressions of occludin and claudin-3 and reduces the blood-milk barrier permeability in this model. Furthermore, in LPS-stimulated mouse mammary epithelial cells (mMECs), LPS increased the expressions of phosphorylated (p)-p65, p-IκB proteins, which is attenuated by sodium propionate. Finally, we examine the possibility that propionate acts as a histone deacetylase (HDAC) inhibitor, the results show that both sodium propionate and trichostatin A increase the level of histone H3 acetylation and inhibit the increased production of TNF-α, IL-6, and IL-1β in LPS-stimulated mMECs. These data suggest that sodium propionate protects against LPS-induced mastitis mainly by restoring blood-milk barrier disruption and suppressing inflammation via NF-κB signaling pathway and HDAC inhibition.

  4. CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice.

    PubMed

    Apostol, Barbara L; Simmons, Danielle A; Zuccato, Chiara; Illes, Katalin; Pallos, Judit; Casale, Malcolm; Conforti, Paola; Ramos, Catarina; Roarke, Margaret; Kathuria, Satish; Cattaneo, Elena; Marsh, J Lawrence; Thompson, Leslie Michels

    2008-09-01

    Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine repeat within the protein Huntingtin (Htt). We previously reported that mutant Htt expression activates the ERK1/2 and JNK pathways [Apostol, B.L., Illes, K., Pallos, J., Bodai, L., Wu, J., Strand, A., Schweitzer, E.S., Olson, J.M., Kazantsev, A., Marsh, J.L., Thompson, L.M., 2006. Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum. Mol. Genet. 15, 273-285]. Chemical and genetic modulation of these pathways promotes cell survival and death, respectively. Here we test the ability of two closely related compounds, CEP-11004 and CEP-1347, which inhibit Mixed Lineage Kinases (MLKs) and are neuroprotective, to suppress mutant Htt-mediated pathogenesis in multiple model systems. CEP-11004/CEP-1347 treatment significantly decreased toxicity in mutant Htt-expressing cells that evoke a strong JNK response. However, suppression of cellular dysfunction in cell lines that exhibit only mild Htt-associated toxicity and little JNK activation was associated with activation of ERK1/2. These compounds also reduced neurotoxicity in immortalized striatal neurons from mutant knock-in mice and Drosophila expressing a mutant Htt fragment. Finally, CEP-1347 improved motor performance in R6/2 mice and restored expression of BDNF, a critical neurotrophic factor that is reduced in HD. These studies suggest a novel therapeutic approach for a currently untreatable neurodegenerative disease, HD, via CEP-1347 up-regulation of BDNF.

  5. Eicosapentaenoic acid but not docosahexaenoic acid restores skeletal muscle mitochondrial oxidative capacity in old mice.

    PubMed

    Johnson, Matthew L; Lalia, Antigoni Z; Dasari, Surendra; Pallauf, Maximilian; Fitch, Mark; Hellerstein, Marc K; Lanza, Ian R

    2015-10-01

    Mitochondrial dysfunction is often observed in aging skeletal muscle and is implicated in age-related declines in physical function. Early evidence suggests that dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) improve mitochondrial function. Here, we show that 10 weeks of dietary eicosapentaenoic acid (EPA) supplementation partially attenuated the age-related decline in mitochondrial function in mice, but this effect was not observed with docosahexaenoic acid (DHA). The improvement in mitochondrial function with EPA occurred in the absence of any changes in mitochondrial abundance or biogenesis, which was evaluated from RNA sequencing, large-scale proteomics, and direct measurements of muscle mitochondrial protein synthesis rates. We find that EPA improves muscle protein quality, specifically by decreasing mitochondrial protein carbamylation, a post-translational modification that is driven by inflammation. These results demonstrate that EPA attenuated the age-related loss of mitochondrial function and improved mitochondrial protein quality through a mechanism that is likely linked with anti-inflammatory properties of n-3 PUFAs. Furthermore, we demonstrate that EPA and DHA exert some common biological effects (anticoagulation, anti-inflammatory, reduced FXR/RXR activation), but also exhibit many distinct biological effects, a finding that underscores the importance of evaluating the therapeutic potential of individual n-3 PUFAs. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  6. Nicotinamide restores cognition in AD transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau

    PubMed Central

    Green, Kim N.; Steffan, Joan S.; Martinez-Coria, Hilda; Sun, Xuemin; Schreiber, Steven S.; Thompson, Leslie Michels; LaFerla, Frank M.

    2008-01-01

    Memory loss is the signature feature of Alzheimer’s disease and therapies that prevent or delay its onset are urgently needed. Effective preventive strategies likely offer the greatest and most widespread benefits. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance memory and synaptic plasticity. We evaluated the efficacy of nicotinamide, a competitive inhibitor of the sirtuins or class III NAD+-dependent HDACs in 3xTg-AD mice, and found that it restored cognitive deficits associated with pathology. Nicotinamide selectively reduces a specific phospho-species of tau (Thr231) that is associated with microtubule depolymerization, in a manner similar to inhibition of SirT1. Nicotinamide also dramatically increased acetylated-α-tubulin, a primary substrate of SirT2, and MAP2c, both of which are linked to increased microtubule stability. Reduced phosphoThr231-tau was related to a reduction of mono-ubiquitin-conjugated tau, suggesting that this post-translationally modified form of tau may be rapidly degraded. Overexpression of a Thr231-phospho-mimic tau in vitro increased clearance and decreased accumulation of tau compared to wild-type tau. These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies, and that phosphorylation of tau at Thr231 may regulate tau stability. PMID:18987186

  7. Rescue of motor coordination by Purkinje cell-targeted restoration of Kv3.3 channels in Kcnc3-null mice requires Kcnc1.

    PubMed

    Hurlock, Edward C; Bose, Mitali; Pierce, Ganon; Joho, Rolf H

    2009-12-16

    The role of cerebellar Kv3.1 and Kv3.3 channels in motor coordination was examined with an emphasis on the deep cerebellar nuclei (DCN). Kv3 channel subunits encoded by Kcnc genes are distinguished by rapid activation and deactivation kinetics that support high-frequency, narrow action potential firing. Previously we reported that increased lateral deviation while ambulating and slips while traversing a narrow beam of ataxic Kcnc3-null mice were corrected by restoration of Kv3.3 channels specifically to Purkinje cells, whereas Kcnc3-mutant mice additionally lacking one Kcnc1 allele were partially rescued. Here, we report mice lacking all Kcnc1 and Kcnc3 alleles exhibit no such rescue. For Purkinje cell output to reach the rest of the brain it must be conveyed by neurons of the DCN or vestibular nuclei. As Kcnc1, but not Kcnc3, alleles are lost, mutant mice exhibit increasing gait ataxia accompanied by spike broadening and deceleration in DCN neurons, suggesting the facet of coordination rescued by Purkinje-cell-restricted Kv3.3 restoration in mice lacking just Kcnc3 is hypermetria, while gait ataxia emerges when additionally Kcnc1 alleles are lost. Thus, fast repolarization in Purkinje cells appears important for normal movement velocity, whereas DCN neurons are a prime candidate locus where fast repolarization is necessary for normal gait patterning.

  8. Mucosal priming of newborn mice with S. Typhi Ty21a expressing anthrax protective antigen (PA) followed by parenteral PA-boost induces B and T cell-mediated immunity that protects against infection bypassing maternal antibodies.

    PubMed

    Ramirez, Karina; Ditamo, Yanina; Galen, James E; Baillie, Les W J; Pasetti, Marcela F

    2010-08-23

    The currently licensed anthrax vaccine has several limitations and its efficacy has been proven only in adults. Effective immunization of newborns and infants requires adequate stimulation of their immune system, which is competent but not fully activated. We explored the use of the licensed live attenuated S. Typhi vaccine strain Ty21a expressing Bacillus anthracis protective antigen [Ty21a(PA)] followed PA-alum as a strategy for immunizing the pediatric population. Newborn mice primed with a single dose of Ty21a(PA) exhibited high frequencies of mucosal IgA-secreting B cells and IFN-gamma-secreting T cells during the neonatal period, none of which was detected in newborns immunized with a single dose of PA-alum. Priming with Ty21a(PA) followed by PA-boost resulted in high levels of PA-specific IgG, toxin neutralizing and opsonophagocytic antibodies and increased frequency of bone marrow IgG plasma cells and memory B cells compared with repeated immunization with PA-alum alone. Robust B and T cell responses developed even in the presence of maternal antibodies. The prime-boost protected against systemic and respiratory infection. Mucosal priming with a safe and effective S. Typhi-based anthrax vaccine followed by PA-boost could serve as a practical and effective prophylactic approach to prevent anthrax early in life.

  9. Mucosal priming of newborn mice with S. Typhi Ty21a expressing anthrax protective antigen (PA) followed by parenteral PA-boost induces B and T cell-mediated immunity that protects against infection bypassing maternal antibodies

    PubMed Central

    Ramirez, Karina; Ditamo, Yanina; Galen, James E.; Baillie, Les W. J.; Pasetti, Marcela F.

    2010-01-01

    The currently licensed anthrax vaccine has several limitations and its efficacy has been proven only in adults. Effective immunization of newborns and infants requires adequate stimulation of their immune system, which is competent but not fully activated. We explored the use of the licensed live attenuated S. Typhi vaccine strain Ty21a expressing Bacillus anthracis protective antigen [Ty21a(PA)] followed PA-alum as a strategy for immunizing the pediatric population. Newborn mice primed with a single dose of Ty21a(PA) exhibited high frequencies of mucosal IgA-secreting B cells and IFN-γ-secreting T cells during the neonatal period, none of which was detected in newborns immunized with a single dose of PA-alum. Priming with Ty21a(PA) followed by PA-boost resulted in high levels of PA-specific IgG, toxin-neutralizing and opsonophagocytic antibodies and increased frequency of bone marrow IgG plasma cells and memory B cells compared with repeated immunization with PA-alum alone. Robust B and T cell responses developed even in the presence of maternal antibodies. The prime-boost protected against systemic and respiratory infection. Mucosal priming with a safe and effective S. Typhi-based anthrax vaccine followed by PA-boost could serve as a practical and effective prophylactic approach to prevent anthrax early in life. PMID:20619377

  10. Nearby Newborns

    NASA Image and Video Library

    2004-12-21

    This image shows six of the three-dozen "ultraviolet luminous galaxies" spotted in our corner of the universe by NASA's Galaxy Evolution Explorer. These massive galaxies greatly resemble newborn galaxies that were common in the early universe. The discovery came as a surprise, because astronomers had thought that the universe's "birth-rate" had declined, and that massive galaxies were no longer forming. The galaxies, located in the center of each panel, were discovered after the Galaxy Evolution Explorer scanned a large portion of the sky with its highly sensitive ultraviolet-light detectors. Because young stars pack most of their light into ultraviolet wavelengths, young galaxies appear to the Galaxy Evolution Explorer like diamonds in a field of stones. Astronomers mined for these rare "gems" before, but missed them because they weren't able to examine a large enough slice of the sky. The Galaxy Evolution Explorer surveyed thousands of nearby galaxies before finding three-dozen newborns. While still relatively close in astronomical terms, these galaxies are far enough away to appear small to the Galaxy Evolution Explorer. Clockwise beginning from the upper left, they are called: GALEX_J232539.24+004507.1, GALEX_J231812.98-004126.1, GALEX_J015028.39+130858.5, GALEX_J021348.52+125951.3, GALEX_J143417.15+020742.5, GALEX_J020354.02-092452.5. http://photojournal.jpl.nasa.gov/catalog/PIA07143

  11. Targeting channelrhodopsin-2 to ON-bipolar cells with vitreally administered AAV Restores ON and OFF visual responses in blind mice.

    PubMed

    Macé, Emilie; Caplette, Romain; Marre, Olivier; Sengupta, Abhishek; Chaffiol, Antoine; Barbe, Peggy; Desrosiers, Mélissa; Bamberg, Ernst; Sahel, Jose-Alain; Picaud, Serge; Duebel, Jens; Dalkara, Deniz

    2015-01-01

    Most inherited retinal dystrophies display progressive photoreceptor cell degeneration leading to severe visual impairment. Optogenetic reactivation of retinal neurons mediated by adeno-associated virus (AAV) gene therapy has the potential to restore vision regardless of patient-specific mutations. The challenge for clinical translatability is to restore a vision as close to natural vision as possible, while using a surgically safe delivery route for the fragile degenerated retina. To preserve the visual processing of the inner retina, we targeted ON bipolar cells, which are still present at late stages of disease. For safe gene delivery, we used a recently engineered AAV variant that can transduce the bipolar cells after injection into the eye's easily accessible vitreous humor. We show that AAV encoding channelrhodopsin under the ON bipolar cell-specific promoter mediates long-term gene delivery restricted to ON-bipolar cells after intravitreal administration. Channelrhodopsin expression in ON bipolar cells leads to restoration of ON and OFF responses at the retinal and cortical levels. Moreover, light-induced locomotory behavior is restored in treated blind mice. Our results support the clinical relevance of a minimally invasive AAV-mediated optogenetic therapy for visual restoration.

  12. Mold-casted non-degradable, islet macro-encapsulating hydrogel devices for restoration of normoglycemia in diabetic mice.

    PubMed

    Rios, Peter Daniel; Zhang, Xiaomin; Luo, Xunrong; Shea, Lonnie D

    2016-11-01

    Islet transplantation is a potential cure for diabetic patients, however this procedure is not widely adopted due to the high rate of graft failure. Islet encapsulation within hydrogels is employed to provide a three-dimensional microenvironment conducive to survival of transplanted islets to extend graft function. Herein, we present a novel macroencapsulation device, composed of PEG hydrogel, that combines encapsulation with lithography techniques to generate polydimethylsiloxane (PDMS) molds. PEG solutions are mixed with islets, which are then cast into PDMS molds for subsequent crosslinking. The molds can also be employed to provide complex architectures, such as microchannels that may allow vascular ingrowth through pre-defined regions of the hydrogel. PDMS molds allowed for the formation of stable gels with encapsulation of islets, and in complex architectures. Hydrogel devices with a thickness of 600 μm containing 500 islets promoted normoglycemia within 12 days following transplantation into the epididymal fat pad, which was sustained over the two-month period of study until removal of the device. The inclusion of microchannels, which had a similar minimum distance between islets and the hydrogel surface, similarly promoted normoglycemia. A glucose challenge test indicated hydrogel devices achieved normoglycemia 90 min post-dextrose injections, similar to control mice with native pancreata. Histochemical staining revealed that transplanted islets, identified as insulin positive, were viable and isolated from host tissue at 8 weeks post-transplantation, yet devices with microchannels had tissue and vascular ingrowth within the channels. Taken together, these results demonstrate a system for creating non-degradable hydrogels with complex geometries for encapsulating islets capable of restoring normoglycemia, which may expand islet transplantation as a treatment option for diabetic patients. Biotechnol. Bioeng. 2016;113: 2485-2495. © 2016 Wiley

  13. BAAV Mediated GJB2 Gene Transfer Restores Gap Junction Coupling in Cochlear Organotypic Cultures from Deaf Cx26Sox10Cre Mice

    PubMed Central

    Crispino, Giulia; Di Pasquale, Giovanni; Scimemi, Pietro; Rodriguez, Laura; Galindo Ramirez, Fabian; De Siati, Romolo Daniele; Santarelli, Rosa Maria; Arslan, Edoardo; Bortolozzi, Mario; Chiorini, John A.; Mammano, Fabio

    2011-01-01

    The deafness locus DFNB1 contains GJB2, the gene encoding connexin26 and GJB6, encoding connexin30, which appear to be coordinately regulated in the inner ear. In this work, we investigated the expression and function of connexin26 and connexin30 from postnatal day 5 to adult age in double transgenic Cx26Sox10Cre mice, which we obtained by crossing connexin26 floxed mice with a deleter Sox10–Cre line. Cx26Sox10Cre mice presented with complete connexin26 ablation in the epithelial gap junction network of the cochlea, whereas connexin30 expression was developmentally delayed; immunolabeling patterns for both connexins were normal in the cochlear lateral wall. In vivo electrophysiological measurements in Cx26Sox10Cre mice revealed profound hearing loss accompanied by reduction of endocochlear potential, and functional experiments performed in postnatal cochlear organotypic cultures showed impaired gap junction coupling. Transduction of these cultures with a bovine adeno associated virus vector restored connexin26 protein expression and rescued gap junction coupling. These results suggest that restoration of normal connexin levels by gene delivery via recombinant adeno associated virus could be a way to rescue hearing function in DFNB1 mouse models and, in future, lead to the development of therapeutic interventions in humans. PMID:21876744

  14. BACE1 RNAi Restores the Composition of Phosphatidylethanolamine-Derivates Related to Memory Improvement in Aged 3xTg-AD Mice

    PubMed Central

    Villamil-Ortiz, Javier G.; Barrera-Ocampo, Alvaro; Piedrahita, Diego; Velásquez-Rodríguez, Claudia M.; Arias-Londoño, Julian D.; Cardona-Gómez, Gloria P.

    2016-01-01

    β-amyloid (Aβ) is produced by the β-secretase 1 (BACE1)-mediated enzymatic cleavage of the amyloid precursor protein through the amyloidogenic pathway, making BACE1 a therapeutic target against Alzheimer’s disease (AD). Alterations in lipid metabolism are a risk factor for AD by an unknown mechanism. The objective of this study was to determine the effect of RNA interference against BACE1 (shBACEmiR) on the phospholipid profile in hippocampal CA1 area in aged 3xTg-AD mice after 6 and 12 months of treatment compared to aged PS1KI mice. The shBACEmiR treatment induced cognitive function recovery and restored mainly the fatty acid composition of lysophosphatidylethanolamine and etherphosphatidylethanolamine, reduced the cPLA2’s phosphorylation, down-regulated the levels of arachidonic acid and COX2 in the hippocampi of 3xTg-AD mice. Together, our findings suggest, for the first time, that BACE1 silencing restores phospholipids composition which could favor the recovery of cellular homeostasis and cognitive function in the hippocampus of triple transgenic AD mice. PMID:27891075

  15. BAAV mediated GJB2 gene transfer restores gap junction coupling in cochlear organotypic cultures from deaf Cx26Sox10Cre mice.

    PubMed

    Crispino, Giulia; Di Pasquale, Giovanni; Scimemi, Pietro; Rodriguez, Laura; Galindo Ramirez, Fabian; De Siati, Romolo Daniele; Santarelli, Rosa Maria; Arslan, Edoardo; Bortolozzi, Mario; Chiorini, John A; Mammano, Fabio

    2011-01-01

    The deafness locus DFNB1 contains GJB2, the gene encoding connexin26 and GJB6, encoding connexin30, which appear to be coordinately regulated in the inner ear. In this work, we investigated the expression and function of connexin26 and connexin30 from postnatal day 5 to adult age in double transgenic Cx26(Sox10Cre) mice, which we obtained by crossing connexin26 floxed mice with a deleter Sox10-Cre line. Cx26(Sox10Cre) mice presented with complete connexin26 ablation in the epithelial gap junction network of the cochlea, whereas connexin30 expression was developmentally delayed; immunolabeling patterns for both connexins were normal in the cochlear lateral wall. In vivo electrophysiological measurements in Cx26(Sox10Cre) mice revealed profound hearing loss accompanied by reduction of endocochlear potential, and functional experiments performed in postnatal cochlear organotypic cultures showed impaired gap junction coupling. Transduction of these cultures with a bovine adeno associated virus vector restored connexin26 protein expression and rescued gap junction coupling. These results suggest that restoration of normal connexin levels by gene delivery via recombinant adeno associated virus could be a way to rescue hearing function in DFNB1 mouse models and, in future, lead to the development of therapeutic interventions in humans.

  16. Interleukin 3 perfusion in W/Wv mice allows the development of macroscopic hematopoietic spleen colonies and restores cutaneous mast cell number

    SciTech Connect

    Ody, C.; Kindler, V.; Vassalli, P. )

    1990-07-01

    The genetically anemic W/Wv mice are characterized by the inability of their bone marrow cells to form macroscopic pluripotent hematopoietic colonies in the spleen of irradiated recipients upon transfer (colony-forming units). Furthermore, they almost totally lack mast cells, notably in the skin. In the present study, we have tested the effect of recombinant murine interleukin 3 (rmIL-3) on W/Wv mice hematopoiesis. Transfer of W/Wv bone marrow cells into lethally irradiated recipients perfused with rmIL-3 is followed by the appearance of macroscopic spleen colonies. Moreover, perfusion of rmIL-3 in W/Wv mice: (a) restores almost normal total numbers of hematopoietic precursors (colony-forming cells), but without modification of anemia; and (b) leads to the appearance of a normal number of mastocytes in the skin.

  17. Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces Aβ level and microglia activation in the brains of 3xTg-AD mice.

    PubMed

    Chen, Yanxing; Zhao, Yang; Dai, Chun-Ling; Liang, Zhihou; Run, Xiaoqin; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

    2014-11-01

    Decreased brain insulin signaling has been found recently in Alzheimer's disease (AD). Intranasal administration of insulin, which delivers the drug directly into the brain, improves memory and cognition in both animal studies and small clinical trials. However, the underlying mechanisms are unknown. Here, we treated 9-month-old 3xTg-AD mice, a commonly used mouse model of AD, with daily intranasal administration of insulin for seven days and then studied brain abnormalities of the mice biochemically and immunohistochemically. We found that intranasal insulin restored insulin signaling, increased the levels of synaptic proteins, and reduced Aβ40 level and microglia activation in the brains of 3xTg-AD mice. However, this treatment did not affect the levels of glucose transporters and O-GlcNAcylation or tau phosphorylation. Our findings provide a mechanistic insight into the beneficial effects of intranasal insulin treatment and support continuous clinical trials of intranasal insulin for the treatment of AD.

  18. Sleep and Newborns

    MedlinePlus

    ... Newborns should get 14 to 17 hours of sleep over a 24-hour period, says the National Sleep Foundation . Some newborns may sleep up to 18 ... breastfeeding is firmly established. continue Helping Your Newborn Sleep Newborns follow their own schedule. Over the next couple of weeks to months, you ...

  19. Behavior of knock-in mice with a cocaine-insensitive dopamine transporter after virogenetic restoration of cocaine sensitivity in the striatum.

    PubMed

    O'Neill, Brian; Tilley, Michael R; Han, Dawn D; Thirtamara-Rajamani, Keerthi; Hill, Erik R; Bishop, Georgia A; Zhou, Fu-Ming; During, Matthew J; Gu, Howard H

    2014-04-01

    Cocaine's main pharmacological actions are the inhibition of the dopamine, serotonin, and norepinephrine transporters. Its main behavioral effects are reward and locomotor stimulation, potentially leading to addiction. Using knock-in mice with a cocaine-insensitive dopamine transporter (DAT-CI mice) we have shown previously that inhibition of the dopamine transporter (DAT) is necessary for both of these behaviors. In this study, we sought to determine brain regions in which DAT inhibition by cocaine stimulates locomotor activity and/or produces reward. We used adeno-associated viral vectors to re-introduce the cocaine-sensitive wild-type DAT in specific brain regions of DAT-CI mice, which otherwise only express a cocaine-insensitive DAT globally. Viral-mediated expression of wild-type DAT in the rostrolateral striatum restored cocaine-induced locomotor stimulation and sensitization in DAT-CI mice. In contrast, the expression of wild-type DAT in the dorsal striatum, or in the medial nucleus accumbens, did not restore cocaine-induced locomotor stimulation. These data help to determine cocaine's molecular actions and anatomical loci that cause hyperlocomotion. Interestingly, cocaine did not produce significant reward - as measured by conditioned place-preference - in any of the three cohorts of DAT-CI mice with the virus injections. Therefore, the locus or loci underlying cocaine-induced reward remain underdetermined. It is possible that multiple dopamine-related brain regions are involved in producing the robust rewarding effect of cocaine. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice

    PubMed Central

    Braudeau, J; Delatour, B; Duchon, A; Pereira, P Lopes; Dauphinot, L; de Chaumont, F; Olivo-Marin, J-C; Dodd, RH; Hérault, Y; Potier, M-C

    2011-01-01

    An imbalance between inhibitory and excitatory neurotransmission has been proposed to contribute to altered brain function in individuals with Down syndrome (DS). Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system and accordingly treatment with GABA-A antagonists can efficiently restore cognitive functions of Ts65Dn mice, a genetic model for DS. However, GABA-A antagonists are also convulsant which preclude their use for therapeutic intervention in DS individuals. Here, we have evaluated safer strategies to release GABAergic inhibition using a GABA-A-benzodiazepine receptor inverse agonist selective for the α5-subtype (α5IA). We demonstrate that α5IA restores learning and memory functions of Ts65Dn mice in the novel-object recognition and in the Morris water maze tasks. Furthermore, we show that following behavioural stimulation, α5IA enhances learning-evoked immediate early gene products in specific brain regions involved in cognition. Importantly, acute and chronic treatments with α5IA do not induce any convulsant or anxiogenic effects that are associated with GABA-A antagonists or non-selective inverse agonists of the GABA-A-benzodiazepine receptors. Finally, chronic treatment with α5IA did not induce histological alterations in the brain, liver and kidney of mice. Our results suggest that non-convulsant α5-selective GABA-A inverse agonists could improve learning and memory deficits in DS individuals. PMID:21693554

  1. Role of newborn nurses in newborn feeding.

    PubMed

    Tengır, Tülay; Cetinkaya, Senay

    2011-01-01

    The aim of this study was to determine the function of newborn nurses given at newborn feeding in the newborn units of public hospitals in Konya, Turkey, besides it was also to determine the effect of nurses which had short-term training, aka education, in practice and in theory. This was an experimental study conducted with a total of 50 newborn nurses between 15 September 2004 and 30 February 2005. In collecting the data, a survey sheet including the demographic characteristics of newborn nurses and their knowledge on newborn feeding was applied, along with another remark form that shows clinical practices about newborn feeding. Considering the nurses, their knowledge mean score 'after education (AE)' was calculated to be 72.4 ± 10.4, which was significantly higher than that of 'before education (BE)', which was 58.0 ± 9.3, (p < 0.05). Likewise, the implementation mean score of these nurses AE (57.2 ± 4.9) was also found higher than the mean score BE (54.4 ± 5.0) (p < 0.05). There were statistically significant differences in the posteducation mean scores of nurses for the number of children they had, and for the hospital they work. In this study, it was determined that the nurses had knowledge deficits about newborn feeding both in theory and practice, but after a short educational program on newborn feeding their theoretical and practical knowledge had shown increases.

  2. Feeding Your Newborn

    MedlinePlus

    ... you choose to breastfeed or formula feed. About Breastfeeding Breastfeeding your newborn has many advantages. Perhaps most ... to care for her newborn. continue Limitations of Breastfeeding With all the good things known about breastfeeding, ...

  3. Your Child's Development: Newborn

    MedlinePlus

    ... Child Too Busy? Helping Your Child Adjust to Preschool School Lunches Kids and Food: 10 Tips for Parents Healthy Habits for TV, Video Games, and the Internet Your Child's Development: Newborn KidsHealth > For Parents > Your Child's Development: Newborn ...

  4. Your Child's Development: Newborn

    MedlinePlus

    ... Your 1- to 2-Year-Old Your Child's Development: Newborn KidsHealth > For Parents > Your Child's Development: Newborn ... changed; or goes to sleep ) Movement and Physical Development moves in response to sights and sounds rooting ...

  5. Communication and Your Newborn

    MedlinePlus

    ... the Classroom What Other Parents Are Reading Your Child's Development (Birth to 3 Years) Feeding Your 1- to ... Sleep and Newborns Jaundice in Healthy Newborns Your Child’s Development: 3-5 Days Contact Us Print Resources Send ...

  6. Hormonal effects in newborns

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/001911.htm Hormonal effects in newborns To use the sharing features on this page, please enable JavaScript. Hormonal effects in newborns occur because in the womb, babies ...

  7. Skin findings in newborns

    MedlinePlus

    Newborn skin characteristics; Infant skin characteristics; Neonatal care - skin ... the first few weeks of the baby's life. Newborn skin will vary, depending on the length of the pregnancy. Premature infants have thin, transparent skin. The skin of a ...

  8. Topical mechlorethamine restores autoimmune-arrested follicular activity in mice with an alopecia areata-like disease by targeting infiltrated lymphocytes.

    PubMed

    Tang, Liren; Cao, Liping; Bernardo, Olga; Chen, Yongliang; Sundberg, John P; Lui, Harvey; Chung, Stephen; Shapiro, Jerry

    2003-03-01

    Alopecia areata is an autoimmune disease targeted at hair follicles with infiltrated T lymphocytes probably playing an important role in the pathogenesis. It was reported in 1985 that mechlorethamine was effective on alopecia areata patients. This has never been confirmed since. The aims of the study were to investigate the effects of mechlorethamine on balding C3H/HeJ mice affected with an alopecia-areata-like disease and to study the underlying mechanisms. Mice were treated on half of the dorsal skin with mechlorethamine and the contralateral side was treated with the vehicle ointment. After 10 wk of mechlorethamine therapy, a full pelage of hair covered the treated side in all the mice and was maintained during the study, whereas the vehicle-treated sides showed either no change or continued hair loss. Immunohistochemistry revealed that infiltrated CD4+ and CD8+ lymphocytes were eliminated from the treated side. In vitro cell viability assay showed that lymphocytes were much more sensitive to the cytotoxic effects of mechlorethamine than skin and hair follicular cells. RNase protection assay and real-time reverse transcription polymerase chain reaction showed that tumor necrosis factor alpha/beta, interleukin-12, and interferon-gamma were inhibited by mechlorethamine upon successful treatment. Our findings support that mechlorethamine restores follicular activity by selectively targeting infiltrated lymphocytes in vivo in alopecia-areata-affected mice.

  9. Restoration of Dlk1 and Rtl1 is necessary but insufficient to rescue lethality in intergenic differentially methylated region (IG-DMR)-deficient mice.

    PubMed

    Takahashi, Nozomi; Kobayashi, Ryota; Kono, Tomohiro

    2010-08-20

    In the Dlk1-Dio3 imprinted domain, an intergenic differentially methylated region (IG-DMR) regulates the parental allele-specific expression of imprinted genes. The maternally inherited deletion of IG-DMR (IG-DMR((-/+))) results in perinatal lethality because of the overexpression of paternally expressed genes and repression of maternally expressed noncoding RNAs (ncRNAs), including Gtl2. To better understand the possible contribution of paternally expressed genes to the lethality, we attempted to rescue the lethality of IG-DMR((-/+)) mutants by restoring the paternally expressed genes. Because the paternally inherited Gtl2 deletion (Gtl2((+/-))) induced a decrease in the expression of paternally expressed genes, we crossed female IG-DMR heterozygous mice and male Gtl2 heterozygous mutant mice. The resultant IG-DMR((-/+))/Gtl2((+/-)) double mutant mice had normal expression levels of paternally expressed genes, and none of them showed perinatal lethality; however, most mice showed postnatal lethality with decreased expression of the maternally expressed ncRNAs. Thus, we inferred that paternally expressed genes are necessary for perinatal survivability and that maternally expressed ncRNAs are involved in postnatal lethality.

  10. Prebiotic inulin supplementation modulates the immune response and restores gut morphology in Giardia duodenalis-infected malnourished mice.

    PubMed

    Shukla, Geeta; Bhatia, Ruchika; Sharma, Anuj

    2016-11-01

    Malnutrition induces a state of growth retardation and immunologic depression, enhancing the host susceptibility to various infections. In the present study, it was observed that prebiotic supplementation either prior or simultaneously with Giardia infection in malnourished mice significantly reduced the severity of giardiasis and increased the body and small intestine mass, along with increased lactobacilli counts in faeces compared with malnourished-Giardia-infected mice. More specifically, prebiotic supplementation significantly increased the levels of anti-giardial IgG and IgA antibodies and anti-inflammatory cytokines IL-6 and IL-10 and reduced the pro-inflammatory cytokine TNF-α, along with increased levels of nitric oxide in both the serum and intestinal fluid of malnourished-prebiotic-Giardia-infected mice compared with malnourished-Giardia-infected mice. Histopathology and scanning electron microscopy of the small intestine also revealed less cellular and mucosal damage in the microvilli of prebiotic-supplemented malnourished-Giardia-infected mice compared with severely damaged mummified and blunted villi of malnourished-Giardia-infected mice. This is the first study to report that prebiotic supplementation modulated the gut morphology and improved the immune status even in malnourished-Giardia-infected mice.

  11. Activity-Based Protein Profiling Reveals Mitochondrial Oxidative Enzyme Impairment and Restoration in Diet-Induced Obese Mice

    SciTech Connect

    Sadler, Natalie C.; Angel, Thomas E.; Lewis, Michael P.; Pederson, Leeanna M.; Chauvigne-Hines, Lacie M.; Wiedner, Susan D.; Zink, Erika M.; Smith, Richard D.; Wright, Aaron T.

    2012-10-24

    High-fat diet (HFD) induced obesity and concomitant development of insulin resistance (IR) and type 2 diabetes mellitus have been linked to mitochondrial dysfunction. However, it is not clear whether mitochondrial dysfunction is a direct effect of a HFD or if the mitochondrial function is reduced with increased HFD duration. We hypothesized that the function of mitochondrial oxidative and lipid metabolism functions in skeletal muscle mitochondria for HFD mice are similar or elevated relative to standard diet (SD) mice, thereby IR is neither cause nor consequence of mitochondrial dysfunction. We applied a chemical probe approach to identify functionally reactive ATPases and nucleotide-binding proteins in mitochondria isolated from skeletal muscle of C57Bl/6J mice fed HFD or SD chow for 2-, 8-, or 16-weeks; feeding time points known to induce IR. A total of 293 probe-labeled proteins were identified by mass spectrometry-based proteomics, of which 54 differed in abundance between HFD and SD mice. We found proteins associated with the TCA cycle, oxidative phosphorylation (OXPHOS), and lipid metabolism were altered in function when comparing SD to HFD fed mice at 2-weeks, however by 16-weeks HFD mice had TCA cycle, β-oxidation, and respiratory chain function at levels similar to or higher than SD mice.

  12. Troxerutin improves hepatic lipid homeostasis by restoring NAD(+)-depletion-mediated dysfunction of lipin 1 signaling in high-fat diet-treated mice.

    PubMed

    Zhang, Zi-Feng; Fan, Shao-Hua; Zheng, Yuan-Lin; Lu, Jun; Wu, Dong-Mei; Shan, Qun; Hu, Bin

    2014-09-01

    Recent evidences suggest that NAD(+) depletion leads to abnormal hepatic lipid metabolism in high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD); however, the contributing mechanism is not well understood. Our previous study showed that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, effectively inhibited obesity, and normalized hyperglycemia and hyperlipidemia in high-cholesterol diet-induced diabetic mice. Here we investigated whether troxerutin improved hepatic lipid metabolism via preventing NAD(+) depletion in HFD-induced NAFLD mouse model and the mechanisms underlying these effects. Our results showed that troxerutin markedly prevented obesity, liver steatosis and injury in HFD-fed mice. Troxerutin largely suppressed oxidative stress-mediated NAD(+)-depletion by increasing nicotinamide phosphoribosyltransferase (NAMPT) protein expression and decreasing poly (ADP-ribose) polymerase-1 (PARP1) protein expression and activity in HFD-treated mouse livers. Consequently, troxerutin remarkably restored Silent mating type information regulation 2 homolog1 (SirT1) protein expression and activity in HFD-treated mouse livers. Therefore, troxerutin promoted SirT1-mediated AMP-activated protein kinase (AMPK) activation to inhibit mammalian target of rapamycin complex 1 (mTORC1) signaling, which enhanced nuclear lipin 1 localization, lowered cytoplasmic lipin 1 localization and the ratio of hepatic Lpin 1β/α. Ultimately, troxerutin improved lipid homeostasis by enhancing fatty acid oxidation and triglyceride secretion, and suppressing lipogenesis in HFD-fed mouse livers. In conclusion, troxerutin displayed beneficial effects on hepatic lipid homeostasis in HFD-induced NAFLD by blocking oxidative stress to restore NAD(+)-depletion-mediated dysfunction of lipin 1 signaling. This study provides novel mechanistic insights into NAFLD pathogenesis and indicates that troxerutin is a candidate for pharmacological intervention of NAFLD

  13. Tetrandrine ameliorates collagen-induced arthritis in mice by restoring the balance between Th17 and Treg cells via the aryl hydrocarbon receptor.

    PubMed

    Yuan, Xusheng; Tong, Bei; Dou, Yannong; Wu, Xin; Wei, Zhifeng; Dai, Yue

    2016-02-01

    Tetrandrine is an alkaloid constituent of the root of Stephania tetrandra S. Moore. The long-term clinical uses of tetrandrine for treatments of rheumatalgia and arthralgia as well as the inhibition of rat adjuvant-induced arthritis imply that tetrandrine may have therapeutic potential in rheumatoid arthritis (RA). Here, we explored its anti-RA mechanism in collagen-induced arthritis (CIA) in relation to the balance between T helper (Th) 17 cells and regulatory T (Treg) cells. DBA/1 mice were immunized with chicken type II collagen and were orally administered tetrandrine for 14 consecutive days. Then, the mice were sacrificed, their joints were removed for histological analysis, and spleens and mesenteric lymph nodes (MLNs) were removed to examine the Th17 and Treg cells. Tetrandrine markedly alleviated the severity of arthritis, reduced the serum levels of pro-inflammatory cytokines, and restored the Th17/Treg balance, as demonstrated by the serum levels of their related cytokines (IL-17 and IL-10) and the proportion of each cell type. Tetrandrine inhibited Th17 cell differentiation and induced Treg cell differentiation in vitro . Notably, aryl hydrocarbon receptor (AhR) was proven to play a crucial role in tetrandrine-mediated T cell differentiation. The correlation between AhR activation, regulation of Th17/Treg and amelioration of arthritis by tetrandrine was verified in the CIA mice. Moreover, tetrandrine might be a ligand of AhR because it facilitated the expression of the AhR target gene cytochrome P450 1A1 (CYP1A1) and the activation of its downstream signaling pathways. Taken together, tetrandrine exerts its anti-arthritis efficacy by restoring Th17/Treg balance via AhR.

  14. Age-dependent effects of esculetin on mood-related behavior and cognition from stressed mice are associated with restoring brain antioxidant status.

    PubMed

    Martín-Aragón, Sagrario; Villar, Ángel; Benedí, Juana

    2016-02-04

    Dietary antioxidants might exert an important role in the aging process by relieving oxidative damage, a likely cause of age-associated brain dysfunctions. This study aims to investigate the influence of esculetin (6,7-dihydroxycoumarin), a naturally occurring antioxidant in the diet, on mood-related behaviors and cognitive function and its relation with age and brain oxidative damage. Behavioral tests were employed in 11-, 17- and 22-month-old male C57BL/6J mice upon an oral 35day-esculetin treatment (25mg/kg). Activity of antioxidant enzymes, GSH and GSSG levels, GSH/GSSG ratio, and mitochondrial function were analyzed in brain cortex at the end of treatment in order to assess the oxidative status related to mouse behavior. Esculetin treatment attenuated the increased immobility time and enhanced the diminished climbing time in the forced swim task elicited by acute restraint stress (ARS) in the 11- and 17-month-old mice versus their counterpart controls. Furthermore, ARS caused an impairment of contextual memory in the step-through passive avoidance both in mature adult and aged mice which was partially reversed by esculetin only in the 11-month-old mice. Esculetin was effective to prevent the ARS-induced oxidative stress mostly in mature adult mice by restoring antioxidant enzyme activities, augmenting the GSH/GSSG ratio and increasing cytochrome c oxidase (COX) activity in cortex. Modulation of the mood-related behavior and cognitive function upon esculetin treatment in a mouse model of ARS depends on age and is partly due to the enhancement of redox status and levels of COX activity in cortex. Copyright © 2015. Published by Elsevier Inc.

  15. Leptin administration restores the altered adipose and hepatic expression of aquaglyceroporins improving the non-alcoholic fatty liver of ob/ob mice.

    PubMed

    Rodríguez, Amaia; Moreno, Natalia R; Balaguer, Inmaculada; Méndez-Giménez, Leire; Becerril, Sara; Catalán, Victoria; Gómez-Ambrosi, Javier; Portincasa, Piero; Calamita, Giuseppe; Soveral, Graça; Malagón, María M; Frühbeck, Gema

    2015-07-10

    Glycerol is an important metabolite for the control of lipid accumulation in white adipose tissue (WAT) and liver. We aimed to investigate whether exogenous administration of leptin improves features of non-alcoholic fatty liver disease (NAFLD) in leptin-deficient ob/ob mice via the regulation of AQP3 and AQP7 (glycerol channels mediating glycerol efflux in adipocytes) and AQP9 (aquaglyceroporin facilitating glycerol influx in hepatocytes). Twelve-week-old male wild type and ob/ob mice were divided in three groups as follows: control, leptin-treated (1 mg/kg/d) and pair-fed. Leptin deficiency was associated with obesity and NAFLD exhibiting an AQP3 and AQP7 increase in WAT, without changes in hepatic AQP9. Adipose Aqp3 and hepatic Aqp9 transcripts positively correlated with markers of adiposity and hepatic steatosis. Chronic leptin administration (4-weeks) was associated with improved body weight, whole-body adiposity, and hepatosteatosis of ob/ob mice and to a down-regulation of AQP3, AQP7 in WAT and an up-regulation of hepatic AQP9. Acute leptin stimulation in vitro (4-h) induced the mobilization of aquaglyceroporins towards lipid droplets (AQP3) and the plasma membrane (AQP7) in murine adipocytes. Our results show that leptin restores the coordinated regulation of fat-specific AQP7 and liver-specific AQP9, a step which might prevent lipid overaccumulation in WAT and liver in obesity.

  16. Leptin administration restores the altered adipose and hepatic expression of aquaglyceroporins improving the non-alcoholic fatty liver of ob/ob mice

    PubMed Central

    Rodríguez, Amaia; Moreno, Natalia R.; Balaguer, Inmaculada; Méndez-Giménez, Leire; Becerril, Sara; Catalán, Victoria; Gómez-Ambrosi, Javier; Portincasa, Piero; Calamita, Giuseppe; Soveral, Graça; Malagón, María M.; Frühbeck, Gema

    2015-01-01

    Glycerol is an important metabolite for the control of lipid accumulation in white adipose tissue (WAT) and liver. We aimed to investigate whether exogenous administration of leptin improves features of non-alcoholic fatty liver disease (NAFLD) in leptin-deficient ob/ob mice via the regulation of AQP3 and AQP7 (glycerol channels mediating glycerol efflux in adipocytes) and AQP9 (aquaglyceroporin facilitating glycerol influx in hepatocytes). Twelve-week-old male wild type and ob/ob mice were divided in three groups as follows: control, leptin-treated (1 mg/kg/d) and pair-fed. Leptin deficiency was associated with obesity and NAFLD exhibiting an AQP3 and AQP7 increase in WAT, without changes in hepatic AQP9. Adipose Aqp3 and hepatic Aqp9 transcripts positively correlated with markers of adiposity and hepatic steatosis. Chronic leptin administration (4-weeks) was associated with improved body weight, whole-body adiposity, and hepatosteatosis of ob/ob mice and to a down-regulation of AQP3, AQP7 in WAT and an up-regulation of hepatic AQP9. Acute leptin stimulation in vitro (4-h) induced the mobilization of aquaglyceroporins towards lipid droplets (AQP3) and the plasma membrane (AQP7) in murine adipocytes. Our results show that leptin restores the coordinated regulation of fat-specific AQP7 and liver-specific AQP9, a step which might prevent lipid overaccumulation in WAT and liver in obesity. PMID:26159457

  17. Bone homeostasis in growth hormone receptor-null mice is restored by IGF-I but independent of Stat5.

    PubMed

    Sims, N A; Clément-Lacroix, P; Da Ponte, F; Bouali, Y; Binart, N; Moriggl, R; Goffin, V; Coschigano, K; Gaillard-Kelly, M; Kopchick, J; Baron, R; Kelly, P A

    2000-11-01

    Growth hormone (GH) regulates both bone growth and remodeling, but it is unclear whether these actions are mediated directly by the GH receptor (GHR) and/or IGF-I signaling. The actions of GH are transduced by the Jak/Stat signaling pathway via Stat5, which is thought to regulate IGF-I expression. To determine the respective roles of GHR and IGF-I in bone growth and remodeling, we examined bones of wild-type, GHR knockout (GHR(-/-)), Stat5ab(-/-), and GHR(-/-) mice treated with IGF-I. Reduced bone growth in GHR(-/-) mice, due to a premature reduction in chondrocyte proliferation and cortical bone growth, was detected after 2 weeks of age. Additionally, although trabecular bone volume was unchanged, bone turnover was significantly reduced in GHR(-/-) mice, indicating GH involvement in the high bone-turnover level during growth. IGF-I treatment almost completely rescued all effects of the GHR(-/-) on both bone growth and remodeling, supporting a direct effect of IGF-I on both osteoblasts and chondrocytes. Whereas bone length was reduced in Stat5ab(-/-) mice, there was no reduction in trabecular bone remodeling or growth-plate width as observed in GHR(-/-) mice, indicating that the effects of GH in bone may not involve Stat5 activation.

  18. Treatment with Interleukin-7 Restores Host Defense against Pneumocystis in CD4+ T-Lymphocyte-Depleted Mice

    PubMed Central

    Samuelson, D. R.; Assouline, B.; Morre, M.; Shellito, J. E.

    2015-01-01

    Pneumocystis pneumonia (PCP) is a major cause of morbidity and mortality in patients with HIV infection. CD4+ T lymphocytes are critical for host defense against this infection, but in the absence of CD4+ T lymphocytes, CD8+ T lymphocytes may provide limited host defense. The cytokine interleukin-7 (IL-7) functions to enhance lymphocyte proliferation, survival, and recruitment of immune cells to sites of infection. However, there is little known about the role of IL-7 in PCP or its potential use as an immunotherapeutic agent. We hypothesized that treatment with recombinant human IL-7 (rhIL-7) would augment host defense against Pneumocystis and accelerate pathogen clearance in CD4-depleted mice. Control and CD4-depleted mice were infected with Pneumocystis, and rhIL-7 was administered via intraperitoneal injection. Our studies indicate that endogenous murine IL-7 is part of the normal host response to Pneumocystis murina and that administration of rhIL-7 markedly enhanced clearance of Pneumocystis in CD4-depleted mice. Additionally, we observed increased recruitment of CD8+ T lymphocytes to the lungs and decreased apoptosis of pulmonary CD8+ T lymphocytes in rhIL-7-treated animals compared to those in untreated mice. The antiapoptotic effect of rhIL-7 was associated with increased levels of Bcl-2 protein in T lymphocytes. rhIL-7 immunotherapy in CD4-depleted mice also increased the number of gamma interferon (IFN-γ)-positive CD8+ central memory T lymphocytes in the lungs. We conclude that rhIL-7 has a potent therapeutic effect in the treatment of murine Pneumocystis pneumonia in CD4-depleted mice. This therapeutic effect is mediated through enhanced recruitment of CD8+ T cells and decreased apoptosis of lung T lymphocytes, with a preferential action on central memory CD8+ T lymphocytes. PMID:26483405

  19. Delineation of biochemical, molecular, and physiological changes accompanying bile acid pool size restoration in Cyp7a1−/− mice fed low levels of cholic acid

    PubMed Central

    Jones, Ryan D.; Repa, Joyce J.; Russell, David W.; Dietschy, John M.

    2012-01-01

    Cholesterol 7α-hydroxylase (CYP7A1) is the initiating and rate-limiting enzyme in the neutral pathway that coverts cholesterol to primary bile acids (BA). CYP7A1-deficient (Cyp7a1−/−) mice have a depleted BA pool, diminished intestinal cholesterol absorption, accelerated fecal sterol loss, and increased intestinal cholesterol synthesis. To determine the molecular and physiological effects of restoring the BA pool in this model, adult female Cyp7a1−/− mice and matching Cyp7a1+/+ controls were fed diets containing cholic acid (CA) at modest levels [0.015, 0.030, and 0.060% (wt/wt)] for 15–18 days. A level of just 0.03% provided a CA intake of ∼12 μmol (4.8 mg) per day per 100 g body wt and was sufficient in the Cyp7a1−/− mice to normalize BA pool size, fecal BA excretion, fractional cholesterol absorption, and fecal sterol excretion but caused a significant rise in the cholesterol concentration in the small intestine and liver, as well as a marked inhibition of cholesterol synthesis in these organs. In parallel with these metabolic changes, there were marked shifts in intestinal and hepatic expression levels for many target genes of the BA sensor farnesoid X receptor, as well as genes involved in cholesterol transport, especially ATP-binding cassette (ABC) transporter A1 (ABCA1) and ABCG8. In Cyp7a1+/+ mice, this level of CA supplementation did not significantly disrupt BA or cholesterol metabolism, except for an increase in fecal BA excretion and marginal changes in mRNA expression for some BA synthetic enzymes. These findings underscore the importance of using moderate dietary BA levels in studies with animal models. PMID:22628034

  20. Delineation of biochemical, molecular, and physiological changes accompanying bile acid pool size restoration in Cyp7a1(-/-) mice fed low levels of cholic acid.

    PubMed

    Jones, Ryan D; Repa, Joyce J; Russell, David W; Dietschy, John M; Turley, Stephen D

    2012-07-15

    Cholesterol 7α-hydroxylase (CYP7A1) is the initiating and rate-limiting enzyme in the neutral pathway that converts cholesterol to primary bile acids (BA). CYP7A1-deficient (Cyp7a1(-/-)) mice have a depleted BA pool, diminished intestinal cholesterol absorption, accelerated fecal sterol loss, and increased intestinal cholesterol synthesis. To determine the molecular and physiological effects of restoring the BA pool in this model, adult female Cyp7a1(-/-) mice and matching Cyp7a1(+/+) controls were fed diets containing cholic acid (CA) at modest levels [0.015, 0.030, and 0.060% (wt/wt)] for 15-18 days. A level of just 0.03% provided a CA intake of ~12 μmol (4.8 mg) per day per 100 g body wt and was sufficient in the Cyp7a1(-/-) mice to normalize BA pool size, fecal BA excretion, fractional cholesterol absorption, and fecal sterol excretion but caused a significant rise in the cholesterol concentration in the small intestine and liver, as well as a marked inhibition of cholesterol synthesis in these organs. In parallel with these metabolic changes, there were marked shifts in intestinal and hepatic expression levels for many target genes of the BA sensor farnesoid X receptor, as well as genes involved in cholesterol transport, especially ATP-binding cassette (ABC) transporter A1 (ABCA1) and ABCG8. In Cyp7a1(+/+) mice, this level of CA supplementation did not significantly disrupt BA or cholesterol metabolism, except for an increase in fecal BA excretion and marginal changes in mRNA expression for some BA synthetic enzymes. These findings underscore the importance of using moderate dietary BA levels in studies with animal models.

  1. Short-term pharmacological suppression of the hyperprolactinemia of infertile hCG-overproducing female mice persistently restores their fertility.

    PubMed

    Ratner, Laura D; Gonzalez, Betina; Ahtiainen, Petteri; Di Giorgio, Noelia P; Poutanen, Matti; Calandra, Ricardo S; Huhtaniemi, Ilpo T; Rulli, Susana B

    2012-12-01

    Female infertility is often associated with deregulation of hormonal networks, and hyperprolactinemia is one of the most common endocrine disorders of the hypothalamic-pituitary axis affecting the reproductive functions. We have shown previously that transgenic female mice overexpressing human chorionic gonadotropin β-subunit (hCGβ+ mice), and producing elevated levels of bioactive LH/hCG, exhibit increased production of testosterone and progesterone, are overweight and infertile, and develop hyperprolactinemia associated with pituitary lactotrope adenomas in adult age. In the present study, we analyzed the influence of the hyperprolactinemia of hCGβ+ females on their reproductive phenotype by treating them with the dopamine agonists, bromocriptine and cabergoline. Long-term bromocriptine treatment of adult mice was effective in the control of obesity, pituitary growth, and disturbances in the hormone profile, demonstrating that hyperprolactinemia was the main cause of the hCGβ+ female phenotype. Interestingly, short-term treatment (1 wk) with cabergoline applied on 5-wk-old mice corrected hyperprolactinemia, hyperandrogenism, and hyperprogesteronemia, prevented pituitary overgrowth, normalized gonadal function, and recovered fertility of adult hCGβ+ females after hormone-induced and natural ovulation. The same cabergoline treatment in the short term applied on 3-month-old hCGβ+ females failed to recover their reproductive function. Hence, we demonstrated that the short-term cabergoline treatment applied at a critical early stage of the phenotype progression effectively prevented the hyperprolactinemia-associated reproductive dysfunction of hCG-overproducing females.

  2. Short-Term Pharmacological Suppression of the Hyperprolactinemia of Infertile hCG-Overproducing Female Mice Persistently Restores Their Fertility

    PubMed Central

    Ratner, Laura D.; Gonzalez, Betina; Ahtiainen, Petteri; Di Giorgio, Noelia P.; Poutanen, Matti; Calandra, Ricardo S.; Huhtaniemi, Ilpo T.

    2012-01-01

    Female infertility is often associated with deregulation of hormonal networks, and hyperprolactinemia is one of the most common endocrine disorders of the hypothalamic-pituitary axis affecting the reproductive functions. We have shown previously that transgenic female mice overexpressing human chorionic gonadotropin β-subunit (hCGβ+ mice), and producing elevated levels of bioactive LH/hCG, exhibit increased production of testosterone and progesterone, are overweight and infertile, and develop hyperprolactinemia associated with pituitary lactotrope adenomas in adult age. In the present study, we analyzed the influence of the hyperprolactinemia of hCGβ+ females on their reproductive phenotype by treating them with the dopamine agonists, bromocriptine and cabergoline. Long-term bromocriptine treatment of adult mice was effective in the control of obesity, pituitary growth, and disturbances in the hormone profile, demonstrating that hyperprolactinemia was the main cause of the hCGβ+ female phenotype. Interestingly, short-term treatment (1 wk) with cabergoline applied on 5-wk-old mice corrected hyperprolactinemia, hyperandrogenism, and hyperprogesteronemia, prevented pituitary overgrowth, normalized gonadal function, and recovered fertility of adult hCGβ+ females after hormone-induced and natural ovulation. The same cabergoline treatment in the short term applied on 3-month-old hCGβ+ females failed to recover their reproductive function. Hence, we demonstrated that the short-term cabergoline treatment applied at a critical early stage of the phenotype progression effectively prevented the hyperprolactinemia-associated reproductive dysfunction of hCG-overproducing females. PMID:23117930

  3. The γ-secretase modulator CHF5074 restores memory and hippocampal synaptic plasticity in plaque-free Tg2576 mice.

    PubMed

    Balducci, Claudia; Mehdawy, Bisan; Mare, Lydia; Giuliani, Alessandro; Lorenzini, Luca; Sivilia, Sandra; Giardino, Luciana; Calzà, Laura; Lanzillotta, Annamaria; Sarnico, Ilenia; Pizzi, Marina; Usiello, Alessandro; Viscomi, Arturo R; Ottonello, Simone; Villetti, Gino; Imbimbo, Bruno P; Nisticò, Giuseppe; Forloni, Gianluigi; Nisticò, Robert

    2011-01-01

    Abnormal amyloid-β (Aβ) production and deposition is believed to represent one of the main causes of Alzheimer's disease (AD). γ-Secretase is the enzymatic complex responsible for Aβ generation from its precursor protein. Inhibition or modulation of γ-secretase represents an attractive therapeutic approach. CHF5074 is a new γ-secretase modulator that has been shown to inhibit brain plaque deposition and to attenuate memory deficit in adult AD transgenic mice after chronic treatment. To date, it is not known whether the positive behavioral effects of this compound also occur in young transgenic mice without plaque deposition. Here, we evaluated the effects of acute and subchronic treatment with CHF5074 on contextual and recognition memory and on hippocampal synaptic plasticity in plaque-free Tg2576 mice. We found that at 5 months of age, contextual memory impairment was significantly attenuated after acute subcutaneous administration of 30 mg/kg CHF5074. At 6 months of age, recognition memory impairment was fully reversed after a 4-week oral treatment in the diet (≈60 mg/kg/day). These cognitive effects were associated with a reversal of long-term potentiation (LTP) impairment in the hippocampus. A significant reduction in brain intraneuronal AβPP/Aβ levels and hyperphosphorylated tau, but no change in soluble or oligomeric Aβ levels was detected in Tg2576 mice showing functional recovery following CHF5074 treatment. We conclude that the beneficial effects of CHF5074 treatment in young transgenic mice occurred at a stage that precedes plaque formation and were associated with a reduction in intraneuronal AβPP/Aβ and hyperphosphorylated tau.

  4. Melatonin Restores White Blood Cell Count, Diminishes Glycated Haemoglobin Level and Prevents Liver, Kidney and Muscle Oxidative Stress in Mice Exposed to Acute Ethanol Intoxication.

    PubMed

    Kurhaluk, Natalia; Sliuta, Alina; Kyriienko, Svitlana; Winklewski, Pawel J

    2017-09-01

    The aim of the study was to examine the effects of melatonin impact on changes in haematological profile, biomarkers of oxidative stress (dienes conjugates, malondialdehyde (MDA), oxidatively modified protein levels, total antioxidant capacity and antioxidant enzyme activity) in liver, muscle, kidney and erythrocytes, and glycated haemoglobin (HBA1c) in mice during acute ethanol stress. Assays were carried out in quadruplicate: control, melatonin (10 mg/kg, 10 days), acute ethanol stress (0.75 g/kg/day, 10 days) and acute ethanol stress plus melatonin groups. Acute ethanol stress caused a significant increase in the total number of white blood cells (WBC), especially neutrophils in the blood, and HBA1c levels vs. control mice. The correlation between lipid peroxidation and the glycated haemoglobin level was shown (r = 0.93, P = 0.007). Ethanol reduced the antioxidant capacity by increasing reactive oxygen species (ROS) production and the level of oxidatively modified protein content, diene conjugates and MDA. Melatonin administration in animals during acute ethanol stress reduced antioxidant stress biomarkers, WBC, HBA1c levels and ROS production. Melatonin had protective effects on liver, kidney and muscle tissues by preventing the intensive lipid peroxidation processes in initial (diene conjugation production) and late stages (MDA level), and significantly reduced the level of aldehyde and ketone protein derivatives. Furthermore, melatonin restored elevated WBC count and HBA1c level and diminished ROS production. Ethanol reduces antioxidant capacity and leads to exaggerated reactive oxygen species production and consequent increases in oxidatively modified proteins. Melatonin exerts protective effects by preventing the intensive lipid peroxidation processes. Melatonin significantly reduces the level of aldehyde and ketone protein derivatives, restores glycated haemoglobin level and white blood cell count.

  5. CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure

    PubMed Central

    Stutchfield, Benjamin M.; Antoine, Daniel J.; Mackinnon, Alison C.; Gow, Deborah J.; Bain, Calum C.; Hawley, Catherine A.; Hughes, Michael J.; Francis, Benjamin; Wojtacha, Davina; Man, Tak Y.; Dear, James W.; Devey, Luke R.; Mowat, Alan M.; Pollard, Jeffrey W.; Park, B. Kevin; Jenkins, Stephen J.; Simpson, Kenneth J.; Hume, David A.; Wigmore, Stephen J.; Forbes, Stuart J.

    2015-01-01

    Background & Aims Liver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised after liver injury. The numbers of liver macrophages are controlled by macrophage colony-stimulating factor (CSF1). We examined the prognostic significance of the serum level of CSF1 in patients with acute liver injury and studied its effects in mice. Methods We measured levels of CSF1 in serum samples collected from 55 patients who underwent partial hepatectomy at the Royal Infirmary Edinburgh between December 2012 and October 2013, as well as from 78 patients with acetaminophen-induced acute liver failure admitted to the Royal Infirmary Edinburgh or the University of Kansas Medical Centre. We studied the effects of increased levels of CSF1 in uninjured mice that express wild-type CSF1 receptor or a constitutive or inducible CSF1-receptor reporter, as well as in chemokine receptor 2 (Ccr2)-/- mice; we performed fate-tracing experiments using bone marrow chimeras. We administered CSF1-Fc (fragment, crystallizable) to mice after partial hepatectomy and acetaminophen intoxication, and measured regenerative parameters and innate immunity by clearance of fluorescent microbeads and bacterial particles. Results Serum levels of CSF1 increased in patients undergoing liver surgery in proportion to the extent of liver resected. In patients with acetaminophen-induced acute liver failure, a low serum level of CSF1 was associated with increased mortality. In mice, administration of CSF1-Fc promoted hepatic macrophage accumulation via proliferation of resident macrophages and recruitment of monocytes. CSF1-Fc also promoted transdifferentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice after partial hepatectomy or acetaminophen-induced injury, with resident hepatic macrophage as the main effector cells. Conclusions Serum CSF1 appears to be a prognostic marker for patients

  6. Inhibitory Interneuron Progenitor Transplantation Restores Normal Learning and Memory in ApoE4 Knock-In Mice without or with Aβ Accumulation

    PubMed Central

    Tong, Leslie M.; Djukic, Biljana; Arnold, Christine; Gillespie, Anna K.; Yoon, Seo Yeon; Wang, Max M.; Zhang, Olivia; Knoferle, Johanna; Rubenstein, John L.R.; Alvarez-Buylla, Arturo

    2014-01-01

    Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory. Apolipoprotein (apo) E4 and amyloid-β (Aβ) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gyrus in AD-related mouse models and humans, leading to learning and memory deficits. To determine whether replacing the lost or impaired interneurons rescues neuronal signaling and behavioral deficits, we transplanted embryonic interneuron progenitors into the hippocampal hilus of aged apoE4 knock-in mice without or with Aβ accumulation. In both conditions, the transplanted cells developed into mature interneurons, functionally integrated into the hippocampal circuitry, and restored normal learning and memory. Thus, restricted hilar transplantation of inhibitory interneurons restores normal cognitive function in two widely used AD-related mouse models, highlighting the importance of interneuron impairments in AD pathogenesis and the potential of cell replacement therapy for AD. More broadly, it demonstrates that excitatory and inhibitory balance are crucial for learning and memory, and suggests an avenue for investigating the processes of learning and memory and their alterations in healthy aging and diseases. PMID:25031394

  7. Inhibitory interneuron progenitor transplantation restores normal learning and memory in ApoE4 knock-in mice without or with Aβ accumulation.

    PubMed

    Tong, Leslie M; Djukic, Biljana; Arnold, Christine; Gillespie, Anna K; Yoon, Seo Yeon; Wang, Max M; Zhang, Olivia; Knoferle, Johanna; Rubenstein, John L R; Alvarez-Buylla, Arturo; Huang, Yadong

    2014-07-16

    Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory. Apolipoprotein (apo) E4 and amyloid-β (Aβ) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gyrus in AD-related mouse models and humans, leading to learning and memory deficits. To determine whether replacing the lost or impaired interneurons rescues neuronal signaling and behavioral deficits, we transplanted embryonic interneuron progenitors into the hippocampal hilus of aged apoE4 knock-in mice without or with Aβ accumulation. In both conditions, the transplanted cells developed into mature interneurons, functionally integrated into the hippocampal circuitry, and restored normal learning and memory. Thus, restricted hilar transplantation of inhibitory interneurons restores normal cognitive function in two widely used AD-related mouse models, highlighting the importance of interneuron impairments in AD pathogenesis and the potential of cell replacement therapy for AD. More broadly, it demonstrates that excitatory and inhibitory balance are crucial for learning and memory, and suggests an avenue for investigating the processes of learning and memory and their alterations in healthy aging and diseases. Copyright © 2014 the authors 0270-6474/14/349506-10$15.00/0.

  8. Vitreal delivery of AAV vectored Cnga3 restores cone function in CNGA3-/-/Nrl-/- mice, an all-cone model of CNGA3 achromatopsia.

    PubMed

    Du, Wei; Tao, Ye; Deng, Wen-Tao; Zhu, Ping; Li, Jie; Dai, Xufeng; Zhang, Yuxin; Shi, Wei; Liu, Xuan; Chiodo, Vince A; Ding, Xi-Qin; Zhao, Chen; Michalakis, Stylianos; Biel, Martin; Zhang, Zuoming; Qu, Jia; Hauswirth, William W; Pang, Ji-Jing

    2015-07-01

    The CNGA3(-/-)/Nrl(-/-) mouse is a cone-dominant model with Cnga3 channel deficiency, which partially mimics the all cone foveal structure of human achromatopsia 2 with CNGA3 mutations. Although subretinal (SR) AAV vector administration can transfect retinal cells efficiently, the injection-induced retinal detachment can cause retinal damage, particularly when SR vector bleb includes the fovea. We therefore explored whether cone function-structure could be rescued in CNGA3(-/-)/Nrl(-/-) mice by intravitreal (IVit) delivery of tyrosine to phenylalanine (Y-F) capsid mutant AAV8. We find that AAV-mediated CNGA3 expression can restore cone function and rescue structure following IVit delivery of AAV8 (Y447, 733F) vector. Rescue was assessed by restoration of the cone-mediated electroretinogram (ERG), optomotor responses, and cone opsin immunohistochemistry. Demonstration of gene therapy in a cone-dominant mouse model by IVit delivery provides a potential alternative vector delivery mode for safely transducing foveal cones in achromatopsia patients and in other human retinal diseases affecting foveal function. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Vitreal delivery of AAV vectored Cnga3 restores cone function in CNGA3−/−/Nrl−/− mice, an all-cone model of CNGA3 achromatopsia†

    PubMed Central

    Du, Wei; Tao, Ye; Deng, Wen-Tao; Zhu, Ping; Li, Jie; Dai, Xufeng; Zhang, Yuxin; Shi, Wei; Liu, Xuan; Chiodo, Vince A.; Ding, Xi-Qin; Zhao, Chen; Michalakis, Stylianos; Biel, Martin; Zhang, Zuoming; Qu, Jia; Hauswirth, William W.; Pang, Ji-jing

    2015-01-01

    The CNGA3−/−/Nrl−/− mouse is a cone-dominant model with Cnga3 channel deficiency, which partially mimics the all cone foveal structure of human achromatopsia 2 with CNGA3 mutations. Although subretinal (SR) AAV vector administration can transfect retinal cells efficiently, the injection-induced retinal detachment can cause retinal damage, particularly when SR vector bleb includes the fovea. We therefore explored whether cone function–structure could be rescued in CNGA3−/−/Nrl−/− mice by intravitreal (IVit) delivery of tyrosine to phenylalanine (Y-F) capsid mutant AAV8. We find that AAV-mediated CNGA3 expression can restore cone function and rescue structure following IVit delivery of AAV8 (Y447, 733F) vector. Rescue was assessed by restoration of the cone-mediated electroretinogram (ERG), optomotor responses, and cone opsin immunohistochemistry. Demonstration of gene therapy in a cone-dominant mouse model by IVit delivery provides a potential alternative vector delivery mode for safely transducing foveal cones in achromatopsia patients and in other human retinal diseases affecting foveal function. PMID:25855802

  10. Insulin Restores an Altered Corneal Epithelium Circadian Rhythm in Mice with Streptozotocin-induced Type 1 Diabetes

    PubMed Central

    Song, Fang; Xue, Yunxia; Dong, Dong; Liu, Jun; Fu, Ting; Xiao, Chengju; Wang, Hanqing; Lin, Cuipei; Liu, Peng; Zhong, Jiajun; Yang, Yabing; Wang, Zhaorui; Pan, Hongwei; Chen, Jiansu; Li, Yangqiu; Cai, Dongqing; Li, Zhijie

    2016-01-01

    The mechanisms of corneal epithelial lesions and delayed wound repair, as well as their association with diabetes mellitus, are critical issues for clinical ophthalmologists. To test whether the diabetic condition alters the circadian rhythm in a mouse cornea and whether insulin can synchronise the corneal clock, we studied the effects of streptozotocin-induced diabetes on the mitosis of epithelial cells, the recruitment of leukocytes to the cornea, and the expression of main core clock genes (Clock, Bmal1, Per2, Cry1, and Rev-erbα) in the corneal epithelium. We also assessed the possible effect of insulin on these modifications. Diabetes downregulated Clock, Bmal1, and Per2 expression, upregulated Cry1 and Rev-erbα expression, reduced corneal epithelial mitosis, and increased leukocyte (neutrophils and γδ T-cells) recruitment to the cornea. Early treatments with insulin partially restored the altered rhythmicity in the diabetic cornea. In conclusion, insulin-dependent diabetes altered the normal rhythmicity of the cornea, and insulin administration had a beneficial effect on restoring normal rhythmicity in the diabetic cornea. PMID:27611469

  11. Conjunctivitis (Pink Eye) in Newborns

    MedlinePlus

    ... Antibiotics Work Adenovirus Non-Polio Enterovirus Parent Portal Conjunctivitis (Pink Eye) in Newborns Language: English Español (Spanish) ... can be very serious. Symptoms and Causes of Conjunctivitis in Newborns Newborns with conjunctivitis develop drainage from ...

  12. Arjunolic acid protects against DNCB-induced atopic dermatitis-like symptoms in mice by restoring a normal cytokine balance.

    PubMed

    Alyoussef, Abdullah

    2015-01-01

    Atopic dermatitis (AD) is a chronically relapsing, pruritic, eczematous skin disorder accompanying allergic inflammation. AD is triggered by oxidative stress and immune imbalance. The effect of oral arjunolic acid (AA) on 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis in mice was investigated. Repeated epicutaneous application of DNCB to the ear and shaved dorsal skin of mice was performed to induce AD-like symptoms and skin lesions: 250mg/kg AA was given orally for three weeks to assess its anti-pruritic effects. Serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-10, immunoglobulin (Ig)E and caspase-3 were assessed by ELISA. We found that AA alleviated DNCB-induced AD-like symptoms as quantified by skin lesions, dermatitis score, ear thickness and scratching behavior. Levels of reactive oxygen species in the AA group were significantly inhibited compared with those in the DNCB group. In parallel, AA blocked a DNCB-induced reduction in serum levels of IL-4 and IL-10 associated with an attenuation of DNCB-induced increases in serum TNF-α, IL-6, IgE and caspase-3. The results indicate that AA suppresses DNCB-induced AD in mice via redox balance and immune modulation, and could be a safe clinical treatment for AD.

  13. ABLATION OF THE UPR–MEDIATOR CHOP RESTORES MOTOR FUNCTION AND REDUCES DEMYELINATION IN CHARCOT MARIE TOOTH 1B MICE

    PubMed Central

    Pennuto, Maria; Tinelli, Elisa; Malaguti, MariaChiara; Del Carro, Ubaldo; D'Antonio, Maurizio; Ron, David; Quattrini, Angelo; Feltri, M. Laura; Wrabetz, Lawrence

    2008-01-01

    SUMMARY Deletion of serine 63 from P0 glycoprotein (P0S63del) causes Charcot-Marie-Tooth 1B neuropathy in humans, and P0S63del produces a very similar demyelinating neuropathy in transgenic mice. P0S63del is retained in the endoplasmic reticulum and fails to be incorporated into myelin. Here we report that P0S63del is globally misfolded and Schwann cells mount a consequential canonical unfolded protein response (UPR), that includes expression of the transcription factor CHOP, previously associated with apoptosis in ER-stressed cells. UPR activation and CHOP expression respond dynamically to P0S63del levels and are reversible, but are associated with only limited apoptosis of Schwann cells. Nonetheless, Chop ablation in S63del mice completely rescues their motor deficit and reduces active demyelination two-fold. This is the first indication that signaling through the CHOP arm of the UPR provokes demyelination in inherited neuropathy. In addition, S63del mice provide a unique opportunity to explore how cells can dysfunction yet survive in prolonged ER stress—important for neurodegeneration related to misfolded proteins. PMID:18255032

  14. β-Elemene attenuates atherosclerosis in apolipoprotein E-deficient mice via restoring NO levels and alleviating oxidative stress.

    PubMed

    Liu, Meng; Chen, Xiaotong; Ma, Ji; Hassan, Waseem; Wu, Huali; Ling, Jiawei; Shang, Jing

    2017-09-25

    β-Elemene is a major bioactive sesquiterpenoids compound isolated from the essential oils of Curcuma Wenyujin, a Chinese medicinal herb that treats tumor in clinics. However anti-atherosclerotic effects of β-elemene have not been fully investigated in vivo. The objective of this study is to further elucidate the anti-atherosclerotic activities of β-elemene in ApoE(-/-) mice. Staining techniques and immunohistochemistry were used to validate atherosclerosis. Serum lipids, plasma nitrite and nitrate were analyzed by colorometric methods. ROS and antioxidative enzymes were measured through kits. Proteome profiler array was performed to analyze atherosclerosis-related inflammatory Cytokine. Western blot was used for measuring various proteins expressions. These results revealed that β-elemene inhibited atherosclerotic lesion size and increased stability of plaques in ApoE(-/-) mice by alleviating levels of vascular oxidative stress and preventing pro-inflammatory cytokine production. In addition β-elemene maintained endothelial function by significantly improving plasma nitrite and nitrate levels and expression of phosphorylation-eNOS in vivo. β-elemene also increased the production of the nitric oxide (NO) in human umbilical vein endothelial cells (HUVECs) and promoted phosphorylation of eNOS(ser1177) and Akt in vitro. In Conclusive, data revealed that β-elemene attenuated atherosclerosis and enhanced stability of plaques at least partially through its antioxidative and anti-inflammatory features and protected against endothelial dysfunction in ApoE(-/-) mice. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  15. Reduced Diabetes in btk-Deficient Nonobese Diabetic Mice and Restoration of Diabetes with Provision of an Anti-Insulin IgH Chain Transgene1

    PubMed Central

    Kendall, Peggy L.; Moore, Daniel J.; Hulbert, Chrys; Hoek, Kristen L.; Khan, Wasif N.; Thomas, James W.

    2010-01-01

    Type 1 diabetes results from T cell-mediated destruction of insulin-producing β cells. Although elimination of B lymphocytes has proven successful at preventing disease, modulation of B cell function as a means to prevent type 1 diabetes has not been investigated. The development, fate, and function of B lymphocytes depend upon BCR signaling, which is mediated in part by Bruton’s tyrosine kinase (BTK). When introduced into NOD mice, btk deficiency only modestly reduces B cell numbers, but dramatically protects against diabetes. In NOD, btk deficiency mirrors changes in B cell subsets seen in other strains, but also improves B cell-related tolerance, as indicated by failure to generate insulin autoantibodies. Introduction of an anti-insulin BCR H chain transgene restores diabetes in btk-deficient NOD mice, indicating that btk-deficient B cells are functionally capable of promoting autoimmune diabetes if they have a critical autoimmune specificity. This suggests that the disease-protective effect of btk deficiency may reflect a lack of autoreactive specificities in the B cell repertoire. Thus, signaling via BTK can be modulated to improve B cell tolerance, and prevent T cell-mediated autoimmune diabetes. PMID:19841184

  16. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease

    PubMed Central

    Lin, Ai-Ling; Zheng, Wei; Halloran, Jonathan J; Burbank, Raquel R; Hussong, Stacy A; Hart, Matthew J; Javors, Martin; Shih, Yen-Yu Ian; Muir, Eric; Solano Fonseca, Rene; Strong, Randy; Richardson, Arlan G; Lechleiter, James D; Fox, Peter T; Galvan, Veronica

    2013-01-01

    Vascular pathology is a major feature of Alzheimer's disease (AD) and other dementias. We recently showed that chronic administration of the target-of-rapamycin (TOR) inhibitor rapamycin, which extends lifespan and delays aging, halts the progression of AD-like disease in transgenic human (h)APP mice modeling AD when administered before disease onset. Here we demonstrate that chronic reduction of TOR activity by rapamycin treatment started after disease onset restored cerebral blood flow (CBF) and brain vascular density, reduced cerebral amyloid angiopathy and microhemorrhages, decreased amyloid burden, and improved cognitive function in symptomatic hAPP (AD) mice. Like acetylcholine (ACh), a potent vasodilator, acute rapamycin treatment induced the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) and NO release in brain endothelium. Administration of the NOS inhibitor L-NG-Nitroarginine methyl ester reversed vasodilation as well as the protective effects of rapamycin on CBF and vasculature integrity, indicating that rapamycin preserves vascular density and CBF in AD mouse brains through NOS activation. Taken together, our data suggest that chronic reduction of TOR activity by rapamycin blocked the progression of AD-like cognitive and histopathological deficits by preserving brain vascular integrity and function. Drugs that inhibit the TOR pathway may have promise as a therapy for AD and possibly for vascular dementias. PMID:23801246

  17. Estrogen response element-independent estrogen receptor (ER)-alpha signaling does not rescue sexual behavior but restores normal testosterone secretion in male ERalpha knockout mice.

    PubMed

    McDevitt, Melissa A; Glidewell-Kenney, Christine; Weiss, Jeffrey; Chambon, Pierre; Jameson, J Larry; Levine, Jon E

    2007-11-01

    Estrogen receptor (ER)-alpha mediates estradiol (E(2)) actions in the male gonads and brain and is critical for normal male reproductive function. In the classical pathway, ERalpha binds to estrogen response elements (EREs) to regulate gene transcription. ERalpha can also regulate gene transcription independently of EREs via protein-protein interactions with transcription factors and additionally signal via rapid, nongenomic pathways originating at the cell membrane. This study assessed the degree to which ERE-independent ERalpha signaling can rescue the disrupted masculine sexual behaviors and elevated serum testosterone (T) levels that have been shown to result from ERalpha gene deletion. We utilized male ERalpha null mice that possess a ER knock-in mutation (E207A/G208A; AA), in which the mutant ERalpha is incapable of binding to DNA and can signal only through ERE-independent pathways (ERalpha(-/AA) mice). We found that sexual behavior, including mounting, is virtually absent in ERalpha(-/-) and ERalpha(-/AA) males, suggesting that ERE-independent signaling is insufficient to maintain any degree of normal sexual behavior in the absence of ERE binding. By contrast, ERE-independent signaling in the ERalpha(-/AA) mouse is sufficient to restore serum T levels to values observed in wild-type males. These data indicate that binding of ERs to EREs mediates most if not all of E(2)'s effects on male sexual behavior, whereas ERE-independent ERalpha signaling may mediate E(2)'s inhibitory effects on T production.

  18. Gene dysregulation is restored in the Parkinson’s disease MPTP neurotoxic mice model upon treatment of the therapeutic drug CuII(atsm)

    PubMed Central

    Cheng, Lesley; Quek, Camelia Y. J.; Hung, Lin W.; Sharples, Robyn A.; Sherratt, Nicki A.; Barnham, Kevin J.; Hill, Andrew F.

    2016-01-01

    The administration of MPTP selectively targets the dopaminergic system resulting in Parkinsonism-like symptoms and is commonly used as a mice model of Parkinson’s disease. We previously demonstrated that the neuroprotective compound CuII(atsm) rescues nigral cell loss and improves dopamine metabolism in the MPTP model. The mechanism of action of CuII(atsm) needs to be further defined to understand how the compound promotes neuronal survival. Whole genome transcriptomic profiling has become a popular method to examine the relationship between gene expression and function. Substantia nigra samples from MPTP-lesioned mice were evaluated using whole transcriptome sequencing to investigate the genes altered upon CuII(atsm) treatment. We identified 143 genes affected by MPTP lesioning that are associated with biological processes related to brain and cognitive development, dopamine synthesis and perturbed synaptic neurotransmission. Upon CuII(atsm) treatment, the expression of 40 genes involved in promoting dopamine synthesis, calcium signaling and synaptic plasticity were restored which were validated by qRT-PCR. The study provides the first detailed whole transcriptomic analysis of pathways involved in MPTP-induced Parkinsonism. In addition, we identify key therapeutic pathways targeted by a potentially new class of neuroprotective agents which may provide therapeutic benefits for other neurodegenerative disorders. PMID:26928495

  19. Preexposure to Olive Oil Polyphenols Extract Increases Oxidative Load and Improves Liver Mass Restoration after Hepatectomy in Mice via Stress-Sensitive Genes

    PubMed Central

    Marinić, Jelena; Broznić, Dalibor; Milin, Čedomila

    2016-01-01

    Polyphenols can act as oxidants in some conditions, inducing redox-sensitive genes. We investigated the effect of preexposure to the olive oil polyphenols extract (PFE) on time-dependent changes in the hepatic oxidative state in a model of liver regeneration—a process in which oxidative stress associated with the metabolic overload accounts for the early events that contribute to the onset of liver self-repair. Liver regeneration was induced by one-third hepatectomy in mice. Prior to hepatectomy, mice were intraperitoneally given either PFE (50 mg/kg body weight) or saline for seven consecutive days, while respective controls received vehicle alone. Redox state-regulating enzymes and thiol proteins along with the mRNA levels of Nrf2 gene and its targets γ-glutamylcysteine synthetase and heme oxygenase-1 were determined at different time intervals after hepatectomy. The liver mass restoration was calculated to assess hepatic regeneration. The resulting data demonstrate the effectiveness of preexposure to PFE in stimulating liver regeneration in a model of a small tissue loss which may be ascribed to the transient increase in oxidant load during the first hours after hepatectomy and associated induction of stress response gene-profiles under the control of Nrf2. PMID:26925195

  20. Gene dysregulation is restored in the Parkinson's disease MPTP neurotoxic mice model upon treatment of the therapeutic drug Cu(II)(atsm).

    PubMed

    Cheng, Lesley; Quek, Camelia Y J; Hung, Lin W; Sharples, Robyn A; Sherratt, Nicki A; Barnham, Kevin J; Hill, Andrew F

    2016-03-01

    The administration of MPTP selectively targets the dopaminergic system resulting in Parkinsonism-like symptoms and is commonly used as a mice model of Parkinson's disease. We previously demonstrated that the neuroprotective compound Cu(II)(atsm) rescues nigral cell loss and improves dopamine metabolism in the MPTP model. The mechanism of action of Cu(II)(atsm) needs to be further defined to understand how the compound promotes neuronal survival. Whole genome transcriptomic profiling has become a popular method to examine the relationship between gene expression and function. Substantia nigra samples from MPTP-lesioned mice were evaluated using whole transcriptome sequencing to investigate the genes altered upon Cu(II)(atsm) treatment. We identified 143 genes affected by MPTP lesioning that are associated with biological processes related to brain and cognitive development, dopamine synthesis and perturbed synaptic neurotransmission. Upon Cu(II)(atsm) treatment, the expression of 40 genes involved in promoting dopamine synthesis, calcium signaling and synaptic plasticity were restored which were validated by qRT-PCR. The study provides the first detailed whole transcriptomic analysis of pathways involved in MPTP-induced Parkinsonism. In addition, we identify key therapeutic pathways targeted by a potentially new class of neuroprotective agents which may provide therapeutic benefits for other neurodegenerative disorders.

  1. The natural killer cell dysfunction of aged mice is due to the bone marrow stroma and is not restored by IL-15/IL-15Rα treatment

    PubMed Central

    Nair, Savita; Fang, Min; Sigal, Luis J

    2015-01-01

    Immune dysfunctions in the elderly result in increased susceptibility to infectious diseases, cancer, and autoimmune diseases. Natural killer (NK) cells are bone marrow-derived lymphocytes crucial for host defense against several infections and cancer. We have previously shown that compared to young, aged C57BL/6 mice have decreased numbers of mature NK cells in the blood, spleen, and bone marrow, resulting in susceptibility to mousepox, a lethal disease caused by ectromelia virus. Here, we describe further age-related defects in NK cells including reduced proliferation in vivo, additional signs of immaturity, and dysregulated expression of activating and inhibitory receptors. Aging also alters the expression of collagen-binding integrins in conventional NK cells and the frequency and phenotype of liver tissue-resident NK cells. We additionally show that the defect in NK maturation is the consequence of deficient maturational cues provided by bone marrow stromal cells. Moreover, we demonstrate that in aged mice, treatment with complexes of the cytokine IL-15 and IL-15Rα induce massive expansion of the NK cells, but most of these NK cells remain immature and are unable to restore resistance to mousepox. The use of rodent model to understand immunosenescence may help the development of treatments to improve the immune fitness of the aged. Our work with NK cells should contribute toward this goal. PMID:25399821

  2. Preexposure to Olive Oil Polyphenols Extract Increases Oxidative Load and Improves Liver Mass Restoration after Hepatectomy in Mice via Stress-Sensitive Genes.

    PubMed

    Marinić, Jelena; Broznić, Dalibor; Milin, Čedomila

    2016-01-01

    Polyphenols can act as oxidants in some conditions, inducing redox-sensitive genes. We investigated the effect of preexposure to the olive oil polyphenols extract (PFE) on time-dependent changes in the hepatic oxidative state in a model of liver regeneration-a process in which oxidative stress associated with the metabolic overload accounts for the early events that contribute to the onset of liver self-repair. Liver regeneration was induced by one-third hepatectomy in mice. Prior to hepatectomy, mice were intraperitoneally given either PFE (50 mg/kg body weight) or saline for seven consecutive days, while respective controls received vehicle alone. Redox state-regulating enzymes and thiol proteins along with the mRNA levels of Nrf2 gene and its targets γ-glutamylcysteine synthetase and heme oxygenase-1 were determined at different time intervals after hepatectomy. The liver mass restoration was calculated to assess hepatic regeneration. The resulting data demonstrate the effectiveness of preexposure to PFE in stimulating liver regeneration in a model of a small tissue loss which may be ascribed to the transient increase in oxidant load during the first hours after hepatectomy and associated induction of stress response gene-profiles under the control of Nrf2.

  3. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease.

    PubMed

    Lin, Ai-Ling; Zheng, Wei; Halloran, Jonathan J; Burbank, Raquel R; Hussong, Stacy A; Hart, Matthew J; Javors, Martin; Shih, Yen-Yu Ian; Muir, Eric; Solano Fonseca, Rene; Strong, Randy; Richardson, Arlan G; Lechleiter, James D; Fox, Peter T; Galvan, Veronica

    2013-09-01

    Vascular pathology is a major feature of Alzheimer's disease (AD) and other dementias. We recently showed that chronic administration of the target-of-rapamycin (TOR) inhibitor rapamycin, which extends lifespan and delays aging, halts the progression of AD-like disease in transgenic human (h)APP mice modeling AD when administered before disease onset. Here we demonstrate that chronic reduction of TOR activity by rapamycin treatment started after disease onset restored cerebral blood flow (CBF) and brain vascular density, reduced cerebral amyloid angiopathy and microhemorrhages, decreased amyloid burden, and improved cognitive function in symptomatic hAPP (AD) mice. Like acetylcholine (ACh), a potent vasodilator, acute rapamycin treatment induced the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) and NO release in brain endothelium. Administration of the NOS inhibitor L-NG-Nitroarginine methyl ester reversed vasodilation as well as the protective effects of rapamycin on CBF and vasculature integrity, indicating that rapamycin preserves vascular density and CBF in AD mouse brains through NOS activation. Taken together, our data suggest that chronic reduction of TOR activity by rapamycin blocked the progression of AD-like cognitive and histopathological deficits by preserving brain vascular integrity and function. Drugs that inhibit the TOR pathway may have promise as a therapy for AD and possibly for vascular dementias.

  4. Melanin nanoparticles (MNPs) provide protection against whole-body ɣ-irradiation in mice via restoration of hematopoietic tissues.

    PubMed

    Rageh, Monira M; El-Gebaly, Reem H; Abou-Shady, H; Amin, Doaa G

    2015-01-01

    During radiotherapy, ionizing irradiation interacts with biological systems to produce free radicals, which attack various cellular components. The hematopoietic system is easily recognized to be radiosensitive and its damage may be severe. Melanin nanoparticles (MNPs) act as free radical scavengers prepared by polymerization of dopamine. In this study, a total of 110 male BALB/C mice were divided into five equal groups. Each group contained 22 mice. Mice of group A did not receive MNPs or irradiation (control group), group B was injected intraperitoneally (i.p.) with 50 mg/kg MNPs. Mice of group C and D were exposed to a dose of 7 Gy ɣ-irradiation and injected with the same dose of MNPs as in group B either 30 min pre- or post-irradiation, and group E was exposed to a dose of 7 Gy ɣ-irradiation only. The impact of MNPs on peripheral blood, spleen, and DNA damage induced by irradiation was evaluated by blood count, histopathology of the spleen, and comet assay for the DNA in the bone marrow at 1, 4, 8, and 12 days post-irradiation. Results of group E compared with control group (A) showed a significant depression in complete blood count. Additionally, histopathological observation showed the absence of megakaryocytes with delayed time post-irradiation, deposition of eosinophilic protein of their spleen appeared, as well as a remarkable decrease in spleen size was observed. Moreover, ɣ-irradiation-induced DNA damage as can be inferred from a significant increase by about 5-10 folds in all comet parameters (% of DNA, tail length, tail moment, and olive moment) in the DNA of the bone marrow. In contrast, pre-post treatment with MNPs protected hematopoietic tissues against radiation damage, and therefore, enhanced the survival of mice with 40 % in groups (C&D) compared with 10 % to group (E) till 30 days post-irradiation. In conclusion, these results demonstrated that synthetic MNPs provide significant radioprotection to the hematopoietic tissues.

  5. Bifidobacterium pseudocatenulatum CECT 7765 Reduces Obesity-Associated Inflammation by Restoring the Lymphocyte-Macrophage Balance and Gut Microbiota Structure in High-Fat Diet-Fed Mice

    PubMed Central

    Moya-Pérez, Angela; Neef, Alexander; Sanz, Yolanda

    2015-01-01

    Background/Objectives The role of intestinal dysbiosis in obesity-associated systemic inflammation via the cross-talk with peripheral tissues is under debate. Our objective was to decipher the mechanisms by which intervention in the gut ecosystem with a specific Bifidobacterium strain reduces systemic inflammation and improves metabolic dysfunction in obese high-fat diet (HFD) fed mice. Methods Adult male wild-type C57BL-6 mice were fed either a standard or HFD, supplemented with placebo or Bifidobacterium pseudocatenulatum CECT 7765, for 14 weeks. Lymphocytes, macrophages and cytokine/chemokine concentrations were quantified in blood, gut, liver and adipose tissue using bead-based multiplex assays. Biochemical parameters in serum were determined by ELISA and enzymatic assays. Histology was assessed by hematoxylin-eosin staining. Microbiota was analyzed by 16S rRNA gene pyrosequencing and quantitative PCR. Results B. pseudocatenulatum CECT 7765 reduced obesity-associated systemic inflammation by restoring the balance between regulatory T cells (Tregs) and B lymphocytes and reducing pro-inflammatory cytokines of adaptive (IL-17A) and innate (TNF-α) immunity and endotoxemia. In the gut, the bifidobacterial administration partially restored the HFD-induced alterations in microbiota, reducing abundances of Firmicutes and of LPS-producing Proteobacteria, paralleled to reductions in B cells, macrophages, and cytokines (IL-6, MCP-1, TNF-α, IL-17A), which could contribute to systemic effects. In adipose tissue, bifidobacterial administration reduced B cells whereas in liver the treatment increased Tregs and shifted different cytokines (MCP-1 plus ILP-10 in adipose tissue and INF-γ plus IL-1β in liver). In both tissues, the bifidobacteria reduced pro-inflammatory macrophages and, TNF-α and IL-17A concentrations. These effects were accompanied by reductions in body weight gain and in serum cholesterol, triglyceride, glucose and insulin levels and improved oral glucose

  6. Adult Hippocampal Neurogenesis and mRNA Expression are Altered by Perinatal Arsenic Exposure in Mice and Restored by Brief Exposure to Enrichment

    PubMed Central

    Tyler, Christina R.; Allan, Andrea M.

    2013-01-01

    Arsenic is a common and pervasive environmental contaminant found in drinking water in varying concentrations depending on region. Exposure to arsenic induces behavioral and cognitive deficits in both human populations and in rodent models. The Environmental Protection Agency (EPA) standard for the allotment of arsenic in drinking water is in the parts-per-billion range, yet our lab has shown that 50 ppb arsenic exposure during development can have far-reaching consequences into adulthood, including deficits in learning and memory, which have been linked to altered adult neurogenesis. Given that the morphological impact of developmental arsenic exposure on the hippocampus is unknown, we sought to evaluate proliferation and differentiation of adult neural progenitor cells in the dentate gyrus after 50 ppb arsenic exposure throughout the perinatal period of development in mice (equivalent to all three trimesters in humans) using a BrdU pulse-chase assay. Proliferation of the neural progenitor population was decreased by 13% in arsenic-exposed mice, but was not significant. However, the number of differentiated cells was significantly decreased by 41% in arsenic-exposed mice compared to controls. Brief, daily exposure to environmental enrichment significantly increased proliferation and differentiation in both control and arsenic-exposed animals. Expression levels of 31% of neurogenesis-related genes including those involved in Alzheimer’s disease, apoptosis, axonogenesis, growth, Notch signaling, and transcription factors were altered after arsenic exposure and restored after enrichment. Using a concentration previously considered safe by the EPA, perinatal arsenic exposure altered hippocampal morphology and gene expression, but did not inhibit the cellular neurogenic response to enrichment. It is possible that behavioral deficits observed during adulthood in animals exposed to arsenic during development derive from the lack of differentiated neural progenitor

  7. Communication and Your Newborn

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Communication and Your Newborn KidsHealth > For Parents > Communication and Your Newborn Print A A A What's ... first smile — a welcome addition to your baby's communication skills! continue What Should I Do? As soon ...

  8. Newborn screening fact sheets.

    PubMed

    Kaye, Celia I; Accurso, Frank; La Franchi, Stephen; Lane, Peter A; Hope, Northrup; Sonya, Pang; G Bradley, Schaefer; Michele A, Lloyd-Puryear

    2006-09-01

    Newborn screening fact sheets were last revised in 1996 by the American Academy of Pediatrics Committee on Genetics. This revision was prompted by advances in the field since 1996, including technologic innovations, as well as greater appreciation of ethical issues such as those surrounding informed consent. The following disorders are discussed in this revision of the newborn screening fact sheets: biotinidase deficiency, congenital adrenal hyperplasia, congenital hearing loss, congenital hypothyroidism, cystic fibrosis, galactosemia, homocystinuria, maple syrup urine disease, medium-chain acyl-coenzyme A dehydrogenase deficiency, phenylketonuria, sickle cell disease and other hemoglobinopathies, and tyrosinemia. A series of topics related to newborn screening is discussed in a companion publication to this electronic publication of the fact sheets (available at: www.pediatrics.org/cgi/content/full/118/3/1304). These topics are newborn screening as a public health system; factors contributing to the need for review of the newborn screening system; informed consent; tandem mass spectrometry; DNA analysis in newborn screening; status of newborn screening in the United States; and the effect of sample timing, preterm birth, diet, transfusion, and total parenteral nutrition on newborn screening results.

  9. Amebiasis in the newborn.

    PubMed

    Güven, Ayla

    2003-05-01

    Infestation with Entamoeba histolytica is especially common in areas with low socioeconomic status. Extra intestinal invasive involvement is more frequent in young children with significant mortality. This disease is rarely reported in the newborns. This 19-day-old newborn who was infected with orally given surgar solution is presented. He was successfully treated with omidazole.

  10. Vesicular stomatitis virus-based vaccines expressing EV71 virus-like particles elicit strong immune responses and protect newborn mice from lethal challenges.

    PubMed

    Yan, Qin; Wu, Linjuan; Chen, Longyun; Qin, Yali; Pan, Zishu; Chen, Mingzhou

    2016-07-29

    Enterovirus 71 (EV71) belonging to the Picornaviridae family is considered the most frequently detected causative agent in hand-foot-and-mouth disease (HFMD) and is a serious threat to public health in the Asia-Pacific region. There are currently no approved vaccines or effective drugs for EV71. In this study, using recombinant vesicular stomatitis virus (rVSV) expressing viral VP1 protein (mVP1) of EV71 as a control, we generated two types of rVSVs that can form EV71 virus-like particles (VLPs). First, we co-infected two rVSVs singly expressing P1 (mP1) and 3CD (m3CD) of EV71. Second, we inserted P1 and 3CD into one VSV backbone to generate an rVSV expressing P1 and 3CD together (mP1-3CD). When P1 and 3CD were expressed in the cells either co-infected with mP1 and m3CD (mP1/m3CD) or infected with mP1-3CD, P1 was cleaved by 3CD and produced VP1, VP3, and VP0 to form VLPs. Furthermore, mice immunized with mP1/m3CD or mP1-3CD showed higher humoral and cellular immunity responses than mice immunized with mVP1. Finally, the rVSVs expressing the EV71 proteins were evaluated in mice to determine their potential to protect against a lethal EV71 virus challenge, and among all the rVSVs, the mP1-3CD was shown to be the most promising vaccine candidate for EV71 protection.

  11. Pharmacological inhibitors of TRPV4 channels reduce cytokine production, restore endothelial function and increase survival in septic mice.

    PubMed

    Dalsgaard, Thomas; Sonkusare, Swapnil K; Teuscher, Cory; Poynter, Matthew E; Nelson, Mark T

    2016-09-22

    Sepsis is characterized by systemic inflammation, edema formation and hypo-perfusion leading to organ dysfunction and ultimately death. Activation of the transient receptor potential vanilloid type 4 (TRPV4) channel is associated with edema formation and circulatory collapse. Here, we show that TRPV4 channels are involved in the hyper-inflammatory response and mortality associated with sepsis. Pharmacological inhibition of TRPV4 channels in mice reduced mortality in lipopolysaccharide and cecal-ligation-and-puncture models of sepsis, but not in a tumor necrosis factor-α (TNFα)-induced sepsis model. These protective effects of TRPV4 channel inhibition were attributable to prevention of the sepsis-induced surge of a broad spectrum of pro-inflammatory cytokines, including TNFα, interleukin (IL)-1 and IL-6, and subsequent preservation of endothelial cell function, including Ca(2+) signaling, integrity and endothelium-dependent vasodilation. These results suggest that TRPV4 antagonists may be of therapeutic utility in the management of sepsis.

  12. Physiological Characterization of Muscle Strength With Variable Levels of Dystrophin Restoration in mdx Mice Following Local Antisense Therapy

    PubMed Central

    Sharp, Paul S; Bye-a-Jee, Hema; Wells, Dominic J

    2011-01-01

    Antisense-induced exon skipping can restore the open reading frame, and thus correct the dystrophin deficiency that causes Duchenne muscular dystrophy (DMD), a lethal muscle wasting condition. Successful proof-of-principle in preclinical models has led to human clinical trials. However, it is still not known what percentage of dystrophin-positive fibers and what level of expression is necessary for functional improvement. This study directly address these key questions in the mdx mouse model of DMD. To achieve a significant variation in dystrophin expression, we locally administered into tibialis anterior muscles various doses of a phosphorodiamidate morpholino oligomer (PMO) designed to skip the mutated exon 23 from the mRNA of murine dystrophin. We found a highly significant correlation between the number of dystrophin-positive fibers and resistance to contraction-induced injury, with a minimum of 20% of dystrophin-positive fibers required for meaningful improvement. Furthermore, our results also indicate that a relatively low level of dystrophin expression in muscle fibers may have significant clinical benefits. In contrast, improvements in muscle force were not correlated with either the number of positive fibers or total dystrophin levels, which highlight the need to conduct appropriate functional assessments in preclinical testing using the mdx mouse. PMID:20924363

  13. A Special Extract of Bacopa monnieri (CDRI-08) Restores Learning and Memory by Upregulating Expression of the NMDA Receptor Subunit GluN2B in the Brain of Scopolamine-Induced Amnesic Mice

    PubMed Central

    Rai, Rakesh; Singh, Hemant K.; Prasad, S.

    2015-01-01

    In the present communication, we have investigated effects of the CDRI-08, a well characterized extract of Bacopa monnieri, on expression of the GluN2B subunit of NMDAR in various brain regions of the scopolamine-induced amnesic mice. Our behavioral data reveal that scopolamine-treated amnesic mice exhibit significant decline in the spatial memory compared to the normal control mice. Our RT-PCR and immunoblotting data revealed that the scopolamine treatment resulted in a significant downregulation of the NMDAR GluN2B subunit expression in prefrontal cortex and hippocampus. Our enzyme assay data revealed that scopolamine caused a significant increase in the acetylcholinesterase activity in both the brain regions. Further, oral administration of the CDRI-08 to scopolamine-treated amnesic mice restored the spatial memory which was found to be associated with significant upregulation of the GluN2B subunit expression and decline in the acetylcholinesterase activity in prefrontal cortex as well as hippocampus towards their levels in the normal control mice. Our study provides the evidence for the mechanism underlying role of the Bacopa monnieri extract (CDRI-08) in restoring spatial memory in amnesic mice, which may have therapeutic implications. PMID:26413117

  14. Newborn Respiratory Distress.

    PubMed

    Hermansen, Christian L; Mahajan, Anand

    2015-12-01

    Newborn respiratory distress presents a diagnostic and management challenge. Newborns with respiratory distress commonly exhibit tachypnea with a respiratory rate of more than 60 respirations per minute. They may present with grunting, retractions, nasal flaring, and cyanosis. Common causes include transient tachypnea of the newborn, respiratory distress syndrome, meconium aspiration syndrome, pneumonia, sepsis, pneumothorax, persistent pulmonary hypertension of the newborn, and delayed transition. Congenital heart defects, airway malformations, and inborn errors of metabolism are less common etiologies. Clinicians should be familiar with updated neonatal resuscitation guidelines. Initial evaluation includes a detailed history and physical examination. The clinician should monitor vital signs and measure oxygen saturation with pulse oximetry, and blood gas measurement may be considered. Chest radiography is helpful in the diagnosis. Blood cultures, serial complete blood counts, and C-reactive protein measurement are useful for the evaluation of sepsis. Most neonates with respiratory distress can be treated with respiratory support and noninvasive methods. Oxygen can be provided via bag/mask, nasal cannula, oxygen hood, and nasal continuous positive airway pressure. Ventilator support may be used in more severe cases. Surfactant is increasingly used for respiratory distress syndrome. Using the INSURE technique, the newborn is intubated, given surfactant, and quickly extubated to nasal continuous positive airway pressure. Newborns should be screened for critical congenital heart defects via pulse oximetry after 24 hours but before hospital discharge. Neonatology consultation is recommended if the illness exceeds the clinician's expertise and comfort level or when the diagnosis is unclear in a critically ill newborn.

  15. Immunization of Newborn Mice Accelerates the Architectural Maturation of Lymph Nodes, But AID-Dependent IgG Responses Are Still Delayed Compared to the Adult

    PubMed Central

    Munguía-Fuentes, Rosario; Yam-Puc, Juan Carlos; Silva-Sánchez, Aarón; Marcial-Juárez, Edith; Gallegos-Hernández, Isis Amara; Calderón-Amador, Juana; Randall, Troy D.; Flores-Romo, Leopoldo

    2017-01-01

    Lymph nodes (LNs) have evolved to maximize antigen (Ag) collection and presentation as well as lymphocyte proliferation and differentiation—processes that are spatially regulated by stromal cell subsets, including fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs). Here, we showed that naïve neonatal mice have poorly organized LNs with few B and T cells and undetectable FDCs, whereas adult LNs have numerous B cells and large FDC networks. Interestingly, immunization on the day of birth accelerated B cell accumulation and T cell recruitment into follicles as well as FDC maturation and FRC organization in neonatal LNs. However, compared to adults, the formation of germinal centers was both delayed and reduced following immunization of neonatal mice. Although immunized neonates poorly expressed activation-induced cytidine deaminase (AID), they were able to produce Ag-specific IgGs, but with lower titers than adults. Interestingly, the Ag-specific IgM response in neonates was similar to that in adults. These results suggest that despite an accelerated structural maturation of LNs in neonates following vaccination, the B cell response is still delayed and reduced in its ability to isotype switch most likely due to poor AID expression. Of note, naïve pups born to Ag-immunized mothers had high titers of Ag-specific IgGs from day 0 (at birth). These transferred antibodies confirm a mother-derived coverage to neonates for Ags to which mothers (and most likely neonates) are exposed, thus protecting the neonates while they produce their own antibodies. Finally, the type of Ag used in this study and the results obtained also indicate that T cell help would be operating at this stage of life. Thus, neonatal immune system might not be intrinsically immature but rather evolutionary adapted to cope with Ags at birth. PMID:28154564

  16. Newborn screening: current status.

    PubMed

    Arn, Pamela H

    2007-01-01

    Newborn screening, which represents one of the major advances in child health of the past century, has been carried out in all fifty U.S. states since the 1970s. Newborn screening programs are state-run, and decisions are left to the individual states regarding the conditions to be screened for, the mechanism for confirmatory testing, follow-up care, and financing of the programs. Laboratory advances in tandem mass spectrometry make it possible to screen newborns for many rare inborn errors of metabolism. This raises many policy issues including screening's cost-effectiveness, ethics, quality, and oversight.

  17. Pharmacological activation of PPARbeta/delta stimulates utrophin A expression in skeletal muscle fibers and restores sarcolemmal integrity in mature mdx mice.

    PubMed

    Miura, Pedro; Chakkalakal, Joe V; Boudreault, Louise; Bélanger, Guy; Hébert, Richard L; Renaud, Jean-Marc; Jasmin, Bernard J

    2009-12-01

    A therapeutic strategy to treat Duchenne muscular dystrophy (DMD) involves identifying compounds that can elevate utrophin A expression in muscle fibers of affected patients. The dystrophin homologue utrophin A can functionally substitute for dystrophin when its levels are enhanced in the mdx mouse model of DMD. Utrophin A expression in skeletal muscle is regulated by mechanisms that promote the slow myofiber program. Since activation of peroxisome proliferator-activated receptor (PPAR) beta/delta promotes the slow oxidative phenotype in skeletal muscle, we initiated studies to determine whether pharmacological activation of PPARbeta/delta provides functional benefits to the mdx mouse. GW501516, a PPARbeta/delta agonist, was found to stimulate utrophin A mRNA levels in C2C12 muscle cells through an element in the utrophin A promoter. Expression of PPARbeta/delta was greater in skeletal muscles of mdx versus wild-type mice. We treated 5-7-week-old mdx mice with GW501516 for 4 weeks. This treatment increased the percentage of muscle fibers expressing slower myosin heavy chain isoforms and stimulated utrophin A mRNA levels leading to its increased expression at the sarcolemma. Expression of alpha1-syntrophin and beta-dystroglycan was restored to the sarcolemma. Improvement of mdx sarcolemmal integrity was evidenced by decreased intracellular IgM staining and decreased in vivo Evans blue dye (EBD) uptake. GW501516 treatment also conferred protection against eccentric contraction (ECC)-induced damage of mdx skeletal muscles, as shown by a decreased contraction-induced force drop and reduction of dye uptake during ECC. These results demonstrate that pharmacological activation of PPARbeta/delta might provide functional benefits to DMD patients through enhancement of utrophin A expression.

  18. A Novel Arginase Inhibitor Derived from Scutellavia indica Restored Endothelial Function in ApoE-Null Mice Fed a High-Cholesterol Diet.

    PubMed

    Hwang, Hye Mi; Lee, Jeong Hyung; Min, Byung Sun; Jeon, Byeong Hwa; Hoe, Kwang Lae; Kim, Young Myeong; Ryoo, Sungwoo

    2015-10-01

    Elevated endothelial arginase activity decreases nitric oxide (NO) production by competing with the substrate l-arginine, previously reported, and reciprocally regulating endothelial nitric oxide synthase (eNOS) activity. Thus, arginase inhibitors may help treat vascular diseases associated with endothelial dysfunction. A screening of metabolites from medicinal plants revealed that (2S)-5,2',5'-trihydroxy-7,8-dimethoxy flavanone (TDF) was a noncompetitive inhibitor of arginase. We investigated whether TDF reciprocally regulated endothelial NO production and its possible mechanism. TDF noncompetitively inhibited arginase I and II activity in a dose-dependent manner. TDF incubation decreased arginase activity and increased NO production in human umbilical vein endothelial cells and isolated mouse aortic vessels and reduced reactive oxygen species (ROS) generation in the endothelium of the latter. These TDF-mediated effects were associated with increased eNOS phosphorylation and dimerization but not with changes in protein content. Endothelium-dependent vasorelaxant responses to acetylcholine (Ach) were significantly increased in TDF-incubated aortic rings and attenuated by incubation with soluble guanylyl cyclase inhibitor. Phenylephrine-induced vasoconstrictor responses were markedly attenuated in TDF-treated vessels from wild-type mice. In atherogenic-prone ApoE(-/-) mice, TDF attenuated the high-cholesterol diet (HCD)-induced increase in arginase activity, which was accompanied by restoration of NO production and reduction of ROS generation. TDF incubation induced eNOS dimerization and phosphorylation at Ser1177. In addition, TDF improved Ach-dependent vasorelaxation responses and attenuated U46619-dependent contractile responses but did not change sodium nitroprusside-induced vasorelaxation or N-NAME-induced vasoconstriction. The findings suggest that TDF may help treat cardiovascular diseases by reducing pathophysiology derived from HCD-mediated endothelial

  19. Restoration of bone mass and strength in glucocorticoid-treated mice by systemic transplantation of CXCR4 and cbfa-1 co-expressing mesenchymal stem cells.

    PubMed

    Lien, Chun-Yang; Chih-Yuan Ho, Kevin; Lee, Oscar K; Blunn, Gordon W; Su, Yeu

    2009-05-01

    Transplantation of gene-modified mesenchymal stem cells (MSCs) in animals for bone regeneration therapy has been evaluated extensively in recent years. However, increased endosteal bone formation by intravenous injection of MSCs ectopically expressing a foreign gene has not yet been shown. Aside from the clearance by lung and other tissues, the surface compositions of MSCs may not favor their bone marrow (BM) migration and engraftment. To overcome these hurdles, a gene encoding the chemokine receptor largely responsible for stromal-derived factor-1 (SDF-1)-mediated BM homing and engraftment of hematopoietic stem cells (HSCs), CXCR4, was transduced into mouse C3H10T1/2 cells by adenovirus infection. A dose-dependent increase of CXCR4 surface expression with a parallel enhanced chemotaxis toward SDF-1 in these cells after virus infection was clearly observed. Higher BM retention and homing of CXCR4-expressing MSCs were also found after they were transplanted by intramedullary and tail vein injections, respectively, into immunocompetent C3H/HeN mice. Interestingly, a full recovery of bone mass and a partial restoration of bone formation in glucocorticoid-induced osteoporotic mice were observed 4 wk after a single intravenous infusion of one million CXCR4-expressing C3H10T1/2 cells. In the meantime, complete recovery of bone stiffness and strength in these animals was consistently detected only after a systemic transplantation of CXCR4 and Cbfa-1 co-transduced MSCs. To our knowledge, this is the first report to show unequivocally the feasibility of ameliorating glucocorticoid-induced osteoporosis by systemic transplantation of genetically manipulated MSCs.

  20. Pharmacological inhibitors of TRPV4 channels reduce cytokine production, restore endothelial function and increase survival in septic mice

    PubMed Central

    Dalsgaard, Thomas; Sonkusare, Swapnil K.; Teuscher, Cory; Poynter, Matthew E.; Nelson, Mark T.

    2016-01-01

    Sepsis is characterized by systemic inflammation, edema formation and hypo-perfusion leading to organ dysfunction and ultimately death. Activation of the transient receptor potential vanilloid type 4 (TRPV4) channel is associated with edema formation and circulatory collapse. Here, we show that TRPV4 channels are involved in the hyper-inflammatory response and mortality associated with sepsis. Pharmacological inhibition of TRPV4 channels in mice reduced mortality in lipopolysaccharide and cecal-ligation-and-puncture models of sepsis, but not in a tumor necrosis factor-α (TNFα)-induced sepsis model. These protective effects of TRPV4 channel inhibition were attributable to prevention of the sepsis-induced surge of a broad spectrum of pro-inflammatory cytokines, including TNFα, interleukin (IL)-1 and IL-6, and subsequent preservation of endothelial cell function, including Ca2+ signaling, integrity and endothelium-dependent vasodilation. These results suggest that TRPV4 antagonists may be of therapeutic utility in the management of sepsis. PMID:27653046

  1. Melatonin restores hippocampal neural precursor cell proliferation and prevents cognitive deficits induced by jet lag simulation in adult mice.

    PubMed

    Iggena, Deetje; Winter, York; Steiner, Barbara

    2017-05-01

    Frequent flyers and shift workers undergo circadian dysrhythmia with adverse impact on body and mind. The circadian rhythm disorder "jet lag" disturbs hippocampal neurogenesis and spatial cognition, which represent morphological and functional adult brain plasticity. This raises the question if pro-neurogenic stimuli might prevent those consequences. However, suitable measures to mitigate jet lag-induced adverse effects on brain plasticity have been neglected so far. Here, we used adult C57Bl6 mice to investigate the pro-neurogenic stimuli melatonin (8 mg/kg i.p.) as well as environmental enrichment as potential measures. We applied photoperiod alterations to simulate "jet lag" by shortening the dark period every third day by 6 hours for 3 weeks. We found that "jet lag" simulation reduced hippocampal neural precursor cell proliferation by 24% and impaired spatial memory performance in the water maze indicated by a prolonged swim path to the target (~23%). While melatonin prevented both the cellular (~1%) as well as the cognitive deficits (~5%), environmental enrichment only preserved precursor cell proliferation (~12%). Our results indicate that lifestyle interventions are insufficient to completely compensate jet lag-induced consequences. Instead, melatonin is required to prevent cognitive impairment caused by the same environmental factors to which frequent flyers and shift workers are typically exposed to.

  2. Improving metabolic health in obese male mice via diet and exercise restores embryo development and fetal growth.

    PubMed

    McPherson, Nicole O; Bakos, Hassan W; Owens, Julie A; Setchell, Brian P; Lane, Michelle

    2013-01-01

    Paternal obesity is now clearly associated with or causal of impaired embryo and fetal development and reduced pregnancy rates in humans and rodents. This appears to be a result of reduced blastocyst potential. Whether these adverse embryo and fetal outcomes can be ameliorated by interventions to reduce paternal obesity has not been established. Here, male mice fed a high fat diet (HFD) to induce obesity were used, to determine if early embryo and fetal development is improved by interventions of diet (CD) and/or exercise to reduce adiposity and improve metabolism. Exercise and to a lesser extent CD in obese males improved embryo development rates, with increased cell to cell contacts in the compacting embryo measured by E-cadherin in exercise interventions and subsequently, increased blastocyst trophectoderm (TE), inner cell mass (ICM) and epiblast cell numbers. Implantation rates and fetal development from resulting blastocysts were also improved by exercise in obese males. Additionally, all interventions to obese males increased fetal weight, with CD alone and exercise alone, also increasing fetal crown-rump length. Measures of embryo and fetal development correlated with paternal measures of glycaemia, insulin action and serum lipids regardless of paternal adiposity or intervention, suggesting a link between paternal metabolic health and subsequent embryo and fetal development. This is the first study to show that improvements to metabolic health of obese males through diet and exercise can improve embryo and fetal development, suggesting such interventions are likely to improve offspring health.

  3. Jaundice in Healthy Newborns

    MedlinePlus

    ... Development Infections Diseases & Conditions Pregnancy & Baby Nutrition & Fitness Emotions & Behavior School & Family Life First Aid & Safety Doctors & ... common condition in newborns, refers to the yellow color of the skin and whites of the eyes ...

  4. Growth and Your Newborn

    MedlinePlus

    ... the Classroom What Other Parents Are Reading Your Child's Development (Birth to 3 Years) Feeding Your 1- to ... Your Child's Growth Breastfeeding vs. Formula Feeding Your Child's Development: Newborn Contact Us Print Resources Send to a ...

  5. Newborn head molding

    MedlinePlus

    ... childbirth. Information The bones of a newborn baby's skull are soft and flexible, with gaps between the ... The spaces between the bony plates of the skull are called cranial sutures . The front ( anterior ) and ...

  6. Senses and Your Newborn

    MedlinePlus

    ... especially mom's and dad's, are a baby's favorite "music." Your baby already knows that this is where ... your baby react to soft lullabies or other music? Even if your child passed the newborn hearing ...

  7. Growth and Your Newborn

    MedlinePlus

    ... dimpled thighs was many people's picture of a healthy newborn. But a baby born much larger than average may have special medical problems that need attention. Some exceptionally large babies — especially those born to ...

  8. Newborn jaundice - discharge

    MedlinePlus

    ... FAQs Customer Support Health Topics Drugs & Supplements Videos & Tools Español You Are Here: Home → Medical Encyclopedia → Newborn jaundice - discharge URL of this page: //medlineplus.gov/ency/ ...

  9. Jaundice in Healthy Newborns

    MedlinePlus

    ... eyes that happens when there is too much bilirubin in the blood. Bilirubin (bill-uh-ROO-bin) is produced by the ... liquid that helps with digestion). Jaundice happens when bilirubin builds up faster than a newborn's liver can ...

  10. Newborn Screening Tests Approved

    MedlinePlus

    ... The screens are used to detect four rare metabolic disorders To use the sharing features on this page, ... of screening tests designed to detect four rare metabolic disorders in newborns has been approved by the U.S. ...

  11. Mifepristone Prevents Stress-Induced Apoptosis in Newborn Neurons and Increases AMPA Receptor Expression in the Dentate Gyrus of C57/BL6 Mice

    PubMed Central

    Llorens-Martín, María; Trejo, José L.

    2011-01-01

    Chronic stress produces sustained elevation of corticosteroid levels, which is why it is considered one of the most potent negative regulators of adult hippocampal neurogenesis (AHN). Several mood disorders are accompanied by elevated glucocorticoid levels and have been linked to alterations in AHN, such as major depression (MD). Nevertheless, the mechanism by which acute stress affects the maturation of neural precursors in the dentate gyrus is poorly understood. We analyzed the survival and differentiation of 1 to 8 week-old cells in the dentate gyrus of female C57/BL6 mice following exposure to an acute stressor (the Porsolt or forced swimming test). Furthermore, we evaluated the effects of the glucocorticoid receptor (GR) antagonist mifepristone on the cell death induced by the Porsolt test. Forced swimming induced selective apoptotic cell death in 1 week-old cells, an effect that was abolished by pretreatment with mifepristone. Independent of its antagonism of GR, mifepristone also induced an increase in the percentage of 1 week-old cells that were AMPA+. We propose that the induction of AMPA receptor expression in immature cells may mediate the neuroprotective effects of mifepristone, in line with the proposed antidepressant effects of AMPA receptor potentiators. PMID:22140582

  12. Clostridium butyricum Combined with Bifidobacterium infantis Probiotic Mixture Restores Fecal Microbiota and Attenuates Systemic Inflammation in Mice with Antibiotic-Associated Diarrhea

    PubMed Central

    Ling, Zongxin; Liu, Xia; Cheng, Yiwen; Luo, Yueqiu; Yuan, Li; Li, Lanjuan; Xiang, Charlie

    2015-01-01

    Antibiotic-associated diarrhea (AAD) is one of the most common complications of most types of antibiotics. Our aim was to determine the efficacy of Clostridium butyricum, Bifidobacterium infantis, and their mixture for AAD treatment in mice. AAD models were administered with single probiotic strain and probiotic mixture for short term and long term to evaluate the changes of the composition and diversity of intestinal microbiota, histopathology of the colon, and the systemic inflammation. Our data indicated that long-term probiotic therapy, but not short-term course, exerted beneficial effects on the restoration of the intestinal microbiota, the recovery of the tissue architecture, and attenuation of systemic inflammation. All predominant fecal bacteria reached normal level after the long-term probiotic mixture treatment, while IL-10, IFN-γ, and TNF-α also returned to normal level. However, the efficacy for AAD was time dependent and probiotic strain specific. Short-term administration of probiotic strains or mixture showed no apparent positive effects for AAD. In addition, the beneficial effects of C. butyricum combined with B. infantis probiotic mixture were superior to their single strain. This research showed that supplementation with C. butyricum combined with B. infantis probiotic mixture may be a simple and effective method for AAD treatment. PMID:25802855

  13. Minocycline restores sAPPα levels and reduces the late histopathological consequences of traumatic brain injury in mice.

    PubMed

    Siopi, Eleni; Cho, Angelo H; Homsi, Shadi; Croci, Nicole; Plotkine, Michel; Marchand-Leroux, Catherine; Jafarian-Tehrani, Mehrnaz

    2011-10-01

    Traumatic brain injury (TBI) induces both focal and diffuse lesions that are concurrently responsible for the ensuing morbidity and mortality and for which no established treatment is available. It has been recently reported that an endogenous neuroprotector, the soluble form α of the amyloid precursor protein (sAPPα), exerts neuroprotective effects following TBI. However, the emergent post-traumatic neuroinflammatory environment compromises sAPPα production and may promote neuronal degeneration and consequent brain atrophy. Hence, the aim of this study was to examine the effects of the anti-inflammatory drug minocycline on sAPPα levels, as well as on long-term histological consequences post-TBI. The weight-drop model was used to induce TBI in mice. Minocycline or its vehicle were administered three times: at 5 min (90 mg/kg, i.p.) and at 3 and 9 h (45 mg/kg, i.p.) post-TBI. The levels of sAPPα, the extent of brain atrophy, and reactive gliosis were evaluated by ELISA, cresyl violet, and immunolabeling of GFAP and CD11b, respectively. Our results revealed a post-TBI sAPPα decrease that was significantly attenuated by minocycline. Additionally, corpus callosum and striatal atrophy, ventriculomegaly, astrogliosis, and microglial activation were observed at 3 months post-TBI. All the above consequences were significantly reduced by minocycline. In conclusion, inhibition of the acute phase of post-TBI neuroinflammation was associated with the sparing of sAPPα and the protection of brain tissue in the long-term, emphasizing the potential role of minocycline as an effective treatment for TBI.

  14. Simulating newborn face perception.

    PubMed

    von Hofsten, Olov; von Hofsten, Claes; Sulutvedt, Unni; Laeng, Bruno; Brennen, Tim; Magnussen, Svein

    2014-11-18

    A frequently asked question concerns what a newborn infant can actually see. The contrast sensitivity function of newborn infants is well known, but its implications for the ability of newborns to perceive faces of adults remain unclear. We filtered gray scale animations of facial expressions in terms of both spatial frequency and contrast to correspond to the properties of newborn infants' acuity and showed them to adult participants. We reasoned that if adults were unable to identify the depicted facial expressions, then it would also seem unlikely that newborn infants could identify the same expressions. We found that for the simulated acuity the different expressions could be rather well identified at a distance of 30 cm, but when the distance was increased to 120 cm their discriminability was much degraded. This shows that although the perception of faces and facial expressions can function at the low visual resolution of the newborn infant, it is insufficient for distinguishing faces and facial expressions at moderate distances. © 2014 ARVO.

  15. Central anatomy of individual rapidly adapting low-threshold mechanoreceptors innervating the "hairy" skin of newborn mice: early maturation of hair follicle afferents.

    PubMed

    Woodbury, C J; Ritter, A M; Koerber, H R

    2001-07-30

    Adult skin sensory neurons exhibit characteristic projection patterns in the dorsal horn of the spinal gray matter that are tightly correlated with modality. However, little is known about how these patterns come about during the ontogeny of the distinct subclasses of skin sensory neurons. To this end, we have developed an intact ex vivo somatosensory system preparation in neonatal mice, allowing single, physiologically identified cutaneous afferents to be iontophoretically injected with Neurobiotin for subsequent histological analyses. The present report, centered on rapidly adapting mechanoreceptors, represents the first study of the central projections of identified skin sensory neurons in neonatal animals. Cutaneous afferents exhibiting rapidly adapting responses to sustained natural stimuli were encountered as early as recordings were made. Well-stained representatives of coarse (tylotrich and guard) and fine-diameter (down) hair follicle afferents, along with a putative Pacinian corpuscle afferent, were recovered from 2-7-day-old neonates. All were characterized by narrow, uninflected somal action potentials and generally low mechanical thresholds, and many could be activated via deflection of recently erupted hairs. The central collaterals of hair follicle afferents formed recurrent, flame-shaped arbors that were essentially miniaturized replicas of their adult counterparts, with identical laminar terminations. The terminal arbors of down hair afferents, previously undescribed in rodents, were distinct and consistently occupied a more superficial position than tylotrich and guard hair afferents. Nevertheless, the former extended no higher than the middle of the incipient substantia gelatinosa, leaving a clear gap more dorsally. In all major respects, therefore, hair follicle afferents display the same laminar specificity in neonates as they do in adults. The widely held misperception that their collaterals extend exuberant projections into pain

  16. A Novel Human PTH Analog [Cys25]hPTH(1-34) Restores Bone Mass in Ovariectomized Mice.

    PubMed

    Bae, Chu Hyun; Kang, Myeongmo; Park, Clara Yongjoo; Park, Bo Mi; Zhang, Dongdong; Nam, Hee Jin; Yang, Yu-Mi; Shin, Dong Min; Choi, Je-Yong; Lim, Sung-Kil

    2016-10-01

    Recently, an arginine-to-cysteine homozygous mutation at position 25 in mature PTH was reported in a Korean patient with hypoparathyroidism. To clarify whether the high bone mass phenotype observed in this patient was related to the hypoparathyroidism itself or to chronic elevation of mutant PTH. A series of in vitro and in vivo experiments were performed in MC3T3E1, ROS 17/2.8, and SAOS2 cells treated with human (h)PTH(1-34), Cys(25)hPTH(1-34), Ala(1)Cys(25)hPTH(1-34), and Bpa(1)Cys(25)hPTH(1-34). The peptides were then sc delivered to ovariectomized mice as daily single injections. Compared with hPTH(1-34) and Ala(1)Cys(25)hPTH(1-34), treatment with Cys(25)hPTH(1-34) or Bpa(1)Cys(25)hPTH(1-34) resulted in decreases in the cAMP response and promoter-cAMP-response element luciferase reporter activity. Although the cAMP response was sustained with hPTH(1-34) in MC3T3E1 cells, such response was not observed with the other mutated peptides. Meanwhile, all PTH analogues exhibited ERK phosphorylation and cytoplasmic Ca(++) signals comparable with hPTH(1-34). On microcomputed tomography analyses, trabecular and cortical bone parameters improved after 6 weeks of respective treatments as follows: hPTH(1-34) (80 μg/kg) = Ala(1)Cys(25)hPTH(1-34) (80 μg/kg) = Cys(25)hPTH(1-34) (80 μg/kg) > Bpa(1)Cys(25)hPTH(1-34) (80 μg/kg) > hPTH(1-34) (40 μg/kg). The increment of RANKL to OPG mRNA ratio in the MC3T3E1 cells after 6 hours of treatment of Cys(25)hPTH(1-34), AL(1)Cys(25)hPTH(1-34), and Bpa(1)Cys(25)hPTH(1-34) was less than that was obtained after hPTH(1-34) treatment. On bone histomorphometric analysis, AL(1)Cys(25)hPTH(1-34) increased the bone formation rate in both trabecular and periosteal bones compared with the control group. The high bone mass phenotype observed in this patient with hypoparathyrodism caused by a Cys mutation at the 25th residue of hPTH(1-84) may have arisen from both direct and indirect effects exerted by the mutant PTH itself on bone.

  17. Brief Report: Treatment of Tumor Necrosis Factor-Transgenic Mice With Anti-Tumor Necrosis Factor Restores Lymphatic Contractions, Repairs Lymphatic Vessels, and May Increase Monocyte/Macrophage Egress.

    PubMed

    Bouta, Echoe M; Kuzin, Igor; de Mesy Bentley, Karen; Wood, Ronald W; Rahimi, Homaira; Ji, Rui-Cheng; Ritchlin, Christopher T; Bottaro, Andrea; Xing, Lianping; Schwarz, Edward M

    2017-06-01

    Recent studies have demonstrated that there is an inverse relationship between lymphatic egress and inflammatory arthritis in affected joints. As a model, tumor necrosis factor (TNF)-transgenic mice develop advanced arthritis following draining lymph node (LN) collapse, and loss of lymphatic contractions downstream of inflamed joints. It is unknown if these lymphatic deficits are reversible. This study was undertaken to test the hypothesis that anti-TNF therapy reduces advanced erosive inflammatory arthritis, associated with restoration of lymphatic contractions, repair of damaged lymphatic vessels, and evidence of increased monocyte egress. TNF-transgenic mice with advanced arthritis and collapsed popliteal LNs were treated with anti-TNF monoclonal antibody (10 mg/kg weekly) or placebo for 6 weeks, and effects on knee synovitis, lymphatic vessel ultrastructure and function, and popliteal LN cellularity were assessed by ultrasound, histology, transmission electron microscopy (TEM), near-infrared indocyanine green imaging, and flow cytometry. Anti-TNF therapy significantly decreased synovitis (∼5-fold; P < 0.05 versus placebo), restored lymphatic contractions, and significantly increased the number of popliteal LN monocyte/macrophages (∼2-fold; P < 0.05 versus placebo). TEM demonstrated large activated macrophages attached to damaged lymphatic endothelium in mice with early arthritis, extensively damaged lymphatic vessels in placebo-treated mice with advanced arthritis, and rolling leukocytes in repaired lymphatic vessels in mice responsive to anti-TNF therapy. These findings support the concept that anti-TNF therapy ameliorates erosive inflammatory arthritis, in part via restoration of lymphatic vessel contractions and potential enhancement of inflammatory cell egress. © 2017, American College of Rheumatology.

  18. Gene therapy for newborns.

    PubMed

    Kohn, D B; Parkman, R

    1997-07-01

    Application of gene therapy to treat genetic and infectious diseases may have several advantages if performed in newborns. Because of the minimal adverse effect of the underlying disease on cells of the newborn, the relatively small size of infants, and the large amount of future growth, gene therapy may be more successful in newborns than in older children or adults. The presence of umbilical cord blood from newborns provides a unique and susceptible target for the genetic modification of hematopoietic stem cells. In our first trial of gene therapy in newborns, we inserted a normal adenosine deaminase gene into umbilical cord blood cells of three neonates with a congenital immune deficiency. The trial demonstrated the successful transduction and engraftment of stem cells, which continue to contribute to leukocyte production more than 3 years later. A similar approach may be taken to insert genes that inhibit replication of HIV-1 into umbilical cord blood cells of HIV-1-infected neonates. Many other metabolic and infectious disorders could be treated by gene therapy during the neonatal period if prenatal diagnoses are made and the appropriate technical and regulatory requirements have been met.

  19. Newborn Screening in Slovenia

    PubMed Central

    ŠMON, Andraž; GROŠELJ, Urh; ŽERJAV TANŠEK, Mojca; BIČEK, Ajda; OBLAK, Adrijana; ZUPANČIČ, Mirjana; KRŽIŠNIK, Ciril; REPIČ LAMPR ET, Barbka; MURKO, Simona; HOJKER, Sergej; BATTELINO, Tadej

    2015-01-01

    Introduction Newborn screening in whole Slovenia started in 1979 with screening for phenylketonuria (PKU). Congenital hypothyroidism (CH) was added into the programme in 1981. The aim of this study was to analyse the data of neonatal screening in Slovenia from 1993 to 2012 for PKU, and from 1991 to 2012 for CH. Methods Blood samples were collected from the heels of newborns between the third and the fifth day after birth. Fluorometric method was used for screening for PKU, CH screening was done by dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA). Results From 1993 to 2012, from 385,831 newborns 57 were identified with PKU. 184 newborns out of 427,396 screened from 1991 to 2012, were confirmed for CH. Incidences of PKU and CH in the periods stated are 1:6769 and 1:2323, respectively. Conclusions Successful implementation of newborn screening for PKU and CH has helped in preventing serious disabilities of the affected children. Adding screening for new metabolic diseases in the future would be beneficial. PMID:27646913

  20. Mutations in the Schmallenberg Virus Gc Glycoprotein Facilitate Cellular Protein Synthesis Shutoff and Restore Pathogenicity of NSs Deletion Mutants in Mice.

    PubMed

    Varela, Mariana; Pinto, Rute Maria; Caporale, Marco; Piras, Ilaria M; Taggart, Aislynn; Seehusen, Frauke; Hahn, Kerstin; Janowicz, Anna; de Souza, William Marciel; Baumgärtner, Wolfgang; Shi, Xiaohong; Palmarini, Massimo

    2016-06-01

    Serial passage of viruses in cell culture has been traditionally used to attenuate virulence and identify determinants of viral pathogenesis. In a previous study, we found that a strain of Schmallenberg virus (SBV) serially passaged in tissue culture (termed SBVp32) unexpectedly displayed increased pathogenicity in suckling mice compared to wild-type SBV. In this study, we mapped the determinants of SBVp32 virulence to the viral genome M segment. SBVp32 virulence is associated with the capacity of this virus to reach high titers in the brains of experimentally infected suckling mice. We also found that the Gc glycoprotein, encoded by the M segment of SBVp32, facilitates host cell protein shutoff in vitro Interestingly, while the M segment of SBVp32 is a virulence factor, we found that the S segment of the same virus confers by itself an attenuated phenotype to wild-type SBV, as it has lost the ability to block the innate immune system of the host. Single mutations present in the Gc glycoprotein of SBVp32 are sufficient to compensate for both the attenuated phenotype of the SBVp32 S segment and the attenuated phenotype of NSs deletion mutants. Our data also indicate that the SBVp32 M segment does not act as an interferon (IFN) antagonist. Therefore, SBV mutants can retain pathogenicity even when they are unable to fully control the production of IFN by infected cells. Overall, this study suggests that the viral glycoprotein of orthobunyaviruses can compensate, at least in part, for the function of NSs. In addition, we also provide evidence that the induction of total cellular protein shutoff by SBV is determined by multiple viral proteins, while the ability to control the production of IFN maps to the NSs protein. The identification of viral determinants of pathogenesis is key to the development of prophylactic and intervention measures. In this study, we found that the bunyavirus Gc glycoprotein is a virulence factor. Importantly, we show that mutations in the Gc

  1. Mutations in the Schmallenberg Virus Gc Glycoprotein Facilitate Cellular Protein Synthesis Shutoff and Restore Pathogenicity of NSs Deletion Mutants in Mice

    PubMed Central

    Pinto, Rute Maria; Caporale, Marco; Piras, Ilaria M.; Taggart, Aislynn; Seehusen, Frauke; Hahn, Kerstin; Janowicz, Anna; de Souza, William Marciel; Baumgärtner, Wolfgang; Shi, Xiaohong

    2016-01-01

    ABSTRACT Serial passage of viruses in cell culture has been traditionally used to attenuate virulence and identify determinants of viral pathogenesis. In a previous study, we found that a strain of Schmallenberg virus (SBV) serially passaged in tissue culture (termed SBVp32) unexpectedly displayed increased pathogenicity in suckling mice compared to wild-type SBV. In this study, we mapped the determinants of SBVp32 virulence to the viral genome M segment. SBVp32 virulence is associated with the capacity of this virus to reach high titers in the brains of experimentally infected suckling mice. We also found that the Gc glycoprotein, encoded by the M segment of SBVp32, facilitates host cell protein shutoff in vitro. Interestingly, while the M segment of SBVp32 is a virulence factor, we found that the S segment of the same virus confers by itself an attenuated phenotype to wild-type SBV, as it has lost the ability to block the innate immune system of the host. Single mutations present in the Gc glycoprotein of SBVp32 are sufficient to compensate for both the attenuated phenotype of the SBVp32 S segment and the attenuated phenotype of NSs deletion mutants. Our data also indicate that the SBVp32 M segment does not act as an interferon (IFN) antagonist. Therefore, SBV mutants can retain pathogenicity even when they are unable to fully control the production of IFN by infected cells. Overall, this study suggests that the viral glycoprotein of orthobunyaviruses can compensate, at least in part, for the function of NSs. In addition, we also provide evidence that the induction of total cellular protein shutoff by SBV is determined by multiple viral proteins, while the ability to control the production of IFN maps to the NSs protein. IMPORTANCE The identification of viral determinants of pathogenesis is key to the development of prophylactic and intervention measures. In this study, we found that the bunyavirus Gc glycoprotein is a virulence factor. Importantly, we show that

  2. Assessment of Risk in Newborns.

    ERIC Educational Resources Information Center

    Umansky, Warren; Seaton, Jane B.

    1979-01-01

    To assess risk status of newborns, data were collected on 776 newborns using a high risk register. Analysis of high risk characteristics revealed 261 primary risk incidents in the sample and 292 secondary risk factors. (Author/PHR)

  3. Assessment of Risk in Newborns.

    ERIC Educational Resources Information Center

    Umansky, Warren; Seaton, Jane B.

    1979-01-01

    To assess risk status of newborns, data were collected on 776 newborns using a high risk register. Analysis of high risk characteristics revealed 261 primary risk incidents in the sample and 292 secondary risk factors. (Author/PHR)

  4. Jaundice in the newborn.

    PubMed

    Agrawal, R; Aggarwal, R; Deorari, A K; Paul, V K

    2001-10-01

    Hyperbilirubinemia is the commonest morbidity in the neonatal period and 5-10% of all newborns require intervention for pathological jaundice. Neonates on exclusive breast-feeding have a different pattern of physiological jaundice as compared to artificially fed babies. Guidelines from American Academy of Pediatrics (AAP) for management of jaundice in a normal term newborn have been included in the protocol. Separate guidelines have been provided for the management of jaundice in sick term babies, preterm and low birth weight babies, for jaundice secondary to hemolysis and for prolonged hyperbilirubinemia. Although hour specific bilirubin charts are available, these have to be validated in Indian infants before they are accepted for widespread use.

  5. What's New with Newborn Screening

    ERIC Educational Resources Information Center

    Exceptional Parent, 2008

    2008-01-01

    Newborn screening is the process of testing and screening newborns shortly after birth for certain, potentially dangerous, conditions and/or impairments--conditions that include everything from inborn errors of metabolism and other genetic disorders to hearing impairment. Early detection through newborn screening is paramount, often allowing the…

  6. What's New with Newborn Screening

    ERIC Educational Resources Information Center

    Exceptional Parent, 2008

    2008-01-01

    Newborn screening is the process of testing and screening newborns shortly after birth for certain, potentially dangerous, conditions and/or impairments--conditions that include everything from inborn errors of metabolism and other genetic disorders to hearing impairment. Early detection through newborn screening is paramount, often allowing the…

  7. Analysis of Spine Motility of Newborn Granule Cells in Acute Brain Slices.

    PubMed

    Tashiro, Ayumu; Zhao, Chunmei; Suh, Hoonkyo; Gage, Fred H

    2015-10-01

    In this protocol, acute brain slices are prepared from mice in which newborn granule cells have been labeled using retroviral vector technology. Using a live-cell imaging stage and confocal microscopy coupled to imaging software, dendritic spines are analyzed.

  8. Newborn Black Holes

    ERIC Educational Resources Information Center

    Science Teacher, 2005

    2005-01-01

    Scientists using NASA's Swift satellite say they have found newborn black holes, just seconds old, in a confused state of existence. The holes are consuming material falling into them while somehow propelling other material away at great speeds. "First comes a blast of gamma rays followed by intense pulses of x-rays. The energies involved are much…

  9. Nail care for newborns

    MedlinePlus

    ... MedlinePlus GO GO About MedlinePlus Site Map FAQs Customer Support Health Topics Drugs & Supplements Videos & Tools Español You Are Here: Home → Medical Encyclopedia → Nail care for newborns URL of this page: //medlineplus.gov/ ...

  10. Newborn Black Holes

    ERIC Educational Resources Information Center

    Science Teacher, 2005

    2005-01-01

    Scientists using NASA's Swift satellite say they have found newborn black holes, just seconds old, in a confused state of existence. The holes are consuming material falling into them while somehow propelling other material away at great speeds. "First comes a blast of gamma rays followed by intense pulses of x-rays. The energies involved are much…

  11. Naturally occurring antibodies for the group B streptococcal surface immunogenic protein (Sip) in pregnant women and newborn babies.

    PubMed

    Manning, Shannon D; Wood, Stephen; Kasha, Katherine; Martin, Denis; Rioux, Stéphane; Brodeur, Bernard; Davies, H Dele

    2006-11-17

    Sip is a surface-exposed protein of GBS, which causes severe neonatal disease. Because Sip elicits a protective immune response in mice, we assessed whether pregnant women and newborns have Sip antibodies. Sera were collected from 644 pregnant women and 176 of their healthy newborns, and 10 newborns with GBS disease and their mothers. Using ELISA, most (99%) women and newborns (97%) had serum Sip antibodies, as did most newborns followed through 6 months. This suggests that naturally occurring Sip antibodies cross the placenta and persist into infancy, which underscores the need to study Sip further as a potential vaccine candidate.

  12. Oral supplementation of diabetic mice with propolis restores the proliferation capacity and chemotaxis of B and T lymphocytes towards CCL21 and CXCL12 by modulating the lipid profile, the pro-inflammatory cytokine levels and oxidative stress.

    PubMed

    Al Ghamdi, Ahmad A; Badr, Gamal; Hozzein, Wael N; Allam, Ahmed; Al-Waili, Noori S; Al-Wadaan, Mohammed A; Garraud, Olivier

    2015-09-15

    Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the selective destruction of pancreatic β cells, followed by hyperglycemia, oxidative stress and the subsequent extensive impairment of immune cell functions, a phenomenon responsible for the development of chronic diabetic complications. Propolis, a natural bee product that is extensively used in foods and beverages, significantly benefits human health. Specifically, propolis exerts antioxidant, anti-inflammatory and analgesic effects that may improve diabetic complications. To further elucidate the potential benefits of propolis, the present study investigated the effect of dietary supplementation with propolis on the plasma cytokine profiles, free radical levels, lipid profile and lymphocyte proliferation and chemotaxis in a streptozotocin (STZ)-induced type I diabetic mouse model. Thirty male mice were equally distributed into 3 experimental groups: group 1, non-diabetic control mice; group 2, diabetic mice; and group 3, diabetic mice supplemented daily with an ethanol-soluble derivative of propolis (100 mg/kg body weight) for 1 month. First, the induction of diabetes in mice was associated with hyperglycemia and significant decreases in the insulin level and the lymphocyte count. In this context, diabetic mice exhibited severe diabetic complications, as demonstrated by a significant decrease in the levels of IL-2, IL-4 and IL-7, prolonged elevation of the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and reactive oxygen species (ROS) and altered lipid profiles compared with control non-diabetic mice. Moreover, antigen stimulation of B and T lymphocytes markedly reduced the proliferative capacity and chemotaxis of these cells towards CCL21 and CXCL12 in diabetic mice compared with control mice. Interestingly, compared with diabetes induction alone, treatment of diabetic mice with propolis significantly restored the plasma cytokine and ROS levels and the lipid profile to

  13. Restoration of pharyngeal dilator muscle force in dystrophin-deficient (mdx) mice following co-treatment with neutralizing interleukin-6 receptor antibodies and urocortin 2.

    PubMed

    Burns, David P; Rowland, Jane; Canavan, Leonie; Murphy, Kevin H; Brannock, Molly; O'Malley, Dervla; O'Halloran, Ken D; Edge, Deirdre

    2017-09-01

    What is the central question of this study? We previously reported impaired upper airway dilator muscle function in the mdx mouse model of Duchenne muscular dystrophy (DMD). Our aim was to assess the effect of blocking interleukin-6 receptor signalling and stimulating corticotrophin-releasing factor receptor 2 signalling on mdx sternohyoid muscle structure and function. What is the main finding and its importance? The interventional treatment had a positive inotropic effect on sternohyoid muscle force, restoring mechanical work and power to wild-type values, reduced myofibre central nucleation and preserved the myosin heavy chain type IIb fibre complement of mdx sternohyoid muscle. These data might have implications for development of pharmacotherapies for DMD with relevance to respiratory muscle performance. The mdx mouse model of Duchenne muscular dystrophy shows evidence of impaired pharyngeal dilator muscle function. We hypothesized that inflammatory and stress-related factors are implicated in airway dilator muscle dysfunction. Six-week-old mdx (n = 26) and wild-type (WT; n = 26) mice received either saline (0.9% w/v) or a co-administration of neutralizing interleukin-6 receptor antibodies (0.2 mg kg(-1) ) and corticotrophin-releasing factor receptor 2 agonist (urocortin 2; 30 μg kg(-1) ) over 2 weeks. Sternohyoid muscle isometric and isotonic contractile function was examined ex vivo. Muscle fibre centronucleation and muscle cellular infiltration, collagen content, fibre-type distribution and fibre cross-sectional area were determined by histology and immunofluorescence. Muscle chemokine content was examined by use of a multiplex assay. Sternohyoid peak specific force at 100 Hz was significantly reduced in mdx compared with WT. Drug treatment completely restored force in mdx sternohyoid to WT levels. The percentage of centrally nucleated muscle fibres was significantly increased in mdx, and this was partly ameliorated after drug treatment. The

  14. River restoration

    NASA Astrophysics Data System (ADS)

    Wohl, Ellen; Angermeier, Paul L.; Bledsoe, Brian; Kondolf, G. Mathias; Macdonnell, Larry; Merritt, David M.; Palmer, Margaret A.; Poff, N. Leroy; Tarboton, David

    2005-10-01

    River restoration is at the forefront of applied hydrologic science. However, many river restoration projects are conducted with minimal scientific context. We propose two themes around which a research agenda to advance the scientific basis for river restoration can be built. First, because natural variability is an inherent feature of all river systems, we hypothesize that restoration of process is more likely to succeed than restoration aimed at a fixed end point. Second, because physical, chemical, and biological processes are interconnected in complex ways across watersheds and across timescales, we hypothesize that restoration projects are more likely to be successful in achieving goals if undertaken in the context of entire watersheds. To achieve restoration objectives, the science of river restoration must include (1) an explicit recognition of the known complexities and uncertainties, (2) continued development of a theoretical framework that enables us to identify generalities among river systems and to ask relevant questions, (3) enhancing the science and use of restoration monitoring by measuring the most effective set of variables at the correct scales of measurement, (4) linking science and implementation, and (5) developing methods of restoration that are effective within existing constraints. Key limitations to river restoration include a lack of scientific knowledge of watershed-scale process dynamics, institutional structures that are poorly suited to large-scale adaptive management, and a lack of political support to reestablish delivery of the ecosystem amenities lost through river degradation. This paper outlines an approach for addressing these shortcomings.

  15. T cells from baxalpha transgenic mice show accelerated apoptosis in response to stimuli but do not show restored DNA damage-induced cell death in the absence of p53.

    PubMed Central

    Brady, H J; Salomons, G S; Bobeldijk, R C; Berns, A J

    1996-01-01

    Baxalpha was isolated due to its interaction with Bcl-2. Baxalpha overexpression in an interleukin (IL)-3 dependent cell line accelerates apoptosis upon removal of the cytokine. The ratio of Baxalpha to Bcl-2 appears to be crucial for the effect. To study the action of the bax gene product in vivo, we have generated transgenic mice overexpressing Baxalpha specifically in T cells. Such T cells show accelerated apoptosis in response to gamma-radiation, dexamethasone and etoposide. By crossing baxalpha mice with bcl-2 transgenics we show that the critical nature of the Baxalpha:Bcl-2 ratio holds in primary T cells and that it can be manipulated to elicit a strong response to previously resisted stimuli. p53 has a role in the regulation of apoptosis in response to DNA-damaging agents. p53 directly activates transcription of the bax gene. The presence of the baxalpha transgene accelerated apoptosis in thymocytes from both p53-l- and p53+l- mice in response to dexamethasone. Thymocytes from p53-l- mice with the baxalpha transgene showed similar resistance to apoptosis by DNA-damaging agents as did p53-l- mice without the transgene. Baxalpha overexpression alone cannot restore the DNA damage apoptosis pathway, suggesting that p53 is required to induce or activate other factor(s) to reconstitute the response fully. Images PMID:8635454

  16. Systemic transforming growth factor-beta1 gene therapy induces Foxp3+ regulatory cells, restores self-tolerance, and facilitates regeneration of beta cell function in overtly diabetic nonobese diabetic mice.

    PubMed

    Luo, Xunrong; Yang, Hua; Kim, Il Soo; Saint-Hilaire, Fludd; Thomas, Dolca A; De, Bishnu P; Ozkaynak, Engin; Muthukumar, Thangamani; Hancock, Wayne W; Crystal, Ronald G; Suthanthiran, Manikkam

    2005-05-15

    Type 1 diabetes results from auto-aggressive T-cell-mediated destruction of beta cells of the pancreas. Recent data suggest that restoration of self-tolerance may facilitate islet-cell regeneration/recovery. In view of the immunoregulatory activity of transforming growth factor (TGF)-beta1, we investigated whether systemic TGF-beta1 gene therapy blocks islet destructive autoimmunity and facilitates regeneration of beta-cell function in overtly diabetic nonobese diabetic (NOD) mice. We used site-directed mutagenesis to create cysteine to serine mutation at sites 224 and 226 and constructed a replication deficient adenovirus (Ad) vector encoding active form of human TGF-beta1 (Ad-hTGF-beta1). Overtly diabetic NOD mice received intravenous injection of Ad-hTGF-beta1. Seven to 14 days after the injection, the mice received transplants with 500 syngeneic islets under the kidney capsule. Islet-graft survival and regeneration of endogenous beta-cell function were examined. Syngeneic islet grafts failed by day 17 in all untreated mice, whereas Ad-hTGF-beta1 therapy prolonged survival of islet grafts. Islet grafts from treated mice showed well-preserved islets with a peri-islet infiltrate primarily of CD4+ T cells and expression of CD25 and Foxp3. Systemic TGF-beta1 gene therapy was associated with islet regeneration in the native pancreas. Native pancreas of treated mice revealed islets staining strongly for insulin. Similar to what was found in the syngeneic islet graft, there were well-demarcated peri-islet infiltrates that were positive for CD4, TGF-beta1, and Foxp3. Our data demonstrate that systemic TGF-beta1 gene therapy blocks islet destructive autoimmunity, facilitates islet regeneration, and cures diabetes in diabetic NOD mice.

  17. Newborn male circumcision.

    PubMed

    Sorokan, S Todd; Finlay, Jane C; Jefferies, Ann L

    2015-01-01

    The circumcision of newborn males in Canada has become a less frequent practice over the past few decades. This change has been significantly influenced by past recommendations from the Canadian Paediatric Society and the American Academy of Pediatrics, who both affirmed that the procedure was not medically indicated. Recent evidence suggesting the potential benefit of circumcision in preventing urinary tract infection and some sexually transmitted infections, including HIV, has prompted the Canadian Paediatric Society to review the current medical literature in this regard. While there may be a benefit for some boys in high-risk populations and circumstances where the procedure could be considered for disease reduction or treatment, the Canadian Paediatric Society does not recommend the routine circumcision of every newborn male.

  18. Newborn male circumcision

    PubMed Central

    Sorokan, S Todd; Finlay, Jane C; Jefferies, Ann L

    2015-01-01

    The circumcision of newborn males in Canada has become a less frequent practice over the past few decades. This change has been significantly influenced by past recommendations from the Canadian Paediatric Society and the American Academy of Pediatrics, who both affirmed that the procedure was not medically indicated. Recent evidence suggesting the potential benefit of circumcision in preventing urinary tract infection and some sexually transmitted infections, including HIV, has prompted the Canadian Paediatric Society to review the current medical literature in this regard. While there may be a benefit for some boys in high-risk populations and circumstances where the procedure could be considered for disease reduction or treatment, the Canadian Paediatric Society does not recommend the routine circumcision of every newborn male. PMID:26435672

  19. Advancing newborn health: The Saving Newborn Lives initiative

    PubMed Central

    Tinker, A.; Parker, R.; Lord, D.; Grear, K.

    2009-01-01

    Until recently, newborn health was virtually absent from the global health agenda. Now, assistance agencies, national governments and non-governmental organisations are increasingly addressing this previously neglected issue of close to four million newborns dying every year. The experience of the Saving Newborn Lives initiative documents some of the progress that has been made and the challenges and opportunities that lie ahead. Since the start of the initiative in 2000, targeted research, focused on overcoming the key barriers to improved newborn survival, has demonstrated low-cost, community-based interventions and strategies that can significantly reduce newborn mortality. Building on what has been learned from this and other efforts to date, the challenge now is to reach the millions of newborns still at risk. PMID:19851911

  20. Gingival Cyst of Newborn.

    PubMed

    Moda, Aman

    2011-01-01

    Gingival cyst of newborn is an oral mucosal lesion of transient nature. Although it is very common lesion within 3 to 6 weeks of birth, it is very rare to visualize the lesion thereafter. Presented here is a case report of gingival cyst, which was visible just after 15 days of birth. Clinical diagnoses of these conditions are important in order to avoid unnecessary therapeutic procedure and provide suitable information to parents about the nature of the lesion.

  1. Gingival Cyst of Newborn

    PubMed Central

    2011-01-01

    ABSTRACT Gingival cyst of newborn is an oral mucosal lesion of transient nature. Although it is very common lesion within 3 to 6 weeks of birth, it is very rare to visualize the lesion thereafter. Presented here is a case report of gingival cyst, which was visible just after 15 days of birth. Clinical diagnoses of these conditions are important in order to avoid unnecessary therapeutic procedure and provide suitable information to parents about the nature of the lesion. PMID:27616865

  2. Newborn screening in India.

    PubMed

    Rama Devi, A Radha; Naushad, S M

    2004-02-01

    Expanded newborn screening (NBS) is aimed for early detection and intervention of treatable inborn errors of metabolism and also to establish incidence of these disorders in this part of the globe. The first expanded NBS programme initiated in the capital city of Andhra Pradesh to screen all the newborns born in four major Government Maternity Hospitals in Hyderabad by heel prick capillary blood collected on S&S 903 filter paper. Chromatographic (TLC and HPLC), electrophoretic (cellulose acetate and agarose) and ELISA based assays have been employed for screening of common inborn errors of metabolism. This study has shown a high prevalence of treatable Inborn errors of metabolism. Congenital hypothyroidsm is the most common disorder (1 in 1700) followed by congenital Adrenal Hyperplasia (1 in 2575) and Hyperhomocystenemia (1 in 100). Interestingly, a very high prevalence of inborn errors of metabolism to the extent of 1 in every thousand newborns was observed. The study reveals the importance of screening in India, necessitating nation wide large-scale screening.

  3. Killing fetuses and killing newborns.

    PubMed

    Di Nucci, Ezio

    2013-05-01

    The argument for the moral permissibility of killing newborns is a challenge to liberal positions on abortion because it can be considered a reductio of their defence of abortion. Here I defend the liberal stance on abortion by arguing that the argument for the moral permissibility of killing newborns on ground of the social, psychological and economic burden on the parents recently put forward by Giubilini and Minerva is not valid; this is because they fail to show that newborns cannot be harmed and because there are morally relevant differences between fetuses and newborns.

  4. Preservation & Restoration.

    ERIC Educational Resources Information Center

    Online-Offline, 2000

    2000-01-01

    This theme issue on preservation and restoration presents selected resources for elementary and secondary education that include Web sites, CD-ROM and software, videos, books, magazines, and professional resources as well as classroom activities. Age levels are specified for most materials. I Sidebars discuss restoring a masterpiece, a bug's life,…

  5. Hepatic selenoprotein P (SePP) expression restores selenium transport and prevents infertility and motor-incoordination in Sepp-knockout mice.

    PubMed

    Renko, Kostja; Werner, Margarethe; Renner-Müller, Ingrid; Cooper, Trevor G; Yeung, Ching Hei; Hollenbach, Birgit; Scharpf, Marcus; Köhrle, Josef; Schomburg, Lutz; Schweizer, Ulrich

    2008-02-01

    SePP (selenoprotein P) is central for selenium transport and distribution. Targeted inactivation of the Sepp gene in mice leads to reduced selenium content in plasma, kidney, testis and brain. Accordingly, activities of selenoenzymes are reduced in Sepp(-/-) organs. Male Sepp(-/-) mice are infertile. Unlike selenium deficiency, Sepp deficiency leads to neurological impairment with ataxia and seizures. Hepatocyte-specific inactivation of selenoprotein biosynthesis reduces plasma and kidney selenium levels similarly to Sepp(-/-) mice, but does not result in neurological impairment, suggesting a physiological role of locally expressed SePP in the brain. In an attempt to define the role of liver-derived circulating SePP in contrast with locally expressed SePP, we generated Sepp(-/-) mice with transgenic expression of human SePP under control of a hepatocyte-specific transthyretin promoter. Secreted human SePP was immunologically detectable in serum from SEPP1-transgenic mice. Selenium content and selenoenzyme activities in serum, kidney, testis and brain of Sepp(-/-;SEPP1) (SEPP1-transgenic Sepp(-/-)) mice were increased compared with Sepp(-/-) controls. When a selenium-adequate diet (0.16-0.2 mg/kg of body weight) was fed to the mice, liver-specific expression of SEPP1 rescued the neurological defects of Sepp(-/-) mice and rendered Sepp(-/-) males fertile. When fed on a low-selenium diet (0.06 mg/kg of body weight), Sepp(-/-;SEPP1) mice survived 4 weeks longer than Sepp(-/-) mice, but ultimately developed the neurodegenerative phenotype. These results indicate that plasma SePP derived from hepatocytes is the main transport form of selenium supporting the kidney, testis and brain. Nevertheless, local Sepp expression is required to maintain selenium content in selenium-privileged tissues such as brain and testis during dietary selenium restriction.

  6. [Bednar's aphthae in newborn].

    PubMed

    Fariñas Salto, Mercedes; Menéndez Hernando, Cristina; Martín Molina, Raquel; Galán Gómez, Víctor; García de Pedro, Fernando J

    2017-02-01

    The description of the Bednar's ulcer is uncommon in the current literature. It has been associated with the traumatic effect of the bottle's nipple and/or no orthodontic soothers while breastfeeding. We present a newborn of 20 days of life attended at the emergency room for irritability, with the only finding on physical examination of two oral ulcers. We describe the clinical presentation, evolution and treatment. The normality of the diagnostic test, clinical characteristics and evolution lead to the diagnosis of Bednar´s ulcer.

  7. Central Vision in the Newborn.

    ERIC Educational Resources Information Center

    Lewis, Terri L.; Maurer, Daphne

    1980-01-01

    Tests newborns' ability to detect a dot with central vision and compares both the proportion of time the infants fixated centrally and the duration of each central fixation. Subjects were 46 newborns ranging in age from 1 to 7 days. (MP)

  8. Management of the depressed newborn.

    PubMed

    Welch, K A; Philips, J B

    1984-03-01

    The experienced obstetrician knows that depressed neonates do not always herald their coming, and that the potential liability for failure to intervene promptly is great. It is imperative that all personnel involved in the delivery and care of newborns be familiar with these principles of newborn resuscitation.

  9. Newborn Screening Information System (NBSIS)

    PubMed Central

    Dayhoff, R. E.; Ledley, R. S.; Rotolo, L. S.

    1984-01-01

    A Newborn Screening Information System (NBSIS) has been developed to handle the information processing needs of State Newborn Screening Laboratories. Systems have been customized for use by the States of Maryland and Florida. These systems track clients (babies) from their first contact with the Screening Center through their last follow-up test, producing worksheets, result reports, letters, and summaries for archival storage.

  10. Newborn screening for homocystinuria.

    PubMed

    Walter, John H; Jahnke, Nikki; Remmington, Tracey

    2013-08-01

    Homocystinuria is a rare inherited disorder due to a deficiency in cystathionine beta synthase. Individuals with this condition appear normal at birth but develop serious complications in childhood. Diagnosis and treatment started sufficiently early in life can effectively prevent or reduce the severity of these complications. To determine if newborn population screening for the diagnosis of homocystinuria due to cystathionine beta synthase deficiency leads to clinical benefit compared to later clinical diagnosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register.Date of the most recent search of the Inborn Errors of Metabolism Register: 15 May 2013. Randomised controlled trials and controlled clinical trials assessing the use of any neonatal screening test to diagnose infants with homocystinuria before the condition becomes clinically evident. Eligible studies compare a screened population versus a non-screened population. No studies were identified for inclusion in the review. No studies were identified for inclusion in the review. We were unable to identify eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on controlled studies; however, we are aware of uncontrolled case-series which support the efficacy of newborn screening for homocystinuria and its early treatment. Any future randomised controlled trial would need to be both multicentre and long term in order to provide robust evidence for or against screening and to allow a cost effectiveness analysis to be undertaken.

  11. Newborn screening for homocystinuria.

    PubMed

    Walter, John H; Jahnke, Nikki; Remmington, Tracey

    2015-10-01

    Homocystinuria is a rare inherited disorder due to a deficiency in cystathionine beta synthase. Individuals with this condition appear normal at birth but develop serious complications in childhood. Diagnosis and treatment started sufficiently early in life can effectively prevent or reduce the severity of these complications. This is an update of a previously published review. To determine if newborn population screening for the diagnosis of homocystinuria due to cystathionine beta synthase deficiency leads to clinical benefit compared to later clinical diagnosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register.Date of the most recent search of the Inborn Errors of Metabolism Register: 08 June 2015. Randomised controlled trials and controlled clinical trials assessing the use of any neonatal screening test to diagnose infants with homocystinuria before the condition becomes clinically evident. Eligible studies compare a screened population versus a non-screened population. No studies were identified for inclusion in the review. No studies were identified for inclusion in the review. We were unable to identify eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on controlled studies; however, we are aware of uncontrolled case-series which support the efficacy of newborn screening for homocystinuria and its early treatment. Any future randomised controlled trial would need to be both multicentre and long term in order to provide robust evidence for or against screening and to allow a cost effectiveness analysis to be undertaken.

  12. Restoration of adrenal steroidogenesis by adenovirus-mediated transfer of human cytochromeP450 21-hydroxylase into the adrenal gland of21-hydroxylase-deficient mice.

    PubMed

    Tajima, T; Okada, T; Ma, X M; Ramsey, W; Bornstein, S; Aguilera, G

    1999-11-01

    21-Hydroxylase deficiency, a potentially fatal disease due to deletions or mutations of the cytochrome P450 21-hydroxylase gene (CYP21), causes congenital adrenal hyperplasia (CAH) with low or absent glucocorticoid and mineralocorticoid production. The feasibility of gene therapy for CAH was studied using 21OH-deficient mice (21OH-) and a replication-deficient adenovirus containing the genomic sequence of human CYP21 (hAdCYP21). Intra-adrenal injection of hAdCYP21 in 21OH- mice induced hCYP21 mRNA with the highest expression from 2 to 7 days before a gradual decline. 21OH activity measured in adrenal tissue increased from undetectable to levels found in wild-type mice 2 to 7 days after AdhCYP21 injection. Adrenal morphology of 21OH- mice showed lack of zonation, and hypertrophy and hyperplasia of adrenocortical mitochondria with few tubulovesicular christae. These morphological abnormalities were markedly improved 7 days after hAdCYP21 gene therapy. Plasma corticosterone increased from undetectable levels to values similar in wild-type mice by 7 and 14 days, declining over the next 40 days. This is the first demonstration that a single intra-adrenal injection of an adenoviral vector encoding CYP21 can compensate for the biochemical, endocrine and histological alterations in 21OH-deficient mice, and shows that gene therapy could be a feasible option for treatment of CAH.

  13. The Inhibitory Effects of Purple Sweet Potato Color on Hepatic Inflammation Is Associated with Restoration of NAD⁺ Levels and Attenuation of NLRP3 Inflammasome Activation in High-Fat-Diet-Treated Mice.

    PubMed

    Wang, Xin; Zhang, Zi-Feng; Zheng, Gui-Hong; Wang, Ai-Min; Sun, Chun-Hui; Qin, Su-Ping; Zhuang, Juan; Lu, Jun; Ma, Dai-Fu; Zheng, Yuan-Lin

    2017-08-08

    Purple sweet potato color (PSPC), a class of naturally occurring anthocyanins, exhibits beneficial effects on metabolic syndrome. Sustained inflammation plays a crucial role in the pathogenesis of metabolic syndrome. Here we explored the effects of PSPC on high-fat diet (HFD)-induced hepatic inflammation and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + PSPC group, and PSPC group. PSPC was administered by daily oral gavage at doses of 700 mg/kg/day for 20 weeks. Nicotinamide riboside (NR) was used to increase NAD⁺ levels. Our results showed that PSPC effectively ameliorated obesity and liver injuries in HFD-fed mice. Moreover, PSPC notably blocked hepatic oxidative stress in HFD-treated mice. Furthermore, PSPC dramatically restored NAD⁺ level to abate endoplasmic reticulum stress (ER stress) in HFD-treated mouse livers, which was confirmed by NR treatment. Consequently, PSPC remarkably suppressed the nuclear factor-κB (NF-κB) p65 nuclear translocation and nucleotide oligomerization domain protein1/2 (NOD1/2) signaling in HFD-treated mouse livers. Thereby, PSPC markedly diminished the NLR family, pyrin domain containing 3 (NLRP3) inflammasome activation, ultimately lowering the expressions of inflammation-related genes in HFD-treated mouse livers. In summary, PSPC protected against HFD-induced hepatic inflammation by boosting NAD⁺ level to inhibit NLRP3 inflammasome activation.

  14. Lithium rescues synaptic plasticity and memory in Down syndrome mice

    PubMed Central

    Contestabile, Andrea; Greco, Barbara; Ghezzi, Diego; Tucci, Valter; Benfenati, Fabio; Gasparini, Laura

    2012-01-01

    Down syndrome (DS) patients exhibit abnormalities of hippocampal-dependent explicit memory, a feature that is replicated in relevant mouse models of the disease. Adult hippocampal neurogenesis, which is impaired in DS and other neuropsychiatric diseases, plays a key role in hippocampal circuit plasticity and has been implicated in learning and memory. However, it remains unknown whether increasing adult neurogenesis improves hippocampal plasticity and behavioral performance in the multifactorial context of DS. We report that, in the Ts65Dn mouse model of DS, chronic administration of lithium, a clinically used mood stabilizer, promoted the proliferation of neuronal precursor cells through the pharmacological activation of the Wnt/β-catenin pathway and restored adult neurogenesis in the hippocampal dentate gyrus (DG) to physiological levels. The restoration of adult neurogenesis completely rescued the synaptic plasticity of newborn neurons in the DG and led to the full recovery of behavioral performance in fear conditioning, object location, and novel object recognition tests. These findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult DS mice rescues hippocampal plasticity and memory and implicate adult neurogenesis as a promising therapeutic target to alleviate cognitive deficits in DS patients. PMID:23202733

  15. Arabinoxylan rice bran (MGN-3/Biobran) provides protection against whole-body γ-irradiation in mice via restoration of hematopoietic tissues

    PubMed Central

    Ghoneum, Mamdooh; Badr El-Din, Nariman K.; Abdel Fattah, Salma M.; Tolentino, Lucilene

    2013-01-01

    The aim of the current study is to examine the protective effect of MGN-3 on overall maintenance of hematopoietic tissue after γ-irradiation. MGN-3 is an arabinoxylan from rice bran that has been shown to be a powerful antioxidant and immune modulator. Swiss albino mice were treated with MGN-3 prior to irradiation and continued to receive MGN-3 for 1 or 4 weeks. Results were compared with mice that received radiation (5 Gy γ rays) only, MGN-3 (40 mg/kg) only and control mice (receiving neither radiation nor MGN-3). At 1 and 4 weeks post-irradiation, different hematological, histopathological and biochemical parameters were examined. Mice exposed to irradiation alone showed significant depression in their complete blood count (CBC) except for neutrophilia. Additionally, histopathological studies showed hypocellularity of their bone marrow, as well as a remarkable decrease in splenic weight/relative size and in number of megakaryocytes. In contrast, pre-treatment with MGN-3 resulted in protection against irradiation-induced damage to the CBC parameters associated with complete bone marrow cellularity, as well as protection of the aforementioned splenic changes. Furthermore, MGN-3 exerted antioxidative activity in whole-body irradiated mice, and provided protection from irradiation-induced loss of body and organ weight. In conclusion, MGN-3 has the potential to protect progenitor cells in the bone marrow, which suggests the possible use of MGN-3/Biobran as an adjuvant treatment to counteract the severe adverse side effects associated with radiation therapy. PMID:23287771

  16. Restoration of dopamine release deficits during object recognition memory acquisition attenuates cognitive impairment in a triple transgenic mice model of Alzheimer's disease.

    PubMed

    Guzmán-Ramos, Kioko; Moreno-Castilla, Perla; Castro-Cruz, Monica; McGaugh, James L; Martínez-Coria, Hilda; LaFerla, Frank M; Bermúdez-Rattoni, Federico

    2012-09-14

    Previous findings indicate that the acquisition and consolidation of recognition memory involves dopaminergic activity. Although dopamine deregulation has been observed in Alzheimer's disease (AD) patients, the dysfunction of this neurotransmitter has not been investigated in animal models of AD. The aim of this study was to assess, by in vivo microdialysis, cortical and hippocampal dopamine, norepinephrine, and glutamate release during the acquisition of object recognition memory (ORM) in 5- and 10-mo-old triple-transgenic Alzheimer's disease mice (3xTg-AD) and to relate the extracellular changes to 24-h memory performance. Five- and 10-mo-old wild-type mice and 5-mo-old 3xTg-AD showed significant cortical but not hippocampal dopamine increase during object exploration. On a 24-h ORM test, these three groups displayed significant ORM. In contrast, 10-mo-old 3xTg-AD mice showed impaired dopamine release in the insular cortex during ORM acquisition, as well as significant impairment in ORM. In addition, cortical administration of a dopamine reuptake blocker produced an increase of dopamine levels in the 10-mo-old 3xTg-AD mice and attenuated the memory impairment. These data suggest that activation of the dopaminergic system in the insular cortex is involved in object recognition memory, and that dysfunction of this system contributes to the age-related decline in cognitive functioning of the 3xTg-AD mice.

  17. Tianeptine, olanzapine and fluoxetine show similar restoring effects on stress induced molecular changes in mice brain: An FT-IR study

    NASA Astrophysics Data System (ADS)

    Türker-Kaya, Sevgi; Mutlu, Oğuz; Çelikyurt, İpek K.; Akar, Furuzan; Ulak, Güner

    2016-05-01

    Chronic stress which can cause a variety of disorders and illness ranging from metabolic and cardiovascular to mental leads to alterations in content, structure and dynamics of biomolecules in brain. The determination of stress-induced changes along with the effects of antidepressant treatment on these parameters might bring about more effective therapeutic strategies. In the present study, we investigated unpredictable chronic mild stress (UCMS)-induced changes in biomolecules in mouse brain and the restoring effects of tianeptine (TIA), olanzapine (OLZ) and fluoxetine (FLX) on these variations, by Fourier transform infrared (FT-IR) spectroscopy. The results revealed that chronic stress causes different membrane packing and an increase in lipid peroxidation, membrane fluidity. A significant increment for lipid/protein, Cdbnd O/lipid, CH3/lipid, CH2/lipid, PO-2/lipid, COO-/lipid and RNA/protein ratios but a significant decrease for lipid/protein ratios were also obtained. Additionally, altered protein secondary structure components were estimated, such as increment in random coils and beta structures. The administration of TIA, OLZ and FLX drugs restored these stress-induced variations except for alterations in protein structure and RNA/protein ratio. This may suggest that these drugs have similar restoring effects on the consequences of stress activity in brain, in spite of the differences in their action mechanisms. All findings might have importance in understanding molecular mechanisms underlying chronic stress and contribute to studies aimed for drug development.

  18. Tianeptine, olanzapine and fluoxetine show similar restoring effects on stress induced molecular changes in mice brain: An FT-IR study.

    PubMed

    Türker-Kaya, Sevgi; Mutlu, Oğuz; Çelikyurt, İpek K; Akar, Furuzan; Ulak, Güner

    2016-05-15

    Chronic stress which can cause a variety of disorders and illness ranging from metabolic and cardiovascular to mental leads to alterations in content, structure and dynamics of biomolecules in brain. The determination of stress-induced changes along with the effects of antidepressant treatment on these parameters might bring about more effective therapeutic strategies. In the present study, we investigated unpredictable chronic mild stress (UCMS)-induced changes in biomolecules in mouse brain and the restoring effects of tianeptine (TIA), olanzapine (OLZ) and fluoxetine (FLX) on these variations, by Fourier transform infrared (FT-IR) spectroscopy. The results revealed that chronic stress causes different membrane packing and an increase in lipid peroxidation, membrane fluidity. A significant increment for lipid/protein, C=O/lipid, CH3/lipid, CH2/lipid, PO(-)2/lipid, COO(-)/lipid and RNA/protein ratios but a significant decrease for lipid/protein ratios were also obtained. Additionally, altered protein secondary structure components were estimated, such as increment in random coils and beta structures. The administration of TIA, OLZ and FLX drugs restored these stress-induced variations except for alterations in protein structure and RNA/protein ratio. This may suggest that these drugs have similar restoring effects on the consequences of stress activity in brain, in spite of the differences in their action mechanisms. All findings might have importance in understanding molecular mechanisms underlying chronic stress and contribute to studies aimed for drug development. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Newborn Physiological Immaturity

    PubMed Central

    Fabrellas-Padrés, Núria; Delgado-Hito, Pilar; Hurtado-Pardos, Bárbara; Martí-Cavallé, Montserrat; Gironès-Nogué, Marta; García-Berman, Rosa-Maria; Alonso-Fernandez, Sergio

    2015-01-01

    Background: Most standardized nursing care plans for healthy neonates include multiple nursing diagnoses to reflect nurses' judgments on the infant's status; however scientific literature concerning this issue is scarce. Newborn physiological immaturity is a concept in the ATIC terminology (architecture, terminology, interface, information, nursing [infermeria], and knowledge [coneixement]) to represent the natural status of vulnerability of the healthy neonate. Purpose: To identify the essential attributes of the concept and provide its conceptual and operational definition, using the Wilsonian approach. Findings: The concept under analysis embeds a natural cluster of vulnerabilities and environmental interactions that enhance the evolving maturation process. Implications for Practice: The use of this diagnosis may simplify the process of charting the nursing care plans and reduce time needed for documentation while maintaining the integrity of the information. Implications for Research: Consistent development and use of nursing concepts is essential for knowledge building. Studies on the actual use of nursing diagnoses are needed to inform decision making. PMID:25822514

  20. Newborn skin care.

    PubMed

    Dyer, Jonathan A

    2013-02-01

    Many organ systems undergo significant and rapid changes during the transition from an intrauterine to an extrauterine environment, especially those which serve as interfaces between the infant and the external environment. Historically the skin care methods employed during and after this period of rapid physiologic change have been derived from individual anecdotal experience or cultural tradition, rather than evidence-based or pathomechanistically derived data. While research in this area has historically been limited, it is increasing in scope and volume, and recent work has shed light on the changes experienced by the cutaneous organ during this period of transition. This increased understanding has driven new recommendations in skin care protocols for newborn infants and neonates. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Leucine metabolism in human newborns

    SciTech Connect

    Denne, S.C.; Kalhan, S.C. )

    1987-12-01

    The present study was designed to (1) determine whether a relationship exists between newborn birth weight and leucine metabolism and (2) compare leucine and energy metabolism in a period of rapid growth and development (i.e., newborn) with a constant nongrowth period (i.e., adult). Leucine kinetics and energy expenditure were measured in the postabsorptive state in 12 normal full-term newborns in early neonatal life and in 11 normal adults using a primed constant L-(1-{sup 13}C)leucine infusion combined with respiratory calorimetry. A significant positive correlation between newborn birth weight and leucine flux was observed. These data suggest the following. (1) A relationship exists between newborn birth weight and protein metabolism, as reflected by the correlation between leucine flux when expressed as micromoles per kilogram per hour and birth weight. (2) The high rate of leucine flux measured in newborns probably reflects the rapid remodeling of protein that occurs in this period of development, even during fasting. (3) The similar values in newborns and adults of leucine kinetics and energy expenditure when normalized to metabolic body weight and the nearly equivalent allometric exponents relating body weight to leucine flux and energy expenditure support a close relationship between leucine and energy metabolism, at least at the extremes of human growth.

  2. Glycogen storage disease type Ia mice with less than 2% of normal hepatic glucose-6-phosphatase-α activity restored are at risk of developing hepatic tumors.

    PubMed

    Kim, Goo-Young; Lee, Young Mok; Kwon, Joon Hyun; Cho, Jun-Ho; Pan, Chi-Jiunn; Starost, Matthew F; Mansfield, Brian C; Chou, Janice Y

    2017-03-01

    Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA) and carcinoma (HCC), is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC). We have previously shown that G6pc-/- mice receiving gene transfer mediated by rAAV-G6PC, a recombinant adeno-associated virus (rAAV) vector expressing G6Pase-α, and expressing 3-63% of normal hepatic G6Pase-α activity maintain glucose homeostasis and do not develop HCA/HCC. However, the threshold of hepatic G6Pase-α activity required to prevent tumor formation remained unknown. In this study, we constructed rAAV-co-G6PC, a rAAV vector expressing a codon-optimized (co) G6Pase-α and showed that rAAV-co-G6PC was more efficacious than rAAV-G6PC in directing hepatic G6Pase-α expression. Over an 88-week study, we showed that both rAAV-G6PC- and rAAV-co-G6PC-treated G6pc-/- mice expressing 3-33% of normal hepatic G6Pase-α activity (AAV mice) maintained glucose homeostasis, lacked HCA/HCC, and were protected against age-related obesity and insulin resistance. Of the eleven rAAV-G6PC/rAAV-co-G6PC-treated G6pc-/- mice harboring 0.9-2.4% of normal hepatic G6Pase-α activity (AAV-low mice), 3 expressing 0.9-1.3% of normal hepatic G6Pase-α activity developed HCA/HCC, while 8 did not (AAV-low-NT). Finally, we showed that the AAV-low-NT mice exhibited a phenotype indistinguishable from that of AAV mice expressing ≥3% of normal hepatic G6Pase-α activity. The results establish the threshold of hepatic G6Pase-α activity required to prevent HCA/HCC and show that GSD-Ia mice harboring <2% of normal hepatic G6Pase-α activity are at risk of tumor development. Published by Elsevier Inc.

  3. Healthy Start, Grow Smart: Your Newborn.

    ERIC Educational Resources Information Center

    Department of Education, Washington, DC.

    This booklet offers guidance to parents in caring for their newborn babies. Advice is given on the following topics: (1) newborn health screening; (2) what a healthy newborn looks like; (3) newborn reflexes; (4) baby checkups; (5) fathers' role; (6) the baby blues; (7) sleeping position; (8) breast milk; (9) breast feeding; (10) bottle feeding;…

  4. Basic consciousness of the newborn.

    PubMed

    Lagercrantz, Hugo; Changeux, Jean-Pierre

    2010-06-01

    The newborn shows several signs of consciousness, such as being awake and aware of him/herself and mother. The infant processes olfactory and painful inputs in the cortex, where consciousness is believed to be localized. Furthermore, the newborn expresses primary emotions such as joy, disgust, and surprise and remember rhymes and vowels to which he or she has been exposed during fetal life. Thus, the newborn infant fulfills the criteria of displaying a basic level of consciousness, being aware of its body and him/her-self and somewhat about the external world. Preterm infants may be conscious to a limited degree from about 25 weeks, when the thalamocortical connections are established.

  5. Antifungal Immunological Defenses in Newborns

    PubMed Central

    Michalski, Christina; Kan, Bernard; Lavoie, Pascal M.

    2017-01-01

    Newborns are prone to fungal infections, largely due to Candida species. The immunological basis for this vulnerability is not yet fully understood. However, useful insights can be gained from the knowledge of the maturation of immune pathways during ontogeny, particularly when placed in context with how rare genetic mutations in humans predispose to fungal diseases. In this article, we review these most current data on immune functions in human newborns, highlighting pathways most relevant to the response to Candida. While discussing these data, we propose a framework of why deficiencies in these pathways make newborns particularly vulnerable to this opportunistic pathogen. PMID:28360910

  6. A novel cognitive enhancer, ZSET1446/ST101, promotes hippocampal neurogenesis and ameliorates depressive behavior in olfactory bulbectomized mice.

    PubMed

    Shioda, Norifumi; Yamamoto, Yui; Han, Feng; Moriguchi, Shigeki; Yamaguchi, Yoshimasa; Hino, Masataka; Fukunaga, Kohji

    2010-04-01

    In the adult brain, neurogenesis persistently occurs in the subgranular zone of the hippocampal dentate gyrus (DG), and impaired neurogenesis is implicated in depressive behaviors and poor learning memory. Here, we investigated the effects of oral administration of spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101), a novel cognitive enhancer stimulating acetylcholine release, on adult neurogenesis in olfactory bulbectomized (OBX) mice. OBX mice showed significant decreases in the number of newborn cells in the DG by immunohistochemical analysis of 5-bromo-2-deoxyuridine incorporation. Impaired neurogenesis observed in OBX mice was significantly improved by chronic administration with ZSET1446. We confirmed that administration with mecamylamine, a nicotinic acetylcholine receptor antagonist, inhibits ZSET1446-enhanced neurogenesis in the DG. ZSET1446 administration also restored decreased phosphorylation of Akt and extracellular signal-regulated kinase in the DG of OBX mice. Consistent with restored neurogenesis, chronic but not single ZSET1446 administration promoted significant decreases in immobility in tail suspension tests and improved cognitive behaviors in OBX mice. Taken together, chronic ZSET1446 administration antagonized impaired neurogenesis seen in OBX mice, an effect closely associated with improvement of depressive behavior.

  7. Selective restoration of male fertility in mice lacking angiotensin-converting enzymes by sperm-specific expression of the testicular isozyme.

    PubMed Central

    Ramaraj, P; Kessler, S P; Colmenares, C; Sen, G C

    1998-01-01

    Although angiotensin-converting enzyme (ACE) has been studied primarily in the context of its role in blood pressure regulation, this widely distributed enzyme has many other physiological functions. The ACE gene encodes two isozymes. The somatic isozyme is expressed in many tissues, including vascular endothelial cells, renal epithelial cells, and testicular Leydig cells, whereas the testicular or germinal angiotensin-converting enzyme is expressed only in sperm. The ACE gene knockout mice lack both isozymes and they exhibit low blood pressure, kidney dysfunctions, and male infertility. Here, we report the use of a sperm-specific promoter and interbreeding of transgenic and gene knockout mice for generating a mouse strain that expressed ACE only in sperm. The experimental mice maintained the kidney defects of ACE-/- mice, but unlike the knockout strain, the males were fertile. Thus, we established that the role of ACE in male fertility is completely dependent on its exclusive expression in sperm. Our study clearly demonstrated how transgenic and knockout techniques can be combined for ascribing a specific physiological function to the expression of a multifunctional protein in a given tissue. PMID:9664078

  8. Tissue-Specific Expression of Transgenic Secreted ACE in Vasculature Can Restore Normal Kidney Functions, but Not Blood Pressure, of Ace-/- Mice

    PubMed Central

    Chattopadhyay, Saurabh; Kessler, Sean P.; Colucci, Juliana Almada; Yamashita, Michifumi; Senanayake, Preenie deS; Sen, Ganes C.

    2014-01-01

    Angiotensin-converting enzyme (ACE) regulates normal blood pressure and fluid homeostasis through its action in the renin-angiotensin-system (RAS). Ace-/- mice are smaller in size, have low blood pressure and defective kidney structure and functions. All of these defects are cured by transgenic expression of somatic ACE (sACE) in vascular endothelial cells of Ace-/- mice. sACE is expressed on the surface of vascular endothelial cells and undergoes a natural cleavage secretion process to generate a soluble form in the body fluids. Both the tissue-bound and the soluble forms of ACE are enzymatically active, and generate the vasoactive octapeptide Angiotensin II (Ang II) with equal efficiency. To assess the relative physiological roles of the secreted and the cell-bound forms of ACE, we expressed, in the vascular endothelial cells of Ace-/- mice, the ectodomain of sACE, which corresponded to only the secreted form of ACE. Our results demonstrated that the secreted form of ACE could normalize kidney functions and RAS integrity, growth and development of Ace-/- mice, but not their blood pressure. This study clearly demonstrates that the secreted form of ACE cannot replace the tissue-bound ACE for maintaining normal blood pressure; a suitable balance between the tissue-bound and the soluble forms of ACE is essential for maintaining all physiological functions of ACE. PMID:24475296

  9. Diagnostic guidelines for newborns who screen positive in newborn screening.

    PubMed

    Kronn, David; Mofidi, Shideh; Braverman, Nancy; Harris, Katharine

    2010-12-01

    Recent expansion of the newborn screening panels has presented an interesting challenge to specialty care centers, especially the clinical genetics community. Some of the conditions in the core and secondary newborn screening panels have extremely variable clinical presentations; others are so rare that only a handful of newborns have been diagnosed with them to date (Region 4 Collaborative MS/MS project-http://region4genetics.org/msms_data_project/data_project_home.aspx). Definition of some disorders is problematic-does continued abnormality of the screening analyte constitute diagnosis or is further testing necessary? A work group of the New York Mid-Atlantic Consortium for Genetic and Newborn Screening Services (region 2), one of seven regional collaboratives funded by the Federal Health Resources and Services Administration and administered by the Maternal and Child Health Bureau (U22MC03956), has developed guidelines for the confirmation of diagnosis of the conditions in the newborn screening panels for use by the specialty care centers. The diagnostic guidelines are a work in progress and are being reviewed and revised regularly as our understanding of the newborn screened disorders improves. The aim is to make it a relevant guide for specialty care physicians and other healthcare professionals in the diagnostic workup of these patients.

  10. Purpose of Newborn Hearing Screening

    MedlinePlus

    ... Breastfeeding Crying & Colic Diapers & Clothing Feeding & Nutrition Preemie Sleep Teething & Tooth Care Toddler Preschool Gradeschool Teen Young Adult Healthy Children > Ages & Stages > Baby > Purpose of Newborn Hearing Screening Ages & Stages ...

  11. Medical Care and Your Newborn

    MedlinePlus

    ... Weight, length, and head circumference will be measured. Temperature will be taken, and your baby's breathing and ... an eye infection. Fever in a newborn (rectal temperature above 100.4°F or 38°C) should ...

  12. Learning, Play, and Your Newborn

    MedlinePlus

    ... their backs to reduce the risk of SIDS (sudden infant death syndrome) . Talk to your baby. Keep in mind ... For Kids For Parents MORE ON THIS TOPIC Sudden Infant Death Syndrome (SIDS) Movement, Coordination, and Your Newborn Your ...

  13. Screening Newborns' Hearing Now Standard

    MedlinePlus

    ... Javascript on. Feature: Taste, Smell, Hearing, Language, Voice, Balance Screening Newborns' Hearing Now Standard Past Issues / Fall ... gov . Read More "Taste, Smell, Hearing, Language, Voice, Balance" Articles At Last: A National Test of Taste ...

  14. Restoration of on-time embryo implantation corrects the timing of parturition in cytosolic phospholipase A2 group IVA deficient mice.

    PubMed

    Brown, Naoko; Morrow, Jason D; Slaughter, James C; Paria, Bibhash C; Reese, Jeff

    2009-12-01

    Cytosolic phospholipase A2 (cPLA2, PLA2G4A) catalyzes the release of arachidonic acid for prostaglandin synthesis by cyclooxygenase 1 (PTGS1) and cyclooxygenase 2 (PTGS2). Mice with Pla2g4a deficiency have parturition delay and other reproductive deficits, including deferred onset of implantation, crowding of implantation sites, and small litters. In this study, we examined the contribution of PLA2G4A to parturition in mice. Pla2g4a mRNA and protein expression were discretely localized in the term and preterm uterine luminal epithelium and colocalized with Ptgs1, but not Ptgs2, expression. The levels of PGE2, PGF2alpha, 6-keto-PGF1alpha, and TxB2 were significantly decreased in Pla2g4a-null uterine tissues, similar to Ptgs1-null uteri, consistent with predominance of PLA2G4A-PTGS1-mediated prostaglandin synthesis in preparation for murine parturition. Litter size was strongly associated with the timing of parturition in Pla2g4a-null mice but could not fully account for the parturition delay. Pla2g4a-null females that received PGE2 + carbaprostacyclin at the time of implantation delivered earlier (20.5 +/- 0.2 days vs. 21.6 +/- 0.2 days, P < 0.01), although litter size was not improved (4.6 vs. 4.4 pups per litter, P = 0.6). After correction for small litter size, multivariate analysis indicated that Pla2g4a-null mice given prostaglandin treatment to improve implantation timing had gestational length that was similar to wild-type and Pla2g4a heterozygous mice. These results indicate that, despite specific Pla2g4a expression and function in term gestation uteri, the delayed parturition phenotype in Pla2g4a-null mice is primarily due to deferral of implantation. The role of PLA2G4A in timely parturition appears to be critically related to its actions in early pregnancy.

  15. Restoration of On-Time Embryo Implantation Corrects the Timing of Parturition in Cytosolic Phospholipase A2 Group IVA Deficient Mice1

    PubMed Central

    Brown, Naoko; Morrow, Jason D.; Slaughter, James C.; Paria, Bibhash C.; Reese, Jeff

    2009-01-01

    Cytosolic phospholipase A2 (cPLA2, PLA2G4A) catalyzes the release of arachidonic acid for prostaglandin synthesis by cyclooxygenase 1 (PTGS1) and cyclooxygenase 2 (PTGS2). Mice with Pla2g4a deficiency have parturition delay and other reproductive deficits, including deferred onset of implantation, crowding of implantation sites, and small litters. In this study, we examined the contribution of PLA2G4A to parturition in mice. Pla2g4a mRNA and protein expression were discretely localized in the term and preterm uterine luminal epithelium and colocalized with Ptgs1, but not Ptgs2, expression. The levels of PGE2, PGF2alpha, 6-keto-PGF1alpha, and TxB2 were significantly decreased in Pla2g4a-null uterine tissues, similar to Ptgs1-null uteri, consistent with predominance of PLA2G4A-PTGS1-mediated prostaglandin synthesis in preparation for murine parturition. Litter size was strongly associated with the timing of parturition in Pla2g4a-null mice but could not fully account for the parturition delay. Pla2g4a-null females that received PGE2 + carbaprostacyclin at the time of implantation delivered earlier (20.5 ± 0.2 days vs. 21.6 ± 0.2 days, P < 0.01), although litter size was not improved (4.6 vs. 4.4 pups per litter, P = 0.6). After correction for small litter size, multivariate analysis indicated that Pla2g4a-null mice given prostaglandin treatment to improve implantation timing had gestational length that was similar to wild-type and Pla2g4a heterozygous mice. These results indicate that, despite specific Pla2g4a expression and function in term gestation uteri, the delayed parturition phenotype in Pla2g4a-null mice is primarily due to deferral of implantation. The role of PLA2G4A in timely parturition appears to be critically related to its actions in early pregnancy. PMID:19684335

  16. Trimodal Gadolinium-Gold Microcapsules Containing Pancreatic Islet Cells Restore Normoglycemia in Diabetic Mice and Can Be Tracked by Using US, CT, and Positive-Contrast MR Imaging

    PubMed Central

    Arifin, Dian R.; Long, Christopher M.; Gilad, Assaf A.; Alric, Christophe; Roux, Stéphane; Tillement, Olivier; Link, Thomas W.; Arepally, Aravind; Bulte, Jeff W. M.

    2011-01-01

    Purpose: To develop microcapsules that immunoprotect pancreatic islet cells for treatment of type I diabetes and enable multimodal cellular imaging of transplanted islet cells. Materials and Methods: All animal experiments were approved by the institutional animal care and use committee. Gold nanoparticles functionalized with DTDTPA (dithiolated diethylenetriaminepentaacetic acid):gadolinium chelates (GG) were coencapsulated with pancreatic islet cells by using protamine sulfate as a clinical-grade alginate cross linker. Conventional poly-l-lysine–cross-linked microcapsules and unencapsulated islets were included as controls. The viability and glucose responsiveness of islet cells were assessed in vitro, and in vivo insulin (C-peptide) secretion was monitored for 6 weeks in (streptozotocin-induced) diabetic mice with (n = 7) or without (n = 8) intraabdominally engrafted islet cells. Five nondiabetic mice were included as controls. Differences between samples were calculated by using a nonparametric Wilcoxon Mann-Whitney method. To adjust for multiple comparisons, a significance level of P < .01 was chosen. Generalized estimating equations were used to model cell function over time. Three mice with engrafted capsules were imaged in vivo with high-field-strength (9.4-T) magnetic resonance (MR) imaging, micro–computed tomography (CT), and 40-MHz ultrasonography (US). Results: Encapsulated human pancreatic islets were functional in vitro for at least 2 weeks after encapsulation. Blood glucose levels in the diabetic mice transplanted with GG-labeled encapsulated mouse βTC6 insulinoma cells returned to normal within 1 week after transplantation, and normoglycemia was sustained for at least 6 weeks without the use of immunosuppressive drugs. GG microcapsules could be readily visualized with positive-contrast high-field-strength MR imaging, micro-CT, and US both in vitro and in vivo. Conclusion: Cell encapsulation with GG provides a means of trimodal noninvasive

  17. Total glucosides of paeony inhibit the inflammatory responses of mice with allergic contact dermatitis by restoring the balanced secretion of pro-/anti-inflammatory cytokines.

    PubMed

    Wang, Chun; Yuan, Jun; Wu, Hua-Xun; Chang, Yan; Wang, Qing-Tong; Wu, Yu-Jing; Zhou, Peng; Yang, Xiao-Dan; Yu, Jun; Wei, Wei

    2015-02-01

    The present study aimed to investigate the regulation exerted by the total glucosides of paeony (TGP) on the production of interleukin-2 (IL-2), IL-4, IL-10 and IL-17 in the serum and lymphocytes of mice with allergic contact dermatitis (ACD). ACD in mice was induced by the repeated application of 2,4-dinitrochlorobenzene (DNCB) to their skins. The mice were orally administered TGP (35, 70, and 140mg/kg/d) and prednisone (Pre, 5mg/kg/d) from day 1 to day 7 after immunization. The inflammatory responses were evaluated by ear swelling and histological examination. Thymocyte proliferation was assayed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide assay. The cytokine production in the serum and lymphocytes supernatant was measured by enzyme-linked immunosorbent assay. The results indicated that the topical application of DNCB to the skin provoked obvious inflammatory responses. The oral administration of TGP (70 and 140mg/kg/d) and Pre (5mg/kg/d) significantly inhibited skin inflammation, decreased the thymus and spleen indices, and inhibited thymocyte proliferation in mice treated with DNCB. Further study indicated that TGP increased IL-4 and IL-10 production but decreased the production of IL-2 and IL-17 in the serum and lymphocyte supernatant. The correlation analysis suggested significantly positive correlations between IL-2 and IL-17 production and the severity of skin inflammation, whereas negative correlations were obtained for IL-4 and IL-10 production and skin inflammation. In summary, these results suggest that the therapeutic effects of TGP on ACD may result from its regulation of the imbalanced secretion of IL-2/IL-4 and IL-10/IL-17.

  18. Single administration of recombinant IL-6 restores the gene expression of lipogenic enzymes in liver of fasting IL-6-deficient mice.

    PubMed

    Gavito, A L; Cabello, R; Suarez, J; Serrano, A; Pavón, F J; Vida, M; Romero, M; Pardo, V; Bautista, D; Arrabal, S; Decara, J; Cuesta, A L; Valverde, A M; Rodríguez de Fonseca, F; Baixeras, E

    2016-03-01

    Lipogenesis is intimately controlled by hormones and cytokines as well as nutritional conditions. IL-6 participates in the regulation of fatty acid metabolism in the liver. We investigated the role of IL-6 in mediating fasting/re-feeding changes in the expression of hepatic lipogenic enzymes. Gene and protein expression of lipogenic enzymes were examined in livers of wild-type (WT) and IL-6-deficient (IL-6(-/-) ) mice during fasting and re-feeding conditions. Effects of exogenous IL-6 administration on gene expression of these enzymes were evaluated in vivo. The involvement of STAT3 in mediating these IL-6 responses was investigated by using siRNA in human HepG2 cells. During feeding, the up-regulation in the hepatic expression of lipogenic genes presented similar time kinetics in WT and IL-6(-/-) mice. During fasting, expression of lipogenic genes decreased gradually over time in both strains, although the initial drop was more marked in IL-6(-/-) mice. Protein levels of hepatic lipogenic enzymes were lower in IL-6(-/-) than in WT mice at the end of the fasting period. In WT, circulating IL-6 levels paralleled gene expression of hepatic lipogenic enzymes. IL-6 administration in vivo and in vitro showed that IL-6-mediated signalling was associated with the up-regulation of hepatic lipogenic enzyme genes. Moreover, silencing STAT3 in HepG2 cells attenuated IL-6 mediated up-regulation of lipogenic gene transcription levels. IL-6 sustains levels of hepatic lipogenic enzymes during fasting through activation of STAT3. Our findings indicate that clinical use of STAT3-associated signalling cytokines, particularly against steatosis, should be undertaken with caution. © 2016 The British Pharmacological Society.

  19. Single administration of recombinant IL‐6 restores the gene expression of lipogenic enzymes in liver of fasting IL‐6‐deficient mice

    PubMed Central

    Gavito, AL; Cabello, R; Suarez, J; Serrano, A; Pavón, F J; Vida, M; Romero, M; Pardo, V; Bautista, D; Arrabal, S; Decara, J; Cuesta, AL; Valverde, A M; Rodríguez de Fonseca, F

    2016-01-01

    Background and Purpose Lipogenesis is intimately controlled by hormones and cytokines as well as nutritional conditions. IL‐6 participates in the regulation of fatty acid metabolism in the liver. We investigated the role of IL‐6 in mediating fasting/re‐feeding changes in the expression of hepatic lipogenic enzymes. Experimental Approach Gene and protein expression of lipogenic enzymes were examined in livers of wild‐type (WT) and IL‐6‐deficient (IL‐6−/−) mice during fasting and re‐feeding conditions. Effects of exogenous IL‐6 administration on gene expression of these enzymes were evaluated in vivo. The involvement of STAT3 in mediating these IL‐6 responses was investigated by using siRNA in human HepG2 cells. Key Results During feeding, the up‐regulation in the hepatic expression of lipogenic genes presented similar time kinetics in WT and IL‐6−/− mice. During fasting, expression of lipogenic genes decreased gradually over time in both strains, although the initial drop was more marked in IL‐6−/− mice. Protein levels of hepatic lipogenic enzymes were lower in IL‐6−/− than in WT mice at the end of the fasting period. In WT, circulating IL‐6 levels paralleled gene expression of hepatic lipogenic enzymes. IL‐6 administration in vivo and in vitro showed that IL‐6‐mediated signalling was associated with the up‐regulation of hepatic lipogenic enzyme genes. Moreover, silencing STAT3 in HepG2 cells attenuated IL‐6 mediated up‐regulation of lipogenic gene transcription levels. Conclusions and Implications IL‐6 sustains levels of hepatic lipogenic enzymes during fasting through activation of STAT3. Our findings indicate that clinical use of STAT3‐associated signalling cytokines, particularly against steatosis, should be undertaken with caution. PMID:26750868

  20. Natural restoration

    SciTech Connect

    Kamlet, K.S.

    1993-02-01

    After a company pays millions of dollars to clean up contaminated site, its liability may not be over. It may have to spend tens of millions more to restore damaged natural resources under an oft-overlooked Superfund program. Examples of liability are cited in this report from the Exxon Valdez oil spill and a pcb leak which contaminated a harbor.

  1. Ecological restoration

    Treesearch

    Christopher D. Barton; John I. Blake; Donald W. Imm

    2005-01-01

    The long history of human settlement, agriculture, and industry at the Savannah River Site (SRS) has created extensive opportunities for ecological restoration. Two hundred years of farming, drainage, dam construction, stream channeling, fire protection, subsistence hunting and fishing, exotic animal and plant introduction, and selective timber harvesting have caused...

  2. History and Current Status of Newborn Screening for Severe Combined Immunodeficiency

    PubMed Central

    Kwan, Antonia; Puck, Jennifer M.

    2015-01-01

    The development of a T cell receptor excision circle (TREC) assay utilizing dried blood spots in universal newborn screening has allowed the early detection of T cell lymphopenia in newborns. Diagnosis of severe combined immunodeficiency (SCID) in affected infants in the neonatal period while asymptomatic permits early treatment and restoration of a functional immune system. SCID was the first immunodeficiency disease to be added to the Recommended Uniform Screening Panel of Core Conditions in the United States in 2010, and is now implemented in 26 states in the U.S. This review covers the development of newborn screening for SCID, the biology of the TREC test, its current implementation in the U.S., new findings for SCID in the newborn screening era, and future directions. PMID:25937517

  3. History and current status of newborn screening for severe combined immunodeficiency.

    PubMed

    Kwan, Antonia; Puck, Jennifer M

    2015-04-01

    The development of a T-cell receptor excision circle (TREC) assay utilizing dried blood spots in universal newborn screening has allowed the early detection of T-cell lymphopenia in newborns. Diagnosis of severe combined immunodeficiency (SCID) in affected infants in the neonatal period, while asymptomatic, permits early treatment and restoration of a functional immune system. SCID was the first immunodeficiency disease to be added to the Recommended Uniform Screening Panel of Core Conditions in the United States in 2010, and it is now implemented in 26 states in the U.S. This review covers the development of newborn screening for SCID, the biology of the TREC test, its current implementation in the U.S., new findings for SCID in the newborn screening era, and future directions.

  4. Acute inhibition of central c-Jun N-terminal kinase restores hypothalamic insulin signalling and alleviates glucose intolerance in diabetic mice.

    PubMed

    Benzler, J; Ganjam, G K; Legler, K; Stöhr, S; Krüger, M; Steger, J; Tups, A

    2013-05-01

    The hypothalamus has been identified as a main insulin target tissue for regulating normal body weight and glucose metabolism. Recent observations suggest that c-Jun-N-terminal kinase (JNK)-signalling plays a crucial role in the development of obesity and insulin resistance because neuronal JNK-1 ablation in the mouse prevented high-fat diet-induced obesity (DIO) and increased energy expenditure, as well as insulin sensitivity. In the present study, we investigated whether central JNK inhibition is associated with sensitisation of hypothalamic insulin signalling in mice fed a high-fat diet for 3 weeks and in leptin-deficient mice. We determined whether i.c.v. injection of a pharmacological JNK-inhibitor (SP600125) improved impaired glucose homeostasis. By immunohistochemistry, we first observed that JNK activity was increased in the arcuate nucleus (ARC) and the ventromedial hypothalamus (VMH) in both mouse models, relative to normoglycaemic controls. This suggests that up-regulation of JNK in these regions is associated with glucose intolerance and obesity, independent of leptin levels. Acute i.c.v. injection of SP600125 ameliorated glucose tolerance within 30 min in both leptin-deficient and DIO mice. Given the acute nature of i.c.v. injections, these effects cannot be attributed to changes in food intake or energy balance. In a hypothalamic cell line, and in the ARC and VMH of leptin-deficient mice, JNK inhibition by SP600125 consistently improved impaired insulin signalling. This was determined by a reduction of phospho-insulin receptor substrate-1 [IRS-1(Ser612)] protein in a hypothalamic cell line and a decline in the number of pIRS-1(Ser612) immunoreactive cells in the ARC and VMH. Serine 612 phosphorylation of IRS-1 is assumed to negatively regulate insulin signalling. In leptin-deficient mice, in both nuclei, central inhibition of JNK increased the number of cells immunoreactive for phospho-Akt (Ser473) and phospho-GSK-3β (Ser9), which are important

  5. Pain Management in Newborns

    PubMed Central

    Hall, Richard W.; Anand, Kanwaljeet J. S.

    2014-01-01

    Effective pain management is a desirable standard of care for preterm and term newborns and may potentially improve their clinical and neurodevelopmental outcomes. Neonatal pain should be assessed routinely using context-specific, validated and objective pain methods, despite the limitations of currently available tools. Reducing invasive procedures, and using pharmacological, behavioral or environmental measures can be used to manage neonatal pain. Non-pharmacologic approaches include kangaroo care, facilitated tucking, non-nutritive sucking, sucrose and other sweeteners, massage and acupuncture therapy. They are used for procedures causing acute, transient, or mild pain, or as adjunctive therapy for moderate or severe pain. Local and topical anesthetics can reduce the acute pain caused by skin-breaking or mucosa-injuring procedures. Opioids form the mainstay for treatment of severe pain; morphine and fentanyl are the most commonly used drugs, although other opioids are also available. Non-opioid drugs include various sedatives and anesthetic agents, mostly used as adjunctive therapy in ventilated neonates. Acetaminophen, ibuprofen and other drugs are used for neonates, although their efficacy and safety remains unproven. Approaches for implementing an effective pain management program in the Neonatal ICU are summarized, together with practical protocols for procedural, postoperative, and mechanical ventilation-associated neonatal pain and stress. PMID:25459780

  6. Thrombosis in newborn infants.

    PubMed

    Bacciedoni, Viviana; Attie, Myriam; Donato, Hugo

    2016-04-01

    The incidence of thrombosis is higher among newborn infants than in any other stage of pediatric development. This fact is the consequence of labile characteristics of the neonatal hemostatic system, in addition to exposure to multiple risk factors and the wide use of vascular catheters. Venous thromboses, which mainly affect the limbs, the right atrium and renal veins, are more frequently seen than arterial thromboses. A stroke may be caused by the occlusion of the arterial flow entering the brain or by occlusion of its venous drainage system. Purpura fulminans is a very severe condition that should be treated as a medical emergency, and is secondary to severe protein C deficiency or, less frequently, protein S or antithrombin deficiency. Most thrombotic events should be managed with antithrombotic therapy, which is done with unfractionated and/or low molecular weight heparins. Purpura fulminans requires protein C replacement and/or fresh frozen plasma infusion. Thrombolytic therapy is done using tissue plasminogen activator and should only be used for life-, or limb-, or organ-threatening thrombosis.

  7. Azilsartan, an angiotensin II type 1 receptor blocker, restores endothelial function by reducing vascular inflammation and by increasing the phosphorylation ratio Ser1177/Thr497 of endothelial nitric oxide synthase in diabetic mice

    PubMed Central

    2014-01-01

    Background Azilsartan, an angiotensin II type 1 (AT1) receptor blocker (ARB), has a higher affinity for and slower dissociation from AT1 receptors and shows stronger inverse agonism compared to other ARBs. Possible benefits of azilsartan in diabetic vascular dysfunction have not been established. Methods We measured vascular reactivity of aortic rings in male KKAy diabetic mice treated with vehicle, 0.005% azilsartan, or 0.005% candesartan cilexetil for 3 weeks. Expression of markers of inflammation and oxidative stress was measured using semiquantitative RT-PCR in the vascular wall, perivascular fat, and skeletal muscle. Phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and Thr495 was measured using Western blotting, and the ratio of phosphorylation at Ser1177 to phosphorylation at Thr495 was used as a putative indicator of vascular eNOS activity. Results (1) Vascular endothelium–dependent relaxation with acetylcholine in KKAy mice was improved by azilsartan treatment compared to candesartan cilexetil; (2) the ratio of Ser1177/Thr495 phosphorylation of eNOS was impaired in KKAy and was effectively restored by azilsartan; (3) anomalies in the expression levels of monocyte chemotactic protein 1 (MCP1), F4/80, NAD(P)H oxidase (Nox) 2, and Nox4 of the aortic wall and in the expression of TNFα in the perivascular fat were strongly attenuated by azilsartan compared to candesartan cilexetil. Conclusions These results provide evidence that azilsartan prevents endothelial dysfunction in diabetic mice, more potently than does candesartan cilexetil. Azilsartan’s higher affinity for and slower dissociation from AT1 receptors may underlie its efficacy in diabetic vascular dysfunction via a dual effect on uncoupled eNOS and on Nox. PMID:24485356

  8. Azilsartan, an angiotensin II type 1 receptor blocker, restores endothelial function by reducing vascular inflammation and by increasing the phosphorylation ratio Ser(1177)/Thr(497) of endothelial nitric oxide synthase in diabetic mice.

    PubMed

    Matsumoto, Sachiko; Shimabukuro, Michio; Fukuda, Daiju; Soeki, Takeshi; Yamakawa, Ken; Masuzaki, Hiroaki; Sata, Masataka

    2014-01-31

    Azilsartan, an angiotensin II type 1 (AT1) receptor blocker (ARB), has a higher affinity for and slower dissociation from AT1 receptors and shows stronger inverse agonism compared to other ARBs. Possible benefits of azilsartan in diabetic vascular dysfunction have not been established. We measured vascular reactivity of aortic rings in male KKAy diabetic mice treated with vehicle, 0.005% azilsartan, or 0.005% candesartan cilexetil for 3 weeks. Expression of markers of inflammation and oxidative stress was measured using semiquantitative RT-PCR in the vascular wall, perivascular fat, and skeletal muscle. Phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and Thr495 was measured using Western blotting, and the ratio of phosphorylation at Ser1177 to phosphorylation at Thr495 was used as a putative indicator of vascular eNOS activity. (1) Vascular endothelium-dependent relaxation with acetylcholine in KKAy mice was improved by azilsartan treatment compared to candesartan cilexetil; (2) the ratio of Ser1177/Thr495 phosphorylation of eNOS was impaired in KKAy and was effectively restored by azilsartan; (3) anomalies in the expression levels of monocyte chemotactic protein 1 (MCP1), F4/80, NAD(P)H oxidase (Nox) 2, and Nox4 of the aortic wall and in the expression of TNFα in the perivascular fat were strongly attenuated by azilsartan compared to candesartan cilexetil. These results provide evidence that azilsartan prevents endothelial dysfunction in diabetic mice, more potently than does candesartan cilexetil. Azilsartan's higher affinity for and slower dissociation from AT1 receptors may underlie its efficacy in diabetic vascular dysfunction via a dual effect on uncoupled eNOS and on Nox.

  9. Restoration Process

    NASA Technical Reports Server (NTRS)

    1979-01-01

    In the accompanying photos, a laboratory technician is restoring the once-obliterated serial number of a revolver. The four-photo sequence shows the gradual progression from total invisibility to clear readability. The technician is using a new process developed in an applications engineering project conducted by NASA's Lewis Research Center in conjunction with Chicago State University. Serial numbers and other markings are frequently eliminated from metal objects to prevent tracing ownership of guns, motor vehicles, bicycles, cameras, appliances and jewelry. To restore obliterated numbers, crime laboratory investigators most often employ a chemical etching technique. It is effective, but it may cause metal corrosion and it requires extensive preparatory grinding and polishing. The NASA-Chicago State process is advantageous because it can be applied without variation to any kind of metal, it needs no preparatory work and number recovery can be accomplished without corrosive chemicals; the liquid used is water.

  10. Normalizing the environment recapitulates adult human immune traits in laboratory mice.

    PubMed

    Beura, Lalit K; Hamilton, Sara E; Bi, Kevin; Schenkel, Jason M; Odumade, Oludare A; Casey, Kerry A; Thompson, Emily A; Fraser, Kathryn A; Rosato, Pamela C; Filali-Mouhim, Ali; Sekaly, Rafick P; Jenkins, Marc K; Vezys, Vaiva; Haining, W Nicholas; Jameson, Stephen C; Masopust, David

    2016-04-28

    Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside. Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice--like newborn, but not adult, humans--lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.

  11. Restoration of human B-cell differentiation into NOD-SCID mice engrafted with gene-corrected CD34+ cells isolated from Artemis or RAG1-deficient patients.

    PubMed

    Lagresle-Peyrou, Chantal; Benjelloun, Fatine; Hue, Christophe; Andre-Schmutz, Isabelle; Bonhomme, Delphine; Forveille, Monique; Beldjord, Kheira; Hacein-Bey-Abina, Salima; De Villartay, Jean-Pierre; Charneau, Pierre; Durandy, Anne; Fischer, Alain; Cavazzana-Calvo, Marina

    2008-02-01

    Severe combined immunodeficiency (SCID) caused by mutation of the recombination-activating gene 1 (RAG1) or Artemis gene lead to the absence of B- and T-cell differentiation. The only curative treatment is allogeneic bone marrow (BM) transplantation, which displays a high survival rate when an HLA compatible donor is available but has a poorer prognosis when the donor is partially compatible. Consequently, gene therapy may be a promising alternative strategy for these diseases. Here, we report that lentiviral gene-corrected BM CD34(+) cells (isolated from Artemis- or RAG1-deficient patients) sustain human B-cell differentiation following injection into non-obese diabetic/SCID (NOD-SCID) mice previously infused with anti-interleukin-2 receptor beta chain monoclonal antibody. In most of the mice BM, engrafted with Artemis-transduced cells, human B-cell differentiation occurred until the mature stage. The B cells were functional as human immunoglobulin M (IgM) was present in the serum. Following injection with RAG1-transduced cells, human engraftment occurred in vivo but B-cell differentiation until the mature stage was less frequent. However, when it occurred, it was always associated with human IgM production. This overall approach represents a useful tool for evaluating gene transfer efficiency in human SCID forms affecting B-cell development (such as Artemis deficiency) and for testing new vectors for improving in vivo RAG1 complementation.

  12. PI3Kγ Deficient NOD-Mice Are Protected from Diabetes by Restoring the Balance of Regulatory to Effector-T-Cells

    PubMed Central

    Azzi, Jamil; Thueson, Lindsay; Moore, Robert; Abdoli, Rozita; Reijonen, Helena; Abdi, Reza

    2017-01-01

    With a steady increase in its incidence and lack of curative treatment, type 1 diabetes (T1D) has emerged as a major health problem worldwide. To design novel effective therapies, there is a pressing need to identify regulatory targets controlling the balance of autoreactive to regulatory-T-cells (Tregs). We previously showed that the inhibition of the γ-subunit of the Phosphoinositide-3-kinase (PI3K), significantly suppress autoimmune-diabetes. To further delineate the mechanisms and the selectivity of specific immune modulation by PI3Kγ-inhibition, we developed a new NOD mouse model of T1D lacking the γ-subunit of PI3K. Strikingly, the loss of PI3Kγ protected 92% of the NOD-mice from developing spontaneous diabetes. The NOD.PI3Kγ-/- mice are protected from insulitis secondary to a defect in CD4 and CD8 autoreactive-T-cells activation and survival. In addition, PI3Kγ-deficiency promoted Treg generation in-vitro and in-vivo. Furthermore, PI3Kγ-inhibitor (AS605240) inhibited proliferation and cytokine production of a human CD4+ T-cell clone specific for GAD555-567 peptide that was isolated from a patient with T1D. These studies demonstrate the key role of the PI3Kγ pathway in regulating autoimmune-diabetes and provide rationales for future devise of anti- PI3Kγ therapy in T1D. PMID:28081180

  13. Newborn Screening and the Obstetrician

    PubMed Central

    Dolan, Siobhan M

    2012-01-01

    Newborn screening is the largest genetic screening program in the United States, with approximately four million infants screened yearly. It has been available and in continuous development for over 50 years. Each state manages, funds, and maintains its own individual program, which encompasses newborn screening as well as the diagnosis and coordination of care for affected infants and children. The ideal disorder for screening is one in which newborn intervention prevents later disabilities or death for infants who may appear normal at birth. There are 31 core conditions that are currently recommended for incorporation into state screening programs. To obtain a sample, several drops of blood are collected from the newborn’s heel and applied to filter paper. Although testing for core disorders is fairly standardized, more extensive screening varies by state and the rigorous evaluation of new disorders for inclusion in state screening panels is ongoing. As genomic medicine becomes more accessible, screening newborns for chronic diseases that may affect their long-term health will need to be addressed, as well the use of the residual blood spots for research. Obstetric providers should, at some time during pregnancy, review the basic process of newborn screening with parents to prepare them for this testing in the neonatal period. This information can be reviewed as it best suits incorporation in an individual’s practice; verbal discussion and the distribution of written materials with resources for further information is encouraged. PMID:22996108

  14. The α7 nicotinic acetylcholine receptor agonist GTS-21 improves bacterial clearance in mice by restoring hyperoxia-compromised macrophage function.

    PubMed

    Sitapara, Ravikumar A; Antoine, Daniel J; Sharma, Lokesh; Patel, Vivek S; Ashby, Charles R; Gorasiya, Samir; Yang, Huan; Zur, Michelle; Mantell, Lin L

    2014-06-19

    Mechanical ventilation with supraphysiological concentrations of oxygen (hyperoxia) is routinely used to treat patients with respiratory distress. However, prolonged exposure to hyperoxia compromises the ability of the macrophage to phagocytose and clear bacteria. Previously, we showed that the exposure of mice to hyperoxia elicits the release of the nuclear protein high mobility group box-1 (HMGB1) into the airways. Extracellular HMGB1 impairs macrophage phagocytosis and increases the mortality of mice infected with Pseudomonas aeruginosa (PA). The aim of this study was to determine whether GTS-21 [3-(2,4 dimethoxybenzylidene)-anabaseine dihydrochloride], an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, could inhibit hyperoxia-induced HMGB1 release into the airways, enhance macrophage function and improve bacterial clearance from the lungs in a mouse model of ventilator-associated pneumonia. GTS-21 (0.04, 0.4 and 4 mg/kg) or saline was systemically administered via intraperitoneal injection to mice that were exposed to hyperoxia (≥99% O2) and subsequently challenged with PA. We found that systemic administration of 4 mg/kg GTS-21 significantly increased bacterial clearance, decreased acute lung injury and decreased accumulation of airway HMGB1. To investigate the cellular mechanism of these observations, RAW 264.7 cells, a macrophagelike cell line, were incubated with different concentrations of GTS-21 in the presence of 95% O2. The phagocytic activity of macrophages was significantly increased by GTS-21 in a dose-dependent manner. In addition, hyperoxia-induced hyperacetylation of HMGB1 was significantly reduced in macrophages incubated with GTS-21. Furthermore, GTS-21 significantly inhibited the cytoplasmic translocation and release of HMGB1 from these macrophages. Our results indicate that GTS-21 is effective in improving bacterial clearance and reducing acute lung injury by enhancing macrophage function via inhibiting the release of nuclear HMGB1

  15. Impact of Chronodisruption during Primate Pregnancy on the Maternal and Newborn Temperature Rhythms

    PubMed Central

    Serón-Ferré, María; Forcelledo, María Luisa; Torres-Farfan, Claudia; Valenzuela, Francisco J.; Rojas, Auristela; Vergara, Marcela; Rojas-Garcia, Pedro P.; Recabarren, Monica P.; Valenzuela, Guillermo J.

    2013-01-01

    Disruption of the maternal environment during pregnancy is a key contributor to offspring diseases that develop in adult life. To explore the impact of chronodisruption during pregnancy in primates, we exposed pregnant capuchin monkeys to constant light (eliminating the maternal melatonin rhythm) from the last third of gestation to term. Maternal temperature and activity circadian rhythms were assessed as well as the newborn temperature rhythm. Additionally we studied the effect of daily maternal melatonin replacement during pregnancy on these rhythms. Ten pregnant capuchin monkeys were exposed to constant light from 60% of gestation to term. Five received a daily oral dose of melatonin (250 µg kg/body weight) at 1800 h (LL+Mel) and the other five a placebo (LL). Six additional pregnant females were maintained in a 14∶10 light:dark cycles and their newborns were used as controls (LD). Rhythms were recorded 96 h before delivery in the mother and at 4–6 days of age in the newborn. Exposure to constant light had no effect on the maternal body temperature rhythm however it delayed the acrophase of the activity rhythm. Neither rhythm was affected by melatonin replacement. In contrast, maternal exposure to constant light affected the newborn body temperature rhythm. This rhythm was entrained in control newborns whereas LL newborns showed a random distribution of the acrophases over 24-h. In addition, mean temperature was decreased (34.0±0.6 vs 36.1±0.2°C, in LL and control, respectively P<0.05). Maternal melatonin replacement during pregnancy re-synchronized the acrophases and restored mean temperature to the values in control newborns. Our findings demonstrate that prenatal melatonin is a Zeitgeber for the newborn temperature rhythm and supports normal body temperature maintenance. Altogether these prenatal melatonin effects highlight the physiological importance of the maternal melatonin rhythm during pregnancy for the newborn primate. PMID:23469055

  16. Precondition of right frontal region with anodal tDCS can restore the fear memory impairment induced by ACPA in male mice

    PubMed Central

    Manteghi, Fariborz; Nasehi, Mohammad; Zarrindast, Mohammad-Reza

    2017-01-01

    Fear memory and learning cause behavioural patterns such as fight or flight responses, which increase survival probability, but unfit processing of fear memory and learning can lead to maladaptive behaviours and maladies such as phobias, Post-Traumatic Stress Disorder (PTSD) and anxiety disorders. The growing prevalence of these maladies shows the need to quest novel methods for their treatment. We used anodal transcranial direct current stimulation (tDCS) on the right frontal region as a precondition neuromodulator and arachidonylcyclopropylamide (ACPA), a selective CB1 cannabinoid receptor agonist, as a fear memory impairing agent to assess their effects on contextual and auditory fear conditioning (reliable model for fear studies). Right frontal anodal tDCS (0.2 mA for. 20 minutes) 24 hours before the train did not alter contextual and auditory learning and memory in short-term (24 hrs after the training phase). Moreover, intraperitoneal pre-train injection of ACPA (0.1 mg/kg) alone, decreased both contextual and auditory learning and memory in short- but not long-term. Right frontal anodal tDCS improved short-term contextual fear memory in subthreshold doses of ACPA. On the other hand, right frontal anodal tDCS in long-term improved (lower doses of ACPA) and restored (higher doses of ACPA) both fear memories. These findings showed that, aforementioned approach could cause durable learning and memory improvements. Also this combined modality could be useful for fear extinction training and maladies which inflict amnesia. PMID:28337114

  17. Mitochondrial quality control, promoted by PGC-1α, is dysregulated by Western diet-induced obesity and partially restored by moderate physical activity in mice

    PubMed Central

    Greene, Nicholas P; Lee, David E; Brown, Jacob L; Rosa, Megan E; Brown, Lemuel A; Perry, Richard A; Henry, Jordyn N; Washington, Tyrone A

    2015-01-01

    Skeletal muscle mitochondrial degeneration is a hallmark of insulin resistance/obesity marked by lost function, enhanced ROS emission, and altered morphology which may be ameliorated by physical activity (PA). However, no prior report has examined mitochondrial quality control regulation throughout biogenesis, fusion/fission dynamics, autophagy, and mitochondrial permeability transition pore (MPTP) in obesity. Therefore, we determined how each process is impacted by Western diet (WD)-induced obesity and whether voluntary PA may alleviate derangements in mitochondrial quality control mechanisms. Despite greater mitochondrial content following WD (COX-IV and Cytochrome C), induction of biogenesis controllers appears impaired (failed induction of PGC-1α). Mitochondrial fusion seems diminished (reduced MFN2, Opa1 proteins), with no significant changes in fission, suggesting a shift in balance of dynamics regulation favoring fission. Autophagy flux was promoted in WD (reduced p62, increased LC3II:I ratio); however, mitophagy marker BNIP3 is reduced in WD which may indicate reduced mitophagy despite enhanced total autophagy flux. MPTP regulator Ant mRNA is reduced by WD. Few processes were impacted by physical activity. Finally, mitochondrial quality control processes are partially promoted by PGC-1α, as PGC-1α transgenic mice display elevated mitochondrial biogenesis and autophagy flux. Additionally, these mice exhibit elevated Mfn1 and Opa1 mRNA, with no change in protein content suggesting these factors are transcriptionally promoted by PGC-1α overexpression. These data demonstrate dysfunctions across mitochondrial quality control in obesity and that PGC-1α is sufficient to promote multiple, but not necessarily all, aspects of mitochondrial quality control. Mitochondrial quality control may therefore be an opportune target to therapeutically treat metabolic disease. PMID:26177961

  18. Spherical nucleic acid targeting microRNA-99b enhances intestinal MFG-E8 gene expression and restores enterocyte migration in lipopolysaccharide-induced septic mice

    PubMed Central

    Wang, Xiao; Hao, Liangliang; Bu, Heng-Fu; Scott, Alexander W.; Tian, Ke; Liu, Fangyi; De Plaen, Isabelle G.; Liu, Yulan; Mirkin, Chad A.; Tan, Xiao-Di

    2016-01-01

    Milk fat globule-EGF factor 8 (MFG-E8) maintains the intestinal homeostasis by enhancing enterocyte migration and attenuating inflammation. We previously reported that sepsis is associated with down-regulation of intestinal MFG-E8 and impairment of enterocyte migration. Here, we showed that impairment of intestinal epithelial cell migration occurred in lipopolysaccharide (LPS)-induced septic mice. Treatment of RAW264.7 cells (a murine macrophage-like cell line) with LPS increased expression of miR-99b, a microRNA that is predicted to target mouse MFG-E8 3′UTR. Using a luciferase assay, we showed that miR-99b mimic suppressed the activity of a reporter containing MFG-E8 3′UTR. This suggests the role of miR-99b in inhibition of MFG-E8 gene expression. In addition, we developed an anti-miR99b spherical nucleic acid nanoparticle conjugate (SNA-NCanti-miR99b). Treatment of both naïve and LPS-challenged cells with SNA-NCanti-miR99b enhanced MFG-E8 expression in the cells. Administration of SNA-NCanti-miR99b rescued intestinal MFG-E8 expression in LPS-induced septic mice and attenuated LPS inhibitory effects on intestinal epithelial cell migration along the crypt-villus axis. Collectively, our study suggests that LPS represses MFG-E8 expression and disrupts enterocyte migration via a miR-99b dependent mechanism. Furthermore, this work shows that SNA-NCanti-miR99b is a novel nanoparticle-conjugate capable of rescuing MFG-E8 gene expression and maintaining intestinal epithelial homeostasis in sepsis. PMID:27538453

  19. The ethics of newborn resuscitation.

    PubMed

    Mercurio, Mark R

    2009-12-01

    It is widely believed in neonatology and obstetrics that there are situations in which it is inappropriate to attempt newborn resuscitation, and other times when newborn resuscitation is obligatory despite parental refusal. In each case, an ethical justification for the decision needs to be identified. This essay is intended to provide guidance in deciding when resuscitation should be attempted, and in identifying ethical considerations that should be taken into account. It specifically addresses the issue of extreme prematurity, including an analysis of current recommendations, the data, relevant rights of patient and parents, and a discussion of the relative merits of withholding resuscitation vs providing resuscitation and possibly withdrawing intensive care later. In addition to extreme prematurity, the considerations presented are also relevant to a wider spectrum of newborn problems, including Trisomy 13, Trisomy 18, and severe congenital anomalies.

  20. Skin care for the newborn.

    PubMed

    Sarkar, Rashmi; Basu, Srikanta; Agrawal, R K; Gupta, Piyush

    2010-07-01

    Skin of the newborn differs from that of an adult in several ways. It is more susceptible to trauma and infection and requires special care. Certain principles of skin care have to be emphasized to the mother or caregiver such as gentle cleansing, adequate hydration and moisturization of the skin, preventing friction and maceration in body folds, and protection from irritants and bright sunlight. The initial bath in full term infants can be given once the baby's temperature has stabilized and the infant is hemodynamically stable. All soaps, cleansers, and syndets should be used infrequently during the newborn period and it is better if their use is limited to groins, axillae and napkin areas. The use of emollients on newborns should be limited in warm weather.

  1. Forest restoration paradigms

    Treesearch

    John Stanturf; Brian J. Palik; Mary I. Williams; R. Kasten Dumroese

    2014-01-01

    An estimated 2 billion ha of forests are degraded globally and global change suggests even greater need for forest restoration. Four forest restoration paradigms are identified and discussed: revegetation, ecological restoration, functional restoration, and forest landscape restoration. Restoration is examined in terms of a degraded starting point and an ending point...

  2. Newborns' Discrimination of Chromatic from Achromatic Stimuli.

    ERIC Educational Resources Information Center

    Adams, Russell J.; And Others

    1986-01-01

    Two experiments assessed the extent of newborns' ability to discriminate color. Results imply that newborns have some, albeit limited, capacity to discriminate chromatic from achromatic stimuli, and hence, are at least dichromats. (Author/DR)

  3. Vitamin K deficiency bleeding of the newborn

    MedlinePlus

    Vitamin K deficiency bleeding of the newborn (VKDB) is a bleeding disorder in babies. It most often ... A lack of vitamin K may cause severe bleeding in newborn babies. Vitamin K plays an important role in blood clotting. Babies often ...

  4. Group B streptococcal septicemia of the newborn

    MedlinePlus

    ... septicemia is a severe bacterial infection that affects newborn infants . Causes Septicemia is an infection in the bloodstream ... in which it may be passed to a newborn baby: The infant can become infected as the baby passes through ...

  5. Newborn Screening: MedlinePlus Health Topic

    MedlinePlus

    ... away. NIH: National Institute of Child Health and Human Development Start Here How Are Newborn Screening Tests Done? (National Institute of Child Health and Human Development) Also in Spanish Newborn Screening (Centers for Disease ...

  6. Craniocerebral gunshot injury in newborn

    PubMed Central

    Dabdoub, CB; Serra, SM; da Cunha, AH; Silveira, EN; Lopez, A; Azevedo-Filho, H

    2012-01-01

    Head wounds caused by firearms in newborns are an under-studied phenomenon in Latin America due to either the low frequency of such events or inadequate documentation. Nonetheless, a progressive increase is noted, with different frequencies reported for different geographic areas. We present the case of a 28-day-old newborn who suffered traumatic brain injury from a gunshot wound stemming from urban violence. This is one of the youngest patients reported with this type of head trauma in the literature. PMID:24960794

  7. Can Newborns Discriminate between Their Own Cry and the Cry of Another Newborn Infant?

    ERIC Educational Resources Information Center

    Dondi, Marco; Simion, Francesca; Caltran, Giovanna

    1999-01-01

    Two experiments tested whether newborns could discriminate their own and another newborn's cry. Results indicated that awake newborns expressed facial distress more frequently and longer to another newborn's cry than to their own. Sucking decreased significantly between pretest phase and first minute of another infant's cry. Asleep infants'…

  8. Newborn metabolic screening and related pitfalls.

    PubMed

    Eddy, Mark; Gottesman, Gary S

    2009-01-01

    Newborn screening has recently been transformed by our enhanced knowledge of medical disorders and our ability to detect and manage them. The Missouri State Newborn Screening Laboratory incorporated tandem mass spectrometry into the newborn screening protocol in 2005. This review will highlight the new capabilities of the newborn screening laboratory and the pitfalls of screening related to preterm birth, blood transfusion and intravenous fluid administration that complicate the interpretation of screening results.

  9. Newborns' Head Orientation toward Sounds Within Hemifields.

    ERIC Educational Resources Information Center

    Fenwick, Kimberley; And Others

    This experiment examined the accuracy with which newborn infants orient their heads toward a sound positioned off midline within hemifields. The study also evaluated newborns' ability to update the angle of their head turn to match a change in localization of an ongoing sound. Alert newborns were held in a supine position and presented a sound at…

  10. Newborns' Head Orientation toward Sounds Within Hemifields.

    ERIC Educational Resources Information Center

    Fenwick, Kimberley; And Others

    This experiment examined the accuracy with which newborn infants orient their heads toward a sound positioned off midline within hemifields. The study also evaluated newborns' ability to update the angle of their head turn to match a change in localization of an ongoing sound. Alert newborns were held in a supine position and presented a sound at…

  11. Newborn Screening: Characteristics of State Programs.

    ERIC Educational Resources Information Center

    Toiv, Helene F.; Austin, Janina; Gardiner, Emily Gamble; Tynan, Ann; Hill, Ariel; Milne, Kevin; Moon, Cindy; Lawes, Susan

    Each year, state newborn screening programs test 4 million newborns for disorders that require early detection and treatment to prevent serious illness or death. The U.S. General Accounting Office (GAO) was asked to provide Congress with information on variations among state newborn screening programs. Based on surveys of such programs in all 50…

  12. 42 CFR 435.117 - Newborn children.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 4 2010-10-01 2010-10-01 false Newborn children. 435.117 Section 435.117 Public..., Children Under 8, and Newborn Children § 435.117 Newborn children. (a) The agency must provide Medicaid eligibility to a child born to a woman who has applied for, has been determined eligible and is...

  13. 42 CFR 435.117 - Newborn children.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 4 2012-10-01 2012-10-01 false Newborn children. 435.117 Section 435.117 Public..., Children Under 8, and Newborn Children § 435.117 Newborn children. (a) The agency must provide Medicaid eligibility to a child born to a woman who has applied for, has been determined eligible and is...

  14. 42 CFR 435.117 - Newborn children.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 4 2013-10-01 2013-10-01 false Newborn children. 435.117 Section 435.117 Public..., AND AMERICAN SAMOA Mandatory Coverage Mandatory Coverage of Pregnant Women, Children Under 19, and Newborn Children § 435.117 Newborn children. (a) The agency must provide Medicaid eligibility to a...

  15. 42 CFR 435.117 - Newborn children.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 4 2014-10-01 2014-10-01 false Newborn children. 435.117 Section 435.117 Public..., AND AMERICAN SAMOA Mandatory Coverage Mandatory Coverage of Pregnant Women, Children Under 19, and Newborn Children § 435.117 Newborn children. (a) The agency must provide Medicaid eligibility to a...

  16. 42 CFR 435.117 - Newborn children.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 4 2011-10-01 2011-10-01 false Newborn children. 435.117 Section 435.117 Public..., Children Under 8, and Newborn Children § 435.117 Newborn children. (a) The agency must provide Medicaid eligibility to a child born to a woman who has applied for, has been determined eligible and is...

  17. Retina Restored and Brain Abnormalities Ameliorated by Single-Copy Knock-In of Human NR2E1 in Null Mice

    PubMed Central

    Schmouth, J.-F.; Banks, K. G.; Mathelier, A.; Gregory-Evans, C. Y.; Castellarin, M.; Holt, R. A.; Gregory-Evans, K.; Wasserman, W. W.

    2012-01-01

    Nr2e1 encodes a stem cell fate determinant of the mouse forebrain and retina. Abnormal regulation of this gene results in retinal, brain, and behavioral abnormalities in mice. However, little is known about the functionality of human NR2E1. We investigated this functionality using a novel knock-in humanized-mouse strain carrying a single-copy bacterial artificial chromosome (BAC). We also documented, for the first time, the expression pattern of the human BAC, using an NR2E1-lacZ reporter strain. Unexpectedly, cerebrum and olfactory bulb hypoplasia, hallmarks of the Nr2e1-null phenotype, were not fully corrected in animals harboring one functional copy of human NR2E1. These results correlated with an absence of NR2E1-lacZ reporter expression in the dorsal pallium of embryos and proliferative cells of adult brains. Surprisingly, retinal histology and electroretinograms demonstrated complete correction of the retina-null phenotype. These results correlated with appropriate expression of the NR2E1-lacZ reporter in developing and adult retina. We conclude that the human BAC contained all the elements allowing correction of the mouse-null phenotype in the retina, while missing key regulatory regions important for proper spatiotemporal brain expression. This is the first time a separation of regulatory mechanisms governing NR2E1 has been demonstrated. Furthermore, candidate genomic regions controlling expression in proliferating cells during neurogenesis were identified. PMID:22290436

  18. Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice.

    PubMed

    Xu, Jian; Kurup, Pradeep; Baguley, Tyler D; Foscue, Ethan; Ellman, Jonathan A; Nairn, Angus C; Lombroso, Paul J

    2016-04-01

    Brain-derived neurotrophic factor (BDNF) and STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) have opposing functions in the brain, with BDNF supporting and STEP61 opposing synaptic strengthening. BDNF and STEP61 also exhibit an inverse pattern of expression in a number of brain disorders, including schizophrenia (SZ). NMDAR antagonists such as phencyclidine (PCP) elicit SZ-like symptoms in rodent models and unaffected individuals, and exacerbate psychotic episodes in SZ. Here we characterize the regulation of BDNF expression by STEP61, utilizing PCP-treated cortical culture and PCP-treated mice. PCP-treated cortical neurons showed both an increase in STEP61 levels and a decrease in BDNF expression. The reduction in BDNF expression was prevented by STEP61 knockdown or use of the STEP inhibitor, TC-2153. The PCP-induced increase in STEP61 expression was associated with the inhibition of CREB-dependent BDNF transcription. Similarly, both genetic and pharmacologic inhibition of STEP prevented the PCP-induced reduction in BDNF expression in vivo and normalized PCP-induced hyperlocomotion and cognitive deficits. These results suggest a mechanism by which STEP61 regulates BDNF expression, with implications for cognitive functioning in CNS disorders.

  19. The genetic ablation or pharmacological inhibition of TRPV1 signalling is beneficial for the restoration of quiescent osteoclast activity in ovariectomized mice.

    PubMed

    Rossi, F; Bellini, G; Torella, M; Tortora, C; Manzo, I; Giordano, C; Guida, F; Luongo, L; Papale, F; Rosso, F; Nobili, B; Maione, S

    2014-05-01

    Osteoporosis is a condition characterized by a decrease in bone density, which decreases its strength and results in fragile bones. The endocannabinoid/endovanilloid system has been shown to be involved in the regulation of skeletal remodelling. The aim of this study was to investigate the possible modulation of bone mass mediated by the transient receptor potential vanilloid type 1 channel (TRPV1) in vivo and in vitro. A multidisciplinary approach, including biomolecular, biochemical and morphological analysis, was used to investigate the involvement of TRPV1 in changes in bone density in vivo and osteoclast activity in vitro, in wild-type and Trpv1(-/-) mice, that had undergone ovariectomy or had a sham operation. Genetic deletion of Trpv1 as well as pharmacological inhibition/desensitization of TRPV1 signalling dramatically reduced the osteoclast activity in vitro and prevented the ovariectomy-induced bone loss in vivo, whereas the expression of cannabinoid type 2 (CB2 ) receptors was increased. These findings highlight the pivotal role TRPV1 channels play in bone resorption and suggest a possible cross-talk between TRPV1 and CB2 receptors. Based on these results, hybrid compounds acting on both TRPV1 and CB2 receptors in an opposite manner could provide a future pharmacological tool for the treatment of diseases associated with disturbances in the bone remodelling process. © 2013 The British Pharmacological Society.

  20. Moringa oleifera Lam. leaf extract prevents early liver injury and restores antioxidant status in mice fed with high-fat diet.

    PubMed

    Das, Nilanjan; Sikder, Kunal; Ghosh, Santinath; Fromenty, Bernard; Dey, Sanjit

    2012-06-01

    Consumption of high-fat diet (HFD) induces nonalcoholic fatty liver disease (NAFLD) and may lead to multiple complications affecting human health. In the present study, effect of Moringa oleifera leaf extract (MoLE) in alleviating HFD induced liver injury in mice has been reported. Liver histology and serum activity of hepatic marker enzymes i.e. aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) have been studied. Lipid peroxidation (LPO), ferric reducing antioxidant power (FRAP) and reduced glutathione (GSH) were also estimated using liver homogenate. Results of the study suggested that MoLE treatment protected HFD-induced liver damage as indicated by histopathology and liver enzyme activity compared to only-HFD fed group (P < 0.05). Interestingly, early signs of HFD-induced fatty liver were also alleviated by MoLE. Moreover, significant increase in endogenous antioxidant parameters and lower lipid peroxidation were found in liver of all MoLE treated groups. Results of the study indicated that MoLE has both preventive as also curative hepatoprotective activity.

  1. Endothelial nitric oxide synthase activation through obacunone-dependent arginase inhibition restored impaired endothelial function in ApoE-null mice.

    PubMed

    Yoon, Jeongyeon; Park, Minjin; Lee, Jeong hyung; Min, Byung Sun; Ryoo, Sungwoo

    2014-03-01

    Endothelial arginase constrains the activity of endothelial nitric oxide synthase (eNOS) by substrate depletion and reduces nitric oxide bioavailability. During the screening course of arginase inhibitor, we found obacunone as an arginase inhibitor. We tested the hypothesis that obacunone regulates vascular endothelial NO production. Obacunone incubation inhibited arginase I and II activities in liver and kidney lysates, respectively, in dose-dependent manner. Obacunone reciprocally increased nitrite/nitrate (NOx) production in HUVECs. In isolated aortic rings, obacunone increased intracellular l-arginine concentration and enhanced eNOS coupling, leading to increased NO and decreased superoxide production, with no changes in protein expression. Vasoconstriction response to U46619 was attenuated in obacunone-treated aortic vessels compared to that in untreated vessels. Endothelium-dependent vasorelaxant response to acetylcholine was significantly increased in obacunone-treated vessels and was modulated by the NO-dependent signaling cascade. The dose-dependent vasorelaxant response to Ach was reduced in the aortic vessels of ApoE-/- mice fed a high-cholesterol diet. Obacunone incubation increased vasorelaxation to the level of a WT mouse, although the endothelium-independent response to sodium nitroprusside was identical among the groups. Therefore, obacunone may help treat cardiovascular diseases derived from endothelial dysfunction and may be useful for designing pharmaceutical compounds.

  2. Medical Care and Your Newborn

    MedlinePlus

    ... Lessons? Visit KidsHealth in the Classroom What Other Parents Are Reading Your Child's Development (Birth to 3 Years) Feeding Your 1- to 3-Month-Old Feeding Your 4- to 7-Month-Old Feeding Your 8- to 12-Month-Old Feeding Your 1- to 2-Year-Old ... > For Parents > Medical Care and Your Newborn Print A A ...

  3. Newborn screening in North America.

    PubMed

    Therrell, Bradford L; Adams, John

    2007-08-01

    Newborn screening in North America dates to the early work of Bob Guthrie in the USA. Screening programmes in both the USA and Canada began in the early 1960s, with documented programmes in both countries as early as 1962. Throughout the 1960s and 1970s, many of the screening tests that later became part of routine screening around the world were developed in US and Canadian laboratories, including tests for phenylketonuria, other inborn errors of metabolism, congenital hypothyroidism, congenital adrenal hyperplasia, and haemoglobinopathies. An automated punching machine developed in the USA facilitated screening expansion by significantly reducing sample preparation time and effort. US and Canadian programmes were leaders in applying computerized data management to newborn screening in the 1980s. In the 1990s, DNA and tandem mass spectrometry testing protocols were developed in the USA and applied to newborn screening. US programmes have continually expanded over time, while most Canadian programmes have not. With impetus from private laboratories and professional and consumer groups, many US programmes now screen for more than 50 conditions and there is increased expansion activity in Canada. NBS research in the USA is focused on improving system efficiency and translating other genetic testing to NBS, particularly where new technologies and treatment therapies exist. Although national newborn screening policies do not exist in either Canada or the USA, there are intense efforts to provide uniform access to screening nationwide in both countries. New partnerships between health professionals, consumers and politicians are benefiting the overall screening systems in both countries.

  4. Orthopaedic conditions in the newborn.

    PubMed

    Sankar, Wudbhav N; Weiss, Jennifer; Skaggs, David L

    2009-02-01

    The occasional consultation on a neonate can be unfamiliar territory for many orthopaedic surgeons. Just as children are not little adults, newborns are not just little children; rather, they have a unique physiology that affects the presentation of their orthopaedic concerns. Careful physical examination with appropriate understanding of neonatal development is essential to making the proper diagnosis. A flail extremity in the newborn is most commonly attributed to fracture or brachial plexus palsy; however, infection must also be considered and ruled out to prevent long-term morbidity. Metatarsus adductus is the most common foot abnormality, but clubfoot, calcaneovalgus deformity, and congenital vertical talus may also be encountered. Joint contractures that spontaneously improve are normal in the newborn, but it is important to identify and institute proper treatment for early developmental dysplasia of the hip, congenital knee dislocation, and torticollis. Clavicular pseudarthrosis and periosteal reactions may be discovered on radiographic examination. A basic understanding of the relevant conditions will help the orthopaedist with the initial diagnosis and management of orthopaedic issues in the newborn.

  5. Pilot Programs in Newborn Screening

    ERIC Educational Resources Information Center

    Pass, Kenneth; Green, Nancy S.; Lorey, Fred; Sherwin, John; Comeau, Anne Marie

    2006-01-01

    The term "pilot study" has been used over the years to describe the evaluation of the many elements involved in deciding whether a proposed condition should be added to a newborn screening (NBS) panel, and until recently, was unilaterally used to describe the evaluation of the assay to be used before the condition was officially adopted by a state…

  6. Protecting Your Newborn. Instructor's Guide.

    ERIC Educational Resources Information Center

    Bhatia, Esha

    This guide is intended to help instructors educate new and expectant parents about safely transporting their newborn babies. The guide accompanies a 27-minute video, developed by the National Traffic Safety Administration, which introduces some of the key safety issues that new parents should consider during their baby's first 6 months of life.…

  7. Newborns' Mooney-Face Perception

    ERIC Educational Resources Information Center

    Leo, Irene; Simion, Francesca

    2009-01-01

    The aim of this study is to investigate whether newborns detect a face on the basis of a Gestalt representation based on first-order relational information (i.e., the basic arrangement of face features) by using Mooney stimuli. The incomplete 2-tone Mooney stimuli were used because they preclude focusing both on the local features (i.e., the fine…

  8. Newborns' Mooney-Face Perception

    ERIC Educational Resources Information Center

    Leo, Irene; Simion, Francesca

    2009-01-01

    The aim of this study is to investigate whether newborns detect a face on the basis of a Gestalt representation based on first-order relational information (i.e., the basic arrangement of face features) by using Mooney stimuli. The incomplete 2-tone Mooney stimuli were used because they preclude focusing both on the local features (i.e., the fine…

  9. Newborn Infants Orient to Sounds.

    ERIC Educational Resources Information Center

    Muir, Darwin; Field, Jeffrey

    1979-01-01

    In two experiments, the majority of 21 newborn infants who were maintained in an alert state consistently turned their heads toward a continuous sound source presented 90 degrees from midline. For most infants, this orientation response was rather slow, taking median latencies of 2.5 seconds to begin and 5.5 seconds to end. (JMB)

  10. Kluyvera meningitis in a newborn.

    PubMed

    Rosso, Marisa; Rojas, Pilar; Garcia, Elisa; Marquez, Javier; Losada, Antonio; Muñoz, Miguel

    2007-11-01

    Kluyvera is described infrequently in association with clinically significant infections in humans. It can produce a wide range of clinically significant manifestations. We describe a newborn with ventriculoperitoneal shunt, who was successfully treated for Kluyvera meningitis. We believe that this is the first case of Kluyvera central nervous system infection reported in a child.

  11. Hemolytic disease of the newborn

    MedlinePlus

    ... is a blood disorder in a fetus or newborn infant. In some infants, it can be life threatening. Normally, red blood cells last for about 120 days in the body. In this disorder, red blood cells in the blood are destroyed earlier than normal.

  12. Newborn Infants Orient to Sounds.

    ERIC Educational Resources Information Center

    Muir, Darwin; Field, Jeffrey

    1979-01-01

    In two experiments, the majority of 21 newborn infants who were maintained in an alert state consistently turned their heads toward a continuous sound source presented 90 degrees from midline. For most infants, this orientation response was rather slow, taking median latencies of 2.5 seconds to begin and 5.5 seconds to end. (JMB)

  13. Hepatitis B virus HBx protein localized to the nucleus restores HBx-deficient virus replication in HepG2 cells and in vivo in hydrodynamically-injected mice

    SciTech Connect

    Keasler, Victor V.; Hodgson, Amanda J.; Madden, Charles R.; Slagle, Betty L.

    2009-07-20

    Identifying the requirements for the regulatory HBx protein in hepatitis B virus (HBV) replication is an important goal. A plasmid-based HBV replication assay was used to evaluate whether HBx subcellular localization influences its ability to promote virus replication, as measured by real time PCR quantitation of viral capsid-associated DNA. HBx targeted to the nucleus by a nuclear localization signal (NLS-HBx) was able to restore HBx-deficient HBV replication, while HBx containing a nuclear export signal (NES-HBx) was not. Both NLS-HBx and NES-HBx were expressed at similar levels (by immunoprecipitation and Western blotting), and proper localization of the signal sequence-tagged proteins was confirmed by deconvolution microscopy using HBx, NLS-HBx, and NES-HBx proteins fused to GFP. Importantly, these findings were confirmed in vivo by hydrodynamic injection into mice. Our results demonstrate that in these HBV replication assays, at least one function of HBx requires its localization to the nucleus.

  14. The genetic ablation or pharmacological inhibition of TRPV1 signalling is beneficial for the restoration of quiescent osteoclast activity in ovariectomized mice

    PubMed Central

    Rossi, F; Bellini, G; Torella, M; Tortora, C; Manzo, I; Giordano, C; Guida, F; Luongo, L; Papale, F; Rosso, F; Nobili, B; Maione, S

    2014-01-01

    Background and Purpose Osteoporosis is a condition characterized by a decrease in bone density, which decreases its strength and results in fragile bones. The endocannabinoid/endovanilloid system has been shown to be involved in the regulation of skeletal remodelling. The aim of this study was to investigate the possible modulation of bone mass mediated by the transient receptor potential vanilloid type 1 channel (TRPV1) in vivo and in vitro. Experimental Approach A multidisciplinary approach, including biomolecular, biochemical and morphological analysis, was used to investigate the involvement of TRPV1 in changes in bone density in vivo and osteoclast activity in vitro, in wild-type and Trpv1−/− mice, that had undergone ovariectomy or had a sham operation. Key Results Genetic deletion of Trpv1 as well as pharmacological inhibition/desensitization of TRPV1 signalling dramatically reduced the osteoclast activity in vitro and prevented the ovariectomy-induced bone loss in vivo, whereas the expression of cannabinoid type 2 (CB2) receptors was increased. Conclusions and Implications These findings highlight the pivotal role TRPV1 channels play in bone resorption and suggest a possible cross-talk between TRPV1 and CB2 receptors. Based on these results, hybrid compounds acting on both TRPV1 and CB2 receptors in an opposite manner could provide a future pharmacological tool for the treatment of diseases associated with disturbances in the bone remodelling process. Linked Articles This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10 PMID:24308803

  15. Expression of the Full-Length Form of gp2 of Equine Herpesvirus 1 (EHV-1) Completely Restores Respiratory Virulence to the Attenuated EHV-1 Strain KyA in CBA Mice

    PubMed Central

    Smith, Patrick M.; Kahan, Shannon M.; Rorex, Colin B.; von Einem, Jens; Osterrieder, Nikolaus; O'Callaghan, Dennis J.

    2005-01-01

    Wild-type equine herpesvirus 1 (EHV-1) strains express a large (250-kDa) glycoprotein, gp2, that is encoded by EUs4 (gene 71) located within the unique short region of the genome. DNA sequence analysis revealed that EUs4 of the pathogenic EHV-1 strain RacL11 is an open reading frame of 2,376 bp that encodes a protein of 791 amino acids. The attenuated EHV-1 vaccine strain KyA harbors an in-frame deletion of 1,242 bp from bp 222 to 1461 and expresses a truncated gp2 of 383 amino acids. To determine the relative contribution of gp2 to EHV-1 pathogenesis, we compared the course of respiratory infection of CBA mice infected with either wild-type RacL11, attenuated KyA, or a recombinant KyA that expresses the full-length gp2 protein (KyARgp2F). Mice infected with KyA lost a negligible amount of body weight (0.18% total weight loss) on day 1 postinfection and regained weight thereafter, whereas mice infected with KyARgp2F or RacL11 steadily lost weight beginning on day 1 and experienced a 20 and 18% loss in body weight, respectively, by day 3. Immunohistochemical and flow cytometric analyses revealed higher numbers of T and B lymphocytes and an extensive consolidation consisting of large numbers of Mac-1-positive cells in the lungs of animals infected with KyARgp2F compared to animals infected with KyA. RNase protection analyses revealed increased expression of numerous cytokines and chemokines, including interleukin-1β (IL-1β), IL-6, tumor necrosis factor alpha, macrophage inflammatory protein 1α (MIP-1α), MIP-1β, MIP-2, interferon γ-inducible protein, monocyte chemotactic protein 1, and T-cell activation gene 3 at 12 h postinfection with KyARgp2F. Three independent DNA array experiments confirmed these results and showed a 2- to 13-fold increase in the expression of 31 inflammatory genes at 8 and 12 h postinfection with KyARgp2F compared to infection with KyA. Taken together, the results indicate that expression of full-length gp2 is sufficient to restore full

  16. Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation.

    PubMed

    Cotter, David G; Schugar, Rebecca C; Wentz, Anna E; d'Avignon, D André; Crawford, Peter A

    2013-02-15

    During states of low carbohydrate intake, mammalian ketone body metabolism transfers energy substrates originally derived from fatty acyl chains within the liver to extrahepatic organs. We previously demonstrated that the mitochondrial enzyme coenzyme A (CoA) transferase [succinyl-CoA:3-oxoacid CoA transferase (SCOT), encoded by nuclear Oxct1] is required for oxidation of ketone bodies and that germline SCOT-knockout (KO) mice die within 48 h of birth because of hyperketonemic hypoglycemia. Here, we use novel transgenic and tissue-specific SCOT-KO mice to demonstrate that ketone bodies do not serve an obligate energetic role within highly ketolytic tissues during the ketogenic neonatal period or during starvation in the adult. Although transgene-mediated restoration of myocardial CoA transferase in germline SCOT-KO mice is insufficient to prevent lethal hyperketonemic hypoglycemia in the neonatal period, mice lacking CoA transferase selectively within neurons, cardiomyocytes, or skeletal myocytes are all viable as neonates. Like germline SCOT-KO neonatal mice, neonatal mice with neuronal CoA transferase deficiency exhibit increased cerebral glycolysis and glucose oxidation, and, while these neonatal mice exhibit modest hyperketonemia, they do not develop hypoglycemia. As adults, tissue-specific SCOT-KO mice tolerate starvation, exhibiting only modestly increased hyperketonemia. Finally, metabolic analysis of adult germline Oxct1(+/-) mice demonstrates that global diminution of ketone body oxidation yields hyperketonemia, but hypoglycemia emerges only during a protracted state of low carbohydrate intake. Together, these data suggest that, at the tissue level, ketone bodies are not a required energy substrate in the newborn period or during starvation, but rather that integrated ketone body metabolism mediates adaptation to ketogenic nutrient states.

  17. [THE COMPARATIVE CHARACTERISTIC OF KAOLIN-ACTIVATED THROMBOELASTOGRAPHY IN HEALTHY NEWBORNS AND NEWBORNS WITH HEART AILMENTS].

    PubMed

    Leonov, N P; Karas'kov, A M; Litasova, E E; Strunin, O V; Karmadonova, N A; Akopov, G D; Vishegorodtseva, L I

    2016-02-01

    The study was carried out to diferentiate reference values for kaolin-activated thromboelastography in newborns with congenital heart disease. The study included two groups ofpatients. The first one consisted of 62 newborns with congenital heart disease and the second one consisted of 35 healthy newborns. The results of kaolin-activated thromboelastography implemented in groups are evaluated as condition of normal coagulation. The valuable diferences of homeostasis system in healthy newborns and newborns with congenital heart disease (without severe concomitant pathology) are not established. They have similar indicators of kaolin-activated thromboelastography. The derived results can be applied as standards in full-term newborns with congenital heart disease.

  18. [Congenital ranula in a newborn].

    PubMed

    Bernhard, M K; Hückel, D; Hamala, D

    2007-05-01

    Ranulas are cystic lesions in the floor of the mouth. They are either retention cysts of the excretory duct of the sublingual gland or pseudocysts formed by excretory duct rupture followed by extravasation and accumulation of mucus in the surrounding tissue. We report the case of a premature newborn with a congenital ranula in the floor of mouth. The ranula caused no discomfort or complications, so that immediate intervention was not necessary. The cyst resolved completely by the age of 4 months. Complications in newborns especially include airway obstruction and feeding difficulties. Surgical treatment options are needle aspiration, excision of the ranula, marsupialization, cryosurgery, and--in addition to excision of the cyst--removal of the ipsilateral sublingual gland. Sclerotherapy has shown good results as well. As many congenital cysts resolve or rupture spontaneously, they should be observed for potential resolution for several months in uncomplicated cases.

  19. Postpartum maternal and newborn discharge.

    PubMed

    Cargill, Yvonne; Martel, Marie-Jocelyne

    2007-04-01

    To summarize the evidence available with regard to discharge planning for mothers and newborns. Assessment of maternal and neonatal morbidity and mortality as it relates to length of hospital stay. A Medline database search of articles from January 1995 to December 2004, using the key words early postpartum discharge. 1. Early discharge from hospital postnatally increases the risk of neonatal mortality and morbidity. Follow-up programs should take account of this. (II-2B) 2. The physical, psychological, and social wellbeing of the mother and newborn must be assessed when discharge planning takes place. Primiparous, young, single women are most likely to return to emergency departments with their neonates. (II-2A) 3. Programs in place for postpartum care in the community are well used and appreciated. Additional programs in the community may decrease neonatal mortality, morbidity, and readmissions. (II-2).

  20. Newborn healthcare in urban India

    PubMed Central

    Sharma, J; Osrin, D; Patil, B; Neogi, S B; Chauhan, M; Khanna, R; Kumar, R; Paul, V K; Zodpey, S

    2016-01-01

    The rapid population growth in urban India has outpaced the municipal capacity to build essential infrastructures that make life in cities safe and healthy. Local and national governments alike are grappling with the challenges of urbanization with thousands migrating from villages to cities. Thus, urbanization in India has been accompanied by a concentration of poverty and urban public healthcare has emerged as one of the most pressing priorities facing our country. Newborn mortality rates in urban settings are lower than rural areas, early neonatal deaths account for greater proportion than late neonatal deaths. The available evidence suggests that socio-economic inequalities and poor environment pose major challenges for newborn health. Moreover, fragmented and weak public health system, multiplicity of actors and limited capacity of public health planning further constrain the delivery of quality and affordable health care service. Though healthcare is concentrated in urban areas, delay in deciding to seek health care, reaching a source of it and receiving appropriate care affects the health outcomes disproportionately. However, a few city initiatives and innovations piloted in different states and cities have brought forth the evidences of effectiveness of different strategies. Recently launched National Urban Health Mission (NUHM) provides an opportunity for strategic thinking and actions to improve newborn health outcomes in India. There is also an opportunity for coalescence of activities around National Health Mission (NHM) and Reproductive, Maternal, Newborn and Child Health+Adolescent (RMNCH+A) strategy to develop feasible and workable models in different urban settings. Concomitant operational research needs to be carried out so that the obstacles, approaches and response to the program can be understood. PMID:27924107

  1. Newborn healthcare in urban India.

    PubMed

    Sharma, J; Osrin, D; Patil, B; Neogi, S B; Chauhan, M; Khanna, R; Kumar, R; Paul, V K; Zodpey, S

    2016-12-01

    The rapid population growth in urban India has outpaced the municipal capacity to build essential infrastructures that make life in cities safe and healthy. Local and national governments alike are grappling with the challenges of urbanization with thousands migrating from villages to cities. Thus, urbanization in India has been accompanied by a concentration of poverty and urban public healthcare has emerged as one of the most pressing priorities facing our country. Newborn mortality rates in urban settings are lower than rural areas, early neonatal deaths account for greater proportion than late neonatal deaths. The available evidence suggests that socio-economic inequalities and poor environment pose major challenges for newborn health. Moreover, fragmented and weak public health system, multiplicity of actors and limited capacity of public health planning further constrain the delivery of quality and affordable health care service. Though healthcare is concentrated in urban areas, delay in deciding to seek health care, reaching a source of it and receiving appropriate care affects the health outcomes disproportionately. However, a few city initiatives and innovations piloted in different states and cities have brought forth the evidences of effectiveness of different strategies. Recently launched National Urban Health Mission (NUHM) provides an opportunity for strategic thinking and actions to improve newborn health outcomes in India. There is also an opportunity for coalescence of activities around National Health Mission (NHM) and Reproductive, Maternal, Newborn and Child Health+Adolescent (RMNCH+A) strategy to develop feasible and workable models in different urban settings. Concomitant operational research needs to be carried out so that the obstacles, approaches and response to the program can be understood.

  2. Newborn Screening for Biliary Atresia.

    PubMed

    Wang, Kasper S

    2015-12-01

    Biliary atresia is the most common cause of pediatric end-stage liver disease and the leading indication for pediatric liver transplantation. Affected infants exhibit evidence of biliary obstruction within the first few weeks after birth. Early diagnosis and successful surgical drainage of bile are associated with greater survival with the child's native liver. Unfortunately, because noncholestatic jaundice is extremely common in early infancy, it is difficult to identify the rare infant with cholestatic jaundice who has biliary atresia. Hence, the need for timely diagnosis of this disease warrants a discussion of the feasibility of screening for biliary atresia to improve outcomes. Herein, newborn screening for biliary atresia in the United States is assessed by using criteria established by the Discretionary Advisory Committee on Heritable Disorders in Newborns and Children. Published analyses indicate that newborn screening for biliary atresia by using serum bilirubin concentrations or stool color cards is potentially life-saving and cost-effective. Further studies are necessary to evaluate the feasibility, effectiveness, and costs of potential screening strategies for early identification of biliary atresia in the United States.

  3. Rapid integration of young newborn dentate gyrus granule cells in the adult hippocampal circuitry.

    PubMed

    Ide, Yoko; Fujiyama, Fumino; Okamoto-Furuta, Keiko; Tamamaki, Nobuaki; Kaneko, Takeshi; Hisatsune, Tatsuhiro

    2008-12-01

    Newborn dentate gyrus granule cells (DGCs) are integrated into the hippocampal circuitry and contribute to the cognitive functions of learning and memory. The dendritic maturation of newborn DGCs in adult mice occurs by the first 3-4 weeks, but DGCs seem to receive a variety of neural inputs at both their dendrites and soma even shortly after their birth. However, few studies on the axonal maturation of newborn DGCs have focused on synaptic structure. Here, we investigated the potentiality of output and input in newborn DGCs, especially in the early period after terminal mitosis. We labeled nestin-positive progenitor cells by injecting GFP Cre-reporter adenovirus into Nestin-Cre mice, enabling us to trace the development of progenitor cells by their GFP expression. In addition to GABAergic input from interneurons, we observed that the young DGCs received axosomatic input from the medial septum as early as postinfection day 7 (PID 7). To evaluate the axonal maturation of the newborn DGCs compared with mature DCGs, we performed confocal and electron microscopic analyses. We observed that newborn DGCs projected their mossy fibers to the CA3 region, forming small terminals on hilar or CA3 interneurons and large boutons on CA3 pyramidal cells. These terminals expressed vesicular glutamate transporter 1, indicating they were glutamatergic terminals. Intriguingly, the terminals at PID 7 had already formed asymmetric synapses, similar to those of mature DGCs. Together, our findings suggest that newborn DGCs may form excitatory synapses on both interneurons and CA3 pyramidal cells within 7 days of their terminal mitosis.

  4. Prevalence of systemic air-embolism after prolonged cardiopulmonary resuscitation in newborns: A pilot study.

    PubMed

    Halbertsma, Feico J J; Mohns, Thilo; Bok, Levinus A; Niemarkt, Hendrik J; Kramer, Boris W

    2015-08-01

    Chest compressions (CC) during cardiopulmonary resuscitation (CPR) are the cornerstone of adult CPR protocols and are meant to restore circulation and improve outcome. Although adverse effects such as air-embolisms have been reported, these are rare and considered to be outweighed by beneficial effect. In newborns, however, the lung tissue is more fragile. Thus, the high intra-thoracic pressures resulting from CC may make the newborns more vulnerable for air-embolisms. We studied the postmortem prevalence of air-embolism in neonates that have received CPR. Prospective cohort analysis of newborns receiving CC during CPR. CPR was performed by trained staff according to ILCOR guidelines, in a tertiary hospital. Air-embolisms were sought after using CT/MRI and autopsy. During a 61/2 year period (2007-2014), n = 56 newborns received CC. Newborns were resuscitated following severe perinatal hypoxia, or due to complications during NICU treatment. In n = 14 (25.0%) circulation could not be restored (mean CPR duration: 32.7 ± 15.2 min). Post-mortem CT/MRI was performed in n = 9, of whom n = 8 (88.9%) had air-embolisms. Autopsy was performed in n = 9. The air-embolisms could not be retraced on autopsy except for n = 1 patient. In patients with CPR resulting in restored circulation (n = 42), no CT or MRI was performed for comparison due to radiation and/or hemodynamic instability. Cerebral ultrasound could not identify or exclude air-embolisms in this subgroup. Post-mortem CT after prolonged resuscitation showed a high prevalence of intravascular air-embolism. Autopsy was not suited to detect air-embolism. The clinical importance of air-embolisms on the lethal outcome needs further research. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. Hospital stay for healthy term newborn infants.

    PubMed

    Benitz, William E

    2015-05-01

    The hospital stay of the mother and her healthy term newborn infant should be long enough to allow identification of problems and to ensure that the mother is sufficiently recovered and prepared to care for herself and her newborn at home. The length of stay should be based on the unique characteristics of each mother-infant dyad, including the health of the mother, the health and stability of the newborn, the ability and confidence of the mother to care for herself and her newborn, the adequacy of support systems at home, and access to appropriate follow-up care in a medical home. Input from the mother and her obstetrical care provider should be considered before a decision to discharge a newborn is made, and all efforts should be made to keep a mother and her newborn together to ensure simultaneous discharge.

  6. Therapeutic effects of L-Cysteine in newborn mice subjected to hypoxia-ischemia brain injury via the CBS/H2S system: Role of oxidative stress and endoplasmic reticulum stress.

    PubMed

    Liu, Song; Xin, Danqing; Wang, Lingxiao; Zhang, Tiantian; Bai, Xuemei; Li, Tong; Xie, Yunkai; Xue, Hao; Bo, Shishi; Liu, Dexiang; Wang, Zhen

    2017-10-01

    Neonatal hypoxic-ischemic (HI) injury is a major cause of neonatal death and neurological dysfunction. H2S has been shown to protect against hypoxia-induced injury and apoptosis of neurons. L-Cysteine is catalyzed by cystathionine-β-synthase (CBS) in the brain and sequentially produces endogenous H2S. The present study was designed to investigate whether L-Cysteine could attenuate the acute brain injury and improve neurobehavioral outcomes following HI brain injury in neonatal mice by releasing endogenous H2S. L-Cysteine treatment significantly attenuated brain edema and decreased infarct volume and neuronal cell death, as shown by a decrease in the Bax/Bcl-2 ratio, suppression of caspase-3 activation, and reduced phosphorylation of Akt and ERK at 72h after HI. Additionally, L-Cysteine substantially up-regulated NF-E2-related factor 2 and heme oxygenase-1 expression. L-Cysteine also decreased endoplasmic reticulum (ER) stress-associated pro-apoptotic protein expression. Furthermore, L-Cysteine had long-term effects by protecting against the loss of ipsilateral brain tissue and improving neurobehavioral outcomes. Importantly, pre-treatment with a CBS inhibitor significantly attenuated the neuroprotection of L-Cysteine on HI insult. Thus, L-Cysteine exerts neuroprotection against HI-induced injury in neonates via the CBS/H2S pathway, mediated in part by anti-apoptotic effects and reduced oxidative stress and ER stress. Thus, L-Cysteine may be a promising treatment for HI. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  7. Modeling normal and malignant human hematopoiesis in vivo through newborn NSG xenotransplantation.

    PubMed

    Ishikawa, Fumihiko

    2013-12-01

    Various strains of immune-compromised mice have been developed to investigate human normal and malignant stem cells in vivo. NOD/SCID mice harboring complete null mutation of Il2rg (NSG mice) lack T cells, B cells, and NK cells, and support high levels of engraftment by human cord blood hematopoietic stem cells (CB HSCs) and acute myeloid leukemia stem cells (AML LSCs). In addition to achieving high levels of human hematopoietic cell engraftment, use of newborn NSG mice as recipients has enabled the investigation into how human CB HSCs generate mature immune subsets in vivo. Moreover, through establishing an in vivo model of human primary AML by xenotransplantation of human LSCs into newborn NSG mice, functional properties of human AML such as cell cycle, location, and self-renewal capacity can be examined in vivo. Newborn NSG xenogeneic transplantation model may facilitate the understanding of human normal and malignant hematopoiesis and contribute to the development of novel therapies against hematologic diseases.

  8. Lubricin restoration in a mouse model of congenital deficiency

    PubMed Central

    Hill, Adele; Waller, Kimberly A.; Cui, Yajun; Allen, Justin M.; Smits, Patrick; Zhang, Ling X.; Ayturk, Ugur M.; Hann, Steven; Lessard, Samantha G.; Zurakowski, David; Warman, Matthew L.; Jay, Gregory D.

    2015-01-01

    Objective Congenital deficiency of the principal boundary lubricant in cartilage (lubricin, encoded by the gene PRG4) increases joint friction and causes progressive joint failure. This study was undertaken to determine whether restoring lubricin expression would prevent, delay, or reverse the disease process caused by congenital deficiency. Methods Using genetically engineered lubricin deficient mice, we restored gene function before conception or at 3 weeks, 2 months, or 6 months after birth. We evaluated the effect of restoring gene function (i.e., expressing lubricin) on the tibial-femoral-patellar joints of mice, histologically and by ex vivo biomechanical testing. Results Restoring gene function prior to conception prevented disease. Restoring gene function at 3 weeks of age improved, but did not normalize, joint histology and whole joint friction; cyclic loading produced fewer activated caspase-3 containing chondrocytes when lubricin expression was restored at three weeks of age compared to non-restored littermates. Restoring lubricin expression in 2-month-old or 6-month-old mice had no beneficial effect on histology, whole joint friction, or activation of caspase-3 compared to non-restored littermates. Conclusions When boundary lubrication is congenitally deficient and cartilage becomes damaged, the window of opportunity for restoring lubrication and slowing disease progression is limited. PMID:26216721

  9. State of the World's Newborns: A Report from Saving Newborn Lives.

    ERIC Educational Resources Information Center

    Costello, Anthony; Francis, Victoria; Byrne, Ali; Puddephatt, Claire

    There has been little change in newborn mortality in the past 20 years, even through proven, cost-effective solutions exist to save many of these young lives. This report reviews the most recent data on the newborn, revealing the alarming poor health and quality of health care for mothers and newborns in virtually all impoverished countries. The…

  10. Metabolic screening for the newborn.

    PubMed

    Parini, Rossella; Corbetta, Carlo

    2011-10-01

    The advent of tandem mass spectrometry (MS/MS) around 10 years ago allowed to enlarge consistently the spectrum of metabolic diseases that might be easily and quickly detected. MS/MS was applied to newborn screening in many developed countries, with a wide use, to detect as many as 55 abnormal biochemical conditions (USA), or a restricted one detecting only few diseases (Germany, UK, and Switzerland). Many factors were probably contributing to these very different health organization policies. Although neonatal screening is widely considered extremely useful and efficacious to improve prognosis of many metabolic disorders, the statistically significant demonstration of benefit is quite hard to reach for reasons mainly incidental to the characteristics of these disorders. The expanded newborn screening, in its wide application, includes at present severe diseases presenting in the first days of life, diseases for which treatment is not available, conditions with uncertain significance which are probably not diseases, detection of metabolic disturbances of the mother and all the mildest forms of organic acidurias, urea cycle disorders, fatty acid beta-oxidation defects that may have the possibility to remain asymptomatic for the whole life or may have an acute life-threatening onset of the disease many years later. Which could be the better approach to newborn screening is not clear at present, and probably, it will not be the same for each country. Results of regional screening programs need to be carefully collected and analyzed in future years, with the aim to optimize screening practice in the different countries. Efforts should also be addressed to improve screening programs in the developing countries.

  11. Isolated penile torsion in newborns

    PubMed Central

    Eroglu, Egemen; Gundogdu, Gokhan

    2015-01-01

    Introduction: We reported on the incidence of isolated penile torsion among our healthy children and our approach to this anomaly. Methods: Between 2011 and 2014, newborn babies with penile torsion were classified according to the angle of torsion. Surgical correction (penile degloving and reattachment for moderate cases and dorsal dartos flap technique in case of resistance) after 6 months was advised to the babies with rotations more than 45°. Results: Among 1000 newborn babies, 200 isolated penile torsions were found, and among these, 43 had torsions more than 45°, and 4 of these had angles greater than 90°. The mean angle of the rotations was found 30.45° (median: 20°). In total, 8 children with 60° torsions were previously circumcised. Surgery was performed on 19 patients, with a mean patient age of 12 ± 2 months. Of these 19, 13 babies were corrected with degloving and reattachment. This technique was not enough on the remaining 6 patients; therefore, derotational dorsal dartos flap was added to correct the torsion. After a mean of 15.6 ± 9.8 months, residual penile rotation, less than 15°, was found only in 2 children. Conclusion: The incidence of isolated penile torsion is 20% in newborns. However, rotation more than 45° angles are seen in 4.3% of male babies. Correction is not necessary in mild degrees, and penile degloving with reattachment is enough in most cases. If the initial correction is insufficient, dorsal dartos flap rotation is easy and effective. Prior circumcision neither disturbs the operative procedure nor affects the outcomes. PMID:26600889

  12. Newborn infants perceive abstract numbers.

    PubMed

    Izard, Véronique; Sann, Coralie; Spelke, Elizabeth S; Streri, Arlette

    2009-06-23

    Although infants and animals respond to the approximate number of elements in visual, auditory, and tactile arrays, only human children and adults have been shown to possess abstract numerical representations that apply to entities of all kinds (e.g., 7 samurai, seas, or sins). Do abstract numerical concepts depend on language or culture, or do they form a part of humans' innate, core knowledge? Here we show that newborn infants spontaneously associate stationary, visual-spatial arrays of 4-18 objects with auditory sequences of events on the basis of number. Their performance provides evidence for abstract numerical representations at the start of postnatal experience.

  13. Iodine Supplementation in the Newborn

    PubMed Central

    Ghirri, Paolo; Lunardi, Sara; Boldrini, Antonio

    2014-01-01

    Iodine deficiency can be defined as the world’s greatest single cause of preventable brain damage. Fetal and neonatal hypothyroidism, caused by iodine deficiency can be prevented prior to conception and then during pregnancy and lactation when an adequate iodine supplementation is ensured. Extremely low birth weight preterm babies risk having a negative iodine balance status in the first weeks of life, exacerbating the hypothyroxinaemia of the prematurity. It is important to ensure that these babies are provided with an adequate iodine intake from the first days of life. Mothers and newborns should avoid environmental iodine excess during pregnancy or lactation. PMID:24448111

  14. Newborn piglet model for campylobacteriosis.

    PubMed Central

    Babakhani, F K; Bradley, G A; Joens, L A

    1993-01-01

    An in vivo model system for human campylobacteriosis has been developed in which colostrum-deprived newborn piglets are orally challenged with an invasive strain of Campylobacter jejuni. Piglets developed clinical symptoms and histopathological lesions similar to those observed in humans infected with C. jejuni. Gross lesion examination at autopsy revealed the presence of edema, hyperemia, and mucus. Histopathologic examinations by light and transmission electron microscopy demonstrated damage to surface epithelial cells with the presence of intracellular bacteria, mainly in the large intestine. Similar lesions were not demonstrated in control piglets. Images PMID:8335377

  15. Epinephrine Use during Newborn Resuscitation

    PubMed Central

    Kapadia, Vishal S.; Wyckoff, Myra H.

    2017-01-01

    Epinephrine use in the delivery room for resuscitation of the newborn is associated with significant morbidity and mortality. Evidence for optimal dose, timing, and route of administration of epinephrine during neonatal resuscitation comes largely from extrapolated adult or animal literature. In this review, we provide the current recommendations for use of epinephrine during neonatal resuscitation and also the evidence behind these recommendations. In addition, we review the current proposed mechanism of action of epinephrine during neonatal resuscitation, review its adverse effects, and identify gaps in knowledge requiring urgent research. PMID:28507983

  16. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice.

    PubMed

    Jaskelioff, Mariela; Muller, Florian L; Paik, Ji-Hye; Thomas, Emily; Jiang, Shan; Adams, Andrew C; Sahin, Ergun; Kost-Alimova, Maria; Protopopov, Alexei; Cadiñanos, Juan; Horner, James W; Maratos-Flier, Eleftheria; Depinho, Ronald A

    2011-01-06

    An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase-deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signalling activation in vivo. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses. Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice have short dysfunctional telomeres and sustain increased DNA damage signalling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2(+) neural progenitors, Dcx(+) newborn neurons, and Olig2(+) oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons, this wave of telomerase

  17. Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

    PubMed Central

    Stefano, Daniela De; Villella, Valeria R; Esposito, Speranza; Tosco, Antonella; Sepe, Angela; Gregorio, Fabiola De; Salvadori, Laura; Grassia, Rosa; Leone, Carlo A; Rosa, Giuseppe De; Maiuri, Maria C; Pettoello-Mantovani, Massimo; Guido, Stefano; Bossi, Anna; Zolin, Anna; Venerando, Andrea; Pinna, Lorenzo A; Mehta, Anil; Bona, Gianni; Kroemer, Guido; Maiuri, Luigi; Raia, Valeria

    2014-01-01

    Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in CftrF508del homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation. PMID:25350163

  18. Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation.

    PubMed

    De Stefano, Daniela; Villella, Valeria R; Esposito, Speranza; Tosco, Antonella; Sepe, Angela; De Gregorio, Fabiola; Salvadori, Laura; Grassia, Rosa; Leone, Carlo A; De Rosa, Giuseppe; Maiuri, Maria C; Pettoello-Mantovani, Massimo; Guido, Stefano; Bossi, Anna; Zolin, Anna; Venerando, Andrea; Pinna, Lorenzo A; Mehta, Anil; Bona, Gianni; Kroemer, Guido; Maiuri, Luigi; Raia, Valeria

    2014-01-01

    Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in Cftr(F508del) homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation.

  19. Zif268/egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning.

    PubMed

    Veyrac, Alexandra; Gros, Alexandra; Bruel-Jungerman, Elodie; Rochefort, Christelle; Kleine Borgmann, Felix B; Jessberger, Sebastian; Laroche, Serge

    2013-04-23

    New neurons are continuously added to the dentate gyrus of the adult mammalian brain. During the critical period of a few weeks after birth when newborn neurons progressively mature, a restricted fraction is competitively selected to survive in an experience-dependent manner, a condition for their contribution to memory processes. The mechanisms that control critical stages of experience-dependent functional incorporation of adult newborn neurons remain largely unknown. Here, we identify a unique transcriptional regulator of the functional integration of newborn neurons, the inducible immediate early gene zif268/egr1. We show that newborn neurons in zif268-KO mice undergo accelerated death during the critical period of 2-3 wk around their birth and exhibit deficient neurochemical and morphological maturation, including reduced GluR1 expression, increased NKCC1/KCC2b chloride cotransporter ratio, altered dendritic development, and marked spine growth defect. Investigating responsiveness of newborn neurons to activity-dependent expression of zif268 in learning, we demonstrate that in the absence of zif268, training in a spatial learning task during this critical period fails to recruit newborn neurons and promote their survival, leading to impaired long-term memory. This study reveals a previously unknown mechanism for the control of the selection, functional maturation, and experience-dependent recruitment of dentate gyrus newborn neurons that depends on the inducible immediate early gene zif268, processes that are critical for their contribution to hippocampal-dependent long-term memory.