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Sample records for induced cold hypersensitivity

  1. A Polyamine-Deficient Diet Prevents Oxaliplatin-Induced Acute Cold and Mechanical Hypersensitivity in Rats

    PubMed Central

    Ferrier, Jérémy; Bayet-Robert, Mathilde; Pereira, Bruno; Daulhac, Laurence; Eschalier, Alain; Pezet, Denis; Moulinoux, Jacques-Philippe; Balayssac, David

    2013-01-01

    Background Oxaliplatin is an anticancer drug used for the treatment of advanced colorectal cancer, but it can also cause painful peripheral neuropathies. The pathophysiology of these neuropathies has not been yet fully elucidated, but may involve spinal N-methyl-D-aspartate (NMDA) receptors, particularly the NR2B subunit. As polyamines are positive modulators of NMDA-NR2B receptors and mainly originate from dietary intake, the modulation of polyamines intake could represent an interesting way to prevent/modulate neuropathic pain symptoms by opposing glutamate neurotransmission. Methods The effect of a polyamine deficient diet was investigated in an animal model of oxaliplatin-induced acute pain hypersensitivity using behavioral tests (mechanical and cold hypersensitivity). The involvement of spinal glutamate neurotransmission was monitored by using a proton nuclear magnetic resonance spectroscopy based metabolomic approach and by assessing the expression and phosphorylation of the NR2B subunit of the NMDA receptor. Results A 7-day polyamine deficient diet totally prevented oxaliplatin-induced acute cold hypersensitivity and mechanical allodynia. Oxaliplatin-induced pain hypersensitivity was not associated with an increase in NR2B subunit expression or phosphorylation, but with an increase of glutamate level in the spinal dorsal horn which was completely prevented by a polyamine deficient diet. As a validation that the oxaliplatin-induced hypersensitivity could be due to an increased activity of the spinal glutamate system, an intrathecal administration of the specific NR2B antagonist, ifenprodil, totally reversed oxaliplatin-induced mechanical and cold hypersensitivity. Conclusion A polyamine deficient diet could represent a promising and valuable nutritional therapy to prevent oxaliplatin-induced acute pain hypersensitivity. PMID:24204988

  2. The roles of iPLA2, TRPM8 and TRPA1 in chemically induced cold hypersensitivity

    PubMed Central

    2010-01-01

    Background The cooling agents menthol and icilin act as agonists at TRPM8 and TRPA1. In vitro, activation of TRPM8 by icilin and cold, but not menthol, is dependent on the activity of a sub-type of phospholipase A2, iPLA2. Lysophospholipids (e.g. LPC) produced by PLA2 activity can also activate TRPM8. The role of TRPA1 as a primary cold sensor in vitro is controversial, although there is evidence that TRPA1 plays a role in behavioural responses to noxious cold stimuli. In this study, we have investigated the roles of TRPM8 and TRPA1 and the influence of iPLA2 on noxious cold sensitivities in naïve animals and after local administration of menthol, icilin and LPC. The roles of the channels in cold sensitivity were investigated in mice lacking either TRPM8 (Trpm8-/-) or TRPA1 (Trpa1-/-). Results Intraplantar administration of icilin evoked a dose-dependent increase in sensitivity to a 10°C stimulus that was inhibited by iPLA2 inhibition with BEL. In contrast the cold hypersensitivities elicited by intraplantar menthol and LPC were not inhibited by BEL treatment. BEL had no effect on basal cold sensitivity and mechanical hypersensitivities induced by the TRPV1 agonist, capsaicin, and the P2X3 agonist α,β-methylene ATP. Both Trpm8-/- and Trpa1-/- mice showed longer latencies for paw withdrawal from a 10°C stimulus than wild-type littermates. Cold hypersensitivities induced by either icilin or LPC were absent in Trpm8-/- mice but were retained in Trpa1-/- mice. In contrast, cold hypersensitivity evoked by menthol was present in Trpm8-/- mice but was lost in Trpa1-/- mice. Conclusions The findings that iPLA2 inhibition blocked the development of cold hypersensitivity after administration of icilin but failed to affect menthol-induced hypersensitivity agree well with our earlier in vitro data showing a differential effect of iPLA2 inhibition on the agonist activities of these agents. The ability of LPC to induce cold hypersensitivity supports a role for iPLA2 in

  3. TRPA1 Contributes to Cold Hypersensitivity

    PubMed Central

    Camino, Donato del; Murphy, Sarah; Heiry, Melissa; Barrett, Lee B.; Earley, Taryn J.; Cook, Colby A.; Petrus, Matt J.; Zhao, Michael; D'Amours, Marc; Deering, Nate; Brenner, Gary J.; Costigan, Michael; Hayward, Neil J.; Chong, Jayhong A.; Fanger, Christopher M.; Woolf, Clifford J.; Patapoutian, Ardem; Moran, Magdalene M.

    2010-01-01

    TRPA1 is a non-selective cation channel expressed by nociceptors. While it is widely accepted that TRPA1 serves as a broad irritancy receptor for a variety of reactive chemicals, its role in cold sensation remains controversial. Here, we demonstrate that mild cooling markedly increases agonist-evoked rat TRPA1 currents. In the absence of an agonist, even noxious cold only increases current amplitude slightly. These results suggest that TRPA1 is a key mediator of cold hypersensitivity in pathological conditions where reactive oxygen species and pro-inflammatory activators of the channel are present, but likely plays a comparatively minor role in acute cold sensation. Supporting this, cold hypersensitivity can be induced in wild-type but not Trpa1-/- mice by subcutaneous administration of a TRPA1 agonist. Furthermore, the selective TRPA1 antagonist HC-030031 reduces cold hypersensitivity in rodent models of inflammatory and neuropathic pain. PMID:21068322

  4. TRPA1 contributes to cold hypersensitivity.

    PubMed

    del Camino, Donato; Murphy, Sarah; Heiry, Melissa; Barrett, Lee B; Earley, Taryn J; Cook, Colby A; Petrus, Matt J; Zhao, Michael; D'Amours, Marc; Deering, Nate; Brenner, Gary J; Costigan, Michael; Hayward, Neil J; Chong, Jayhong A; Fanger, Christopher M; Woolf, Clifford J; Patapoutian, Ardem; Moran, Magdalene M

    2010-11-10

    TRPA1 is a nonselective cation channel expressed by nociceptors. Although it is widely accepted that TRPA1 serves as a broad irritancy receptor for a variety of reactive chemicals, its role in cold sensation remains controversial. Here, we demonstrate that mild cooling markedly increases agonist-evoked rat TRPA1 currents. In the absence of an agonist, even noxious cold only increases current amplitude slightly. These results suggest that TRPA1 is a key mediator of cold hypersensitivity in pathological conditions in which reactive oxygen species and proinflammatory activators of the channel are present, but likely plays a comparatively minor role in acute cold sensation. Supporting this, cold hypersensitivity can be induced in wild-type but not Trpa1(-/-) mice by subcutaneous administration of a TRPA1 agonist. Furthermore, the selective TRPA1 antagonist HC-030031 [2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide] reduces cold hypersensitivity in rodent models of inflammatory and neuropathic pain.

  5. Cannabinoid 1 receptor knockout mice display cold allodynia, but enhanced recovery from spared-nerve injury-induced mechanical hypersensitivity.

    PubMed

    Sideris, Alexandra; Piskoun, Boris; Russo, Lori; Norcini, Monica; Blanck, Thomas; Recio-Pinto, Esperanza

    2016-01-01

    significant recovery from spared-nerve injury-induced mechanical hypersensitivity are two novel phenotypes which characterize the global CB1R-/- mice. An increase in transient receptor potential channel of melastatin 8 channel function in DRG neurons may underlie the cold phenotype. Recovery of mechanical thresholds in the CB1R knockouts was independent of motor function. These results indicate that CB1R expression contributes to the development of persistent mechanical hypersensitivity, protects against the development of robust cold allodynia but is not involved in motor impairment following spared-nerve injury in mice. © The Author(s) 2016.

  6. Cannabinoid 1 receptor knockout mice display cold allodynia, but enhanced recovery from spared-nerve injury-induced mechanical hypersensitivity

    PubMed Central

    Piskoun, Boris; Russo, Lori; Norcini, Monica; Blanck, Thomas; Recio-Pinto, Esperanza

    2016-01-01

    among genotypes. Conclusion Cold allodynia and significant recovery from spared-nerve injury-induced mechanical hypersensitivity are two novel phenotypes which characterize the global CB1R−/− mice. An increase in transient receptor potential channel of melastatin 8 channel function in DRG neurons may underlie the cold phenotype. Recovery of mechanical thresholds in the CB1R knockouts was independent of motor function. These results indicate that CB1R expression contributes to the development of persistent mechanical hypersensitivity, protects against the development of robust cold allodynia but is not involved in motor impairment following spared-nerve injury in mice. PMID:27206660

  7. Cold and L-menthol-induced sensitization in healthy volunteers--a cold hypersensitivity analogue to the heat/capsaicin model.

    PubMed

    Andersen, Hjalte H; Poulsen, Jeppe N; Uchida, Yugo; Nikbakht, Anahita; Arendt-Nielsen, Lars; Gazerani, Parisa

    2015-05-01

    Topical high-concentration L-menthol is the only established human experimental pain model to study mechanisms underlying cold hyperalgesia. We aimed at investigating the combinatorial effect of cold stimuli and topical L-menthol on cold pain and secondary mechanical hyperalgesia. Analogue to the heat-capsaicin model on skin sensitization, we proposed that cold/menthol enhances or prolong L-menthol-evoked sensitization. Topical 40% L-menthol or vehicle was applied (20 minutes) on the volar forearms of 20 healthy females and males (age, 28.7 ± 0.6 years). Cold stimulation of 5°C for 5 minutes was then applied to the treated area 3 times with 40-minute intervals. Cold detection threshold and pain, mechanical hyperalgesia (pinprick), static and dynamic mechanical allodynia (von Frey and brush), skin blood flow (laser speckle), and temperature (thermocamera) were assessed. Cold detection threshold and cold pain threshold (CPT) increased after L-menthol and remained high after the cold rekindling cycles (P < 0.001). L-menthol evoked secondary hyperalgesia to pinprick (P < 0.001) particularly in females (P < 0.05) and also induced secondary allodynia to von Frey and brush (P < 0.001). Application of cold stimuli kept these areas enlarged with a higher response in females to brush after the third cold cycle (P < 0.05). Skin blood flow increased after L-menthol (P < 0.001) and stayed stable after cold cycles. Repeated application of cold on skin treated by L-menthol facilitated and prolonged L-menthol-induced cold pain and hyperalgesia. This model may prove beneficial for testing analgesic compounds when a sufficient duration of time is needed to see drug effects on CPT or mechanical hypersensitivity.

  8. Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera.

    PubMed

    Patel, Ryan; Brice, Nicola L; Lewis, Richard J; Dickenson, Anthony H

    2015-12-01

    Cold hypersensitivity is evident in a range of neuropathies and can evoke sensations of paradoxical burning cold pain. Ciguatoxin poisoning is known to induce a pain syndrome caused by consumption of contaminated tropical fish that can persist for months and include pruritus and cold allodynia; at present no suitable treatment is available. This study examined, for the first time, the neural substrates and molecular components of Pacific ciguatoxin-2-induced cold hypersensitivity. Electrophysiological recordings of dorsal horn lamina V/VI wide dynamic range neurones were made in non-sentient rats. Subcutaneous injection of 10 nm ciguatoxin-2 into the receptive field increased neuronal responses to innocuous and noxious cooling. In addition, neuronal responses to low-threshold but not noxious punctate mechanical stimuli were also elevated. The resultant cold hypersensitivity was not reversed by 6-({2-[2-fluoro-6-(trifluoromethyl)phenoxy]-2-methylpropyl}carbamoyl)pyridine-3-carboxylic acid, an antagonist of transient receptor potential melastatin 8 (TRPM8). Both mechanical and cold hypersensitivity were completely prevented by co-injection with the Nav 1.8 antagonist A803467, whereas the transient receptor potential ankyrin 1 (TRPA1) antagonist A967079 only prevented hypersensitivity to innocuous cooling and partially prevented hypersensitivity to noxious cooling. In naive rats, neither innocuous nor noxious cold-evoked neuronal responses were inhibited by antagonists of Nav 1.8, TRPA1 or TRPM8 alone. Ciguatoxins may confer cold sensitivity to a subpopulation of cold-insensitive Nav 1.8/TRPA1-positive primary afferents, which could underlie the cold allodynia reported in ciguatera. These data expand the understanding of central spinal cold sensitivity under normal conditions and the role of these ion channels in this translational rat model of ciguatoxin-induced hypersensitivity.

  9. The relationship of bone-tumor-induced spinal cord astrocyte activation and aromatase expression to mechanical hyperalgesia and cold hypersensitivity in intact female and ovariectomized mice.

    PubMed

    Smeester, B A; O'Brien, E E; Michlitsch, K S; Lee, J-H; Beitz, A J

    2016-06-02

    Recently, our group established a relationship between tumor-induced spinal cord astrocyte activation and aromatase expression and the development of bone tumor nociception in male mice. As an extension of this work, we now report on the association of tumor-induced mechanical hyperalgesia and cold hypersensitivity to changes in spinal cord dorsal horn GFAP and aromatase expression in intact (INT) female mice and the effect of ovariectomy on these parameters. Implantation of fibrosarcoma cells produced robust mechanical hyperalgesia in INT animals, while ovariectomized (OVX) females had significantly less mechanical hyperalgesia. Cold hypersensitivity was apparent by post-implantation day 7 in INT and OVX females compared to their saline-injected controls and increased throughout the experiment. The decrease in mechanical hyperalgesia in OVX females was mirrored by significant decreases in spinal astrocyte activity in laminae I-II, III-IV, V-VI and X and aromatase expression in laminae V-VI and X in the dorsal horn of tumor-bearing animals. Administration of the aromatase inhibitor letrozole reduced tumor-induced hyperalgesia in INT females only suggesting that the tumor-induced increase in aromatase expression and its associated increase in spinal estrogen play a role in the development of bone tumor-induced hyperalgesia. Finally, intrathecal (i.t.) administration of 17β-estradiol caused a significant increase in tumor-induced hyperalgesia in INT tumor-bearing females. Since i.t. 17β-estradiol increases tumor pain and ovariectomy significantly decreases tumor pain, as well as spinal aromatase, estrogen may play a critical role in the spinal cord response to the changing tumor environment and the development of tumor-induced nociception.

  10. Topical capsaicin application causes cold hypersensitivity in awake monkeys.

    PubMed

    Kamo, Hiroshi; Honda, Kuniya; Kitagawa, Junichi; Tsuboi, Yoshiyuki; Kondo, Masahiro; Taira, Masato; Yamashita, Akiko; Katsuyama, Narumi; Masuda, Yuji; Kato, Takafumi; Iwata, Koichi

    2008-06-01

    Recent animal studies have demonstrated that many trigeminal ganglion neurons co-express TRPV1 and TRPA1 receptors following peripheral inflammation. In the present study, we examined whether cold receptors were sensitized by capsaicin in awake monkeys. Two monkeys were trained to detect a change in cold stimulus temperature (30 degrees C to 0.5, 1.0, 1.5 or 2.0 degrees C) applied to the facial skin. A total of 589 trials were studied, and the number of escape and hold-through trials and detection latency were measured. The number of escape trials was increased after capsaicin treatment, whereas that of hold-through trials was decreased. Detection latency was significantly decreased after capsaicin treatment. The present findings suggest that topical application of capsaicin to the facial skin induces reversible hypersensitivity to a facial cold stimulus in behaving monkeys.

  11. Ibuprofen-induced hypersensitivity syndrome.

    PubMed

    Nanau, Radu M; Neuman, Manuela G

    2010-06-01

    Ibuprofen is a widely used antipyretic and analgesic nonsteroidal antiinflammatory drug (NSAID). With the aging of the population, there will be a significant increase in the prevalence of painful degenerative and inflammatory rheumatic conditions. This increase likely will lead to a parallel increase in the use of NSAIDs, including ibuprofen. The primary effect of the NSAIDs is to inhibit cyclooxygenase (prostaglandin synthase), thereby impairing the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. Although in the majority of cases it is safe, this NSAID, ibuprofen, can produce an unpredictable, idiosyncratic, type B reaction that may pose a major concern in clinical practice. Type B reactions are known to occur in susceptible individuals. The true hypersensitivity reaction (HSR) is a systemic disease defined by the triad of fever, rash, and internal organ involvement that starts 1 day to 12 weeks after the initiation of therapy. HSR has limited the therapeutic use of many drugs, including ibuprofen. Hypersensitivity syndrome associated with ibuprofen is a host-dependent drug reaction that is idiosyncratic in nature. This reaction likely is caused by a combination of metabolic and immunologic factors. Immune mediated components, such as T-cell and their products cytokines and chemokines, can exacerbate cellular responses and create complex pathways that lead to a variety of clinical manifestations. Our review presents an ibuprofen-induced clinical manifestation of hypersensitivity syndrome and the necessity of wisely monitoring the patients clinically and by laboratory investigations when prescribing this drug.

  12. Cytomegalovirus reactivation in drug induced hypersensitivity syndrome.

    PubMed

    Mathuram, Alice J; George, Renu E

    2014-06-01

    Drug induced hypersensitivity syndrome has been reported to a variety of drugs. Reactivation of herpes viruses is associated with relapse of symptoms even as late as five weeks after stopping the inciting drug. We report here a case of drug hypersensitivity with CMV reactivation which was treated successfully.

  13. Jaundice induced by stanozolol hypersensitivity

    PubMed Central

    Slater, S. D.; Davidson, J. F.; Patrick, R. S.

    1976-01-01

    A 66-year-old male patient developed jaundice after 7 months of treatment with the anabolic steroid, stanozolol. When the drug was withdrawn he made a full and uneventful recovery. A liver biopsy showed the histology of a hypersensitivity reaction. This is believed to be the first time jaundice has been recorded with stanozolol therapy and the first time a hypersensitivity-type jaundice has been recorded with any anabolic steroid. ImagesFig. 2Fig. 3 PMID:1273017

  14. Drug Induced Hypersensitivity and the HLA Complex

    PubMed Central

    Alfirevic, Ana; Pirmohamed, Munir

    2011-01-01

    Drug-induced hypersensitivity reactions are of major concern and present a burden for national healthcare systems due to their often severe nature, high rate of hospital admissions and high mortality. They manifest with a wide range of symptoms and signs, and can be initiated by a wide range of structurally diverse chemical compounds. The pathophysiological mechanisms underlying hypersensitivity reactions are not well understood, but it is thought that they are immune mediated. MHC region on Chromosome 6 contains many genes with immune function. Classical MHC molecules are highly polymorphic cell surface glycoproteins whose function is to present peptide antigens to T cells. In addition to conferring protection from some diseases, HLA alleles are also associated with an increased risk of other diseases, including drug-induced hypersensitivity. Pharmacogenetic approach to predict the risk of drug-induced hypersensitivity has been established for several drugs. We will discuss the progress of hypersensitivity pharmacogenetics over the last few years and focus on current efforts of the international community to develop consortia which aim to standardize disease phenotypes and to identify affected individuals through international collaborations. In addition, we will discuss the clinical utility of HLA typing as predictive or diagnostic testing for drug-induced hypersensitivity.

  15. Rituximab-Induced Hypersensitivity Pneumonitis

    PubMed Central

    Tonelli, Adriano R.; Lottenberg, Richard; Allan, Robert W.; Sriram, P.S.

    2009-01-01

    Rituximab is a chimeric anti-CD20 monoclonal antibody used to treat CD20+ non-Hodgkin's lymphoma. Although pulmonary adverse reactions such as cough, rhinitis, bronchospasm, dyspnea and sinusitis are relatively common, other respiratory conditions like cryptogenic organizing pneumonia, interstitial pneumonitis and diffuse alveolar hemorrhage have rarely been reported. Only 2 possible cases of rituximab-associated hypersensitivity pneumonitis have been described to date. We present a case of hypersensitivity pneumonitis with classic radiographic and histopathologic findings in a patient treated with rituximab who responded to prednisone. PMID:18843175

  16. Pharmacogenetics of antiepileptic drug-induced hypersensitivity.

    PubMed

    Bloch, Katarzyna M; Sills, Graeme J; Pirmohamed, Munir; Alfirevic, Ana

    2014-04-01

    Antiepileptic drugs can induce potentially life-threatening hypersensitivity reactions such as Stevens-Johnson syndrome at a frequency of one in 10,000 to one in 1000 treated patients. There is a considerable cross-reactivity among different antiepileptic drugs but the mechanisms are not known. In this review we have summarized current evidence on antiepileptic drug-induced hypersensitivity reactions and performed meta-analyses of published case-control studies that investigated associations between HLA alleles and several antiepileptic drugs in diverse populations. As the heterogeneity between studies was high, we conducted subsequent subgroup analyses and showed that HLA-B*15:02 was associated with carbamazepine, lamotrigine and phenytoin-induced Stevens-Johnson syndrome in Asian populations indicating that pretreatment testing may prevent cross-reactivity. Additionally, we explored the potential of new, high-throughput technologies that may help to understand the mechanisms and predict the risk of adverse drug reactions in the future.

  17. Drug hypersensitivity syndrome induced by meglumine antimoniate.

    PubMed

    Jeddi, Fakhri; Caumes, Eric; Thellier, Marc; Jauréguiberry, Stéphane; Mazier, Dominique; Buffet, Pierre A

    2009-06-01

    We report a case of drug hypersensitivity syndrome (drug reaction with eosinophilia and systemic symptoms [DRESS]) induced by parenteral meglumine antimoniate (Glucantime) in a 40-year-old man who traveled to Bolivia and was treated for mucocutaneous leishmaniasis. Two weeks after starting therapy, the patient had fever, joint pain, a cutaneous eruption, and hypereosinophilia (1,358 cells/mm(3)). These symptoms resolved after drug withdrawal but reappeared upon reintroduction of the drug. Pentavalent antimonials should be definitively withdrawn in patients with hypereosinophilia > 1,000 cells/mm(3) accompanied by systemic manifestations consistent with DRESS.

  18. Stress induces transient auditory hypersensitivity in rats.

    PubMed

    Mazurek, Birgit; Haupt, Heidemarie; Joachim, Ricarda; Klapp, Burghard F; Stöver, Timo; Szczepek, Agnieszka J

    2010-01-01

    Exposure to harsh environment induces stress reactions that increase probability of survival. Stress influences the endocrine, nervous and immune systems and affects the functioning of a variety of organs. Numerous researchers demonstrated that a 24-h exposure to an acoustic rodent repellent provokes stress reaction in exposed animals. In addition to the activated hypothalamic-pituitary-adrenal (HPA) axis, exposed animals had pathological reactions in the reproductive organs, bronchia and skin. Here, we examined the effect of above stress model on the auditory system of Wistar rats. We found that 24-h stress decreases the thresholds and increases the amplitudes of auditory brainstem responses and distortion product otoacoustic emissions. Resultant auditory hypersensitivity was transient and most pronounced between 3 and 6h post-stress, returning to control levels one week later. The concentration of corticosterone and tumor necrosis factor alpha was systemically elevated in stressed animals between 3 and 6h post-stress, confirming the activation of the HPA axis. In addition, expression of the HPA-axis-associated genes: glucocorticoid receptor (GR) and hypoxia-inducible factor 1 alpha (Hif1a) was modulated in the auditory tissues. In detail, in the inferior colliculus, we found an up-regulation of GR mRNA 3h post-stress and continuous up-regulation of Hif1a up to 24h post-stress. In the spiral ganglion, we found no differences in gene expression between stressed and control animals. In the organ of Corti, expression of GR mRNA remained stable, whereas that of Hif1a was significantly down-regulated one week after stress. In addition, the expression of an outer hair cell marker prestin was significantly up-regulated 6h post-stress. We conclude that 24-h stress induces transient hypersensitivity of the auditory system and modulates gene expression in a tissue-specific manner. Stress-induced auditory hypersensitivity could have evolutionary consequence by giving animals

  19. Self-management strategies used by patients who are hypersensitive to cold following a hand injury. A prospective study with two years follow-up.

    PubMed

    Vaksvik, Tone; Kjeken, Ingvild; Holm, Inger

    2015-01-01

    Prospective cohort study. Knowledge of the strategies used by patients with injuries of the hand to manage cold hypersensitivity should guide information given by health-care workers. To explore the use of cold-associated self-management strategies in patients with severe hand injuries. Seventy patients being cold hypersensitive following a hand injury, reported use of strategies to limit cold-induced symptoms in the injured hand(s) and the severity of cold-associated activity limitations one and two years after surgery. The patients used several strategies, including clothing (100%), use of own body (movement/use of muscles to produce heat or massage of the fingers) (94%), and heating aids (48%), but were still limited in valued cold-associated activities two years after surgery. The number of patients staying indoors, using heating aids and hand wear indoors and during summer-time increased with severity of cold hypersensitivity. Patients both implemented and discontinued different strategies after the first year, but for most strategies, the proportions of users were quite stable. The most common strategies used to limit cold-induced symptoms in the injured hand(s) were clothing and use of own body. Many patients also seemed to benefit from using heating aids. After one year, a number of patients still experimented in finding the best strategies and were still limited in valued cold-associated activities. 2b. Copyright © 2015 Hanley & Belfus. Published by Elsevier Inc. All rights reserved.

  20. [Cold-induced urticaria].

    PubMed

    Delorme, N; Drouet, M; Thibaudeau, A; Verret, J L

    2002-09-01

    Cold urticaria is characterized by the development of urticaria, usually superficial and/or angioedematous reaction after cold contact. It was found predominantly in young women. The diagnosis is based on the history and ice cube test. Patients with a negative ice cube test may have represented systemic cold urticaria (atypical acquired cold urticaria) induced by general body cooling. The pathogenesis is poorly understood. Cold urticaria can be classified into acquired and familial disorders, with an autosomal dominant inheritance. Idiopathic cold urticaria is most common type but the research of a cryopathy is necessary. Therapy is often difficult. It is essential that the patient be warned of the dangers of swimming in cold water because systemic hypotension can occur. H1 antihistamines can be used for treatment of cold urticaria but the clinical responses are highly variable. The combination with an H2 antagonists is more effective. Doxepin may be useful in the treatment. Leukotriene receptor antagonists may be a novel, promising drug entity. In patients who do not respond to previous treatments, induction of cold tolerance may be tried.

  1. Cold hypersensitivity 6 to 10 years after replantation or revascularisation of fingers: consequences for work and leisure activities.

    PubMed

    Vaksvik, T; Hetland, K; Røkkum, M; Holm, I

    2009-02-01

    We investigated cold hypersensitivity and activity in 81 adults (male/female 76/5), 6 to 10 years after finger replantation/revascularisation (mean age at injury 43 (SD 15) years). Questionnaires included the McCabe Cold Sensitivity Severity Scale, Potential Work-Exposure Scale and the Disabilities of the Arm, Shoulder and Hand (DASH) score. Eighty per cent of the respondents were cold hypersensitive; 20% were severely or extremely cold hypersensitive. Of the 74 patients employed at injury, 7% had changed work and 4% were not working due to cold hypersensitivity. The median score for cold exposure at work at follow-up was 153 (scale 0-300). The correlation between cold sensitivity and DASH work was low. One-third of the respondents experienced limitations in their leisure activities because of cold complaints. Long-term cold sensitivity was mild or moderate for most patients. Many cold hypersensitive patients managed to continue to work even under cold conditions and cold hypersensitivity was a greater problem in leisure activities.

  2. A case of chlorpheniramine maleate-induced hypersensitivity with aspirin intolerance.

    PubMed

    Kim, Min-Hye; Lee, Sang-Min; Lee, So-Hee; Kwon, Hyouk-Soo; Kim, Sae-Hoon; Cho, Sang-Heon; Min, Kyung-Up; Kim, You-Young; Chang, Yoon-Seok

    2011-01-01

    Antihistamines are commonly used to treat allergic disease, such as allergic rhinitis, urticaria, and angioedema. Although several previous reports describe hypersensitivity to antihistamines such as cetirizine and hydroxyzine, documented cases of chlorpheniramine hypersensitivity are extremely rare. Here, we report the case of a 45-year-old Korean woman who presented with urticaria after ingesting a cold medication. Over the previous 5 years, she had also experienced a food allergy to crab and shrimp, allergic rhinitis, and repeated urticaria after ingesting cold medication. Provocation with aspirin elicited generalized urticaria. Intravenous chlorpheniramine and methylprednisolone was injected for symptom control, but in fact appeared to aggravate urticaria. A second round of skin and provocation tests for chlorpheniramine and methylprednisolone showed positive results only for chlorpheniramine. She was diagnosed with aspirin intolerance and chlorpheniramine hypersensitivity, and was instructed to avoid these drugs. To date, this is the second of only two cases of chlorpheniramine-induced type I hypersensitivity with aspirin intolerance. Although the relationship between aspirin intolerance and chlorpheniramine-induced type I hypersensitivity is unclear, physicians should be aware of the possibility of urticaria or other allergic reactions in response to antihistamines.

  3. Chemotherapy and biotherapy-induced hypersensitivity reactions.

    PubMed

    Van Gerpen, Ruth

    2009-01-01

    Nearly all chemotherapy and biotherapy drugs used in cancer treatment today can cause hypersensitivity reactions. Certain groups of drugs frequently associated with these reactions include the asparaginases, taxanes, platinum compounds, epipodophyllotoxins, and the monoclonal antibodies. Recognizing and managing hypersensitivity reactions are critical when caring for patients receiving these drugs because the reactions are potentially life-threatening. A thorough understanding of the drugs is necessary to assist the nurse in prevention, early recognition, and timely management.

  4. Assessing the potential to induce respiratory hypersensitivity.

    PubMed

    Holsapple, Michael P; Jones, David; Kawabata, Thomas T; Kimber, Ian; Sarlo, Kathy; Selgrade, MaryJane K; Shah, Jui; Woolhiser, Michael R

    2006-05-01

    Acute and repeat dose inhalation studies have been an important part of the safety assessment of drugs, chemicals, and other products throughout the world for many years. It is known that damage to the respiratory tract can be triggered either by nonspecific irritation or by specific immune-mediated pathogenesis, and it is acknowledged that traditional inhalation studies are not designed to address fully the impact of the latter. It is also recognized that different types of immune-mediated responses can be triggered by different classes of compounds and that some immune reactions in the lung are life threatening. As such, it is important to understand as fully as possible the basis for the immune-mediated damage to the lung in order to characterize adequately the risks of individual chemicals or proteins. It is against this background that a review of the methods used to assess the potential for immune-mediated respiratory hypersensitivity was conducted. The primary objectives of this review are to discuss appropriate methods for identifying and characterizing respiratory hypersensitivity hazards and risks; and to identify key data gaps and related research needs with respect to respiratory hypersensitivity testing. The following working definition of respiratory hypersensitivity was formulated: a hypersensitivity response in the respiratory tract precipitated by a specific immune response, mediated by multiple mechanisms, including IgE antibody. Because of the importance played by various classes of compounds, the subsequent sections of this review will consider protein-specific, chemical-specific, and drug-specific aspects of respiratory hypersensitivity.

  5. Cold hypersensitivity increases with age in mice with sickle cell disease

    PubMed Central

    Zappia, Katherine J.; Garrison, Sheldon R.; Hillery, Cheryl A.; Stucky, Cheryl L.

    2014-01-01

    Sickle cell disease (SCD) is associated with acute vaso-occlusive crises that trigger painful episodes and frequently involves ongoing, chronic pain. Additionally, both humans and mice with SCD experience heighted cold sensitivity. However, studies have not addressed the mechanism(s) underlying the cold sensitization, nor its progression with age. Here we measured thermotaxis behavior in young and aged mice with severe SCD. Sickle mice had a marked increase in cold sensitivity measured by a cold preference test. Further, cold hypersensitivity worsened with advanced age. We assessed whether enhanced peripheral input contributes to the chronic cold pain behavior by recording from C fibers, many of which are cold-sensitive, in skin-nerve preparations. We observed that C fibers from sickle mice displayed a shift to warmer (more sensitive) cold-detection thresholds. To address mechanisms underlying the cold sensitization in primary afferent neurons, we quantified mRNA expression levels for ion channels thought to be involved in cold detection. These included the Transient Receptor Potential Melastatin 8 (Trpm8) and TRP Ankyrin 1 (Trpa1) channels, as well as the two-pore domain potassium channels, TREK-1 (Kcnk2), TREK-2 (Kcnk4), and TRAAK (Kcnk10). Surprisingly, transcript expression levels of all of these channels were comparable between sickle and control mice. We further examined transcript expression of 83 additional pain-related genes and found increased mRNA levels for endothelin 1 and tachykinin receptor 1. These factors may contribute to hypersensitivity in sickle mice at both the afferent and behavioral levels. Sensory neurons from sickle cell disease mice are sensitized to cold, mirroring behavioral observations, and have increased expression of endothelin 1 and tachykinin receptor 1. PMID:24953902

  6. Novel TRPM8 antagonist attenuates cold hypersensitivity after peripheral nerve injury in rats.

    PubMed

    Patel, Ryan; Gonçalves, Leonor; Newman, Robert; Jiang, Feng Li; Goldby, Anne; Reeve, Jennifer; Hendrick, Alan; Teall, Martin; Hannah, Duncan; Almond, Sarah; Brice, Nicola; Dickenson, Anthony H

    2014-04-01

    Abnormal cold sensitivity is a common feature of a range of neuropathies. In the murine somatosensory system, multiple aspects of cold sensitivity are dependent on TRPM8, both short term and in response to peripheral nerve injury. The specialized nature of cold-sensitive afferents and the restricted expression of TRPM8 render it an attractive target for the treatment of cold hypersensitivity. This current study examines the effect of a novel TRPM8 antagonist (M8-An) in naive and spinal nerve-ligated rats through behavioral and in vivo electrophysiological approaches. In vitro, M8-An inhibited icilin-evoked Ca(2+) currents in HEK293 cells stably expressing human TRPM8 with an IC(50) of 10.9 nM. In vivo, systemic M8-An transiently decreased core body temperature. Deep dorsal horn recordings were made in vivo from neurons innervating the hind paw. M8-An inhibited neuronal responses to innocuous and noxious cooling of the receptive field in spinal nerve-ligated rats but not in naive rats. No effect on neuronal responses to mechanical and heat stimulation was observed. In addition, M8-An also attenuated behavioral responses to cold but not mechanical stimulation after nerve ligation without affecting the uninjured contralateral response. The data presented here support a contribution of TRPM8 to the pathophysiology of cold hypersensitivity in this model and highlight the potential of the pharmacological block of TRPM8 in alleviating the associated symptoms.

  7. Overexpression of Ran gene from Lepidium latifolium L. (LlaRan) renders transgenic tobacco plants hypersensitive to cold stress.

    PubMed

    Sinha, Vimlendu Bhushan; Grover, Atul; Singh, Sadhana; Pande, Veena; Ahmed, Zakwan

    2014-09-01

    Ran is a multifunctional small GTPase involved in important cellular activities like nucleocytoplasmic transport, mitotic spindle assembly, nuclear envelope formation, etc., but is also known to be differentially expressed in response to abiotic stress, particularly low temperature. We have over-expressed Lepidium latifolium (Fam. Brassicaceae) Ran gene in tobacco to study the response of the plants to cold stress (24 h; 4 °C). Transformation of the tobacco plants was verified using PCR targeting Ran gene and co-transformed selectable marker gene nptII. Segregation in Mendelian ratios was validated in five transgenic lines by germination of T1 and T2 seeds on moist filter papers containing 150 mg/l kanamycin. Higher levels of electrolyte leakage and lipid peroxidation pointed towards hypersensitivity of plants. Similarly, lesser proline accumulation compared to wild types also indicated susceptibility of plants to death under chilling conditions. Specific activity of antioxidant enzymes superoxide dismutase and glutathione reductase was also measured under stressed and control conditions. A variation was observed across the different lines, and four out of five lines showed lesser specific activity compared to wild type plants, thus indicating reduced capability of scavenging free radicals. In totality, a strong evidence on induced hypersensitivity to cold stress has been collected which may further be helpful in designing appropriate strategies for engineering crop plants for survival under cold stress conditions.

  8. Delayed-type hypersensitivity, contact sensitivity, and phytohemagglutinin skin-test responses of heat- and cold-stressed calves.

    PubMed

    Kelley, K W; Greenfield, R E; Evermann, J F; Parish, S M; Perryman, L E

    1982-05-01

    Three-week-old Holstein bull calves were used to investigate the effect of a 2-week chronic heat (35 C) or cold (-5 C) exposure on delayed-type hypersensitivity (DTH) reactions to purified protein derivative after sensitization with heat-killed Mycobacterium tuberculosis, contact sensitivity (CS) reactions to 1-fluoro-2,4-dinitrobenzene, and phytohemagglutinin (PHA) skin tests. Heat exposure reduced expression of DTH reactions by 42% and CS reactions by 38% at 24 hours after elicitation of the responses. The PHA-induced skin tests were not affected after 1 week of heat exposure, but this reaction was reduced by 20% after 2 weeks of heat exposure. The immune response of calves exposed to cold air temperatures was more complex. Cold exposure suppressed CS reactions by 39% at the end of both the 1st and 2nd weeks. The PHA response was reduced by 39% after 2 weeks of cold exposure. The DTH response depended on duration of cold exposure. The DTH reaction was increased by 42% after 1 week, but was reduced by 14% after 2 weeks. These data are consistent with the hypothesis that environmental stressors alter host resistance by affecting the immune system. Furthermore, these stress-induced changes in immune events depend on the type of immune response, the nature of the environmental stressor, and the length of time that calves are exposed to the stressor.

  9. Phenytoin-induced acute hypersensitivity pneumonitis.

    PubMed

    Periwal, Pallavi; Joshi, Sharad; Gothi, Rajesh; Talwar, Deepak

    2015-01-01

    Lungs are target organs for toxic effects of various drugs due to many reasons. Diphenylhydantoin (DPH) is reported to have many extrapulmonary side effects. We are presenting a case of acute hypersensitivity pneumonitis (HP) secondary to DPH, presenting with respiratory failure. Acute HP with respiratory failure is an uncommon drug side effect of the DPH therapy and is a diagnosis of exclusion. It requires detailed workup and exclusion of other causes along with evidence of improvement in the patient's condition after withholding DPH.

  10. Visceral and Somatic Hypersensitivity in TNBS induced Colitis in Rats

    PubMed Central

    Zhou, QiQi; Price, Donald D.; Caudle, Robert M.; Verne, G. Nicholas

    2010-01-01

    Inflammation of visceral structures in rats has been shown to produce visceral/somatic hyperalgesia. Our objectives were to determine if trinitrobenzene sulfonic acid (TNBS) induced colitis in rats leads to visceral/somatic hypersensitivity. Male Sprague-Dawley rats (200g–250g) were treated with 20 mg of TNBS in 50% ethanol (n=40) or an equivalent volume of ethanol (n=40) or saline (n=25) via the colon. Colonic distension, Von-Frey, Hargreaves, and tail reflex test were used to evaluate for visceral, mechanical, and thermal sensitivity. The rats demonstrated visceral hypersensitivity at 2–28 days following TNBS (p<0.0001). The ethanol treated rats also demonstrated visceral hypersensitivity that resolved after day 14. TNBS treated rats demonstrated somatic hypersensitivity at days 14–28 (p<0.0001) in response to somatic stimuli of the hind-paw. TNBS colitis is associated with visceral and somatic hypersensitivity in areas of somatotopic overlap. This model of colitis should allow further investigation into the mechanisms of visceral and somatic hypersensitivity. PMID:17703363

  11. Colloidal silica-induced hypersensitivity: myth or reality.

    PubMed

    Ben Fredj, Nadia; Ben Fadhel, Najeh; Chaabane, Amel; Chadly, Zohra; Ben Romdhane, Haifa; Boughattas, Abderrazzek; Aouam, Karim

    2016-02-01

    Many excipients have been reported to induce drug hypersensitivity (e.g. colouring additives, preservatives). Colloidal silica has never been reported to induce drug hypersensitivity reactions. We report herein a 40-year-old patient who developed a skin eruption 2 days after Voltarene(®) (diclofenac) intake, confirmed by a positive patch test. Investigation of cross reactivity, assessed by patch testing to other non steroidal anti-inflammatory drugs, have showed a positive reaction only to piroxicam (Piroxen(®)), ketoprofen (Oki(®)) and indometacin (Indocid(®)). A hypersensivity to colloidal silica, a common excipient, was suspected. A patch test to this compound was performed showing a positive reaction. Colloidal silica, a compound widely used in drug manufacturing, could be another culprit excipient in inducing skin hypersensitivity reactions.

  12. Acute kidney injury caused by zonisamide-induced hypersensitivity syndrome.

    PubMed

    Fujita, Yoshiro; Hasegawa, Midori; Nabeshima, Kuihiro; Tomita, Makoto; Murakami, Kazutaka; Nakai, Shigeru; Yamakita, Takashi; Matsunaga, Kayoko

    2010-01-01

    Drug rash with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DIHS), is a severe adverse drug reaction affecting multiple organs caused by drug treatment. The current report describes a man who was prescribed zonisamide for epilepsy and subsequently developed widespread skin rash, acute kidney injury, high-grade fever, eosinophilia, liver dysfunction, lymphadenopathy and an increase in antihuman herpesvirus-6 immunoglobulin G titer. Hypersensitivity to zonisamide was confirmed by the skin patch test. Based on these findings, the patient was diagnosed with DRESS/DIHS caused by zonisamide. This is the first report of acute kidney injury due to zonisamide-induced DRESS/DIHS.

  13. Hypersensitivity pneumonitis induced by Shiitake mushroom spores.

    PubMed

    Ampere, Alexandre; Delhaes, Laurence; Soots, Jacques; Bart, Frederic; Wallaert, Benoit

    2012-08-01

    Hypersensitivity pneumonitis (HP) is a pulmonary granulomatosis involving an immunoallergic mechanism caused by chronic inhalation of antigens, most frequently organic substances, as well as chemicals. We report the first European case of hypersensitivity pneumonitis due to the inhalation of Shiitake mushroom spores. A 37-year-old French Caucasian man with a one-month history of persistent dry cough, shortness of breath and loss of weight was admitted to our hospital on December 2010. Anamnesis showed he was involved in mushroom production beginning in the summer of 2010. His temperature on admission was 36.6°C and he had a normal blood pressure (135/90 mmHg). Bilateral fine crackles were audible in the base of both lungs. Pulmonary function tests showed a mild restrictive pattern with decreased DLco and a PaO(2) of 65 mmHg, Chest CT scan revealed reticulo-nodular shadows, slight ground glass opacities, liner atelectasis, and subpleural opacities in both lung fields. Bronchoscopy was normal but cytological examination of BAL revealed a predominant lymphocytosis (55%). Serum precipitins to the Shiitake mushroom spores were positive (3 precipitins arcs with high intensity) and as a result we advised the patient to cease his mushroom production activities. The diagnosis of hypersensitivity pneumonitis due to inhalation of Shiitake mushroom spores was established as a result of the improvement of all of his clinical symptoms, i.e., cough, weight loss, bilateral fine crackles, mild restrictive pattern of pulmonary function, and reticulo-nodular shadows on chest CT, once exposure was eliminated. Recent interest in exotic mushrooms varieties, e.g., Shiitake, in developed countries because of their possible medicinal properties might increase the potential risk of HP among mushrooms workers. Therefore, healthcare professionals have to take this new potential respiratory disease into account.

  14. Hypersensitivity to Cold Stimuli in Symptomatic Contact Lens Wearers

    PubMed Central

    Situ, Ping; Simpson, Trefford; Begley, Carolyn

    2016-01-01

    Purpose To examine the cooling thresholds and the estimated sensation magnitude at stimulus detection in controls and symptomatic and asymptomatic contact lens (CL) wearers, in order to determine whether detection thresholds depend on the presence of symptoms of dryness and discomfort. Methods 49 adapted CL wearers and 15 non-lens wearing controls had room temperature pneumatic thresholds measured using a custom Belmonte esthesiometer, during Visits 1 and 2 (Baseline CL), Visit 3 (2 weeks no CL wear) and Visit 4 (2 weeks after resuming CL wear). CL wearers were subdivided into symptomatic and asymptomatic groups based on comfortable wearing time (CWT) and CLDEQ-8 score (<8 hours CWT and ≥14 CLDEQ-8 stratified the symptom groups). Detection thresholds were estimated using an ascending method of limits and each threshold was the average of the three first-reported flow rates. The magnitude of intensity, coolness, irritation and pain at detection of the stimulus were estimated using a 1-100 scale (1 very mild, 100 very strong). Results In all measurement conditions, the symptomatic CL wearers were the most sensitive, the asymptomatic CL wearers were the least sensitive and the control group was between the two CL wearing groups (group factor p < 0.001, post hoc asymptomatic vs. symptomatic group, all p’s < 0.015). Similar patterns were found for the estimated magnitude of intensity and irritation (group effect p=0.027 and 0.006 for intensity and irritation, respectively) but not for cooling (p>0.05) at detection threshold. Conclusions Symptomatic CL wearers have higher cold detection sensitivity and report greater intensity and irritation sensation at stimulus detection than the asymptomatic wearers. Room temperature pneumatic esthesiometry may help to better understand the process of sensory adaptation to CL wear. PMID:27046090

  15. Clozapine-induced hypersensitivity myocarditis presenting as sudden cardiac death

    PubMed Central

    Balla, Sudarshan; Aggarwal, Kul

    2016-01-01

    Hypersensitivity myocarditis is a rare but serious adverse effect of clozapine, a commonly used psychiatric drug. We report the case of sudden cardiac death from clozapine-induced hypersensitivity myocarditis diagnosed at autopsy. A 54-year-old Caucasian male on clozapine therapy for bipolar disorder presented with a sudden onset of shortness of breath. Laboratory studies were significant for elevated N-terminal prohormone of brain natriuretic peptide. During his hospital stay, the patient died of sudden cardiac arrest from ventricular tachycardia. The autopsy revealed hypersensitivity myocarditis, which usually occurs in the first 4 weeks after the initiation of clozapine. A 4-week monitoring protocol, including laboratory assessment of troponin and C-reactive protein, may assist in the early diagnosis of this potentially fatal condition. PMID:28210568

  16. A novel bacterial Water Hypersensitivity-like protein shows in vivo protection against cold and freeze damage.

    PubMed

    Anderson, Dominique; Ferreras, Eloy; Trindade, Marla; Cowan, Don

    2015-08-01

    Metagenomic library screening, by functional or sequence analysis, has become an established method for the identification of novel genes and gene products, including genetic elements implicated in microbial stress response and adaptation. We have identified, using a sequence-based approach, a fosmid clone from an Antarctic desert soil metagenome library containing a novel gene which codes for a protein homologous to a Water Hypersensitivity domain (WHy). The WHy domain is typically found as a component of specific LEA (Late Embryogenesis Abundant) proteins, particularly the LEA-14 (LEA-8) variants, which occur widely in plants, nematodes, bacteria and archaea and which are typically induced by exposure to stress conditions. The novel WHy-like protein (165 amino acid, 18.6 kDa) exhibits a largely invariant NPN motif at the N-terminus and has high sequence identity to genes identified in Pseudomonas genomes. Expression of this protein in Escherichia coli significantly protected the recombinant host against cold and freeze stress.

  17. Maternal Separation Induced Visceral Hypersensitivity from Childhood to Adulthood.

    PubMed

    Yi, Lisha; Zhang, Haiqin; Sun, Huihui; Zhou, Lu; Chen, Ying; Xuan, Liqian; Jiang, Yuanxi; Xu, Shuchang

    2017-04-30

    Early adverse life events (EALs) are relevant to irritable bowel syndrome in adulthood. Maternal separation (MS), as one of the EALs, has proved to induce visceral hypersensitivity in adult rats. However, the effect of MS on visceral hypersensitvity from the post-weaning period to adulthood remains unknown. One hundred and ten neonatal Sprague-Dawley rats were randomly divided into 2 groups: rats in the MS group were exposed to 3 hours daily MS on postnatal day (PND) 2-14; the normal control (NC) group remained undisturbed. Visceral sensitivity was determined by measuring the visceromotor response to colorectal distention on PND21, 35, and 56. Anxiety-like behaviors were measured by the open field test. Compared with NC rats, MS rats showed significant visceral hypersensitivity from the post-weaning period to adult. The proportion of visceral hypersensitive rats decreased with age from 87.5% to 70.0% in the female MS group and from 90.0% to 66.7% in the male MS group. The relative VMR ratio of MS and NC on PND21 was higher than PND35 and PND56. MS rats showed decreased ability of movement and exploration to the novel environment in the post-weaning period, obesity in the prepubertal period, and more anxiety-like behaviors in adulthood. MS can significantly affect visceral sensitivity and behaviors of rats in different age stages, especially in the post-weaning period. Visceral hypersensitivity of MS rats is more pronounced in the post-weaning period and slightly restored in adults. Thus, visceral hypersensitivity in the post-weaning period might play a more meaningful pathophysiologic role in the formation of adult irritable bowel syndrome.

  18. Maternal Separation Induced Visceral Hypersensitivity from Childhood to Adulthood

    PubMed Central

    Yi, Lisha; Zhang, Haiqin; Sun, Huihui; Zhou, Lu; Chen, Ying; Xuan, Liqian; Jiang, Yuanxi; Xu, Shuchang

    2017-01-01

    Background/Aims Early adverse life events (EALs) are relevant to irritable bowel syndrome in adulthood. Maternal separation (MS), as one of the EALs, has proved to induce visceral hypersensitivity in adult rats. However, the effect of MS on visceral hypersensitvity from the post-weaning period to adulthood remains unknown. Methods One hundred and ten neonatal Sprague-Dawley rats were randomly divided into 2 groups: rats in the MS group were exposed to 3 hours daily MS on postnatal day (PND) 2–14; the normal control (NC) group remained undisturbed. Visceral sensitivity was determined by measuring the visceromotor response to colorectal distention on PND21, 35, and 56. Anxiety-like behaviors were measured by the open field test. Results Compared with NC rats, MS rats showed significant visceral hypersensitivity from the post-weaning period to adult. The proportion of visceral hypersensitive rats decreased with age from 87.5% to 70.0% in the female MS group and from 90.0% to 66.7% in the male MS group. The relative VMR ratio of MS and NC on PND21 was higher than PND35 and PND56. MS rats showed decreased ability of movement and exploration to the novel environment in the post-weaning period, obesity in the prepubertal period, and more anxiety-like behaviors in adulthood. Conclusions MS can significantly affect visceral sensitivity and behaviors of rats in different age stages, especially in the post-weaning period. Visceral hypersensitivity of MS rats is more pronounced in the post-weaning period and slightly restored in adults. Thus, visceral hypersensitivity in the post-weaning period might play a more meaningful pathophysiologic role in the formation of adult irritable bowel syndrome. PMID:28238254

  19. [Drug-induced hypersensitivity syndrome and HHV-6 reactivation].

    PubMed

    Tohyama, Mikiko; Hashimoto, Koji

    2009-06-01

    Drug-induced hypersensitivity syndrome (DIHS) is an adverse reaction with clinical signs of fever, rash, and internal organ involvement. The culprit drugs of DIHS are limited to several drugs such as carbamazepine, phenytoin, phenobarbital, zonisamide, allopurinol, salazosulfapyridine, diaphenylsulphone, and mexiletine. The association of HHV-6 reactivation with DIHS has been known. Flaring of symptoms such as fever and hepatitis is closely related to HHV-6 reactivation. A combination of immunologic reaction to a drug and HHV-6 reactivation results in the severe course of DIHS.

  20. Peripheral NMDA Receptors Mediate Antidromic Nerve Stimulation-Induced Tactile Hypersensitivity in the Rat

    PubMed Central

    Jang, Jun Ho; Nam, Taick Sang; Jun, Jaebeom; Jung, Se Jung; Kim, Dong-Wook; Leem, Joong Woo

    2015-01-01

    We investigated the role of peripheral NMDA receptors (NMDARs) in antidromic nerve stimulation-induced tactile hypersensitivity outside the skin area innervated by stimulated nerve. Tetanic electrical stimulation (ES) of the decentralized L5 spinal nerve, which induced enlargement of plasma extravasation, resulted in tactile hypersensitivity in the L4 plantar dermatome of the hind-paw. When intraplantar (i.pl.) injection was administered into the L4 dermatome before ES, NMDAR and group-I metabotropic Glu receptor (mGluR) antagonists and group-II mGluR agonist but not AMPA/kainate receptor antagonist prevented ES-induced hypersensitivity. I.pl. injection of PKA or PKC inhibitors also prevented ES-induced hypersensitivity. When the same injections were administered after establishment of ES-induced hypersensitivity, hypersensitivity was partially reduced by NMDAR antagonist only. In naïve animals, i.pl. Glu injection into the L4 dermatome induced tactile hypersensitivity, which was blocked by NMDAR antagonist and PKA and PKC inhibitors. These results suggest that the peripheral release of Glu, induced by antidromic nerve stimulation, leads to the expansion of tactile hypersensitive skin probably via nociceptor sensitization spread due to the diffusion of Glu into the skin near the release site. In addition, intracellular PKA- and PKC-dependent mechanisms mediated mainly by NMDAR activation are involved in Glu-induced nociceptor sensitization and subsequent hypersensitivity. PMID:26770021

  1. Peripheral NMDA Receptors Mediate Antidromic Nerve Stimulation-Induced Tactile Hypersensitivity in the Rat.

    PubMed

    Jang, Jun Ho; Nam, Taick Sang; Jun, Jaebeom; Jung, Se Jung; Kim, Dong-Wook; Leem, Joong Woo

    2015-01-01

    We investigated the role of peripheral NMDA receptors (NMDARs) in antidromic nerve stimulation-induced tactile hypersensitivity outside the skin area innervated by stimulated nerve. Tetanic electrical stimulation (ES) of the decentralized L5 spinal nerve, which induced enlargement of plasma extravasation, resulted in tactile hypersensitivity in the L4 plantar dermatome of the hind-paw. When intraplantar (i.pl.) injection was administered into the L4 dermatome before ES, NMDAR and group-I metabotropic Glu receptor (mGluR) antagonists and group-II mGluR agonist but not AMPA/kainate receptor antagonist prevented ES-induced hypersensitivity. I.pl. injection of PKA or PKC inhibitors also prevented ES-induced hypersensitivity. When the same injections were administered after establishment of ES-induced hypersensitivity, hypersensitivity was partially reduced by NMDAR antagonist only. In naïve animals, i.pl. Glu injection into the L4 dermatome induced tactile hypersensitivity, which was blocked by NMDAR antagonist and PKA and PKC inhibitors. These results suggest that the peripheral release of Glu, induced by antidromic nerve stimulation, leads to the expansion of tactile hypersensitive skin probably via nociceptor sensitization spread due to the diffusion of Glu into the skin near the release site. In addition, intracellular PKA- and PKC-dependent mechanisms mediated mainly by NMDAR activation are involved in Glu-induced nociceptor sensitization and subsequent hypersensitivity.

  2. Airway Inflammation and Hypersensitivity Induced by Chronic Smoking

    PubMed Central

    Kou, Yu Ru; Kwong, Kevin; Lee, Lu-Yuan

    2011-01-01

    Airway hypersensitivity, characterized by enhanced excitability of airway sensory nerves, is a prominent pathophysiological feature in patients with airway inflammatory diseases. Although the underlying pathogenic mechanism is not fully understood, chronic airway inflammation is believed to be primarily responsible. Cigarette smoking is known to cause chronic airway inflammation, accompanied by airway hyperresponsiveness. Experimental evidence indicates that enhanced excitability of vagal bronchopulmonary sensory nerves and increased tachykinin synthesis in these nerves resulting from chronic inflammation are important contributing factors to the airway hyperresponsiveness. Multiple inflammatory mediators released from various types of structural and inflammatory cells are involved in the smoking-induced airway inflammation, which is mainly regulated by redox-sensitive signaling pathways and transcription factors. Furthermore, recent studies have reported potent sensitizing and stimulatory effects of these inflammatory mediators such as prostanoids and reactive oxygen species on these sensory nerves. In summary, these studies using cigarette smoking as an experimental approach have identified certain potentially important cell signaling pathways and underlying mechanisms of the airway hypersensitivity induced by chronic airway inflammation. PMID:21397052

  3. Drug-induced hypersensitivity syndrome due to carbapenem antibiotics.

    PubMed

    Goto, Mizuki; Shimizu, Fumiaki; Takeo, Naoko; Okamoto, Osamu; Katagiri, Kazumoto; Ikewaki, Junji; Ogata, Masao; Kadota, Jun-ichi; Fujiwara, Sakuhei

    2010-04-01

    Drug-induced hypersensitivity syndrome (DIHS) is characterized by a serious adverse systemic reaction that usually appears after a 3-6-week exposure to certain drugs, for example, anticonvulsants. Many different precipitating factors have been reported, but the pathophysiology of DIHS remains unknown. However, reactivation of members of the human herpesvirus (HHV) family, and of HHV-6 in particular, has been reported in patients with DIHS. We report the case of a 64-year-old man who developed a generalized erythematous rash, fever, hepatic failure, lymphadenopathy and an increased number of atypical lymphocytes. In addition, reactivation of HHV-6 and cytomegalovirus (CMV) was demonstrated by real-time quantitative amplification by polymerase chain reaction. The patient was given a diagnosis of DIHS due to carbapenem antibiotics based on his clinical course, laboratory data, and results of lymphocyte-stimulation tests with various drugs. This is the first report, to our knowledge, of DIHS induced by carbapenem antibiotics.

  4. Drug-induced hypersensitivity syndrome with human herpesvirus-6 reactivation.

    PubMed

    Riyaz, Najeeba; Sarita, S; Arunkumar, G; Sabeena, S; Manikoth, Neeraj; Sivakumar, C P

    2012-01-01

    A 45-year-old man, on carbamazepine for the past 3 months, was referred as a case of atypical measles. On examination, he had high-grade fever, generalized itchy rash, cough, vomiting and jaundice. A provisional diagnosis of drug hypersensitivity syndrome to carbamazepine was made with a differential diagnosis of viral exanthema with systemic complications. Laboratory investigations revealed leukocytosis with eosnophilia and elevated liver enzymes. Real-time multiplex polymerase chain reaction (PCR) on throat swab and blood was suggestive of human herpesvirus-6 (HHV-6). Measles was ruled out by PCR and serology. The diagnosis of drug-induced hypersensitivity syndrome (DIHS) was confirmed, which could explain all the features manifested by the patient. HHV-6 infects almost all humans by age 2 years. It infects and replicates in CD4 T lymphocytes and establishes latency in human peripheral blood monocytes or macrophages and early bone marrow progenitors. In DIHS, allergic reaction to the causative drug stimulates T cells, which leads to reactivation of the herpesvirus genome. DIHS is treated by withdrawal of the culprit drug and administration of systemic steroids. Our patient responded well to steroids and HHV-6 was negative on repeat real-time multiplex PCR at the end of treatment.

  5. Identification of MHC Haplotypes Associated with Drug-induced Hypersensitivity Reactions in Cynomolgus Monkeys.

    PubMed

    Wu, Hong; Whritenour, Jessica; Sanford, Jonathan C; Houle, Christopher; Adkins, Karissa K

    2017-01-01

    Drug-induced hypersensitivity reactions can significantly impact drug development and use. Studies to understand risk factors for drug-induced hypersensitivity reactions have identified genetic association with specific human leukocyte antigen (HLA) alleles. Interestingly, drug-induced hypersensitivity reactions can occur in nonhuman primates; however, association between drug-induced hypersensitivity reactions and major histocompatibility complex (MHC) alleles has not been described. In this study, tissue samples were collected from 62 cynomolgus monkeys from preclinical studies in which 9 animals had evidence of drug-induced hypersensitivity reactions. Microsatellite analysis was used to determine MHC haplotypes for each animal. A total of 7 haplotypes and recombinant MHC haplotypes were observed, with distribution frequency comparable to known MHC I allele frequency in cynomolgus monkeys. Genetic association analysis identified alleles from the M3 haplotype of the MHC I B region (B*011:01, B*075:01, B*079:01, B*070:02, B*098:05, and B*165:01) to be significantly associated (χ(2) test for trend, p < 0.05) with occurrence of drug-induced hypersensitivity reactions. Sequence similarity from alignment of alleles in the M3 haplotype B region and HLA alleles associated with drug-induced hypersensitivity reactions in humans was 86% to 93%. These data demonstrate that MHC alleles in cynomolgus monkeys are associated with drug-induced hypersensitivity reactions, similar to HLA alleles in humans.

  6. Dentin hypersensitivity induces anxiety and increases corticosterone serum levels in rats.

    PubMed

    Bergamini, Marcelo R; Bernardi, Maria M; Sufredini, Ivana B; Ciaramicoli, Marcia T; Kodama, Ricardo M; Kabadayan, Fernanda; Saraceni, Cintia H C

    2014-03-11

    Investigate the relationships between experimentally induced dentin hypersensitivity (DH) with behavioral, endocrine and dentin erosion data. Male Wistar rats divided into four groups, two controls and two experimental, received tap water or isotonic solution (Gatorade®, lemon, pH2.7) for 30 or 45 days. The DH test was performed by a cold water stimulus on molars. A score (0-3) was given to the rats' pain response. Anxiety was evaluated by the elevated plus maze model and by serum corticosterone levels. The dentin erosion was observed by scanning electron microscopy (SEM). Anatomopathological studies were performed on the stomach, adrenal, kidney, and liver. Relative to control groups, experimental rats showed: 1) increased hypersensitivity scores (control group, 0; experimental groups, 2 (limits 0.5-3) on the 30th day and 2 (limits 1-3) on the 45th day); 2) reduced percentage of time and entries in the open arms and in serum corticosterone levels; 3) totally exposed dentinal tubules on the 30th day in SEM analysis of the teeth; and 4) no alterations in the anatomopathological and histological evaluations. The treatment with isotonic solution for 30 days was able to induce DH after erosive challenge and severe DH was observed after isotonic solution treatment for 45 days. The pain induced by cold stimuli was consistent with the grade of DH. The close relationships between dental erosion, response to pain, serum levels of corticosterone and the EPM behavior responses reveal the effects of DH at several levels. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Jasmonic acid signaling modulates ozone-induced hypersensitive cell death.

    PubMed

    Rao, M V; Lee, H; Creelman, R A; Mullet, J E; Davis, K R

    2000-09-01

    Recent studies suggest that cross-talk between salicylic acid (SA)-, jasmonic acid (JA)-, and ethylene-dependent signaling pathways regulates plant responses to both abiotic and biotic stress factors. Earlier studies demonstrated that ozone (O(3)) exposure activates a hypersensitive response (HR)-like cell death pathway in the Arabidopsis ecotype Cvi-0. We now have confirmed the role of SA and JA signaling in influencing O(3)-induced cell death. Expression of salicylate hydroxylase (NahG) in Cvi-0 reduced O(3)-induced cell death. Methyl jasmonate (Me-JA) pretreatment of Cvi-0 decreased O(3)-induced H(2)O(2) content and SA concentrations and completely abolished O(3)-induced cell death. Cvi-0 synthesized as much JA as did Col-0 in response to O(3) exposure but exhibited much less sensitivity to exogenous Me-JA. Analyses of the responses to O(3) of the JA-signaling mutants jar1 and fad3/7/8 also demonstrated an antagonistic relationship between JA- and SA-signaling pathways in controlling the magnitude of O(3)-induced HR-like cell death.

  8. Gastroenterology case report of mesalazine-induced cardiopulmonary hypersensitivity.

    PubMed

    Ferrusquía, José; Pérez-Martínez, Isabel; Gómez de la Torre, Ricardo; Fernández-Almira, María Luisa; de Francisco, Ruth; Rodrigo, Luis; Riestra, Sabino

    2015-04-07

    Mesalazine is a 5-aminosalicylic acid derivative that has been widely used to treat patients with inflammatory bowel disease. Accumulating evidence indicates that mesalazine has a very low rate of adverse drug reactions and is well tolerated by patients. However, a few cases of pulmonary and cardiac disease related to mesalazine have been reported in the past, though infrequently, preventing clinicians from diagnosing the conditions early. We describe the case of a 32-year-old man with ulcerative colitis who was admitted with a two-month history of persistent fever following mesalazine treatment initiated 14 mo earlier. At the time of admission, mesalazine dose was increased from 1.5 to 3.0 g/d, and antibiotic therapy was started with no improvement. Three weeks after admission, the patient developed dyspnea, non-productive cough, and chest pain. Severe eosinophilia was detected in laboratory tests, and a computed tomography scan revealed interstitial infiltrates in both lungs, as well as a large pericardial effusion. The bronchoalveolar lavage reported a CD4/CD8 ratio of 0.5, and an increased eosinophil count. Transbronchial biopsy examination showed a severe eosinophilic infiltrate of the lung tissue. Mesalazine-induced cardiopulmonary hypersensitivity was suspected after excluding other possible etiologies. Consequently, mesalazine treatment was suspended, and corticosteroid therapy was initiated, resulting in resolution of symptoms and radiologic abnormalities. We conclude that mesalazine-induced pulmonary and cardiac hypersensitivity should always be considered in the differential diagnosis of unexplained cardiopulmonary symptoms and radiographic abnormalities in patients with inflammatory bowel disease.

  9. Gastroenterology case report of mesalazine-induced cardiopulmonary hypersensitivity

    PubMed Central

    Ferrusquía, José; Pérez-Martínez, Isabel; Gómez de la Torre, Ricardo; Fernández-Almira, María Luisa; de Francisco, Ruth; Rodrigo, Luis; Riestra, Sabino

    2015-01-01

    Mesalazine is a 5-aminosalicylic acid derivative that has been widely used to treat patients with inflammatory bowel disease. Accumulating evidence indicates that mesalazine has a very low rate of adverse drug reactions and is well tolerated by patients. However, a few cases of pulmonary and cardiac disease related to mesalazine have been reported in the past, though infrequently, preventing clinicians from diagnosing the conditions early. We describe the case of a 32-year-old man with ulcerative colitis who was admitted with a two-month history of persistent fever following mesalazine treatment initiated 14 mo earlier. At the time of admission, mesalazine dose was increased from 1.5 to 3.0 g/d, and antibiotic therapy was started with no improvement. Three weeks after admission, the patient developed dyspnea, non-productive cough, and chest pain. Severe eosinophilia was detected in laboratory tests, and a computed tomography scan revealed interstitial infiltrates in both lungs, as well as a large pericardial effusion. The bronchoalveolar lavage reported a CD4/CD8 ratio of 0.5, and an increased eosinophil count. Transbronchial biopsy examination showed a severe eosinophilic infiltrate of the lung tissue. Mesalazine-induced cardiopulmonary hypersensitivity was suspected after excluding other possible etiologies. Consequently, mesalazine treatment was suspended, and corticosteroid therapy was initiated, resulting in resolution of symptoms and radiologic abnormalities. We conclude that mesalazine-induced pulmonary and cardiac hypersensitivity should always be considered in the differential diagnosis of unexplained cardiopulmonary symptoms and radiographic abnormalities in patients with inflammatory bowel disease. PMID:25852295

  10. New insights into cold-induced sweetening

    USDA-ARS?s Scientific Manuscript database

    Potato tubers accumulate sugars when exposed to low temperatures. This process is referred to as cold-induced sweetening or low-temperature sweetening. The importance of cold-induced sweetening to the potato processing industry cannot be overemphasized. Cold-induced sweetening decreases potato tuber...

  11. Chronic mouse model of TMA-induced contact hypersensitivity.

    PubMed

    Schneider, Claudia; Döcke, Wolf-Dietrich F; Zollner, Thomas M; Röse, Lars

    2009-04-01

    Due to the steadily increasing incidence of atopic dermatitis (AD), especially in children, there is a high medical need for new therapies and improved animal models. In mice, trimellitic anhydride (TMA) is routinely used to trigger T-cell-dependent contact hypersensitivity (CHS) reactions. In this study, we compared the standard acute TMA-induced CHS in Balb/c mice with subacute and chronic models of TMA-induced ear inflammation. Compared to the acute model, the chronic CHS model more closely reflects characteristics of AD, such as typical morphological changes of the inflamed skin, strong infiltration with T cells, major histocompatibility complex II-positive cells, eosinophils, and mast cells, a T-helper cell-type (Th) 2 cytokine profile and a strong increase of serum IgE levels. Moreover, a strong lymph node involvement with T-helper cell dominance and a mixed Th1/Th2 T-cell differentiation and activation pattern was demonstrated. Importantly, as demonstrated by successful therapy with prednisolone, the chronic TMA-induced CHS model, in contrast to acute and subacute models, made prolonged therapeutic treatment of a pre-established skin inflammation possible. Altogether, we present an improved model of mouse T-cell-dependent skin inflammation for AD. We hope this model will enhance the predictive value of animal models for therapeutic treatment of atopic eczema.

  12. Cold sensitivity of TRPA1 is unveiled by the prolyl hydroxylation blockade-induced sensitization to ROS.

    PubMed

    Miyake, Takahito; Nakamura, Saki; Zhao, Meng; So, Kanako; Inoue, Keisuke; Numata, Tomohiro; Takahashi, Nobuaki; Shirakawa, Hisashi; Mori, Yasuo; Nakagawa, Takayuki; Kaneko, Shuji

    2016-09-15

    Mammalian transient receptor potential ankyrin 1 (TRPA1) is a polymodal nociceptor that plays an important role in pain generation, but its role as a cold nociceptor is still controversial. Here, we propose that TRPA1 can sense noxious cold via transduction of reactive oxygen species (ROS) signalling. We show that inhibiting hydroxylation of a proline residue within the N-terminal ankyrin repeat of human TRPA1 by mutation or using a prolyl hydroxylase (PHD) inhibitor potentiates the cold sensitivity of TRPA1 in the presence of hydrogen peroxide. Inhibiting PHD in mice triggers mouse TRPA1 sensitization sufficiently to sense cold-evoked ROS, which causes cold hypersensitivity. Furthermore, this phenomenon underlies the acute cold hypersensitivity induced by the chemotherapeutic agent oxaliplatin or its metabolite oxalate. Thus, our findings provide evidence that blocking prolyl hydroxylation reveals TRPA1 sensitization to ROS, which enables TRPA1 to convert ROS signalling into cold sensitivity.

  13. Cold sensitivity of TRPA1 is unveiled by the prolyl hydroxylation blockade-induced sensitization to ROS

    PubMed Central

    Miyake, Takahito; Nakamura, Saki; Zhao, Meng; So, Kanako; Inoue, Keisuke; Numata, Tomohiro; Takahashi, Nobuaki; Shirakawa, Hisashi; Mori, Yasuo; Nakagawa, Takayuki; Kaneko, Shuji

    2016-01-01

    Mammalian transient receptor potential ankyrin 1 (TRPA1) is a polymodal nociceptor that plays an important role in pain generation, but its role as a cold nociceptor is still controversial. Here, we propose that TRPA1 can sense noxious cold via transduction of reactive oxygen species (ROS) signalling. We show that inhibiting hydroxylation of a proline residue within the N-terminal ankyrin repeat of human TRPA1 by mutation or using a prolyl hydroxylase (PHD) inhibitor potentiates the cold sensitivity of TRPA1 in the presence of hydrogen peroxide. Inhibiting PHD in mice triggers mouse TRPA1 sensitization sufficiently to sense cold-evoked ROS, which causes cold hypersensitivity. Furthermore, this phenomenon underlies the acute cold hypersensitivity induced by the chemotherapeutic agent oxaliplatin or its metabolite oxalate. Thus, our findings provide evidence that blocking prolyl hydroxylation reveals TRPA1 sensitization to ROS, which enables TRPA1 to convert ROS signalling into cold sensitivity. PMID:27628562

  14. Total Knee Arthroplasty Failure Induced by Metal Hypersensitivity.

    PubMed

    Gupta, Ryan; Phan, Duy; Schwarzkopf, Ran

    2015-08-17

    Metal hypersensitivity is an uncommon complication after total knee arthroplasty (TKA) that can lead to significant functional impairment and aseptic prosthesis failure. We describe a 70-year-old patient who presented with persistent pain, swelling, and instability 2 years after a primary TKA. The patient had a history of metal hypersensitivity following bilateral metal-on-metal total hip arthroplasty (THA) that was revised to ceramic-on-polyethylene implants. Knee radiographs showed severe osteolysis with implant loosening. Serum cobalt was elevated and serum chromium was significantly elevated, while joint aspiration and inflammatory marker levels ruled out a periprosthetic infection. Revision TKA was performed, with intraoperative tissue pathology and postoperative leukocyte transformation testing confirming metal hypersensitivity as the cause for aseptic implant failure. This case report demonstrates the clinical and laboratory signs that suggest metal hypersensitivity in total knee arthroplasty and the potential for joint function restoration with revision surgery.

  15. Gastric hypersensitivity induced by oesophageal acid infusion in healthy volunteers.

    PubMed

    van den Elzen, B D J; Tytgat, G N J; Boeckxstaens, G E E

    2009-02-01

    Distal oesophageal acid exposure has been shown to increase visceral sensitivity of the proximal oesophagus via central sensitization. Here we evaluated whether acidification of the distal oesophagus also affects the sensorimotor function of the proximal stomach. A gastric barostat study combined with a 30-min acid (HCl 0.15 mol L(-1)) or saline infusion in the distal oesophagus was performed in 18 healthy volunteers. Gastric and cutaneous sensitivity was assessed before and up to 2 h after the start of infusion. Directly after acid infusion, but not after saline, the threshold for discomfort decreased (-6.4 +/- 1.7 vs 0.4 +/- 0.4 mmHg; P = 0.028) and distension-induced symptoms increased significantly compared with the baseline (122 +/- 49% vs -3 +/- 9%). Cutaneous sensitivity remained unaffected by acid infusion. In contrast, when the infused liquid was aspirated 3 cm more distally, at the level of the lower oesophageal sphincter, the effect of acid infusion on gastric sensitivity was abolished and the increase in distension-induced symptoms was reduced (61 +/- 24%). Distal oesophageal acid infusion induces visceral hypersensitivity without affecting somatic sensitivity arguing against a similar mechanism of central sensitization as observed in non-cardiac chest pain. As reduction of the acid load to the stomach prevented this effect, our findings indicate that either gastric and/or duodenal acidification is involved. It should be emphasized though that aspiration from distal oesophagus may have attenuated the effect by reducing the acid-exposed area or by reducing the contact time.

  16. Reversal of peripheral nerve injury-induced hypersensitivity in the postpartum period: role of spinal oxytocin.

    PubMed

    Gutierrez, Silvia; Liu, Baogang; Hayashida, Ken-ichiro; Houle, Timothy T; Eisenach, James C

    2013-01-01

    Physical injury, including surgery, can result in chronic pain; yet chronic pain following childbirth, including cesarean delivery in women, is rare. The mechanisms involved in this protection by pregnancy or delivery have not been explored. We examined the effect of pregnancy and delivery on hypersensitivity to mechanical stimuli of the rat hindpaw induced by peripheral nerve injury (spinal nerve ligation) and after intrathecal oxytocin, atosiban, and naloxone. Additionally, oxytocin concentration in lumbar spinal cerebrospinal fluid was determined. Spinal nerve ligation performed at mid-pregnancy resulted in similar hypersensitivity to nonpregnant controls, but hypersensitivity partially resolved beginning after delivery. Removal of pups after delivery prevented this partial resolution. Cerebrospinal fluid concentrations of oxytocin were greater in normal postpartum rats prior to weaning. To examine the effect of injury at the time of delivery rather than during pregnancy, spinal nerve ligation was performed within 24 h of delivery. This resulted in acute hypersensitivity that partially resolved over the next 2-3 weeks. Weaning of pups resulted only in a temporary return of hypersensitivity. Intrathecal oxytocin effectively reversed the hypersensitivity following separation of the pups. Postpartum resolution of hypersensitivity was transiently abolished by intrathecal injection of the oxytocin receptor antagonist, atosiban. These results suggest that the postpartum period rather than pregnancy protects against chronic hypersensitivity from peripheral nerve injury and that this protection may reflect sustained oxytocin signaling in the central nervous system during this period.

  17. Drug hypersensitivity.

    PubMed

    Yawalkar, N

    2009-01-01

    Drug hypersensitivity represents an immune-mediated reaction to a drug. Although several drug hypersensitivity reactions are confined to the skin and rather mild, some may be life threatening and also involve further organs such as liver, kidney and bone marrow. The exact pathogenesis of many drug hypersensitivity reactions is still obscure. In this review the concepts on how small molecular drugs can activate the immune system are discussed and the hapten, prohapten and p-i concept are explained. Furthermore, the classification of drug hypersensitivity reactions and some common and severe clinical manifestations of drug-induced T cell mediated reactions are presented.

  18. Stachybotrys chartarum-Induced Hypersensitivity Pneumonitis Is TLR9 Dependent

    PubMed Central

    Bhan, Urvashi; Newstead, Michael J.; Zeng, Xianying; Ballinger, Megan N.; Standiford, Louis R.; Standiford, Theodore J.

    2011-01-01

    Hypersensitivity pneumonitis (HP), an inflammatory lung disease, develops after repeated exposure to inhaled particulate antigen and is characterized by a vigorous T helper type 1-mediated immune response, resulting in the release of IL-12 and interferon (IFN)-γ. These T helper type 1 cytokines may participate in the pathogenesis of HP. Stachybotrys chartarum (SC) is a dimorphic fungus implicated in a number of respiratory illnesses, including HP. Here, we have developed a murine model of SC-induced HP that reproduces pathology observed in human HP and hypothesized that toll receptor-like 9 (TLR9)-mediated dendritic cell responses are required for the generation of granulomatous inflammation induced by inhaled SC. Mice sensitized and challenged with 106 SC spores develop granulomatous inflammation with multinucleate giant cells, accompanied by increased accumulation of neutrophils and CD4+ and CD8+ T cells. SC sensitization and challenge resulted in robust pulmonary expression of tumor necrosis factor-α, IL-12, and IFN-γ. SC-mediated granulomatous inflammation required IFN-γ and was TLR9 dependent, because TLR9−/− mice displayed reduced peribronchial inflammation, decreased accumulation and/or activation of polymorphonuclear (PMN) and CD4+ and CD8+ T cells, and reduced lung expression of type 1 cytokines and chemokines. T-cell production of IFN-γ was IL-12 dependent. Our studies suggest that TLR9 is critical for dendritic cell-mediated development of a type 1 granulomatous inflammation in the lung in response to SC. PMID:21982832

  19. Stachybotrys chartarum-induced hypersensitivity pneumonitis is TLR9 dependent.

    PubMed

    Bhan, Urvashi; Newstead, Michael J; Zeng, Xianying; Ballinger, Megan N; Standiford, Louis R; Standiford, Theodore J

    2011-12-01

    Hypersensitivity pneumonitis (HP), an inflammatory lung disease, develops after repeated exposure to inhaled particulate antigen and is characterized by a vigorous T helper type 1-mediated immune response, resulting in the release of IL-12 and interferon (IFN)-γ. These T helper type 1 cytokines may participate in the pathogenesis of HP. Stachybotrys chartarum (SC) is a dimorphic fungus implicated in a number of respiratory illnesses, including HP. Here, we have developed a murine model of SC-induced HP that reproduces pathology observed in human HP and hypothesized that toll receptor-like 9 (TLR9)-mediated dendritic cell responses are required for the generation of granulomatous inflammation induced by inhaled SC. Mice sensitized and challenged with 10(6) SC spores develop granulomatous inflammation with multinucleate giant cells, accompanied by increased accumulation of neutrophils and CD4(+) and CD8(+) T cells. SC sensitization and challenge resulted in robust pulmonary expression of tumor necrosis factor-α, IL-12, and IFN-γ. SC-mediated granulomatous inflammation required IFN-γ and was TLR9 dependent, because TLR9(-/-) mice displayed reduced peribronchial inflammation, decreased accumulation and/or activation of polymorphonuclear (PMN) and CD4(+) and CD8(+) T cells, and reduced lung expression of type 1 cytokines and chemokines. T-cell production of IFN-γ was IL-12 dependent. Our studies suggest that TLR9 is critical for dendritic cell-mediated development of a type 1 granulomatous inflammation in the lung in response to SC. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  20. Pharmacological attenuation of chronic alcoholic pancreatitis induced hypersensitivity in rats

    PubMed Central

    McIlwrath, Sabrina L; Westlund, Karin N

    2015-01-01

    AIM: To characterize an alcohol and high fat diet induced chronic pancreatitis rat model that mimics poor human dietary choices. METHODS: Experimental rats were fed a modified Lieber-DeCarli alcohol (6%) and high-fat (65%) diet (AHF) for 10 wk while control animals received a regular rodent chow diet. Weekly behavioral tests determined mechanical and heat sensitivity. In week 10 a fasting glucose tolerance test was performed, measuring blood glucose levels before and after a 2 g/kg bodyweight intraperitoneal (i.p.) injection of glucose. Post mortem histological analysis was performed by staining pancreas and liver tissue sections with hematoxylin and eosin. Pancreas sections were also stained with Sirius red and fast green to quantify collagen content. Insulin-expressing cells were identified immunohistochemically in separate sections. Tissue staining density was quantified using Image J software. After mechanical and heat sensitivity became stable (weeks 6-10) in the AHF-fed animals, three different drugs were tested for their efficacy in attenuating pancreatitis associated hypersensitivity: a Group II metabotropic glutamate receptor specific agonist (2R,4R)-4-Aminopyrrolidine-2,4-dicarboxylate (APDC, 3 mg/kg, ip; Tocris, Bristol, United Kingdom), nociceptin (20, 60, 200 nmol/kg, ip; Tocris), and morphine sulfate (3 mg/kg, μ-opioid receptor agonist; Baxter Healthcare, Deerfield, IL, United States). RESULTS: Histological analysis of pancreas and liver determined that unlike control rats, AHF fed animals had pancreatic fibrosis, acinar and beta cell atrophy, with steatosis in both organs. Fat vacuolization was significantly increased in AHF fed rats (6.4% ± 1.1% in controls vs 23.8% ± 4.2%, P < 0.05). Rats fed the AHF diet had reduced fasting glucose tolerance in week 10 when peak blood glucose levels reached significantly higher concentrations than controls (127.4 ± 9.2 mg/dL in controls vs 161.0 ± 8.6 mg/dL, P < 0.05). This concurred with a 3.5 fold higher

  1. Hypersensitivity to proton pump inhibitors: lansoprazole-induced Kounis syndrome.

    PubMed

    Vlahos, Nicholas P; Vavilis, George K; Giannelou, Ageliki G; Georgopoulou, Christina N; Kommata, Varvara J; Kougias, Constantinos T; Tsartsalis, Dimitrios N; Kounis, George N; Mazarakis, Andreas; Batsolaki, Maria; Gouvelou-Deligianni, Geogia V; Hahalis, George; Kounis, Nicholas G

    2009-05-29

    Proton pump inhibitors are commonly used in clinical practice for the treatment of peptic ulcer and gastroesophageal reflux and are well tolerated by the patients. Their use is rarely associated with hypersensitivity and anaphylactic reactions. According to the reports in the Uppsala Monitoring Center database the frequency of hypersensitivity reactions out of all reported adverse reactions for proton pump inhibitors and H2-histamine receptor antagonists was between 0.2% and 0.7%. A few cases of hypersensitivity to lansoprazole have been reported. We report a patient who developed Kounis syndrome after taking 30 mg of lansoprazole. This is the first report of Kounis syndrome associated with lansoprazole administration in the world literature.

  2. FcγRIIa ligation induces platelet hypersensitivity to thrombotic stimuli.

    PubMed

    Berlacher, Mark D; Vieth, Joshua A; Heflin, Brittany C; Gay, Steven R; Antczak, Adam J; Tasma, Brian E; Boardman, Holly J; Singh, Navinderjit; Montel, Angela H; Kahaleh, M Bashar; Worth, Randall G

    2013-01-01

    Platelets are known for their important role in hemostasis, however their significance in other functions, including inflammation and infection, are becoming more apparent. Patients with systemic lupus erythematosus (SLE) are known to have circulating IgG complexes in their blood and are highly susceptible to thrombotic events. Because platelets express a single receptor for IgG, we tested the hypothesis that ligation of this receptor (FcγRIIa) induces platelet hypersensitivity to thrombotic stimuli. Platelets from SLE patients were considerably more sensitive to thrombin compared to healthy volunteers, and this correlated with elevated levels of surface IgG on SLE platelets. To test whether FcγRIIa ligation stimulated thrombin hypersensitivity, platelets from healthy volunteers were incubated with buffer or heat-aggregated IgG, then stimulated with increasing concentrations of thrombin. Interestingly, heat-aggregated IgG-stimulated platelets, but not buffer-treated platelets, were hypersensitive to thrombin, and hypersensitivity was blocked by an anti-FcγRIIa monoclonal antibody (mAb). Thrombin hypersensitivity was not due to changes in thrombin receptor expression (GPIbα or PAR1) but is dependent on activation of shared signaling molecules. These observations suggest that ligation of platelet FcγRIIa by IgG complexes induces a hypersensitive state whereby small changes in thrombotic stimuli may result in platelet activation and subsequent vascular complications such as transient ischemic attacks or stroke.

  3. Aminophylline suppresses stress-induced visceral hypersensitivity and defecation in irritable bowel syndrome

    PubMed Central

    Asano, Teita; Tanaka, Ken-ichiro; Tada, Arisa; Shimamura, Hikaru; Tanaka, Rikako; Maruoka, Hiroki; Takenaga, Mitsuko; Mizushima, Tohru

    2017-01-01

    Pharmacological therapy for irritable bowel syndrome (IBS) has not been established. In order to find candidate drugs for IBS with diarrhea (IBS-D), we screened a compound library of drugs clinically used for their ability to prevent stress-induced defecation and visceral hypersensitivity in rats. We selected the bronchodilator aminophylline from this library. Using a specific inhibitor for each subtype of adenosine receptors (ARs) and phosphodiesterases (PDEs), we found that both A2BARs and PDE4 are probably mediated the inhibitory effect of aminophylline on wrap restraint stress (WRS)-induced defecation. Aminophylline suppressed maternal separation- and acetic acid administration-induced visceral hypersensitivity to colorectal distension (CRD), which was mediated by both A2AARs and A2BARs. We propose that aminophylline is a candidate drug for IBS-D because of its efficacy in both of stress-induced defecation and visceral hypersensitivity, as we observed here, and because it is clinically safe. PMID:28054654

  4. Ulcerative colitis flair induced by mesalamine suppositories hypersensitivity.

    PubMed

    Ding, Hao; Liu, Xiao-Chang; Mei, Qiao; Xu, Jian-Ming; Hu, Xiang-Yang; Hu, Jing

    2014-04-07

    Mesalamine suppositories have been used widely for the treatment of distal ulcerative colitis and considered to be safer than systemic administration for its limited systemic absorption. However, previous studies have shown that mesalamine suppository occasionally causes severe hypersensitivity reactions including fever, rashes, colitis exacerbation and acute eosinophilic pneumonia. Here we present a 25-year-old woman with ulcerative colitis with bloody diarrhea accompanied by abdominal pain and fever which were aggravated after introduction of mesalamine suppositories. In light of symptom exacerbation of ulcerative colitis, increased inflammatory injury of colon mucosa shown by colonoscopy and elevated peripheral eosinophil count after mesalamine suppositories administration, and the Naranjo algorithm score of 10, the possibility of hypersensitivity reaction to mesalamine suppositories should be considered, warning us to be aware of this potential reaction after administration of mesalamine formulations even if it is the suppositories.

  5. Ulcerative colitis flair induced by mesalamine suppositories hypersensitivity

    PubMed Central

    Ding, Hao; Liu, Xiao-Chang; Mei, Qiao; Xu, Jian-Ming; Hu, Xiang-Yang; Hu, Jing

    2014-01-01

    Mesalamine suppositories have been used widely for the treatment of distal ulcerative colitis and considered to be safer than systemic administration for its limited systemic absorption. However, previous studies have shown that mesalamine suppository occasionally causes severe hypersensitivity reactions including fever, rashes, colitis exacerbation and acute eosinophilic pneumonia. Here we present a 25-year-old woman with ulcerative colitis with bloody diarrhea accompanied by abdominal pain and fever which were aggravated after introduction of mesalamine suppositories. In light of symptom exacerbation of ulcerative colitis, increased inflammatory injury of colon mucosa shown by colonoscopy and elevated peripheral eosinophil count after mesalamine suppositories administration, and the Naranjo algorithm score of 10, the possibility of hypersensitivity reaction to mesalamine suppositories should be considered, warning us to be aware of this potential reaction after administration of mesalamine formulations even if it is the suppositories. PMID:24707159

  6. Antibiotic hypersensitivity in CF: drug-induced life-threatening hemolytic anemia in a pediatric patient.

    PubMed

    Chavez, Alma; Mian, Amir; Scurlock, Amy M; Blackall, Douglas; Com, Gulnur

    2010-12-01

    Adverse reactions to antibiotics in patients with cystic fibrosis (CF) are a growing concern. We report the case of a pediatric patient with CF with multiple comorbidities and a history of drug reactions, who developed life-threatening piperacillin-induced immune hemolytic anemia. We review drug-induced hemolytic anemia (DIIHA) in particular, and antibiotic hypersensitivity in CF in general, including the frequency, pathogenesis, and risk factors. Finally, we discuss the treatment options and propose an algorithm for the management of drug-induced hypersensitivity reactions in patients with CF.

  7. Genetics Home Reference: cold-induced sweating syndrome

    MedlinePlus

    ... Health Conditions cold-induced sweating syndrome cold-induced sweating syndrome Enable Javascript to view the expand/collapse ... PDF Open All Close All Description Cold-induced sweating syndrome is characterized by problems with regulating body ...

  8. Visceral and somatic hypersensitivity in TNBS-induced colitis in rats.

    PubMed

    Zhou, QiQi; Price, Donald D; Caudle, Robert M; Verne, G Nicholas

    2008-02-01

    Inflammation of visceral structures in rats has been shown to produce visceral/somatic hyperalgesia. Our objectives were to determine if trinitrobenzene sulfonic acid (TNBS) induced colitis in rats leads to visceral/somatic hypersensitivity. Male Sprague-Dawley rats (200-250 g) were treated with 20 mg of TNBS in 50% ethanol (n = 40) or an equivalent volume of ethanol (n = 40) or saline (n = 25) via the colon. Colonic distension, Von Frey, Hargreaves, and tail reflex tests were used to evaluate for visceral, mechanical, and thermal sensitivity. The rats demonstrated visceral hypersensitivity at 2-28 days following TNBS administration (P < 0.0001). The ethanol-treated rats also demonstrated visceral hypersensitivity that resolved after day 14. TNBS-treated rats demonstrated somatic hypersensitivity at days 14-28 (P < 0.0001) in response to somatic stimuli of the hind paw. TNBS colitis is associated with visceral and somatic hypersensitivity in areas of somatotopic overlap. This model of colitis should allow further investigation into the mechanisms of visceral and somatic hypersensitivity.

  9. Development and pharmacological characterization of a model of sleep disruption-induced hypersensitivity in the rat.

    PubMed

    Wodarski, R; Schuh-Hofer, S; Yurek, D A; Wafford, K A; Gilmour, G; Treede, R-D; Kennedy, J D

    2015-04-01

    Sleep disturbance is a commonly reported co-morbidity in chronic pain patients, and conversely, disruption of sleep can cause acute and long-lasting hypersensitivity to painful stimuli. The underlying mechanisms of sleep disruption-induced pain hypersensitivity are poorly understood. Confounding factors of previous studies have been the sleep disruption protocols, such as the 'pedestal over water' or 'inverted flower pot' methods, that can cause large stress responses and therefore may significantly affect pain outcome measures. Sleep disruption was induced by placing rats for 8 h in a slowly rotating cylindrical cage causing arousal via the righting reflex. Mechanical (Von Frey filaments) and thermal (Hargreaves) nociceptive thresholds were assessed, and plasma corticosterone levels were measured (mass spectroscopy). Sleep disruption-induced hypersensitivity was pharmacologically characterized with drugs relevant for pain treatment, including gabapentin (30 mg/kg and 50 mg/kg), Ica-6p (Kv7.2/7.3 potassium channel opener; 10 mg/kg), ibuprofen (30 mg/kg and 100 mg/kg) and amitriptyline (10 mg/kg). Eight hours of sleep disruption caused robust mechanical and heat hypersensitivity in the absence of a measurable change in plasma corticosterone levels. Gabapentin had no effect on reduced nociceptive thresholds. Ibuprofen attenuated mechanical thresholds, while Ica-6p and amitriptyline attenuated only reduced thermal nociceptive thresholds. These results show that acute and low-stress sleep disruption causes mechanical and heat hypersensitivity in rats. Mechanical and heat hypersensitivity exhibited differential sensitivity to pharmacological agents, thus suggesting dissociable mechanisms for those two modalities. Ultimately, this model could help identify underlying mechanisms linking sleep disruption and hypersensitivity. © 2014 European Pain Federation - EFIC®

  10. Colonic mast cell infiltration in rats with TNBS-induced visceral hypersensitivity.

    PubMed

    Ohashi, Katsuyo; Sato, Yasushi; Iwata, Hiroshi; Kawai, Mitsuhisa; Kurebayashi, Yoichi

    2007-12-01

    Colonic mucosal mast cells are implicated in the pathogenesis of visceral hypersensitivity associated with irritable bowel syndromes. This study was designed to investigate the roles of mucosal mast cells in development of an experimental visceral hypersensitivity induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in rats. TNBS, when injected into the proximal colon through laparotomy, produced a significant decrease in pain threshold of the distal colon to mechanical distention, indicating a visceral hypersensitivity. In the proximal colon that was directly insulted by TNBS, mucosal necrosis and extensive inflammatory cell infiltration were observed with concomitant increase in tissue myeloperoxide (MPO) activity. In the distal colon where distention stimuli were applied, the number of mucosal mast cells significantly increased following TNBS treatment, although neither mucosal injury nor increase in tissue MPO activity was observed. In an organ culture, spontaneous release of a mucosal mast cell-specific protease (RMCP-2) from the distal colon tissue of TNBS-treated rats was significantly larger than that of sham animals. Furthermore, TNBS-induced visceral hypersensitivity was significantly suppressed by subcutaneous pretreatment with a mast cell stabilizer doxantrazole in a dose-dependent manner. These findings suggest that prominent colonic mast cell infiltration associated with an enhanced spontaneous mediator release is responsible, at least partly, for development of visceral hypersensitivity induced by TNBS in rats.

  11. Unusual formaldehyde-induced hypersensitivity in two schoolgirls

    SciTech Connect

    Gammage, R.B. ); Hanna, W.T.; Painter, P.B. )

    1990-01-01

    Two schoolgirls developed a syndrome resembling Henoch-Schonlein purpura while attending a recently opened school insulated with urea-formaldehyde foam (UFFI). Skin rashes and swellings were accompanied by bizarre, blue-green discoloration of the skin. Subsequent investigations by county, state and federal authorities, and low measured concentrations of formaldehyde, prompted initial conclusions that in-school formaldehyde exposures were not responsible for the girls' problems. Subsequent controlled exposures to UFFI and formaldehyde while in hospital elicited the whole cascade of symptoms. The chronology of the onset and amplification of systems make it probable that the formaldehyde exposures precipitating the girls' hypersensitivity, occurred in the school. 3 refs.

  12. HLA-A★3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans

    PubMed Central

    McCormack, Mark; Alfirevic, Ana; Bourgeois, Stephane; Farrell, John J.; Kasperavičiūtė, Dalia; Carrington, Mary; Sills, Graeme J.; Marson, Tony; Jia, Xiaoming; de Bakker, Paul I.W.; Chinthapalli, Krishna; Molokhia, Mariam; Johnson, Michael R.; O’Connor, Gerard D.; Chaila, Elijah; Alhusaini, Saud; Shianna, Kevin V.; Radtke, Rodney A.; Heinzen, Erin L.; Walley, Nicole; Pandolfo, Massimo; Pichler, Werner; Park, B. Kevin; Depondt, Chantal; Sisodiya, Sanjay M.; Goldstein, David B.; Deloukas, Panos; Delanty, Norman; Cavalleri, Gianpiero L.; Pirmohamed, Munir

    2011-01-01

    BACKGROUND Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B★1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS–TEN) in the Han Chinese and other Asian populations but not in European populations. METHODS We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. RESULTS The HLA-A★3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P = 3.5×10−8). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A★3101 allele (P = 1.1×10−6). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS–TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). CONCLUSIONS The presence of the HLA-A★3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.) PMID:21428769

  13. Effects of Vibration Therapy on Immobilization-Induced Hypersensitivity in Rats.

    PubMed

    Hamaue, Yohei; Nakano, Jiro; Sekino, Yuki; Chuganji, Sayaka; Sakamoto, Junya; Yoshimura, Toshiro; Okita, Minoru; Origuchi, Tomoki

    2015-07-01

    Cast immobilization induces mechanical hypersensitivity, which disturbs rehabilitation. Although vibration therapy can reduce various types of pain, whether vibration reduces immobilization-induced hypersensitivity remains unclear. The purpose of this study was to investigate the preventive and therapeutic effects of vibration therapy on immobilization-induced hypersensitivity. The experimental design of the study involved conducting behavioral, histological, and immunohistochemical studies in model rats. Thirty-five Wistar rats (8 weeks old, all male) were used. The right ankle joints of 30 rats were immobilized by plaster cast for 8 weeks, and 5 rats were used as controls. The immobilized rats were divided randomly into the following 3 groups: (1) immobilization-only group (Im, n=10); (2) vibration therapy group 1, for which vibration therapy was initiated immediately after the onset of immobilization (Im+Vib1, n=10); and (3) vibration therapy group 2, for which vibration therapy was initiated 4 weeks after the onset of immobilization (Im+Vib2, n=10). Vibration was applied to the hind paw. The mechanical hypersensitivity and epidermal thickness of the hind paw skin were measured. To investigate central sensitization, calcitonin gene-related peptide (CGRP) expression in the spinal cord and dorsal root ganglion (DRG) was analyzed. Immobilization-induced hypersensitivity was inhibited in the Im+Vib1 group but not in the Im+Vib2 group. Central sensitization, which was indicated by increases in CGRP expression in the spinal cord and the size of the area of CGRP-positive neurons in the DRG, was inhibited in only the Im+Vib1 group. Epidermal thickness was not affected by vibration stimulation. A limitation of this study is that the results were limited to an animal model and cannot be generalized to humans. The data suggest that initiation of vibration therapy in the early phase of immobilization may inhibit the development of immobilization-induced hypersensitivity.

  14. Drug-induced hypersensitivity reactions and pharmacogenomics: past, present and future.

    PubMed

    Alfirevic, Ana; Pirmohamed, Munir

    2010-04-01

    Drug-induced hypersensitivity reactions represent a major concern for clinicians, patients, regulators and drug developers. Severe hypersensitivity is associated with high morbidity and mortality, it cannot be predicted from the known pharmacology of the drug and it is usually detected post-marketing when a large number of patients have been exposed to a particular drug. Recent success in developing clinically useful genetic tests that have allowed us to predict the risk of abacavir-induced hypersensitivity has helped to pave the path for a pharmacogenetic approach. However, the loop from identifying a genetic association to improving clinical outcome is still lacking for many drugs. In this commentary, we discuss the progress of hypersensitivity pharmacogenomics over the last decade and point out what remains to be done in the future. The current efforts of the international community are focused on the development of consortia, which aim to standardize disease phenotypes, but also to collect larger numbers of well-phenotyped patients and to pool biological samples through these collaborations. In addition, it is necessary to advance our knowledge of hypersensitivity mechanisms through functional studies, which will lead to the development of predictive and diagnostic tests.

  15. Evidence for reactivation of human herpesvirus 6 in generalized lymphadenopathy in a patient with drug-induced hypersensitivity syndrome.

    PubMed

    Saraya, Takeshi; Mikoshiba, Michiaki; Kamiyama, Harumi; Yoshizumi, Masakazu; Tsuchida, Shigeru; Tsukagoshi, Hiroyuki; Ishioka, Taisei; Terada, Miho; Tanabe, Eiichi; Tomioka, Chizuko; Ishii, Haruyuki; Kimura, Hirokazu; Kozawa, Kunihisa; Shiohara, Tetsuo; Takizawa, Hajime; Goto, Hajime

    2013-06-01

    The present case provides direct evidence of human herpesvirus 6 reactivation in resected lymph node tissue in a patient with drug-induced hypersensitivity syndrome. This case clearly demonstrates that appropriate pathological evaluation of lymphadenopathy for drug-induced hypersensitivity syndrome, which mimics malignant lymphoma in clinical, radiological, and pathological findings, is required.

  16. Fanconi anemia complementation group A cells are hypersensitive to chromium(VI)-induced toxicity.

    PubMed Central

    Vilcheck, Susan K; O'Brien, Travis J; Pritchard, Daryl E; Ha, Linan; Ceryak, Susan; Fornsaglio, Jamie L; Patierno, Steven R

    2002-01-01

    Fanconi anemia (FA) is an autosomal recessive disorder characterized by diverse developmental abnormalities, progressive bone marrow failure, and a markedly increased incidence of malignancy. FA cells are hypersensitive to DNA cross-linking agents, suggesting a general defect in the repair of DNA cross-links. Some forms of hexavalent chromium [Cr(VI)] are implicated as respiratory carcinogens and induce several types of DNA lesions, including ternary DNA-Cr-DNA interstrand cross-links (Cr-DDC). We hypothesized that human FA complementation group A (FA-A) cells would be hypersensitive to Cr(VI) and Cr(VI)-induced apoptosis. Using phosphatidylserine translocation and caspase-3 activation, human FA-A fibroblasts were found to be markedly hypersensitive to chromium-induced apoptosis compared with CRL-1634 cells, which are normal human foreskin fibroblasts (CRL). The clonogenicity of FA-A cells was also significantly decreased compared with CRL cells after Cr(VI) treatment. There was no significant difference in either Cr(VI) uptake or Cr-DNA adduct formation between FA-A and CRL cells. These results show that FA-A cells are hypersensitive to Cr(VI) and Cr-induced apoptosis and that this hypersensitivity is not due to increased Cr(VI) uptake or increased Cr-DNA adduct formation. The results also suggest that Cr-DDC may be proapoptotic lesions. These results are the first to show that FA cells are hypersensitive to an environmentally relevant DNA cross-linking agent. PMID:12426130

  17. Altered colorectal afferent function associated with TNBS-induced visceral hypersensitivity in mice.

    PubMed

    Feng, Bin; La, Jun-Ho; Tanaka, Takahiro; Schwartz, Erica S; McMurray, Timothy P; Gebhart, G F

    2012-10-01

    Inflammation of the distal bowel is often associated with abdominal pain and hypersensitivity, but whether and which colorectal afferents contribute to the hypersensitivity is unknown. Using a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, we investigated colorectal hypersensitivity following intracolonic TNBS and associated changes in colorectum and afferent functions. C57BL/6 mice were treated intracolonically with TNBS or saline. Visceromotor responses to colorectal distension (15-60 mmHg) were recorded over 8 wk in TNBS- and saline-treated (control) mice. In other mice treated with TNBS or saline, colorectal inflammation was assessed by myeloperoxidase assay and immunohistological staining. In vitro single-fiber recordings were conducted on both TNBS and saline-treated mice to assess colorectal afferent function. Mice exhibited significant colorectal hypersensitivity through day 14 after TNBS treatment that resolved by day 28 with no resensitization through day 56. TNBS induced a neutrophil- and macrophage-based colorectal inflammation as well as loss of nerve fibers, all of which resolved by days 14-28. Single-fiber recordings revealed a net increase in afferent drive from stretch-sensitive colorectal afferents at day 14 post-TNBS and reduced proportions of mechanically insensitive afferents (MIAs) at days 14-28. Intracolonic TNBS-induced colorectal inflammation was associated with the development and recovery of hypersensitivity in mice, which correlated with a transient increase and recovery of sensitization of stretch-sensitive colorectal afferents and MIAs. These results indicate that the development and maintenance of colorectal hypersensitivity following inflammation are mediated by peripheral drive from stretch-sensitive colorectal afferents and a potential contribution from MIAs.

  18. Adrenergic β2-receptors mediates visceral hypersensitivity induced by heterotypic intermittent stress in rats.

    PubMed

    Zhang, Chunhua; Rui, Yun-Yun; Zhou, Yuan-Yuan; Ju, Zhong; Zhang, Hong-Hong; Hu, Chuang-Ying; Xiao, Ying; Xu, Guang-Yin

    2014-01-01

    Chronic visceral pain in patients with irritable bowel syndrome (IBS) has been difficult to treat effectively partially because its pathophysiology is not fully understood. Recent studies show that norepinephrine (NE) plays an important role in the development of visceral hypersensitivity. In this study, we designed to investigate the role of adrenergic signaling in visceral hypersensitivity induced by heterotypical intermittent stress (HIS). Abdominal withdrawal reflex scores (AWRs) used as visceral sensitivity were determined by measuring the visceromoter responses to colorectal distension. Colon-specific dorsal root ganglia neurons (DRGs) were labeled by injection of DiI into the colon wall and were acutely dissociated for whole-cell patch-clamp recordings. Blood plasma level of NE was measured using radioimmunoassay kits. The expression of β2-adrenoceptors was measured by western blotting. We showed that HIS-induced visceral hypersensitivity was attenuated by systemic administration of a β-adrenoceptor antagonist propranolol, in a dose-dependent manner, but not by a α-adrenoceptor antagonist phentolamine. Using specific β-adrenoceptor antagonists, HIS-induced visceral hypersensitivity was alleviated by β2 adrenoceptor antagonist but not by β1- or β3-adrenoceptor antagonist. Administration of a selective β2-adrenoceptor antagonist also normalized hyperexcitability of colon-innervating DRG neurons of HIS rats. Furthermore, administration of β-adrenoceptor antagonist suppressed sustained potassium current density (IK) without any alteration of fast-inactivating potassium current density (IA). Conversely, administration of NE enhanced the neuronal excitability and produced visceral hypersensitivity in healthy control rats, and blocked by β2-adrenoceptor antagonists. In addition, HIS significantly enhanced the NE concentration in the blood plasma but did not change the expression of β2-adrenoceptor in DRGs and the muscularis externa of the colon. The

  19. Abolishment of TNBS-induced visceral hypersensitivity in mast cell deficient rats.

    PubMed

    Ohashi, Katsuyo; Sato, Yasushi; Kawai, Mitsuhisa; Kurebayashi, Yoichi

    2008-02-13

    Mucosal mast cells are implicated in visceral hypersensitivity associated with irritable bowel syndrome (IBS). In this study, we investigated the role of mast cells in the development of visceral hypersensitivity by using mast cell deficient (Ws/Ws) rats and their control (W+/W+). In W+/W+ rats, an injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the proximal colon produced a significant decrease in pain threshold of the distal colon. Severe mucosal necrosis and inflammatory cell infiltration with concomitant increase in tissue myeloperoxidase activity were observed in the proximal colon that was directly insulted by TNBS, whereas neither necrosis nor increased myeloperoxidase activity occurred in the distal colon, indicating that TNBS-induced hypersensitivity is not caused by the local tissue damage or inflammation in the region of the gut where distention stimuli were applied. On the other hand, TNBS failed to elicit visceral hypersensitivity in Ws/Ws rats. This finding indicates that mast cells are essential for development of TNBS-induced visceral hypersensitivity in rats. Since the severity of TNBS-induced proximal colon injury and MPO activity was not affected by mast cell deficiency, it is unlikely that abolishment of visceral hypersensitivity in mast cell deficient rats was a result of altered development of the primary injury in the proximal colon. There was no difference between sham-operated Ws/Ws and W+/W+ rats in colonic pain threshold to distention stimuli, indicating that mast cells play no modulatory roles in normal colonic nociception. The present results support the view that mucosal mast cells play key roles in the pathogenesis of IBS.

  20. Hypersensitivity pneumonitis induced by Penicillium expansum in a home environment.

    PubMed

    Park, H S; Jung, K S; Kim, S O; Kim, S J

    1994-04-01

    An episode of fever, cough, shortness of breath and leucocytosis developed in a 31-year-old atopic housewife from mould exposure in her home environment is evaluated. A chest radiograph revealed diffuse tiny nodular infiltrations in both whole lung fields. Spirometry revealed a severe restrictive type of ventilation impairment. Bronchoalveolar lavage (BAL) showed an increased lymphocyte count with reversed CD4+/CD8+ ratio and transbronchial lung biopsy showed markedly increased lymphocytic infiltration in alveolar septa. Fungal cultures in the air of her home were positive for Penicillium expansum and other fungi. Double immunodiffusion test with the patient's serum showed two precipitin bands to P. expansum antigens. Her symptoms, abnormal findings of radiograph, and spirometric abnormalities disappeared after 2 months' avoidance. The serum precipitin disappeared after 1 month's avoidance. This study indicates that the patient had hypersensitivity pneumonitis (HP) on exposure to P. expansum in her home environment.

  1. Persistent Skin Reactions and Aluminium Hypersensitivity Induced by Childhood Vaccines.

    PubMed

    Salik, Elaha; Løvik, Ida; Andersen, Klaus E; Bygum, Anette

    2016-11-02

    There is increasing awareness of reactions to vaccination that include persistent skin reactions. We present here a retrospective investigation of long-lasting skin reactions and aluminium hypersensitivity in children, based on medical records and questionnaires sent to the parents. In the 10-year period 2003 to 2013 we identified 47 children with persistent skin reactions caused by childhood vaccinations. Most patients had a typical presentation of persisting pruritic subcutaneous nodules. Five children had a complex diagnostic process involving paediatricians, orthopaedics and plastic surgeons. Two patients had skin biopsies performed from their skin lesions, and 2 patients had the nodules surgically removed. Forty-two children had a patch-test performed with 2% aluminium chloride hexahydrate in petrolatum and 39 of them (92%) had a positive reaction. The persistent skin reactions were treated with potent topical corticosteroids and disappeared slowly. Although we advised families to continue vaccination of their children, one-third of parents omitted or postponed further vaccinations.

  2. DIESEL AND CARBON PARTICLES ENHANCE HOUSE DUST MITE-INDUCED PULMONARY HYPERSENSITIVITY IN BROWN NORWAY RATS

    EPA Science Inventory

    Diesel and Carbon Particles Enhance House Dust Mite-Induced Pulmonary Hypersensitivity in Brown Norway Rats. P. Singh1, M.J. Daniels2, D. Winsett2, J. Richards2, K. Crissman2, M. Madden2 and M.I. Gilmour2. 1NCSU, Raleigh, NC and 2 USEPA, Research Triangle Park, NC.

    Ep...

  3. DIESEL AND CARBON PARTICLES ENHANCE HOUSE DUST MITE-INDUCED PULMONARY HYPERSENSITIVITY IN BROWN NORWAY RATS

    EPA Science Inventory

    Diesel and Carbon Particles Enhance House Dust Mite-Induced Pulmonary Hypersensitivity in Brown Norway Rats. P. Singh1, M.J. Daniels2, D. Winsett2, J. Richards2, K. Crissman2, M. Madden2 and M.I. Gilmour2. 1NCSU, Raleigh, NC and 2 USEPA, Research Triangle Park, NC.

    Ep...

  4. Brain damage resembling acute necrotizing encephalopathy as a specific manifestation of haemophagocytic lymphohistiocytosis - induced by hypersensitivity.

    PubMed

    Dai, Dongling; Wen, Feiqiu; Liu, Sixi; Zhou, Shaoming

    2016-08-31

    Both haemophagocytic lymphohistiocytosis and acute necrotizing encephalopathy are life-threatening condition. It presents major diagnostic difficulties, since it may have a diversity in clinical picture and with many conditions leading to the same clinical presentation. So it is key important to understand the disorders. We report a pediatric case of haemophagocytic lymphohistiocytosis with specific presentation which predominantly featured as acute necrotizing encephalopathy of childhood. We discuss the diagnosis and differential diagnosis, and speculate the etiology of haemophagocytic lymphohistiocytosis is due to hypersensitivity. Haemophagocytic lymphohistiocytosis and brain damage in this case may be induced by hypersensitivity, which have good clinical outcome if diagnosed and treated early.

  5. Carbamazepine-induced anticonvulsant hypersensitivity syndrome--pathogenic and diagnostic considerations.

    PubMed

    Scerri, L; Shall, L; Zaki, I

    1993-11-01

    Two epileptic patients developed an infectious mononucleosis-like illness which subsequently proved to be a carbamazepine-induced anticonvulsant hypersensitivity syndrome. Patch testing to carbamazepine 3 years later was positive in the one patient tested and negative in normal controls. The second patient died a few weeks after the illness, secondary to long-standing cardiac disease without having undergone patch testing. A skin biopsy was, however, consistent with an immune complex mediated drug reaction. Patch testing for systemically administered drugs is generally believed to be of little value in diagnosing drug allergies. However, we reinforce a previous suggestion that this investigation may be helpful in some cases of anticonvulsant hypersensitivity syndrome caused by carbamazepine. The pathogenic role of type 3 and 4 hypersensitivity is also discussed.

  6. Opioid-induced latent sensitization in a model of non-inflammatory viscerosomatic hypersensitivity

    PubMed Central

    Lian, Bo; Vera-Portocarrero, Louis; King, Tamara; Ossipov, Michael H.; Porreca, Frank

    2014-01-01

    Exposure to opioids can induce a state of “latent sensitization” characterized by long-lasting enhanced responses to subsequent cutaneous injury. Here, we explored the possibility that prior treatment with morphine could induce a state of latent sensitization to visceral pain conditions. Following butyrate enemas to induce non-inflammatory visceral pain, acute morphine administration produced dose-related inhibition of referred viscerosomatic hypersensitivity. Treatment with morphine for a period of six days resulted in a persistent hyperalgesia that resolved many days after termination of drug administration. In morphine pre-exposed rats, butyrate-induced referred hypersensitivity was enhanced and extended in duration. No differences were observed in the morphine dose-response curve in suppression of acute nociception (i.e., the hot-plate assay) when morphine pre-exposed rats were compared to naïve rats indicating that opioid antinociceptive tolerance was not present. However, the morphine dose-response curve to suppress evoked viscerosomaticl hypersensitivity was displaced to the right by approximately 4-fold in morphine pre-exposed rats. Induction of viscerosomativ hypersensitivity resulted in an increased labeling of CGRP-, but not substance P-positive cells in the lumbar dorsal root ganglia; increased labeling was not affected by prior exposure to morphine. The data indicate that a period of morphine exposure can induce a state of “latent-sensitization” to subsequent visceral pain characterized by extended duration of hypersensitivity. This condition likely reflects enhanced visceral “pain” intensity as a consequence of persistent pronociceptive adaptive changes. PMID:20727859

  7. Electroacupuncture alleviates stress-induced visceral hypersensitivity through an opioid system in rats

    PubMed Central

    Zhou, Yuan-Yuan; Wanner, Natalie J; Xiao, Ying; Shi, Xuan-Zheng; Jiang, Xing-Hong; Gu, Jian-Guo; Xu, Guang-Yin

    2012-01-01

    AIM: To investigate whether stress-induced visceral hypersensitivity could be alleviated by electroacupuncture (EA) and whether EA effect was mediated by endogenous opiates. METHODS: Six to nine week-old male Sprague-Dawley rats were used in this study. Visceral hypersensitivity was induced by a 9-d heterotypic intermittent stress (HIS) protocol composed of 3 randomly stressors, which included cold restraint stress at 4 °C for 45 min, water avoidance stress for 60 min, and forced swimming stress for 20 min, in adult male rats. The extent of visceral hypersensitivity was quantified by electromyography or by abdominal withdrawal reflex (AWR) scores of colorectal distension at different distention pressures (20 mmHg, 40 mmHg, 60 mmHg and 80 mmHg). AWR scores either 0, 1, 2, 3 or 4 were obtained by a blinded observer. EA or sham EA was performed at classical acupoint ST-36 (Zu-San-Li) or BL-43 (Gao-Huang) in both hindlimbs of rats for 30 min. Naloxone (NLX) or NLX methiodide (m-NLX) was administered intraperitoneally to HIS rats in some experiments. RESULTS: HIS rats displayed an increased sensitivity to colorectal distention, which started from 6 h (the first measurement), maintained for 24 h, and AWR scores returned to basal levels at 48 h and 7 d after HIS compared to pre-HIS baseline at different distention pressures. The AWR scores before HIS were 0.6 ± 0.2, 1.3 ± 0.2, 1.9 ± 0.2 and 2.3 ± 0.2 for 20 mmHg, 40 mmHg, 60 mmHg and 80 mmHg distention pressures, respectively. Six hours after termination of the last stressor, the AWR scores were 2.0 ± 0.1, 2.5 ± 0.1, 2.8 ± 0.2 and 3.5 ± 0.2 for 20 mmHg, 40 mmHg, 60 mmHg and 80 mmHg distention pressures, respectively. EA given at classical acupoint ST-36 in both hindlimbs for 30 min significantly attenuated the hypersensitive responses to colorectal distention in HIS rats compared with sham EA treatment [AWRs at 20 mmHg: 2.0 ± 0.2 vs 0.7 ± 0.1, P = 4.23 711 E-4; AWRs at 40 mmHg: 2.6 ± 0.2 vs 1.5 ± 0.2, P

  8. Activated platelets release sphingosine 1-phosphate and induce hypersensitivity to noxious heat stimuli in vivo

    PubMed Central

    Weth, Daniela; Benetti, Camilla; Rauch, Caroline; Gstraunthaler, Gerhard; Schmidt, Helmut; Geisslinger, Gerd; Sabbadini, Roger; Proia, Richard L.; Kress, Michaela

    2015-01-01

    At the site of injury activated platelets release various mediators, one of which is sphingosine 1-phosphate (S1P). It was the aim of this study to explore whether activated human platelets had a pronociceptive effect in an in vivo mouse model and whether this effect was based on the release of S1P and subsequent activation of neuronal S1P receptors 1 or 3. Human platelets were prepared in different concentrations (105/μl, 106/μl, 107/μl) and assessed in mice with different genetic backgrounds (WT, S1P1fl/fl, SNS-S1P1−/−, S1P3−/−). Intracutaneous injections of activated human platelets induced a significant, dose-dependent hypersensitivity to noxious thermal stimulation. The degree of heat hypersensitivity correlated with the platelet concentration as well as the platelet S1P content and the amount of S1P released upon platelet activation as measured with LC MS/MS. Despite the significant correlations between S1P and platelet count, no difference in paw withdrawal latency (PWL) was observed in mice with a global null mutation of the S1P3 receptor or a conditional deletion of the S1P1 receptor in nociceptive primary afferents. Furthermore, neutralization of S1P with a selective anti-S1P antibody did not abolish platelet induced heat hypersensitivity. Our results suggest that activated platelets release S1P and induce heat hypersensitivity in vivo. However, the platelet induced heat hypersensitivity was caused by mediators other than S1P. PMID:25954148

  9. Necrotizing lymphadenitis associated with the phenytoin-induced hypersensitivity syndrome.

    PubMed

    Subbannan, Karthi; Gujral, Jaspal S

    2005-09-01

    A 32-year-old black female was started on phenytoin for seizure prophylaxis following the clipping of an aneurysm. This was stopped after 3 weeks when she developed a generalized skin rash. Over the next week she developed fever, sore throat, dysphagia, and headache. She had an erythematous throat with white exudates on the right tonsil and 1 to 3 cm firm, tender lymphadenopathy in multiple regions. Blood, throat swab and cerebrospinal fluid studies were negative for bacterial or viral infections, except for elevated liver enzymes. CT scan of chest, abdomen, and pelvis showed no lymphadenopathy. Lymph node biopsy suggested necrosis but no evidence of infection, granuloma, or lymphoma. Her lymphadenopathy resolved spontaneously and liver enzymes normalized in 3 weeks. Hypersensitivity syndrome due to antiepileptics manifests as fever, rash, generalized lymphadenopathy, and probably represents a T-cell mediated drug reaction. This reaction may persist despite cessation of the drug, and it may engender expensive evaluation. Careful observation up to 3 weeks after drug cessation may be the best management.

  10. Cold-induced changes in amphibian oocytes

    SciTech Connect

    Angelier, N.; Moreau, N.A.; N'Da, E.A.; Lautredou, N.F. )

    1989-08-01

    Female Pleurodeles waltl newts (Amphibia, urodele), usually raised at 20 degrees C, were submitted to low temperatures; oocytes responded to this cold stress by drastic changes both in lampbrush chromosome structure and in protein pattern. Preexisting lateral loops of lampbrush chromosomes were reduced in size and number, while cold-induced loops which were tremendously developed, occurred on defined bivalents of the oocyte at constant, reproducible sites. A comparison of protein patterns in control and stressed oocytes showed two main differences: in stressed oocytes, overall protein synthesis was reduced, except for a set of polypeptides, the cold-stress proteins; second, there was a striking inversion of the relative amount of beta- and gamma-actin found in the oocyte nucleus before and after cold stress. Whereas beta-actin was the predominant form in control oocytes, gamma-actin became the major form in stressed oocytes.

  11. Cold stress induces lower urinary tract symptoms.

    PubMed

    Imamura, Tetsuya; Ishizuka, Osamu; Nishizawa, Osamu

    2013-07-01

    Cold stress as a result of whole-body cooling at low environmental temperatures exacerbates lower urinary tract symptoms, such as urinary urgency, nocturia and residual urine. We established a model system using healthy conscious rats to explore the mechanisms of cold stress-induced detrusor overactivity. In this review, we summarize the basic findings shown by this model. Rats that were quickly transferred from room temperature (27 ± 2°C) to low temperature (4 ± 2°C) showed detrusor overactivity including increased basal pressure and decreased voiding interval, micturition volume, and bladder capacity. The cold stress-induced detrusor overactivity is mediated through a resiniferatoxin-sensitve C-fiber sensory nerve pathway involving α1-adrenergic receptors. Transient receptor potential melastatin 8 channels, which are sensitive to thermal changes below 25-28°C, also play an important role in mediating the cold stress responses. Additionally, the sympathetic nervous system is associated with transient hypertension and decreases of skin surface temperature that are closely correlated with the detrusor overactivity. With this cold stress model, we showed that α1-adrenergic receptor antagonists have the potential to treat cold stress-exacerbated lower urinary tract symptoms. In addition, we showed that traditional Japanese herbal mixtures composed of Hachimijiogan act, in part, by increasing skin temperature and reducing the number of cold sensitive transient receptor potential melastatin channels in the skin. The effects of herbal mixtures have the potential to treat and/or prevent the exacerbation of lower urinary tract symptoms by providing resistance to the cold stress responses. Our model provides new opportunities for utilizing animal disease models with altered lower urinary tract functions to explore the effects of novel therapeutic drugs.

  12. Genetic AVP deficiency abolishes cold-induced diuresis but does not attenuate cold-induced hypertension.

    PubMed

    Sun, Zhongjie

    2006-06-01

    Chronic cold exposure causes hypertension and diuresis. The aim of this study was to determine whether vasopressin (AVP) plays a role in cold-induced hypertension and diuresis. Two groups of Long-Evans (LE) and two groups of homozygous AVP-deficient Brattleboro (VD) rats were used. Blood pressure (BP) was not different among the four groups during a 2-wk control period at room temperature (25 degrees C, warm). After the control period, one LE group and one VD group were exposed to cold (5 degrees C); the remaining groups were kept at room temperature. BP and body weight were measured weekly during exposure to cold. Food intake, water intake, urine output, and urine osmolality were measured during weeks 1, 3, and 5 of cold exposure. At the end of week 5, all animals were killed and blood was collected for measurement of plasma AVP. Kidneys were removed for measurement of renal medulla V2 receptor mRNA and aquaporin-2 (AQP-2) protein expression. BP of LE and VD rats increased significantly by week 2 of cold exposure and reached a high level by week 5. BP elevations developed at approximately the same rate and to the same degree in LE and VD rats. AVP deficiency significantly increased urine output and solute-free water clearance and decreased urine osmolality. Chronic cold exposure increased urine output and solute-free water clearance and decreased urine osmolality in LE rats, indicating that cold exposure caused diuresis in LE rats. Cold exposure failed to affect these parameters in VD rats, suggesting that the AVP system is responsible for cold-induced diuresis. Cold exposure did not alter plasma AVP in LE rats. Renal medulla V2 receptor mRNA and AQP-2 protein expression levels were decreased significantly in the cold-exposed LE rats, suggesting that cold exposure inhibited renal V2 receptors and AVP-inducible AQP-2 water channels. We conclude that 1) AVP may not be involved in the pathogenesis of cold-induced hypertension, 2) the AVP system plays a critical role

  13. Histone hyperacetylation modulates spinal type II metabotropic glutamate receptor alleviating stress-induced visceral hypersensitivity in female rats

    PubMed Central

    Cao, Dong-Yuan; Bai, Guang; Ji, Yaping; Karpowicz, Jane

    2016-01-01

    Stress is often a trigger to exacerbate chronic pain including visceral hypersensitivity associated with irritable bowel syndrome, a female predominant functional bowel disorder. Epigenetic mechanisms that mediate stress responses are a potential target to interfere with visceral pain. The purpose of this study was to examine the effect of a histone deacetylase inhibitor, suberoylanilide hydroxamic acid, on visceral hypersensitivity induced by a subchronic stressor in female rats and to investigate the involvement of spinal glutamate receptors. Three daily sessions of forced swim induced visceral hypersensitivity. Intrathecal suberoylanilide hydroxamic acid prevented or reversed the stress-induced visceral hypersensitivity, increased spinal histone 3 acetylation and increased mGluR2 and mGluR3 expression. Chromatin immunoprecipitation (ChIP) analysis revealed enrichment of H3K9Ac and H3K18Ac at several promoter Grm2 and Grm3 regions. The mGluR2/3 antagonist LY341495 reversed the inhibitory effect of suberoylanilide hydroxamic acid on the stress-induced visceral hypersensitivity. In surprising contrast, stress and/or suberoylanilide hydroxamic acid had no effect on spinal NMDA receptor expression or function. These data reveal histone modification modulates mGluR2/3 expression in the spinal cord to attenuate stress-induced visceral hypersensitivity. HDAC inhibitors may provide a potential approach to relieve visceral hypersensitivity associated with irritable bowel syndrome. PMID:27385724

  14. Association of CYP1B1 with hypersensitivity induced by taxane therapy in breast cancer patients.

    PubMed

    Rizzo, Roberta; Spaggiari, Federica; Indelli, Monica; Lelli, Giorgio; Baricordi, Olavio R; Rimessi, Paola; Ferlini, Alessandra

    2010-11-01

    Taxanes represent a group of anticancer drugs with a wide range of activity against breast cancer. Therapy side effects include haematologic toxicity (neutropenia, leucopenia), peripheral neuropathy and hypersensitivity, and demonstrate inter-individual variations. Since it is known that three genes are implicated in taxane turnover, namely ABCB1 in the transport, CYP2C8 in the metabolism and CYP1B1 in the activity, we explored the association among polymorphisms (single nucleotide polymorphisms, SNPs) in these three genes and the occurrence of taxane-induced toxicity. We studied 95 patients affected by breast cancer and under treatment with taxanes as adjuvant, metastatic or neo-adjuvant therapy. We genotyped them for SNPs in the CYP2C8 (alleles *1, *2, *3 and *4), CYP1B1 (alleles *1 and *3) and ABCB1 (1236 C>T; 2677 G>T/A; 3435 C>T) genes by real-time PCR assay. We observed a significant association between the CYP1B1*3 allele and a lower occurrence of hypersensitivity reactions to taxane treatment. We speculate that the highest production of 4-hydroxyestradiol (4-OHE2) metabolite by CYP1B1*3 allele could increase the formation of the 4-OHE2-taxane adduct and possibly inhibit taxane toxicity. We suggest that CYP1B1 might affect taxane hypersensitivity therefore representing, if confirmed in a large cohort of patients, an exploratory hypersensitivity predictive biomarker.

  15. Pharmacogenomics of drug-induced hypersensitivity reactions: challenges, opportunities and clinical implementation.

    PubMed

    Sukasem, Chonlaphat; Puangpetch, Apichaya; Medhasi, Sadeep; Tassaneeyakul, Wichittra

    2014-06-01

    Drug hypersensitivity reactions affect many patients leading to a variety of clinical manifestations, mainly the cutaneous adverse reactions ranging from milder skin reactions to severe cutaneous adverse reactions (SCARs). Hypersensitivity reactions are unpredictable and are thought to have an underlying genetic etiology, as suggested by case reports. With the scientific knowledge of pharmacogenomics and the evidence based on the genomic testing, it is possible to identify genetic predisposing factors for these serious adverse reactions and personalize drug therapy. The most significant genetic associations have been identified in the major histocompatibility complex (MHC) genes encoded for human leukocyte antigens (HLA) alleles. Drugs associated with hypersensitivity reactions with strong genetic predisposing factors include abacavir, nevirapine, carbamazepine, and allopurinol. In this review, strong genetic associations of drug-induced SCARs are highlighted so as to improve drug safety and help to select optimal drugs for individual patients. Further investigation, however, is essential for the characterization of other genes involved in the hypersensitivity reactions with the use of several genetic strategies and technologies.

  16. Oncostatin M induces heat hypersensitivity by gp130-dependent sensitization of TRPV1 in sensory neurons.

    PubMed

    Langeslag, Michiel; Constantin, Cristina E; Andratsch, Manfred; Quarta, Serena; Mair, Norbert; Kress, Michaela

    2011-12-23

    Oncostatin M (OSM) is a member of the interleukin-6 cytokine family and regulates eg. gene activation, cell survival, proliferation and differentiation. OSM binds to a receptor complex consisting of the ubiquitously expressed signal transducer gp130 and the ligand binding OSM receptor subunit, which is expressed on a specific subset of primary afferent neurons. In the present study, the effect of OSM on heat nociception was investigated in nociceptor-specific gp130 knock-out (SNS-gp130-/-) and gp130 floxed (gp130fl/fl) mice.Subcutaneous injection of pathophysiologically relevant concentrations of OSM into the hind-paw of C57BL6J wild type mice significantly reduced paw withdrawal latencies to heat stimulation. In contrast to gp130fl/fl mice, OSM did not induce heat hypersensitivity in vivo in SNS-gp130-/- mice. OSM applied at the receptive fields of sensory neurons in in vitro skin-nerve preparations showed that OSM significantly increased the discharge rate during a standard ramp-shaped heat stimulus. The capsaicin- and heat-sensitive ion channel TRPV1, expressed on a subpopulation of nociceptive neurons, has been shown to play an important role in inflammation-induced heat hypersensitivity. Stimulation of cultured dorsal root ganglion neurons with OSM resulted in potentiation of capsaicin induced ionic currents. In line with these recordings, mice with a null mutation of the TRPV1 gene did not show any signs of OSM-induced heat hypersensitivity in vivo.The present data suggest that OSM induces thermal hypersensitivity by directly sensitizing nociceptors via OSMR-gp130 receptor mediated potentiation of TRPV1.

  17. Systemic cold-induced urticaria--clinical and laboratory characterization.

    PubMed

    Kivity, S; Schwartz, Y; Wolf, R; Topilsky, M

    1990-01-01

    Six patients are described with a history of cold-related urticaria in whom standard tests (water-immersion and ice-cube) did not induce symptoms. Only total-body cold exposure induced generalized urticaria. Systemic cold urticaria should, therefore, be included in the differential diagnosis of cold-dependent allergic disorders.

  18. Molecular Mechanisms for Drug Hypersensitivity Induced by the Malaria Parasite’s Chloroquine Resistance Transporter

    PubMed Central

    Baker, Eileen S.; Webster, Michael W.; Lehane, Adele M.; Shafik, Sarah H.; Martin, Rowena E.

    2016-01-01

    Mutations in the Plasmodium falciparum ‘chloroquine resistance transporter’ (PfCRT) confer resistance to chloroquine (CQ) and related antimalarials by enabling the protein to transport these drugs away from their targets within the parasite’s digestive vacuole (DV). However, CQ resistance-conferring isoforms of PfCRT (PfCRTCQR) also render the parasite hypersensitive to a subset of structurally-diverse pharmacons. Moreover, mutations in PfCRTCQR that suppress the parasite’s hypersensitivity to these molecules simultaneously reinstate its sensitivity to CQ and related drugs. We sought to understand these phenomena by characterizing the functions of PfCRTCQR isoforms that cause the parasite to become hypersensitive to the antimalarial quinine or the antiviral amantadine. We achieved this by measuring the abilities of these proteins to transport CQ, quinine, and amantadine when expressed in Xenopus oocytes and complemented this work with assays that detect the drug transport activity of PfCRT in its native environment within the parasite. Here we describe two mechanistic explanations for PfCRT-induced drug hypersensitivity. First, we show that quinine, which normally accumulates inside the DV and therewithin exerts its antimalarial effect, binds extremely tightly to the substrate-binding site of certain isoforms of PfCRTCQR. By doing so it likely blocks the normal physiological function of the protein, which is essential for the parasite’s survival, and the drug thereby gains an additional killing effect. In the second scenario, we show that although amantadine also sequesters within the DV, the parasite’s hypersensitivity to this drug arises from the PfCRTCQR-mediated transport of amantadine from the DV into the cytosol, where it can better access its antimalarial target. In both cases, the mutations that suppress hypersensitivity also abrogate the ability of PfCRTCQR to transport CQ, thus explaining why rescue from hypersensitivity restores the parasite

  19. A Case of Mexiletine-induced Hypersensitivity Syndrome Presenting as Eosinophilic Pneumonia

    PubMed Central

    Lee, Sang-Pyo; Kim, Sang-Heon; Kim, Tae Hyung; Sohn, Jang Won; Shin, Dong Ho; Park, Sung Soo

    2010-01-01

    An 82-yr-old man was presented with fever and cough accompanied by generalized erythematous rash. He had taken mexiletine for 5 months, as he had been diagnosed with dilated cardiomyopathy and ventricular arrhythmia. Laboratory studies showed peripheral blood eosinophilia and elevated liver transaminase levels. Chest radiographs showed multiple nodular consolidations in both lungs. Biopsies of the lung and skin lesions revealed eosinophilic infiltration. After a thorough review of his medication history, mexiletine was suspected as the etiologic agent. After discontinuing the mexiletine and starting oral prednisolone, the patient improved, and the skin and lung lesions disappeared. Subsequently, mexiletine was confirmed as the causative agent based on a positive patch test. Drug-induced hypersensitivity syndrome is a severe adverse reaction to drugs and results from treatment with anticonvulsants, allopurinol, sulfonamides, and many other drugs. Several cases of mexiletine-induced hypersensitivity syndrome have been reported in older Japanese males with manifestation of fever, rash, peripheral blood eosinophilia, liver dysfunction without other organ involvement. Here, we report a case of mexiletine-induced hypersensitivity syndrome which presented as eosinophilic pneumonia in a Korean male. PMID:20052362

  20. Norepinephrine-induced nociception and vasoconstrictor hypersensitivity in rats with chronic post-ischemia pain

    PubMed Central

    Xanthos, Dimitris N.; Bennett, Gary J.; Coderre, Terence J.

    2015-01-01

    Painful hypersensitivity to norepinephrine (NE) has been reported in various chronic pain conditions that exhibit sympathetically-maintained pain (SMP), particularly CRPS-I and II. We investigated the parallels between the nociceptive and vascular sensitivity to NE in rats with chronic post-ischemia pain (CPIP), an animal model of CRPS-I induced by hind paw ischemia-reperfusion injury. Intradermal injections of NE to the affected hind paw induced dose-dependent nociceptive behaviours in CPIP rats, but not sham animals. These behaviours were blocked by α1- and α 2-adrenergic receptor antagonists, or a nitric oxide (NO) donor. Using laser Doppler flowmetry, we detected vasoconstrictor hypersensitivity in the ipsilateral CPIP hind paw, as compared to responses in sham animals or the contralateral hind paw. The vasoconstrictor hypersensitivity was also attenuated by adrenergic antagonists. Intradermal injection of [Arg8] vasopressin (AVP) or the endothelial NO synthase (eNOS) inhibitor, L-NIO, to the affected paw also induced nociceptive behaviours in CPIP rats, but not sham rats. These results suggest CPIP rats display abnormal nociceptive responses to adrenergic and non-adrenergic vasoconstrictive agents. Furthermore, the nociceptive responses to NE in CPIP rats are paralleled by enhanced vasoconstrictive responses to NE, and are relieved by α-adrenergic antagonists or a vasodilator. We conclude that persistent tissue ischemia and hypersensitivity to sympathetic vasoconstriction are important mechanisms for pain in CPIP rats, and that either reducing vasoconstriction or enhancing vasodilatation may be effective methods of relieving the pain of CRPS-I. PMID:18079061

  1. A Hyperresponsive HPA Axis May Confer Resilience Against Persistent Paclitaxel-Induced Mechanical Hypersensitivity

    PubMed Central

    Kozachik, Sharon L.; Page, Gayle G.

    2016-01-01

    Paclitaxel (PAC) treatment is associated with persistent, debilitating neuropathic pain that affects the hands and feet. Female sex and biological stress responsivity are risk factors for persistent pain, but it is unclear whether these important biologically based factors confer risk for PAC-induced neuropathic pain. To determine the relative contributions of sex and hypothalamic–pituitary–adrenal (HPA)-axis stress responsivity to PAC-induced mechanical hypersensitivity, we employed a PAC protocol consisting of three, 2-week cycles of every-other-day doses of PAC 1 mg/kg versus saline (Week 1) and recovery (Week 2), totaling 42 days, in mature male and female Fischer 344, Lewis, and Sprague Dawley (SD) rats, known to differ in HPA axis stress responsivity. Mechanical sensitivity was operationalized using von Frey filaments, per the up–down method. Among PAC-injected rats, SD rats exhibited significantly greater mechanical hypersensitivity relative to accumulative PAC doses compared to Fischer 344 rats. Lewis rats were not significantly different in mechanical hypersensitivity from SD or Fischer 344 rats. At the end of the protocol, PAC-injected SD rats exhibited profound mechanical hypersensitivity, whereas the PAC-injected Fischer 344 rats appeared relatively resilient to the long-term effects of PAC and exhibited mechanical sensitivity that was not statistically different from their saline-injected counterparts. Sex differences were mixed and noted only early in the PAC protocol. Moderate HPA axis stress responsivity may confer additional risk for the painful effects of PAC. If these findings hold in humans, clinicians may be better able to identify persons who may be at increased risks for developing neuropathic pain during PAC therapy. PMID:26512050

  2. Bronchoscopic Investigation of Atypical Drug-induced Hypersensitivity Syndrome Showing Viral Lung Involvement.

    PubMed

    Hase, Isano; Arakawa, Hiroaki; Sakuma, Hideo; Kaneko, Fumio; Watanabe, Yuzuru; Fujiu, Koichi; Miyamoto, Hideaki; Ishii, Yoshiki

    We herein report a case of atypical drug-induced hypersensitivity syndrome (DIHS) involving serological reactivation of cytomegalovirus induced by carbamazepine with pulmonary and skin manifestations. These lesions were not present on admission, but developed on virus reactivation as indicated by the presence of inclusion bodies and multinucleated giant cells in alveolar cells with CD8(+) T lymphocyte infiltration on a transbronchial lung biopsy. Although the precise mechanism of DIHS remains unknown, this case suggests the crucial role of viral reactivation in pulmonary lesions in DIHS.

  3. Beryllium-Induced Hypersensitivity: Genetic Susceptibility and Neoantigen Generation.

    PubMed

    Fontenot, Andrew P; Falta, Michael T; Kappler, John W; Dai, Shaodong; McKee, Amy S

    2016-01-01

    Chronic beryllium (Be) disease is a granulomatous lung disorder that results from Be exposure in a genetically susceptible host. The disease is characterized by the accumulation of Be-responsive CD4(+) T cells in the lung, and genetic susceptibility is primarily linked to HLA-DPB1 alleles possessing a glutamic acid at position 69 of the β-chain. Recent structural analysis of a Be-specific TCR interacting with a Be-loaded HLA-DP2-peptide complex revealed that Be is coordinated by amino acid residues derived from the HLA-DP2 β-chain and peptide and showed that the TCR does not directly interact with the Be(2+) cation. Rather, the TCR recognizes a modified HLA-DP2-peptide complex with charge and conformational changes. Collectively, these findings provide a structural basis for the development of this occupational lung disease through the ability of Be to induce posttranslational modifications in preexisting HLA-DP2-peptide complexes, resulting in the creation of neoantigens. Copyright © 2015 by The American Association of Immunologists, Inc.

  4. Beryllium-Induced Hypersensitivity: Genetic Susceptibility and Neoantigen Generation1

    PubMed Central

    Fontenot, Andrew P.; Falta, Michael T.; Kappler, John W.; Dai, Shaodong; McKee, Amy S.

    2015-01-01

    Chronic beryllium disease (CBD) is a granulomatous lung disorder that results from beryllium (Be) exposure in a genetically-susceptible host. The disease is characterized by the accumulation of Be-responsive CD4+ T cells in the lung, and genetic susceptibility is primarily linked to HLA-DPB1 alleles possessing a glutamic acid at position 69 of the β-chain. Recent structural analysis of a Be-specific T cell receptor (TCR) interacting with a Be-loaded HLA-DP2-peptide complex revealed that Be is coordinated by amino acid residues derived from the HLA-DP2 β-chain and peptide and showed that the TCR does not directly interact with the Be2+ cation. Rather, the TCR recognizes a modified HLA-DP2-peptide complex with charge and conformational changes. Collectively, these findings provide a structural basis for the development of this occupational lung disease through the ability of Be to induce post-translational modifications in preexisting HLA-DP2-peptide complexes, resulting in the creation of neoantigens. PMID:26685315

  5. Anisakis simplex: from obscure infectious worm to inducer of immune hypersensitivity.

    PubMed

    Audicana, M Teresa; Kennedy, Malcolm W

    2008-04-01

    Infection of humans with the nematode worm parasite Anisakis simplex was first described in the 1960s in association with the consumption of raw or undercooked fish. During the 1990s it was realized that even the ingestion of dead worms in food fish can cause severe hypersensitivity reactions, that these may be more prevalent than infection itself, and that this outcome could be associated with food preparations previously considered safe. Not only may allergic symptoms arise from infection by the parasites ("gastroallergic anisakiasis"), but true anaphylactic reactions can also occur following exposure to allergens from dead worms by food-borne, airborne, or skin contact routes. This review discusses A. simplex pathogenesis in humans, covering immune hypersensitivity reactions both in the context of a living infection and in terms of exposure to its allergens by other routes. Over the last 20 years, several studies have concentrated on A. simplex antigen characterization and innate as well as adaptive immune response to this parasite. Molecular characterization of Anisakis allergens and isolation of their encoding cDNAs is now an active field of research that should provide improved diagnostic tools in addition to tools with which to enhance our understanding of pathogenesis and controversial aspects of A. simplex allergy. We also discuss the potential relevance of parasite products such as allergens, proteinases, and proteinase inhibitors and the activation of basophils, eosinophils, and mast cells in the induction of A. simplex-related immune hypersensitivity states induced by exposure to the parasite, dead or alive.

  6. High cytokinin levels induce a hypersensitive-like response in tobacco

    PubMed Central

    Novák, Jan; Pavlů, Jaroslav; Novák, Ondřej; Nožková-Hlaváčková, Vladimíra; Špundová, Martina; Hlavinka, Jan; Koukalová, Šárka; Skalák, Jan; Černý, Martin; Brzobohatý, Břetislav

    2013-01-01

    Background and Aims Cytokinins are positive regulators of shoot development. However, it has previously been demonstrated that efficient activation of the cytokinin biosynthesis gene ipt can cause necrotic lesions and wilting in tobacco leaves. Some plant pathogens reportedly use their ability to produce cytokinins in disease development. In response to pathogen attacks, plants can trigger a hypersensitive response that rapidly kills cells near the infection site, depriving the pathogen of nutrients and preventing its spread. In this study, a diverse set of processes that link ipt activation to necrotic lesion formation were investigated in order to evaluate the potential of cytokinins as signals and/or mediators in plant defence against pathogens. Methods The binary pOp-ipt/LhGR system for dexamethasone-inducible ipt expression was used to increase endogenous cytokinin levels in transgenic tobacco. Changes in the levels of cytokinins and the stress hormones salicylic, jasmonic and abscisic acid following ipt activation were determined by ultra-performance liquid chromatography–electrospray tandem mass spectrometry (UPLC-MS/MS). Trends in hydrogen peroxide content and lipid peroxidation were monitored using the potassium iodide and malondialdehyde assays. The subcellular distribution of hydrogen peroxide was investigated using 3,3′-diaminobenzidine staining. The dynamics of transcripts related to photosynthesis and pathogen response were analysed by reverse transcription followed by quantitative PCR. The effects of cytokinins on photosynthesis were deciphered by analysing changes in chlorophyll fluorescence and leaf gas exchange. Key Results Plants can produce sufficiently high levels of cytokinins to trigger fast cell death without any intervening chlorosis – a hallmark of the hypersensitive response. The results suggest that chloroplastic hydrogen peroxide orchestrates the molecular responses underpinning the hypersensitive-like response, including the

  7. Giardia duodenalis induces paracellular bacterial translocation and causes postinfectious visceral hypersensitivity

    PubMed Central

    Halliez, Marie C. M.; Motta, Jean-Paul; Feener, Troy D.; Guérin, Gaetan; LeGoff, Laetitia; François, Arnaud; Colasse, Elodie; Favennec, Loic; Gargala, Gilles; Lapointe, Tamia K.; Altier, Christophe

    2016-01-01

    Irritable bowel syndrome (IBS) is the most frequent functional gastrointestinal disorder. It is characterized by abdominal hypersensitivity, leading to discomfort and pain, as well as altered bowel habits. While it is common for IBS to develop following the resolution of infectious gastroenteritis [then termed postinfectious IBS (PI-IBS)], the mechanisms remain incompletely understood. Giardia duodenalis is a cosmopolitan water-borne enteropathogen that causes intestinal malabsorption, diarrhea, and postinfectious complications. Cause-and-effect studies using a human enteropathogen to help investigate the mechanisms of PI-IBS are sorely lacking. In an attempt to establish causality between giardiasis and postinfectious visceral hypersensitivity, this study describes a new model of PI-IBS in neonatal rats infected with G. duodenalis. At 50 days postinfection with G. duodenalis (assemblage A or B), long after the parasite was cleared, rats developed visceral hypersensitivity to luminal balloon distension in the jejunum and rectum, activation of the nociceptive signaling pathway (increased c-fos expression), histological modifications (villus atrophy and crypt hyperplasia), and proliferation of mucosal intraepithelial lymphocytes and mast cells in the jejunum, but not in the rectum. G. duodenalis infection also disrupted the intestinal barrier, in vivo and in vitro, which in turn promoted the translocation of commensal bacteria. Giardia-induced bacterial paracellular translocation in vitro correlated with degradation of the tight junction proteins occludin and claudin-4. The extensive observations associated with gut hypersensitivity described here demonstrate that, indeed, in this new model of postgiardiasis IBS, alterations to the gut mucosa and c-fos are consistent with those associated with PI-IBS and, hence, offer avenues for new mechanistic research in the field. PMID:26744469

  8. Giardia duodenalis induces paracellular bacterial translocation and causes postinfectious visceral hypersensitivity.

    PubMed

    Halliez, Marie C M; Motta, Jean-Paul; Feener, Troy D; Guérin, Gaetan; LeGoff, Laetitia; François, Arnaud; Colasse, Elodie; Favennec, Loic; Gargala, Gilles; Lapointe, Tamia K; Altier, Christophe; Buret, André G

    2016-04-15

    Irritable bowel syndrome (IBS) is the most frequent functional gastrointestinal disorder. It is characterized by abdominal hypersensitivity, leading to discomfort and pain, as well as altered bowel habits. While it is common for IBS to develop following the resolution of infectious gastroenteritis [then termed postinfectious IBS (PI-IBS)], the mechanisms remain incompletely understood. Giardia duodenalis is a cosmopolitan water-borne enteropathogen that causes intestinal malabsorption, diarrhea, and postinfectious complications. Cause-and-effect studies using a human enteropathogen to help investigate the mechanisms of PI-IBS are sorely lacking. In an attempt to establish causality between giardiasis and postinfectious visceral hypersensitivity, this study describes a new model of PI-IBS in neonatal rats infected with G. duodenalis At 50 days postinfection with G. duodenalis (assemblage A or B), long after the parasite was cleared, rats developed visceral hypersensitivity to luminal balloon distension in the jejunum and rectum, activation of the nociceptive signaling pathway (increased c-fos expression), histological modifications (villus atrophy and crypt hyperplasia), and proliferation of mucosal intraepithelial lymphocytes and mast cells in the jejunum, but not in the rectum. G. duodenalis infection also disrupted the intestinal barrier, in vivo and in vitro, which in turn promoted the translocation of commensal bacteria. Giardia-induced bacterial paracellular translocation in vitro correlated with degradation of the tight junction proteins occludin and claudin-4. The extensive observations associated with gut hypersensitivity described here demonstrate that, indeed, in this new model of postgiardiasis IBS, alterations to the gut mucosa and c-fos are consistent with those associated with PI-IBS and, hence, offer avenues for new mechanistic research in the field. Copyright © 2016 the American Physiological Society.

  9. Cold-induced thermogenesis in humans.

    PubMed

    Brychta, R J; Chen, K Y

    2017-03-01

    A basic property of endothermic thermoregulation is the ability to generate heat by increasing metabolism in response to cold ambient temperatures to maintain a stable core body temperature. This process, known as cold-induced thermogenesis (CIT), has been measured in humans as early as 1780 by Antoine Lavoisier, but has found renewed interest because of the recent 'rediscovery' of thermogenic, cold-activated brown adipose tissue (BAT) in adult humans. In this review, we summarize some of the key findings of the work involving CIT over the past two centuries and highlight some of the seminal studies focused on this topic. There has been a substantial range of variability in the reported CIT in these studies, from 0 to 280% above basal metabolism. We identify and discuss several potential sources of this variability, including both methodological (measurement device, cold exposure temperature and duration) and biological (age and body composition of subject population) discrepancies. These factors should be considered when measuring CIT going forward to better assess whether BAT or other thermogenic organs are viable targets to combat chronic positive energy balance based on their relative capacities to elevate human metabolism.

  10. Immunoadjuvant properties of glove cornstarch powder in latex-induced hypersensitivity.

    PubMed

    Barbara, J; Santais, M-C; Levy, D A; Ruff, F; Leynadier, F

    2003-01-01

    Cornstarch powder present in medical gloves plays an important role in latex-induced hypersensitivity as allergen carrier either, by the inhalation route, by skin contact or by direct contact with mucous membranes. Our objective was to test the hypothesis that cornstarch could act as an immunoadjuvant in immediate type-I latex-induced hypersensitivity. Guinea-pigs were sensitized by intraperitoneal route with two different antigens (latex proteins and ovalbumin) with or without cornstarch powder. Airway responsiveness after specific bronchial provocation was evaluated and specific IgG and IgG1 levels were determined by enzyme-linked immunosorbent assay (ELISA). Controls were treated with cornstarch powder or saline alone. Animals sensitized with latex proteins (n = 7 in each group) showed significant bronchoconstriction (P < 0.03) and higher anti-latex antibody levels than the controls (P < 0.005). Guinea-pigs sensitized with latex-contaminated cornstarch had higher levels of specific antibodies than those sensitized with latex alone (P < 0.05). Animals sensitized to latex mixed with cornstarch showed higher bronchospasm than those treated with latex alone (P < 0.003). Animals sensitized to ovalbumin mixed with cornstarch also showed higher antibody and bronchoconstriction levels (P < 0.05) than those immunized with ovalbumin alone but antibody titres were significantly lower than those of the animals treated with ovalbumin and Freund's complete adjuvant (P < 0.01; n = 5 in each group). Our findings show that cornstarch powder increases antigen-induced bronchoconstriction and antibody production. This role of immunoadjuvant is not antigen-specific. The cornstarch powder used as donning agent in latex gloves is an allergen carrier and it can enhance latex-induced hypersensitivity.

  11. Vitamin C and common cold-induced asthma: a systematic review and statistical analysis.

    PubMed

    Hemilä, Harri

    2013-11-26

    Asthma exacerbations are often induced by the common cold, which, in turn, can be alleviated by vitamin C. To investigate whether vitamin C administration influences common cold-induced asthma. Systematic review and statistical analysis of the identified trials. Medline, Scopus and Cochrane Central were searched for studies that give information on the effects of vitamin C on common cold-induced asthma. All clinically relevant outcomes related to asthma were included in this review. The estimates of vitamin C effect and their confidence intervals [CI] were calculated for the included studies. Three studies that were relevant for examining the role of vitamin C on common cold-induced asthma were identified. The three studies had a total of 79 participants. Two studies were randomized double-blind placebo-controlled trials. A study in Nigeria on asthmatics whose asthma attacks were precipitated by respiratory infections found that 1 g/day vitamin C decreased the occurrence of asthma attacks by 78% (95% CI: 19% to 94%). A cross-over study in former East-Germany on patients who had infection-related asthma found that 5 g/day vitamin C decreased the proportion of participants who had bronchial hypersensitivity to histamine by 52 percentage points (95% CI: 25 to 71). The third study did not use a placebo. Administration of a single dose of 1 gram of vitamin C to Italian non-asthmatic common cold patients increased the provocative concentration of histamine (PC20) 3.2-fold (95% CI: 2.0 to 5.1), but the vitamin C effect was significantly less when the same participants did not suffer from the common cold. The three reviewed studies differed substantially in their methods, settings and outcomes. Each of them found benefits from the administration of vitamin C; either against asthma attacks or against bronchial hypersensitivity, the latter of which is a characteristic of asthma. Given the evidence suggesting that vitamin C alleviates common cold symptoms and the findings

  12. Human Telomeres Are Hypersensitive to UV-Induced DNA Damage and Refractory to Repair

    PubMed Central

    Rochette, Patrick J.; Brash, Douglas E.

    2010-01-01

    Telomeric repeats preserve genome integrity by stabilizing chromosomes, a function that appears to be important for both cancer and aging. In view of this critical role in genomic integrity, the telomere's own integrity should be of paramount importance to the cell. Ultraviolet light (UV), the preeminent risk factor in skin cancer development, induces mainly cyclobutane pyrimidine dimers (CPD) which are both mutagenic and lethal. The human telomeric repeat unit (5′TTAGGG/CCCTAA3′) is nearly optimal for acquiring UV-induced CPD, which form at dipyrimidine sites. We developed a ChIP–based technique, immunoprecipitation of DNA damage (IPoD), to simultaneously study DNA damage and repair in the telomere and in the coding regions of p53, 28S rDNA, and mitochondrial DNA. We find that human telomeres in vivo are 7-fold hypersensitive to UV-induced DNA damage. In double-stranded oligonucleotides, this hypersensitivity is a property of both telomeric and non-telomeric repeats; in a series of telomeric repeat oligonucleotides, a phase change conferring UV-sensitivity occurs above 4 repeats. Furthermore, CPD removal in the telomere is almost absent, matching the rate in mitochondria known to lack nucleotide excision repair. Cells containing persistent high levels of telomeric CPDs nevertheless proliferate, and chronic UV irradiation of cells does not accelerate telomere shortening. Telomeres are therefore unique in at least three respects: their biophysical UV sensitivity, their prevention of excision repair, and their tolerance of unrepaired lesions. Utilizing a lesion-tolerance strategy rather than repair would prevent double-strand breaks at closely-opposed excision repair sites on opposite strands of a damage-hypersensitive repeat. PMID:20442874

  13. Prevention of ultraviolet radiation-induced immunosuppression by sunscreen in Candida albicans-induced delayed-type hypersensitivity

    PubMed Central

    CHEN, QUAN; LI, RUNXIANG; ZHAO, XIAOXIA; LIANG, BIHUA; MA, SHAOYIN; LI, ZHENJIE; ZHU, HUILAN

    2016-01-01

    Ultraviolet (UV) radiation-induced immunosuppression leading to skin cancer has received increased attention in previous years. The present study aimed to investigate the immunoprotection offered by Anthelios sunscreen in a mouse model of Candida albicans-induced delayed-type hypersensitivity. Anthelios sunscreen was applied to the skin on the dorsal skin of BALB/c mice treated with a sub-erythema dose of solar-simulated radiation. Delayed-type hypersensitivity was induced by immunization with Candida albicans. Changes in the skin thickness of the foot pads were measured, and immunosuppression rates were also evaluated. The expression levels of CD207, CD80 and CD86 in the Langerhans cells were semi-quantitatively detected using Western blotting and immunohistochemical assays. The delayed-type hypersensitivity mouse model was successfully established. The minimal erythema doses of UVA and UVB exposure to the mice were 2,000 and 145 mJ/cm2, respectively. The immunosuppression rates in the sunscreen group and non-sunscreen group were 24.39 and 65.85%, respectively (P<0.01). The results of the Western blotting and immunohistochemistry showed that the expression levels of CD207 (P<0.01), CD80 (P<0.05) and CD86 (P<0.01) were higher in the sunscreen group, compared with those in the non-sunscreen group. UV exposure reduced Candida albicans antigen-induced delayed-type hypersensitivity. Anthelios sunscreen was found to protect the skin from immunosuppression through the activation of epidermal Langerhans cells. PMID:27175551

  14. Prevention of ultraviolet radiation‑induced immunosuppression by sunscreen in Candida albicans‑induced delayed‑type hypersensitivity.

    PubMed

    Chen, Quan; Li, Runxiang; Zhao, Xiaoxia; Liang, Bihua; Ma, Shaoyin; Li, Zhenjie; Zhu, Huilan

    2016-07-01

    Ultraviolet (UV) radiation-induced immunosuppression leading to skin cancer has received increased attention in previous years. The present study aimed to investigate the immunoprotection offered by Anthelios sunscreen in a mouse model of Candida albicans‑induced delayed‑type hypersensitivity. Anthelios sunscreen was applied to the skin on the dorsal skin of BALB/c mice treated with a sub‑erythema dose of solar‑simulated radiation. Delayed‑type hypersensitivity was induced by immunization with Candida albicans. Changes in the skin thickness of the foot pads were measured, and immunosuppression rates were also evaluated. The expression levels of CD207, CD80 and CD86 in the Langerhans cells were semi‑quantitatively detected using Western blotting and immunohistochemical assays. The delayed‑type hypersensitivity mouse model was successfully established. The minimal erythema doses of UVA and UVB exposure to the mice were 2,000 and 145 mJ/cm2, respectively. The immunosuppression rates in the sunscreen group and non‑sunscreen group were 24.39 and 65.85%, respectively (P<0.01). The results of the Western blotting and immunohistochemistry showed that the expression levels of CD207 (P<0.01), CD80 (P<0.05) and CD86 (P<0.01) were higher in the sunscreen group, compared with those in the non‑sunscreen group. UV exposure reduced Candida albicans antigen‑induced delayed‑type hypersensitivity. Anthelios sunscreen was found to protect the skin from immunosuppression through the activation of epidermal Langerhans cells.

  15. Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients.

    PubMed

    Wang, Danxin; Curtis, Amanda; Papp, Audrey C; Koletar, Susan L; Para, Michael F

    2012-07-23

    Sulfamethoxazole (SMX) is a commonly used antibiotic for prevention of infectious diseases associated with HIV/AIDS and immune-compromised states. SMX-induced hypersensitivity is an idiosyncratic cutaneous drug reaction with genetic components. Here, we tested association of candidate genes involved in SMX bioactivation and antioxidant defense with SMX-induced hypersensitivity. Seventy seven single nucleotide polymorphisms (SNPs) from 14 candidate genes were genotyped and assessed for association with SMX-induced hypersensitivity, in a cohort of 171 HIV/AIDS patients. SNP rs761142 T > G, in glutamate cysteine ligase catalytic subunit (GCLC), was significantly associated with SMX-induced hypersensitivity, with an adjusted p value of 0.045. This result was replicated in a second cohort of 249 patients (p = 0.025). In the combined cohort, heterozygous and homozygous carriers of the minor G allele were at increased risk of developing hypersensitivity (GT vs TT, odds ratio = 2.2, 95% CL 1.4-3.7, p = 0.0014; GG vs TT, odds ratio = 3.3, 95% CL 1.6 - 6.8, p = 0.0010). Each minor allele copy increased risk of developing hypersensitivity 1.9 fold (95% CL 1.4 - 2.6, p = 0.00012). Moreover, in 91 human livers and 84 B-lymphocytes samples, SNP rs761142 homozygous G allele carriers expressed significantly less GCLC mRNA than homozygous TT carriers (p < 0.05). rs761142 in GCLC was found to be associated with reduced GCLC mRNA expression and with SMX-induced hypersensitivity in HIV/AIDS patients. Catalyzing a critical step in glutathione biosynthesis, GCLC may play a broad role in idiosyncratic drug reactions.

  16. Hapten-Induced Contact Hypersensitivity, Autoimmune Reactions, and Tumor Regression: Plausibility of Mediating Antitumor Immunity

    PubMed Central

    Erkes, Dan A.; Selvan, Senthamil R.

    2014-01-01

    Haptens are small molecule irritants that bind to proteins and elicit an immune response. Haptens have been commonly used to study allergic contact dermatitis (ACD) using animal contact hypersensitivity (CHS) models. However, extensive research into contact hypersensitivity has offered a confusing and intriguing mechanism of allergic reactions occurring in the skin. The abilities of haptens to induce such reactions have been frequently utilized to study the mechanisms of inflammatory bowel disease (IBD) to induce autoimmune-like responses such as autoimmune hemolytic anemia and to elicit viral wart and tumor regression. Hapten-induced tumor regression has been studied since the mid-1900s and relies on four major concepts: (1) ex vivo haptenation, (2) in situ haptenation, (3) epifocal hapten application, and (4) antigen-hapten conjugate injection. Each of these approaches elicits unique responses in mice and humans. The present review attempts to provide a critical appraisal of the hapten-mediated tumor treatments and offers insights for future development of the field. PMID:24949488

  17. Noninflammatory upregulation of nerve growth factor underlies gastric hypersensitivity induced by neonatal colon inflammation

    PubMed Central

    Li, Qingjie; Winston, John H.

    2015-01-01

    Gastric hypersensitivity is one of the key contributors to the postprandial symptoms of epigastric pain/discomfort, satiety, and fullness in functional dyspepsia patients. Epidemiological studies found that adverse early-life experiences are risk factors for the development of gastric hypersensitivity. Preclinical studies found that neonatal colon inflammation elevates plasma norepinephrine (NE), which upregulates expression of nerve growth factor (NGF) in the muscularis externa of the gastric fundus. Our goal was to investigate the cellular mechanisms by which NE upregulates the expression of NGF in gastric hypersensitive (GHS) rats, which were subjected previously to neonatal colon inflammation. Neonatal colon inflammation upregulated NGF protein, but not mRNA, in the gastric fundus of GHS rats. Western blotting showed upregulation of p110γ of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1), pAKT(Ser473), and phosphorylated 4E-binding protein (p4E-BP1)(Thr70), suggesting AKT activation and enhanced NGF protein translation. AKT inhibitor MK-2206 blocked the upregulation of NGF in the fundus of GHS rats. Matrix metalloproteinase 9 (MMP-9), the major NGF-degrading protease, was suppressed, indicating that NGF degradation was impeded. Incubation of fundus muscularis externa with NE upregulated NGF by modulating the protein translation and degradation pathways. Yohimbine, an α2-adrenergic receptor antagonist, upregulated plasma NE and NGF expression by activating the protein translation and degradation pathways in naive rats. In contrast, a cocktail of adrenergic receptor antagonists suppressed the upregulation of NGF by blocking the activation of the protein translation and degradation pathways. Our findings provide evidence that the elevation of plasma NE induces NGF expression in the gastric fundus. PMID:26608656

  18. Anisakis simplex: from Obscure Infectious Worm to Inducer of Immune Hypersensitivity

    PubMed Central

    Audicana, M. Teresa; Kennedy, Malcolm W.

    2008-01-01

    Summary: Infection of humans with the nematode worm parasite Anisakis simplex was first described in the 1960s in association with the consumption of raw or undercooked fish. During the 1990s it was realized that even the ingestion of dead worms in food fish can cause severe hypersensitivity reactions, that these may be more prevalent than infection itself, and that this outcome could be associated with food preparations previously considered safe. Not only may allergic symptoms arise from infection by the parasites (“gastroallergic anisakiasis”), but true anaphylactic reactions can also occur following exposure to allergens from dead worms by food-borne, airborne, or skin contact routes. This review discusses A. simplex pathogenesis in humans, covering immune hypersensitivity reactions both in the context of a living infection and in terms of exposure to its allergens by other routes. Over the last 20 years, several studies have concentrated on A. simplex antigen characterization and innate as well as adaptive immune response to this parasite. Molecular characterization of Anisakis allergens and isolation of their encoding cDNAs is now an active field of research that should provide improved diagnostic tools in addition to tools with which to enhance our understanding of pathogenesis and controversial aspects of A. simplex allergy. We also discuss the potential relevance of parasite products such as allergens, proteinases, and proteinase inhibitors and the activation of basophils, eosinophils, and mast cells in the induction of A. simplex-related immune hypersensitivity states induced by exposure to the parasite, dead or alive. PMID:18400801

  19. Hippocampal microglial activation and glucocorticoid receptor down-regulation precipitate visceral hypersensitivity induced by colorectal distension in rats.

    PubMed

    Zhang, Gongliang; Zhao, Bing-Xue; Hua, Rong; Kang, Jie; Shao, Bo-Ming; Carbonaro, Theresa M; Zhang, Yong-Mei

    2016-03-01

    Visceral hypersensitivity is a common characteristic in patients suffering from irritable bowel syndrome (IBS) and other disorders with visceral pain. Although the pathogenesis of visceral hypersensitivity remains speculative due to the absence of pathological changes, the long-lasting sensitization in neuronal circuitry induced by early life stress may play a critical role beyond the digestive system even after complete resolution of the initiating event. The hippocampus integrates multiple sources of afferent inputs and sculpts integrated autonomic outputs for pain and analgesia regulation. Here, we examined the hippocampal mechanism in the pathogenesis of visceral hypersensitivity with a rat model induced by neonatal and adult colorectal distensions (CRDs). Neither neonatal nor adult CRD evoked behavioral abnormalities in adulthood; however, adult re-exposure to CRD induced persistent visceral hypersensitivity, depression-like behaviors, and spatial learning impairment in rats that experienced neonatal CRD. Rats that experienced neonatal and adult CRDs presented a decrease in hippocampal glucocorticoid receptor (GR) immunofluorescence staining and protein expression, and increases in hippocampal microglial activation and cytokine (IL-1β and TNF-α) accumulation. The decrease in hippocampal GR expression and increase in hippocampal IL-1β and TNF-α accumulation could be prevented by hippocampal local infusion of minocycline, a microglial inhibitor. These results suggest that neonatal CRD can increase the vulnerability of hippocampal microglia, and adult CRD challenge facilitates the hippocampal cytokine release from the sensitized microglia, which down-regulates hippocampal GR protein expression and, subsequently, precipitates visceral hypersensitivity.

  20. Evaluation of bronchial hypersensitivity in veterans with sulfur mustard gas-induced skin or eye manifestations without respiratory symptoms: 15 years after exposure.

    PubMed

    Assadsangabi, Arash; Emad, Ali

    2006-01-01

    The authors evaluated the prevalence of bronchial hypersensitivity in subjects who had confirmed exposure to sulfur mustard gas (SMG) but no overt respiratory manifestations. They chose 30 patients who had proven skin or eye manifestations secondary to SMG, and performed baseline and provocative pulmonary function testing with cold air and methacholine. The authors performed the same procedure on 30 control volunteers. After challenge testing with cold air and methacholine, bronchial hypersensitivity was detected in 7 (23.3%) and 9 (30%) of cases, respectively. Only 1 control subject showed hypersensitivity after provocation testing with cold air (p = approximately .05); the same control subject showed a positive challenge testing result with 10 mg/ml of methacholine (p < .02). The kappa coefficient for evaluating the effectiveness of the cold air, as a provocative agent for challenge testing, was 93.3%.

  1. Drug-Induced Hypersensitivity Syndrome Caused by Carbamazepine Used for the Treatment of Trigeminal Neuralgia

    PubMed Central

    Ono, Yuko; Shirafuji, Yoshinori; Hamada, Toshihisa; Masui, Masanori; Obata, Kyoichi; Yao, Mayumi; Kishimoto, Koji; Sasaki, Akira

    2016-01-01

    An 88-year-old man was diagnosed with trigeminal neuralgia, and treatment of carbamazepine 200 mg/day was initiated. About 6 weeks later, the patient developed a skin rash accompanied by fever. He was admitted to hospital and diagnosed with drug-induced hypersensitivity syndrome (DIHS) caused by carbamazepine. Oral carbamazepine treatment was stopped, but blood tests showed acute liver and acute renal failure. Drug-induced lymphocyte stimulation test (DLST) for carbamazepine, human herpes virus-6 (HHV-6) IgG, and CMV-HRP were negative. Oral prednisolone therapy was begun 18 days later. The titer of HHV-6 IgG antibodies was then detected (640 times). Following treatment, liver and renal function improved and the erythema disappeared. PMID:27885344

  2. Visceral Hypersensitivity Is Provoked by 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Ileitis in Rats.

    PubMed

    Shah, Manoj K; Wan, Juan; Janyaro, Habibullah; Tahir, Adnan H; Cui, Luying; Ding, Ming-Xing

    2016-01-01

    Crohn's Disease (CD), a chronic Inflammatory Bowel Disease, can occur in any part of the gastrointestinal tract, but most frequently in the ileum. Visceral hypersensitivity contributes for development of chronic abdominal pain in this disease. Currently, the understanding of the mechanism underlying hypersensitivity of Crohn's ileitis has been hindered by a lack of specific animal model. The present study is undertaken to investigate the visceral hypersensitivity provoked by 2,4,6-trinitrobenzene sulfonic (TNBS)-induced ileitis rats. Male Sprague-Dawley rats were anaesthetized and laparotomized for intraileal injection of TNBS (0.6 ml, 80 mg/kg body weight in 30% ethanol, n = 48), an equal volume of 30% Ethanol (n = 24), and Saline (n = 24), respectively. Visceral hypersensitivity was assessed by visceromotor responses (VMR) to 20, 40, 60, 80, and 100 mmHg colorectal distension pressure (CRD) at day 1, 3, 7, 14, 21, and 28. Immediately after CRD test, the rats were euthanized for collecting the terminal ileal segment for histopathological examinations and ELISA of myleoperoxidase and cytokines (TNF-α, IL-1β, IL-6), and dorsal root ganglia (T11) for determination of calcitonin gene-related peptide by immunohistochemistry, respectively. Among all groups, TNBS-treatment showed transmural inflammation initially at 3 days, reached maximum at 7 days and persisted up to 21 days. The rats with ileitis exhibited (P < 0.05) VMR to CRD at day 7 to day 21. The calcitonin gene-related peptide-immunoreactive positive cells increased (P < 0.05) in dorsal root ganglia at day 7 to 21, which was persistently consistent with visceral hypersensitivity in TNBS-treated rats. TNBS injection into the ileum induced transmural ileitis including granuloma and visceral hypersensitivity. As this model mimics clinical manifestations of CD, it may provide a road map to probe the pathogenesis of gut inflammation and visceral hypersensitivity, as well as for establishing the therapeutic protocol

  3. Small bowel transplantation induces adrenergic hypersensitivity in ileal longitudinal smooth muscle in rats.

    PubMed

    Ohtani, N; Balsiger, B M; Anding, W J; Duenes, J A; Sarr, M G

    2000-01-01

    Our aim was to determine the effects of small bowel transplantation on contractility of longitudinal muscle in the rat ileum. Full-thickness longitudinal muscle strips from four groups of rats (naive controls, sham-operated controls, and 1 week and 8 weeks after syngeneic orthotopic small bowel transplantation) were studied in vitro. Neither baseline contractility nor response to neural blockade (tetrodotoxin) or adrenergic/cholinergic blockade differed among the groups. Although the dose response to the cholinergic agonist bethanechol and to nitric oxide did not differ among groups, the ED50 (negative log of concentration giving half-maximal effect) for the adrenergic agonist norepinephrine was increased l week and 8 weeks after transplantation, indicating a hypersensitivity response not blocked by tetrodotoxin. Nonadrenergic, noncholinergic inhibitory responses to electrical field stimulation were of greater amplitude and occurred at lesser frequencies (>/=5 Hz) 1 week after small bowel transplantation, but returned to control values 8 weeks postoperatively. These inhibitory responses were blocked by the nitric oxide synthase inhibitor L-NMMA but not by methylene blue, a nonspecific inhibitor of guanylate cyclase. Small bowel transplantation induces a persistent adrenergic denervation hypersensitivity at the muscle and appears to upregulate, at least transiently, other inhibitory mechanisms mediated by neural release of nitric oxide. Small bowel transplantation does not alter muscle response to cholinergic pathways. These alterations in smooth muscle contractility may affect gut function early after clinical small bowel transplantation.

  4. Drug-reaction eosinophilia and systemic symptoms and drug-induced hypersensitivity syndrome.

    PubMed

    Fernando, Suran L

    2014-02-01

    Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DIHS), is a rare, severe cutaneous adverse reaction characterised by fever, rash, lymphadenopathy, eosinophilia and/or other leukocyte abnormalities, and internal organ involvement and often has a relapsing-remitting course despite withdrawal of the drug. The drugs that are most implicated include aromatic anticonvulsants, allopurinol, sulphonamides, antiretrovirals (abacavir and nevirapine), and minocycline. The pathogenesis of DRESS/DIHS is far from clear but probably involves a combination of impaired pharmacokinetics and the accumulation of drug metabolites, the sequential reactivation of the herpesvirus family and genetic susceptibility conferred by the association with certain human leukocyte antigen (HLA) class I alleles. The strong association between abacavir and HLA-B*5701 has enabled pharmacogenetics screening to be employed successfully to minimise the occurrence of hypersensitivity. A prolonged course of oral corticosteroids is required to treat DRESS/DIHS, given the relapsing-remitting nature of the condition with i.v. immunoglobulin and valgangciclovir reserved for refractory or life-threatening cases. © 2013 The Australasian College of Dermatologists.

  5. Proteomics Study on Nonallergic Hypersensitivity Induced by Compound 4880 and Ovalbumin.

    PubMed

    Xu, Yubin; Guo, Na; Dou, Deqiang; Ran, Xiaoku; Ma, Xiande; Kuang, Haixue

    2016-01-01

    Nonallergic hypersensitivity reaction (NHR) accounts for more than 77% of all immune-mediated immediate hypersensitivity reactions and has become a serious threat to public health. Here, proteomics was used to study the NHR mechanism of two typical substances, the compound 4880 and ovalbumin. Twelve different proteins were suggested as potential biomarkers for examining the NHR mechanism, and our results revealed that the mechanism mainly encompassed 2 processes, i.e., generation and effect processes. The generation process could be classified as direct stimulation, complement (classical and alternative), coagulation, kallikrein-kinin, and integrated pathways. Thus glutathione peroxidase 1, terminal complement complex (complement factor 4d and Bb), coagulation 13, kininogen-1, and IgE could be used as candidate biomarkers for the indication of the corresponding pathways respectively, the proteins were further confirmed by ELISA. And the effect process was mainly composed of histamine as well as proteins such as DCD and MYLPF, which could be used as important indices for the symptoms of NHR. Our study differs from previous studies in that C4880 was found to not only be involved in the direct stimulation pathway, but also in the activated complement and kallikrein-kinin pathways through the coagulation pathway. We also report for the first time that ovalbumin-induced NHR could be a combination of the coagulation, classical complement, and integrated pathways.

  6. Cold Suppresses Agonist-induced Activation of TRPV1

    PubMed Central

    Chung, M.-K.; Wang, S.

    2011-01-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction. PMID:21666106

  7. Cold suppresses agonist-induced activation of TRPV1.

    PubMed

    Chung, M-K; Wang, S

    2011-09-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction.

  8. Endothelial dysfunction in cold-induced hypertensive rats.

    PubMed

    Zhu, Zhiming; Zhu, Shanjun; Zhu, Jijun; van der Giet, Markus; Tepel, Martin

    2002-02-01

    Endothelial dysfunction can be observed in preatherosclerotic conditions. However, its pathogenetic role in hypertension is still controversial. Endothelial-dependent changes of blood pressure (BP) and expression of endothelial nitric oxide synthase (eNOS) were evaluated in cold-induced hypertensive rats. Wistar rats were exposed to cold stress for 8 weeks. Exposure to cold stress significantly increased the systolic BP in rats. The infusion of acetylcholine significantly lowered mean arterial BP in control rats by 48 +/- 2% and by 32 +/- 1% in cold-induced hypertensive rats. The acetylcholine-induced reduction of mean arterial BP was significantly attenuated in cold-induced hypertensive rats (control rats, 45 +/- 2 mm Hg; cold-induced hypertensive rats, 34 +/- 3 mm Hg; P < .05). Administration of N(G)-nitro-L-arginine-methyl ester for 1 week significantly increased BP in control rats, whereas no effect could be observed in cold-induced hypertensive rats. In cold-induced hypertensive rats eNOS in aortic vessels was significantly reduced compared to control rats. In this nongenetic, nonsurgical animal model of cold-induced hypertensive rats an endothelial dysfunction can be observed due to reduced eNOS.

  9. Alcohol and High Fat Induced Chronic Pancreatitis: TRPV4 Antagonist Reduces Hypersensitivity

    PubMed Central

    Zhang, Liping; Kline, Robert H; Deevska, Gergana; Ma, Fei; Nikolova-Karakashian, Mariana; Westlund, Karin N

    2015-01-01

    The pathogenesis of pain in chronic pancreatitis is poorly understood, and its treatment can be a major clinical challenge. Surgical and other invasive methods have variable outcomes that can be unsatisfactory. Therefore, there is a great need for further discovery of the pathogenesis of pancreatitis pain and new therapeutic targets. Human and animal studies indicate a critical role for oxidative stress and activation of transient receptor potential (TRP) cation channel subfamily members TRPV1 and TRPA1 on pancreatic nociceptors in sensitization mechanisms that result in pain. However, the in vivo role of TRPV4 in chronic pancreatitis needs further evaluation. The present study characterized a rat alcohol/high fat diet (AHF) induced chronic pancreatitis model with hypersensitivity, fibrotic pathology, and fat vacuolization consistent with the clinical syndrome. The rats with AHF induced pancreatitis develop referred visceral pain-like behaviors, i.e. decreased hindpaw mechanical thresholds and shortened abdominal and hindpaw withdrawal latency to heat. In this study, oxidative stress was characterized as well as the role of TRPV4 in chronic visceral hypersensitivity. Lipid peroxidase and oxidative stress were indicated by increased plasma thiobarbituric acid reactive substances (TBARS) and diminished pancreatic manganese superoxide dismutase (MnSOD). The secondary sensitization associated with AHF induced pancreatitis was effectively alleviated by the TRPV4 antagonist, HC 067047. Similarity of the results to those with the peripherally restricted µ-opiate receptor agonist, loperamide, suggested TRPV4 channel activated peripheral sensitization. This study using a reliable model that provides pre-clinical correlates of human chronic pancreatitis provides further evidence that TRPV4 channel is a potential therapeutic target for treatment of pancreatitis pain. PMID:26480812

  10. Manual acupuncture inhibits mechanical hypersensitivity induced by spinal nerve ligation in rats.

    PubMed

    Cidral-Filho, F J; da Silva, M D; Moré, A O O; Córdova, M M; Werner, M F; Santos, A R S

    2011-10-13

    Manual acupuncture (MA) has presented analgesic activity against neuropathic pain in patients and animal models, yet a series of questions remain: Is MA effectiveness dependent of acupoint selection or combination? Is it equally efficient when treatment starts on the initial (acute) or sub-chronic phase of spinal nerve ligation (SNL)-induced neuropathy? Is MA effect related to the release of endogenous opioids? Does MA produce similar effects to gabapentin? To answer these questions rats submitted to the L5/L6 SNL injury were treated with unilateral MA (ST36 (Zusanli), SP6 (Sanyingjiao) or ST36+SP6 acupoint stimulation); or with gabapentin (30 mg/kg i.p., used as positive control). Both acupoints have been demonstrated to present analgesic activity and are used in clinical practice and basic science research. In addition, we investigated the influence of naloxone (1 mg/kg i.p., a nonselective opioid receptor antagonist) on MA treatment and also the effect of unilateral ST36+SP6 MA treatment beginning acutely (5 days) or sub-chronically (14 days) after SNL. Our results demonstrate that single or combined unilateral stimulation was able to reduce mechanical hypersensitivity with treatment beginning in both acute and sub-chronic phases of SNL-induced neuropathy; MA effect was blocked by naloxone, and finally; SP6+ST36 MA presented similar effect to gabapentin (30 mg/kg). In conclusion, our results demonstrate, for the first time, that unilateral MA (ST36, SP6 or ST36+SP6) reduces hypersensitivity induced by the SNL with effect dependent of the opioid system and comparable with the one obtained with gabapentin (used as positive control). Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. Role of the Excitability Brake Potassium Current IKD in Cold Allodynia Induced by Chronic Peripheral Nerve Injury.

    PubMed

    González, Alejandro; Ugarte, Gonzalo; Restrepo, Carlos; Herrera, Gaspar; Piña, Ricardo; Gómez-Sánchez, José Antonio; Pertusa, María; Orio, Patricio; Madrid, Rodolfo

    2017-03-22

    Cold allodynia is a common symptom of neuropathic and inflammatory pain following peripheral nerve injury. The mechanisms underlying this disabling sensory alteration are not entirely understood. In primary somatosensory neurons, cold sensitivity is mainly determined by a functional counterbalance between cold-activated TRPM8 channels and Shaker-like Kv1.1-1.2 channels underlying the excitability brake current IKD Here we studied the role of IKD in damage-triggered painful hypersensitivity to innocuous cold. We found that cold allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in mice, was related to both an increase in the proportion of cold-sensitive neurons (CSNs) in DRGs contributing to the sciatic nerve, and a decrease in their cold temperature threshold. IKD density was reduced in high-threshold CSNs from CCI mice compared with sham animals, with no differences in cold-induced TRPM8-dependent current density. The electrophysiological properties and neurochemical profile of CSNs revealed an increase of nociceptive-like phenotype among neurons from CCI animals compared with sham mice. These results were validated using a mathematical model of CSNs, including IKD and TRPM8, showing that a reduction in IKD current density shifts the thermal threshold to higher temperatures and that the reduction of this current induces cold sensitivity in former cold-insensitive neurons expressing low levels of TRPM8-like current. Together, our results suggest that cold allodynia is largely due to a functional downregulation of IKD in both high-threshold CSNs and in a subpopulation of polymodal nociceptors expressing TRPM8, providing a general molecular and neural mechanism for this sensory alteration.SIGNIFICANCE STATEMENT This paper unveils the critical role of the brake potassium current IKD in damage-triggered cold allodynia. Using a well-known form of nerve injury and combining behavioral analysis, calcium imaging, patch clamping, and pharmacological

  12. Neurological and cellular regulation of visceral hypersensitivity induced by chronic stress and colonic inflammation in rats.

    PubMed

    Chen, J; Winston, J H; Sarna, S K

    2013-09-17

    The role of inflammation in inducing visceral hypersensitivity (VHS) in ulcerative colitis patients remains unknown. We tested the hypothesis that acute ulcerative colitis-like inflammation does not induce VHS. However, it sets up molecular conditions such that chronic stress following inflammation exaggerates single-unit afferent discharges to colorectal distension. We used dextran sodium sulfate (DSS) to induce ulcerative colitis-like inflammation and a 9-day heterotypic chronic stress protocol in rats. DSS upregulated Nav1.8 mRNA in colon-responsive dorsal root ganglion (DRG) neurons, TRPV1 in colonic muscularis externae (ME) and BDNF in spinal cord without affecting the spike frequency in spinal afferents or VMR to CRD. By contrast, chronic stress did not induce inflammation but it downregulated Kv1.1 and Kv1.4 mRNA in DRG neurons, and upregulated TRPA1 and nerve growth factor in ME, which mediated the increase of spike frequency and VMR to CRD. Chronic stress following inflammation exacerbated spike frequency in spinal afferent neurons. TRPA1 antagonist suppressed the sensitization of afferent neurons. DSS-inflammation did not affect the composition or excitation thresholds of low-threshold and high-threshold fibers. Chronic stress following inflammation increased the percent composition of high-threshold fibers and lowered the excitation threshold of both types of fibers. We conclude that not all types of inflammation induce VHS, whereas chronic stress induces VHS in the absence of inflammation.

  13. Inhibition of phosphodiesterase-1 attenuates cold-induced pulmonary hypertension.

    PubMed

    Crosswhite, Patrick; Sun, Zhongjie

    2013-03-01

    Chronic exposure to cold caused pulmonary arterial hypertension (cold-induced pulmonary hypertension [CIPH]) and increased phosphodiesterase-1C (PDE-1C) expression in pulmonary arteries (PAs) in rats. The purpose of this study is to investigate a hypothesis that inhibition of PDE-1 would decrease inflammatory infiltrates and superoxide production leading to attenuation of CIPH. Three groups of male rats were exposed to moderate cold (5±1°C) continuously, whereas 3 groups were maintained at room temperature (23.5±1°C, warm; 6 rats/group). After 8-week exposure to cold, 3 groups in each temperature condition received continuous intravenous infusion of 8-isobutyl-methylxanthine (8-IBMX) (PDE-1 inhibitor), apocynin (NADPH oxidase inhibitor) or vehicle, respectively, for 1 week. Cold exposure significantly increased right-ventricular systolic pressure compared with warm groups (33.8±3.2 versus 18.6±0.3 mm Hg), indicating that animals developed CIPH. Notably, treatment with 8-IBMX significantly attenuated the cold-induced increase in right ventricular pressure (23.5±1.8 mm Hg). Cold exposure also caused right-ventricular hypertrophy, whereas 8-IBMX reversed cold-induced right ventricular hypertrophy. Cold exposure increased PDE-1C protein expression, macrophage infiltration, NADPH oxidase activity, and superoxide production in PAs and resulted in PA remodeling. 8-IBMX abolished cold-induced upregulation of PDE-1C in PAs. Interestingly, inhibition of PDE-1 eliminated cold-induced macrophage infiltration, NADPH oxidase activation, and superoxide production in PAs and reversed PA remodeling. Inhibition of NADPH oxidase by apocynin abolished cold-induced superoxide production and attenuated CIPH and PA remodeling. In conclusion, inhibition of PDE-1 attenuated CIPH and reversed cold-induced PA remodeling by suppressing macrophage infiltration and superoxide production, suggesting that upregulation of PDE-1C expression may be involved in the pathogenesis of CIPH.

  14. Cold-induced urticaria: challenges in diagnosis and management

    PubMed Central

    Hochstadter, Elana Fay; Ben-Shoshan, Moshe

    2013-01-01

    Cold-induced urticaria (CU) is a chronic physical urticaria that can be hard to diagnose and manage. Symptoms of CU can vary from mild localised urticaria, angio-oedema to anaphylaxis. CU may be induced by a wide range of cold triggers from aquatic activities to ingestions of cold substances. This exemplifies the importance of accurate diagnosis and management of patients with CU. We present three cases of CU that demonstrate the variability in triggers and clinical presentation. PMID:23839613

  15. Molecular cloning and characterization of two hypersensitive induced reaction genes from wheat infected by stripe rust pathogen

    USDA-ARS?s Scientific Manuscript database

    A novel gene induced during hypersensitive reaction (HIR) in wheat was identified using in silico cloning and designated as TaHIR2. The TaHIR2 gene was deduced to encode a 284-amino acid protein, whose molecular mass and isoelectric point (pI) were 31.05 kD and 5.18, respectively. Amino acid sequenc...

  16. Disruption of Microtubular Cytoskeleton Induced by Cryptogein, an Elicitor of Hypersensitive Response in Tobacco Cells1

    PubMed Central

    Binet, Marie-Noëlle; Humbert, Claude; Lecourieux, David; Vantard, Marylin; Pugin, Alain

    2001-01-01

    The dynamics of microtubular cytoskeleton were studied in tobacco (Nicotiana tabacum cv Xanthi) cells in response to two different plant defense elicitors: cryptogein, a protein secreted by Phytophthora cryptogea and oligogalacturonides (OGs), derived from the plant cell wall. In tobacco plants cryptogein triggers a hypersensitive-like response and induces systemic resistance against a broad spectrum of pathogens, whereas OGs induce defense responses, but fail to trigger cell death. The comparison of the microtubule (MT) dynamics in response to cryptogein and OGs in tobacco cells indicates that MTs appear unaffected in OG-treated cells, whereas cryptogein treatment caused a rapid and severe disruption of microtubular network. When hyperstabilized by the MT depolymerization inhibitor, taxol, the MT network was still disrupted by cryptogein treatment. On the other hand, the MT-depolymerizing agent oryzalin and cryptogein had different and complementary effects. In addition to MT destabilization, cryptogein induced the death of tobacco cells, whereas OG-treated cells did not die. We demonstrated that MT destabilization and cell death induced by cryptogein depend on calcium influx and that MT destabilization occurs independently of active oxygen species production. The molecular basis of cryptogein-induced MT disruption and its potential significance with respect to cell death are discussed. PMID:11161014

  17. Altered sympathovagal balance and pain hypersensitivity in TNBS-induced colitis.

    PubMed

    Ciesielczyk, Katarzyna; Furgała, Agata; Dobrek, Łukasz; Juszczak, Kajetan; Thor, Piotr

    2017-02-01

    Pain hypersensitivity, abnormal motility and autonomic dysfunction contribute to functional symptoms of inflammatory bowel disease (IBD). The aim of this study was to assess: nociceptive thresholds for mechanical allodynia (MA) and thermal hyperalgesia (TH), intestinal motility (distal colonic transit and emptying), and cardiac autonomic neuropathy (indices of heart rate variability - HRV) in male Wistar rats with experimental trinitrobenzene sulfonic acid (TNBS) induced colitis. To identify a potential vagal contribution the bilateral subdiaphragmatic vagotomy (SDV) was performed. Experimental colitis resulted in a significant decrease in pain threshold (MA 23.60 ±2.12, p < 0.001, TH 8.51 ±1.49, p < 0.001), reduced expulsion time (6.2 ±3.5, p < 0,01) and increase in the sympathetic autonomic activity (LFnu 32.54 ±21.16, p < 0.03). The animals with diminished vagal integrity presented with reduced gastrointestinal motility (39.8 ±25.1, p < 0.01) and a decrease in the parasympathetic high-frequency domain of HRV (HFnu 55.37 ±22.80, p < 0.002). The vagotomized rats with colitis showed the strongest nociceptive response (MA 22.46 ±3.02, p < 0.004; TH 7.99 ±1.12, p < 0.003) as well as significant changes in sympatho-vagal balance on HRV testing (LFnu 28.25 ±14.66, p < 0.04; HFnu 71.34 ±14.55, p < 0.04). The relationship between the cardiovascular and gastrointestinal system is modulated by neural, hormonal and inflammatory factors. This leads to dysregulation of the brain-gut interactions in the course of IBD. Sensitization and visceral-somatic convergence trigger pain hypersensitivity and autonomic sympathovagal imbalance. While integral vagal innervation impacts analgesic mechanisms via modulation of the immune response, SDV raises sympathetic activity and induces excessive hyperalgesia.

  18. Altered sympathovagal balance and pain hypersensitivity in TNBS-induced colitis

    PubMed Central

    Furgała, Agata; Dobrek, Łukasz; Juszczak, Kajetan; Thor, Piotr

    2016-01-01

    Introduction Pain hypersensitivity, abnormal motility and autonomic dysfunction contribute to functional symptoms of inflammatory bowel disease (IBD). Material and methods The aim of this study was to assess: nociceptive thresholds for mechanical allodynia (MA) and thermal hyperalgesia (TH), intestinal motility (distal colonic transit and emptying), and cardiac autonomic neuropathy (indices of heart rate variability – HRV) in male Wistar rats with experimental trinitrobenzene sulfonic acid (TNBS) induced colitis. To identify a potential vagal contribution the bilateral subdiaphragmatic vagotomy (SDV) was performed. Results Experimental colitis resulted in a significant decrease in pain threshold (MA 23.60 ±2.12, p < 0.001, TH 8.51 ±1.49, p < 0.001), reduced expulsion time (6.2 ±3.5, p < 0,01) and increase in the sympathetic autonomic activity (LFnu 32.54 ±21.16, p < 0.03). The animals with diminished vagal integrity presented with reduced gastrointestinal motility (39.8 ±25.1, p < 0.01) and a decrease in the parasympathetic high-frequency domain of HRV (HFnu 55.37 ±22.80, p < 0.002). The vagotomized rats with colitis showed the strongest nociceptive response (MA 22.46 ±3.02, p < 0.004; TH 7.99 ±1.12, p < 0.003) as well as significant changes in sympatho-vagal balance on HRV testing (LFnu 28.25 ±14.66, p < 0.04; HFnu 71.34 ±14.55, p < 0.04). Conclusions The relationship between the cardiovascular and gastrointestinal system is modulated by neural, hormonal and inflammatory factors. This leads to dysregulation of the brain-gut interactions in the course of IBD. Sensitization and visceral-somatic convergence trigger pain hypersensitivity and autonomic sympathovagal imbalance. While integral vagal innervation impacts analgesic mechanisms via modulation of the immune response, SDV raises sympathetic activity and induces excessive hyperalgesia. PMID:28144278

  19. Relationships of self-identified cold tolerance and cold-induced vasodilatation in the finger

    NASA Astrophysics Data System (ADS)

    Park, Joonhee; Lee, Joo-Young

    2016-04-01

    This study was conducted to investigate relationships of self-identified cold tolerance and cold-induced vasodilatation (CIVD) in the finger. Nine males and 34 females participated in the following 2 tests: a CIVD test and a self-reported survey. The CIVD test was conducted 30-min cold-water immersion (3.8 ± 0.3 °C) of the middle finger at an air temperature of 27.9 ± 0.1 °C. The self-reported questionnaire consisted of 28 questions about whole and local body cold and heat tolerances. By a cluster analysis on the survey results, the participants were divided into two groups: high self-identified cold tolerance (HSCT, n = 25) and low self-identified cold tolerance (LSCT, n = 18). LSCT had lower self-identified cold tolerance ( P < 0.001), preferred hot thermal stimulation ( P = 0.006), and wore heavier clothing during daily life ( P < 0.001) than HSCT. LSCT had significantly lower maximal finger temperatures ( T max) ( P = 0.040), smaller amplitude ( P = 0.029), and delayed onset time of CIVD ( P = 0.080) when compared to HSCT. Some questions examining the self-identified cold or heat tolerance had relationships with cold tolerance index, T max, and amplitude ( P < 0.1). These results indicate that self-identified cold tolerance classified through a standardized survey could be a good index to predict physiological cold tolerance.

  20. Relationships of self-identified cold tolerance and cold-induced vasodilatation in the finger.

    PubMed

    Park, Joonhee; Lee, Joo-Young

    2016-04-01

    This study was conducted to investigate relationships of self-identified cold tolerance and cold-induced vasodilatation (CIVD) in the finger. Nine males and 34 females participated in the following 2 tests: a CIVD test and a self-reported survey. The CIVD test was conducted 30-min cold-water immersion (3.8 ± 0.3 °C) of the middle finger at an air temperature of 27.9 ± 0.1 °C. The self-reported questionnaire consisted of 28 questions about whole and local body cold and heat tolerances. By a cluster analysis on the survey results, the participants were divided into two groups: high self-identified cold tolerance (HSCT, n = 25) and low self-identified cold tolerance (LSCT, n = 18). LSCT had lower self-identified cold tolerance (P < 0.001), preferred hot thermal stimulation (P = 0.006), and wore heavier clothing during daily life (P < 0.001) than HSCT. LSCT had significantly lower maximal finger temperatures (T max) (P = 0.040), smaller amplitude (P = 0.029), and delayed onset time of CIVD (P = 0.080) when compared to HSCT. Some questions examining the self-identified cold or heat tolerance had relationships with cold tolerance index, T max, and amplitude (P < 0.1). These results indicate that self-identified cold tolerance classified through a standardized survey could be a good index to predict physiological cold tolerance.

  1. A single-arm Phase II validation study of preventing oxaliplatin-induced hypersensitivity reactions by dexamethasone: the AVOID trial

    PubMed Central

    Yoshida, Yoichiro; Hirata, Keiji; Matsuoka, Hiroshi; Iwamoto, Shigeyoshi; Kotaka, Masahito; Fujita, Hideto; Aisu, Naoya; Hoshino, Seiichiro; Kosaka, Takeo; Maeda, Kotaro; Kiyomi, Fumiaki; Yamashita, Yuichi

    2015-01-01

    Background Patients with colorectal cancer treated with oxaliplatin are at risk of hypersensitivity reactions, with the incidence estimated to be 12%–20%. Coinfusion of dexamethasone and oxaliplatin could potentially reduce the incidence of these reactions, but oxaliplatin is reported to be incompatible with alkaline compounds in solution. However, in a previous retrospective study we found that the pH of a solution of dexamethasone and oxaliplatin was less than 7.4, and that hypersensitivity to oxaliplatin could have been prevented by coinfusion of dexamethasone. We aimed to evaluate the effectiveness of coinfusion of dexamethasone and oxaliplatin to prevent oxaliplatin-induced hypersensitivity reactions. Patients and methods The AVOID trial was a prospective, multicenter, open-label, single-arm Phase II trial conducted from January to September 2013. The study included 73 patients who received capecitabine plus oxaliplatin (XELOX) or XELOX plus bevacizumab therapy for colorectal cancer. In all patients, oxaliplatin was administered in combination with dexamethasone. The primary outcome measure was the presence of hypersensitivity reactions. Results Hypersensitivity reactions occurred in three patients (4.1%); all three experienced a cutaneous reaction (grade 1 erythema). None of the 73 patients developed respiratory symptoms, ocular symptoms, or anaphylaxis. Grade 3 or higher hemotoxicity occurred in 13.7% of the patients and grade 3 or higher nonhematological toxicity occurred in 13.7%. The response rate to treatment was 64.4%. Conclusion The coinfusion of dexamethasone and oxaliplatin effectively reduced oxaliplatin-induced hypersensitivity reactions in patients with colorectal cancer. This approach should be considered for all patients treated with oxaliplatin, allowing treatment to be completed as planned. PMID:26648694

  2. Reversibility of cold-induced hypertension after removal of rats from cold.

    PubMed

    Shechtman, O; Papanek, P E; Fregly, M J

    1990-07-01

    Chronic exposure of rats to cold air induces hypertension, including elevation of blood pressure and cardiac hypertrophy. The present study was designed to assess reversibility of these changes after removal from cold. Five groups of six male rats each were exposed to cold (5 +/- 2 degrees C) for 39 days, while six control rats were maintained at 26 +/- 2 degrees C. Systolic blood pressures of the rats in one of the cold-treated groups, as well as the controls, were measured twice weekly throughout the experiment. Blood pressure of the cold-exposed rats (150 +/- 3 mmHg; 1 mmHg = 133.3 Pa) became elevated significantly above that of controls (129 +/- 3 mmHg) within 4 weeks. On day 39 of cold exposure, one group (six rats) of the cold-treated rats was sacrificed while still in the cold. The remaining four groups of cold-treated rats were than removed from cold and kept at 26 +/- 2 degrees C. One group of cold-treated rats was sacrificed weekly thereafter. During the last week, the six control rats were also sacrificed. At death, the heart, kidneys, and adrenal glands were removed and weighed. Mean heart weight of the cold-treated group (346 +/- 7 mg/100 g body weight), sacrificed prior to removal from cold, was significantly (p less than 0.01) greater than that of controls (268 +/- 5 mg/100 g body weight). The increased heart weight of the cold-treated group appeared to result mainly from an increase in left ventricular weight.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Hypersensitivity Pneumonitis

    MedlinePlus

    ... Hypersensitivity Pneumonitis Also known as extrinsic allergic alveolitis, bird fancier’s lung, farmer’s lung, hot tub lung, and humidifier lung. Hypersensitivity pneumonitis is a rare immune system disorder that affects the lungs. It occurs in ...

  4. Pure Cold-Induced Cholinergic Urticaria in a Pediatric Patient

    PubMed Central

    Abraham, Tina; Frith, John; Tcheurekdjian, Haig; Hostoffer, Robert

    2016-01-01

    Cold urticaria and cholinergic urticaria are two distinct entities. The presentation of exclusive cold-induced cholinergic urticaria is very rare. The patient described herein had experienced urticaria in the exclusive setting of exercising in a cold environment. Urticarial testing including laboratory and in-office testing was all negative. The patient has prevented urticaria symptoms with oral antihistamine therapy. Pure cold-induced cholinergic urticaria is rarely described in literature. This form of urticaria has yet to be described in a pediatric patient. PMID:28025628

  5. Effects of cold environment exposure and cold acclimatization on exercise-induced salivary cortisol response.

    PubMed

    Izawa, Shuhei; Kim, Kijin; Akimoto, Takayuki; Ahn, Nayoung; Lee, Hoseong; Suzuki, Katsuhiko

    2009-01-01

    Considering the adverse effects of exercise-induced cortisol secretion on health in athletes, it is important to determine the environmental and individual factors that contribute to the variations in exercise-induced cortisol secretion. In this study, the effects of cold environment exposure and cold acclimatization on exercise-induced salivary cortisol responses were investigated. Short track skaters (n = 11), who usually practice under cold conditions, and inline skaters (n = 11), who usually practice under room temperature conditions, participated in a randomized crossover study. All participants cycled for 60 minutes at 65% Vo2 max under cold (ambient temperature: 5 +/- 1 degrees C, relative humidity 41% +/- 9%) and room temperature (ambient temperature: 21 +/- 1 degrees C, relative humidity 35% +/- 5%) conditions. The participants had a 120-minute bed rest recovery phase at room temperature after both exercise bouts. Cortisol levels were measured in saliva samples collected pre-exercise and postexercise at 1 minute, 30 minutes, 60 minutes, and 120 minutes. Both short track and inline skaters exhibited clear cortisol responses to exercise under cold and room temperature conditions. The magnitude of the cortisol response, however, was different between skaters and conditions. The inline skaters exhibited significantly higher cortisol values under cold conditions than under room temperature conditions (7.6 nmol/L and 4.2 nmol/L, respectively). However, the short track skaters exhibited significantly higher cortisol values under cold conditions compared to room temperature conditions (8.7 nmol/L and 5.4 nmol/L, respectively). The effects of cold environment exposure on exercise-induced cortisol response were different between skaters who usually practice under cold or room temperature conditions. These results can be interpreted as acclimatization to either cold or room temperature conditions attenuating the cortisol response, suggesting that acclimatization may

  6. A critical role of spinal Shank2 proteins in NMDA-induced pain hypersensitivity

    PubMed Central

    Yoon, Seo-Yeon; Kwon, Soon-Gu; Kim, Yong Ho; Yeo, Ji-Hee; Ko, Hyoung-Gon; Roh, Dae-Hyun; Kaang, Bong-Kiun; Beitz, Alvin J; Lee, Jang-Hern

    2017-01-01

    Background Self-injurious behaviors (SIBs) are devastating traits in autism spectrum disorder (ASD). Although deficits in pain sensation might be one of the contributing factors underlying the development of SIBs, the mechanisms have yet to be addressed. Recently, the Shank2 synaptic protein has been considered to be a key component in ASD, and mutations of SHANK2 gene induce the dysfunction of N-methyl-D-aspartate (NMDA) receptors, suggesting a link between Shank2 and NMDA receptors in ASD. Given that spinal NMDA receptors play a pivotal role in pain hypersensitivity, we investigated the possible role of Shank2 in nociceptive hypersensitivity by examining changes in spontaneous pain following intrathecal NMDA injection in Shank2−/− (Shank2 knock-out, KO) mice. Results Intrathecal NMDA injection evoked spontaneous nociceptive behaviors. These NMDA-induced nociceptive responses were significantly reduced in Shank2 KO mice. We also observed a significant decrease of NMDA currents in the spinal dorsal horn of Shank2 KO mice. Subsequently, we examined whether mitogen-activated protein kinase or AKT signaling is involved in this reduced pain behavior in Shank2 KO mice because the NMDA receptor is closely related to these signaling molecules. Western blotting and immunohistochemistry revealed that spinally administered NMDA increased the expression of a phosphorylated form of extracellular signal-regulated kinase (p-ERK) which was significantly reduced in Shank2 KO mice. However, p38, JNK, or AKT were not changed by NMDA administration. The ERK inhibitor, PD98059, decreased NMDA-induced spontaneous pain behaviors in a dose-dependent manner in wild-type mice. Moreover, it was found that the NMDA-induced increase in p-ERK was primarily colocalized with Shank2 proteins in the spinal cord dorsal horn. Conclusion Shank2 protein is involved in spinal NMDA receptor-mediated pain, and mutations of Shank2 may suppress NMDA-ERK signaling in spinal pain transmission. This study

  7. Forsythia suspensa extract alleviates hypersensitivity induced by soybean beta-conglycinin in weaned piglets.

    PubMed

    Hao, Yue; Li, Defa; Piao, Xianglan; Piao, Xiangshu

    2010-03-24

    Soybeans are known to stimulate food allergies; however, current therapies are lacking in alleviating hypersensitivity. The present study investigated whether Forsythia suspensa extract could attenuate purified soybean beta-conglycinin-induced anaphylactic reactions in weaned piglets. Eighteen 14-day-old piglets were sensitized and boosted by oral administration of purified beta-conglycinin. Forsythia suspensa extract was supplemented in the diet after the initial sensitization and continued for the remainder of the experiment. Piglets were challenged on day 28, and anaphylactic symptoms, passive cutaneous anaphylaxis, plasma histamine and intestinal microbial flora were analyzed. T-cell proliferative responses and cytokine production were also determined. Forsythia suspensa extract alleviated beta-conglycinin-induced anaphylactic symptoms by markedly reducing anaphylactic antibodies, mast cell degranulation, and histamine release while improving intestinal microbial flora. Furthermore, Forsythia suspensa extract significantly suppressed beta-conglycinin-induced T lymphocyte proliferation and IL-4 synthesis. Forsythia suspensa extract protected beta-conglycinin-sensitized piglets from anaphylactic reactions. Forsythia suspensa extract may provide a novel effective therapy for soybean allergy. Crown Copyright (c) 2010. Published by Elsevier Ireland Ltd. All rights reserved.

  8. The G2A receptor (GPR132) contributes to oxaliplatin-induced mechanical pain hypersensitivity.

    PubMed

    Hohmann, Stephan W; Angioni, Carlo; Tunaru, Sorin; Lee, Seungkyu; Woolf, Clifford J; Offermanns, Stefan; Geisslinger, Gerd; Scholich, Klaus; Sisignano, Marco

    2017-03-27

    Chemotherapy-induced peripheral neuropathic pain (CIPN) is a common and severe debilitating side effect of many widely used cytostatics. However, there is no approved pharmacological treatment for CIPN available. Among other substances, oxaliplatin causes CIPN in up to 80% of treated patients. Here, we report the involvement of the G-protein coupled receptor G2A (GPR132) in oxaliplatin-induced neuropathic pain in mice. We found that mice deficient in the G2A-receptor show decreased mechanical hypersensitivity after oxaliplatin treatment. Lipid ligands of G2A were found in increased concentrations in the sciatic nerve and dorsal root ganglia of oxaliplatin treated mice. Calcium imaging and patch-clamp experiments show that G2A activation sensitizes the ligand-gated ion channel TRPV1 in sensory neurons via activation of PKC. Based on these findings, we conclude that targeting G2A may be a promising approach to reduce oxaliplatin-induced TRPV1-sensitization and the hyperexcitability of sensory neurons and thereby to reduce pain in patients treated with this chemotherapeutic agent.

  9. Extended DNFB-induced contact hypersensitivity models display characteristics of chronic inflammatory dermatoses.

    PubMed

    Röse, Lars; Schneider, Claudia; Stock, Christine; Zollner, Thomas M; Döcke, Wolf-Dietrich

    2012-01-01

    Despite recent developments, there is a high medical need for new treatment options for chronic inflammatory dermatoses like allergic contact dermatitis (ACD) and psoriasis. Particularly, more predictive skin inflammation models are required to facilitate the process of drug discovery. Murine contact hypersensitivity (CHS) models adequately reflect ACD and are also used to characterize therapeutic approaches for psoriasis. Using the hapten 2,4-dinitrofluorobenzene (DNFB), we established new subacute and subchronic DNFB-induced CHS models in C57BL/6 mice, which more closely reflect the characteristics of chronic T-cell-dependent inflammatory dermatoses as pronounced keratinocyte proliferation, strong hypervascularization, immune cell infiltration and overexpression of T cell and inflammatory cytokines. For the subacute DNFB model, we demonstrated anti-inflammatory activity of the glucocorticoid, prednisolone, as well as of neutralization of TNFα, IL-12/IL-23 or IL-18. In the subchronic DNFB-induced CHS model, deficiency for MyD88 and IL-12/IL-35 p35 chain but not IL-12/IL-23 p40 chain led to decreased skin inflammation. Furthermore, as exemplified by the dose-dependently effective therapeutic prednisolone treatment, the subchronic model allows the continuous therapy of a pre-established stable contact dermatitis. Altogether, prolonged DNFB-induced mouse CHS models closely reflect ACD sensitive to glucocorticoids as standard therapy, reveal a more chronic skin inflammation and are responsive to cytokine antagonization.

  10. NMDA receptor subunit expression and PAR2 receptor activation in colospinal afferent neurons (CANs) during inflammation induced visceral hypersensitivity

    PubMed Central

    Suckow, Shelby K; Caudle, Robert M

    2009-01-01

    Background Visceral hypersensitivity is a clinical observation made when diagnosing patients with functional bowel disorders. The cause of visceral hypersensitivity is unknown but is thought to be attributed to inflammation. Previously we demonstrated that a unique set of enteric neurons, colospinal afferent neurons (CANs), co-localize with the NR1 and NR2D subunits of the NMDA receptor as well as with the PAR2 receptor. The aim of this study was to determine if NMDA and PAR2 receptors expressed on CANs contribute to visceral hypersensitivity following inflammation. Recently, work has suggested that dorsal root ganglion (DRG) neurons expressing the transient receptor potential vanilloid-1 (TRPV1) receptor mediate inflammation induced visceral hypersensitivity. Therefore, in order to study CAN involvement in visceral hypersensitivity, DRG neurons expressing the TRPV1 receptor were lesioned with resiniferatoxin (RTX) prior to inflammation and behavioural testing. Results CANs do not express the TRPV1 receptor; therefore, they survive following RTX injection. RTX treatment resulted in a significant decrease in TRPV1 expressing neurons in the colon and immunohistochemical analysis revealed no change in peptide or receptor expression in CANs following RTX lesioning as compared to control data. Behavioral studies determined that both inflamed non-RTX and RTX animals showed a decrease in balloon pressure threshold as compared to controls. Immunohistochemical analysis demonstrated that the NR1 cassettes, N1 and C1, of the NMDA receptor on CANs were up-regulated following inflammation. Furthermore, inflammation resulted in the activation of the PAR2 receptors expressed on CANs. Conclusion Our data show that inflammation causes an up-regulation of the NMDA receptor and the activation of the PAR2 receptor expressed on CANs. These changes are associated with a decrease in balloon pressure in response to colorectal distension in non-RTX and RTX lesioned animals. Therefore

  11. NMDA receptor subunit expression and PAR2 receptor activation in colospinal afferent neurons (CANs) during inflammation induced visceral hypersensitivity.

    PubMed

    Suckow, Shelby K; Caudle, Robert M

    2009-09-22

    Visceral hypersensitivity is a clinical observation made when diagnosing patients with functional bowel disorders. The cause of visceral hypersensitivity is unknown but is thought to be attributed to inflammation. Previously we demonstrated that a unique set of enteric neurons, colospinal afferent neurons (CANs), co-localize with the NR1 and NR2D subunits of the NMDA receptor as well as with the PAR2 receptor. The aim of this study was to determine if NMDA and PAR2 receptors expressed on CANs contribute to visceral hypersensitivity following inflammation. Recently, work has suggested that dorsal root ganglion (DRG) neurons expressing the transient receptor potential vanilloid-1 (TRPV1) receptor mediate inflammation induced visceral hypersensitivity. Therefore, in order to study CAN involvement in visceral hypersensitivity, DRG neurons expressing the TRPV1 receptor were lesioned with resiniferatoxin (RTX) prior to inflammation and behavioural testing. CANs do not express the TRPV1 receptor; therefore, they survive following RTX injection. RTX treatment resulted in a significant decrease in TRPV1 expressing neurons in the colon and immunohistochemical analysis revealed no change in peptide or receptor expression in CANs following RTX lesioning as compared to control data. Behavioral studies determined that both inflamed non-RTX and RTX animals showed a decrease in balloon pressure threshold as compared to controls. Immunohistochemical analysis demonstrated that the NR1 cassettes, N1 and C1, of the NMDA receptor on CANs were up-regulated following inflammation. Furthermore, inflammation resulted in the activation of the PAR2 receptors expressed on CANs. Our data show that inflammation causes an up-regulation of the NMDA receptor and the activation of the PAR2 receptor expressed on CANs. These changes are associated with a decrease in balloon pressure in response to colorectal distension in non-RTX and RTX lesioned animals. Therefore, these data suggest that CANs

  12. Spinal histamine in attenuation of mechanical hypersensitivity in the spinal nerve ligation-induced model of experimental neuropathy.

    PubMed

    Wei, Hong; Viisanen, Hanna; You, Hao-Jun; Pertovaara, Antti

    2016-02-05

    Here we studied whether and through which mechanisms spinal administration of histamine dihydrochloride (histamine) attenuates pain behavior in neuropathic animals. Experiments were performed in rats with spinal nerve ligation-induced neuropathy and a chronic intrathecal catheter for spinal drug delivery. Mechanical hypersensitivity was assessed with monofilaments while radiant heat was used for assessing nociception. Ongoing neuropathic pain and its attenuation by histamine was assessed using conditioned place-preference test. Following spinal administration, histamine at doses 0.1-10µg produced a dose-related mechanical antihypersensitivity effect. With prolonged treatment (twice daily 10µg for five days), the antihypersensitivity effect of spinal histamine was reduced. In place-preference test, neuropathic animals preferred the chamber paired with histamine (10µg). Histamine (10µg) failed to influence heat nociception in neuropathic animals or mechanically induced pain behavior in a group of healthy control rats. Histamine-induced mechanical antihypersensitivity effect was prevented by spinal pretreatment with zolantidine (histamine H2 receptor antagonist), prazosine (α1-adrenoceptor antagonist) and bicuculline (γ-aminobutyric acid subtype A, GABA(A), receptor antagonist), but not by pyrilamine (histamine H1 receptor antagonist), atipamezole (α2-adrenoceptor antagonist), or raclopride (dopamine D2 receptor antagonist). A-960656, a histamine H3 receptor antagonist alone that presumably increased endogenous histamine levels reduced hypersensitivity. Additionally, histamine prevented central (presumably postsynaptically-induced) facilitation of hypersensitivity induced by N-methyl-d-aspartate. The results indicate that spinal histamine at the dose range of 0.1-10µg selectively attenuates mechanical hypersensitivity and ongoing pain in neuropathy. The spinal histamine-induced antihypersensitivity effect involves histamine H2 and GABA(A) receptors and

  13. Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice.

    PubMed

    Yan, Shengmin; Zhang, Hongxia; Zheng, Fei; Sheng, Nan; Guo, Xuejiang; Dai, Jiayin

    2015-06-12

    Perfluoroalkyl acids (PFAAs) are widely used in many applications due to their unique physical and chemical characteristics. Because of the increasing prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, concern has arisen about the roles of environmental pollutants in such diseases. Earlier epidemiologic studies showed a potential association between perfluorooctanoic acid (PFOA) and glucose metabolism, but how PFOA influences glucose homeostasis is still unknown. Here, we report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver. Tolerance tests further indicated that PFOA exposure induced higher insulin sensitivity and glucose tolerance in mice. Biochemical analysis revealed that PFOA exposure reduced hepatic glycogen synthesis, which might be attributed to gluconeogenesis inhibition. The levels of several circulating proteins were altered after PFOA exposure, including proteins potentially related to diabetes and liver disease. Our results suggest that PFOA affected glucose metabolism and induced insulin hypersensitivity in mice.

  14. Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice

    PubMed Central

    Yan, Shengmin; Zhang, Hongxia; Zheng, Fei; Sheng, Nan; Guo, Xuejiang; Dai, Jiayin

    2015-01-01

    Perfluoroalkyl acids (PFAAs) are widely used in many applications due to their unique physical and chemical characteristics. Because of the increasing prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, concern has arisen about the roles of environmental pollutants in such diseases. Earlier epidemiologic studies showed a potential association between perfluorooctanoic acid (PFOA) and glucose metabolism, but how PFOA influences glucose homeostasis is still unknown. Here, we report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver. Tolerance tests further indicated that PFOA exposure induced higher insulin sensitivity and glucose tolerance in mice. Biochemical analysis revealed that PFOA exposure reduced hepatic glycogen synthesis, which might be attributed to gluconeogenesis inhibition. The levels of several circulating proteins were altered after PFOA exposure, including proteins potentially related to diabetes and liver disease. Our results suggest that PFOA affected glucose metabolism and induced insulin hypersensitivity in mice. PMID:26066376

  15. Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock▿ †

    PubMed Central

    Sekine, Hiroki; Mimura, Junsei; Oshima, Motohiko; Okawa, Hiromi; Kanno, Jun; Igarashi, Katsuhide; Gonzalez, Frank J.; Ikuta, Togo; Kawajiri, Kaname; Fujii-Kuriyama, Yoshiaki

    2009-01-01

    Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is known to mediate a wide variety of pharmacological and toxicological effects caused by polycyclic aromatic hydrocarbons. Recent studies have revealed that AhR is involved in the normal development and homeostasis of many organs. Here, we demonstrate that AhR knockout (AhR KO) mice are hypersensitive to lipopolysaccharide (LPS)-induced septic shock, mainly due to the dysfunction of their macrophages. In response to LPS, bone marrow-derived macrophages (BMDM) of AhR KO mice secreted an enhanced amount of interleukin-1β (IL-1β). Since the enhanced IL-1β secretion was suppressed by supplementing Plasminogen activator inhibitor-2 (Pai-2) expression through transduction with Pai-2-expressing adenoviruses, reduced Pai-2 expression could be a cause of the increased IL-1β secretion by AhR KO mouse BMDM. Analysis of gene expression revealed that AhR directly regulates the expression of Pai-2 through a mechanism involving NF-κB but not AhR nuclear translocator (Arnt), in an LPS-dependent manner. Together with the result that administration of the AhR ligand 3-methylcholanthrene partially protected mice with wild-type AhR from endotoxin-induced death, these results raise the possibility that an appropriate AhR ligand may be useful for treating patients with inflammatory disorders. PMID:19822660

  16. Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice

    NASA Astrophysics Data System (ADS)

    Yan, Shengmin; Zhang, Hongxia; Zheng, Fei; Sheng, Nan; Guo, Xuejiang; Dai, Jiayin

    2015-06-01

    Perfluoroalkyl acids (PFAAs) are widely used in many applications due to their unique physical and chemical characteristics. Because of the increasing prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, concern has arisen about the roles of environmental pollutants in such diseases. Earlier epidemiologic studies showed a potential association between perfluorooctanoic acid (PFOA) and glucose metabolism, but how PFOA influences glucose homeostasis is still unknown. Here, we report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver. Tolerance tests further indicated that PFOA exposure induced higher insulin sensitivity and glucose tolerance in mice. Biochemical analysis revealed that PFOA exposure reduced hepatic glycogen synthesis, which might be attributed to gluconeogenesis inhibition. The levels of several circulating proteins were altered after PFOA exposure, including proteins potentially related to diabetes and liver disease. Our results suggest that PFOA affected glucose metabolism and induced insulin hypersensitivity in mice.

  17. Prevention of ultraviolet radiation-induced suppression of contact hypersensitivity by Aloe vera gel components.

    PubMed

    Lee, C K; Han, S S; Shin, Y K; Chung, M H; Park, Y I; Lee, S K; Kim, Y S

    1999-05-01

    We have recently reported that Aloe vera gel contains small molecular weight immunomodulators, G1C2F1, that restore ultraviolet B (UVB)-suppressed accessory cell function of epidermal Langerhans cells (LC) in vitro. In the present study we evaluated the UVB-protective activity of G1C2F1 in vivo. Exposure of the shaved abdominal skin of mice to 2.4 KJ/m2 of UVB radiation resulted in suppression of contact sensitization through the skin to 41.1%, compared to normal unirradiated skin. Topical application of G1C2F1 immediately after irradiation reduced this suppression significantly. The percentage recovery of UVB-suppressed contact hypersensitivity (CHS) response was 52.3, 77.3, and 86.6% when the irradiated skin was treated once with 0.1, 0.5, and 2.5 mg/ml of G1C2F1-containing cream, respectively. G1C2F1 did not show nonspecific stimulatory activity on CHS response. The present study, together with the previous observation, show that Aloe vera gel contains small molecular weight immunomodulators that prevent UVB-induced immune suppression in the skin by restoration of UVB-induced damages on epidermal LC.

  18. Drug-induced hypersensitivity syndrome: recent advances in the diagnosis, pathogenesis and management.

    PubMed

    Shiohara, Tetsuo; Kano, Yoko; Takahashi, Ryo; Ishida, Tadashi; Mizukawa, Yoshiko

    2012-01-01

    Drug-induced hypersensitivity syndrome (DIHS), also referred to as drug reaction with eosinophilia with systemic symptoms, is a life-threatening multiorgan system reaction caused by a limited number of drugs such as anticonvulsants. This syndrome is characterized by fever, rash, lymphadenopathy, hepatitis, and leukocytosis with eosinophilia. DIHS has several unique features that include the delayed onset, paradoxical deterioration of clinical symptoms after withdrawal of the causative drug and unexplained cross-reactivity to multiple drugs with different structures. Because of these features and a lack of awareness of this syndrome, DIHS is undoubtedly underdiagnosed in many countries despite its worldwide distribution. The clinical variability in the presentation and course of clinical symptoms of DIHS could now be interpreted as an indication that several herpesviruses reactivate in a sequential manner independently in the different organs. Dramatic expansions of functional regulatory T (Treg) cells observed in the acute stage would serve to induce such sequential reactivations of herpesviruses while a gradual loss of Treg function occurring after resolution of DIHS could increase the risk of subsequently developing autoimmune disease. Although systemic corticosteroids are the mainstay of treatment, it remains to be determined whether this treatment is beneficial from a viewpoint of disease outcome and sequelae.

  19. [Case of drug-induced hypersensitivity syndrome due to lamotrigine: demonstration of sequential reactivation of herpesviruses].

    PubMed

    Sato, Tatsuharu; Kuniba, Hideo; Matsuo, Mitsuhiro; Matsuzaka, Tetsuo; Moriuchi, Hiroyuki

    2012-01-01

    Drug-induced hypersensitivity syndrome (DIHS) is a rare but severe multiorgan disorder. The reactivation of human herpesvirus-6 (HHV-6) and other human herpesviruses has been reported to be associated with its pathogenesis. We herein report a case of 14-year-old female who developed DIHS during the treatment with lamotrigine, a novel antiepileptic drug. She initially presented with fever, skin rash, cervical lymphadenopathy, leukocytosis with eosinophilia and atypical lymphocytosis, liver dysfunction and hypogammaglobulinemia. Discontinuation of the drug and administration of prednisolone led to improvement;however, tapering of prednisolone and administration of midazolam and ketamine thereafter triggered clinical deterioration. She subsequently developed hyperthyroidism followed by hypothyroidism. Herpesviral loads were determined in her peripheral blood by real-time PCR during the course of the treatment, and sequential reactivation of Epstein-Barr virus (EBV), HHV-6 and cytomegalovirus was demonstrated. EBV viremia was detected throughout the course, except for a short period when HHV-6 viremia was at the peak. HHV-6 viremia developed after the secondary deterioration. Cytomegalovirus viremia appeared transiently before the hyperthyroidic state reversed and became hypothyroidic. Although this syndrome should be regarded as a systemic reaction induced by a complex interplay among herpesviruses and the immune responses against viral infections and drugs, it remains unknown how such a sequential reactivation is related to the pathogenesis of the condition.

  20. Establishment of diagnostic criteria for feline nonflea-induced hypersensitivity dermatitis.

    PubMed

    Favrot, Claude; Steffan, Jean; Seewald, Wolfgang; Hobi, Stefan; Linek, Monika; Marignac, Geneviève; Olivry, Thierry; Beco, Luc; Nett, Claudia; Fontaine, Jacques; Roosje, Petra; Bergvall, Kerstin; Belova, Svetlana; Koebrich, Stefanie; Pin, Didier; Kovalik, Marcel; Meury, Sabrina; Wilhelm, Sylvia

    2012-02-01

    Hypersensitivity dermatitides (HD) are commonly seen in cats, and they are usually caused by environmental, food and/or flea allergens. Affected cats normally present with one of the following clinical reaction patterns: head and neck excoriations, usually symmetrical self-induced alopecia, eosinophilic skin lesions or miliary dermatitis. Importantly, none of these clinical presentations is considered to be pathognomonic for HD skin diseases, and the diagnosis of HD is usually based on the exclusion of other pruritic diseases and on a positive response to therapy. The objectives of this study were to propose sets of criteria for the diagnosis of nonflea-induced HD (NFHD). We recruited 501 cats with pruritus and skin lesions and compared clinical parameters between cats with NFHD (encompassing those with nonflea, nonfood HD and those with food HD), flea HD and other pruritic conditions. Using simulated annealing techniques, we established two sets of proposed criteria for the following two different clinical situations: (i) the diagnosis of NFHD in a population of pruritic cats; and (ii) the diagnosis of NFHD after exclusion of cats with flea HD. These criteria sets were associated with good sensitivity and specificity and may be useful for homogeneity of enrolment in clinical trials and to evaluate the probability of diagnosis of NFHD in clinical practice. Finally, these criteria were not useful to differentiate cats with NFHD from those with food HD.

  1. The hypersensitive induced reaction and leucine-rich repeat proteins regulate plant cell death associated with disease and plant immunity.

    PubMed

    Choi, Hyong Woo; Kim, Young Jin; Hwang, Byung Kook

    2011-01-01

    Pathogen-induced programmed cell death (PCD) is intimately linked with disease resistance and susceptibility. However, the molecular components regulating PCD, including hypersensitive and susceptible cell death, are largely unknown in plants. In this study, we show that pathogen-induced Capsicum annuum hypersensitive induced reaction 1 (CaHIR1) and leucine-rich repeat 1 (CaLRR1) function as distinct plant PCD regulators in pepper plants during Xanthomonas campestris pv. vesicatoria infection. Confocal microscopy and protein gel blot analyses revealed that CaLRR1 and CaHIR1 localize to the extracellular matrix and plasma membrane (PM), respectively. Bimolecular fluorescent complementation and coimmunoprecipitation assays showed that the extracellular CaLRR1 specifically binds to the PM-located CaHIR1 in pepper leaves. Overexpression of CaHIR1 triggered pathogen-independent cell death in pepper and Nicotiana benthamiana plants but not in yeast cells. Virus-induced gene silencing (VIGS) of CaLRR1 and CaHIR1 distinctly strengthened and compromised hypersensitive and susceptible cell death in pepper plants, respectively. Endogenous salicylic acid levels and pathogenesis-related gene transcripts were elevated in CaHIR1-silenced plants. VIGS of NbLRR1 and NbHIR1, the N. benthamiana orthologs of CaLRR1 and CaHIR1, regulated Bax- and avrPto-/Pto-induced PCD. Taken together, these results suggest that leucine-rich repeat and hypersensitive induced reaction proteins may act as cell-death regulators associated with plant immunity and disease.

  2. Involvement of the central tachykinin NK1 receptor during maintenance of mechanical hypersensitivity induced by diabetes in the rat.

    PubMed

    Field, M J; McCleary, S; Boden, P; Suman-Chauhan, N; Hughes, J; Singh, L

    1998-06-01

    Our study examines the role of central and peripheral neurokinin1 (NK1) receptors in diabetes-induced mechanical hypersensitivity. Glycine, N, N-dimethyl-, 2-[[2-[[(2-benzofuranylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2 -me thyl-1-oxopropyl] amino]-2-phenylethylester, bisulfate, [R-(R*,R*)] (PD 156982) is a selective NK1 receptor antagonist with nanomolar affinity for the human (IC50 = 1.4 nM) and guinea pig (IC50 = 9.6 nM) NK1 receptors. However, it has approximately two orders of magnitude lower affinity for the rodent NK1 receptor (IC50 = 820 nM). In electrophysiological studies, PD 156982 inhibited NK1 receptor-mediated responses in the guinea pig locus ceruleus, in a competitive manner, with an equilibrium constant of 13.9 nM. The intracerebroventricular (10-100 microg/animal) but not systemic administration of PD 156982 (1-100 mg/kg, s.c.) blocked the [Sar9, Met(O2)11] substance P-induced gerbil foot tapping response. This indicates that PD 156982 is unable to penetrate into the central nervous system. However, PD 156982 (10-100 mg/kg, s.c.) blocked the mechanical hypersensitivity induced by administration of substance P into the plantar surface of a rat paw. This suggests that PD 156982 can effectively antagonize peripheral NK1 receptors in vivo. The chemically related compound carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]et hyl ]-, 2-benzofuranylmethyl ester, [R-(R*,S*)] (CI-1021) is also a selective NK1 receptor antagonist but can penetrate into the central nervous system. PD 156982 (10-100 mg/kg, s.c.) failed to block streptozocin (75 mg/kg, i.p.) induced mechanical hypersensitivity. In contrast, CI-1021 dose-dependently (3-100 mg/kg, s.c.) blocked this hypersensitivity state with a minimum effective dose of 10 mg/kg. At these doses CI-1021 also antagonized mechanical hypersensitivity mediated by central NK1 but not NK2 receptors in the rat. It is suggested that the central NK1 receptor may play an important role in

  3. In vitro Models to Evaluate Drug-Induced Hypersensitivity: Potential Test Based on Activation of Dendritic Cells

    PubMed Central

    Galbiati, Valentina; Papale, Angela; Kummer, Elena; Corsini, Emanuela

    2016-01-01

    Hypersensitivity drug reactions (HDRs) are the adverse effect of pharmaceuticals that clinically resemble allergy. HDRs account for approximately 1/6 of drug-induced adverse effects, and include immune-mediated (“allergic”) and non-immune-mediated (“pseudo allergic”) reactions. In recent years, the severe and unpredicted drug adverse events clearly indicate that the immune system can be a critical target of drugs. Enhanced prediction in preclinical safety evaluation is, therefore, crucial. Nowadays, there are no validated in vitro or in vivo methods to screen the sensitizing potential of drugs in the pre-clinical phase. The problem of non-predictability of immunologically-based hypersensitivity reactions is related to the lack of appropriate experimental models rather than to the lack of -understanding of the adverse phenomenon. We recently established experimental conditions and markers to correctly identify drug associated with in vivo hypersensitivity reactions using THP-1 cells and IL-8 production, CD86 and CD54 expression. The proposed in vitro method benefits from a rationalistic approach with the idea that allergenic drugs share with chemical allergens common mechanisms of cell activation. This assay can be easily incorporated into drug development for hazard identification of drugs, which may have the potential to cause in vivo hypersensitivity reactions. The purpose of this review is to assess the state of the art of in vitro models to assess the allergenic potential of drugs based on the activation of dendritic cells. PMID:27462271

  4. Cold-induced cholinergic urticaria--case report.

    PubMed

    Geller, M

    1989-07-01

    A 9-year-old child with cold-induced cholinergic urticaria was studied. When exposed to cold water or ambient cold air, the patient developed generalized urticaria. The lesions consisted of punctate wheals and surrounding erythema similar to that seen in cholinergic urticaria. The patient did not react to cutaneous challenge with an ice cube and a cold water immersion test was negative. Urticaria was not provoked by vigorous exercise sufficient to cause profuse sweating. The methacholine skin test was reactive. The patient was well controlled by combination therapy with hydroxyzine plus cyproheptadine.

  5. Transcriptome analysis of a bacterially induced basal and hypersensitive response of Medicago truncatula.

    PubMed

    Bozsó, Zoltán; Maunoury, Nicolas; Szatmari, Agnes; Mergaert, Peter; Ott, Péter G; Zsíros, László R; Szabó, Erika; Kondorosi, Eva; Klement, Zoltán

    2009-08-01

    Research using the well-studied model legume Medicago truncatula has largely focused on rhizobium symbiosis, while little information is currently available for this species on pathogen-induced transcriptome changes. We have performed a transcriptome analysis of this species with the objective of studying the basal (BR, no visible symptoms) and hypersensitive response (HR, plant cell death) in its leaves at 6 and at 24 h after infection by HR-negative (hrcC mutant) and HR-inducing Pseudomonas syringae pv. syringae strains, respectively. Although there were no visible symptoms at the BR, the alterations in gene expression were comparable to those found with the HR. Both responses resulted in the transcriptional alteration of hundreds of plant genes; however, the responses in the HR were usually more intense. The reactions to HR-inducing and HR-negative bacterial strains were significantly overlapping. Parallel up- or down-regulation of genes with the same function occurred frequently. However, some plant processes were regulated in one direction; for example, most of the protein synthesis-related genes were activated and all of the photosynthetic/chloroplast genes were suppressed during BR. The possible roles of several functional classes (e.g., cell rescue, signaling, defense, cell death, etc.) of transcriptionally altered genes are discussed. The results of the comparison with available mycorrhizal and nodule expression data show that there is a significant overlap between nodulation and the leaf defense response and that during the early stage of the nodulation in roots, Sinorhizobium meliloti induces a fluctuation in the transcription of BR- and HR-responsive genes.

  6. Colon distention induces persistent visceral hypersensitivity by mechanotranscription of pain mediators in colonic smooth muscle cells.

    PubMed

    Lin, You-Min; Fu, Yu; Wu, Chester C; Xu, Guang-Yin; Huang, Li-Yen; Shi, Xuan-Zheng

    2015-03-01

    Abdominal pain and distention are major complaints in irritable bowel syndrome. Abdominal distention is mainly attributed to intraluminal retention of gas or solid contents, which may cause mechanical stress to the gut wall. Visceral hypersensitivity (VHS) may account for abdominal pain. We sought to determine whether tonic colon distention causes persistent VHS and if so whether mechanical stress-induced expression (mechanotranscription) of pain mediators in colonic smooth muscle cells (SMCs) plays a role in VHS. Human colonic SMCs were isolated and stretched in vitro to investigate whether mechanical stress upregulates expression of the pain mediator cyclooxygenase-2 (COX-2). Rat colon was distended with a 5-cm-long balloon, and gene expression of COX-2, visceromotor response (VMR), and sensory neuron excitability were determined. Static stretch of colonic SMCs induced marked expression of COX-2 mRNA and protein in a force- and time-dependent manner. Subnoxious tonic distention of the distal colon at ∼30-40 mmHg for 20 or 40 min induced COX-2 expression and PGE2 production in colonic smooth muscle, but not in the mucosa layer. Lumen distention also increased VMR in a force- and time-dependent manner. The increase of VMR persisted for at least 3 days. Patch-clamp experiments showed that the excitability of colon projecting sensory neurons in the dorsal root ganglia was markedly augmented, 24 h after lumen distention. Administration of COX-2 inhibitor NS-398 partially but significantly attenuated distention-induced VHS. In conclusion, tonic lumen distention upregulates expression of COX-2 in colonic SMC, and COX-2 contributes to persistent VHS. Copyright © 2015 the American Physiological Society.

  7. Modality-specific mechanisms of protein kinase C-induced hypersensitivity of TRPV1: S800 is a polymodal sensitization site.

    PubMed

    Wang, Sen; Joseph, John; Ro, Jin Y; Chung, Man-Kyo

    2015-05-01

    TRPV1 is a nociceptive ion channel activated by polymodal stimuli such as capsaicin, proton, and noxious heat. Multiple inflammatory mediators activate protein kinases, especially protein kinase C (PKC), which phosphorylates TRPV1. Emerging evidence suggests that phosphorylation of TRPV1 constitutes specific signals underpinning pathological nociception. Although the mechanisms of hypersensitivity of TRPV1 to capsaicin are well studied, the phosphorylation residues that contribute to hypersensitivity to heat or acid have not been identified. In this study, we investigated modality-specific mechanisms of PKC-induced hypersensitivity using mutagenic ablation of PKC-associated phosphorylation sites in TRPV1. In heterologous systems, TRPV1 S502 and S800, but not T704, are known to be involved in hypersensitivity to capsaicin after the application of phorbol myristate acetate (PMA), a PKC agonist. Unlike capsaicin, PMA-induced hypersensitivity to heat was attenuated in TRPV1 mutants T704A and S800A, but not in S502A. In contrast, PMA-induced hypersensitivity to acid was attenuated only in S800A. To examine the roles of these phosphorylation sites in more physiologically relevant conditions, TRPV1 and mutants were tested in sensory neurons from TRPV1-null mice. In sensory neurons expressing mutated TRPV1, we found that alanine mutation of S800 commonly attenuates PMA-induced hypersensitivity to capsaicin, heat, and acid. Moreover, bradykinin-induced hypersensitivity to capsaicin was largely attenuated by the S800A mutation. These results suggest that mechanisms of PKC-induced hypersensitivity of TRPV1 are modality specific and that S800 is a polymodal sensitization site integrating multiple inflammatory signals in nociceptors. Our data provide a rationale for a novel approach targeting TRPV1 S800 for antihyperalgesia.

  8. Role of mast cell in the late phase of contact hypersensitivity induced by trimellitic anhydride

    PubMed Central

    Chai, Ok Hee

    2015-01-01

    Mast cells are known as effector cells of IgE-mediated allergic responses, but role of mast cells in contact hypersensitivity (CHS) has been considered controversial. In this study, we investigated role of mast cell in trimellitic anhydride (TMA)-induced CHS. The mice were sensitized to TMA on the back and repeatedly challenged with TMA on the left ear at 1-week intervals. The ear after challenge showed biphasic responses. The repetition of TMA challenge shifted in time course of ear response and enlarged the extent of early and late phase reactions in proportion to the frequency of TMA challenges in C57BL/6 mice. In late phase reaction, peak of ear response by single challenge showed at 24 hours after challenge, but the peak by repeat challenges at 8 hours after the last challenge. Number of mast cells and eosinophils per unit area increased in proportion to frequency of TMA challenges. However, mast cell-deficient WBB6F1/J-KitW/KitW-v mice developed the late phase reaction without the early phase reaction. The repetition of TMA challenge shifted in time course of ear response and enlarged the extent of ear response and the infiltration of eosinophils. The magnitude of these responses observed according to the frequency of the TMA challenge in mast cell-deficient WBB6F1/J-KitW/KitW-v mice was significantly lower than that in C57BL/6 mice. Also TMA elicited mast cell degranulation and histamine release from rat peritoneal mast cells in a concentration-dependent manner. Conclusively, TMA induces the early and late phase reactions in CHS, and mast cells may be required for TMA-induced CHS. PMID:26770872

  9. Inhibitory effects of dietary soyasaponin on 2,4-dinitrofluorobenzene-induced contact hypersensitivity in mice.

    PubMed

    Nagano, Takao; Katase, Mitsuru; Tsumura, Kazunobu; Saito, Mineki; Matsuda, Tsukasa

    2017-03-01

    Soyasaponins (SSs) abundant in soybean have anti-inflammatory activities; however, their therapeutic effects on allergic contact dermatitis (ACD) remain unknown. To assess the effects of SS-enriched diets on ACD, we used a mouse model of contact hypersensitivity (CHS). Mice were fed low-dose or high-dose SS-containing diets for 3 weeks prior to CHS induction with 2,4-dinitrofluorobenzene (DNFB). The low-dose SS diet attenuated DNFB-induced ear swelling and tissue oedema, and reduced the number of infiltrating Gr-1-positive myeloid cells. Low-dose, but not high-dose, SSs decreased chemokine (C-X-C motif) ligand 2 (CXCL2) and triggering receptor expressed on myeloid cells (TREM)-1 production in ear tissues, compared to a control. Taxonomic 16S rRNA analysis revealed significant alterations in faecal microbiota caused by CHS, which were reversed by low-dose SSs. The low-dose SS and non-CHS groups clustered together, while the high-dose SS group split between CHS and non-CHS clusters. Our results demonstrated that low-dose SSs alleviated CHS symptoms by attenuating inflammation and improving the intestinal microbiota composition, suggesting that dietary SSs may have beneficial effects on ACD.

  10. Performance of genetic risk factors in prediction of trichloroethylene induced hypersensitivity syndrome

    PubMed Central

    Dai, Yufei; Chen, Ying; Huang, Hanlin; Zhou, Wei; Niu, Yong; Zhang, Mingrong; Bin, Ping; Dong, Haiyan; Jia, Qiang; Huang, Jianxun; Yi, Juan; Liao, Qijun; Li, Haishan; Teng, Yanxia; Zang, Dan; Zhai, Qingfeng; Duan, Huawei; Shen, Juan; He, Jiaxi; Meng, Tao; Sha, Yan; Shen, Meili; Ye, Meng; Jia, Xiaowei; Xiang, Yingping; Huang, Huiping; Wu, Qifeng; Shi, Mingming; Huang, Xianqing; Yang, Huanming; Luo, Longhai; Li, Sai; Li, Lin; Zhao, Jinyang; Li, Laiyu; Wang, Jun; Zheng, Yuxin

    2015-01-01

    Trichloroethylene induced hypersensitivity syndrome is dose-independent and potentially life threatening disease, which has become one of the serious occupational health issues and requires intensive treatment. To discover the genetic risk factors and evaluate the performance of risk prediction model for the disease, we conducted genomewide association study and replication study with total of 174 cases and 1761 trichloroethylene-tolerant controls. Fifty seven SNPs that exceeded the threshold for genome-wide significance (P < 5 × 10−8) were screened to relate with the disease, among which two independent SNPs were identified, that is rs2857281 at MICA (odds ratio, 11.92; Pmeta = 1.33 × 10−37) and rs2523557 between HLA-B and MICA (odds ratio, 7.33; Pmeta = 8.79 × 10−35). The genetic risk score with these two SNPs explains at least 20.9% of the disease variance and up to 32.5-fold variation in inter-individual risk. Combining of two SNPs as predictors for the disease would have accuracy of 80.73%, the area under receiver operator characteristic curves (AUC) scores was 0.82 with sensitivity of 74% and specificity of 85%, which was considered to have excellent discrimination for the disease, and could be considered for translational application for screening employees before exposure. PMID:26190474

  11. Acute liver failure caused by drug-induced hypersensitivity syndrome associated with hyperferritinemia.

    PubMed

    Miyazaki, Masayuki; Tanaka, Masatake; Ueda, Akihiro; Yoshimoto, Tsuyoshi; Kato, Masaki; Nakamuta, Makoto; Kotoh, Kazuhiro; Takayanagi, Ryoichi

    2011-11-28

    Drug-induced hypersensitivity syndrome (DIHS) is a severe reaction usually characterized by fever, rash, and multiorgan failure, occurring 2-6 wk after drug introduction. It is an immune-mediated reaction involving macrophage and T-lymphocyte activation and cytokine release. A 54-year-old woman was diagnosed with rheumatic arthritis and initiated salazosulfapyridine by mouth. About 10 d later, she had a high fever, skin rash and liver dysfunction. She was admitted to hospital and diagnosed with a drug eruption. She was treated with oral prednisolone 30 mg/d; however, she developed high fever again and her blood tests showed acute liver failure and cytopenia associated with hyperferritinemia. She was diagnosed with acute liver failure and hemophagocytosis caused by DIHS. She was transferred to the Department of Medicine and Bioregulatory Science, Kyushu University, where she was treated with arterial steroid injection therapy. Following this treatment, her liver function improved and serum ferritin immediately decreased. We hypothesized that an immune-mediated reaction in DIHS may have generated over-activation of macrophages and T-lymphocytes, followed by a cytokine storm that affected various organs. The measurement of serum ferritin might be a useful marker of the severity of DIHS.

  12. Analysis of the N Gene Hypersensitive Response Induced by a Fluorescently Tagged Tobacco Mosaic Virus1

    PubMed Central

    Wright, Kathryn M.; Duncan, George H.; Pradel, Katja S.; Carr, Fiona; Wood, Susannah; Oparka, Karl J.; Cruz, Simon Santa

    2000-01-01

    The hypersensitive response (HR) triggered on Nicotiana edwardsonii by tobacco mosaic virus was studied using a modified viral genome that directed expression of the green fluorescent protein. Inoculated plants were initially incubated at 32°C to inhibit the N gene-mediated HR. Transfer to 20°C initiated the HR, and fluorescent infection foci were monitored for early HR-associated events. Membrane damage, which preceded visible cell collapse by more than 3 h, was accompanied by a transient restriction of the xylem within infection sites. Following cell collapse and the rapid desiccation of tissue undergoing the HR, isolated, infected cells were detected at the margin of necrotic lesions. These virus-infected cells were able to reinitiate infection on transfer to 32°C, however, if maintained at 20°C they eventually died. The results indicate that the tobacco mosaic virus-induced HR is a two-phase process with an early stage culminating in rapid cell collapse and tissue desiccation followed by a more extended period during which the remaining infected cells are eliminated. PMID:10938355

  13. Performance of genetic risk factors in prediction of trichloroethylene induced hypersensitivity syndrome.

    PubMed

    Dai, Yufei; Chen, Ying; Huang, Hanlin; Zhou, Wei; Niu, Yong; Zhang, Mingrong; Bin, Ping; Dong, Haiyan; Jia, Qiang; Huang, Jianxun; Yi, Juan; Liao, Qijun; Li, Haishan; Teng, Yanxia; Zang, Dan; Zhai, Qingfeng; Duan, Huawei; Shen, Juan; He, Jiaxi; Meng, Tao; Sha, Yan; Shen, Meili; Ye, Meng; Jia, Xiaowei; Xiang, Yingping; Huang, Huiping; Wu, Qifeng; Shi, Mingming; Huang, Xianqing; Yang, Huanming; Luo, Longhai; Li, Sai; Li, Lin; Zhao, Jinyang; Li, Laiyu; Wang, Jun; Zheng, Yuxin

    2015-07-20

    Trichloroethylene induced hypersensitivity syndrome is dose-independent and potentially life threatening disease, which has become one of the serious occupational health issues and requires intensive treatment. To discover the genetic risk factors and evaluate the performance of risk prediction model for the disease, we conducted genomewide association study and replication study with total of 174 cases and 1761 trichloroethylene-tolerant controls. Fifty seven SNPs that exceeded the threshold for genome-wide significance (P < 5 × 10(-8)) were screened to relate with the disease, among which two independent SNPs were identified, that is rs2857281 at MICA (odds ratio, 11.92; P meta = 1.33 × 10(-37)) and rs2523557 between HLA-B and MICA (odds ratio, 7.33; P meta = 8.79 × 10(-35)). The genetic risk score with these two SNPs explains at least 20.9% of the disease variance and up to 32.5-fold variation in inter-individual risk. Combining of two SNPs as predictors for the disease would have accuracy of 80.73%, the area under receiver operator characteristic curves (AUC) scores was 0.82 with sensitivity of 74% and specificity of 85%, which was considered to have excellent discrimination for the disease, and could be considered for translational application for screening employees before exposure.

  14. Pharmacological modulation of cold-induced pain in cutaneous leiomyomata.

    PubMed

    Archer, C B; Whittaker, S; Greaves, M W

    1988-02-01

    In two patients with painful cutaneous leiomyomata, induction of pain by the application of an ice cube allowed assessment of a number of topical and systemic treatments aimed at reducing or preventing the pain. In one patient the alpha-adrenoceptor blocker, phenoxybenzamine alleviated cold-induced pain. In the second patient, topical 9% hyoscine hydrobromide (an anticholinergic agent) decreased pain induced by the ice cube, but was not helpful in reducing lesional pain due to cold weather.

  15. HLA-DR9 and DR14 are associated with the allopurinol-induced hypersensitivity in hematologic malignancy.

    PubMed

    Jung, Jae-Woo; Kim, Ju-Young; Yoon, Sung-Soo; Cho, Sang-Heon; Park, Seon-Yang; Kang, Hye-Ryun

    2014-06-01

    Allopurinol, a widely used urate-lowering agent, is a leading cause of severe cutaneous adverse reactions (SCARs), especially in patients with HLA-B*58:01. Despite its routine use for the prevention of tumor lysis-related hyperuricemia prior to chemotherapy, the risk of allopurinol-induced hypersensitivity has not been investigated in patients with hematologic malignancies. This retrospective cohort study was conducted to investigate the incidence and risk factors of allopurinol-induced hypersensitivity in patients at least 18 years of age with hematologic malignancies. We reviewed 463 patients who had ever taken allopurinol for the prevention of hyperuricemia prior to chemotherapy and had undergone serologic HLA typing as a pre-transplant evaluation from January 2000 to May 2010. Thirteen (2.8%) patients experienced maculopapular eruptions (MPE) and none experienced SCARs. Among subtypes of underlying hematologic malignancies, percentage of chronic myeloid leukemia was significantly higher in the allopurinol hypersensitivity group compared with the tolerant group (23.1% (3/13) vs. 5.9% (26/440), P = 0.044). According to HLA subtypes, the incidence of allopurinol-induced MPE was 4.0% in HLA-B58 (+) patients (2/50) and 2.7% in HLA-B58 (-) patients (11/403) but this difference was statistically insignificant. In contrast to HLA-B58, the frequencies of DR9 and DR14 were significantly higher in the allopurinol-induced MPE group compared with the allopurinol tolerant group (38.5% (5/13) vs. 13.6% (53/443), P = 0.019, and 38.5% (5/13) vs. 15.6% (41/440), P = 0.038, respectively). In conclusion, HLA-DR9 and DR14, but not HLA-B58, are associated with hypersensitivity reaction by allopurinol when administered in patients with hematologic malignancy prior to chemotherapy.

  16. Antibiotic-induced immediate type hypersensitivity is a risk factor for positive allergy skin tests for neuromuscular blocking agents.

    PubMed

    Hagau, Natalia; Gherman, Nadia; Cocis, Mihaela; Petrisor, Cristina

    2016-01-01

    Skin tests for neuromuscular blocking agents (NMBAs) are not currently recommended for the general population undergoing general anaesthesia. In a previous study we have reported a high incidence of positive allergy tests for NMBAs in patients with a positive history of non-anaesthetic drug allergy, a larger prospective study being needed to confirm those preliminary results. The objective of this study was to compare the skin tests results for patients with a positive history of antibiotic-induced immediate type hypersensitivity reactions to those of controls without drug allergies. Ninety eight patients with previous antibiotic hypersensitivity and 72 controls were prospectively included. Skin tests were performed for atracurium, pancuronium, rocuronium, and suxamethonium. We found 65 positive skin tests from the 392 tests performed in patients with a positive history of antibiotic hypersensitivity (1 6.58%) and 23 positive skin tests from the 288 performed in controls (7.98%), the two incidences showing significant statistical difference (p = 0.0011). The relative risk for having a positive skin test for NMBAs for patients versus controls was 1.77 (1.15-2.76). For atracurium, skin tests were more often positive in patients with a positive history of antibiotic hypersensitivity versus controls (p = 0.02). For pancuronium, rocuronium and suxamethonium the statistical difference was not attained (p-values 0.08 for pancuronium, 0.23 for rocuronium, and 0.26 for suxamethonium). Patients with a positive history of antibiotic hypersensitivity seem to have a higher incidence of positive skin tests for NMBAs. They might represent a group at higher risk for developing intraoperative anaphylaxis compared to the general population. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  17. Angiotensinogen gene knockout delays and attenuates cold-induced hypertension.

    PubMed

    Sun, Zhongjie; Cade, Robert; Zhang, Zhonge; Alouidor, James; Van, Huong

    2003-02-01

    The aim of the present study was to assess our hypothesis that the renin-angiotensin system (RAS) is responsible for cold-induced hypertension and cardiac hypertrophy. Two groups of wild-type (WT) mice and 2 groups of angiotensinogen gene knockout (Agt-KO) mice (6 per group) were used. After blood pressures (BP) of the four groups were measured 3 times at room temperature (25 degrees C), 1 WT and 1 Agt-KO group were exposed to cold (5 degrees C). The remaining groups were kept at 25 degrees C. BP of the cold-exposed WT group increased significantly in 1 week of cold exposure and rose gradually to 168+/-7 mm Hg by week 5, whereas the BP of the Agt-KO group did not increase until week 3. The cold-induced increase in BP (DeltaBP) was decreased significantly in the Agt-KO mice (19+/-3 mm Hg) compared with that of the WT mice (61+/-5 mm Hg) by 5 weeks of exposure to cold. Both WT and Agt-KO groups had cardiac hypertrophy in cold to the same extent. Agt-KO caused a significant increase in nitric oxide (NO) production. Thus, the RAS may inhibit NO formation. Chronic cold exposure decreased NO production, which may be mediated partially by activation of the RAS. These results strongly support that the RAS plays a critical role in the development of cold-induced hypertension but not cardiac hypertrophy. Moreover, the role of the RAS in cold-induced hypertension may be mediated in part by its inhibition on NO production. The findings also reveal the possible relation between the RAS and NO in cardiovascular regulation.

  18. [Administration of premedication with fexofenadine for paclitaxel-induced hypersensitive reactions in breast cancer patients complicated with closed-angle glaucoma].

    PubMed

    Komatsubara, Kazuo; Miyoshi, Kyoko; Kogure, Yuuki; Matsuhisa, Tetsuaki; Eguchi, Hisae

    2010-01-01

    Paclitaxel (PTX) is one of the most important breast cancer treatment drugs. However, severe hypersensitivity reactions such as decreases in blood pressure and impaired breathing occur with high frequency. For the prevention of such hypersensitivity reactions, administration of a premedication composed of three components, diphenhydramine, ranitidine (or famotidine), and dexamethasone, has been advised in package insert information of medicine. Administration of diphenhydramine is difficult in breast cancer patients complicated with closed-angle glaucoma, because diphenhydramine has a weak anticholinergic adverse effect which can induce mydriasis and glaucoma attack. We studied the prevention of severe hypersensitivity reactions and of glaucoma attack in 2 breast cancer patients complicated with closed angle glaucoma at our hospital from April 2007 to March 2008. We switched from diphenhydramine to fexofenadine as the medicine to prevent hypersensitivity reactions. Hypersensitivity reactions were not observed throughout all courses in both patients, and no glaucoma attack was observed.

  19. Intrathecal administration of nociceptin/orphanin FQ receptor agonists in rats: A strategy to relieve chemotherapy-induced neuropathic hypersensitivity.

    PubMed

    Micheli, Laura; Di Cesare Mannelli, Lorenzo; Rizzi, Anna; Guerrini, Remo; Trapella, Claudio; Calò, Girolamo; Ghelardini, Carla

    2015-11-05

    Oxaliplatin and paclitaxel are considered central components in the treatment of colorectal and breast cancer, respectively. The development of neuropathy during chronic treatment represents the major dose-limiting side effect that leads to discontinuation or interruption of therapies. The management of neuropathy is a challenge to individuate innovative therapeutic strategies based on new targets and correct routes of administration. We evaluated the hypersensitivity reliever effect of different opioid receptor agonists in rat models of oxaliplatin and paclitaxel-induced neuropathy. Compounds were spinally infused by intrathecal catheter. In oxaliplatin-treated rats, 0.3 nmol morphine induced the reversion of the mechanical hypersensitivity (Paw-pressure test), nociceptin/orphanin FQ (N/OFQ; 0.3-3 nmol) significantly increased the pain threshold without reaching the values of the control animals. The N/OFQ peptide (NOP) receptor full agonist UFP-112 reverted pain threshold alterations at lower dosage (0.1 nmol) vs morphine and N/OFQ, the partial agonist UFP-113 (0.1-1 nmol) was similar to N/OFQ. The higher efficacy of morphine vs N/OFQ was highlighted also in paclitaxel-treated rats. The mechanical hypersensitivity was fully reverted by 0.1 nmol UFP-112 and UFP-113. In conclusion, intrathecal μ opioid peptide (MOP) and NOP receptor agonists relieved chemotherapy-induced neuropathic pain. The synthetic peptides showed valuable potency and efficacy suggesting the NOP system as an exploitable target.

  20. Changes in mast cell infiltration: a possible mechanism in detrusor overactivity induced by visceral hypersensitivity.

    PubMed

    Zhang, Nian-Zhao; Ma, Lin; Jun, Chen; Guo, Yan-Xia; Yuan, Hui-Qing

    2016-01-01

    To establish the detrusor overactivity (DO) model induced by visceral hypersensitivity (VH) and investigate the relationship between mast cell (MC) infiltration and DO. Sixty rats are divided into 4 groups randomly: Group 1:Baseline group; Group 2: DO group; Group 3: CON group; Group 4: VH group. The colorectal distension (CRD) and abdominal withdral reflex (AWR) scores are performed to evaluate VH. The cystometric investigation and histological test of MC infiltration are assessed. The threshold pressure of CRD in the VH group is significantly lower than that in the CON group (P<0.001). At the distension pressure ≥20 mmHg, the AWR scores of the VH group are significantly higher than those of the CON group (10 mmHg: P=0.33; 20 mmHg: P=0.028; 40 mmHg: P<0.001; 60 mmHg: P<0.001; 80 mmHg: P<0.001). DO model is successfully established in the VH group (DO rate=100%). Compared with the CON group, the numbers of MC infiltration are significantly increased in the VH group, including submucosa of bladder (P<0.001), mucosa lamina propria/mesentery of small intestine (P<0.001), and mucosa lamina propria/mesentery of large intestine (P<0.001). Furthermore, more MC activation as well as degranulation are observed in the VH group. It is indicated that DO model can be established in the VH rats. The MC infiltration may play an important role in DO induced by VH, and may be helpful to understand the mechanisms of DO in VH patients.

  1. Serious carbamazepine-induced hypersensitivity reactions associated with the HSP70 gene cluster.

    PubMed

    Alfirevic, Ana; Mills, Tracy; Harrington, Pauline; Pinel, Tracy; Sherwood, James; Jawaid, Ansar; Smith, John C; March, Ruth E; Barratt, Bryan J; Chadwick, David W; Kevin Park, B; Pirmohamed, Munir

    2006-04-01

    The use of carbamazepine (CBZ), the most commonly prescribed antiepileptic drug, is hampered by the occurrence of severe, potentially lethal hypersensitivity reactions. The pathogenesis of hypersensitivity is not yet known, but immune mechanisms are involved. Predisposition to CBZ hypersensitivity is likely to be genetically determined, and genes within the major histocompatibility complex (MHC) have been implicated. The heat shock protein (HSP70) gene cluster is located in the MHC class III region. Using a case-control study design, we compared 61 patients with CBZ hypersensitivity (22 with a severe reaction) to 44 patients on CBZ with no signs of hypersensitivity and 172 healthy controls. The genotyping strategy involved identification of common and rare single nucleotide polymorphisms (SNPs) within the HSP70 gene cluster by sequencing, estimation of linkage disequilibrium (LD) and haplotype structure, and thereafter, analysis of SNP/haplotype frequencies in the cases and controls. Population substructure was evaluated by genotyping of 34 microsatellites. Twenty-five SNPs were detected across the three HSP70 genes. Analyses revealed that alleles G, T and C at the SNPs HSPA1A +1911 C/G, HSPA1A +438 C/T and HSPA1L +2437 T/C, respectively, were associated with protection from serious hypersensitivity reactions to CBZ, with the associated alleles falling on a common haplotype. We were unable to detect the presence of population stratification in our patients and controls. Our data show that HSP70 gene variants are associated with serious CBZ hypersensitivity reactions, but whether this is causal or reflects LD with another gene within the MHC requires further study.

  2. Topical imiquimod treatment prevents UV-light induced loss of contact hypersensitivity and immune tolerance.

    PubMed

    Thatcher, Thomas H; Luzina, Irina; Fishelevich, Rita; Tomai, Mark A; Miller, Richard L; Gaspari, Anthony A

    2006-04-01

    Imiquimod (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine) is a TLR7 agonist that induces cytokine production in TLR7 bearing antigen-presenting cells (APCs), including IL-12, a cytokine that has been demonstrated to be a critical effector molecule for contact hypersensitivity (CHS). To test our hypothesis that topical applications of imiquimod may protect the skin immune system against the deleterious effects of UV light exposures, we treated animals with this agent, or its vehicle or nothing before UV exposures. Although topical imiquimod exposures before UV light did not prevent the depletion of epidermal Langerhans cells, it did prevent the loss of CHS. IL-12 was important in the protective role of imiquimod in preventing UV-induced loss of CHS, as systemic treatment of mice with an anti-IL-12 p70 monoclonal antibody blocked the protective effects of imiquimod. Additionally, only imiquimod-treated mice were resistant to hapten-specific tolerance induction after UV irradiation at the site of the initial sensitization with the hapten 2,4 dinitro-1-fluorobenzene. To model for the effects of TLR7 activation on the UV effect on antigen-APCs, XS52 cell line was used to study this interaction in an in vitro model system. This cell line expressed mRNA for TLR7, downregulated IkappaB, phosphorylated c-Jun N-terminal kinase, and secreted cytokines after exposure to imiquimod or lipopolysaccharide. Activation of the TLR7 signaling pathway on XS52 before UV-light exposures enhanced IL-12p70 secretion by this cell line. Similarly, activation of TLR7 on XS52 before UV-light exposure also prevented the UV-induced loss of IFN-gamma triggering in T cells during an allogeneic mixed lymphocyte reaction. Imiquimod-treated, UV-irradiated XS52 triggered a more vigorous IFN-gamma production than did either imiquimod-treated XS52 or UV-irradiated XS52, again suggesting a synergy between the two treatments. Lastly, enriched lymph node CD11c+ APCs from mice treated with UV

  3. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans.

    PubMed

    Tamura, Akitoshi; Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-08-15

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence.

  4. Activation of the Extracellular Signal-Regulated Kinase in the Amygdale Modulates Fentanyl-Induced Hypersensitivity in Rats.

    PubMed

    Li, Zhen; Yin, Pingping; Chen, Jian; Li, Chenhong; Liu, Jieqiong; Rambojan, Hemanshu; Luo, Fang

    2017-02-01

    Opioid-induced hyperalgesia (OIH) is one of the major problems associated with use of opioids in perioperative and chronic pain management. The mechanism underlying this paradoxical phenomenon needs to be fully elucidated. Laterocapsular division of the central nucleus of amygdale (CeLC) has emerged as an important brain center for pain modulation, so we hypothesize that the activation of extracellular signal-regulated kinase (ERK) in CeLC may modulate OIH through strengthening synaptic transmission between neurons in the CeLC. Phospho-ERK in CeLC was first found to be increased significantly in OIH rats induced by repeated subcutaneous injection of fentanyl. Blockade of this fentanyl-induced ERK activation by microinjection of U0126, an ERK inhibitor, into the CeLC reversed the behavioral hypersensitivity in a dose-dependent manner. In vitro whole-cell recordings evaluating the change in synaptic transmission found that the frequency as well as amplitude of miniature excitatory postsynaptic currents recorded on CeLC neurons from OIH rats were fundamentally increased and were completely reversed by acutely applied U0126 (10 μM in the recording well). In vivo microinjection of U0126 into the CeLC reversed the spinal long-term potentiation in OIH rats. These results showed that fentanyl-induced hypersensitivity may occur partly through the mechanism of ERK activation and followed by the strengthening of synaptic transmission in CeLC neurons. This study provides evidence that ERK in the laterocapsular division of the CeLC is a key contributor to the development of fentanyl-induced hypersensitivity. Targeting the superspinal central CeLC can inhibit spinal long-term potentiation and alleviate behavioral hyperreflexia induced by fentanyl. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

  5. Ralstonia solanacearum type III secretion system effector Rip36 induces a hypersensitive response in the nonhost wild eggplant Solanum torvum.

    PubMed

    Nahar, Kamrun; Matsumoto, Iyo; Taguchi, Fumiko; Inagaki, Yoshishige; Yamamoto, Mikihiro; Toyoda, Kazuhiro; Shiraishi, Tomonori; Ichinose, Yuki; Mukaihara, Takafumi

    2014-04-01

    Ralstonia solanacearum is a Gram-negative soil-borne bacterium that causes bacterial wilt disease in more than 200 plant species, including economically important Solanaceae species. In R. solanacearum, the hypersensitive response and pathogenicity (Hrp) type III secretion system is required for both the ability to induce the hypersensitive response (HR) in nonhost plants and pathogenicity in host plants. Recently, 72 effector genes, called rip (Ralstonia protein injected into plant cells), have been identified in R. solanacearum RS1000. RS1002, a spontaneous nalixidic acid-resistant derivative of RS1000, induced strong HR in the nonhost wild eggplant Solanum torvum in an Hrp-dependent manner. An Agrobacterium-mediated transient expression system revealed that Rip36, a putative Zn-dependent protease effector of R. solanacearum, induced HR in S. torvum. A mutation in the putative Zn-binding motif (E149A) completely abolished the ability to induce HR. In agreement with this result, the RS1002-derived Δrip36 and rip36E149A mutants lost the ability to induce HR in S. torvum. An E149A mutation had no effect on the translocation of Rip36 into plant cells. These results indicate that Rip36 is an avirulent factor that induces HR in S. torvum and that a putative Zn-dependent protease motif is essential for this activity.

  6. The Triaging and Treatment of Cold-Induced Injuries.

    PubMed

    Sachs, Christoph; Lehnhardt, Marcus; Daigeler, Adrien; Goertz, Ole

    2015-10-30

    In Central Europe, cold-induced injuries are much less common than burns. In a burn center in western Germany, the mean ratio of these two types of injury over the past 10 years was 1 to 35. Because cold-induced injuries are so rare, physicians often do not know how to deal with them. This article is based on a review of publications (up to December 2014) retrieved by a selective search in PubMed using the terms "freezing," "frostbite injury," "non-freezing cold injury," and "frostbite review," as well as on the authors' clinical experience. Freezing and cold-induced trauma are part of the treatment spectrum in burn centers. The treatment of cold-induced injuries is not standardized and is based largely on case reports and observations of use. distinction is drawn between non-freezing injuries, in which there is a slow temperature drop in tissue without freezing, and freezing injuries in which ice crystals form in tissue. In all cases of cold-induced injury, the patient should be slowly warmed to 22°-27°C to prevent reperfusion injury. Freezing injuries are treated with warming of the body's core temperature and with the bathing of the affected body parts in warm water with added antiseptic agents. Any large or open vesicles that are already apparent should be debrided. To inhibit prostaglandin-mediated thrombosis, ibuprofen is given (12 mg/kg body weight b.i.d.). The treatment of cold-induced injuries is based on their type, severity, and timing. The recommendations above are grade C recommendations. The current approach to reperfusion has yielded promising initial results and should be further investigated in prospective studies.

  7. Disrupting spinal noradrenergic activation delays recovery of acute incision induced hypersensitivity and increases spinal glial activation in the rat

    PubMed Central

    Arora, Vipin; Morado-Urbina, Carlos Eduardo; Aschenbrenner, Carol A.; Hayashida, Ken-ichiro; Wang, FuZhou; Martin, Thomas J.; Eisenach, James C.; Peters, Christopher M.

    2016-01-01

    Clinical studies suggest that descending inhibitory controls from the brainstem are important for speeding recovery from pain following surgery. We examined the effects of destroying spinally projecting noradrenergic neurons via intrathecally administered antibody to dopamine β-hydroxylase conjugated to saporin (DβH-saporin) on recovery in an acute incisional pain model. Mechanical and thermal paw withdrawal thresholds and non-evoked spontaneous guarding scores were tested for several weeks postoperatively and analyzed using mixed effects growth curve modeling. DβH-saporin treatment resulted in a significant prolongation in the duration of mechanical and to a lesser degree thermal hypersensitivity in the ipsilateral paw of incised rats but did not increase the duration of spontaneous guarding. DβH-saporin treatment was also associated with increased microglial and astrocyte activation in the ipsilateral spinal cord 21 days post-incision compared to IgG-saporin treated controls. Chronic intrathecal administration of the α2 adrenergic receptor antagonist atipamezole (50-200 μg/day) produced similar effects. These data suggest that spinally projecting noradrenergic pathways and spinal α2 adrenergic receptor activation are important for speeding recovery from hypersensitivity following surgical incision possibly by reducing spinal glial activation. Interventions that augment the noradrenergic system may be important to speed recovery from pain after surgery. Perspective Endogenous descending spinal noradrenergic activation promotes resolution of incision induced hypersensitivity and inhibits spinal microglial and astrocyte activation in part through α2 adrenergic receptors. PMID:26545342

  8. Transfection of normal human and Chinese hamster DNA corrects diepoxybutane-induced chromosomal hypersensitivity of Fanconi anemia fibroblasts

    SciTech Connect

    Shaham, M.; Adler, B.; Ganguly, S.; Chaganti, R.S.K.

    1987-08-01

    Cultured cells from individuals affected with Fanconi anemia (FA) exhibit spontaneous chromosome breakage and hypersensitivity to the cell killing and clastogenic effects of the difunctional alkylating agent diepoxybutane (DEB). The authors report here the correction of both of these DEB-hypersensitivity phenotypes of FA cells achieved by cotransfection of normal placental of Chinese hamster lung cell DNA and the plasmid pSV2-neo-SVgpt. Transfectants were selected for clonogenic survival after treatment with DEB at a dose of 5 ..mu..gml. At this dose of DEB, the clonogenicity of normal fibroblasts was reduced to 50% and that of FA fibroblasts was reduced to zero. DEB-resistant (DEB/sup r/) colonies selected in this system exhibited a normal response to DEB-induced chromosome breakage and resistance to repeated DEB treatment. The neo and gpt sequences were detected by Southern blot analysis of DNA from one of four DEB/sup r/ colonies independently derived from transfection of human DNA and one of three DEB/sup r/ colonies independently derived from transfection of Chinese hamster DNA. The results demonstrate that DNA sequences that complement the two hallmark cellular phenotypes (cellular and chromosomal hypersensitivity to alkylating agents) of FA are present in human as well as Chinese hamster DNA. The cloning of these genes using transfection strategies can be expected to enable molecular characterization of FA

  9. Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patients.

    PubMed

    Ben m'rad, Mona; Leclerc-Mercier, Stéphanie; Blanche, Philippe; Franck, Nathalie; Rozenberg, Flore; Fulla, Yvonne; Guesmi, Myriam; Rollot, Florence; Dehoux, Monique; Guillevin, Loïc; Moachon, Laurence

    2009-05-01

    Drug-induced hypersensitivity syndrome (DIHS), also called drug rash with eosinophilia and systemic symptoms (DRESS), is a severe reaction usually characterized by fever, rash, and multiorgan failure, occurring 1-8 weeks after drug introduction. It is an immune-mediated reaction involving macrophage and T-lymphocyte activation and cytokine release, although no consensus has been reached as to its etiology. The skin, hematopoietic system, and liver are frequently involved. DIHS can mimic severe sepsis, viral infection, adult-onset Still disease (AOSD), or lymphoproliferation.We describe 24 consecutive patients with DIHS who were hospitalized between September 2004 and March 2008. Criteria for inclusion in this observational study were suspected drug reaction, eosinophilia >or=500/microL and/or atypical lymphocytes, involvement of at least 2 organs (skin being 1 of them), with suggestive chronology and exclusion of other diagnoses. Our cohort of 12 women and 12 men had a median age of 49 years (range, 22-82 yr), and 11 had skin phototype V or VI. Patients with mild or no rash were immunocompromised (7/24)- defined as treatment with prednisone (>or=10 mg/d) and another immunosuppressant drug, or human immunodeficiency virus infection. All patients were febrile (>38 degrees C), 14 had localized or generalized edema, 7 had pharyngitis, 8 had lymphadenopathy, 22 had hepatitis, 4 had nephritis, 2 had noninfectious and nonlithiasic angiocholitis or cholecystitis. Ten patients were hypotensive, 5 of whom had associated laboratory signs and/or imaging findings suggestive of acute myocardial dysfunction. Half of the patients had hemogram abnormalities, including eosinophilia. Nine DIHS patients fulfilled the Fautrel criteria for AOSD diagnosis, including glycosylated ferritin <20% in 4/11, with or without laboratory characteristics of hemophagocytosis. Twenty DIHS episodes occurred during the less sunny months of October to March.We determined 25-hydroxyvitamin D3 (25[OH]D3

  10. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

    SciTech Connect

    Tamura, Akitoshi Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-08-15

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased

  11. Enhancement of nerve-injury-induced thermal and mechanical hypersensitivity in adult male and female mice following early life stress.

    PubMed

    Nishinaka, Takashi; Nakamoto, Kazuo; Tokuyama, Shogo

    2015-01-15

    Early life stress contributes to the pathogenesis of psychiatric disorders and chronic pain in adult patients. However, information about the effect of early life stress on chronic pain in mice is limited. In the present study, we evaluated the effect of early life stress on baseline pain sensitivity and thermal or mechanical hypersensitivity induced by nerve injury in male and female mice. Early life stress was induced by maternal separation and social isolation (MSSI). Mice were separated from dam and littermates for 6h/day during postnatal days 15-21 and then were housed individually until the end of the study. At 9 weeks of age, the sciatic nerve was partially ligated to elicit neuropathic pain. Thermal and mechanical sensitivity were measured by plantar and von Frey tests. At 7 weeks of age, MSSI induced depression-like behaviors in both male and female mice, but induced anxiety-like behaviors only in female mice. MSSI had no effect on thermal and mechanical sensitivity before nerve injury. However, MSSI enhanced nerve-injury-induced thermal and mechanical hypersensitivity in both male and female mice. MSSI exacerbated neuropathic pain in adult male and female mice. Overall, this model may be useful for understanding the molecular mechanisms underlying the reciprocal relationship between early life stress and chronic pain. Copyright © 2014. Published by Elsevier Inc.

  12. Factors affecting cold-induced hypertension in rats.

    PubMed

    Shechtman, O; Fregly, M J; Papanek, P E

    1990-12-01

    A 3- to 4-week exposure of rats to a cold environment (5 +/- 2 degrees C) induces hypertension, including elevation of systolic, diastolic, and mean blood pressures and cardiac (left ventricular) hypertrophy. The studies described here were designed to investigate some factors affecting both the magnitude and the time course for development of cold-induced hypertension. The objective of the first study was to determine whether there was an ambient temperature at which the cold-induced elevation of blood pressure did not occur. The objective of the second experiment was to determine whether body weight at the time of exposure to cold affected the magnitude and time course for development of hypertension. To assess the first objective, male rats were housed in a chamber whose temperature was maintained at 5 +/- 2 degrees C while others were housed in an identical chamber at 9 +/- 2 degrees C. After 7 days of exposure to cold, the rats exposed to the colder temperature had a significant elevation of blood pressure (140 +/- 2 mm Hg) compared with the group maintained at 9 degrees C (122 +/- 3 mm Hg). The rats exposed to 9 degrees C had no significant elevation of systolic blood pressure at either 27 or 40 days after initiation of exposure to cold. At the latter time, the temperature in the second chamber was reduced to 5 +/- 2 degrees C. By the 25th day of exposure to this ambient temperature, the rats had a significant increase in systolic blood pressure above their levels at 9 degrees C. Thus, there appears to be a threshold ambient temperature for elevation of blood pressure during exposure to cold. That temperature appears to lie somewhere between 5 and 9 degrees C. The second objective was assessed by placing rats varying in weight from approximately 250 to 430 g in air at 5 degrees C. There was a highly significant direct relationship (r = 0.96) between body weight at the time of introduction to cold and the number of days required to increase systolic blood

  13. Effect of gene-targeted mutation in TNF receptor (p55) on contact hypersensitivity and ultraviolet B-induced immunosuppression

    SciTech Connect

    Kondo, Seiji; Wang, Binghe; Fujisawa, Hiroshi

    1995-10-15

    Tumor necrosis factor {alpha} (TNF-{alpha}) is a pleiotropic proinflammatory cytokine. TNF-{alpha} has been implicated in the pathogenesis of delayed-type hypersensitivity reactions such as allergic contact hypersensitivity and has been suggested as a mediator of ultraviolet B (UVB)-induced immunosuppression. Conflicting reports, however, exist concerning the effects of TNF-{alpha} on contact hypersensitivity (CHS). To determine the role of TNF-{alpha} in the generation and regulation of CHS, gene-targeted mutant mice lacking TNF-receptor (p55) gene (TNF-R1(-) mice) were treated with dinitrofluorobenzene (DNFB) to induce CHS. TNF-R1(-) mice showed significant hyperresponsiveness in CHS (152.8 {+-} 20.9%, p < 0.025) compared with normal syngeneic mice (C57BL/6) assessed by ear swelling. To determine whether UVB can induce suppression in TNF-R1(-) mice, mice were irradiated on the shaved abdomen with 96 ml/cm{sup 2} UVB and 3 days later they were painted with 0.5% DNFB (sensitization dose), followed 5 days later with 0.2% DNFB to the left ear (challenge dose). Significant suppression of CHS was observed both locally (sensitization on irradiated site) and systemically (sensitization on unirradiated site) in UVB-irradiated TNF-R1(-) mice as well as in normal mice. To rule out possible signaling through p75 TNF-R, the mice were treated with anti-TNF-{alpha} Ab (V1q), which can neutralize any TNF effects through either receptor. V1q had no effect on these phenomena observed in TNF-R1(-) mice. These results suggest that TNF-{alpha} plays a regulatory role in CHS but is not required to induce UVB-mediated immunosuppression. 45 refs., 5 figs.

  14. Lactobacillus farciminis treatment suppresses stress induced visceral hypersensitivity: a possible action through interaction with epithelial cell cytoskeleton contraction

    PubMed Central

    Ait‐Belgnaoui, A; Han, W; Lamine, F; Eutamene, H; Fioramonti, J; Bueno, L; Theodorou, V

    2006-01-01

    Background Stress induced increase in colonic paracellular permeability results from epithelial cell cytoskeleton contraction and is responsible for stress induced hypersensitivity to colorectal distension (CRD). The probiotic Lactobacillus farciminis releases spontaneously nitric oxide (NO) in the colonic lumen in vivo and exerts anti‐inflammatory effects. This study aimed: (i) to evaluate the effects of L farciminis on stress induced hypersensitivity to CRD and increase in colonic paracellular permeability; and (ii) to ascertain whether these effects are NO mediated and related to changes in colonocyte myosin light chain phosphorylation (p‐MLC). Methods Female Wistar rats received either 1011 CFU/day of L farciminis or saline orally over 15 days before partial restraint stress (PRS) or sham‐PRS application. Visceral sensitivity to CRD and colonic paracellular permeability was assessed after PRS or sham‐PRS. Haemoglobin was used as an NO scavenger. Western blotting for MLC kinase, MLC, and p‐MLC were performed in colonic mucosa from L farciminis treated and control rats after PRS or sham‐PRS. Results PRS significantly increased the number of spike bursts for CRD pressures of 30–60 mm Hg as well as colonic paracellular permeability. L farciminis treatment prevented both effects, while haemoglobin reversed the protective effects of L farciminis. p‐MLC expression increased significantly from 15 to 45 minutes after PRS, and L farciminis treatment prevented this increase. Conclusion L farciminis treatment prevents stress induced hypersensitivity, increase in colonic paracellular permeability, and colonocyte MLC phosphorylation. This antinociceptive effect occurs via inhibition of contraction of colonic epithelial cell cytoskeleton and the subsequent tight junction opening, and may also involve direct or indirect effects of NO produced by this probiotic. PMID:16507583

  15. Gender and dose dependent ovalbumin induced hypersensitivity responses in murine model of food allergy

    USDA-ARS?s Scientific Manuscript database

    While federal regulations mandate the labeling of major food allergens, allowable food allergen thresholds have yet to be determined. Therefore the aim of this project was to identify the lowest egg allergen ovalbumin (OVA) dose causing hypersensitization using a validated murine model. Mice were o...

  16. Gender and dose dependent ovalbumin induced hypersensitivity responses in murine model of food allergy

    USDA-ARS?s Scientific Manuscript database

    While federal regulations mandate the labeling of major food allergens, allowable food allergen thresholds have yet to be determined. Therefore the aim of this project was to identify the lowest egg allergen ovalbumin (OVA) dose causing hypersensitization using a validated murine model. Mice were or...

  17. Protein(s) from the Gram-Positive Bacterium Clavibacter michiganensis subsp. michiganensis Induces a Hypersensitive Response in Plants.

    PubMed

    Alarcón, C; Castro, J; Muñoz, F; Arce-Johnson, P; Delgado, J

    1998-04-01

    ABSTRACT The gram-positive tomato pathogen Clavibacter michiganensis subsp. michiganensis induced a local necrotic response on four-o'clock (Mirabilis jalapa) and tobacco (Nicotiana tabacum) plants. This necrosis response was characteristic of the hypersensitive response (HR). The cell-free culture supernatant from strain CMM623 also induced a necrosis that was phenotypically similar to that induced by the bacteria. Inhibitors of plant metabolism suppressed the necrotic reaction of both M. jalapa and tobacco. The HR-inducing activity present in the supernatant was heat stable, sensitive to proteases, and had an apparent molecular mass in the range of 35 to 50 kDa as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The properties observed for the necrosis-inducing activity resembled harpin and PopA described from gram-negative phytopathogenic bacteria.

  18. Hypersensitivity pneumonitis

    MedlinePlus

    Hypersensitivity pneumonitis usually occurs in people who work in places where there are high levels of organic dusts, fungus, or molds. Long-term exposure can lead to lung inflammation and acute lung disease . ...

  19. A novel model for studying ileitis-induced visceral hypersensitivity in goats.

    PubMed

    Tahir, Adnan Hassan; Wan, Juan; Shah, Manoj Kumar; Janyaro, Habibullah; Li, Xiao-Jing; Ding, Ming-Xing

    2016-10-06

    Visceral hypersensitivity (VH) is a common condition in many gastrointestinal disorders such as inflammatory bowel diseases (IBDs) in human and animals. Most studies often induce Crohn's disease/colitis to investigate VH in small experimental animals. Although farm animals commonly suffer from IBDs, their VH has not been investigated so far. Because goats can suffer from Johne's disease, a naturally occurring Crohn's-like disease, they may be suitable to be used for studying the mechanism underlying VH in common intestinal disorders of large animals. In the present study, 60 healthy goats of either sex were equally divided into a 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) group and saline group. A volume of 1.2 ml of TNBS-ethanol solution (30 mg TNBS in 40 % ethanol) or an equal volume of isotonic saline was injected into the wall of the terminal ileum through laparotomy. The severity of the developing ileitis was determined according to macro- and microscopic pathologic scores and the levels of myeloperoxidase, interleukin-1β, interleukin-6 and tumor necrosis factor-α, and VH was evaluated with visceromotor responses (VMR) to colorectal distension on days 3, 7, 14, 21 and 28. VMRs were assessed with a continuous ramp distention mode with 6 s for each pressure (20, 40, 60, 80 and 100 mmHg). Compared to the saline group, the TNBS-treated goats showed apparent transmural pathological changes and a significant increase (P < 0.05) in macroscopic and microscopic change scores, and levels of myeloperoxidase, interleukin-1β, interleukin-6 and tumor necrosis factor-α in the ileum, and VMR to colorectal distension. The goats exhibited apparent ileitis at days 3 to 21, and VH at days 7 to 28 following TNBS treatment. This experiment successfully established a reproducible ileitis and VH with administration of TNBS-ethanol solution in the ileal wall of goats. This model is useful for studying the pathogenesis of the IBD and the mechanism underlying VH, and for

  20. Spinal toll-like receptor 4-mediated signalling pathway contributes to visceral hypersensitivity induced by neonatal colonic irritation in rats.

    PubMed

    Chen, Z-Y; Zhang, X-W; Yu, L; Hua, R; Zhao, X-P; Qin, X; Zhang, Y-M

    2015-02-01

    Although visceral hypersensitivity is a major pathophysiological feature of irritable bowel syndrome (IBS), its underlying mechanisms remain elusive. Toll-like receptor 4 (TLR4) is a critical pattern recognition molecule of the innate immune system. In this study, we investigated whether the TLR4/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) signalling pathway in the spinal cord contributed to the visceral hypersensitivity induced by neonatal colonic irritation (CI) in rats. The Sprague-Dawley rat model of IBS was induced by colon irritation on post-natal day (PND) 8, PND10 and PND12. Experiments were conducted in adult rats. TLR4 mRNA and protein, and its downstream signalling molecules, MyD88, inhibitory nuclear factor-kappa B (IκB) and NF-κB protein expressions in L2-S4 spinal segments were detected by quantitative real-time reverse transcription-polymerase chain reaction as well as Western blotting. TLR4 co-localization was determined by immunohistochemistry. Levels of tumour necrosis factor-alpha (TNF-α) and interleukin 1β (IL-1β) were measured with enzyme-linked immunosorbent assay. We found that neonatal CI treatment induced long-lasting visceral hypersensitivity without identifiable structural abnormalities in descending colons of adult rats. Neonatal CI treatment evoked a significant up-regulation of the expressions of TLR4 in glia, MyD88, p-IκB-α and NF-κB in adult rats. Neonatal CI treatment also increased the levels of its downstream inflammatory agents TNF-α and IL-1β in the L2-S4 regions of the spinal cord of adult rats. These results suggest that neonatal CI stimulates the production of IL-1β and TNF-α through the TLR4/MyD88/NF-κB signalling pathway in the spinal cord, which contributed to visceral hypersensitivity induced by neonatal CI in rats. © 2014 European Pain Federation - EFIC®

  1. Chronic prenatal stress epigenetically modifies spinal cord BDNF expression to induce sex specific visceral hypersensitivity in offspring

    PubMed Central

    Winston, John H.; Li, Qingjie; Sarna, Sushil K.

    2014-01-01

    Background Irritable bowel syndrome (IBS) is a heterogeneous disorder with abdomen pain as one of the primary symptoms. The etiology of IBS remains unknown. Epidemiological studies found that a subset of these patients have a history of adverse early-life events. We tested the hypothesis that chronic prenatal stress (CPS) epigenetically enhances brain-derived neurotrophic factor (BDNF) in spinal cord to aggravate colon sensitivity to colorectal distension (CRD) differentially in male and female offspring. Methods We used heterotypic intermittent chronic stress (HeICS) protocols in pregnant dams from E11 until delivery. Results CPS induced significant visceral hypersensitivity (VHS) to CRD in male and female offspring. A second exposure to HeICS in adult offspring exacerbated VHS greater in female offspring that persisted longer than in male offspring. CPS upregulated BDNF expression in the lumbar-sacral dorsal horn that correlated with the exacerbation of VHS in female, but not in male offspring. The upregulation of BDNF was due to a significant increase in RNA Pol II binding, histone H3 acetylation and significant decrease in histone deacetylase 1 association with the core promoter of BDNF in female offspring. Other chronic prenatal and neonatal stress protocols were less effective than HeICS. Conclusion & Inferences The development of visceral hypersensitivity, which contributes to the symptom of intermittent abdominal pain, is a two-step process, chronic in utero stress followed by chronic stress in adult-life. This two-step process induces aggravated and persistent colon hypersensitivity in female than in male offspring. Our preclinical model explains several clinical features in IBS patients. PMID:24588943

  2. Enhanced sympathetic nerve activity induced by neonatal colon inflammation induces gastric hypersensitivity and anxiety-like behavior in adult rats.

    PubMed

    Winston, John H; Sarna, Sushil K

    2016-07-01

    Gastric hypersensitivity (GHS) and anxiety are prevalent in functional dyspepsia patients; their underlying mechanisms remain unknown largely because of lack of availability of live visceral tissues from human subjects. Recently, we demonstrated in a preclinical model that rats subjected to neonatal colon inflammation show increased basal plasma norepinephrine (NE), which contributes to GHS through the upregulation of nerve growth factor (NGF) expression in the gastric fundus. We tested the hypothesis that neonatal colon inflammation increases anxiety-like behavior and sympathetic nervous system activity, which upregulates the expression of NGF to induce GHS in adult life. Chemical sympathectomy, but not adrenalectomy, suppressed the elevated NGF expression in the fundus muscularis externa and GHS. The measurement of heart rate variability showed a significant increase in the low frequency-to-high frequency ratio in GHS vs. the control rats. Stimulus-evoked release of NE from the fundus muscularis externa strips was significantly greater in GHS than in the control rats. Tyrosine hydroxylase expression was increased in the celiac ganglia of the GHS vs. the control rats. We found an increase in trait but not stress-induced anxiety-like behavior in GHS rats in an elevated plus maze. We concluded that neonatal programming triggered by colon inflammation upregulates tyrosine hydroxylase in the celiac ganglia, which upregulates the release of NE in the gastric fundus muscularis externa. The increase of NE release from the sympathetic nerve terminals concentration dependently upregulates NGF, which proportionately increases the visceromotor response to gastric distention. Neonatal programming concurrently increases anxiety-like behavior in GHS rats. Copyright © 2016 the American Physiological Society.

  3. A novel cold-inducible expression system for Bacillus subtilis.

    PubMed

    Thuy Le, Ai Thi; Schumann, Wolfgang

    2007-06-01

    Production of recombinant proteins at low temperatures is one strategy to prevent formation of protein aggregates and the use of an expensive inducer such as IPTG. We report on the construction of two expression vectors both containing the cold-inducible des promoter of Bacillus subtilis, where one allows intra- and the other extracellular synthesis of recombinant proteins. Production of recombinant proteins started within the first 30min after temperature downshock to 25 degrees C and continued for about 5h.

  4. Analgesic treatment of ciguatoxin-induced cold allodynia.

    PubMed

    Zimmermann, Katharina; Deuis, Jennifer R; Inserra, Marco C; Collins, Lindon S; Namer, Barbara; Cabot, Peter J; Reeh, Peter W; Lewis, Richard J; Vetter, Irina

    2013-10-01

    Ciguatera, the most common form of nonbacterial ichthyosarcotoxism, is caused by consumption of fish that have bioaccumulated the polyether sodium channel activator ciguatoxin. The neurological symptoms of ciguatera include distressing, often persistent sensory disturbances such as paraesthesias and the pathognomonic symptom of cold allodynia. We show that intracutaneous administration of ciguatoxin in humans elicits a pronounced axon-reflex flare and replicates cold allodynia. To identify compounds able to inhibit ciguatoxin-induced Nav responses, we developed a novel in vitro ciguatoxin assay using the human neuroblastoma cell line SH-SY5Y. Pharmacological characterisation of this assay demonstrated a major contribution of Nav1.2 and Nav1.3, but not Nav1.7, to ciguatoxin-induced Ca2+ responses. Clinically available Nav inhibitors, as well as the Kv7 agonist flupirtine, inhibited tetrodotoxin-sensitive ciguatoxin-evoked responses. To establish their in vivo efficacy, we used a novel animal model of ciguatoxin-induced cold allodynia. However, differences in the efficacy of these compounds to reverse ciguatoxin-induced cold allodynia did not correlate with their potency to inhibit ciguatoxin-induced responses in SH-SY5Y cells or at heterologously expressed Nav1.3, Nav1.6, Nav1.7, or Nav1.8, indicating cold allodynia might be more complex than simple activation of Nav channels. These findings highlight the need for suitable animal models to guide the empiric choice of analgesics, and suggest that lamotrigine and flupirtine could be potentially useful for the treatment of ciguatera. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  5. Heat hyperalgesia and mechanical hypersensitivity induced by calcitonin gene-related peptide in a mouse model of neurofibromatosis.

    PubMed

    White, Stephanie; Marquez de Prado, Blanca; Russo, Andrew F; Hammond, Donna L

    2014-01-01

    This study examined whether mice with a deficiency of neurofibromin, a Ras GTPase activating protein, exhibit a nociceptive phenotype and probed a possible contribution by calcitonin gene-related peptide. In the absence of inflammation, Nf1+/- mice (B6.129S6 Nf1/J) and wild type littermates responded comparably to heat or mechanical stimuli, except for a subtle enhanced mechanical sensitivity in female Nf1+/- mice. Nociceptive phenotype was also examined after inflammation induced by capsaicin and formalin, which release endogenous calcitonin gene-related peptide. Intraplantar injection of capsaicin evoked comparable heat hyperalgesia and mechanical hypersensitivity in Nf1+/- and wild type mice of both genders. Formalin injection caused a similar duration of licking in male Nf1+/- and wild type mice. Female Nf1+/- mice licked less than wild type mice, but displayed other nociceptive behaviors. In contrast, intraplantar injection of CGRP caused greater heat hyperalgesia in Nf1+/- mice of both genders compared to wild type mice. Male Nf1+/- mice also exhibited greater mechanical hypersensitivity; however, female Nf1+/- mice exhibited less mechanical hypersensitivity than their wild type littermates. Transcripts for calcitonin gene-related peptide were similar in the dorsal root ganglia of both genotypes and genders. Transcripts for receptor activity-modifying protein-1, which is rate-limiting for the calcitonin gene-related peptide receptor, in the spinal cord were comparable for both genotypes and genders. The increased responsiveness to intraplantar calcitonin gene-related peptide suggests that the peripheral actions of calcitonin gene-related peptide are enhanced as a result of the neurofibromin deficit. The analgesic efficacy of calcitonin gene-related peptide receptor antagonists may therefore merit investigation in neurofibromatosis patients.

  6. Heat Hyperalgesia and Mechanical Hypersensitivity Induced by Calcitonin Gene-Related Peptide in a Mouse Model of Neurofibromatosis

    PubMed Central

    White, Stephanie; Marquez de Prado, Blanca; Russo, Andrew F.; Hammond, Donna L.

    2014-01-01

    This study examined whether mice with a deficiency of neurofibromin, a Ras GTPase activating protein, exhibit a nociceptive phenotype and probed a possible contribution by calcitonin gene-related peptide. In the absence of inflammation, Nf1+/− mice (B6.129S6 Nf1/J) and wild type littermates responded comparably to heat or mechanical stimuli, except for a subtle enhanced mechanical sensitivity in female Nf1+/− mice. Nociceptive phenotype was also examined after inflammation induced by capsaicin and formalin, which release endogenous calcitonin gene-related peptide. Intraplantar injection of capsaicin evoked comparable heat hyperalgesia and mechanical hypersensitivity in Nf1+/− and wild type mice of both genders. Formalin injection caused a similar duration of licking in male Nf1+/− and wild type mice. Female Nf1+/− mice licked less than wild type mice, but displayed other nociceptive behaviors. In contrast, intraplantar injection of CGRP caused greater heat hyperalgesia in Nf1+/− mice of both genders compared to wild type mice. Male Nf1+/− mice also exhibited greater mechanical hypersensitivity; however, female Nf1+/− mice exhibited less mechanical hypersensitivity than their wild type littermates. Transcripts for calcitonin gene-related peptide were similar in the dorsal root ganglia of both genotypes and genders. Transcripts for receptor activity-modifying protein-1, which is rate-limiting for the calcitonin gene-related peptide receptor, in the spinal cord were comparable for both genotypes and genders. The increased responsiveness to intraplantar calcitonin gene-related peptide suggests that the peripheral actions of calcitonin gene-related peptide are enhanced as a result of the neurofibromin deficit. The analgesic efficacy of calcitonin gene-related peptide receptor antagonists may therefore merit investigation in neurofibromatosis patients. PMID:25184332

  7. Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia.

    PubMed

    Gong, Kerui; Jasmin, Luc

    2017-02-01

    It is not uncommon for patients chronically treated with opioids to exhibit opioid-induced hyperalgesia, and this has been widely reported clinically and experimentally. The molecular substrate for this hyperalgesia is multifaceted, and associated with a complex neural reorganization even in the periphery. For instance, we have recently shown that chronic morphine-induced heat hyperalgesia is associated with an increased expression of GluN2B containing N-methyl-D-aspartate receptors, as well as of the neuronal excitatory amino acid transporter 3/excitatory amino acid carrier 1, in small-diameter primary sensory neurons only. Cold allodynia is also a common complaint of patients chronically treated with opioids, yet its molecular mechanisms remain to be understood. Here we present evidence that the cold sensor TRPM8 channel is involved in opioid-induced hyperalgesia. After 7 days of morphine administration, we observed an upregulation of TRPM8 channels using patch clamp recording on sensory neurons and Western blot analysis on dorsal root ganglia. The selective TRPM8 antagonist RQ-00203078 blocked cold hyperalgesia in morphine-treated rats. Also, TRPM8 knockout mice failed to develop cold hyperalgesia after chronic administration of morphine. Our results show that chronic morphine upregulates TRPM8 channels, which is in contrast with the previous finding that acute morphine triggers TRPM8 internalization.

  8. A non-cold-inducible cold shock protein homolog mainly contributes to translational control under optimal growth conditions.

    PubMed

    Tanaka, Toshiko; Mega, Ryosuke; Kim, Kwang; Shinkai, Akeo; Masui, Ryoji; Kuramitsu, Seiki; Nakagawa, Noriko

    2012-03-01

    Cold shock proteins (Csps) include both cold-induced and non-cold-induced proteins, contrary to their name. Cold-induced Csps are well studied; they function in cold acclimation by controlling transcription and translation. Some Csps have been reported to contribute to other cellular processes. However, the functions of non-cold-induced Csps under optimal growth conditions remain unknown. To elucidate these functions, we used transcriptome and proteome analyses as comprehensive approaches and have compared the outputs of wild-type and non-cold-induced Csp-deletion mutant cells. As a model organism, we selected Thermus thermophilus HB8 because it has only two csp genes (ttcsp1 and ttcsp2); ttCsp1 is the only non-cold-induced Csp. Surprisingly, the amount of transcripts and proteins upon deletion of the ttcsp1 gene was quite different. DNA microarray analysis revealed that the deletion of ttcsp1 did not affect the amount of transcripts, although the ttcsp1 gene was constantly expressed in the wild-type cell. Nonetheless, proteomic analysis revealed that the expression levels of many proteins were significantly altered when ttcsp1 was deleted. These results suggest that ttCsp1 functions in translation independent of transcription. Furthermore, ttCsp1 is involved in both the stimulation and inhibition of translation of specific proteins. Here, we have determined the crystal structure of ttCsp1 at 1.65 Å. This is the first report to present the structure of a non-cold-inducible cold shock protein. We also report the nucleotide binding affinity of ttCsp1. Finally, we discuss the functions of non-cold-induced Csps and propose how they modulate the levels of specific proteins to suit the prevailing environmental conditions.

  9. Obesity Takes Its Toll on Visceral Pain: High-Fat Diet Induces Toll-Like Receptor 4-Dependent Visceral Hypersensitivity.

    PubMed

    Tramullas, Mónica; Finger, Beate C; Dinan, Timothy G; Cryan, John F

    2016-01-01

    Exposure to high-fat diet induces both, peripheral and central alterations in TLR4 expression. Moreover, functional TLR4 is required for the development of high-fat diet-induced obesity. Recently, central alterations in TLR4 expression have been associated with the modulation of visceral pain. However, it remains unknown whether there is a functional interaction between the role of TLR4 in diet-induced obesity and in visceral pain. In the present study we investigated the impact of long-term exposure to high-fat diet on visceral pain perception and on the levels of TLR4 and Cd11b (a microglial cell marker) protein expression in the prefrontal cortex (PFC) and hippocampus. Peripheral alterations in TLR4 were assessed following the stimulation of spleenocytes with the TLR4-agonist LPS. Finally, we evaluated the effect of blocking TLR4 on visceral nociception, by administering TAK-242, a selective TLR4-antagonist. Our results demonstrated that exposure to high-fat diet induced visceral hypersensitivity. In parallel, enhanced TLR4 expression and microglia activation were found in brain areas related to visceral pain, the PFC and the hippocampus. Likewise, peripheral TLR4 activity was increased following long-term exposure to high-fat diet, resulting in an increased level of pro-inflammatory cytokines. Finally, TLR4 blockage counteracted the hyperalgesic phenotype present in mice fed on high-fat diet. Our data reveal a role for TLR4 in visceral pain modulation in a model of diet-induced obesity, and point to TLR4 as a potential therapeutic target for the development of drugs to treat visceral hypersensitivity present in pathologies associated to fat diet consumption.

  10. Effect of transient receptor potential vanilloid-1 on cough hypersensitivity induced by particulate matter 2.5.

    PubMed

    Lv, Haining; Yue, Jianliang; Chen, Zhe; Chai, Senlin; Cao, Xu; Zhan, Jie; Ji, Zhenjun; Zhang, Hui; Dong, Rong; Lai, Kefang

    2016-04-15

    The mechanism of cough hypersensitivity induced by particulate matter 2.5 (PM2.5) remains elusive. The current study was designed to explore the effect of transient receptor potential vanilloid-1 (TRPV1) on cough hypersensitivity in airway and central nervous system. The PM2.5-induced chronic cough model of guinea pig was established by exposure to different doses of PM2.5 for three weeks. After exposure, the animals were microinjected with TRPV1 agonist capsaicine, antagonist capsazepine in the dorsal vagal complex respectively. Cough sensitivity was measured by determining the provocative concentration of citric acid inducing 5 or more coughs (C5). Airway inflammation was detected by hematoxylin eosin (HE) staining and Evans blue fluorescence, and substance P (SP) and TRPV1 expressions in airway were observed by immunohistochemical staining. TRPV1 expressions in the dorsal vagal complex were observed by immunofluorescence. Retrograde tracing by pseudorabies virus-Bartha (PRV-Bartha) was conducted to confirm the regulatory pathway between airway and central nervous system. PM2.5 induced TRPV1 expressions in both of airway and dorsal vagal complex and airway neurogenic inflammation. Airway vascular permeability increased after being exposed to PM2.5. The expressions of SP in the airway and airway inflammation was increased after microinjecting TRPV1 agonist, and decreased after microinjecting TRPV1 antagonist. PRV infected neurons in medulla oblongata mainly located in the dorsal vagal complex. These findings show that TRPV1 in the dorsal vagal complex could promote airway neurogenic inflammation and cough reflex sensitivity through neural pathways of vagal complex-airways, which indicate the therapeutic potential of specific inhibition of TRPV1 for chronic cough induced by PM2.5. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Cold-induced vasodilatation in the foot is not homogenous or trainable over repeated cold exposure.

    PubMed

    Reynolds, Luke F; Mekjavic, Igor B; Cheung, Stephen S

    2007-12-01

    Cold-induced vasodilatation (CIVD) is proposed to be a protective response to preserve tissue integrity in the extremities during cold exposure, but little research exists on either the trainability or the spatial pattern of CIVD response in the foot. We investigated the thermal response across the foot with repeated cold exposure. Ten healthy subjects immersed their left foot to the ankle in 8 degrees C water for 30 min 5 days/week for 3 weeks. Skin temperature was recorded on the medial side of the nail bed of the 5 toes and the dorsum of the foot. The presence of CIVD, defined as an increase of 1 degrees C at any time during cooling, was rare with our protocol. While a CIVD response was observed at least once in 8 of the 10 subjects, only 122 instances of CIVD were observed out of a total of 900 possible observations (10 subjects x 6 sites x 15 trials). Furthermore, thermal habituation was not evident, with toe temperatures at the end of each immersion (8-11 degrees C) remaining near water temperature throughout the 15 sessions. Even within the two subjects exhibiting the most incidence of CIVD, high variability existed in the occurrence, magnitude, and/or onset times. Synchronicity was often observed where more than one toe exhibited CIVD, though the magnitude varied greatly (range 1-9 degrees C). We conclude that, under realistic conditions of whole-foot immersion in cold water, CIVD is not a common or trainable response.

  12. Identification of cold-inducible microRNAs in grapevine.

    PubMed

    Sun, Xiaoming; Fan, Gaotao; Su, Lingye; Wang, Wanjun; Liang, Zhenchang; Li, Shaohua; Xin, Haiping

    2015-01-01

    Low temperature is one of the most important environmental factors that limits the geographical distribution and productivity of grapevine. However, the molecular mechanisms on how grapevine responds to cold stress remains to be elucidated. MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs that play an essential role during plant development and stress responses. Although miRNAs and their targets have been identified in several Vitis species, their participation during cold accumulation in grapevine remains unknown. In this study, two small RNA libraries were generated from micropropagated 'Muscat Hamburg' (V. vinifera) plantlets under normal and low temperatures (4°C). A total of 163 known miRNAs and 67 putative novel miRNAs were detected from two small RNA libraries by Solexa sequencing. Forty-four cold-inducible miRNAs were identified through differentially expressed miRNAs (DEMs) analysis; among which, 13 belonged to upregulated DEMs while 31 belonged downregulated DEMs. The expression patterns of the 13 DEMs were verified by real-time RT-PCR analysis. The prediction of the target genes for DEMs indicated that miRNA may regulate transcription factors, including AP2, SBP, MYB, bHLH, GRAS, and bZIP under cold stress. The 5'-RLM RACE were conducted to verify the cleavage site of predicted targets. Seven predicted target genes for four known and three novel vvi-miRNAs showed specific cleavage sites corresponding to their miRNA complementary sequences. The expression pattern of these seven target genes revealed negative correlation with the expression level of the corresponding vvi-miRNAs. Our results indicated that a diverse set of miRNAs in V. vinifera are cold-inducible and may play an important role in cold stress response.

  13. Liver dysfunction induced by systemic hypersensitivity reaction to lamotrigine: case report.

    PubMed

    Im, Sung Gyu; Yoo, Sun Hong; Park, Young Min; Lee, Sang Jin; Jang, Sun Kyung; Jeon, Dong Ok; Cho, Hyo Jin; Oh, Mi Jung

    2015-06-01

    Lamotrigine is an anticonvulsant drug used to treat partial and generalized seizure disorders. Hypersensitivity to lamotrigine usually causes mild symptoms such as fever, rash, and slight invasion of internal organs. However, a 33-year-old male patient who was admitted with Stevens-Johnson syndrome after taking lamotrigine for 15 days experienced hepatic failure and died 5 days after admission. This case demonstrates the importance of realizing that lamotrigine can lead to fatal hepatic failure, and that tests for the normal liver function should be performed when administering lamotrigine.

  14. Therapeutic benefits of the methyl donor S-adenosylmethionine on nerve injury-induced mechanical hypersensitivity and cognitive impairment in mice.

    PubMed

    Grégoire, Stéphanie; Millecamps, Magali; Naso, Lina; Do Carmo, Sonia; Cuello, A Claudio; Szyf, Moshe; Stone, Laura S

    2017-05-01

    Despite considerable advances in understanding mechanisms involved in chronic pain, effective treatment remains elusive. Comorbid conditions including anxiety, depression, and cognitive impairment further impact quality of life. Chronic pain is associated with reversible changes in brain anatomy and function and with long-term changes in gene expression. Epigenetic mechanisms, including DNA methylation, contribute to wide-spread and long-lasting reprogramming of gene expression. We previously reported decreases in global DNA methylation in the mouse frontal cortex 6 months after induction of neuropathic pain using the spared nerve injury (SNI) model. Here, we examined the therapeutic effect of increasing DNA methylation using the methyl donor S-adenosylmethionine (SAM). S-adenosylmethionine is marketed as a nutritional supplement for a range of conditions including liver disease, depression, osteoarthritis, fibromyalgia, and dementia. Three months after SNI or sham surgery, animals were treated with SAM (20 mg/kg, 3×/week) or saline orally for 4 months, and the impact on sensory, motor, motivational, and cognitive indices was measured. S-adenosylmethionine attenuated SNI-induced mechanical hypersensitivity and reduced active avoidance of mechanical stimuli but had no effect on cold sensitivity or motor capacity. S-adenosylmethionine completely blocked nerve injury-induced cognitive impairment and attenuated SNI-induced decreases in global DNA methylation in the frontal cortex. In summary, chronic oral administration of the methyl donor, SAM, attenuated sensory and cognitive symptoms associated with nerve injury in mice. These effects may be mediated, in part, through modulation of DNA methylation in the central nervous system by systemic administration of the methyl donor SAM.

  15. Mechanical and thermal hypersensitivities associated with orthodontic tooth movement: a behavioral rat model for orthodontic tooth movement-induced pain.

    PubMed

    Sood, Mandeep; Bhatt, Poolak; Sessle, Barry J

    2015-01-01

    To test whether orofacial mechanical and thermal hypersensitivities occur in rats during orthodontic tooth movement (OTM). Sprague-Dawley rats (140 to 160 g) were divided into an experimental (E) group (n =7), with an active orthodontic spring placed in the right side of their mouth, and a sham (S) group (n = 7), with an inactive orthodontic spring. Mechanical sensitivity was tested preoperatively (1 day before attaching the orthodontic spring) and postoperatively (1 hour, 3 hours, 6 hours, days 1 to 7, day 14, day 21, and day 28 after orthodontic spring attachment) on the cheek, upper lip, and maxillary incisor labial gingiva bilaterally by recording the threshold for a head withdrawal response evoked by von Frey filaments. Thermal sensitivity was also tested preoperatively and postoperatively on the cheek bilaterally by applying a noxious thermal stimulus and measuring head withdrawal response duration, response score, and response percentile rate. Statistical analyses involved a mixed-model repeated-measures analysis of variance (MMRM ANOVA). The mechanical and thermal sensitivities at all bilateral sites were significantly increased (P < .01) in the E group in the early postoperative period (1 to 5 days), with peaks reached on day 1, and then returned to and remained at preoperative levels until postoperative day 28. However, there was no significant change from the preoperative levels in mechanical and thermal sensitivities for the S group for all the tested sites. This rat OTM-induced pain model correlates with the time course of OTM-induced pain in humans and suggests that OTM-induced mechanical and thermal hypersensitivities may be useful measures of OTM-induced pain.

  16. The excitatory amino acid receptor antagonist MK-801 prevents the hypersensitivity induced by spinal cord ischemia in the rat

    SciTech Connect

    Hao, J.X.; Xu, X.J.; Aldskogius, H.; Seiger, A.; Wiesenfeld-Hallin, Z. )

    1991-08-01

    Protection by the NMDA receptor antagonist MK-801 against transient spinal cord ischemia-induced hypersensitivity was studied in rats. The spinal ischemia was initiated by vascular occlusion resulting from the interaction between the photosensitizing dye Erythrosin B and an argon laser beam. The hypersensitivity, termed allodynia, where the animals reacted by vocalization to nonnoxious mechanical stimuli in the flank area, was consistently observed during several days after induction of the ischemia. Pretreatment with MK-801 (0.1-0.5 mg/kg, iv) 10 min before laser irradiation dose dependently prevented the occurrence of allodynia. The neuroprotective effect of MK-801 was not reduced by maintaining normal body temperature during and after irradiation. There was a significant negative correlation between the delay in the administration of MK-801 after irradiation and the protective effect of the drug. Histological examination revealed slight morphological damage in the spinal cord in 38% of control rats after 1 min of laser irradiation without pretreatment with MK-801. No morphological abnormalities were observed in rats after pretreatment with MK-801 (0.5 mg/kg). The present results provide further evidence for the involvement of excitatory amino acids, through activation of the NMDA receptor, in the development of dysfunction following ischemic trauma to the spinal cord.

  17. Immunological mechanisms of antitumor activity of some kinds of Chinese herbs: Meth A-induced delayed type hypersensitivity.

    PubMed

    Mori, H; Xu, Q A; Sakamoto, O; Uesugi, Y; Ono, Y; Koda, A; Nishioka, I

    1988-09-01

    In the present paper, we confirmed that a delayed type hypersensitivity response can be elicited against Meth A tumor (Meth A-DTH) in BALB/c mice bearing the primary tumor. This response was augmented by lipopolysaccharide. We examined the effects of 4 kinds of Chinese herbs including A. capillaris, S. doederleinii, A. macrocephala and S. subprostrata on the Meth A-DTH, and the results were compared with that of the herbs on picryl chloride-induced delayed type hypersensitivity (PC-DTH). All of the herbs examined augmented the Meth A-DTH 10 days after the primary tumor transplantation, and S. doederleinii, A. macrocephala and S. subprostrata prevented the decay of the response on the 20th day, but A. capillaris did not. On the other hand, none of the herbs affected the PC-DTH. When both DTH responses were caused simultaneously in the same mouse, Meth A-DTH decayed 20 days after the transplantation but PC-DTH did not. In this case, the effects of these 4 herbs on Meth A-DTH and PC-DTH were essentially the same as those seen in the case of separate experiments. The previous and present results suggest that A. capillaris shows antitumor activity mainly through a direct cytotoxicity, although this herb might have certain components to enhance Meth A-DTH, and the other herbs display the activity through the enhancement of T cell-mediated tumor immunity, particularly tumor specific DTH.

  18. Combined cold- and heat-induced cholinergic urticaria.

    PubMed

    Farnam, J; Grant, J A; Lett-Brown, M A; Lord, R A; Russell, W L; Henry, D P

    1986-08-01

    A 36-year-old white woman with a 20-year history of cutaneous, respiratory, and cardiovascular symptoms triggered by physical activity and by exposure to either heat or cold was evaluated. A routine evaluation for the cause of her condition was positive only for certain physical factors. Cutaneous testing for dermatographism, ice-cube challenge, and exposure to ultraviolet A and ultraviolet B light were negative. A methacholine skin test was positive. Sitting in a cold room (4 degrees C) induced micropapular wheals on exposed areas similar to those classically associated with cholinergic urticaria. Placing both feet in warm water (44 degrees C) induced similar but more intense cutaneous lesions at sites not exposed to heat, light headedness, and severe asthma. Exercise for 10 minutes caused confluent and punctate urticarial lesions. Simultaneous measurement of plasma histamine during cold and heat challenges revealed increases paralleling the course of symptoms. Repeat challenge with cold, heat, and exercise after beginning treatment with both H1 and H2 histamine antagonists resulted in marked reduction in symptoms; however, significant rises in plasma histamines were still noted.

  19. Unmyelinated Low Threshold Mechanoreceptors are Required for Injury-induced Mechanical Hypersensitivity

    PubMed Central

    Seal, Rebecca P.; Wang, Xidao; Guan, Yun; Raja, Srinivasa N.; Woodbury, C. Jeffery; Basbaum, Allan I.; Edwards, Robert H.

    2009-01-01

    Mechanical pain contributes to the morbidity associated with inflammation and trauma, but primary sensory neurons that convey the sensation of acute and persistent mechanical pain have not been identified. Dorsal root ganglion (DRG) neurons transmit sensory information to the spinal cord using the excitatory transmitter glutamate1, a process that depends on glutamate transport into synaptic vesicles for regulated exocytotic release. Here we report that a small subset of cells in the DRG expresses the low abundance vesicular glutamate transporter VGLUT3. In the dorsal horn of the spinal cord, these afferents project to lamina I and the innermost layer of lamina II, which has previously been implicated in persistent pain caused by injury2. Since the different VGLUT isoforms generally exhibit a nonredundant pattern of expression3, we used VGLUT3 knock-out (KO) mice to assess the role of VGLUT3+ primary afferents in the behavioral response to somatosensory input. The loss of VGLUT3 specifically impairs mechanical pain sensation and in particular the mechanical hypersensitivity to normally innocuous stimuli that accompanies inflammation, nerve injury and trauma. Direct recording from VGLUT3+ neurons in the DRG further identifies them as a poorly understood population of unmyelinated, low threshold mechanoreceptors (C-LTMRs)4,5. The analysis of VGLUT3 KO mice now indicates a critical role for C-LTMRs in the mechanical hypersensitivity caused by injury. PMID:19915548

  20. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors.

    PubMed

    Seal, Rebecca P; Wang, Xidao; Guan, Yun; Raja, Srinivasa N; Woodbury, C Jeffery; Basbaum, Allan I; Edwards, Robert H

    2009-12-03

    Mechanical pain contributes to the morbidity associated with inflammation and trauma, but primary sensory neurons that convey the sensation of acute and persistent mechanical pain have not been identified. Dorsal root ganglion (DRG) neurons transmit sensory information to the spinal cord using the excitatory transmitter glutamate, a process that depends on glutamate transport into synaptic vesicles for regulated exocytotic release. Here we report that a small subset of cells in the DRG expresses the low abundance vesicular glutamate transporter VGLUT3 (also known as SLC17A8). In the dorsal horn of the spinal cord, these afferents project to lamina I and the innermost layer of lamina II, which has previously been implicated in persistent pain caused by injury. Because the different VGLUT isoforms generally have a non-redundant pattern of expression, we used Vglut3 knockout mice to assess the role of VGLUT3(+) primary afferents in the behavioural response to somatosensory input. The loss of VGLUT3 specifically impairs mechanical pain sensation, and in particular the mechanical hypersensitivity to normally innocuous stimuli that accompanies inflammation, nerve injury and trauma. Direct recording from VGLUT3(+) neurons in the DRG further identifies them as a poorly understood population of unmyelinated, low threshold mechanoreceptors (C-LTMRs). The analysis of Vglut3(-/-) mice now indicates a critical role for C-LTMRs in the mechanical hypersensitivity caused by injury.

  1. Selective class I histone deacetylase inhibitors suppress persistent spontaneous nociception and thermal hypersensitivity in a rat model of bee venom-induced inflammatory pain.

    PubMed

    Yang, Fan; Yang, Yan; Wang, Yan; Yang, Fei; Li, Chun-Li; Wang, Xiao-Liang; Li, Zhen; Chen, Jun

    2015-10-25

    To confirm whether class I histone deacetylase inhibitors (HDACIs) are effective in relief of peripheral inflammatory pain, the effects of two selective inhibitors, MS-275 and MGCD0103, were studied in rats inflamed by subcutaneous (s.c.) injection of bee venom (BV). The BV test is characterized by displaying both persistent spontaneous nociception (PSN) and primary hypersensitivity. Intrathecal (i.t.) pre-treatment of either MS-275 or MGCD0103 with a single dose of 60 nmol/20 μL resulted in profound suppression of both PSN and primary thermal hypersensitivity but without significant influence upon the primary mechanical hypersensitivity and mirror-image thermal hypersensitivity. Moreover, the up-regulation of both HDAC1 and HDAC2 induced by s.c. BV injection was completely suppressed by i.t. pre-treatment of MS-275. The present results provide with another new line of evidence showing involvement of epigenetic regulation of chromatin structure by HDAC1/2-mediated histone hypoacetylation in the BV-induced PSN and thermal hypersensitivity and demonstrate the beneficial effects of class I HDACIs in prevention of peripheral inflammatory pain from occurring.

  2. Hypersensitivity Pneumonitis.

    PubMed

    Wysong, Kristi; Phillips, Jennan A; Hammond, Stephanie

    2016-06-01

    Chronic exposure to a broad array of antigens after workers inhale aerosolized organic dust particles from mold, animal dander, bird droppings, and chemicals, especially pesticides or herbicides, increases risk for hypersensitivity pneumonitis. Several demographic characteristics of immigrant workers in farming, poultry processing, construction, and landscaping increase this worker population's risk. © 2016 The Author(s).

  3. Effect of body temperature on cold induced vasodilation.

    PubMed

    Flouris, Andreas D; Westwood, David A; Mekjavic, Igor B; Cheung, Stephen S

    2008-10-01

    Cold-induced vasodilation (CIVD) is an acute increase in peripheral blood flow observed during cold exposures. It is hypothesized to protect against cold injuries, yet despite continuous research it remains an unexplained phenomenon. Contrary to the traditionally held view, we propose that CIVD is a thermoregulatory reflex mechanism contributing to heat loss. Ten adults (4 females; 23.8 +/- 2.0 years) randomly underwent three 130-min exposures to -20 degrees C incorporating a 10-min moderate exercise period at the 65th min, while wearing a liquid conditioning garment (LCG) and military arctic clothing. In the pre-warming condition, rectal temperature was increased by 0.5 degrees C via the LCG before the cold exposure. In the warming condition, participants regulated the LCG throughout the cold exposure to subjective comfort. In the control condition, the LCG was worn but was not operated either before or during the cold exposure. Results demonstrated that the majority of CIVD occurred during the warming condition when the thermometrically-estimated mean body temperature (T (b)) was at its highest. A thermoregulatory pattern was identified whereby CIVD occurred soon after T (b) increased past a threshold (approximately 36.65 degrees C in warming and pre-warming; approximately 36.4 degrees C in control). When CIVD occurred, T (b) was reduced and CIVD ceased when T (b) fell below the threshold. These findings were independent of extremity temperature since CIVD episodes occurred at a large range of finger temperatures (7.2-33.5 degrees C). These observations were statistically confirmed by auto-regressive integrated moving average analysis (t = 9.602, P < 0.001). We conclude that CIVD is triggered by increased T (b) supporting the hypothesis that CIVD is a thermoregulatory mechanism contributing to heat loss.

  4. Minocycline-Induced Drug Hypersensitivity Syndrome Followed by Multiple Autoimmune Sequelae

    PubMed Central

    Brown, Rebecca J.; Rother, Kristina I.; Artman, Henry; Mercurio, Mary Gail; Wang, Roger; Looney, R. John; Cowen, Edward W.

    2010-01-01

    Background Drug hypersensitivity syndrome (DHS) is a severe, multisystem adverse drug reaction that may occur following the use of numerous medications, including anticonvulsants, sulfonamides, and minocycline hydrochloride. Long-term autoimmune sequelae of DHS have been reported, including hypothyroidism. Observations A 15-year-old female adolescent developed DHS 4 weeks after starting minocycline therapy for acne vulgaris. Seven weeks later she developed autoimmune hyperthyroidism (Graves disease), and 7 months after discontinuing minocycline therapy she developed autoimmune type 1 diabetes mellitus. In addition, she developed elevated titers of several markers of systemic autoimmune disease, including antinuclear, anti-Sjögren syndrome A, and anti-Smith antibodies. Conclusions Minocycline-associated DHS may be associated with multiple autoimmune sequelae, including thyroid disease, type 1 diabetes mellitus, and elevated markers of systemic autoimmunity. Long-term follow-up is needed in patients with DHS to determine the natural history of DHS-associated sequelae. PMID:19153345

  5. Bronchiolitis obliterans organising pneumonia associated with anticonvulsant hypersensitivity syndrome induced by lamotrigine.

    PubMed

    Ghandourah, Hasan; Bhandal, Samarjeet; Brundler, Marie-Anne; Noseworthy, Mary

    2016-01-29

    A 14-year-old girl who was known to have a seizure disorder and on lamotrigine treatment was admitted to the hospital, with a history of rash, fever and cough. Her condition deteriorated with clinical features suggestive of anticonvulsant hypersensitivity syndrome (ACHS) complicated with bronchiolitis obliterans organising pneumonia (BOOP). Her chest CT showed multifocal parenchymal opacities and lung biopsy was typical for BOOP. Initially, the lamotrigine was discontinued since the onset of the rash, then she was treated for pneumonia with antibiotics, which may have delayed the diagnosis. Eventually, BOOP was considered and she was treated with a high dose of corticosteroid. She improved clinically and her repeated chest CT showed a marked resolution of the lesions. This case illustrates the possible occurrence of BOOP as a complication of ACHS secondary to lamotrigine treatment. 2016 BMJ Publishing Group Ltd.

  6. Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity.

    PubMed

    Kawata, Hiromitsu; Ishikura, Nobuyuki; Watanabe, Miho; Nishimoto, Ayako; Tsunenari, Toshiaki; Aoki, Yuko

    2010-05-15

    Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen-depletion independent status. However, the mechanism of bicalutamide resistance remains unclear because few cell models have been generated. We generated a bicalutamide-resistant subline, LNCaP-BC2, from LNCaP after prolonged treatment with bicalutamide. Androgen and/or bicalutamide responsiveness for proliferation and prostate-specific antigen (PSA) secretion were examined in vitro and in vivo. Testosterone and dihydrotestosterone (DHT) levels in xenografted tumors were analyzed by liquid chromatography-tandem mass spectrometry. Androgen receptor (AR) gene mutation and amplification and AR and pAR(210) expression were determined. LNCaP-BC2 did not grow in an androgen-depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP. LNCaP-BC2 grew in castrated male mice, and the DHT level in grafted LNCaP-BC2 tumors was 7.7-fold lower than in LNCaP tumors. Bicalutamide stimulated LNCaP-BC2 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP-BC2 was weaker than that of LNCaP in vivo. Additional AR mutation and AR gene amplification were not detected in LNCaP-BC2, but AR and pAR(210) expression and PSA secretion in LNCaP-BC2 were higher than in LNCaP. Bicalutamide-resistant LNCaP-BC2 exhibited AR overexpression and hypersensitivity to low levels of androgen. Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion. In addition, pAR(210) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP-BC2.

  7. Azathioprine Hypersensitivity Syndrome: Two Cases of Febrile Neutrophilic Dermatosis Induced by Azathioprine

    PubMed Central

    Aleissa, Majed; Nicol, Perrine; Godeau, Marion; Tournier, Emilie; de Bellissen, Frederic; Robic, Marie-Angèle; Livideanu, Cristina Bulai; Mazereeuw-Hautier, Juliette; Paul, Carle

    2017-01-01

    Background Azathioprine is an immunosuppressive agent used in the treatment of immune-mediated diseases. Azathioprine hypersensitivity syndrome is a rare adverse reaction occurring a few days to weeks after the administration of azathioprine. Case 1 A 36-year-old male with ulcerative colitis presented with erythematous plaques, pustules and erosions on the lower back, buttocks and thighs associated with high fever (39°C) 2 weeks after the initiation of azathioprine 100 mg/day. Additional findings included leukocytosis (18.6 g/L) with neutrophilia (11.1 g/L) and elevated C-reactive protein (128 mg/L). Histopathology showed a dense infiltrate of neutrophils in the hair follicles. We increased the dose of prednisone to 1 mg/kg/day (60 mg/day) and azathioprine was discontinued. He had marked improvement within 3 weeks and did not have any relapse with a 1-year follow-up. Case 2 A 57-year-old male with ulcerative colitis presented with erythematous plaques and pustules on the lower limbs associated with high fever (40°C) 1 week after the initiation of azathioprine 75 mg/day. Leukocytosis with neutrophilia (13.6 g/L) and elevated C-reactive protein (344 mg/L) were among the laboratory findings. Histopathology showed a dense infiltrate of neutrophils in the hair follicles. The dose of prednisone was increased to 20 mg/day and azathioprine was discontinued, which led to complete remission within 7 days. He did not have any relapse with a 6-month follow-up. Conclusion The development of acute neutrophilic dermatitis 2 weeks after the initiation of azathioprine and the complete resolution after its withdrawal were in favor of azathioprine hypersensitivity syndrome. It should not be confused with Sweet syndrome associated with inflammatory bowel disease, as maintenance of azathioprine treatment may lead to life-threatening reactions. PMID:28203157

  8. A case of drug-induced hypersensitivity syndrome showing transient immunosuppression before viral reactivation during treatment for pemphigus foliaceus.

    PubMed

    Takahashi, H; Tanaka, M; Tanikawa, A; Toyohara, A; Ogo, Y; Morimoto, A; Harato, R; Kobayashi, M; Amagai, M

    2006-01-01

    Drug-induced hypersensitivity syndrome (DIHS) is one of the most severe drug adverse reactions, with characteristic biphasic symptoms. Reactivation of human herpesvirus-6 (HHV-6) is frequently observed, although the cause of DIHS is still unknown. A patient developed DIHS during treatment with diaminodiphenylsulphone for pemphigus foliaceus. The number of lymphocytes in his peripheral blood, and titres of serum total IgG and IgM and anti-desmoglein1 antibody transiently decreased just before reactivation of HHV-6, cytomegalovirus and Epstein-Barr virus. This observation suggests that transient suppression of both cellular and humoral immunity may trigger viral reactivation, which leads to the development of the second phase of DIHS.

  9. Models of Inflammation: Carrageenan- or Complete Freund's Adjuvant (CFA)-Induced Edema and Hypersensitivity in the Rat.

    PubMed

    McCarson, Kenneth E

    2015-09-01

    Animal models of inflammation are used to assess the production of inflammatory mediators at sites of inflammation, the processing of pain sensation at CNS sites, the anti-inflammatory properties of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs), and the efficacy of putative analgesic compounds in reversing cutaneous hypersensitivity. Detailed in this unit are methods to elicit and measure carrageenan- and complete Freund's adjuvant (CFA)-induced cutaneous inflammation. Due to possible differences between the dorsal root sensory system and the trigeminal sensory system, injections into either the footpad or vibrissal pad are described. In this manner, cutaneous inflammation can be assessed in tissue innervated by the lumbar dorsal root ganglion neurons (footpad) or by the trigeminal ganglion neurons (vibrissal pad). Copyright © 2015 John Wiley & Sons, Inc.

  10. A Case of Sublingual Ranula That Responded Successfully to Localized Injection Treatment with OK-432 after Healing from Drug Induced Hypersensitivity Syndrome

    PubMed Central

    Yoshizawa, Kunio; Moroi, Akinori; Kawashiri, Shuichi; Ueki, Koichiro

    2016-01-01

    A ranula is a mucus retention cyst or pseudocyst caused by leakage of mucus from the sublingual gland and generally occurs in the oral floor. In addition, drug induced hypersensitivity syndrome (DIHS) is a rare but well-recognized serious adverse effect characterized by fever, skin rashes, generalized lymphadenopathy, hepatitis, and hepatosplenomegaly and oral stomatitis. This paper presents the first case of successfully treated sublingual ranula with localized injection of OK-432 after healing from drug induced hypersensitivity syndrome, which has previously been unreported in the literature. We present the case of a 38-year-old Japanese woman with sublingual ranula that responded successfully to localized injection treatment with OK-432 after healing from drug induced hypersensitivity syndrome. She was affected with cutaneous myositis and interstitial lung disease when she was 26 years old. At the age 34 years, she received additional oral treatment of diaminodiphenyl-sulfone due to deterioration of the cutaneous myositis, which resulted in drug induced hypersensitivity syndrome (DIHS) with severe oral stomatitis. Local injection of OK-432 to the ranula may be a very safe and useful treatment method even if the patient has a history of drug allergy and has connective tissue disease such as cutaneous myositis. PMID:27144039

  11. A Case of Sublingual Ranula That Responded Successfully to Localized Injection Treatment with OK-432 after Healing from Drug Induced Hypersensitivity Syndrome.

    PubMed

    Yoshizawa, Kunio; Moroi, Akinori; Kawashiri, Shuichi; Ueki, Koichiro

    2016-01-01

    A ranula is a mucus retention cyst or pseudocyst caused by leakage of mucus from the sublingual gland and generally occurs in the oral floor. In addition, drug induced hypersensitivity syndrome (DIHS) is a rare but well-recognized serious adverse effect characterized by fever, skin rashes, generalized lymphadenopathy, hepatitis, and hepatosplenomegaly and oral stomatitis. This paper presents the first case of successfully treated sublingual ranula with localized injection of OK-432 after healing from drug induced hypersensitivity syndrome, which has previously been unreported in the literature. We present the case of a 38-year-old Japanese woman with sublingual ranula that responded successfully to localized injection treatment with OK-432 after healing from drug induced hypersensitivity syndrome. She was affected with cutaneous myositis and interstitial lung disease when she was 26 years old. At the age 34 years, she received additional oral treatment of diaminodiphenyl-sulfone due to deterioration of the cutaneous myositis, which resulted in drug induced hypersensitivity syndrome (DIHS) with severe oral stomatitis. Local injection of OK-432 to the ranula may be a very safe and useful treatment method even if the patient has a history of drug allergy and has connective tissue disease such as cutaneous myositis.

  12. Facial cold-induced vasodilation and skin temperature during exposure to cold wind.

    PubMed

    Brajkovic, Dragan; Ducharme, Michel B

    2006-04-01

    One purpose of this study was to characterize the facial skin temperature and cold-induced vasodilation (CIVD) response of 12 subjects (six males and six females) during exposure to cold wind (i.e., -10 to 10 degrees C; 2, 5, and 8 m/s wind speed). This study found that at each wind speed, facial skin temperature decreased as ambient temperature decreased. The percentage of subjects showing facial CIVD decreased significantly at an ambient temperature above -10 degrees C. A similar CIVD percentage was observed between 0 degrees C dry and 10 degrees C wet (face sprayed with fine water mist) at each wind speed. No CIVDs were observed during the 10 degrees C dry condition at any wind speed. The incidence of CIVD response was more uniform across facial sites when there was a greater cold stress (i.e., -10 degrees C and 8 m/s wind). Another objective of the study was to examine the effect of the thermal state of the body (as reflected by core temperature) on the facial skin temperature response during rest and exercise. This study found that nose skin temperature was significantly higher in exercising subjects with an elevated core temperature even though there was no significant difference in face skin temperature between the two conditions. Therefore, this finding suggests that acral regions of the face, such as the nose, are more sensitive to changes in the thermal state of the body, and hence will stay warmer relative to other parts of the face during exercise in the cold.

  13. Malaria-Induced NLRP12/NLRP3-Dependent Caspase-1 Activation Mediates Inflammation and Hypersensitivity to Bacterial Superinfection

    PubMed Central

    Ataide, Marco A.; Andrade, Warrison A.; Zamboni, Dario S.; Wang, Donghai; Souza, Maria do Carmo; Franklin, Bernardo S.; Elian, Samir; Martins, Flaviano S.; Pereira, Dhelio; Reed, George; Fitzgerald, Katherine A.; Golenbock, Douglas T.; Gazzinelli, Ricardo T.

    2014-01-01

    Cyclic paroxysm and high fever are hallmarks of malaria and are associated with high levels of pyrogenic cytokines, including IL-1β. In this report, we describe a signature for the expression of inflammasome-related genes and caspase-1 activation in malaria. Indeed, when we infected mice, Plasmodium infection was sufficient to promote MyD88-mediated caspase-1 activation, dependent on IFN-γ-priming and the expression of inflammasome components ASC, P2X7R, NLRP3 and/or NLRP12. Pro-IL-1β expression required a second stimulation with LPS and was also dependent on IFN-γ-priming and functional TNFR1. As a consequence of Plasmodium-induced caspase-1 activation, mice produced extremely high levels of IL-1β upon a second microbial stimulus, and became hypersensitive to septic shock. Therapeutic intervention with IL-1 receptor antagonist prevented bacterial-induced lethality in rodents. Similar to mice, we observed a significantly increased frequency of circulating CD14+CD16−Caspase-1+ and CD14dimCD16+Caspase-1+ monocytes in peripheral blood mononuclear cells from febrile malaria patients. These cells readily produced large amounts of IL-1β after stimulation with LPS. Furthermore, we observed the presence of inflammasome complexes in monocytes from malaria patients containing either NLRP3 or NLRP12 pyroptosomes. We conclude that NLRP12/NLRP3-dependent activation of caspase-1 is likely to be a key event in mediating systemic production of IL-1β and hypersensitivity to secondary bacterial infection during malaria. PMID:24453977

  14. Copper hypersensitivity.

    PubMed

    Fage, Simon W; Faurschou, Annesofie; Thyssen, Jacob P

    2014-10-01

    The world production of copper is steadily increasing. Although humans are widely exposed to copper-containing items on the skin and mucosa, allergic reactions to copper are only infrequently reported. To review the chemistry, biology and accessible data to clarify the implications of copper hypersensitivity, a database search of PubMed was performed with the following terms: copper, dermatitis, allergic contact dermatitis, contact hypersensitivity, contact sensitization, contact allergy, patch test, dental, IUD, epidemiology, clinical, and experimental. Human exposure to copper is relatively common. As a metal, it possesses many of the same qualities as nickel, which is a known strong sensitizer. Cumulative data on subjects with presumed related symptoms and/or suspected exposure showed that a weighted average of 3.8% had a positive patch test reaction to copper. We conclude that copper is a very weak sensitizer as compared with other metal compounds. However, in a few and selected cases, copper can result in clinically relevant allergic reactions.

  15. Drug hypersensitivity.

    PubMed

    Bircher, Andreas J

    2014-01-01

    Before the arrival of modern pharmacotherapy, drug hypersensitivity reactions were virtually unknown. Toxicity from the many plant-, animal- and inorganic material-derived remedies must have been much more common. One famous example is the intoxications from mercury, which has been used in many ailments, but particularly for the treatment of syphilis. It was only in the 19th century when more and more active principles from e.g. plants were identified, and when the observations of skin reactions became more prevalent. In 1877, Heinrich Köbner used for the first time the term 'drug exanthema' (Arznei-Exanthem). Since then, many different types of exanthemas from the mild macular-papular forms to the severe life-threatening bullous exanthemas such as toxic epidermal necrolysis have been observed from numerous drugs. The systematic investigation of severe drug reactions has only started in the second half of the 20th century, parallel to the increasing knowledge in immunology. Drug hypersensitivity reactions still remain one of the most challenging problems in allergology due to their manifold clinical manifestations and their very diverse pathophysiology. The introduction of new drugs and in turn the emergence of new hypersensitivity reactions will remain a challenge in the future. © 2014 S. Karger AG, Basel.

  16. TRPA1 in mast cell activation-induced long-lasting mechanical hypersensitivity of vagal afferent C-fibers in guinea pig esophagus.

    PubMed

    Yu, Shaoyong; Gao, Guofeng; Peterson, Blaise Z; Ouyang, Ann

    2009-07-01

    Sensitization of esophageal sensory afferents by inflammatory mediators plays an important role in esophageal nociception. We have shown esophageal mast cell activation induces long-lasting mechanical hypersensitivity in vagal nodose C-fibers. However, the roles of mast cell mediators and downstream ion channels in this process are unclear. Mast cell tryptase via protease-activated receptor 2 (PAR2)-mediated pathways sensitizes sensory nerves and induces hyperalgesia. Transient receptor potential A1 (TRPA1) plays an important role in mechanosensory transduction and nociception. Here we tested the hypothesis that mast cell activation via a PAR2-dependent mechanism sensitizes TRPA1 to induce mechanical hypersensitivity in esophageal vagal C-fibers. The expression profiles of PAR2 and TRPA1 in vagal nodose ganglia were determined by immunostaining, Western blot, and RT-PCR. Extracellular recordings from esophageal nodose neurons were performed in ex vivo guinea pig esophageal-vagal preparations. Action potentials evoked by esophageal distention and chemical perfusion were compared. Both PAR2 and TRPA1 expressions were identified in vagal nodose neurons by immunostaining, Western blot, and RT-PCR. Ninety-one percent of TRPA1-positive neurons were of small and medium diameters, and 80% coexpressed PAR2. Esophageal mast cell activation significantly enhanced the response of nodose C-fibers to esophageal distension (mechanical hypersensitivity). This was mimicked by PAR2-activating peptide, which sustained for 90 min after wash, but not by PAR2 reverse peptide. TRPA1 inhibitor HC-030031 pretreatment significantly inhibited mechanical hypersensitivity induced by either mast cell activation or PAR2 agonist. Collectively, our data provide new evidence that sensitizing TRPA1 via a PAR2-dependent mechanism plays an important role in mast cell activation-induced mechanical hypersensitivity of vagal nodose C-fibers in guinea pig esophagus.

  17. Trainability of cold induced vasodilatation in fingers and toes.

    PubMed

    Daanen, Hein A M; Koedam, Jens; Cheung, Stephen S

    2012-07-01

    Subjects that repeatedly have to expose the extremities to cold may benefit from a high peripheral temperature to maintain dexterity and tissue integrity. Therefore, we investigated if repeated immersions of a hand and a foot in cold water resulted in increased skin temperatures. Nine male and seven female subjects (mean 20.4; SD 2.2 years) immersed their right (trained) hand and foot simultaneously in 8°C water, 30 min daily for 15 days. During the pre and post-test (days 1 and 15, respectively) the left (untrained) hand and foot were immersed as well. Pain, tactile sensitivity and skin temperatures were measured every day. Mean (SD) toe temperature of the trained foot increased from 9.49°C (0.89) to 10.03°C (1.38) (p < 0.05). The trained hand, however, showed a drop in mean finger temperature from 9.28°C (0.54) to 8.91°C (0.44) (p < 0.001) and the number of cold induced vasodilation (CIVD) reactions decreased from 52% during the first test to 24% during the last test. No significant differences occurred in the untrained extremities. Pain diminished over time and tactile sensitivity decreased with skin temperature. The combination of less CIVD responses in the fingers after training, reduced finger skin temperatures in subjects that did show CIVD and the reduced pain and tactile sensitivity over time may lead to an increased risk for finger cold injuries. It is concluded that repeated cold exposure of the fingers does not lead to favorable adaptations, but may instead increase the injury risk.

  18. Method of cold saline storage for prehospital induced hypothermia.

    PubMed

    Kampmeyer, Mitch; Callaway, Clifton

    2009-01-01

    Research over the last decade has supported the use of cold intravenous (IV) fluid as a method for initiating therapeutic hypothermia in post-cardiac arrest resuscitation. However, prehospital care programs employing this treatment have encountered various difficulties. Barriers to prehospital induced hypothermia (IH) protocols include the lack of effective or economically reasonable methods to maintain cold saline in the field. Validation of a simple method could allow agencies to equip numerous rigs with cold saline. The aim of this study was to determine whether a standard commercial cooler can maintain two 1-L normal saline solution (NSS) bags below 4 degrees C in three different environments. Environments simulating those of an ambulance compartment were created for the experiment. NSS temperatures were continuously recorded inside a standard commercial cooler under one of three scenarios: ambient room temperature (25 degrees C) without ice packs, ambient room temperature with ice packs, and 50 degrees C ambient temperature with ice packs. Four trials under each condition were performed. In a room-temperature environment without ice packs, the NSS warmed to 4 degrees C in a mean interval of 1 hour 21 minutes. Using room temperature with ice packs, the NSS warmed to 4 degrees C in a mean interval of 29 hours 53 minutes. In a constant hot environment of 50 degrees C, the NSS warmed to 4 degrees C in a mean interval of 10 hours 50 minutes. A significant difference was found between the three environments (log-rank = 17.90, df = 2, p = 0.0001). Prehospital refrigeration devices are needed for current and future IH protocols. Low-technology methods in the form of a cooler and ice packs can provide cold saline storage for longer than a full 24-hour shift in a room-temperature ambulance. In extremely hot conditions, 4 degrees C NSS can be maintained for nearly 11 hours using this method. This model exhibits an economical, easily deployable cold saline storage unit.

  19. The Relationship between Photosynthesis and a Mastoparan-Induced Hypersensitive Response in Isolated Mesophyll Cells1

    PubMed Central

    Allen, Lisa J.; MacGregor, Kennaway B.; Koop, Randall S.; Bruce, Doug H.; Karner, Julie; Bown, Alan W.

    1999-01-01

    The G-protein activator mastoparan (MP) was found to elicit the hypersensitive response (HR) in isolated Asparagus sprengeri mesophyll cells at micromolar concentrations. The HR was characterized by cell death, extracellular alkalinization, and an oxidative burst, indicated by the reduction of molecular O2 to O2⋅−. To our knowledge, this study was the first to monitor photosynthesis during the HR. MP had rapid and dramatic effects on photosynthetic electron transport and excitation energy transfer as determined by variable chlorophyll a fluorescence measurements. A large increase in nonphotochemical quenching of chlorophyll a fluorescence accompanied the initial stages of the oxidative burst. The minimal level of fluorescence was also quenched, which suggests the origin of this nonphotochemical quenching to be a decrease in the antenna size of photosystem II. In contrast, photochemical quenching of fluorescence decreased dramatically during the latter stages of the oxidative burst, indicating a somewhat slower inhibition of photosystem II electron transport. The net consumption of O2 and the initial rate of O2 uptake, elicited by MP, were higher in the light than in the dark. These data indicate that light enhances the oxidative burst and suggest a complex relationship between photosynthesis and the HR. PMID:10198081

  20. Leishmania tropica infection, in comparison to Leishmania major, induces lower delayed type hypersensitivity in BALB/c mice.

    PubMed

    Mahmoudzadeh-Niknam, Hamid; Kiaei, Simin Sadat; Iravani, Davood

    2007-06-01

    Leishmania tropica and L. major are etiologic agents of human cutaneous leishmaniasis. Delayed type hypersensitivity (DTH) is an immunologic response that has been frequently used as a correlate for protection against or sensitization to leishmania antigen. In BALB/c mice, L. tropica infection results in non-ulcerating disease, whereas L. major infection results in destructive lesions. In order to clarify the immunologic mechanisms of these 2 different outcomes, we compared the ability of these 2 leishmania species in induction of DTH response in this murine model. BALB/c mice were infected with L. major or L. tropica, and disease evolution and DTH responses were determined. The results show that the primary L. major infection can exacerbate the secondary L. major infection and is associated with DTH response. Higher doses of the primary L. major infection result in more disease exacerbation of the secondary L. major infection as well as higher DTH response. L. tropica infection induces lower DTH responses than L. major. We have previously reported that the primary L. tropica infection induces partial protection against the secondary L. major infection in BALB/c mice. Induction of lower DTH response by L. tropica suggests that the protection induced against L. major by prior L. tropica infection may be due to suppression of DTH response.

  1. Leishmania tropica infection, in comparison to Leishmania major, induces lower delayed type hypersensitivity in BALB/c mice

    PubMed Central

    Kiaei, Simin Sadat; Iravani, Davood

    2007-01-01

    Leishmania tropica and L. major are etiologic agents of human cutaneous leishmaniasis. Delayed type hypersensitivity (DTH) is an immunologic response that has been frequently used as a correlate for protection against or sensitization to leishmania antigen. In BALB/c mice, L. tropica infection results in non-ulcerating disease, whereas L. major infection results in destructive lesions. In order to clarify the immunologic mechanisms of these 2 different outcomes, we compared the ability of these 2 leishmania species in induction of DTH response in this murine model. BALB/c mice were infected with L. major or L. tropica, and disease evolution and DTH responses were determined. The results show that the primary L. major infection can exacerbate the secondary L. major infection and is associated with DTH response. Higher doses of the primary L. major infection result in more disease exacerbation of the secondary L. major infection as well as higher DTH response. L. tropica infection induces lower DTH responses than L. major. We have previously reported that the primary L. tropica infection induces partial protection against the secondary L. major infection in BALB/c mice. Induction of lower DTH response by L. tropica suggests that the protection induced against L. major by prior L. tropica infection may be due to suppression of DTH response. PMID:17570972

  2. Cold-induced exodus of postsynaptic proteins from dendritic spines.

    PubMed

    Cheng, Hui-Hsuan; Huang, Zu-Han; Lin, Wei-Hsiang; Chow, Wei-Yuan; Chang, Yen-Chung

    2009-02-01

    Dendritic spines are small protrusions on neuronal dendrites and the major target of the excitatory inputs in mammalian brains. Cultured neurons and brain slices are important tools in studying the biochemical and cellular properties of dendritic spines. During the processes of immunocytochemical studies of neurons and the preparation of brain slices, neurons were often kept at temperatures lower than 37 degrees C for varied lengths of time. This study sought to investigate whether and how cold treatment would affect the protein composition of dendritic spines. The results indicated that upon cold treatment four postsynaptic proteins, namely, alpha,beta-tubulins, calcium, calmodulin-dependent protein kinase IIalpha, and cytoplasmic dynein heavy chain and microtubule-associated protein 2, but not PSD-95 or AMPA receptors, exited from the majority of dendritic spines of cultured rat hippocampal neurons in a Gd(3+)-sensitive manner. The cold-induced exit of tubulins from dendritic spines was further found to be an energy-dependent process involving the activation of Gd(3+)-sensitive calcium channels and ryanodine receptors. The results thus indicate that changes in temperature, calcium concentration, and energy supply of the medium surrounding neurons would affect the protein composition of the dendritic spines and conceivably the protein composition of the subcellular organizations, such as the postsynaptic density, in the cytoplasm of dendritic spines.

  3. Acetaminophen (Paracetamol) Induces Hypothermia During Acute Cold Stress.

    PubMed

    Foster, Josh; Mauger, Alexis R; Govus, Andrew; Hewson, David; Taylor, Lee

    2017-08-01

    Acetaminophen is an over-the-counter drug used to treat pain and fever, but it has also been shown to reduce core temperature (T c) in the absence of fever. However, this side effect is not well examined in humans, and it is unknown if the hypothermic response to acetaminophen is exacerbated with cold exposure. To address this question, we mapped the thermoregulatory responses to acetaminophen and placebo administration during exposure to acute cold (10 °C) and thermal neutrality (25 °C). Nine healthy Caucasian males (aged 20-24 years) participated in the experiment. In a double-blind, randomised, repeated measures design, participants were passively exposed to a thermo-neutral or cold environment for 120 min, with administration of 20 mg/kg lean body mass acetaminophen or a placebo 5 min prior to exposure. T c, skin temperature (T sk), heart rate, and thermal sensation were measured every 10 min, and mean arterial pressure was recorded every 30 min. Data were analysed using linear mixed effects models. Differences in thermal sensation were analysed using a cumulative link mixed model. Acetaminophen had no effect on T c in a thermo-neutral environment, but significantly reduced T c during cold exposure, compared with a placebo. T c was lower in the acetaminophen compared with the placebo condition at each 10-min interval from 80 to 120 min into the trial (all p < 0.05). On average, T c decreased by 0.42 ± 0.13 °C from baseline after 120 min of cold exposure (range 0.16-0.57 °C), whereas there was no change in the placebo group (0.01 ± 0.1 °C). T sk, heart rate, thermal sensation, and mean arterial pressure were not different between conditions (p > 0.05). This preliminary trial suggests that acetaminophen-induced hypothermia is exacerbated during cold stress. Larger scale trials seem warranted to determine if acetaminophen administration is associated with an increased risk of accidental hypothermia, particularly in vulnerable

  4. Minocycline Prevents Muscular Pain Hypersensitivity and Cutaneous Allodynia Produced by Repeated Intramuscular Injections of Hypertonic Saline in Healthy Human Participants.

    PubMed

    Samour, Mohamad Samir; Nagi, Saad Saulat; Shortland, Peter John; Mahns, David Anthony

    2017-08-01

    Minocycline, a glial suppressor, prevents behavioral hypersensitivities in animal models of peripheral nerve injury. However, clinical trials of minocycline in human studies have produced mixed results. This study addressed 2 questions: can repeated injections of hypertonic saline (HS) in humans induce persistent hypersensitivity? Can pretreatment with minocycline, a tetracycline antibiotic with microglial inhibitory effects, prevent the onset of hypersensitivity? Twenty-seven healthy participants took part in this double-blind, placebo-controlled study, consisting of 6 test sessions across 2 weeks. At the beginning of every session, pressure-pain thresholds of the anterior muscle compartment of both legs were measured to determine the region distribution and intensity of muscle soreness. To measure changes in thermal sensitivity in the skin overlying the anterior muscle compartment of both legs, quantitative sensory testing was used to measure the cutaneous thermal thresholds (cold sensation, cold pain, warm sensation, and heat pain) and a mild cooling stimulus was applied to assess the presence of cold allodynia. To induce ongoing hypersensitivity, repeated injections of HS were administered into the right tibialis anterior muscle at 48-hour intervals. In the final 2 sessions (days 9 and 14), only sensory assessments were done to plot the recovery after cessation of HS administrations and drug washout. By day 9, nontreated participants experienced a significant bilateral increase in muscle soreness (P < .0001), accompanied by the emergence of bilateral cold allodynia in 44% of participants, thus confirming the effectiveness of the model. Placebo-treated participants experienced a bilateral 35% alleviation in muscle soreness (P < .0001), with no changes to the prevalence of cold allodynia. In contrast, minocycline-treated participants experienced a bilateral 70% alleviation in muscle soreness (P < .0001), additionally, only 10% of minocycline

  5. Cold-induced vasodilation comparison between Bangladeshi and Japanese natives.

    PubMed

    Khatun, Aklima; Ashikaga, Sakura; Nagano, Hisaho; Hasib, Md Abdul; Taimura, Akihiro

    2016-05-03

    The human thermoregulation system responds to changes in environmental temperature, so humans can self-adapt to a wide range of climates. People from tropical and temperate areas have different cold tolerance. This study compared the tolerance of Bangladeshi (tropical) and Japanese (temperate) people to local cold exposure on cold-induced vasodilation (CIVD). Eight Bangladeshi males (now residing in Japan) and 14 Japanese males (residing in Japan) participated in this study. All are sedentary, regular university students. The Bangladeshi subject's duration of stay in Japan was 2.50 ± 2.52 years. The subject's left hand middle finger was immersed in 5 °C water for 20 min to assess their CIVD response (the experiment was conducted in an artificial climate chamber controlled at 25 °C with 50% RH). Compared with the Bangladeshi (BD) group, the Japanese (JP) group displayed some differences. There were significant differences between the BD and JP groups in temperature before immersion (TBI), which were 33.04 ± 1.98 and 34.62 ± 0.94 °C, and time of temperature rise (TTR), which were 5.35 ± 0.82 and 3.72 ± 0.68 min, respectively. There was also a significant difference in the time of sensation rise (TSR) of 8.69 ± 6.49 and 3.26 ± 0.97 min between the BD and JP groups, respectively (P < 0.05). Moreover, the JP group showed a quick TTR after finishing immersion. The Japanese group (temperate) has a higher tolerance to local cold exposure than the Bangladeshi group (tropical) evaluated by the CIVD test.

  6. Allergen-Specific Cytokine Polarization Protects Shetland Ponies against Culicoides obsoletus-Induced Insect Bite Hypersensitivity

    PubMed Central

    Meulenbroeks, Chantal; van der Lugt, Jaco J.; van der Meide, Nathalie M. A.; Willemse, Ton; Rutten, Victor P. M. G.; Zaiss, Dietmar M. W.

    2015-01-01

    The immunological mechanisms explaining development of an allergy in some individuals and not in others remain incompletely understood. Insect bite hypersensitivity (IBH) is a common, seasonal, IgE-mediated, pruritic skin disorder that affects considerable proportions of horses of different breeds, which is caused by bites of the insect Culicoides obsoletus (C. obsoletus). We investigated the allergen-specific immune status of individual horses that had either been diagnosed to be healthy or to suffer of IBH. Following intradermal allergen injection, skin biopsies were taken of IBH-affected and healthy ponies and cytokine expression was determined by RT-PCR. In addition, allergen-specific antibody titers were measured and cytokine expression of in vitro stimulated, allergen-specific CD4 T-cells was determined. 24 hrs after allergen injection, a significant increase in mRNA expression of the type-2 cytokine IL-4 was observed in the skin of IBH-affected Shetland ponies. In the skin of healthy ponies, however, an increase in IFNγ mRNA expression was found. Analysis of allergen-specific antibody titers revealed that all animals produced allergen-specific antibodies, and allergen-specific stimulation of CD4 T-cells revealed a significant higher percentage of IFNγ-expressing CD4 T-cells in healthy ponies compared to IBH-affected ponies. These data indicate that horses not affected by IBH, in contrast to the so far established dogma, are not immunologically ignorant but have a Th1-skewed allergen-specific immune response that appears to protect against IBH-associated symptoms. To our knowledge this is the first demonstration of a natural situation, in which an allergen-specific immune skewing is protective in an allergic disorder. PMID:25901733

  7. Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions.

    PubMed

    Picard, Matthieu; Pur, Leyla; Caiado, Joana; Giavina-Bianchi, Pedro; Galvão, Violeta Regnier; Berlin, Suzanne T; Campos, Susana M; Matulonis, Ursula A; Castells, Mariana C

    2016-04-01

    The optimal approach to patients with hypersensitivity reactions (HSRs) to taxanes has not been established. We sought to assess the safety and efficacy of risk stratification based on the severity of the initial HSR and skin testing for guiding taxane reintroduction in patients with an HSR to these agents. Data on 164 patients treated for a taxane-related HSR from April 2011 to August 2014 at the Dana-Farber Cancer Institute and Brigham and Women's Hospital were collected retrospectively. Patients were re-exposed to taxanes either through desensitization, challenge, or regular infusion based on the severity of the initial HSR and skin test response. Depending on the initial risk stratification and tolerance to re-exposure, patients were then treated with shorter desensitization protocols, challenge, or both with the aim of resuming regular infusions, except in patients with a severe immediate initial HSR. Of 138 patients desensitized, 29 (21%) had an immediate and 20 (14%) had a delayed HSR with the procedure. Of 49 patients challenged, 2 (4%) had a mild immediate and 1 (2%) had a delayed HSR with the procedure. No patients had a severe immediate HSR with desensitization or challenge. Thirty-six (22%) patients eventually resumed regular infusions. These patients were more likely to have negative skin test responses and to have experienced a delayed or mild immediate initial HSR. Risk stratification based on the severity of the initial HSR and skin testing to guide taxane reintroduction is safe and allows a significant number of patients to resume regular infusions. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  8. Allergen-Specific Cytokine Polarization Protects Shetland Ponies against Culicoides obsoletus-Induced Insect Bite Hypersensitivity.

    PubMed

    Meulenbroeks, Chantal; van der Lugt, Jaco J; van der Meide, Nathalie M A; Willemse, Ton; Rutten, Victor P M G; Zaiss, Dietmar M W

    2015-01-01

    The immunological mechanisms explaining development of an allergy in some individuals and not in others remain incompletely understood. Insect bite hypersensitivity (IBH) is a common, seasonal, IgE-mediated, pruritic skin disorder that affects considerable proportions of horses of different breeds, which is caused by bites of the insect Culicoides obsoletus (C. obsoletus). We investigated the allergen-specific immune status of individual horses that had either been diagnosed to be healthy or to suffer of IBH. Following intradermal allergen injection, skin biopsies were taken of IBH-affected and healthy ponies and cytokine expression was determined by RT-PCR. In addition, allergen-specific antibody titers were measured and cytokine expression of in vitro stimulated, allergen-specific CD4 T-cells was determined. 24 hrs after allergen injection, a significant increase in mRNA expression of the type-2 cytokine IL-4 was observed in the skin of IBH-affected Shetland ponies. In the skin of healthy ponies, however, an increase in IFNγ mRNA expression was found. Analysis of allergen-specific antibody titers revealed that all animals produced allergen-specific antibodies, and allergen-specific stimulation of CD4 T-cells revealed a significant higher percentage of IFNγ-expressing CD4 T-cells in healthy ponies compared to IBH-affected ponies. These data indicate that horses not affected by IBH, in contrast to the so far established dogma, are not immunologically ignorant but have a Th1-skewed allergen-specific immune response that appears to protect against IBH-associated symptoms. To our knowledge this is the first demonstration of a natural situation, in which an allergen-specific immune skewing is protective in an allergic disorder.

  9. Transcriptome Analysis of Capsicum Chlorosis Virus-Induced Hypersensitive Resistance Response in Bell Capsicum.

    PubMed

    Widana Gamage, Shirani M K; McGrath, Desmond J; Persley, Denis M; Dietzgen, Ralf G

    2016-01-01

    Capsicum chlorosis virus (CaCV) is an emerging pathogen of capsicum, tomato and peanut crops in Australia and South-East Asia. Commercial capsicum cultivars with CaCV resistance are not yet available, but CaCV resistance identified in Capsicum chinense is being introgressed into commercial Bell capsicum. However, our knowledge of the molecular mechanisms leading to the resistance response to CaCV infection is limited. Therefore, transcriptome and expression profiling data provide an important resource to better understand CaCV resistance mechanisms. We assembled capsicum transcriptomes and analysed gene expression using Illumina HiSeq platform combined with a tag-based digital gene expression system. Total RNA extracted from CaCV/mock inoculated CaCV resistant (R) and susceptible (S) capsicum at the time point when R line showed a strong hypersensitive response to CaCV infection was used in transcriptome assembly. Gene expression profiles of R and S capsicum in CaCV- and buffer-inoculated conditions were compared. None of the genes were differentially expressed (DE) between R and S cultivars when mock-inoculated, while 2484 genes were DE when inoculated with CaCV. Functional classification revealed that the most highly up-regulated DE genes in R capsicum included pathogenesis-related genes, cell death-associated genes, genes associated with hormone-mediated signalling pathways and genes encoding enzymes involved in synthesis of defense-related secondary metabolites. We selected 15 genes to confirm DE expression levels by real-time quantitative PCR. DE transcript profiling data provided comprehensive gene expression information to gain an understanding of the underlying CaCV resistance mechanisms. Further, we identified candidate CaCV resistance genes in the CaCV-resistant C. annuum x C. chinense breeding line. This knowledge will be useful in future for fine mapping of the CaCV resistance locus and potential genetic engineering of resistance into Ca

  10. Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review.

    PubMed

    Oussalah, A; Mayorga, C; Blanca, M; Barbaud, A; Nakonechna, A; Cernadas, J; Gotua, M; Brockow, K; Caubet, J-C; Bircher, A; Atanaskovic, M; Demoly, P; K Tanno, L; Terreehorst, I; Laguna, J J; Romano, A; Guéant, J-L

    2016-04-01

    Drug hypersensitivity includes allergic (AR) and nonallergic reactions (NARs) influenced by genetic predisposition. We performed a systematic review of genetic predictors of IgE-mediated AR and NAR with MEDLINE and PubMed search engine between January 1966 and December 2014. Among 3110 citations, the search selected 53 studies, 42 of which remained eligible. These eligible studies have evaluated genetic determinants of immediate reactions (IR) to beta-lactams (n = 19), NAR against aspirin (n = 12) and other nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 8), and IR to biologics (n = 3). We reported two genomewide association studies and four case-control studies on candidate genes validated by replication. Genes involved in IR to beta-lactams belonged to HLA type 2 antigen processing, IgE production, atopy, and inflammation, including 4 genes validated by replications, HLA-DRA, ILR4, NOD2, and LGALS3. Genes involved in NAR to aspirin belonged to arachidonic acid pathway, membrane-spanning 4A gene family, histamine production pathway, and pro-inflammatory cytokines, while those involved in NAR to all NSAIDs belonged to arachidonic acid pathway and HLA antigen processing pathway. ALOX5 was a common predictor of studies on NAR to both aspirin and NSAIDs. Although these first conclusions could be drawn, this review highlights also the lack of reliable data and the need for replicating studies in contrasted populations, taking into account worldwide allele frequencies, gene-gene interactions, and contrasted situations of environmental exposure.

  11. ATR signaling cooperates with ATM in the mechanism of low dose hypersensitivity induced by carbon ion beam.

    PubMed

    Xue, Lian; Furusawa, Yoshiya; Yu, Dong

    2015-10-01

    Little work has been done on the mechanism of low dose hyper-radiosensitivity (HRS) and later appeared radioresistance (termed induced radioresistance (IRR)) after irradiation with medium and high linear energy transfer (LET) particles. The aim of this study was to find out whether ATR pathway is involved in the mechanism of HRS induced by high LET radiation. GM0639 cells and two ATM deficient/mutant cells, AT5BIVA and AT2KY were irradiated by carbon ion beam. Thymidine block technique was developed to enrich the G2-phase population. Radiation induced early G2/M checkpoint was quantitatively assess with dual-parameter flow cytometry by detecting the cells positive for phospho-histone H3. The involvement of ATR pathway in HRS/IRR response was detected with pretreatment of specific inhibitors prior to carbon ion beam. The link between the early G2/M checkpoint and HRS/IRR under carbon ion beam was first confirmed in GM0639 cells, through the enrichment of cell population in G2-phase or with Aurora kinase inhibitor that attenuates the transition from G2 to M phase. Interestingly, the early G2/M arrest could still be observed in ATM deficient/mutant cells with an effect of ATR signaling, which was discovered to function in an LET-dependent manner, even as low as 0.2Gy for carbon ion radiation. The involvement of ATR pathway in heavy particles induced HRS/IRR was determined with the specific ATR inhibitor in GM0639 cells, which affected the HRS/IRR occurrence similarly as ATM inhibitor. These data demonstrate that ATR pathway may cooperate with ATM in the mechanism of low dose hypersensitivity induced by carbon ion beam.

  12. The inhibitory effect of soybean and soybean isoflavone diets on 2,4-dinitrofluorobenzene-induced contact hypersensitivity in mice.

    PubMed

    Nagano, Takao; Wu, Woruna; Tsumura, Kazunobu; Yonemoto-Yano, Hiroko; Kamada, Tomoari; Haruma, Ken

    2016-05-01

    Murine contact hypersensitivity (CHS) is one of the most frequently used animal models of human allergic contact dermatitis. We investigated the inhibitory effects of soybean and soy isoflavone (SI) diets on 2,4-dinitrofluorobenzene- (DNFB) induced CHS in mice. The DNFB-induced ear swelling was inhibited in the soy- and SI-treated groups. Histopathological investigations revealed that oral feeding of soybean and SI attenuated ear tissue edema and reduced the number of Gr-1(+) cell infiltrations into ear tissues. DNA microarray analysis showed that the expression of Ccl24, Xcl1, Ifng, and Ccl17 in the ear tissues was lower in the soy-treated mice than in the positive controls. In addition, CCL24 mRNA and protein expression in the ear tissues were more highly suppressed in the soy- and SI-treated groups. These results suggest that soybean and SI consumption downregulated the gene and protein expression of CCL24, thereby affording protection against CHS in mice.

  13. Increased /sup 3/H-spiperone binding sites in mesolimbic area related to methamphetamine-induced behavioral hypersensitivity

    SciTech Connect

    Akiyama, K.; Sato, M.; Otsuki, S.

    1982-02-01

    The specific /sup 3/H-spiperone binding to membrane homogenates of the striatum, mesolimbic area, and frontal cortex was examined in two groups of rats pretreated once daily with saline or 4 mg/kg of methamphetamine (MAP) for 14 days. At 7 days following cessation of chronic pretreatment, all rats received an injection of 4 mg/kg of MAP and were decapitated 1 hr after the injection. In the chronic saline-pretreatment group, the single administration of MAP induced significant changes in the number (Bmax) of specific /sup 3/H-spiperone binding sites (a decrease in the striatum and an increase in the mesolimbic area and frontal cortex), but no significant changes in the affinity (KD) in any brain area. The chronic MAP pretreatment markedly augmented the changes in Bmax in the striatum and mesolimbic area. The increase in specific /sup 3/H-spiperone binding sites in the mesolimbic area is discussed in relation to MAP-induced behavioral hypersensitivity.

  14. Putative Serine Protease Effectors of Clavibacter michiganensis Induce a Hypersensitive Response in the Apoplast of Nicotiana Species.

    PubMed

    Lu, You; Hatsugai, Noriyuki; Katagiri, Fumiaki; Ishimaru, Carol A; Glazebrook, Jane

    2015-11-01

    Clavibacter michiganensis subspp. michiganensis and sepedonicus cause diseases on solanaceous crops. The genomes of both subspecies encode members of the pat-1 family of putative serine proteases known to function in virulence on host plants and induction of hypersensitive responses (HR) on nonhosts. One gene of this family in C. michiganensis subsp. sepedonicus, chp-7, is required for triggering HR in Nicotiana tabacum. Here, further investigation revealed that mutation of the putative catalytic serine residue at position 232 to threonine abolished the HR induction activity of Chp-7, suggesting that enzymatic activity is required. Purified Chp-7 triggered an HR in N. tabacum leaves in the absence of the pathogen, indicating Chp-7 itself is the HR elicitor from C. michiganensis subsp. sepedonicus. Ectopic expression of chp-7 constructs in N. tabacum leaves revealed that Chp-7 targeted to the apoplast triggered an HR while cytoplasmic Chp-7 did not, indicating that Chp-7 induces the HR in the apoplast of N. tabacum leaves. Chp-7 also induced HR in N. sylvestris, a progenitor of N. tabacum, but not in other Nicotiana species tested. ChpG, a related protein from C. michiganensis subsp. michiganensis, also triggered HR in N. tabacum and N. sylvestris. Unlike Chp-7, ChpG triggered HR in N. clevelandii and N. glutinosa.

  15. Suppression of delayed-type hypersensitivity and hemolysis induced by previously photooxidized psoralen: effect of fluence rate and psoralen concentration.

    PubMed

    Kyagova, A A; Zhuravel, N N; Malakhov, M V; Lysenko, E P; Adam, W; Saha-Möller, C R; Potapenko AYa

    1997-04-01

    The kinetics of the formation of biologically active psoralen photooxidation (POP) products were analyzed by the biological effects produced. Effects of the UV light fluence rate and psoralen concentration during the preirradiation were investigated to assess the yield of POP products, which were active in vivo (inducing suppression of delayed-type hypersensitivity [DTH] reaction to sheep red blood cells) and in vitro (altering the human erythrocyte membrane permeability). It was shown that the reciprocity law of the irradiation fluence rate and time was not valid in the case of POP-induced hemolysis and DTH suppression. Immunosuppressive POP products were more efficiently formed at low fluence rate (20.8 W/m2), whereas POP hemolysins were more efficiently produced at a high fluence rate (180 W/m2) of UV light. The yield of immunosuppressive POP products was enhanced in dilute psoralen solutions, while the POP hemolysins yield increased with increasing psoralen concentration. A kinetic scheme for psoralen photoproduct formation was proposed. Kinetic analysis showed that a labile intermediate was produced as the result of excitation of psoralen. This intermediate was either converted to a stable immunosuppressive POP product, or two intermediates combined to form a POP hemolysin. It is proposed that PUVA therapy conditions are more favorable for the formation of immunosuppressive rather than membrane-damaging psoralen photooxidation products.

  16. Synchronized turbo apoptosis induced by cold-shock

    PubMed Central

    Fransen, J. H.; Dieker, J. W.; Hilbrands, L. B.; Berden, J. H.

    2010-01-01

    In our research on the role of apoptosis in the pathogenesis of the autoimmune disease systemic lupus erythematosus (SLE), we aim to evaluate the effects of early and late apoptotic cells and blebs on antigen presenting cells. This requires the in vitro generation of sufficiently large and homogeneous populations of early and late apoptotic cells. Here, we present a quick method encountered by serendipity that results in highly reproducible synchronized homogeneous apoptotic cell populations. In brief, granulocytic 32Dcl3 cells are incubated on ice for 2 h and subsequently rewarmed at 37°C. After 30–90 min at 37°C more than 80–90% of the cells become early apoptotic (Annexin V positive/propidium iodide negative). After 24 h of rewarming at 37°C 98% of the cells were late apoptotic (secondary necrotic; Annexin V positive/propidium iodide positive). Cells already formed apoptotic blebs at their cell surface after approximately 20 min at 37°C. Inter-nucleosomal chromatin cleavage and caspase activation were other characteristics of this cold-shock-induced process of apoptosis. Consequently, apoptosis could be inhibited by a caspase inhibitor. Finally, SLE-derived anti-chromatin autoantibodies showed a high affinity for apoptotic blebs generated by cold-shock. Overall, cold-shock induced apoptosis is achieved without the addition of toxic compounds or antibodies, and quickly leads to synchronized homogeneous apoptotic cell populations, which can be applied for various research questions addressing apoptosis. PMID:20972831

  17. Overexpression of pigeonpea stress-induced cold and drought regulatory gene (CcCDR) confers drought, salt, and cold tolerance in Arabidopsis

    PubMed Central

    Tamirisa, Srinath; Vudem, Dashavantha Reddy; Khareedu, Venkateswara Rao

    2014-01-01

    A potent cold and drought regulatory protein-encoding gene (CcCDR) was isolated from the subtractive cDNA library of pigeonpea plants subjected to drought stress. CcCDR was induced by different abiotic stress conditions in pigeonpea. Overexpression of CcCDR in Arabidopsis thaliana imparted enhanced tolerance against major abiotic stresses, namely drought, salinity, and low temperature, as evidenced by increased biomass, root length, and chlorophyll content. Transgenic plants also showed increased levels of antioxidant enzymes, proline, and reducing sugars under stress conditions. Furthermore, CcCDR-transgenic plants showed enhanced relative water content, osmotic potential, and cell membrane stability, as well as hypersensitivity to abscisic acid (ABA) as compared with control plants. Localization studies confirmed that CcCDR could enter the nucleus, as revealed by intense fluorescence, indicating its possible interaction with various nuclear proteins. Microarray analysis revealed that 1780 genes were up-regulated in CcCDR-transgenics compared with wild-type plants. Real-time PCR analysis on selected stress-responsive genes, involved in ABA-dependent and -independent signalling networks, revealed higher expression levels in transgenic plants, suggesting that CcCDR acts upstream of these genes. The overall results demonstrate the explicit role of CcCDR in conferring multiple abiotic stress tolerance at the whole-plant level. The multifunctional CcCDR seems promising as a prime candidate gene for enhancing abiotic stress tolerance in diverse plants. PMID:24868035

  18. Transcriptome Analysis of Capsicum Chlorosis Virus-Induced Hypersensitive Resistance Response in Bell Capsicum

    PubMed Central

    Widana Gamage, Shirani M. K.; McGrath, Desmond J.; Persley, Denis M.

    2016-01-01

    Background Capsicum chlorosis virus (CaCV) is an emerging pathogen of capsicum, tomato and peanut crops in Australia and South-East Asia. Commercial capsicum cultivars with CaCV resistance are not yet available, but CaCV resistance identified in Capsicum chinense is being introgressed into commercial Bell capsicum. However, our knowledge of the molecular mechanisms leading to the resistance response to CaCV infection is limited. Therefore, transcriptome and expression profiling data provide an important resource to better understand CaCV resistance mechanisms. Methodology/Principal Findings We assembled capsicum transcriptomes and analysed gene expression using Illumina HiSeq platform combined with a tag-based digital gene expression system. Total RNA extracted from CaCV/mock inoculated CaCV resistant (R) and susceptible (S) capsicum at the time point when R line showed a strong hypersensitive response to CaCV infection was used in transcriptome assembly. Gene expression profiles of R and S capsicum in CaCV- and buffer-inoculated conditions were compared. None of the genes were differentially expressed (DE) between R and S cultivars when mock-inoculated, while 2484 genes were DE when inoculated with CaCV. Functional classification revealed that the most highly up-regulated DE genes in R capsicum included pathogenesis-related genes, cell death-associated genes, genes associated with hormone-mediated signalling pathways and genes encoding enzymes involved in synthesis of defense-related secondary metabolites. We selected 15 genes to confirm DE expression levels by real-time quantitative PCR. Conclusion/Significance DE transcript profiling data provided comprehensive gene expression information to gain an understanding of the underlying CaCV resistance mechanisms. Further, we identified candidate CaCV resistance genes in the CaCV-resistant C. annuum x C. chinense breeding line. This knowledge will be useful in future for fine mapping of the CaCV resistance locus and

  19. Changes in cytosolic ATP levels and intracellular morphology during bacteria-induced hypersensitive cell death as revealed by real-time fluorescence microscopy imaging.

    PubMed

    Hatsugai, Noriyuki; Perez Koldenkova, Vadim; Imamura, Hiromi; Noji, Hiroyuki; Nagai, Takeharu

    2012-10-01

    Hypersensitive cell death is known to involve dynamic remodeling of intracellular structures that uses energy released during ATP hydrolysis. However, the relationship between intracellular structural changes and ATP levels during hypersensitive cell death remains unclear. Here, to visualize ATP dynamics directly in real time in individual living plant cells, we applied a genetically encoded Förster resonance energy transfer (FRET)-based fluorescent ATP indicator, ATeam1.03-nD/nA, for plant cells. Intracellular ATP levels increased approximately 3 h after inoculation with the avirulent strain DC3000/avrRpm1 of Pseudomonas syringae pv. tomato (Pst), which was accompanied by the simultaneous disappearance of transvacuolar strands and appearance of bulb-like structures within the vacuolar lumen. Approximately 5 h after bacterial inoculation, the bulb-like structures disappeared and ATP levels drastically decreased. After another 2 h, the large central vacuole was disrupted. In contrast, no apparent changes in intracellular ATP levels were observed in the leaves inoculated with the virulent strain Pst DC3000. The Pst DC3000/avrRpm1-induced hypersensitive cell death was strongly suppressed by inhibiting ATP synthesis after oligomycin A application within 4 h after bacterial inoculation. When the inhibitor was applied 7 h after bacterial inoculation, cell death was unaffected. These observations show that changes in intracellular ATP levels correlate with intracellular morphological changes during hypersensitive cell death, and that ATP is required just before vacuolar rupture in response to bacterial infection.

  20. Transgenic production of cytokinin suppresses bacterially induced hypersensitive response symptoms and increases antioxidative enzyme levels in Nicotiana spp.

    PubMed

    Barna, B; Smigocki, A C; Baker, J C

    2008-11-01

    Responses of cytokinin overproducing transgenic Nicotiana plants to infections with compatible and incompatible Pseudomonas syringae pathovars were compared. Plants used were transformed with the ipt(isopentenyl transferase) gene that catalyzes the synthesis of cytokinin. In cytokinin overproducing lines that carry the ipt gene fused to the CaMV 35S (Nt+ipt), the wound-inducible proteinase inhibitor II (Ntx+ipt), or the light-inducible Rubisco small subunit protein (Npl+ipt) promoter, development of the hypersensitive response (HR) after infection with incompatible bacteria (P. syringae pv. tomato) was significantly inhibited as compared to the untransformed (Nt) controls. Over a 12 h period following inoculation, P. syrinage pv. tomato populations were slightly reduced in leaves of the cytokinin-overproducing Nt-ipt line compared with the Nt control. When the compatible P. syringae. pv. tabaci was used to infect the ipt transformed lines, slight or no significant differences in necrosis development were observed. Following infection, the titer of P. syringae pv. tabaci increased rapidly in both the transgenic and control lines but was higher in Nt+ipt plants. Leaf superoxide dismutase and catalase enzyme activities were about 60% higher in ipt leaf extracts than in the controls. This augmented antioxidant capacity likely decreased the amount of H(2)O(2) that may be associated with the higher tolerance of plants to pathogen-induced necrosis. In addition, the Nt+ipt lines had a significantly lower molar ratio of free sterols to phospholipids. The more stable membrane lipid composition and the higher antioxidant capacity likely contributed to the suppressed HR symptoms in the cytokinin overproducing Nt+ipt plants. In conclusion, the overproduction of cytokinins in tobacco appears to suppress the HR symptoms induced by incompatible bacteria.

  1. Lipopolysaccharide induces visceral hypersensitivity: role of interleukin-1, interleukin-6, and peripheral corticotropin-releasing factor in rats.

    PubMed

    Nozu, Tsukasa; Miyagishi, Saori; Nozu, Rintaro; Takakusaki, Kaoru; Okumura, Toshikatsu

    2017-01-01

    Lipopolysaccharide (LPS) induces visceral hypersensitivity, and corticotropin-releasing factor (CRF) also modulates visceral sensation. Besides, LPS increases CRF immunoreactivity in rat colon, which raises the possibility of the existence of a link between LPS and the CRF system in modulating visceral sensation. The present study tried to clarify this possibility. Visceral sensation was assessed by abdominal muscle contractions induced by colonic balloon distention, i.e., visceromotor response, electrophysiologically in conscious rats. The threshold of visceromotor response was measured before and after administration of drugs. LPS at a dose of 1 mg/kg subcutaneously (sc) decreased the threshold at 3 h after the administration. Intraperitoneal (ip) administration of anakinra (20 mg/kg), an interleukin-1 (IL-1) receptor antagonist, or interleukin-6 (IL-6) antibody (16.6 µg/kg) blocked this effect. Additionally, IL-1β (10 µg/kg, sc) or IL-6 (10 µg/kg, sc) induced visceral allodynia. Astressin (200 µg/kg, ip), a non-selective CRF receptor antagonist, abolished the effect of LPS, but astressin2-B (200 µg/kg, ip), a CRF receptor type 2 (CRF2) antagonist, did not alter it. Peripheral CRF receptor type 1 (CRF1) stimulation by cortagine (60 µg/kg, ip) exaggerated the effect of LPS, but activation of CRF2 by urocortin 2 (60 µg/kg, ip) abolished it. LPS induced visceral allodynia possibly through stimulating IL-1 and IL-6 release. In addition, this effect was mediated through peripheral CRF signaling. Since the LPS-cytokine system is thought to contribute to altered visceral sensation in the patients with irritable bowel syndrome, these results may further suggest that CRF plays a crucial role in the pathophysiology of this disease.

  2. Identification of a new physically induced urticaria: cold-induced cholinergic urticaria.

    PubMed

    Kaplan, A P; Garofalo, J

    1981-12-01

    Four patients with symptoms suggestive of either cold urticaria or a combination of cold and cholinergic urticaria were studied. However, all patients were negative to an ice-cube test or cold-immersion test and had no urticaria after exercise in a warm environment. When each patient was seated in a cold room (4 degree C) for 5 to 15 min, generalized urticaria appeared, consisting of puncture wheals and surrounding erythema as seen in cholinergic urticaria. Two patients had weakly positive methacholine skin tests and the other two had completely negative tests. When serial venous blood samples were obtained to test for mediator release, three of four patients had evidence of histamine release and the time course was similar to that previously reported for patients with cholinergic urticaria. These four cases represent a new syndrome with features suggestive of cold and/or cholinergic urticaria, but the results of all the tests usually utilized to diagnose these conditions were negative. We have called this disorder cold-induced cholinergic urticaria to indicate that it is cold dependent and visually indistinguishable from cholinergic urticaria.

  3. Fever as the only manifestation of hypersensitivity reactions associated with oxaliplatin in a patient with colorectal cancer Oxaliplatin-induced hypersensitivity reaction

    PubMed Central

    Saif, M Wasif; Roy, Shailja; Ledbetter, Leslie; Madison, Jennifer; Syrigos, Kostas

    2007-01-01

    Hypersensitivity reactions (HSR) to oxaliplatin in patients with colorectal cancer include facial flushing, erythema, pruritis, fever, tachycardia, dyspnea, tongue swelling, rash/hives, headache, chills, weakness, vomiting, burning sensations, dizziness, and edema. We report a patient with fever as the sole manifestation of initial HSR, review the literature and discuss the management of HSR. A 57-year-old female with T3N2M0 rectal adenocarcinoma received modified FOLFOX-6. She tolerated the first 8 cycles without any toxicities except grade 1 peripheral neuropathy and nausea. During 9th and 10th infusions, she developed fever to a maximum of 38.3°C with stable hemodynamic status despite medications. During 11th infusion, she developed grade 3 HSR consisting of symptomatic bronchospasm, hypotension, nausea, vomiting, cough, and fever. On examination, she was pale, cyanotic, with a temperature of 38.8°C, BP dropped to 95/43 mm Hg, pulse of 116/min and O2 saturation of 88%-91%. She was hospitalized for management and recovered in 24 h. Fever alone is not a usual symptom of oxaliplatin HSR. It may be indicative that the patient may develop serious reactions subsequently, as did our patient who developed hypotension with the third challenge. Treatment and prevention consists of slowing the infusion rate, use of steroids and antagonists of Type 1 and 2 histamine receptor antagonists, whereas desensitization could help to provide the small number of patients who experience severe HSR with the ability to further receive an effective therapy for their colorectal cancer. PMID:17876901

  4. Suppression of the vacuolar invertase gene prevents cold-induced sweetening in potato

    USDA-ARS?s Scientific Manuscript database

    Storing potato (Solanum tuberosum) tubers at cold temperatures prevents sprouting and minimizes losses due to disease. Unfortunately, cold storage triggers an accumulation of reducing sugars, a phenomenon referred to as cold-induced sweetening (CIS). High-temperature processing of potato tubers wit...

  5. [Electromagnetic fields hypersensitivity].

    PubMed

    Sobiczewska, Elzbieta; Szmigielski, Stanisław

    2009-01-01

    The development of industry, particularly of new technologies in communication systems, gives rise to the number and diversty of electromagnetic field (EMF) sources in the environment. These sources, including power-frequent, radiofrequent and microwaves, make human life richer, safer and easier. But at the same time, there is growing concern about possible health risks connected with EMF exposure. An increasing number of persons have recently reported on a variety of health problems induced, in their opinion, by exposure to EMF. It is important to note that EMF levels to which these individuals are exposed are generally well below the recommended exposure limits and are certainly far below those known to produce any adverse effects. These persons call themselves "electromagnetic hypersensitivity individuals" And complain about experiencing various types of non-specific symptoms, including dermatological, neurological and vegetative. In the present paper, the problem of electromagnetic hypersensitivity phenomenon is discussed based on the recently published literature.

  6. Spinal 5-HT(3) receptor activation induces behavioral hypersensitivity via a neuronal-glial-neuronal signaling cascade.

    PubMed

    Gu, Ming; Miyoshi, Kan; Dubner, Ronald; Guo, Wei; Zou, Shiping; Ren, Ke; Noguchi, Koichi; Wei, Feng

    2011-09-07

    Recent studies indicate that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT(3) receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT(3) receptor and its contribution to facilitation of pain remain unclear. In the present study, activation of spinal 5-HT(3) receptor by intrathecal injection of a selective 5-HT(3) receptor agonist, SR57227, induced spinal glial hyperactivity, neuronal hyperexcitability, and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via chemokine fractalkine, microglia to astrocyte signaling via the cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of GluN (NMDA) receptors in the spinal dorsal horn. In addition, exogenous brain-derived neurotrophic factor-induced descending pain facilitation was accompanied by upregulation of CD11b and GFAP expression in the spinal dorsal horn after microinjection in the RVM, and these events were significantly prevented by functional blockade of spinal 5-HT(3) receptors. Enhanced expression of spinal CD11b and GFAP after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference. Thus, these findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neuron and glia.

  7. Spinal 5-HT3 receptor activation induces behavioral hypersensitivity via a neuronal-glial-neuronal signaling cascade

    PubMed Central

    Gu, Ming; Miyoshi, Kan; Dubner, Ronald; Guo, Wei; Zou, Shiping; Ren, Ke; Noguchi, Koichi; Wei, Feng

    2011-01-01

    Recent studies indicate that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in brainstem and the 5-HT3 receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT3 receptor and its contribution to facilitation of pain remain unclear. In the present study, activation of spinal 5-HT3 receptor by intrathecal injection of a selective 5-HT3 receptor agonist SR 57227 induced spinal glial hyperactivity, neuronal hyperexcitability and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via chemokine fractalkine, microglia to astrocyte signaling via cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of GluN (NMDA) receptors in the spinal dorsal horn. In addition, exogenous BDNF-induced descending pain facilitation was accompanied with up-regulation of CD11b and GFAP expression in the spinal dorsal horn after microinjection in the RVM, which were significantly prevented by functional blockade of spinal 5-HT3 receptors. Enhanced expression of spinal CD11b and GFAP after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference. Thus, these findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neuron and glia. PMID:21900561

  8. Purification and Characterization of a Novel Hypersensitive Response-Inducing Elicitor from Magnaporthe oryzae that Triggers Defense Response in Rice

    PubMed Central

    Chen, Mingjia; Zeng, Hongmei; Qiu, Dewen; Guo, Lihua; Yang, Xiufen; Shi, Huaixing; Zhou, Tingting; Zhao, Jing

    2012-01-01

    Background Magnaporthe oryzae, the rice blast fungus, might secrete certain proteins related to plant-fungal pathogen interactions. Methodology/Principal Findings In this study, we report the purification, characterization, and gene cloning of a novel hypersensitive response-inducing protein elicitor (MoHrip1) secreted by M. oryzae. The protein fraction was purified and identified by de novo sequencing, and the sequence matched the genomic sequence of a putative protein from M. oryzae strain 70-15 (GenBank accession No. XP_366602.1). The elicitor-encoding gene mohrip1 was isolated; it consisted of a 429 bp cDNA, which encodes a polypeptide of 142 amino acids with a molecular weight of 14.322 kDa and a pI of 4.53. The deduced protein, MoHrip1, was expressed in E. coli. And the expression protein collected from bacterium also forms necrotic lesions in tobacco. MoHrip1 could induce the early events of the defense response, including hydrogen peroxide production, callose deposition, and alkalization of the extracellular medium, in tobacco. Moreover, MoHrip1-treated rice seedlings possessed significantly enhanced systemic resistance to M. oryzae compared to the control seedlings. The real-time PCR results indicated that the expression of some pathogenesis-related genes and genes involved in signal transduction could also be induced by MoHrip1. Conclusion/Significance The results demonstrate that MoHrip1 triggers defense responses in rice and could be used for controlling rice blast disease. PMID:22624059

  9. Arginase1 Deficiency in Monocytes/Macrophages Upregulates Inducible Nitric Oxide Synthase To Promote Cutaneous Contact Hypersensitivity.

    PubMed

    Suwanpradid, Jutamas; Shih, Michael; Pontius, Lauren; Yang, Bin; Birukova, Anastasiya; Guttman-Yassky, Emma; Corcoran, David L; Que, Loretta G; Tighe, Robert M; MacLeod, Amanda S

    2017-09-01

    The innate immune components that modulate allergic contact hypersensitivity (CHS) responses are poorly defined. Using human skin from contact dermatitis patients and a mouse model of CHS, we find that hapten allergens disrupt the Arginase1 (Arg1) and inducible NO synthase (iNOS) dynamic in monocytes/macrophages (mono/MΦ), which renders those cells ineffectual in suppressing skin inflammation. Mice lacking Arg1 in MΦ develop increased CHS characterized by elevated ear thickening, mono/MΦ-dominated dermal inflammation, and increased iNOS and IL-6 expression compared with control mice. Treatment of Arg1(flox/flox); LysMCre(+/-) mice with a selective NOS inhibitor or knockout of Nos2, encoding iNOS, significantly ameliorates CHS. Our findings suggest a critical role for Arg1 in mono/MΦ in suppressing CHS through dampening Nos2 expression. These results support that increasing Arg1 may be a potential therapeutic avenue in treating allergic contact dermatitis. Copyright © 2017 by The American Association of Immunologists, Inc.

  10. Drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome: clinical features of 27 patients.

    PubMed

    Avancini, J; Maragno, L; Santi, C G; Criado, P R

    2015-12-01

    Drug reaction with eosinophilia and systemic symptoms (DRESS) [also called drug-induced hypersensitivity syndrome (DIHS)] includes severe reactions to drugs that need to be promptly recognized by physicians. To explore heterogeneity in the clinical presentation of DRESS/DIHS at a large academic hospital in Latin America, using the criteria defined by the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scoring system. A retrospective medical record review of 60 patients with diagnostic suspicion of DRESS/DIHS admitted to our hospital between July 2008 and April 2012 was performed, including demographic data, clinical features, laboratory findings and treatment. Of the 60 patients, 27 fulfilled the criteria for DRESS/DIHS. Maculopapular exanthema (85.1%), fever (96.2%) and hepatic involvement (85.1%) were the most common features. Anticonvulsants were the most common causal drugs (77.7%); Phenytoin was the most common individual drug (44.4%), followed by carbamazepine (29.6%). All patients were treated initially with prednisone 1 mg/kg/day. Mortality rate was 4%. The major findings of this study (to our knowledge the largest collection of data on DRESS/DIHS in Latin America) include a positive statistical association between presence of atypical lymphocytes and higher levels of alanine aminotransferase (P < 0.001) and reinforce the importance of anticonvulsants in the pathogenesis of this severe reaction. © 2015 British Association of Dermatologists.

  11. Drug reaction with Eosinophilia and Systemic Symptoms (DRESS) / Drug-induced Hypersensitivity Syndrome (DIHS): a review of current concepts.

    PubMed

    Criado, Paulo Ricardo; Criado, Roberta Fachini Jardim; Avancini, João de Magalhães; Santi, Claudia Giuli

    2012-01-01

    The Drug Reaction with Eosinophilia and Systemic Symptoms syndrome, also known as Drug Induced Hypersensitivity Syndrome presents clinically as an extensive mucocutaneous rash, accompanied by fever, lymphadenopathy, hepatitis, hematologic abnormalities with eosinophilia and atypical lymphocytes, and may involve other organs with eosinophilic infiltration, causing damage to several systems, especially to the kidneys, heart, lungs, and pancreas. Recognition of this syndrome is of paramount importance, since the mortality rate is about 10% to 20%, and a specific therapy may be necessary. The pathogenesis is related to specific drugs, especially the aromatic anticonvulsants, altered immune response, sequential reactivation of herpes virus and association with HLA alleles. Early recognition of the syndrome and withdrawal of the offending drug are the most important and essential steps in the treatment of affected patients. Corticosteroids are the basis of the treatment of the syndrome, which may be associated with intravenous immunoglobulin and, in selected cases, Ganciclovir. The article reviews the current concepts involving this important manifestation of adverse drug reaction.

  12. Selective antagonism of TRPA1 produces limited efficacy in models of inflammatory- and neuropathic-induced mechanical hypersensitivity in rats.

    PubMed

    Lehto, Sonya G; Weyer, Andy D; Youngblood, Beth D; Zhang, Maosheng; Yin, Ruoyuan; Wang, Weiya; Teffera, Yohannes; Cooke, Melanie; Stucky, Cheryl L; Schenkel, Laurie; Geuns-Meyer, Stephanie; Moyer, Bryan D; Wild, Kenneth D; Gavva, Narender R

    2016-01-01

    The transient receptor potential ankyrin 1 (TRPA1) channel has been implicated in pathophysiological processes that include asthma, cough, and inflammatory pain. Agonists of TRPA1 such as mustard oil and its key component allyl isothiocyanate (AITC) cause pain and neurogenic inflammation in humans and rodents, and TRPA1 antagonists have been reported to be effective in rodent models of pain. In our pursuit of TRPA1 antagonists as potential therapeutics, we generated AMG0902, a potent (IC90 of 300 nM against rat TRPA1), selective, brain penetrant (brain to plasma ratio of 0.2), and orally bioavailable small molecule TRPA1 antagonist. AMG0902 reduced mechanically evoked C-fiber action potential firing in a skin-nerve preparation from mice previously injected with complete Freund's adjuvant, supporting the role of TRPA1 in inflammatory mechanosensation. In vivo target coverage of TRPA1 by AMG0902 was demonstrated by the prevention of AITC-induced flinching/licking in rats. However, oral administration of AMG0902 to rats resulted in little to no efficacy in models of inflammatory, mechanically evoked hypersensitivity; and no efficacy was observed in a neuropathic pain model. Unbound plasma concentrations achieved in pain models were about 4-fold higher than the IC90 concentration in the AITC target coverage model, suggesting that either greater target coverage is required for efficacy in the pain models studied or TRPA1 may not contribute significantly to the underlying mechanisms. © The Author(s) 2016.

  13. Selective antagonism of TRPA1 produces limited efficacy in models of inflammatory- and neuropathic-induced mechanical hypersensitivity in rats

    PubMed Central

    Weyer, Andy D; Youngblood, Beth D; Zhang, Maosheng; Yin, Ruoyuan; Wang, Weiya; Teffera, Yohannes; Cooke, Melanie; Stucky, Cheryl L; Schenkel, Laurie; Geuns-Meyer, Stephanie; Moyer, Bryan D; Wild, Kenneth D; Gavva, Narender R

    2016-01-01

    The transient receptor potential ankyrin 1 (TRPA1) channel has been implicated in pathophysiological processes that include asthma, cough, and inflammatory pain. Agonists of TRPA1 such as mustard oil and its key component allyl isothiocyanate (AITC) cause pain and neurogenic inflammation in humans and rodents, and TRPA1 antagonists have been reported to be effective in rodent models of pain. In our pursuit of TRPA1 antagonists as potential therapeutics, we generated AMG0902, a potent (IC90 of 300 nM against rat TRPA1), selective, brain penetrant (brain to plasma ratio of 0.2), and orally bioavailable small molecule TRPA1 antagonist. AMG0902 reduced mechanically evoked C-fiber action potential firing in a skin-nerve preparation from mice previously injected with complete Freund’s adjuvant, supporting the role of TRPA1 in inflammatory mechanosensation. In vivo target coverage of TRPA1 by AMG0902 was demonstrated by the prevention of AITC-induced flinching/licking in rats. However, oral administration of AMG0902 to rats resulted in little to no efficacy in models of inflammatory, mechanically evoked hypersensitivity; and no efficacy was observed in a neuropathic pain model. Unbound plasma concentrations achieved in pain models were about 4-fold higher than the IC90 concentration in the AITC target coverage model, suggesting that either greater target coverage is required for efficacy in the pain models studied or TRPA1 may not contribute significantly to the underlying mechanisms. PMID:27899696

  14. Acyclovir Has Low but Detectable Influence on HLA-B*57:01 Specificity without Inducing Hypersensitivity.

    PubMed

    Metushi, Imir G; Wriston, Amanda; Banerjee, Priyanka; Gohlke, Bjoern Oliver; English, A Michelle; Lucas, Andrew; Moore, Carrie; Sidney, John; Buus, Soren; Ostrov, David A; Mallal, Simon; Phillips, Elizabeth; Shabanowitz, Jeffrey; Hunt, Donald F; Preissner, Robert; Peters, Bjoern

    2015-01-01

    Immune mediated adverse drug reactions (IM-ADRs) remain a significant source of patient morbidity that have more recently been shown to be associated with specific class I and/or II human leukocyte antigen (HLA) alleles. Abacavir-induced hypersensitivity syndrome is a CD8+ T cell dependent IM-ADR that is exclusively mediated by HLA-B*57:01. We and others have previously shown that abacavir can occupy the floor of the peptide binding groove of HLA-B*57:01 molecules, increasing the affinity of certain self peptides resulting in an altered peptide-binding repertoire. Here, we have identified another drug, acyclovir, which appears to act in a similar fashion. As with abacavir, acyclovir showed a dose dependent increase in affinity for peptides with valine and isoleucine at their C-terminus. In agreement with the binding studies, HLA-B*57:01 peptide-elution studies performed in the presence of acyclovir revealed an increased number of endogenously bound peptides with a C-terminal isoleucine. Accordingly, we have hypothesized that acyclovir acts by the same mechanism as abacavir, although our data also suggest the overall effect is much smaller: the largest changes of peptide affinity for acyclovir were 2-5 fold, whereas for abacavir this effect was as much as 1000-fold. Unlike abacavir, acyclovir is not known to cause IM-ADRs. We conclude that the modest effect of acyclovir on HLA binding affinity in contrast to the large effect of abacavir is insufficient to trigger a hypersensitivity syndrome. We further support this by functional in vitro studies where acyclovir, unlike abacavir, was unable to produce an increase in IFN-γ upon expansion of HLA-B*57:01+ PBMCs from healthy donors. Using abacavir and acyclovir as examples we therefore propose an in vitro pre-clinical screening strategy, whereby thresholds can be applied to MHC-peptide binding assays to determine the likelihood that a drug could cause a clinically relevant IM-ADR.

  15. [Cold-induced urticaria and angioedema. Classification, diagnosis and therapy].

    PubMed

    Krause, K; Degener, F; Altrichter, S; Ardelean, E; Kalogeromitros, D; Magerl, M; Metz, M; Siebenhaar, F; Weller, K; Maurer, M

    2010-09-01

    The onset of wheals and/or angioedema following the exposure to cold may be associated with a number of different diseases. Most frequently this occurs in cold contact urticaria, a type of physical urticaria, which is characterized by a positive cold stimulation test. The clinical symptoms are based on cold-dependent mast cell activation with subsequent release of proinflammatory mediators. In cases of negative or atypical reaction to cold stimulation testing rare acquired atypical or familiar cold urticaria forms may be suspected. Strict avoidance of cold should be recommended as far as possible. As the underlying causes of cold contact urticaria are widely unknown, the symptomatic use of non-sedating antihistamines is the treatment of first choice. The very rare familiar cold auto-inflammatory syndrome (FCAS) is based on CIAS1/NLRP3 mutations and may be treated effectively by neutralization of pathogenic interleukin 1beta.

  16. Similar cold stress induces sex-specific neuroendocrine and working memory responses.

    PubMed

    Solianik, Rima; Skurvydas, Albertas; Urboniene, Daiva; Eimantas, Nerijus; Daniuseviciute, Laura; Brazaitis, Marius

    2015-01-01

    Men have higher cold-induced neuroendocrine response than women; nevertheless, it is not known whether a different stress hormone rise elicits different effects on cognition during whole body cooling. The objective was to compare the effect of cold-induced neuroendocrine responses on the performance of working memory sensitive tasks between men and women. The cold stress continued until rectal temperature reached 35.5 degree C or for a maximum of 170 min. Working memory performance and stress hormone concentrations were monitored. During cold stress, body temperature variables dropped in all subjects (P < 0.001) and did not differ between sexes. Cold stress raised plasma epinephrine and serum cortisol levels only in men (P < 0.05). Cold stress adversely affected memory performance in men but not in women (P < 0.05). The present study indicated that similar moderate cold stress in men and women induces sex-specific neuroendocrine and working memory responses.

  17. Cold/menthol TRPM8 receptors initiate the cold-shock response and protect germ cells from cold-shock–induced oxidation

    PubMed Central

    Borowiec, Anne-Sophie; Sion, Benoit; Chalmel, Frédéric; D. Rolland, Antoine; Lemonnier, Loïc; De Clerck, Tatiana; Bokhobza, Alexandre; Derouiche, Sandra; Dewailly, Etienne; Slomianny, Christian; Mauduit, Claire; Benahmed, Mohamed; Roudbaraki, Morad; Jégou, Bernard; Prevarskaya, Natalia; Bidaux, Gabriel

    2016-01-01

    Testes of most male mammals present the particularity of being externalized from the body and are consequently slightly cooler than core body temperature (4–8°C below). Although, hypothermia of the testis is known to increase germ cells apoptosis, little is known about the underlying molecular mechanisms, including cold sensors, transduction pathways, and apoptosis triggers. In this study, using a functional knockout mouse model of the cold and menthol receptors, dubbed transient receptor potential melastatine 8 (TRPM8) channels, we found that TRPM8 initiated the cold-shock response by differentially modulating cold- and heat-shock proteins. Besides, apoptosis of germ cells increased in proportion to the cooling level in control mice but was independent of temperature in knockout mice. We also observed that the rate of germ cell death correlated positively with the reactive oxygen species level and negatively with the expression of the detoxifying enzymes. This result suggests that the TRPM8 sensor is a key determinant of germ cell fate under hypothermic stimulation.—Borowiec, A.-S., Sion, B., Chalmel, F., Rolland, A. D., Lemonnier, L., De Clerck, T., Bokhobza, A., Derouiche, S., Dewailly, E., Slomianny, C., Mauduit, C., Benahmed, M., Roudbaraki, M., Jégou, B., Prevarskaya, N., Bidaux, G. Cold/menthol TRPM8 receptors initiate the cold-shock response and protect germ cells from cold-shock–induced oxidation. PMID:27317670

  18. Apoptosis in vascular cells induced by cold atmospheric plasma treatment

    NASA Astrophysics Data System (ADS)

    Sladek, Raymond; Stoffels, Eva

    2006-10-01

    Apoptosis is a natural mechanism of cellular self-destruction. It can be triggered by moderate, yet irreversible damage. Apoptosis plays a major role in tissue renewal. Artificial apoptosis induction will become a novel therapy that meets all requirements for tissue-saving surgery. Diseased tissues can disappear without inflammation and scarring. This is particularly important in treatment of blockages in body tracts (e.g. cardiovascular diseases). Artificial induction of apoptosis can be achieved by means of cold plasma treatment. In this work an atmospheric micro-plasma operated in helium/air has been used to induce apoptosis in vascular cells. Parametric studies of apoptosis induction have been conducted; the efficiency is almost 100%. The apoptotic factors are ROS/RNS (reactive oxygen and nitrogen species). Their densities in the plasma have been measured by mass spectrometry. For apoptosis induction, RNS seem to be more important than ROS, because of their relative abundance. Moreover, addition of a ROS scavenger (ascorbic acid) to the cell culture medium does not reduce the occurrence of apoptosis. Cold plasma is a very efficient tool for fundamental studies of apoptosis, and later, for controlled tissue removal in vivo.

  19. Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: studies with selective sigma-1 ligands and sigma-1 knockout mice.

    PubMed

    Entrena, José Manuel; Cobos, Enrique José; Nieto, Francisco Rafael; Cendán, Cruz Miguel; Gris, Georgia; Del Pozo, Esperanza; Zamanillo, Daniel; Baeyens, José Manuel

    2009-06-01

    We evaluated the role of sigma(1) receptors on capsaicin-induced mechanical hypersensitivity and on nociceptive pain induced by punctate mechanical stimuli, using wild-type and sigma(1) receptor knockout (sigma(1)-KO) mice and selective sigma(1) receptor-acting drugs. Mutation in sigma(1)-KO mice was confirmed by PCR analysis of genomic DNA and, at the protein level, by [(3)H](+)-pentazocine binding assays. Both wild-type and sigma(1)-KO mice not treated with capsaicin showed similar responses to different intensities of mechanical stimuli (0.05-8 g force), ranging from innocuous to noxious, applied to the hind paw. This indicates that sigma(1) gene inactivation does not modify the perception of punctate mechanical stimuli. The intraplantar (i.pl.) administration of capsaicin induced dose-dependent mechanical allodynia in wild-type mice (markedly reducing both the threshold force necessary to induce paw withdrawal and the latency to paw withdrawal induced by a given force). In contrast, capsaicin was completely unable to induce mechanical hypersensitivity in sigma(1)-KO mice. The high-affinity and selective sigma(1) antagonists BD-1063, BD-1047 and NE-100, administered subcutaneously (s.c.), dose-dependently inhibited mechanical allodynia induced by capsaicin (1 microg,i.pl.), yielding ED(50) (mg/kg) values of 15.80+/-0.93, 29.31+/-1.65 and 40.74+/-7.20, respectively. The effects of the sigma(1) antagonists were reversed by the sigma(1) agonist PRE-084 (32 mg/kg, s.c.). None of the drugs tested modified the responses induced by a painful mechanical punctate stimulus (4 g force) in nonsensitized animals. These results suggest that sigma(1) receptors are essential for capsaicin-induced mechanical hypersensitivity, but are not involved in mechanical nociceptive pain.

  20. Helium-cold induced hypothermia in the white rat.

    NASA Technical Reports Server (NTRS)

    Musacchia, X. J.; Jacobs, M.

    1973-01-01

    Hypothermia was induced in white rats by exposing them to low ambient temperatures (about 0 C) and a gaseous atmosphere of 80% helium and 20% oxygen (helox). Biological survival, in which revival from hypothermia to normothermia is achieved, and clinical survival, in which one or more functional attributes are monitored in the hypothermic animal until it dies, are examined. The helium-cold method appears to produce a hypothermic state in the rat quite similar to that resulting from such techniques as ice water immersion or hypercapnia + hypoxia. There is a direct relationship between body weight and percent survival. Despite the fact that they require a longer period to become hypothermic, the heavier animals are better able to survive.

  1. Immunization of Macaques with Formalin-Inactivated Respiratory Syncytial Virus (RSV) Induces Interleukin-13-Associated Hypersensitivity to Subsequent RSV Infection

    PubMed Central

    de Swart, Rik L.; Kuiken, Thijs; Timmerman, Helga H.; Amerongen, Geert van; van den Hoogen, Bernadette G.; Vos, Helma W.; Neijens, Herman J.; Andeweg, Arno C.; Osterhaus, Albert D. M. E.

    2002-01-01

    Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and the elderly. RSV vaccine development has been hampered by results of clinical trials in the 1960s, when formalin-inactivated whole-RSV preparations adjuvated with alum (FI-RSV) were found to predispose infants for enhanced disease following subsequent natural RSV infection. We have reproduced this apparently immunopathological phenomenon in infant cynomolgus macaques and identified immunological and pathological correlates. Vaccination with FI-RSV induced specific virus-neutralizing antibody responses accompanied by strong lymphoproliferative responses. The vaccine-induced RSV-specific T cells predominantly produced the Th2 cytokines interleukin-13 (IL-13) and IL-5. Intratracheal challenge with a macaque-adapted wild-type RSV 3 months after the third vaccination elicited a hypersensitivity response associated with lung eosinophilia. The challenge resulted in a rapid boosting of IL-13-producing T cells in the FI-RSV-vaccinated animals but not in the FI-measles virus-vaccinated control animals. Two out of seven FI-RSV-vaccinated animals died 12 days after RSV challenge with pulmonary hyperinflation. Surprisingly, the lungs of these two animals did not show overt inflammatory lesions. However, upon vaccination the animals had shown the strongest lymphoproliferative responses associated with the most pronounced Th2 phenotype within their group. We hypothesize that an IL-13-associated asthma-like mechanism resulted in airway hyperreactivity in these animals. This nonhuman primate model will be an important tool to assess the safety of nonreplicating candidate RSV vaccines. PMID:12388717

  2. Human Monocyte-Derived Dendritic Cells Exposed to Microorganisms Involved in Hypersensitivity Pneumonitis Induce a Th1-Polarized Immune Response

    PubMed Central

    Pallandre, Jean-René; Borg, Christophe; Loeffert, Sophie; Gbaguidi-Haore, Houssein; Millon, Laurence

    2013-01-01

    Hypersensitivity pneumonitis (HP) is an immunoallergic disease characterized by a prominent interstitial infiltrate composed predominantly of lymphocytes secreting inflammatory cytokines. Dendritic cells (DCs) are known to play a pivotal role in the lymphocytic response. However, their cross talk with microorganisms that cause HP has yet to be elucidated. This study aimed to investigate the initial interactions between human monocyte-derived DCs (MoDCs) and four microorganisms that are different in nature (Saccharopolyspora rectivirgula [actinomycetes], Mycobacterium immunogenum [mycobacteria], and Wallemia sebi and Eurotium amstelodami [filamentous fungi]) and are involved in HP. Our objectives were to determine the cross talk between MoDCs and HP-causative agents and to determine whether the resulting immune response varied according to the microbial extract tested. The phenotypic activation of MoDCs was measured by the increased expression of costimulatory molecules and levels of cytokines in supernatants. The functional activation of MoDCs was measured by the ability of MoDCs to induce lymphocytic proliferation and differentiation in a mixed lymphocytic reaction (MLR). E. amstelodami-exposed (EA) MoDCs expressed higher percentages of costimulatory molecules than did W. sebi-exposed (WS), S. rectivirgula-exposed (SR), or M. immunogenum-exposed (MI) MoDCs (P < 0.05, Wilcoxon signed-rank test). EA-MoDCs, WS-MoDCs, SR-MoDCs, and MI-MoDCs induced CD4+ T cell proliferation and a Th1-polarized immune response. The present study provides evidence that, although differences were initially observed between MoDCs exposed to filamentous fungi and MoDCs exposed to bacteria, a Th1 response was ultimately promoted by DCs regardless of the microbial extract tested. PMID:23720369

  3. TLR9-Dependent IL-23/IL-17 is Required for the Generation of Stachybotrys chartarum-induced Hypersensitivity Pneumonitis

    PubMed Central

    Bhan, Urvashi; Newstead, Michael J.; Zeng, Xianying; Podsaid, Amy; Goswami, Moloy; Ballinger, Megan N.; Kunkel, Steven L.; Standiford, Theodore J.

    2012-01-01

    Hypersensitivity pneumonitis (HP) is an inflammatory lung disease that develops following repeated exposure to inhaled particulate antigen. Stachybotrys chartarum (SC) is a dimorphic fungus that has been implicated in a number of respiratory illnesses, including HP (1). In this study we have developed a murine model of SC- induced HP that reproduces pathology observed in human HP and hypothesized that TLR9–mediated IL-23/IL-17 responses are required for the generation of granulomatous inflammation induced by inhaled SC. Mice that undergo i.p. sensitization and i.t. challenge with 106 SC spores developed granulomatous inflammation with multinucleate giant cells, accompanied by increased accumulation of T cells. SC sensitization and challenge resulted in robust pulmonary expression of IL-17 and IL-23. SC-mediated granulomatous inflammation required intact IL-23/IL-17 responses and required TLR9, as TLR9−/− mice displayed reduced IL-17 and IL-23 expression in whole lung associated with decreased accumulation of IL-17 expressing CD4+ and γδ T cells. As compared to SC-sensitized dendritic cells (DC) isolated from WT mice, DC isolated from TLR9−/− mice had a reduced ability to produce IL-23 in responses to SC. Moreover, shRNA knockdown of IL-23 in DC abolished IL-17 production from splenocytes in response to antigen challenge. Finally, the i.t. reconstitution of IL-23 in TLR9−/− mice recapitulated the immunopathology observed in WT mice. In conclusion, our studies suggest that TLR9 is critical for development of Th17-mediated granulomatous inflammation in the lung in response to SC. PMID:23180821

  4. TLR9-dependent IL-23/IL-17 is required for the generation of Stachybotrys chartarum-induced hypersensitivity pneumonitis.

    PubMed

    Bhan, Urvashi; Newstead, Michael J; Zeng, Xianying; Podsaid, Amy; Goswami, Moloy; Ballinger, Megan N; Kunkel, Steven L; Standiford, Theodore J

    2013-01-01

    Hypersensitivity pneumonitis (HP) is an inflammatory lung disease that develops after repeated exposure to inhaled particulate Ag. Stachybotrys chartarum is a dimorphic fungus that has been implicated in a number of respiratory illnesses, including HP. In this study, we have developed a murine model of S. chartarum-induced HP that reproduces pathology observed in human HP, and we have hypothesized that TLR9-mediated IL-23 and IL-17 responses are required for the generation of granulomatous inflammation induced by inhaled S. chartarum. Mice that undergo i.p. sensitization and intratracheal challenge with 10(6) S. chartarum spores developed granulomatous inflammation with multinucleate giant cells, accompanied by increased accumulation of T cells. S. chartarum sensitization and challenge resulted in robust pulmonary expression of IL-17 and IL-23. S. chartarum-mediated granulomatous inflammation required intact IL-23 or IL-17 responses and required TLR9, because TLR9(-/-) mice displayed reduced IL-17 and IL-23 expression in whole lung associated with decreased accumulation of IL-17 expressing CD4(+) and γδ T cells. Compared with S. chartarum-sensitized dendritic cells (DC) isolated from WT mice, DCs isolated from TLR9(-/-) mice had a reduced ability to produce IL-23 in responses to S. chartarum. Moreover, shRNA knockdown of IL-23 in DCs abolished IL-17 production from splenocytes in response to Ag challenge. Finally, the intratracheal reconstitution of IL-23 in TLR9(-/-) mice recapitulated the immunopathology observed in WT mice. In conclusion, our studies suggest that TLR9 is critical for the development of Th17-mediated granulomatous inflammation in the lung in response to S. chartarum.

  5. Finger cold-induced vasodilation of older Korean female divers, haenyeo: effects of chronic cold exposure and aging

    NASA Astrophysics Data System (ADS)

    Lee, Joo-Young; Park, Joonhee; Koh, Eunsook; Cha, Seongwon

    2017-07-01

    The aim of the present study was to evaluate the local cold tolerance of older Korean female divers, haenyeo ( N = 22) in terms of cold acclimatization and ageing. As control groups, older non-diving females ( N = 25) and young females from a rural area ( N = 15) and an urban area ( N = 51) participated in this study. To evaluate local cold tolerance, finger cold-induced vasodilation (CIVD) during finger immersion of 4 °C water was examined. As a result, older haenyeos showed greater minimum finger temperature and recovery finger temperature than older non-diving females ( P < 0.05), but similar responses in onset time, peak time, maximum finger temperature, frequency of CIVD, heart rate, blood pressure, and thermal and pain sensations as those of older non-diving females. Another novel finding was that young urban females showed more vulnerable responses to local cold in CIVD variables and subjective sensations when compared to older females, whereas young rural females had the most excellent cold tolerance in terms of maximum temperature and frequency of CIVD among the four groups ( P < 0.05). The present results imply that older haenyeos still retain cold acclimatized features on the periphery even though they changed their cotton diving suits to wet suits in the early 1980s. However, cardiovascular responses and subjective sensations to cold reflect aging effects. In addition, we suggest that young people who have been adapted to highly insulated clothing and indoor heating systems in winter should be distinguished from young people who were exposed to less modern conveniences when compared to the aged in terms of cold tolerance.

  6. Finger cold-induced vasodilation of older Korean female divers, haenyeo: effects of chronic cold exposure and aging

    NASA Astrophysics Data System (ADS)

    Lee, Joo-Young; Park, Joonhee; Koh, Eunsook; Cha, Seongwon

    2017-02-01

    The aim of the present study was to evaluate the local cold tolerance of older Korean female divers, haenyeo (N = 22) in terms of cold acclimatization and ageing. As control groups, older non-diving females (N = 25) and young females from a rural area (N = 15) and an urban area (N = 51) participated in this study. To evaluate local cold tolerance, finger cold-induced vasodilation (CIVD) during finger immersion of 4 °C water was examined. As a result, older haenyeos showed greater minimum finger temperature and recovery finger temperature than older non-diving females (P < 0.05), but similar responses in onset time, peak time, maximum finger temperature, frequency of CIVD, heart rate, blood pressure, and thermal and pain sensations as those of older non-diving females. Another novel finding was that young urban females showed more vulnerable responses to local cold in CIVD variables and subjective sensations when compared to older females, whereas young rural females had the most excellent cold tolerance in terms of maximum temperature and frequency of CIVD among the four groups (P < 0.05). The present results imply that older haenyeos still retain cold acclimatized features on the periphery even though they changed their cotton diving suits to wet suits in the early 1980s. However, cardiovascular responses and subjective sensations to cold reflect aging effects. In addition, we suggest that young people who have been adapted to highly insulated clothing and indoor heating systems in winter should be distinguished from young people who were exposed to less modern conveniences when compared to the aged in terms of cold tolerance.

  7. Intermixing in Cu/Ni multilayers induced by cold rolling

    NASA Astrophysics Data System (ADS)

    Wang, Z.; Perepezko, J. H.; Larson, D.; Reinhard, D.

    2015-04-01

    Repeated cold rolling was performed on multilayers of Cu60/Ni40 and Cu40/Ni60 foil arrays to study the details of driven atomic scale interfacial mixing. With increasing deformation, there is a significant layer refinement down to the nm level that leads to the formation of a solid solution phase from the elemental end members. Intriguingly, the composition of the solid solution is revealed by an oscillation in the composition profile across the multilayers, which is different from the smoothly varying profile due to thermally activated diffusion. During the reaction, Cu mixed into Ni preferentially compared to Ni mixing into Cu, which is also in contrast to the thermal diffusion behavior. This is confirmed by observations from X-ray diffraction, electron energy loss spectrum and atom probe tomography. The diffusion coefficient induced by cold rolling is estimated as 1.7 × 10-17 m2/s, which cannot be attributed to any thermal effect. The effective temperature due to the deformation induced mixing is estimated as 1093 K and an intrinsic diffusivity db, which quantifies the tendency towards equilibrium in the absence of thermal diffusion, is estimated as 6.38 × 10-18 m2/s. The fraction of the solid solution phase formed is illustrated by examining the layer thickness distribution and is described by using an error function representation. The evolution of mixing in the solid solution phase is described by a simplified sinusoid model, in which the amplitude decays with increased deformation level. The promoted diffusion coefficient could be related to the effective temperature concept, but the establishment of an oscillation in the composition profile is a characteristic behavior that develops due to deformation.

  8. Intermixing in Cu/Ni multilayers induced by cold rolling

    SciTech Connect

    Wang, Z.; Perepezko, J. H.; Larson, D.; Reinhard, D.

    2015-04-28

    Repeated cold rolling was performed on multilayers of Cu60/Ni40 and Cu40/Ni60 foil arrays to study the details of driven atomic scale interfacial mixing. With increasing deformation, there is a significant layer refinement down to the nm level that leads to the formation of a solid solution phase from the elemental end members. Intriguingly, the composition of the solid solution is revealed by an oscillation in the composition profile across the multilayers, which is different from the smoothly varying profile due to thermally activated diffusion. During the reaction, Cu mixed into Ni preferentially compared to Ni mixing into Cu, which is also in contrast to the thermal diffusion behavior. This is confirmed by observations from X-ray diffraction, electron energy loss spectrum and atom probe tomography. The diffusion coefficient induced by cold rolling is estimated as 1.7 × 10{sup −17} m{sup 2}/s, which cannot be attributed to any thermal effect. The effective temperature due to the deformation induced mixing is estimated as 1093 K and an intrinsic diffusivity d{sub b}, which quantifies the tendency towards equilibrium in the absence of thermal diffusion, is estimated as 6.38 × 10{sup −18} m{sup 2}/s. The fraction of the solid solution phase formed is illustrated by examining the layer thickness distribution and is described by using an error function representation. The evolution of mixing in the solid solution phase is described by a simplified sinusoid model, in which the amplitude decays with increased deformation level. The promoted diffusion coefficient could be related to the effective temperature concept, but the establishment of an oscillation in the composition profile is a characteristic behavior that develops due to deformation.

  9. Reversible cold-induced abnormalities in myocardial perfusion and function in systemic sclerosis

    SciTech Connect

    Alexander, E.L.; Firestein, G.S.; Weiss, J.L.; Heuser, R.R.; Leitl, G.; Wagner, H.N. Jr.; Brinker, J.A.; Ciuffo, A.A.; Becker, L.C.

    1986-11-01

    The effects of peripheral cold exposure on myocardial perfusion and function were studied in 13 patients with scleroderma without clinically evident myocardial disease. Ten patients had at least one transient, cold-induced, myocardial perfusion defect visualized by thallium-201 scintigraphy, and 12 had reversible, cold-induced, segmental left ventricular hypokinesis by two-dimensional echocardiography. The 10 patients with transient perfusion defects all had anatomically corresponding ventricular wall motion abnormalities. No one in either of two control groups (9 normal volunteers and 7 patients with chest pain and normal coronary arteriograms) had cold-induced abnormalities. This study is the first to show the simultaneous occurrence of cold-induced abnormalities in myocardial perfusion and function in patients with scleroderma. The results suggest that cold exposure in such patients may elicit transient reflex coronary vasoconstriction resulting in reversible myocardial ischemia and dysfunction. Chronic recurrent episodes of coronary spasm may lead to focal myocardial fibrosis.

  10. Acute experimental endotoxemia induces visceral hypersensitivity and altered pain evaluation in healthy humans.

    PubMed

    Benson, Sven; Kattoor, Joswin; Wegner, Alexander; Hammes, Florian; Reidick, Daniel; Grigoleit, Jan-Sebastian; Engler, Harald; Oberbeck, Reiner; Schedlowski, Manfred; Elsenbruch, Sigrid

    2012-04-01

    Growing evidence suggests that systemic immune activation plays a role in the pathophysiology of pain in functional bowel disorders. By implementing a randomized crossover study with an injection of endotoxin or saline, we aimed to test the hypothesis that endotoxin-induced systemic inflammation increases visceral pain sensitivity in humans. Eleven healthy men (mean ± standard error of the mean age 26.6 ± 1.1 years) received an intravenous injection of either lipopolysaccharide (LPS; 0.4 ng/kg) or saline on 2 otherwise identical study days. Blood samples were collected 15 min before and 1, 2, 3, 4, and 6h after injection to characterize changes in immune parameters including proinflammatory cytokines. Rectal sensory and pain thresholds and subjective pain ratings were assessed with barostat rectal distensions 2h after injection. LPS administration induced an acute inflammatory response indicated by transient increases in tumor necrosis factor alpha, interleukin 6, and body temperature (all P<.001). The LPS-induced immune activation increased sensitivity to rectal distensions as reflected by significantly decreased visceral sensory and pain thresholds (both P<.05) compared to saline control. Visceral stimuli were rated as more unpleasant (P<.05) and inducing increased urge to defecate (P<.01). Pain thresholds correlated with interleukin 6 at +1h (r=0.60, P<.05) and +3h (r=0.67, P<.05) within the LPS condition. This report is novel in that it demonstrates that a transient systemic immune activation results in decreased visceral sensory and pain thresholds and altered subjective pain ratings. Our results support the relevance of inflammatory processes in the pathophysiology of visceral hyperalgesia and underscore the need for studies to further elucidate immune-to-brain communication pathways in gastrointestinal disorders. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  11. Adrenal hypersensitivity precedes chronic hypercorticism in streptozotocin-induced diabetes mice.

    PubMed

    Revsin, Yanina; van Wijk, Diane; Saravia, Flavia E; Oitzl, Melly S; De Nicola, Alejandro F; de Kloet, E Ronald

    2008-07-01

    Previous studies have demonstrated that type 1 diabetes is characterized by hypercorticism and lack of periodicity in adrenal hormone secretion. In the present study, we tested the hypothesis that hypercorticism is initiated by an enhanced release of ACTH leading subsequently to adrenocortical growth and increased output of adrenocortical hormones. To test this hypothesis, we used the streptozotocin (STZ)-induced diabetes mouse model and measured hypothalamic-pituitary-adrenal axis activity at different time points. The results showed that the expected rise in blood glucose levels induced by STZ treatment preceded the surge in corticosterone secretion, which took place 1 d after diabetes onset. Surprisingly, circulating ACTH levels were not increased and even below control levels until 1 d after diabetes onset and remained low until d 11 during hypercorticism. In response to ACTH (but not vasopressin), cultures of adrenal gland cells from 11-d diabetic mice secreted higher amounts of corticosterone than control cells. Real-time quantitative PCR revealed increased expression of melanocortin 2 and melanocortin 5 receptors in the adrenal glands at 2 and 11 d of STZ-induced diabetes. AVP mRNA expression in the paraventricular nucleus of the hypothalamus was increased, whereas hippocampal MR mRNA was decreased in 11-d diabetic animals. GR and CRH mRNAs remained unchanged in hippocampus and paraventricular nucleus of diabetic mice at all time points studied. These results suggest that sensitization of the adrenal glands to ACTH rather than an increase in circulating ACTH level is the primary event leading to hypercorticism in the STZ-induced diabetes mouse model.

  12. Adaptation to cold swim stress-induced hypothermia: Absence of Pavlovian conditional tolerance.

    PubMed

    Kokkinidis, L

    1986-01-01

    Mice subjected to cold swim stress developed pronounced hypothermia. Exposure to warm water swim, however, had little or no effect on body temperature. After repeated exposure to cold swim, the stress-induced hypothermia was attenuated. The finding that cold swim resulted in hypothermia, whereas warm swim had no effect in this respect, provided a useful experimental design by which to assess the role of conditioning factors in the adaptation to the thermic effects of cold swim. In two subsequent experiments, mice received cold swim either in a familiar environment or in a novel environment. Adaptation to the thermic effects of cold swim was observed when mice were tested in the distinctive environment, regardless of the environmental cues previously paired with repeated exposure to the cold swim stress. These findings suggest that contextual cues were not of primary importance in the development of tolerance to the thermic effects of cold swim stress.

  13. Exercise-induced hypersensitivity syndromes in recreational and competitive athletes: a PRACTALL consensus report (what the general practitioner should know about sports and allergy).

    PubMed

    Schwartz, L B; Delgado, L; Craig, T; Bonini, S; Carlsen, K H; Casale, T B; Del Giacco, S; Drobnic, F; van Wijk, R G; Ferrer, M; Haahtela, T; Henderson, W R; Israel, E; Lötvall, J; Moreira, A; Papadopoulos, N G; Randolph, C C; Romano, A; Weiler, J M

    2008-08-01

    Exercise-induced (EI) hypersensitivity disorders are significant problems for both recreational and competitive athletes. These include EI-asthma, EI-bronchoconstriction, EI-rhinitis, EI-anaphylaxis and EI-urticaria. A group of experts from the European Academy of Allergology and Clinical Immunology and the American Academy of Allergy Asthma and Immunology met to discuss the pathogenesis of these disorders and how to diagnose and treat them, and then to develop a consensus report. Key words (exercise with asthma, bronchoconstriction, rhinitis, urticaria or anaphylaxis) were used to search Medline, the Cochrane database and related websites through February 2008 to obtain pertinent information which, along with personal reference databases and institutional experience with these disorders, were used to develop this report. The goal is to provide physicians with guidance in the diagnosis, understanding and management of EI-hypersensitivity disorders to enable their patients to safely return to exercise-related activities.

  14. PDIA3 gene induces visceral hypersensitivity in rats with irritable bowel syndrome through the dendritic cell-mediated activation of T cells

    PubMed Central

    Zhuang, Zhaomeng; Zhang, Lu; Wang, Xiaoteng; Tao, Liyuan

    2016-01-01

    This study investigated the mechanism of protein disulfide-isomerase A3 (PDIA3)-induced visceral hypersensitivity in irritable bowel syndrome (IBS). Rats were treated with saline (control), acetic acid and restraint stress (IBS model), empty vector (RNAi control) and PDIA3-RNAi vector (PDIA3-RNAi). Mesenteric lymph node DCs (MLNDCs) and splenic CD4+/CD8+ T cells were isolated for co-cultivation. Compared with control, MLNDCs co-cultured with CD4+ or CD8+ T cells showed an increased ability to promote T cell proliferation and produced more IL-4 or IL-9 secretion. Compared with the RNAi control, MLNDCs from the PDIA3 knockdown models were less effective in promoting the proliferation of CD4+/CD8+ T cells. It is concluded that PDIA3 plays an important role in the development of IBS through the DC-mediated activation of T cells, resulting in degranulation of MCs and visceral hypersensitivity. PMID:27896022

  15. Ester Hydrolysis Differentially Reduces Aconitine-Induced Anti-hypersensitivity and Acute Neurotoxicity: Involvement of Spinal Microglial Dynorphin Expression and Implications for Aconitum Processing

    PubMed Central

    Li, Teng-Fei; Gong, Nian; Wang, Yong-Xiang

    2016-01-01

    Aconitines, including bulleyaconitine A, probably the most bioactive and abundant alkaloids in Aconitum plant, are a group of diester C19-diterpenoid alkaloids with one acetylester group attached to C8 of the diterpenoid skeleton and one benzoylester group to C14. Hydrolysis of both groups is involved in the processing of Aconitum, a traditional Chinese medicinal approach. We recently demonstrated that bulleyaconitine A produced anti-hypersensitivity, which was mediated by stimulation of spinal microglial dynorphin A expression. This study aimed to elucidate whether the acetylester and benzoylester groups are involved in aconitine-induced dynorphin A expression, anti-hypersensitivity, neurotoxicity in neuropathic rats. Intrathecal administration of aconitine and benzoylaconine (but not aconine) attenuated mechanical allodynia and heat hyperalgesia, with normalized ED50 values of 35 pmol and 3.6 nmol, respectively. Aconitine and benzoylaconine anti-allodynia was completely blocked by the microglial inhibitor, dynorphin A antiserum, and κ-opioid receptor antagonist. Aconitine and benzoylaconine, but not aconine, stimulated dynorphin A expression in cultured primary spinal microglia, with EC50 values of 32 nM and 3 μM, respectively. Intrathecal aconitine, benzoylaconine and aconine induced flaccid paralysis and death, with normalized TD50 values of 0.5 nmol, 0.2 μmol, and 1.6 μmol, respectively. The TD50/ED50 ratios of aconitine and benzolyaconine were 14:1 and 56:1. Our results suggest that both the C8-acetyl and C14-benzoyl groups are essential for aconitine to stimulate spinal microglial dynorphin A expression and subsequent anti-hypersensitivity, which can be separated from neurotoxicity, because both benzoylaconine and aconine differentially produced anti-hypersensitivity and neurotoxicity due to their different stimulatory ability on dynorphin A expression. Our results support the scientific rationale for Aconitum processing, but caution should be taken to

  16. Inducing Cold-Sensitivity in the Frigophilic Fly Drosophila montana by RNAi.

    PubMed

    Vigoder, Felipe M; Parker, Darren J; Cook, Nicola; Tournière, Océane; Sneddon, Tanya; Ritchie, Michael G

    2016-01-01

    Cold acclimation is a critical physiological adaptation for coping with seasonal cold. By increasing their cold tolerance individuals can remain active for longer at the onset of winter and can recover more quickly from a cold shock. In insects, despite many physiological studies, little is known about the genetic basis of cold acclimation. Recently, transcriptomic analyses in Drosophila virilis and D. montana revealed candidate genes for cold acclimation by identifying genes upregulated during exposure to cold. Here, we test the role of myo-inositol-1-phosphate synthase (Inos), in cold tolerance in D. montana using an RNAi approach. D. montana has a circumpolar distribution and overwinters as an adult in northern latitudes with extreme cold. We assessed cold tolerance of dsRNA knock-down flies using two metrics: chill-coma recovery time (CCRT) and mortality rate after cold acclimation. Injection of dsRNAInos did not alter CCRT, either overall or in interaction with the cold treatment, however it did induced cold-specific mortality, with high levels of mortality observed in injected flies acclimated at 5°C but not at 19°C. Overall, injection with dsRNAInos induced a temperature-sensitive mortality rate of over 60% in this normally cold-tolerant species. qPCR analysis confirmed that dsRNA injection successfully reduced gene expression of Inos. Thus, our results demonstrate the involvement of Inos in increasing cold tolerance in D. montana. The potential mechanisms involved by which Inos increases cold tolerance are also discussed.

  17. Inducing Cold-Sensitivity in the Frigophilic Fly Drosophila montana by RNAi

    PubMed Central

    Cook, Nicola; Tournière, Océane; Sneddon, Tanya; Ritchie, Michael G.

    2016-01-01

    Cold acclimation is a critical physiological adaptation for coping with seasonal cold. By increasing their cold tolerance individuals can remain active for longer at the onset of winter and can recover more quickly from a cold shock. In insects, despite many physiological studies, little is known about the genetic basis of cold acclimation. Recently, transcriptomic analyses in Drosophila virilis and D. montana revealed candidate genes for cold acclimation by identifying genes upregulated during exposure to cold. Here, we test the role of myo-inositol-1-phosphate synthase (Inos), in cold tolerance in D. montana using an RNAi approach. D. montana has a circumpolar distribution and overwinters as an adult in northern latitudes with extreme cold. We assessed cold tolerance of dsRNA knock-down flies using two metrics: chill-coma recovery time (CCRT) and mortality rate after cold acclimation. Injection of dsRNAInos did not alter CCRT, either overall or in interaction with the cold treatment, however it did induced cold-specific mortality, with high levels of mortality observed in injected flies acclimated at 5°C but not at 19°C. Overall, injection with dsRNAInos induced a temperature-sensitive mortality rate of over 60% in this normally cold-tolerant species. qPCR analysis confirmed that dsRNA injection successfully reduced gene expression of Inos. Thus, our results demonstrate the involvement of Inos in increasing cold tolerance in D. montana. The potential mechanisms involved by which Inos increases cold tolerance are also discussed. PMID:27832122

  18. Ultra-freeze induced cold contact wheals during cryosurgery: an uncommon subset of acquired cold contact urticaria.

    PubMed

    Giménez-Arnau, Ana; Ali Al-Haqan, Eman; Sacrista, Marc; Curto, Laia; Pujol, Ramon M

    2013-01-01

    Cryosurgery is a safe and effective therapeutic tool for a wide variety of cutaneous and mucocutaneous disorders. Side-effects include transient erythema and oedema. A series of three patients presenting localized contact wheals minutes after contact with liquid nitrogen in the absence of clinical manifestations of cold urticaria is presented. Specific cold diagnostic provocation tests with liquid nitrogen challenge test, ice cube test and Tempt-test® were performed. The three patients showed an immediate wheal after cold contact with liquid nitrogen. The ice cube test, the temperature thresholds and the critical stimulation thresholds at 4◦C assessed with the Tempt-test 3.1® were negative. The induced wheals showed pathological features of urticaria. Eight patients suffering from acquired cold urticarial developed also liquid nitrogen induced wheals but none of the healthy controls. A peculiar subset of cold urticaria secondary to exposure to ultra-freeze temperatures developing in patients treated with cryotherapy is reported. The concept of “ultra-freeze urticaria” is proposed.

  19. Exposure to cold impairs interferon-induced antiviral defense.

    PubMed

    Boonarkart, Chompunuch; Suptawiwat, Ornpreya; Sakorn, Kittima; Puthavathana, Pilaipan; Auewarakul, Prasert

    2017-08-01

    It is commonly believed that exposure to low temperature increases susceptibility to viral infection in the human respiratory tract, but a molecular mechanism supporting this belief has yet to be discovered. In this study, we investigated the effect of low temperature on viral infection and innate defense in cell lines from the human respiratory tract and found that interferon-induced antiviral responses were impaired at low temperatures. Cells maintained at 25°C and 33°C expressed lower levels of myxovirus resistance protein 1 (MxA) and 2'5'-oligoadenylate synthetase 1 (OAS1) mRNAs when compared to cells maintained at 37°C after infection by seasonal influenza viruses. Exogenous β-interferon treatment reduced the viral replication at 37°C, but not at 25°C. Our results suggest that the impairment of interferon-induced antiviral responses by low temperature is one of several mechanisms that could explain an increase in host susceptibility to respiratory viruses after exposure to cold temperature.

  20. Allergen endotoxins induce T-cell-dependent and non-IgE-mediated nasal hypersensitivity in mice.

    PubMed

    Iwasaki, Naruhito; Matsushita, Kazufumi; Fukuoka, Ayumi; Nakahira, Masakiyo; Matsumoto, Makoto; Akasaki, Shoko; Yasuda, Koubun; Shimizu, Takeshi; Yoshimoto, Tomohiro

    2017-01-01

    Allergen-mediated cross-linking of IgE on mast cells/basophils is a well-recognized trigger for type 1 allergic diseases such as allergic rhinitis (AR). However, allergens may not be the sole trigger for AR, and several allergic-like reactions are induced by non-IgE-mediated mechanisms. We sought to describe a novel non-IgE-mediated, endotoxin-triggered nasal type-1-hypersensitivity-like reaction in mice. To investigate whether endotoxin affects sneezing responses, mice were intraperitoneally immunized with ovalbumin (OVA), then nasally challenged with endotoxin-free or endotoxin-containing OVA. To investigate the role of T cells and mechanisms of the endotoxin-induced response, mice were adoptively transferred with in vitro-differentiated OVA-specific TH2 cells, then nasally challenged with endotoxin-free or endotoxin-containing OVA. Endotoxin-containing, but not endotoxin-free, OVA elicited sneezing responses in mice independent from IgE-mediated signaling. OVA-specific TH2 cell adoptive transfer to mice demonstrated that local activation of antigen-specific TH2 cells was required for the response. The Toll-like receptor 4-myeloid differentiation factor 88 signaling pathway was indispensable for endotoxin-containing OVA-elicited rhinitis. In addition, LPS directly triggered sneezing responses in OVA-specific TH2-transferred and nasally endotoxin-free OVA-primed mice. Although antihistamines suppressed sneezing responses, mast-cell/basophil-depleted mice had normal sneezing responses to endotoxin-containing OVA. Clodronate treatment abrogated endotoxin-containing OVA-elicited rhinitis, suggesting the involvement of monocytes/macrophages in this response. Antigen-specific nasal activation of CD4(+) T cells followed by endotoxin exposure induces mast cell/basophil-independent histamine release in the nose that elicits sneezing responses. Thus, environmental or nasal residential bacteria may exacerbate AR symptoms. In addition, this novel phenomenon might explain

  1. Dopaminergic inhibition by G9a/Glp complex on tyrosine hydroxylase in nerve injury-induced hypersensitivity

    PubMed Central

    Wang, Nan; Shen, Xiaofeng; Bao, Senzhu; Feng, Shan-Wu; Wang, Wei; Liu, Yusheng; Wang, Yiquan; Wang, Xian; Guo, Xirong; Shen, Rong; Wu, Haibo; Lei, Liming; Wang, Fuzhou

    2016-01-01

    The neural balance between facilitation and inhibition determines the final tendency of central sensitization. Nerve injury-induced hypersensitivity was considered as the results from the enhanced ascending facilitation and the diminished descending inhibition. The role of dopaminergic transmission in the descending inhibition has been well documented, but its underlying molecular mechanisms are unclear. Previous studies demonstrated that the lysine dimethyltransferase G9a/G9a-like protein (Glp) complex plays a critical role in cocaine-induced central plasticity, and given cocaine’s role in the nerve system is relied on its function on dopamine system, we herein proposed that the reduced inhibition of dopaminergic transmission was from the downregulation of tyrosine hydroxylase expression by G9a/Glp complex through methylating its gene Th. After approval by the Animal Care and Use Committee, C57BL/6 mice were used for pain behavior using von Frey after spared nerve injury, and Th CpG islands methylation was measured using bisulfite sequencing at different nerve areas. The inhibitor of G9a/Glp, BIX 01294, was administered intraventricularly daily with bolus injection. The protein levels of G9a, Glp, and tyrosine hydroxylase were measured with immunoblotting. Dopamine levels were detected using high-performance liquid chromatography. The expression of G9a but not Glp was upregulated in ventral tegmental area at post-injury day 4 till day 49 (the last day of the behavioral test). Correspondingly, the Th CpG methylation is increased, but the tyrosine hydroxylase expression was downregulated and the dopamine level was decreased. After the intracerebroventriclar injection of BIX 01294 since the post-injury days 7 and 14 for consecutive three days, three weeks, and six weeks, the expression of tyrosine hydroxylase was upregulated with a significant decrease in Th methylation and increase in dopamine level. Moreover, the pain after G9a/Glp inhibitor was attenuated

  2. Minocycline-induced hypersensitivity syndrome presenting with meningitis and brain edema: a case report

    PubMed Central

    Lefebvre, Nicolas; Forestier, Emmanuel; Farhi, David; Mahsa, Mohseni Zadeh; Remy, Véronique; Lesens, Olivier; Christmann, Daniel; Hansmann, Yves

    2007-01-01

    Background Hypersentivity Syndrome (HS) may be a life-threatening condition. It frequently presents with fever, rash, eosinophilia and systemic manifestations. Mortality can be as high as 10% and is primarily due to hepatic failure. We describe what we believe to be the first case of minocycline-induced HS with accompanying lymphocytic meningitis and cerebral edema reported in the literature. Case presentation A 31-year-old HIV-positive female of African origin presented with acute fever, lymphocytic meningitis, brain edema, rash, eosinophilia, and cytolytic hepatitis. She had been started on minocycline for inflammatory acne 21 days prior to the onset of symptoms. HS was diagnosed clinically and after exclusion of infectious causes. Minocycline was withdrawn and steroids were administered from the second day after presentation because of the severity of the symptoms. All signs resolved by the seventh day and steroids were tailed off over a period of 8 months. Conclusion Clinicians should maintain a high index of suspicion for serious adverse reactions to minocycline including lymphocytic meningitis and cerebral edema among HIV-positive patients, especially if they are of African origin. Safer alternatives should be considered for treatment of acne vulgaris. Early recognition of the symptoms and prompt withdrawal of the drug are important to improve the outcome. PMID:17511865

  3. Effects of Schisandra chinensis extracts on cough and pulmonary inflammation in a cough hypersensitivity guinea pig model induced by cigarette smoke exposure.

    PubMed

    Zhong, Shan; Nie, Yi-chu; Gan, Zhen-yong; Liu, Xiao-dong; Fang, Zhang-fu; Zhong, Bo-nian; Tian, Jin; Huang, Chu-qin; Lai, Ke-fang; Zhong, Nan-shan

    2015-05-13

    Schisandra chinensis (S. chinensis) is a traditional Chinese medicine commonly used in prescription medications for the treatment of chronic cough. However, the material basis of S. chinensis in relieving cough has not been completely elucidated yet. This study established a guinea pig model of cough hypersensitivity induced by 14 days of cigarette smoke (CS) exposure, to evaluate the antitussive, antioxidant, and anti-inflammatory effects of three S. chinensis extracts. And then the function of four lignans in reducing expression of TRPV1 and TRPA1 was examined using A549 cells induced by cigarette smoke extract (CSE). The results demonstrated that both ethanol extract (EE) and ethanol-water extract (EWE) of S. chinensis, but not water extract (WE), significantly reduced the cough frequency enhanced by 0.4M citric acid solution in these cough hypersensitivity guinea pigs. Meanwhile, pretreatment with EE and EWE both significantly attenuated the CS-induced increase in infiltration of pulmonary neutrophils and total inflammatory cells, as well as pulmonary MDA, TNF-α, and IL-8, while remarkably increased activities of pulmonary SOD and GSH. According to H&E and immunofluorescence staining assays, airway epithelium hyperplasia, smooth muscle thickening, inflammatory cells infiltration, as well as expression of TRPV1 and TRPA1, were significantly attenuated in animals pretreatment with 1g/kg EE. Moreover, four lignans of EE, including schizandrin, schisantherin A, deoxyschizandrin and γ-schisandrin, significantly inhibited CSE-induced expression of TRPV1, TRPA1 and NOS3, as well as NO release in A549 cells. In conclusion, S. chinensis reduces cough frequency and pulmonary inflammation in the CS-induced cough hypersensitivity guinea pigs. Lignans may be the active components. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Visceral hypersensitivity induced by activation of transient receptor potential vanilloid type 1 is mediated through the serotonin pathway in rat colon.

    PubMed

    Qin, Hong-yan; Luo, Jia-lie; Qi, Sheng-da; Xu, Hong-xi; Sung, Joseph J Y; Bian, Zhao-xiang

    2010-11-25

    This study aimed to clarify the relationship between TRPV1 activation-induced visceral pain and the serotonin pathway in the colon of rats. The effects of para-chlorophenylalanine (pCPA) on visceral pain threshold pressure were assessed in capsaicin -induced visceral pain of rats. The expression of TRPV1 in the colon was examined by immunohistochemistry and Western blot analysis, and TRPV1 excitability in dorsal root ganglion (DRG) neurons was examined by whole-cell patch-clamp recording in pCPA-treated rats. Calcineurin and Ca(2+)-calmodulin-dependent kinase II (CaMKII), the important proteins in maintaining TRPV1 function in the colon, were also tested by Western blot analysis and immunofluorescence staining. Results showed that pCPA significantly increased the capsaicin-induced visceral pain threshold by 2.3-fold, and the enhanced visceral pain threshold corresponded with decreased 5-HT content (58% depleted) and enterochromaffin cell number (80% reduced). The reduced excitability of TRPV1 in DRG neurons, instead of changed TRPV1 expression, is responsible for the enhanced visceral pain threshold in 5-HT-depleted rats, and the mechanism may be related to the decreased expression of pCaMKII. These results indicate that visceral hypersensitivity induced by TRPV1 activation is modulated through 5-HT pathways and the attenuated function of TRPV1 and decreased protein expression of pCaMKII may play an important role in capsaicin-induced TRPV1 desensitization under 5-HT-depleted condition. The important role of TRPV1 and 5-HT in generating and maintaining visceral hypersensitivity may provide insights for the treatment of visceral hypersensitivity. Copyright © 2010 Elsevier B.V. All rights reserved.

  5. Isolation and functional characterization of cold-regulated promoters, by digitally identifying peach fruit cold-induced genes from a large EST dataset

    PubMed Central

    Tittarelli, Andrés; Santiago, Margarita; Morales, Andrea; Meisel, Lee A; Silva, Herman

    2009-01-01

    Background Cold acclimation is the process by which plants adapt to the low, non freezing temperatures that naturally occur during late autumn or early winter. This process enables the plants to resist the freezing temperatures of winter. Temperatures similar to those associated with cold acclimation are also used by the fruit industry to delay fruit ripening in peaches. However, peaches that are subjected to long periods of cold storage may develop chilling injury symptoms (woolliness and internal breakdown). In order to better understand the relationship between cold acclimation and chilling injury in peaches, we isolated and functionally characterized cold-regulated promoters from cold-inducible genes identified by digitally analyzing a large EST dataset. Results Digital expression analyses of EST datasets, revealed 164 cold-induced peach genes, several of which show similarities to genes associated with cold acclimation and cold stress responses. The promoters of three of these cold-inducible genes (Ppbec1, Ppxero2 and Pptha1) were fused to the GUS reporter gene and characterized for cold-inducibility using both transient transformation assays in peach fruits (in fruta) and stable transformation in Arabidopsis thaliana. These assays demonstrate that the promoter Pptha1 is not cold-inducible, whereas the Ppbec1 and Ppxero2 promoter constructs are cold-inducible. Conclusion This work demonstrates that during cold storage, peach fruits differentially express genes that are associated with cold acclimation. Functional characterization of these promoters in transient transformation assays in fruta as well as stable transformation in Arabidopsis, demonstrate that the isolated Ppbec1 and Ppxero2 promoters are cold-inducible promoters, whereas the isolated Pptha1 promoter is not cold-inducible. Additionally, the cold-inducible activity of the Ppbec1 and Ppxero2 promoters suggest that there is a conserved heterologous cold-inducible regulation of these promoters in

  6. PI3-kinase/Akt pathway-regulated membrane insertion of acid-sensing ion channel 1a underlies BDNF-induced pain hypersensitivity.

    PubMed

    Duan, Bo; Liu, Di-Shi; Huang, Yu; Zeng, Wei-Zheng; Wang, Xiang; Yu, Hui; Zhu, Michael X; Chen, Zhe-Yu; Xu, Tian-Le

    2012-05-02

    Central neural plasticity plays a key role in pain hypersensitivity. This process is modulated by brain-derived neurotrophic factor (BDNF) and also involves the type 1a acid-sensing ion channel (ASIC1a). However, the interactions between the BDNF receptor, tropomyosin-related kinase B (TrkB), and ASIC1a are unclear. Here, we show that deletion of ASIC1 gene suppressed the sustained mechanical hyperalgesia induced by intrathecal BDNF application in mice. In both rat spinal dorsal horn neurons and heterologous cell cultures, the BDNF/TrkB pathway enhanced ASIC1a currents via phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) cascade and phosphorylation of cytoplasmic residue Ser-25 of ASIC1a, resulting in enhanced forward trafficking and increased surface expression. Moreover, in both rats and mice, this enhanced ASIC1a activity was required for BDNF-mediated hypersensitivity of spinal dorsal horn nociceptive neurons and central mechanical hyperalgesia, a process that was abolished by intrathecal application of a peptide representing the N-terminal region of ASIC1a encompassing Ser-25. Thus, our results reveal a novel mechanism underlying central sensitization and pain hypersensitivity, and reinforce the critical role of ASIC1a channels in these processes.

  7. Cold rolling induced alloying behaviors in metallic multilayers

    NASA Astrophysics Data System (ADS)

    Wang, Zhe

    Phase transformation and atomic scale intermixing induced by deformation are important and fundamental issues in the mechanical alloying processes. Repeated cold rolling and folding experiments were performed on the metallic multilayers in order to study the deformation driven behaviors. Various binary systems such as isomorphous, eutectic and thermodynamically immiscible systems were studied. Moreover, monometallic Pd, Pt and Fe were selected in order to study the deformation driven recrystallization behavior. In Cu/Ni multilayers, the composition of the solid solution is revealed by an oscillation in the composition profile across the multilayers, which is different from the smoothly varying profile due to thermally activated diffusion. During the reaction, Cu mixed into Ni preferentially compared to Ni mixing into Cu, which is also in contrast to the thermal diffusion behavior. During the cold rolling of multilayers of Ni and V, deformation induces phase transformation and an interfacial mixing with suppression of nucleation of intermetallic phases. The results also demonstrate that between pure Ni and V layers a metastable fcc solid solution phase forms in Ni70V30, a metastable bcc solid solution phase forms in Ni30V70 and metastable fcc and bcc solid solution phases form in Ni57V43. Compared to the stored energy due to dislocation and interfaces, the excess chemical free energy from the interfacial mixing is the largest portion of total stored energy from deformation, which represents a form of mechanochemical transduction. The difference in the intermixing behaviors between Cu/Ni and Ni/V systems is due to that the systems have different heat of mixing and interface characters. Deformation of Cu/Fe multilayers yields a smooth and monotonic variation in the composition profile. From the local composition consumption it is revealed that that Fe mixes into Cu preferentially than Cu mixing into Fe. The room temperature deformation driven recrystallization was

  8. Nitric oxide and reactive oxygen species do not elicit hypersensitive cell death but induce apoptosis in the adjacent cells during the defense response of oat.

    PubMed

    Tada, Yasuomi; Mori, Tomoyo; Shinogi, Takeshi; Yao, Nan; Takahashi, Satsuki; Betsuyaku, Shigeyuki; Sakamoto, Masaru; Park, Pyoyun; Nakayashiki, Hitoshi; Tosa, Yukio; Mayama, Shigeyuki

    2004-03-01

    Nitric oxide (NO) acts as a signaling molecule in many cellular responses in plants and animals. Oat plants (Avena sativa L.) evoke the hypersensitive response (HR), which shares morphological and biochemical features with mammalian apoptosis, such as DNA laddering and heterochromatin condensation, in response to the avirulent crown rust fungus (Puccinia coronata f. sp. avenae). We examined the role of NO and reactive oxygen species (ROS) in the initiation of hypersensitive cell death, which is induced by direct contact with the pathogen, and apoptotic cell death in the adjacent cells. Cytofluorimetric analysis using the fluorescent NO probe DAF and the H2O2 probe DCF demonstrated that NO and H2O2 were generated simultaneously in primary leaves at an early stage of the defense response. The NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) markedly enhanced H2O2 accumulation detected by 3,3-diaminobenzidine staining and DCF, whereas treatment with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) strongly suppressed it. Superoxide dismutase (SOD) increased NO accumulation, suggesting that endogenous NO may modulate the level of H2O2 by interacting with O2- in the HR lesion. Cytological observation showed that administration of cPTIO, SNAP, or SOD had no effect on elicitation of hypersensitive cell death, but clearly reduced heterochromatin condensation in the nearby cells and DNA laddering. These findings indicate that NO and ROS are not essential mediators for the initiation of hypersensitive cell death. However, NO and O2- but not H2O2 are required for the onset of apoptotic cell death in the adjacent cells, where excess NO may exert its anti-apoptotic function by regulating cellular redox state.

  9. Disruption of δ-opioid receptor phosphorylation at threonine 161 attenuates morphine tolerance in rats with CFA-induced inflammatory hypersensitivity.

    PubMed

    Chen, Hai-Jing; Xie, Wei-Yan; Hu, Fang; Zhang, Ying; Wang, Jun; Wang, Yun

    2012-04-01

    Our previous study identified Threonine 161 (Thr-161), located in the second intracellular loop of the δ-opioid receptor (DOR), as the only consensus phosphorylation site for cyclin-dependent kinase 5 (Cdk5). The aim of this study was to assess the function of DOR phosphorylation by Cdk5 in complete Freund's adjuvant (CFA)-induced inflammatory pain and morphine tolerance. Dorsal root ganglion (DRG) neurons of rats with CFA-induced inflammatory pain were acutely dissociated and the biotinylation method was used to explore the membrane localization of phosphorylated DOR at Thr-161 (pThr-161-DOR), and paw withdrawal latency was measured after intrathecal delivery of drugs or Tat-peptide, using a radiant heat stimulator in rats with CFA-induced inflammatory pain. Both the total amount and the surface localization of pThr-161-DOR were significantly enhanced in the ipsilateral DRG following CFA injection. Intrathecal delivery of the engineered Tat fusion-interefering peptide corresponding to the second intracellular loop of DOR (Tat-DOR-2L) increased inflammatory hypersensitivity, and inhibited DOR- but not µ-opioid receptor-mediated spinal analgesia in CFA-treated rats. However, intrathecal delivery of Tat-DOR-2L postponed morphine antinociceptive tolerance in rats with CFA-induced inflammatory pain. Phosphorylation of DOR at Thr-161 by Cdk5 attenuates hypersensitivity and potentiates morphine tolerance in rats with CFA-induced inflammatory pain, while disruption of the phosphorylation of DOR at Thr-161 attenuates morphine tolerance.

  10. Influence of different types of contact hypersensitivity on imiquimod-induced psoriasis-like inflammation in mice.

    PubMed

    Bai, Shuang; Zhang, Zhenying; Hou, Suchun; Liu, Xiaoming

    2016-07-01

    It is currently believed that psoriasis and allergic contact dermatitis (ACD) are different diseases; however, they share clinical similarities. The involvement of T helper 17 (Th17) cells in these disorders provides a novel opportunity to investigate the relationship between them. The present study aimed to determine whether the same or overlapping inflammatory pathways are involved in the two diseases, and the influence of different types of ACD on psoriasis. Compound mouse models of Th1 or Th2‑type contact hypersensitivity (CHS) combined with imiquimod (IMQ)‑induced psoriasis‑like inflammation were established, in order to mimic the characteristics of ACD and psoriasis. Histopathology, immunohistochemistry and cytokine detection in blood serum and tissues were used to compare the differences between the mice treated with IMQ alone or IMQ combined with Th1 and Th2‑type CHS. As compared with the IMQ‑treated mice or IMQ-treated Th1‑type CHS mice, the mice with Th2‑type CHS treated with IMQ exhibited more serious psoriasis‑like inflammation with increased epidermal thickness and infiltrating cells in the derma. High mRNA expression levels of interleukin (IL)‑17, IL‑22, IL‑23, TNF‑α and RORγt were detected in back skin lesions. Additionally, high levels of IL‑17 and IL‑22 in blood serum were detected in IMQ‑treated mice combined with Th2‑type CHS. The mice treated with IMQ alone, and IMQ treatment combined with Th1‑type CHS had a comparable psoriasis‑like inflammatory response in the back skin. In conclusion, these data demonstrate that Th2‑type CHS exacerbated the IMQ‑treated psoriatic inflammation of mice via the IL‑23/IL‑17 axis. Th17 cells and associated pathways may link ACD and psoriasis. Therefore, patients with psoriasis should avoid contact with specific sensitizers, such as fragrance and rubber products, which may induce Th2 polarization.

  11. N-Acetylcysteine Attenuates Hexavalent Chromium-Induced Hypersensitivity through Inhibition of Cell Death, ROS-Related Signaling and Cytokine Expression

    PubMed Central

    Huang, Chien-Cheng; Sheu, Hamm-Ming; Tsai, Jui-Chen; Lin, Chia-Ho; Wang, Ying-Jan; Wang, Bour-Jr

    2014-01-01

    Chromium hypersensitivity (chromium-induced allergic contact dermatitis) is an important issue in occupational skin disease. Hexavalent chromium (Cr (VI)) can activate the Akt, Nuclear factor κB (NF-κB), and Mitogen-activated protein kinase (MAPK) pathways and induce cell death, via the effects of reactive oxygen species (ROS). Recently, cell death stimuli have been proposed to regulate the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). However, the exact effects of ROS on the signaling molecules and cytotoxicity involved in Cr(VI)-induced hypersensitivity have not yet been fully demonstrated. N-acetylcysteine (NAC) could increase glutathione levels in the skin and act as an antioxidant. In this study, we investigated the effects of NAC on attenuating the Cr(VI)-triggered ROS signaling in both normal keratinocyte cells (HaCaT cells) and a guinea pig (GP) model. The results showed the induction of apoptosis, autophagy and ROS were observed after different concentrations of Cr(VI) treatment. HaCaT cells pretreated with NAC exhibited a decrease in apoptosis and autophagy, which could affect cell viability. In addition, Cr (VI) activated the Akt, NF-κB and MAPK pathways thereby increasing IL-1α and TNF-α production. However, all of these stimulation phenomena could be inhibited by NAC in both of in vitro and in vivo studies. These novel findings indicate that NAC may prevent the development of chromium hypersensitivity by inhibiting of ROS-induced cell death and cytokine expression. PMID:25248126

  12. N-acetylcysteine attenuates hexavalent chromium-induced hypersensitivity through inhibition of cell death, ROS-related signaling and cytokine expression.

    PubMed

    Lee, Yu-Hsuan; Su, Shih-Bin; Huang, Chien-Cheng; Sheu, Hamm-Ming; Tsai, Jui-Chen; Lin, Chia-Ho; Wang, Ying-Jan; Wang, Bour-Jr

    2014-01-01

    Chromium hypersensitivity (chromium-induced allergic contact dermatitis) is an important issue in occupational skin disease. Hexavalent chromium (Cr (VI)) can activate the Akt, Nuclear factor κB (NF-κB), and Mitogen-activated protein kinase (MAPK) pathways and induce cell death, via the effects of reactive oxygen species (ROS). Recently, cell death stimuli have been proposed to regulate the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). However, the exact effects of ROS on the signaling molecules and cytotoxicity involved in Cr(VI)-induced hypersensitivity have not yet been fully demonstrated. N-acetylcysteine (NAC) could increase glutathione levels in the skin and act as an antioxidant. In this study, we investigated the effects of NAC on attenuating the Cr(VI)-triggered ROS signaling in both normal keratinocyte cells (HaCaT cells) and a guinea pig (GP) model. The results showed the induction of apoptosis, autophagy and ROS were observed after different concentrations of Cr(VI) treatment. HaCaT cells pretreated with NAC exhibited a decrease in apoptosis and autophagy, which could affect cell viability. In addition, Cr (VI) activated the Akt, NF-κB and MAPK pathways thereby increasing IL-1α and TNF-α production. However, all of these stimulation phenomena could be inhibited by NAC in both of in vitro and in vivo studies. These novel findings indicate that NAC may prevent the development of chromium hypersensitivity by inhibiting of ROS-induced cell death and cytokine expression.

  13. Quantitative sensory testing response patterns to capsaicin- and ultraviolet-B-induced local skin hypersensitization in healthy subjects: a machine-learned analysis.

    PubMed

    Lötsch, Jörn; Geisslinger, Gerd; Heinemann, Sarah; Lerch, Florian; Oertel, Bruno G; Ultsch, Alfred

    2017-08-16

    The comprehensive assessment of pain-related human phenotypes requires combinations of nociceptive measures that produce complex high-dimensional data, posing challenges to bioinformatic analysis. In this study, we assessed established experimental models of heat hyperalgesia of the skin, consisting of local ultraviolet-B (UV-B) irradiation or capsaicin application, in 82 healthy subjects using a variety of noxious stimuli. We extended the original heat stimulation by applying cold and mechanical stimuli and assessing the hypersensitization effects with a clinically established quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain). This study provided a 246 × 10-sized data matrix (82 subjects assessed at baseline, following UV-B application, and following capsaicin application) with respect to 10 QST parameters, which we analyzed using machine-learning techniques. We observed statistically significant effects of the hypersensitization treatments in 9 different QST parameters. Supervised machine-learned analysis implemented as random forests followed by ABC analysis pointed to heat pain thresholds as the most relevantly affected QST parameter. However, decision tree analysis indicated that UV-B additionally modulated sensitivity to cold. Unsupervised machine-learning techniques, implemented as emergent self-organizing maps, hinted at subgroups responding to topical application of capsaicin. The distinction among subgroups was based on sensitivity to pressure pain, which could be attributed to sex differences, with women being more sensitive than men. Thus, while UV-B and capsaicin share a major component of heat pain sensitization, they differ in their effects on QST parameter patterns in healthy subjects, suggesting a lack of redundancy between these models.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible

  14. Mechanical and cold hypersensitivity in nerve-injured C57BL/6J mice is not associated with fear-avoidance- and depression-related behaviour

    PubMed Central

    Hasnie, F. S.; Wallace, V. C. J.; Hefner, K.; Holmes, A.; Rice, A. S. C.

    2009-01-01

    Background Neuropathic pain is associated with significant co-morbidity, including anxiety and depression, which impact considerably on the overall patient experience. However, pain co-morbidity symptoms are rarely assessed in animal models of neuropathic pain. To improve the clinical validity of a widely used rodent model of traumatic peripheral neuropathy, we have investigated fear-avoidance- and depression-related behaviours in nerve-injured and sham-operated mice over a 4 week period. Methods Male C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) or sham surgery and were assessed on days 7, 14, and 28 after operation. Withdrawal thresholds to punctate mechanical and cooling stimuli were measured. Mice were tested on the novel open-field and elevated plus-maze tests for fear-avoidance behaviour, and on the tail suspension test for depression-related behaviour. Results Hypersensitivity to punctate mechanical and cool stimuli was evident up to day 28 after PSNL. However, there was no change in fear-avoidance- or depression-related behaviours regardless of interval after-surgery. Conclusion These data demonstrate that pain behaviour in nerve-injured C57BL/6J mice was not associated with alterations in emotion-related behaviours. PMID:17478455

  15. Mechanical and cold hypersensitivity in nerve-injured C57BL/6J mice is not associated with fear-avoidance- and depression-related behaviour.

    PubMed

    Hasnie, F S; Wallace, V C J; Hefner, K; Holmes, A; Rice, A S C

    2007-06-01

    Neuropathic pain is associated with significant co-morbidity, including anxiety and depression, which impact considerably on the overall patient experience. However, pain co-morbidity symptoms are rarely assessed in animal models of neuropathic pain. To improve the clinical validity of a widely used rodent model of traumatic peripheral neuropathy, we have investigated fear-avoidance- and depression-related behaviours in nerve-injured and sham-operated mice over a 4 week period. Male C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) or sham surgery and were assessed on days 7, 14, and 28 after operation. Withdrawal thresholds to punctate mechanical and cooling stimuli were measured. Mice were tested on the novel open-field and elevated plus-maze tests for fear-avoidance behaviour, and on the tail suspension test for depression-related behaviour. Hypersensitivity to punctate mechanical and cool stimuli was evident up to day 28 after PSNL. However, there was no change in fear-avoidance- or depression-related behaviours regardless of interval after-surgery. These data demonstrate that pain behaviour in nerve-injured C57BL/6J mice was not associated with alterations in emotion-related behaviours.

  16. Cold and hunger induce diurnality in a nocturnal mammal.

    PubMed

    van der Vinne, Vincent; Riede, Sjaak J; Gorter, Jenke A; Eijer, Willem G; Sellix, Michael T; Menaker, Michael; Daan, Serge; Pilorz, Violetta; Hut, Roelof A

    2014-10-21

    The mammalian circadian system synchronizes daily timing of activity and rest with the environmental light-dark cycle. Although the underlying molecular oscillatory mechanism is well studied, factors that influence phenotypic plasticity in daily activity patterns (temporal niche switching, chronotype) are presently unknown. Molecular evidence suggests that metabolism may influence the circadian molecular clock, but evidence at the level of the organism is lacking. Here we show that a metabolic challenge by cold and hunger induces diurnality in otherwise nocturnal mice. Lowering ambient temperature changes the phase of circadian light-dark entrainment in mice by increasing daytime and decreasing nighttime activity. This effect is further enhanced by simulated food shortage, which identifies metabolic balance as the underlying common factor influencing circadian organization. Clock gene expression analysis shows that the underlying neuronal mechanism is downstream from or parallel to the main circadian pacemaker (the hypothalamic suprachiasmatic nucleus) and that the behavioral phenotype is accompanied by phase adjustment of peripheral tissues. These findings indicate that nocturnal mammals can display considerable plasticity in circadian organization and may adopt a diurnal phenotype when energetically challenged. Our previously defined circadian thermoenergetics hypothesis proposes that such circadian plasticity, which naturally occurs in nocturnal mammals, reflects adaptive maintenance of energy balance. Quantification of energy expenditure shows that diurnality under natural conditions reduces thermoregulatory costs in small burrowing mammals like mice. Metabolic feedback on circadian organization thus provides functional benefits by reducing energy expenditure. Our findings may help to clarify relationships between sleep-wake patterns and metabolic phenotypes in humans.

  17. Pharmacogenetics of hypersensitivity drug reactions.

    PubMed

    Negrini, Simone; Becquemont, Laurent

    2017-04-01

    Adverse drug reactions are a significant cause of morbidity and mortality and represent a major burden on the healthcare system. Some of those reactions are immunologically mediated (hypersensitivity reactions) and can be clinically subdivided into two categories: immediate reactions (IgE-related) and delayed reactions (T-cell-mediated). Delayed hypersensitivity reactions include both systemic syndromes and organ-specific toxicities and can be triggered by a wide range of chemically diverse drugs. Recent studies have demonstrated a strong genetic association between human leukocyte antigen alleles and susceptibility to delayed drug hypersensitivity. Most notable examples include human leukocyte antigen (HLA)-B*57:01 allele and abacavir hypersensitivity syndrome or HLA-B*15:02 and HLA-B*58:01 alleles related to severe cutaneous reactions induced by carbamazepine and allopurinol, respectively. This review aims to explore our current understanding in the field of pharmacogenomics of HLA-associated drug hypersensitivities and its translation into clinical practice for predicting adverse drug reactions. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  18. Prevention of cold-induced increase in blood pressure of rats by captopril.

    PubMed

    Shechtman, O; Fregly, M J; van Bergen, P; Papanek, P E

    1991-06-01

    To assess the possibility that the renin-angiotensin system may play a role in the development of cold-induced hypertension, three groups of rats were used. Two groups were exposed to cold (5 +/- 2 degrees C) while the remaining group was kept at 26 +/- 2 degrees C. One group of cold-treated rats received food into which captopril (0.06% by weight) had been thoroughly mixed. The remaining two groups received the same food but without captopril. Systolic blood pressure of the untreated, cold-exposed group increased significantly above that of the warm-adapted, control group within 4 weeks of exposure to cold. In contrast, chronic treatment with captopril prevented the elevation of blood pressure. Rats were killed after 4 months of exposure to cold. At death, the heart, kidneys, adrenal glands, and interscapular brown fat pad were removed and weighed. Although captopril prevented the elevation of blood pressure in cold-treated rats, it did not prevent hypertrophy of the kidneys, heart, and interstitial brown adipose tissue that characteristically accompanies exposure to cold. Thus, chronic treatment with captopril prevented the elevation of blood pressure when administered at the time exposure to cold was initiated. It also reduced the elevated blood pressure of cold-treated rats when administered after blood pressure became elevated. This suggests that the renin-angiotensin system may play a role in the elevation of blood pressure during exposure to cold.

  19. Frequent Extreme Cold Exposure and Brown Fat and Cold-Induced Thermogenesis: A Study in a Monozygotic Twin

    PubMed Central

    Vosselman, Maarten J.; Vijgen, Guy H. E. J.; Kingma, Boris R. M.; Brans, Boudewijn; van Marken Lichtenbelt, Wouter D.

    2014-01-01

    Introduction Mild cold acclimation is known to increase brown adipose tissue (BAT) activity and cold-induced thermogenesis (CIT) in humans. We here tested the effect of a lifestyle with frequent exposure to extreme cold on BAT and CIT in a Dutch man known as ‘the Iceman’, who has multiple world records in withstanding extreme cold challenges. Furthermore, his monozygotic twin brother who has a ‘normal’ sedentary lifestyle without extreme cold exposures was measured. Methods The Iceman (subject A) and his brother (subject B) were studied during mild cold (13°C) and thermoneutral conditions (31°C). Measurements included BAT activity and respiratory muscle activity by [18F]FDG-PET/CT imaging and energy expenditure through indirect calorimetry. In addition, body temperatures, cardiovascular parameters, skin perfusion, and thermal sensation and comfort were measured. Finally, we determined polymorphisms for uncoupling protein-1 and β3-adrenergic receptor. Results Subjects had comparable BAT activity (A: 1144 SUVtotal and B: 1325 SUVtotal), within the range previously observed in young adult men. They were genotyped with the polymorphism for uncoupling protein-1 (G/G). CIT was relatively high (A: 40.1% and B: 41.9%), but unlike during our previous cold exposure tests in young adult men, here both subjects practiced a g-Tummo like breathing technique, which involves vigorous respiratory muscle activity. This was confirmed by high [18F]FDG-uptake in respiratory muscle. Conclusion No significant differences were found between the two subjects, indicating that a lifestyle with frequent exposures to extreme cold does not seem to affect BAT activity and CIT. In both subjects, BAT was not higher compared to earlier observations, whereas CIT was very high, suggesting that g-Tummo like breathing during cold exposure may cause additional heat production by vigorous isometric respiratory muscle contraction. The results must be interpreted with caution given the low

  20. De Novo Foliar Transcriptome of Chenopodium amaranticolor and Analysis of Its Gene Expression During Virus-Induced Hypersensitive Response

    PubMed Central

    Zhang, Yongqiang; Pei, Xinwu; Zhang, Chao; Lu, Zifeng; Wang, Zhixing; Jia, Shirong; Li, Weimin

    2012-01-01

    Background The hypersensitive response (HR) system of Chenopodium spp. confers broad-spectrum virus resistance. However, little knowledge exists at the genomic level for Chenopodium, thus impeding the advanced molecular research of this attractive feature. Hence, we took advantage of RNA-seq to survey the foliar transcriptome of C. amaranticolor, a Chenopodium species widely used as laboratory indicator for pathogenic viruses, in order to facilitate the characterization of the HR-type of virus resistance. Methodology and Principal Findings Using Illumina HiSeq™ 2000 platform, we obtained 39,868,984 reads with 3,588,208,560 bp, which were assembled into 112,452 unigenes (3,847 clusters and 108,605 singletons). BlastX search against the NCBI NR database identified 61,698 sequences with a cut-off E-value above 10−5. Assembled sequences were annotated with gene descriptions, GO, COG and KEGG terms, respectively. A total number of 738 resistance gene analogs (RGAs) and homology sequences of 6 key signaling proteins within the R proteins-directed signaling pathway were identified. Based on this transcriptome data, we investigated the gene expression profiles over the stage of HR induced by Tobacco mosaic virus and Cucumber mosaic virus by using digital gene expression analysis. Numerous candidate genes specifically or commonly regulated by these two distinct viruses at early and late stages of the HR were identified, and the dynamic changes of the differently expressed genes enriched in the pathway of plant-pathogen interaction were particularly emphasized. Conclusions To our knowledge, this study is the first description of the genetic makeup of C. amaranticolor, providing deep insight into the comprehensive gene expression information at transcriptional level in this species. The 738 RGAs as well as the differentially regulated genes, particularly the common genes regulated by both TMV and CMV, are suitable candidates which merit further functional characterization

  1. Tuber starch amylose content is associated with cold-induced sweetening in potato

    USDA-ARS?s Scientific Manuscript database

    Cold induced sweetening (CIS) is the accumulation of reducing sugars in potato tubers due to cold storage. It is undesirable because it results in dark fry products. Potato varieties vary in resistance to CIS. Research efforts have focused on enzymes that contribute to the accumulation of reducing s...

  2. Activation of the RAGE/STAT3 Pathway in the Dorsal Root Ganglion Contributes to the Persistent Pain Hypersensitivity Induced by Lumbar Disc Herniation.

    PubMed

    Zhang, Xin-Sheng; Li, Xiao; Luo, Hai-Jie; Huang, Zhu-Xi; Liu, Cui-Cui; Wan, Qing; Xu, Shu-Wei; Wu, Shao-Ling; Ke, Song-Jian; Ma, Chao

    2017-07-01

    Clinically, chronic low back pain and sciatica associated with lumbar disc herniation (LDH) is a common musculoskeletal disorder. Due to the unawareness of detailed mechanisms, it is difficult to get an effective therapy. The aim of the present study was to identify the role of the RAGE/STAT3 pathway in the dorsal root ganglion (DRG) on the formation and development of persistent pain hypersensitivity induced by LDH. Controlled animal study. University laboratory. After LDH induced by implantation of autologous nucleus pulposus (NP, harvested from animal tail) on the left L5 nerve root was established, mechanical thresholds and electrophysiological tests were conducted at relevant time points during an observation period of 28 days. Protein levels and localization of RAGE and p-STAT3 were performed by using Western blotting and immunohistochemistry, respectively. LDH induced persistent pain hypersensitivity, increased excitability of DRG neurons, and upregulated the expression of RAGE and p-STAT3 in the DRG. Consecutive injection of both RAGE antagonist FPS-ZM1 (i.t.) and STAT3 activity inhibitor S3I-201 (i.t.) inhibited the enhanced excitability of DRG neurons and mechanical allodynia induced by NP implantation. Furthermore, local knockdown of STAT3 by intrathecal injection of AAV-Cre-GFP into STAT3flox/flox mice markedly alleviated NP implantation-induced mechanical allodynia in mice. Importantly, the expression of p-STAT3 was colocalized with that of RAGE in the DRG and inhibition of RAGE with FPS-ZM1 prevented NP implantation-induced STAT3 activation. More underlying mechanism(s) of the role of the RAGE/STAT3 pathway on the formation and development of persistent pain hypersensitivity induced by LDH will be needed to be explored in future research. These findings suggest activation of the RAGE/STAT3 pathway plays a critical role in persistent pain induced by LDH, and this pathway may represent novel therapeutic targets for the treatment of LDH-induced

  3. Antinociceptive effects of AS1069562, the (+)-isomer of indeloxazine, on spinal hypersensitivity induced by intrathecal injection of prostaglandin in mice: comparison with duloxetine and amitriptyline.

    PubMed

    Murai, Nobuhito; Tsukamoto, Mina; Tamura, Seiji; Aoki, Toshiaki; Matsuoka, Nobuya

    2014-06-15

    The (+)-isomer of indeloxazine AS1069562 exerts multiple pharmacological actions including the inhibition of serotonin (5-HT) and norepinephrine reuptake and analgesia in experimental animal pain models. Here, we evaluated the antinociceptive effects of AS1069562 and the antidepressants duloxetine and amitriptyline in mouse models of prostaglandin-induced spinal hypersensitivity. Prostaglandin E2 (PGE2) and F2α (PGF2α) were intrathecally administered to induce spinal hypersensitivity, causing tactile allodynia in mice. Allodynia induced by PGF2α but not by PGE2 was suppressed by desensitization of C-fibers with systemic pretreatment with resiniferatoxin. C-fiber hyperexcitability might therefore play a role in allodynia induced by PGF2α but not PGE2. In the PGE2-induced allodynia model, AS1069562 and duloxetine significantly suppressed allodynia, whereas amitriptyline did not. In the PGF2α-induced allodynia model, AS1069562 and amitriptyline significantly ameliorated allodynia, whereas duloxetine did not. To demonstrate the broad effects of AS1069562 compared to duloxetine, additional studies were conducted to elucidate other target mechanisms of AS1069562 beyond 5-HT and norepinephrine reuptake inhibition. AS1069562 exhibited affinity for both 5-HT1A and 5-HT3 receptors, and the analgesic effect of AS1069562 on PGF2α-induced allodynia was significantly blocked by the 5-HT1A receptor antagonist (S)-WAY100135 and the 5-HT3 receptor agonist SR57227. Taken together, these results indicate that AS1069562 inhibits both C-fiber- and non-C-fiber-dependent prostaglandin-induced allodynia, while duloxetine inhibits only non-C-fiber-triggered allodynia, and amitriptyline inhibits only C-fiber-triggered allodynia. These broad antinociceptive effects of AS1069562 may be due not only to 5-HT and norepinephrine reuptake inhibition but also to its effects on 5-HT receptors such as 5-HT1A and 5-HT3 receptors.

  4. In vivo photoacoustic tomography of mouse cerebral edema induced by cold injury

    NASA Astrophysics Data System (ADS)

    Xu, Zhun; Zhu, Quing; Wang, Lihong V.

    2011-06-01

    For the first time, we have implemented photoacoustic tomography (PAT) to image the water content of an edema in vivo. We produced and imaged a cold-induced cerebral edema transcranially, then obtained blood vessel and water accumulation images at 610 and 975 nm, respectively. We tracked the changes at 12, 24, and 36 h after the cold injury. The blood volume decreased after the cold injury, and the maximum area of edema was observed 24 h after the cold injury. We validated PAT of the water content of the edema through magnetic Resonance Imaging and the water spectrum from the spectrophotometric measurement.

  5. Cold gelation of alginates induced by monovalent cations.

    PubMed

    Karakasyan, C; Legros, M; Lack, S; Brunel, F; Maingault, P; Ducouret, G; Hourdet, D

    2010-11-08

    A new reversible gelation pathway is described for alginates in aqueous media. From various samples differing by their mannuronic/guluronic content (M/G), both enthalpic and viscoelastic experiments demonstrate that alginates having a high M content are able to form thermoreversible assemblies in the presence of potassium salts. The aggregation behavior is driven by the low solubility of M-blocks at low temperature and high ionic strength. In semidilute solutions, responsive assemblies induce a strong increase of the viscosity below a critical temperature. A true physical gel is obtained in the entangled regime, although the length scale of specific interactions between M-blocks decreases with increasing density of entanglements. Cold setting takes place at low temperatures, below 0 °C for potassium concentrations lower than 0.2 mol/kg, but the aggregation process can be easily shifted to higher temperatures by increasing the salt concentration. The self-assembling process of alginates in solution of potassium salts is characterized by a sharp gelation exotherm and a broad melting endotherm with a large hysteresis of 20-30 °C between the transition temperatures. The viscoelastic properties of alginate gels in potassium salts closely depend on thermal treatment (rate of cooling, time, and temperature of storage), polymer and salt concentrations, and monomer composition as well. In the case of alginates with a high G content, a similar aggregation behavior is also evidenced at higher salt concentrations, but the extent of the self-assembling process remains too weak to develop a true gelation behavior in solution.

  6. Protein kinase D1 is essential for the pro-inflammatory response induced by hypersensitivity pneumonitis-causing thermophilic actinomycetes Saccharopolyspora rectivirgula

    PubMed Central

    Kim, Young-In; Park, Jeoung-Eun; Brand, David D.; Fitzpatrick, Elizabeth A.; Yi, Ae-Kyung

    2010-01-01

    Hypersensitivity pneumonitis is an interstitial lung disease that results from repeated pulmonary exposure to various organic antigens, including Saccharopolyspora rectivirgula (SR, the causative agent of farmer's lung disease). Although the contributions of pro-inflammatory mediators to the disease pathogenesis are relatively well documented, the mechanism(s) involved in initiation of pro-inflammatory responses against the causative microorganisms, and the contribution of signaling molecules involved in host immune defense have not been fully elucidated. In the present study, we found that SR induces activation of protein kinase D1 (PKD1) in lung cells in vitro and in vivo. Activation of PKD1 by SR was dependent on MyD88. Inhibition of PKD by pharmacological PKD inhibitor Gö6976, and silencing of PKD1 expression by siRNA, revealed that PKD1 is indispensable for SR-mediated activation of MAPKs and NF-κB and expression of various pro-inflammatory cytokines and chemokines. In addition, compared to controls, mice pretreated with Gö6976 showed significantly suppressed alveolitis and neutrophil influx in bronchial alveolar lavage fluid and interstitial lung tissue, and substantially decreased myeloperoxidase activity in the lung after pulmonary exposure to SR. These results demonstrate that PKD1 is essential for SR-mediated pro-inflammatory immune responses and neutrophil influx in the lung. Our findings also imply the possibility that PKD1 might be one of the critical factors that play a regulatory role in development of hypersensitivity pneumonitis caused by microbial antigens, and that inhibition of PKD1 activation could be an effective way to control microbial antigen-induced hypersensitivity pneumonitis. PMID:20142359

  7. Cold-induced organelle relocation in the liverwort Marchantia polymorpha L.

    PubMed

    Ogasawara, Yuka; Ishizaki, Kimitsune; Kohchi, Takayuki; Kodama, Yutaka

    2013-08-01

    Organelles change their subcellular positions in response to various environmental conditions. Recently, we reported that cold treatments alter the intracellular position of chloroplasts and nuclei (cold positioning) in the fern Adiantum capillus-veneris; chloroplasts and nuclei localized to the periclinal cell wall relocated to anticlinal cell wall after cold treatments. To further understand organelle positioning under cold conditions, we studied cold-induced organelle relocation in the liverwort Marchantia polymorpha L. When sporelings and gemmmalings were treated under low temperature (5 °C), chloroplast cold positioning response was successfully induced both in the sporelings and the gemmmalings of M. polymorpha. Using a genetic transformation, nuclei, mitochondria or peroxisomes were visualized with a fluorescent protein, and the transgenic gemmmalings were incubated under the cold condition. Nuclei and peroxisomes, but not mitochondria, clearly relocated from the periclinal cell wall to the anticlinal cell wall after cold treatments. Our findings suggest that several organelles concurrently change their positions in the liverwort cell to cope with cold temperature. © 2013 John Wiley & Sons Ltd.

  8. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

    NASA Astrophysics Data System (ADS)

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2016-08-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  9. Human esophageal response during chest pain induced by swallowing cold liquids.

    PubMed

    Meyer, G W; Castell, D O

    1981-11-06

    Normal persons often note chest or back pain during rapid ingestion of cold liquids, commonly believed to result from cold-induced "spasm" of esophageal muscle. We studied the effects of swallowing cold liquids on esophageal function in five normal subjects, aged 20 to 44 years, by comparing their response to cold ice cream (-5 degrees C) and room temperature ice cream mix (20 degrees C). Decreased peristaltic amplitude was seen during cold ice cream ingestion, primarily in the midesophagus. When seven subjects rapidly ingested ice cream until chest pain was produced and maintained for at least 60 s, complete absence of motor activity in the distal esophagus occurred, with slow return to normal during the ensuing five minutes. Our studies indicate that ingestion of cold liquids significantly depresses peristaltic amplitudes and frequency of peristalsis in normal persons, and pain is associated with complete absence of motor activity in the body of the esophagus, rather than esophageal "spasm" as commonly believed.

  10. Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart

    PubMed Central

    Seeley, Sarah L.; Stoops, Thorne S.; D’Souza, Manoranjan S.

    2017-01-01

    Background We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury. Methods Adult male and female rats received daily injections of methamphetamine (5 mg/kg) or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining. Results Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine. Conclusions Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse. PMID:28575091

  11. Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart.

    PubMed

    Rorabaugh, Boyd R; Seeley, Sarah L; Stoops, Thorne S; D'Souza, Manoranjan S

    2017-01-01

    We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury. Adult male and female rats received daily injections of methamphetamine (5 mg/kg) or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining. Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine. Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse.

  12. Epicutaneous immunization with protein antigen TNP-Ig and NOD2 ligand muramyl dipeptide (MDP) reverses skin-induced suppression of contact hypersensitivity.

    PubMed

    Majewska-Szczepanik, Monika; Dorożyńska, Iwona; Strzępa, Anna; Szczepanik, Marian

    2014-02-01

    Epicutaneous (EC) immunization offers a new method of a needle-free and self-administrable immunization by using a topically applied patch to deliver vaccine. We have previously shown that EC immunization with hapten-conjugated protein antigen TNP-Ig prior to hapten sensitization inhibits Th1-mediated contact hypersensitivity (CHS) in mice. Our further work showed that EC immunization with TNP-Ig and Toll-like receptor (TLR) ligands prior to hapten sensitization reverses skin-induced suppression. Animal model of contact hypersensitivity was used to study reversal of skin-induced suppression. Current work showed that EC immunization with protein antigen TNP-Ig and MDP NOD2 agonist - muramyldipeptide (L isoform) reverses skin-induced suppression of CHS. On the other hand L18-MDP NOD2 agonist - muramyldipeptide with a C18 fatty acid chain and MDP control - negative control for MDP - muramyldipeptide (D isoform, inactive) did not reverse skin-induced suppression. "Transfer in" experiment showed that reversal of skin-induced suppression can be adoptively transferred with lymphoid cells isolated from donors EC treated with TNP-Ig and MDP NOD2 agonist. Moreover, experiment employing two non-cross-reacting antigens TNP-Ig and OX-Ig proved that reversal of skin-induced suppression is antigen specific. Additionally, lymph node cells isolated from mice EC immunized with TNP-Ig and MDP NOD2 agonist produced increased level of IFN-γ suggesting that this cytokine might be involved in reversal of skin-induced suppression. This work shows that EC immunization with protein antigen plus NOD2 ligand MDP may be a potential tool to increase the immunogenicity of weekly immunogenic antigens. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  13. Multiple Drug Hypersensitivity

    PubMed Central

    Pichler, Werner J.; Srinoulprasert, Yuttana; Yun, James; Hausmann, Oliver

    2017-01-01

    Multiple drug hypersensitivity (MDH) is a syndrome that develops as a consequence of massive T-cell stimulations and is characterized by long-lasting drug hypersensitivity reactions (DHR) to different drugs. The initial symptoms are mostly severe exanthems or drug rash with eosinophilia and systemic symptoms (DRESS). Subsequent symptoms due to another drug often appear in the following weeks, overlapping with the first DHR, or months to years later after resolution of the initial presentation. The second DHR includes exanthema, erythroderma, DRESS, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hepatitis, and agranulocytosis. The eliciting drugs can be identified by positive skin or in vitro tests. The drugs involved in starting the MDH are the same as for DRESS, and they are usually given in rather high doses. Fixed drug combination therapies like sulfamethoxazole/trimethoprim or piperacillin/tazobactam are frequently involved in MDH, and 30–40% of patients with severe DHR to combination therapy show T-cell reactions to both components. The drug-induced T-cell stimulation appears to be due to the p-i mechanism. Importantly, a permanent T-cell activation characterized by PD-1+/CD38+ expression on CD4+/CD25low T cells can be found in the circulation of patients with MDH for many years. In conclusion, MDH is a drug-elicited syndrome characterized by a long-lasting hyperresponsiveness to multiple, structurally unrelated drugs with clinically diverse symptoms. PMID:28315874

  14. The association of cholinergic and cold-induced urticaria: diagnosis and management

    PubMed Central

    Torabi, Bahar; Ben-Shoshan, Moshe

    2015-01-01

    Physical urticaria is often challenging to diagnose and manage. We present a case of both cholinergic and cold-induced urticaria and discuss the diagnosis and management strategies of these two important conditions. PMID:25694628

  15. Drug-Hypersensitivity Syndrome: Diagnosis and Treatment

    PubMed Central

    Hamm, Rose L.

    2012-01-01

    Drug-induced hypersensitivity syndrome is a systemic autoimmune disorder that results in mucocutaneous symptoms ranging in severity from mild pruritus to life-threatening skin and mucosal loss, with different nomenclature depending on the severity of the symptoms. The purpose of this article is to review the recent advances in understanding the pathology of drug-induced hypersensitivity syndrome, as well as current recommendations for both medical and wound management. PMID:24527369

  16. Drug-hypersensitivity syndrome: diagnosis and treatment.

    PubMed

    Hamm, Rose L

    2011-12-01

    Drug-induced hypersensitivity syndrome is a systemic autoimmune disorder that results in mucocutaneous symptoms ranging in severity from mild pruritus to life-threatening skin and mucosal loss, with different nomenclature depending on the severity of the symptoms. The purpose of this article is to review the recent advances in understanding the pathology of drug-induced hypersensitivity syndrome, as well as current recommendations for both medical and wound management.

  17. Effect of caffeine intake on finger cold-induced vasodilation.

    PubMed

    Kim, Byeong Jo; Seo, Yongsuk; Kim, Jung-Hyun; Lee, Dae Taek

    2013-12-01

    The purpose of the study was to investigate the effect of caffeine intake on finger cold-induced vasodilation (CIVD). Ten healthy men underwent 6 experimental trials characterized by control (NCAFF) or caffeine intake (CAFF) via chewing gum (300 mg of caffeine) while resting on a chair or performing submaximal (70% maximal oxygen consumption) or maximal (100% maximal oxygen consumption) treadmill exercise (Bruce protocol) followed by immersion of the middle finger in a water bath (5°C) for 20 minutes. Finger temperature (Tf ) and time parameters of the first CIVD cycle and post-test norepinephrine were measured. Exercise duration for submaximal and maximal exercise was 8.9 ± 0.9 and 12.4 ± 0.8 minutes, respectively. CAFF had no effect on Tf, but exercise increased minimal Tf in NCAFF (9.08 ± 1.27°C, 13.02 ± 2.13°C, and 13.25 ± 1.63°C in rest, submaximal, and maximal exercise, respectively) and CAFF (8.76 ± 1.39°C, 12.50 ± 1.91°C, and 12.79 ± 1.20°C). Maximal Tf was significantly higher in NCAFF (15.98 ± 1.04°C, 16.18 ± 1.56°C, and 15.14 ± 1.52°C) than in CAFF (13.56 ± 1.19°C, 15.52 ± 1.31°C, and 14.39 ± 1.43°C), resulting in a significant difference between minimal and maximal Tf in rest (NCAFF, 6.89 ± 1.56°C and CAFF, 4.79 ± 1.23°C), but not in exercise conditions. CAFF had no effect on CIVD time responses, but exercise significantly shortened CIVD onset and peak time compared with rest in both NCAFF and CAFF. Norepinephrine concentration was significantly greater in CAFF (290.6 ± 113.0 pg/mL, 278.1 ± 91.4 pg/mL, and 399.8 ± 125.5 pg/mL) than NCAFF (105.6 ± 29.5 pg/mL, 199.6 ± 89.6 pg/mL, and 361.5 ± 171.3 pg/mL). Caffeine intake before finger immersion in cold water does not result in a thermogenic effect and adversely affects CIVD responses, whereas exercise modifies CIVD temperature and time responses. Copyright © 2013 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

  18. Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid.

    PubMed

    Burgos-Morón, Estefanía; Calderón-Montaño, José Manuel; Orta, Manuel Luis; Guillén-Mancina, Emilio; Mateos, Santiago; López-Lázaro, Miguel

    2016-07-08

    Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder cancer in adults and leukemia in children of mothers who drink coffee during pregnancy. Since cancer is driven by the accumulation of DNA alterations, the ability of the coffee constituent caffeic acid to induce DNA damage in cells may play a role in the carcinogenic potential of this beverage. This carcinogenic potential may be exacerbated in cells with DNA repair defects. People with the genetic disease Fanconi Anemia have DNA repair deficiencies and are predisposed to several cancers, particularly acute myeloid leukemia. Defects in the DNA repair protein Fanconi Anemia D2 (FANCD2) also play an important role in the development of a variety of cancers (e.g., bladder cancer) in people without this genetic disease. This communication shows that cells deficient in FANCD2 are hypersensitive to the cytotoxicity (clonogenic assay) and DNA damage (γ-H2AX and 53BP1 focus assay) induced by caffeic acid and by a commercial lyophilized coffee extract. These data suggest that people with Fanconi Anemia, or healthy people who develop sporadic mutations in FANCD2, may be hypersensitive to the carcinogenic activity of coffee.

  19. Assessment of IgE binding to native and hydrolyzed soy protein in serum obtained from dogs with experimentally induced soy protein hypersensitivity.

    PubMed

    Serra, Montserrat; Brazís, Pilar; Fondati, Alessandra; Puigdemont, Anna

    2006-11-01

    To assess binding of IgE to native, whole hydrolyzed, and separated hydrolyzed fractions of soy protein in serum obtained from dogs with experimentally induced soy protein hypersensitivity. 8 naïve Beagles (6 experimentally sensitized to native soy protein and 2 control dogs). 6 dogs were sensitized against soy protein by administration of allergens during a 90-day period. After the sensitization protocol was completed, serum concentrations of soy-specific IgE were measured and intradermal skin tests were performed in all 6 dogs to confirm that the dogs were sensitized against soy protein. Serum samples from each sensitized and control dog underwent western blot analysis to assess the molecular mass band pattern of the different allergenic soy fractions and evaluate reactivities to native and hydrolyzed soy protein. In sera from sensitized dogs, a characteristic band pattern with 2 major bands (approx 75 and 50 kd) and 2 minor bands (approx 31 and 20 kd) was detected, whereas only a diffuse band pattern associated with whole hydrolyzed soy protein was detected in the most reactive dog. Reactivity was evident only for the higher molecular mass peptide fraction. In control dogs, no IgE reaction to native or hydrolyzed soy protein was detected. Data suggest that the binding of soy-specific IgE to the hydrolyzed soy protein used in the study was significantly reduced, compared with binding of soy-specific IgE to the native soy protein, in dogs with experimentally induced soy hypersensitivity.

  20. Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid

    PubMed Central

    Burgos-Morón, Estefanía; Calderón-Montaño, José Manuel; Orta, Manuel Luis; Guillén-Mancina, Emilio; Mateos, Santiago; López-Lázaro, Miguel

    2016-01-01

    Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder cancer in adults and leukemia in children of mothers who drink coffee during pregnancy. Since cancer is driven by the accumulation of DNA alterations, the ability of the coffee constituent caffeic acid to induce DNA damage in cells may play a role in the carcinogenic potential of this beverage. This carcinogenic potential may be exacerbated in cells with DNA repair defects. People with the genetic disease Fanconi Anemia have DNA repair deficiencies and are predisposed to several cancers, particularly acute myeloid leukemia. Defects in the DNA repair protein Fanconi Anemia D2 (FANCD2) also play an important role in the development of a variety of cancers (e.g., bladder cancer) in people without this genetic disease. This communication shows that cells deficient in FANCD2 are hypersensitive to the cytotoxicity (clonogenic assay) and DNA damage (γ-H2AX and 53BP1 focus assay) induced by caffeic acid and by a commercial lyophilized coffee extract. These data suggest that people with Fanconi Anemia, or healthy people who develop sporadic mutations in FANCD2, may be hypersensitive to the carcinogenic activity of coffee. PMID:27399778

  1. Histone Deacetylase Activity Represses Gamma Interferon-Inducible HLA-DR Gene Expression following the Establishment of a DNase I-Hypersensitive Chromatin Conformation

    PubMed Central

    Osborne, Aaron; Zhang, Hongquan; Yang, Wen-Ming; Seto, Edward; Blanck, George

    2001-01-01

    Expression of the retinoblastoma tumor suppressor protein (Rb) is required for gamma interferon (IFN-γ)-inducible major histocompatibility complex class II gene expression and transcriptionally productive HLA-DRA promoter occupancy in several human tumor cell lines. Treatment of these Rb-defective tumor cell lines with histone deacetylase (HDAC) inhibitors rescued IFN-γ-inducible HLA-DRA and -DRB mRNA and cell surface protein expression, demonstrating repression of these genes by endogenous cellular HDAC activity. Additionally, Rb-defective, transcriptionally incompetent tumor cells retained the HLA-DRA promoter DNase I-hypersensitive site. Thus, HDAC-mediated repression of the HLA-DRA promoter occurs following the establishment of an apparent nucleosome-free promoter region and before transcriptionally productive occupancy of the promoter by the required transactivators. Repression of HLA-DRA promoter activation by HDAC activity likely involves a YY1 binding element located in the first exon of the HLA-DRA gene. Chromatin immunoprecipitation experiments localized YY1 to the HLA-DRA gene in Rb-defective tumor cells. Additionally, mutation of the YY1 binding site prevented repression of the promoter by HDAC1 and partially prevented activation of the promoter by trichostatin A. Mutation of the octamer element also significantly reduced the ability of HDAC1 to confer repression of inducible HLA-DRA promoter activation. Treatment of Rb-defective tumor cells with HDAC inhibitors greatly reduced the DNA binding activity of Oct-1, a repressor of inducible HLA-DRA promoter activation. These findings represent the first evidence that HDAC activity can repress IFN-γ-inducible HLA class II gene expression and also demonstrate that HDAC activity can contribute to promoter repression following the establishment of a DNase I-hypersensitive chromatin conformation. PMID:11533238

  2. An induced hypersensitive-like response limits expression of foreign peptides via a recombinant TMV-based vector in a susceptible tobacco.

    PubMed

    Li, Mangmang; Li, Ping; Song, Rentao; Xu, Zhengkai

    2010-11-29

    By using tobacco mosaic virus (TMV)-based vectors, foreign epitopes of the VP1 protein from food-and-month disease virus (FMDV) could be fused near to the C-terminus of the TMV coat protein (CP) and expressed at high levels in susceptible tobacco plants. Previously, we have shown that the recombinant TMV vaccines displaying FMDV VP1 epitopes could generate protection in guinea pigs and swine against the FMDV challenge. Recently, some recombinant TMV, such as TMVFN20 that contains an epitope FN20 from the FMDV VP1, were found to induce local necrotic lesions (LNL) on the inoculated leaves of a susceptible tobacco, Nicotiana tabacum Samsun nn. This hypersensitive-like response (HLR) blocked amplification of recombinant TMVFN20 in tobacco and limited the utility of recombinant TMV vaccines against FMDV. Here we investigate the molecular mechanism of the HLR in the susceptible Samsun nn. Histochemical staining analyses show that these LNL are similar to those induced in a resistant tobacco Samsun NN inoculated with wild type (wt) TMV. The recombinant CP subunits are specifically related to the HLR. Interestingly, this HLR in Samsun nn (lacking the N/N'-gene) was able to be induced by the recombinant TMV at both 25°C and 33°C, whereas the hypersensitive response (HR) in the resistant tobacco plants induced by wt TMV through the N/N'-gene pathways only at a permissive temperature (below 30°C). Furthermore, we reported for the first time that some of defense response (DR)-related genes in tobacco were transcriptionally upregulated during HLR. Unlike HR, HLR is induced in the susceptible tobacco through N/N'-gene independent pathways. Induction of the HLR is associated with the expression of the recombinant CP subunits and upregulation of the DR-related genes.

  3. Corneal edema induced by cold in trigeminal nerve palsy

    SciTech Connect

    Thorgaard, G.L.; Holland, E.J.; Krachmer, J.H.

    1987-05-15

    We examined a 34-year-old man who complained of decreased visual acuity in the right eye when exposed to cold environmental temperatures. Although examination at room temperature was unremarkable, he developed prominent unilateral corneal edema of the right eye when placed in a cold room at 4 C. Corneal thickness increased from 525 to 789 microns in the affected eye. Further examination disclosed a right-sided trigeminal nerve palsy. He was eventually found to have a 3 X 2-cm tentorial ridge meningioma on the right.

  4. Transient corneal opacification induced by cold in Raynaud's disease.

    PubMed

    McWhae, J A; Andrews, D M

    1991-05-01

    A 48-year-old man presented with longstanding complaints of transient blurring of vision on exposure to cold temperatures. A review of family history was noteworthy in that two of the patient's four sons and the patient's brother had similar complaints. All affected individuals had Raynaud's disease. Results of ophthalmic evaluation showed transient corneal opacities. Slit-lamp video photography under cold stress demonstrated conjunctival vascular changes consistent with Raynaud's phenomenon. An extensive work-up for systemic disease was otherwise negative. To the best of the authors' knowledge, anterior segment changes have not been described previously in idiopathic Raynaud's disease.

  5. Salmon calcitonin reduces oxaliplatin-induced cold and mechanical allodynia in rats.

    PubMed

    Aoki, Manahito; Mori, Asami; Nakahara, Tsutomu; Sakamoto, Kenji; Ishii, Kunio

    2013-01-01

    Oxaliplatin is commonly used anti-cancer drugs, but it frequently causes peripheral neuropathic pain. Recently, we reported that elcatonin, a synthetic analog of eel calcitonin, attenuated the oxaliplatin- and paclitaxel-induced cold and mechanical allodynia in rats. In the present study, we determined whether salmon calcitonin also had anti-allodynic effects on oxaliplatin-induced neuropathy in rats. The rats were treated with a single dose of oxaliplatin (6 mg/kg, intraperitoneally (i.p.)). Oxaliplatin resulted in cold and mechanical allodynia. We assessed the anti-allodynic effects of subcutaneously administered salmon calcitonin (20 U/kg/d) by cold stimulation (8°C) directly to the hind paw of the rats and by using the von Frey test. Salmon calcitonin almost completely reversed the effects of both cold and mechanical allodynia. These results suggest that salmon calcitonin is also useful for treatment of oxaliplatin-induced neuropathy clinically.

  6. Cytokinin response factor 4 (CRF4) is induced by cold and involved in freezing tolerance.

    PubMed

    Zwack, Paul J; Compton, Margaret A; Adams, Cami I; Rashotte, Aaron M

    2016-03-01

    Cytokinin response factor 4 (CRF4) shows a short-term induction by cold (4 °C) that appears to play a role in non-acclimated freezing tolerance as seen in mutant and overexpression lines. Responses to abiotic stresses, such as cold stress, are critical to plant growth and optimal production. Examination of Arabidopsis cytokinin response factors (CRFs) showed transcriptional induction after exposure to cold (4 °C). In particular, CRF4 was strongly induced in both root and shoot tissues. As CRF4 is one of several CRFs not transcriptionally regulated by cytokinin, we further investigated its response to cold. Peak CRF4 induction occurred 6 h post cold exposure, after which expression was maintained at moderately elevated levels during extended cold and subsequent treatment recovery. Examination of CRF4 mutant and overexpression lines under standard (non-cold) conditions revealed little difference from WT. One exception was a small, but significant increase in primary root growth of overexpression plants (CRF4OX). Under cold conditions, the only phenotype observed was a reduction in the rate of germination of CRF4OX seeds. The pattern of CRF4 expression along with the lack of strong phenotype at 4 °C led us to hypothesize that cold induction of CRF4 could play a role in short-term cold acclimation leading to increased freeze tolerance. Examination of CRF4OX and crf4 plants exposed to freezing temperatures revealed mutants lacking expression of CRF4 were more sensitive to freezing, while CRF4OXs with increased levels CRF4 levels were more tolerant. Altered transcript expression of CBF and COR15a cold signaling pathway genes in crf4 mutant and overexpression lines suggest that CRF4 may be potentially connected to this pathway. Overall this indicates that CRF4 plays an important role in both cold response and freezing stress.

  7. Hydrogen peroxide is involved in the cold acclimation-induced chilling tolerance of tomato plants.

    PubMed

    Zhou, Jie; Wang, Jian; Shi, Kai; Xia, Xiao Jian; Zhou, Yan Hong; Yu, Jing Quan

    2012-11-01

    Cold acclimation increases plant tolerance to a more-severe chilling and in this process an accumulation of H(2)O(2) in plants is often observed. To examine the role of H(2)O(2) in cold acclimation in plants, the accumulation of H(2)O(2), antioxidant metabolism, the glutathione redox state, gas exchange and chlorophyll fluorescence were analyzed after cold acclimation at 12/10 °C and during the subsequent chilling at 7/4 °C in tomato (Solanum lycopersicum) plants. Cold acclimation modestly elevated the levels of H(2)O(2), the gene expression of respiratory burst oxidase homolog 1 (Rboh1) and NADPH oxidase activity, leading to the up-regulation of the expression and activity of antioxidant enzymes. In non-acclimated plants chilling caused a continuous rise in the H(2)O(2) content, an increase in the malondialdehyde (MDA) content and in the oxidized redox state of glutathione, followed by reductions in the CO(2) assimilation rate and the maximum quantum yield of photosystem II (F(v)/F(m)). However, in cold-acclimated plants chilling-induced photoinhibition, membrane peroxidation and reductions in the CO(2) assimilation rate were significantly alleviated. Furthermore, a treatment with an NADPH oxidase inhibitor or H(2)O(2) scavenger before the plants subjected to the cold acclimation abolished the cold acclimation-induced beneficial effects on photosynthesis and antioxidant metabolism, leading to a loss of the cold acclimation-induced tolerance against chilling. These results strongly suggest that the H(2)O(2) generated by NADPH oxidase in the apoplast of plant cells plays a crucial role in cold acclimation-induced chilling tolerance. Crown Copyright © 2012. Published by Elsevier Masson SAS. All rights reserved.

  8. Cold exposure induces alterations in porcine triiodothyronine tissue distribution

    SciTech Connect

    Quesada, M.H.; Reed, H.L.; Hesslink, R.; Licauco, G.; Castro, S.; Homer, L.; Young, B. Univ. of Alberta, Edmonton )

    1991-03-11

    Evidence suggests that thyroid hormone plays an active role in modulation of tissue metabolism in response to cold challenge. In an attempts to identify tissues that may have increased capacity for triiodothyronine (T{sub 3}) and be actively involved in the thermogenic process, the authors investigated the T{sub 3} tissue distribution in 5 month old swine exposed to cold (4C) (N = 5) for three weeks, compared with controls at a thermoneutral temperature (20C) (N = 4). Both groups were injected I.V. with ({sup 125}I)T{sub 3} three hours before sacrifice. ({sup 125}I)T{sub 3} was organically extracted from heart, kidney, thyroid gland, adrenal, brain, 4 different types of striated muscles and fat tissues and counted to determine the CPM/gm of tissue. Serum total T{sub 3} and free T{sub 3} were elevated. The bulk of the tissue/serum ratios of cold exposed swine compared with controls were unchanged. However, calculation of the T{sub 3} organ pools revealed that the majority was elevated 2 to 3 times over control. Increases in tissue distribution volume (TVD) occurred in hip fat. Body and organ weights tended to increase but not to a significant degree except for the thyroid gland, which increased 66% over the average control value. The physiological significance of the cold associated augmented organ pool and the increased TCD in hip fat needs to be explored.

  9. Cold-induced alteration of adipokine profile in humans.

    PubMed

    Iwen, K Alexander; Wenzel, Eike T; Ott, Volker; Perwitz, Nina; Wellhöner, Peter; Lehnert, Hendrik; Dodt, Christoph; Klein, Johannes

    2011-03-01

    Adipose tissue function and sympathetic nervous system (SNS) activity are tightly interconnected. Adipose tissue is densely innervated by the SNS. Adipokines secreted by adipose tissue are implicated in maintaining energy homeostasis, the control of blood pressure, immune system function, hemostasis, and atherosclerosis. Little is known about a direct effect of SNS activation on influencing adipose tissue endocrine function in humans. In 10 lean, healthy male volunteers, SNS was activated by whole-body exposure to cold for 2 hours; a group of 10 subjects served as controls. Vital parameters were evaluated, plasma adipokine levels were measured, and adipokine gene expression in subcutaneous abdominal adipose tissue was determined. Cold exposure caused an increase in cold sensation and a drop in body temperature and heart rate. Norepinephrine, but not epinephrine, plasma levels were elevated. Adiponectin plasma concentrations were acutely and significantly decreased. There was a trend of increased monocyte chemoattractant protein-1 plasma concentrations. Interleukin-6 and leptin levels increased and decreased, respectively, in both groups. Vascular endothelial growth factor plasma levels were unaffected. Subcutaneous adipokine gene expression was unchanged. Cold exposure caused SNS activation and differentially influenced adipokine secretion. Adiponectin levels were acutely reduced, whereas monocyte chemoattractant protein-1 concentrations tended to increase. No specific changes in leptin and IL-6 concentrations were detectable. The observed alterations appeared to be posttranscriptional because adipokine gene expression was found to be unaltered. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Effect of the hot water extract of Artocarpus camansi leaves on 2,4,6-trinitrochlorobenzene (TNCB)-induced contact hypersensitivity in mice.

    PubMed

    Salonga, Reginald Bayani; Hisaka, Shinsuke; Nose, Mitsuhiko

    2014-01-01

    Medicinal plants with reported anti-inflammatory activity could have the potential use as anti-allergens and inhibitors of allergic contact dermatitis reactions produced by allergens and chemicals. Some species from the genus Artocarpus were reported to have anti-inflammatory activity. In the Philippines one local source is Artocarpus camansi BLANCO (Moraceae), which is utilized as an ingredient of their cuisine, and decoction of leaves is used for diabetes and baths of people with rheumatism. The objective of this study was to evaluate the effect of the hot water extract of A. camansi leaves on contact hypersensitivity (CHS) in mice. Contact hypersensitivity was induced using 2,4,6-trinitrochlorobenzene (TNCB). The results showed that the A. camansi hot water extract exhibited significant activity against the swelling produced during 24 h and 48 h post-challenge. The same responses were observed from the mice that received the kamansi ethanol-precipitate (KEP) and kamansi ethanol precipitate water-soluble (KEPWS) fractions. Since the high molecular mass fraction showed the significant activity, we therefore speculate that the compound responsible might be a polysaccharide and/or glycoprotein. In conclusion, our results suggest that the hot water extract of A. camansi leaves might be an effective natural product to treat allergic contact dermatitis. However, further investigations are required to understand the mechanisms involved.

  11. hpaA mutants of Xanthomonas campestris pv. vesicatoria are affected in pathogenicity but retain the ability to induce host-specific hypersensitive reaction.

    PubMed

    Huguet, E; Hahn, K; Wengelnik, K; Bonas, U

    1998-09-01

    Xanthomonas campestris pv. vesicatoria is the causal agent of bacterial spot disease on pepper and tomato plants. We reported previously that the main hrp (hypersensitive reaction and pathogenicity) gene cluster in X. c. pv. vesicatoria contains six transcription units, designated hrpA to hrpF. We present here the sequence of the hrpD operon and an analysis of non-polar mutants in each of the six genes. Three genes, hrcQ, hrcR and hrcS, are predicted to encode conserved components of type III protein secretion systems in plant and mammalian pathogenic bacteria. For hrpD5 and hrpD6, homologues have only been found in Ralstonia solanacearum. Interestingly, the hrpD operon contains one gene, hpaA (for hrp-associated), which is specifically required for disease development. hpaA mutants are affected in pathogenicity, but retain in part the ability to induce avirulence gene-mediated, host-specific hypersensitive reaction (HR). In addition, HpaA was found to contain two functional nuclear localization signals, which are important for the interaction with the plant. We propose that HpaA is an effector protein that may be translocated into the host cell via the Hrp secretion pathway.

  12. Pharmacological Blockade of TRPM8 Ion Channels Alters Cold and Cold Pain Responses in Mice

    PubMed Central

    McCoy, Daniel D.; McKemy, David D.

    2011-01-01

    TRPM8 (Transient Receptor Potential Melastatin-8) is a cold- and menthol-gated ion channel necessary for the detection of cold temperatures in the mammalian peripheral nervous system. Functioning TRPM8 channels are required for behavioral responses to innocuous cool, noxious cold, injury-evoked cold hypersensitivity, cooling-mediated analgesia, and thermoregulation. Because of these various roles, the ability to pharmacologically manipulate TRPM8 function to alter the excitability of cold-sensing neurons may have broad impact clinically. Here we examined a novel compound, PBMC (1-phenylethyl-4-(benzyloxy)-3-methoxybenzyl(2-aminoethyl)carbamate) which robustly and selectively inhibited TRPM8 channels in vitro with sub-nanomolar affinity, as determined by calcium microfluorimetry and electrophysiology. The actions of PBMC were selective for TRPM8, with no functional effects observed for the sensory ion channels TRPV1 and TRPA1. PBMC altered TRPM8 gating by shifting the voltage-dependence of menthol-evoked currents towards positive membrane potentials. When administered systemically to mice, PBMC treatment produced a dose-dependent hypothermia in wildtype animals while TRPM8-knockout mice remained unaffected. This hypothermic response was reduced at lower doses, whereas responses to evaporative cooling were still significantly attenuated. Lastly, systemic PBMC also diminished cold hypersensitivity in inflammatory and nerve-injury pain models, but was ineffective against oxaliplatin-induced neuropathic cold hypersensitivity, despite our findings that TRPM8 is required for the cold-related symptoms of this pathology. Thus PBMC is an attractive compound that serves as a template for the formulation of highly specific and potent TRPM8 antagonists that will have utility both in vitro and in vivo. PMID:21984952

  13. Behavioral indices of ongoing pain are largely unchanged in male mice with tissue or nerve injury-induced mechanical hypersensitivity

    PubMed Central

    Urban, Rochelle; Scherrer, Gregory; Goulding, Evan H.; Tecott, Laurence H.; Basbaum, Allan I.

    2010-01-01

    Despite the impact of chronic pain on the quality of life in patients, including changes to affective state and daily life activities, rodent preclinical models rarely address this aspect of chronic pain. To better understand the behavioral consequences of the tissue and nerve injuries typically used to model neuropathic and inflammatory pain in mice, we measured home cage and affective state behaviors in animals with spared nerve injury (SNI), chronic constriction injury (CCI) or intraplantar CFA. Mechanical hypersensitivity is prominent in each of these conditions and persists for many weeks. Home cage behavior was continuously monitored for 16 days in a system that measures locomotion, feeding and drinking and allows for precise analysis of circadian patterns. When monitored after injury, animals with SNI and CFA behaved no differently from controls in any aspect of daily life. Animals with CCI were initially less active, but the difference between CCI and controls disappeared by 2 weeks after injury. Further, in all pain models, there was no change in any measure of affective state. We conclude that in these standard models of persistent pain, despite the development of prolonged hypersensitivity, the mice do not have significantly altered “quality of life”. As alteration in daily life activities is the feature that is so disrupted in patients with chronic pain, our results suggest that the models used here do not fully reflect the human conditions and point to a need for development of a murine chronic pain model in which lifestyle changes are manifest. PMID:21256675

  14. Cold adaptations.

    PubMed

    Launay, Jean-Claude; Savourey, Gustave

    2009-07-01

    Nowdays, occupational and recreational activities in cold environments are common. Exposure to cold induces thermoregulatory responses like changes of behaviour and physiological adjustments to maintain thermal balance either by increasing metabolic heat production by shivering and/or by decreasing heat losses consecutive to peripheral cutaneous vasoconstriction. Those physiological responses present a great variability among individuals and depend mainly on biometrical characteristics, age, and general cold adaptation. During severe cold exposure, medical disorders may occur such as accidental hypothermia and/or freezing or non-freezing cold injuries. General cold adaptations have been qualitatively classified by Hammel and quantitatively by Savourey. This last classification takes into account the quantitative changes of the main cold reactions: higher or lower metabolic heat production, higher or lesser heat losses and finally the level of the core temperature observed at the end of a standardized exposure to cold. General cold adaptations observed previously in natives could also be developed in laboratory conditions by continuous or intermittent cold exposures. Beside general cold adaptation, local cold adaptation exists and is characterized by a lesser decrease of skin temperature, a more pronounced cold induced vasodilation, less pain and a higher manual dexterity. Adaptations to cold may reduce the occurrence of accidents and improve human performance as surviving in the cold. The present review describes both general and local cold adaptations in humans and how they are of interest for cold workers.

  15. Simulation of a cold-stressed finger including the effects of wind, gloves, and cold-induced vasodilatation.

    PubMed

    Shitzer, A; Bellomo, S; Stroschein, L A; Gonzalez, R R; Pandolf, K B

    1998-06-01

    The thermal response of fingers exposed to cold weather conditions has been simulated. Energy balance equations were formulated, in a former study, for the tissue layers and the arterial, venous, and capillary blood vessels. The equations were solved by a finite difference scheme using the Thomas algorithm and the method of alternating directions. At this stage of development the model does not include any autonomic control functions. Model simulations assumed an electrical heating element to be embedded in the glove layers applied on the finger. A 1.3 W power input was calculated for maintaining finger temperatures at their pre-cold exposure level in a 0 degree C environment. Alternate assumptions of nutritional (low) and basal (high) blood flows in the finger demonstrated the dominance of this factor in maintaining finger temperatures at comfortable levels. Simulated exposures to still and windy air, at 4.17 m/s (15 km/h), indicated the profound chilling effects of wind on fingers in cold environments. Finally, the effects of variable blood flow in the finger, known as "cold-induced vasodilatation," were also investigated. Blood flow variations were assumed to be represented by periodic, symmetric triangular waves allowing for gradual opening-closing cycles of blood supply to the tip of the finger. Results of this part of the simulation were compared with measured records of bare finger temperatures. Good conformity was obtained for a plausible pattern of change in blood flow, which was assumed to be provided in its entirety to the tip of the finger alone.

  16. Functional roles of the pepper leucine-rich repeat protein and its interactions with pathogenesis-related and hypersensitive-induced proteins in plant cell death and immunity.

    PubMed

    Hong, Jeum Kyu; Hwang, In Sun; Hwang, Byung Kook

    2017-05-15

    Pepper leucine-rich repeat protein (CaLRR1) interacts with defense response proteins to regulate plant cell death and immunity. This review highlights the current understanding of the molecular functions of CaLRR1 and its interactor proteins. Plant cell death and immune responses to microbial pathogens are controlled by complex and tightly regulated molecular signaling networks. Xanthomonas campestris pv. vesicatoria (Xcv)-inducible pepper (Capsicum annuum) leucine-rich repeat protein 1 (CaLRR1) serves as a molecular marker for plant cell death and immunity signaling. In this review, we discuss recent advances in elucidating the functional roles of CaLRR1 and its interacting plant proteins, and understanding how they are involved in the cell death and defense responses. CaLRR1 physically interacts with pepper pathogenesis-related proteins (CaPR10 and CaPR4b) and hypersensitive-induced reaction protein (CaHIR1) to regulate plant cell death and defense responses. CaLRR1 is produced in the cytoplasm and trafficked to the extracellular matrix. CaLRR1 binds to CaPR10 in the cytoplasm and CaPR4b and CaHIR1 at the plasma membrane. CaLRR1 synergistically accelerates CaPR10-triggered hypersensitive cell death, but negatively regulates CaPR4b- and CaHIR1-triggered cell death. CaHIR1 interacts with Xcv filamentous hemagglutinin (Fha1) to trigger disease-associated cell death. The subcellular localization and cellular function of these CaLRR1 interactors during plant cell death and defense responses were elucidated by Agrobacterium-mediated transient expression, virus-induced gene silencing, and transgenic overexpression studies. CaPR10, CaPR4b, and CaHIR1 positively regulate defense signaling mediated by salicylic acid and reactive oxygen species, thereby activating hypersensitive cell death and disease resistance. A comprehensive understanding of the molecular functions of CaLRR1 and its interacting protein partners in cell death and defense responses will provide valuable

  17. Peripheral nervous control of cold-induced reduction in the respiratory quotient of the rat

    NASA Astrophysics Data System (ADS)

    Refinetti, Roberto

    1990-03-01

    Cold-exposed rats show a reduction in the respiratory quotient which is indicative of a relative shift from carbohydrates to lipids as substrates for oxidative metabolism. In the present study, the effects of food deprivation and cold exposure on the respiratory quotient were observed. In addition, the involvement of the three main branches of the peripheral nervous system (sympathetic, parasympathetic, and somatic) was investigated by means of synaptic blockade with propranolol, atropine, and quinine, respectively. Both propranolol and quinine blocked the cold-induced decrease in respiratory quotient and increase in heat production, whereas atropine had only minor and very brief effects. It is concluded that both the sympathetic and somatic branches are involved in the metabolic changes associated with cold-induced thermogenesis and that the increase in metabolic heat production involves a shift from carbohydrate to lipid utilization irrespective of which of the two branches is activated.

  18. X-ray induction of persistent hypersensitivity to mutation

    SciTech Connect

    Frank, J.P.; Williams, J.R.

    1982-04-16

    The progeny of x-irradiated V79 cells are hypersensitive to PUVA-(8-methoxypsoralen plus longwave ultraviolet light) induced mutation at the locus for hypoxanthine-guanine phosphoribosyl transferase. This hypersensitivity is most evident at low doses of pUVA that do not induce mutation in non-x-irradiated cells. The hypersensitivity is evoked by x-irradiation delivered as a single dose or as multiple fractions over a long period and persists for at least 108 days of exponential growth. This radiation-induced hypersensitivity to subsequent mutation is a new phenomenon that may be relevant to multistage carcinogenesis.

  19. Nerve growth factor-mediated neuronal plasticity in spinal cord contributes to neonatal maternal separation-induced visceral hypersensitivity in rats.

    PubMed

    Tsang, S W; Zhao, M; Wu, J; Sung, J J Y; Bian, Z-X

    2012-04-01

    Visceral hyperalgesia is a multifactorial gastrointestinal disorder which featured with alterations of abdominal motility and/or gut sensitivity, and is believed to be triggered by environmental stressor or psychological factors. However, its etiology remains incompletely understood. In this study, we aimed to investigate whether nerve growth factor (NGF)-mediated neuronal plasticity is involved in neonatal maternal separation (NMS)-induced visceral hypersensitivity in adult rats, and whether NGF antagonist can attenuate or block such development. In our experiments, animals subjected to NMS were developed with visceral hyperalgesia at age of 8 weeks. The threshold for visceral pain among these NMS rats was remarkably lowered than that of the normal handling (NH) rats; however, the expression levels of NGF, c-fos, calcitonin gene-related peptide (CGRP), Substance P, and tyrosine kinases A (TrkA) were notably elevated in lumbosacral spinal cord and/or dorsal root ganglion (DRG) when comparing to those of the NH rats. Further, as intra-peritoneal administration of NGF (10 μl at 1 μg/kg/day) was given to NH rats during neonatal period, effects that comparable to NMS induction were observed in the adulthood. In contrast, when NMS rats were treated with NGF antagonist K252a (10 μl/day from postnatal days 2-14), which acts against tyrosine kinases, the neonatal stress-induced down-shifted visceral pain threshold was restored and neuronal activation, specifically NGF and neuropeptide production, was attenuated. In conclusion, our data strongly suggest that NGF triggers neuronal plasticity and plays a crucial role in NMS-induced visceral hypersensitivity in which NGF antagonism provides positive inhibition via blocking the tyrosine phosphorylation of TrkA.

  20. Lycopene ameliorates thermal hyperalgesia and cold allodynia in STZ-induced diabetic rat.

    PubMed

    Kuhad, Anurag; Chopra, Kanwaljit

    2008-02-01

    Peripheral neuropathy is one of the common complications of diabetes mellitus. It is frequently associated with debilitating pain. The present study was designed to investigate effect of Lycopene, a carotenoid found in tomatoes, on hyperalgesia and cold allodynia in streptozotocin (STZ) induced diabetic rats. After 4-weeks of STZ injection, diabetic mice exhibited a significant thermal hyperalgesia cold allodynia, hyperglycemia and loss of body weights as compared with control rats. Chronic treatment of lycopene for 4 weeks significantly attenuated the cold allodynia and thermal hyperalgesia. The results emphasize the role of antioxidant such as lycopene as an adjuvant therapy in the treatment of diabetic neuropathy.

  1. Cold-atom physics using ultrathin optical fibers: light-induced dipole forces and surface interactions.

    PubMed

    Sagué, G; Vetsch, E; Alt, W; Meschede, D; Rauschenbeutel, A

    2007-10-19

    The strong evanescent field around ultrathin unclad optical fibers bears a high potential for detecting, trapping, and manipulating cold atoms. Introducing such a fiber into a cold-atom cloud, we investigate the interaction of a small number of cold cesium atoms with the guided fiber mode and with the fiber surface. Using high resolution spectroscopy, we observe and analyze light-induced dipole forces, van der Waals interaction, and a significant enhancement of the spontaneous emission rate of the atoms. The latter can be assigned to the modification of the vacuum modes by the fiber.

  2. Cold Temperature Induces the Reprogramming of Proteolytic Pathways in Yeast.

    PubMed

    Isasa, Marta; Suñer, Clara; Díaz, Miguel; Puig-Sàrries, Pilar; Zuin, Alice; Bichman, Anne; Gygi, Steven P; Rebollo, Elena; Crosas, Bernat

    2016-01-22

    Despite much evidence of the involvement of the proteasome-ubiquitin signaling system in temperature stress response, the dynamics of the ubiquitylome during cold response has not yet been studied. Here, we have compared quantitative ubiquitylomes from a strain deficient in proteasome substrate recruitment and a reference strain during cold response. We have observed that a large group of proteins showing increased ubiquitylation in the proteasome mutant at low temperature is comprised by reverses suppressor of Ty-phenotype 5 (Rsp5)-regulated plasma membrane proteins. Analysis of internalization and degradation of plasma membrane proteins at low temperature showed that the proteasome becomes determinant for this process, whereas, at 30 °C, the proteasome is dispensable. Moreover, our observations indicate that proteasomes have increased capacity to interact with lysine 63-polyubiquitylated proteins during low temperature in vivo. These unanticipated observations indicate that, during cold response, there is a proteolytic cellular reprogramming in which the proteasome acquires a role in the endocytic-vacuolar pathway. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Effect of the Forearm Tissue Temperature on the Cold Induced Vasodilation

    DTIC Science & Technology

    2005-05-01

    substantial role in reducing the risk of local cold injuries [ 2 ], and may be beneficial for improving dexterity and tactile sensitivity during exposure...collection of information if it does not display a currently valid OMB control number. 1. REPORT DATE 01 MAY 2005 2 . REPORT TYPE N/A 3. DATES COVERED...ANSI Std Z39-18 Effect of the Forearm Tissue Temperature on the Cold Induced Vasodilation 14 - 2 RTO-MP-HFM-126 skin and core temperatures on

  4. Spin Hall effects for cold atoms in a light induced gauge potential

    SciTech Connect

    Zhu, Shi-Liang; Fu, Hao; Wu, C.-J.; Zhang, S.-C.; Duan, L.-M. /Michigan U., MCTP

    2010-03-16

    We propose an experimental scheme to observe spin Hall effects with cold atoms in a light induced gauge potential. Under an appropriate configuration, the cold atoms moving in a spatially varying laser field experience an effective spin-dependent gauge potential. Through numerical simulation, we demonstrate that such a gauge field leads to observable spin Hall currents under realistic conditions. We also discuss the quantum spin Hall state in an optical lattice.

  5. Cellular origins of cold-induced brown adipocytes in adult mice.

    PubMed

    Lee, Yun-Hee; Petkova, Anelia P; Konkar, Anish A; Granneman, James G

    2015-01-01

    This work investigated how cold stress induces the appearance of brown adipocytes (BAs) in brown and white adipose tissues (WATs) of adult mice. In interscapular brown adipose tissue (iBAT), cold exposure increased proliferation of endothelial cells and interstitial cells expressing platelet-derived growth factor receptor, α polypeptide (PDGFRα) by 3- to 4-fold. Surprisingly, brown adipogenesis and angiogenesis were largely restricted to the dorsal edge of iBAT. Although cold stress did not increase proliferation in inguinal white adipose tissue (ingWAT), the percentage of BAs, defined as multilocular adipocytes that express uncoupling protein 1, rose from undetectable to 30% of total adipocytes. To trace the origins of cold-induced BAs, we genetically tagged PDGFRα(+) cells and adipocytes prior to cold exposure, using Pdgfra-Cre recombinase estrogen receptor T2 fusion protein (CreER(T2)) and adiponectin-CreER(T2), respectively. In iBAT, cold stress triggered the proliferation and differentiation of PDGFRα(+) cells into BAs. In contrast, all newly observed BAs in ingWAT (5207 out of 5207) were derived from unilocular adipocytes tagged by adiponectin-CreER(T2)-mediated recombination. Surgical denervation of iBAT reduced cold-induced brown adipogenesis by >85%, whereas infusion of norepinephrine (NE) mimicked the effects of cold in warm-adapted mice. NE-induced de novo brown adipogenesis in iBAT was eliminated in mice lacking β1-adrenergic receptors. These observations identify a novel tissue niche for brown adipogenesis in iBAT and further define depot-specific mechanisms of BA recruitment.

  6. Drug hypersensitivity reactions involving skin.

    PubMed

    Hausmann, Oliver; Schnyder, Benno; Pichler, Werner J

    2010-01-01

    Immune reactions to drugs can cause a variety of diseases involving the skin, liver, kidney, lungs, and other organs. Beside immediate, IgE-mediated reactions of varying degrees (urticaria to anaphylactic shock), many drug hypersensitivity reactions appear delayed, namely hours to days after starting drug treatment, showing a variety of clinical manifestations from solely skin involvement to fulminant systemic diseases which may be fatal. Immunohistochemical and functional studies of drug-specific T cells in patients with delayed reactions confirmed a predominant role for T cells in the onset and maintenance of immune-mediated delayed drug hypersensitivity reactions (type IV reactions). In these reactions, drug-specific CD4+ and CD8+ T cells are stimulated by drugs through their T cell receptors (TCR). Drugs can stimulate T cells in two ways: they can act as haptens and bind covalently to larger protein structures (hapten-carrier model), inducing a specific immune response. In addition, they may accidentally bind in a labile, noncovalent way to a particular TCR of the whole TCR repertoire and possibly also major histocompatibility complex (MHC)-molecules - similar to their pharmacologic action. This seems to be sufficient to reactivate certain, probably in vivo preactivated T cells, if an additional interaction of the drug-stimulated TCR with MHC molecules occurs. The mechanism was named pharmacological interaction of a drug with (immune) receptor and thus termed the p-i concept. This new concept may explain the frequent skin symptoms in drug hypersensitivity to oral or parenteral drugs. Furthermore, the various clinical manifestations of T cell-mediated drug hypersensitivity may be explained by distinct T cell functions leading to different clinical phenotypes. These data allowed a subclassification of the delayed hypersensitivity reactions (type IV) into T cell reactions which, by releasing certain cytokines and chemokines, preferentially activate and recruit

  7. Oxazolone-induced delayed type hypersensitivity reaction in the adult yucatan pigs. A useful model for drug development and validation.

    PubMed

    Nuhaily, Samer; Damaj, Bassam B; Maghazachi, Azzam A

    2009-09-01

    The purpose of this study was to establish a model of delayed type hypersensitivity (DTH) reaction in the ear skin of large animals such as adult Yucatan pigs, which may aid in evaluating the efficacy of therapeutic modalities of newly developed anti-inflammatory drugs. The pigs were sensitized with oxazolone, re-challenged with the same irritant six days later, and dosed with either vehicle or with cyclosporine A (CsA) before and after challenge. CsA reduced the redness, inhibited the accumulation of ear fluid and inflammatory cells, as well as the release of the inflammatory mediators. Further, CsA inhibited the proliferation of T cells collected from the spleens or PBMCs of CsA-treated pigs when these cells were stimulated in vitro with PMA plus Ionomycin. These results indicate that pig skin can be used to evaluate modalities for the purpose of developing drugs that may be used to treat DTH in humans.

  8. NADPH Oxidase-Derived ROS Induced by Chronic Intermittent Hypoxia Mediates Hypersensitivity of Lung Vagal C Fibers in Rats

    PubMed Central

    Yang, Chang-Huan; Zhuang, Wei-Ling; Shen, Yan-Jhih; Lai, Ching Jung; Kou, Yu Ru

    2016-01-01

    Obstructive sleep apnea (OSA), manifested by exposure to chronic intermittent hypoxia (CIH) and excess production of reactive oxygen species (ROS) in the airways, is associated with hyperreactive airway diseases. ROS, particularly when created by NADPH oxidase, are known to sensitize lung vagal C fibers (LVCFs), which may contribute to airway hypersensitivity pathogenesis. We investigated whether CIH augments the reflex and afferent responses of LVCFs to chemical stimulants and the roles of ROS and NADPH oxidase in such airway hypersensitivity. Rats were exposed to room air (RA) or CIH with/without daily treatment with MnTMPyP (a superoxide anion scavenger), apocynin (an NADPH oxidase inhibitor), or vehicle. At 16 h after their last exposure, intravenous capsaicin, adenosine, or α,β-methylene-ATP evoked an augmented apneic response in anesthetized rats with 14-days CIH exposure, compared to anesthetized rats with 14-days RA exposure. The augmented apneic responses to these LVCF stimulants were abolished by bilateral vagotomy or perivagal capsaicin treatment, which block LVCFs neural conduction and were significantly suppressed by treatment with MnTMPyP or apocynin, but not vehicle. Electrophysiological studies revealed that 14-days CIH exposure potentiated the responses of LVCFs to these stimulants. This effect was inhibited by treatment with MnTMPyP or apocynin treatment and was not seen in rats who received 7-days of CIH exposure. Biochemical analysis indicated that 14-days CIH exposure increased both lung lipid peroxidation, which is indicative of oxidative stress, and expression of the p47phox subunit in the membrane fraction of lung tissue, which is an index of NADPH oxidase activation. The former was prevented by treatment with either MnTMPyP or apocynin, while the later was prevented by treatment with apocynin only. These results suggest that 14-days CIH exposure sensitizes LVCFs in rats, leading to an exaggerated reflex and afferent responses to

  9. Pustular-type drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to carbamazepine with systemic muscle involvement.

    PubMed

    Matsuda, Haruna; Saito, Kanami; Takayanagi, Yoshikazu; Okazaki, Toshio; Kashima, Kenji; Ishikawa, Kazushi; Kai, Yoshitaka; Takeo, Naoko; Hatano, Yutaka; Okamoto, Osamu; Fujiwara, Sakuhei

    2013-02-01

    Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe reaction usually associated with maculopapular eruptions and systemic involvement. Here we report the first case, to our knowledge, of DIHS/DRESS due to carbamazepine with acute generalized pustular bacterid-like (AGPB-like) eruptions and skeletal muscle involvement. Reviewing our case and the published work, we discuss pustular-type DIHS/DRESS which, in most cases, involves acute generalized exanthematous pustulosis (AGEP)-like skin eruptions in response to carbamazepine. Pustular eruptions may appear in relatively few cases of DIHS/DRESS, in particular, when the causative drug is carbamazepine and, even in cases of intractable pustular bacterid-like eruptions, a reaction to a drug should be suspected. Skeletal muscle involvement may be associated with DIHS/DRESS as one of its systemic manifestations. © 2012 Japanese Dermatological Association.

  10. Drug induced hypersensitivity syndrome by triple therapy of peginterferon alpha2b, ribavirin and telaprevir in patient with double positive for HBV and HCV.

    PubMed

    Takagi, Hitoshi; Hoshino, Takashi; Naganuma, Atsushi; Koitabashi, Eri; Uehara, Sanae; Sakamoto, Naomi; Kudo, Tomohiro; Ryusaki, Keiichirou; Kakizaki, Satoru; Okamoto, Hiroaki

    2013-10-01

    Sixty year-old male positive for both HCV-RNA and HBsAg was treated by triple therapy of peginterferon alpha2b, ribavirin and telaprevir. Eight weeks after the beginning of the therapy, the patient developed drug induced hypersensitivity syndrome (DIHS) with general erythema multiforme and 64 times anti-HHV6 antibody elevation. Sixty milligram of prednisolone was administered with gradual dose reduction and the skin lesion was improved. HBV-DNA and transaminase elevated one week after the steroid induction and entecavir improved them. DIHS itself and the aggravation of hepatitis B by corticosteroid should be kept in mind in cases with dual infection of HBV and HCV treated by antivirals including telaprevir.

  11. Investigation of the role of delayed-type-hypersensitivity responses to myelin in the pathogenesis of Theiler's virus-induced demyelinating disease.

    PubMed Central

    Borrow, P; Welsh, C J; Tonks, P; Dean, D; Blakemore, W F; Nash, A A

    1998-01-01

    The contribution of autoimmune responses to the pathogenesis of Theiler's virus-induced demyelinating disease was investigated. Delayed-type hypersensitivity responses to myelin were examined in both symptomatic and asymptomatic mice at different times post-infection, in order to determine whether autoreactivity correlates with the development of demyelination. The results indicate that although autoimmune responses probably do not play a major role in the initiation of demyelination at early times post-infection, autoreactivity to myelin antigens dose eventually develop in symptomatic animals, perhaps through the mechanism of epitope spreading. Autoimmunity to myelin components is therefore an additional factor that may contribute to lesion progression in chronically diseased animals. Images Figure 2 PMID:9659218

  12. AAV Delivery of Endothelin-1 shRNA Attenuates Cold-Induced Hypertension.

    PubMed

    Chen, Peter Gin-Fu; Sun, Zhongjie

    2017-02-01

    Cold temperatures are associated with increased prevalence of hypertension. Cold exposure increases endothelin-1 (ET1) production. The purpose of this study is to determine whether upregulation of ET1 contributes to cold-induced hypertension (CIH). In vivo RNAi silencing of the ET1 gene was achieved by adeno-associated virus 2 (AAV2) delivery of ET1 short-hairpin small interfering RNA (ET1-shRNA). Four groups of male rats were used. Three groups were given AAV.ET1-shRNA, AAV.SC-shRNA (scrambled shRNA), and phosphate-buffered saline (PBS), respectively, before exposure to a moderately cold environment (6.7 ± 2°C), while the last group was given PBS and kept at room temperature (warm, 24 ± 2°C) and served as a control. We found that systolic blood pressure of the PBS-treated and SC-shRNA-treated groups increased significantly within 2 weeks of exposure to cold, reached a peak level (145 ± 4.8 mmHg) by 6 weeks, and remained elevated thereafter. By contrast, blood pressure of the ET1-shRNA-treated group did not increase, suggesting that silencing of ET1 prevented the development of CIH. Animals were euthanized after 10 weeks of exposure to cold. Cold exposure significantly increased the left ventricle (LV) surface area and LV weight in cold-exposed rats, suggesting LV hypertrophy. Superoxide production in the heart was increased by cold exposure. Interestingly, ET1-shRNA prevented cold-induced superoxide production and cardiac hypertrophy. ELISA assay indicated that ET1-shRNA abolished the cold-induced upregulation of ET1 levels, indicating effective silencing of ET1. In conclusion, upregulation of ET1 plays a critical role in the pathogenesis of CIH and cardiac hypertrophy. AAV delivery of ET1-shRNA is an effective therapeutic strategy for cold-related cardiovascular disease.

  13. [Hypersensitivity reactions to insulin].

    PubMed

    Becerril-Ángeles, Martín; Moctezuma-Trejo, Cristina; Espinosa-Larrañaga, Francisco

    2012-01-01

    Hypersensitivity reactions to insulin are infrequent, yet of clinical importance. The mechanisms of hypersensitivity involved can be of three types: I, III and IV. To describe the pathophysiology of hypersensitivity to insulin, its clinical features and diagnostic and therapeutic approach, that help identify the cases of allergy to insulin and begin a treatment, or if necessary, to refer patients to a specialists or appropriate medical attention. An electronic search of papers related to insulin hypersensitivity was performed in PubMed and the articles selected were those considered the most relevant for this review. Thirty eight papers about pathophysiology, mechanisms of injury and the different types of insulin involved in hypersensitivity reactions were included. Likewise, information for the diagnosis of insulin hypersensitivity and some options of treatment for first contact physicians or the referral of patients to specialists in endocrinology and allergy were included. Insulin hypersensitivity has a low prevalence and diverse clinical manifestations. The different types of insulin suitable allow the majority of cases of hypersensitivity to continue the treatment in a efficient and flexible manner.

  14. Treating dentin hypersensitivity

    PubMed Central

    Cunha-Cruz, Joana; Wataha, John C.; Zhou, Lingmei; Manning, Walter; Trantow, Michael; Bettendorf, Meishan M.; Heaton, Lisa J.; Berg, Joel

    2011-01-01

    Background Methods used by dental practitioners to diagnose and treat dentin hypersensitivity are not well documented. The authors conducted a survey of dentists in the Northwest Practice-based REsearch Collaborative in Evidence-based DENTistry (PRECEDENT) to ascertain the treatment methods they used. Methods Via an Internet survey, the authors collected data regarding methods used for diagnosis and treatment of dentin hypersensitivity from 209 Northwest PRECEDENT dentists. Results The PRECEDENT dentists indicated that they most often used fluoride varnishes and gels, advice regarding toothbrushing and diet, bonding agents, restorative materials and glutaraldehyde/2-hydroxyethyl methacrylate (HEMA) to treat dentin hypersensitivity. They reported that the most successful treatments were fluorides, glutaraldehyde/HEMA, bonding agents, potassium nitrates and restorative treatments; they considered observation, advice regarding toothbrushing and diet and laser therapy to be the least successful. Dentists listed fluorides, calcium phosphates, glutaraldehyde/HEMA and bonding agents as the treatments most desirable for inclusion in a future randomized clinical trial of dental hypersensitivity treatments. Conclusions Dentists rely on patients to assess the severity of dentin hypersensitivity. Modalities for the diagnosis and treatment of hypersensitivity are diverse. Methods used to diagnose and treat dentin hypersensitivity in practice are challenging to justify. Clinical Implications Practitioners should be aware of the diversity of methods available for diagnosing and treating dentin hypersensitivity as they manage the care of their patients with this condition. PMID:20807910

  15. Frequency of the HLA-B*1502 allele contributing to carbamazepine-induced hypersensitivity reactions in a cohort of Malaysian epilepsy patients.

    PubMed

    Then, Sue-Mian; Rani, Zam Zureena Mohd; Raymond, Azman Ali; Ratnaningrum, Safrina; Jamal, Rahman

    2011-09-01

    We describe the association of the HLA-B*1502 allele in 27 epilepsy patients (19 Malays, 8 Chinese) treated with carbamazepine (CBZ) at the UKM Medical Center (UKMMC), 6 with CBZ-Steven Johnson Syndrome (CBZ-SJS), 11 with CBZ-induced rash, 2 with suspected phenytoin-induced rash and 8 negative controls. Our study showed that 10 (6 Malay, 4 Chinese) patients were positive for HLA-B*1502. Out of the 10 patients, six were confirmed to have CBZ-SJS (p = 0.0006), while four patients developed a skin rash. However there were 6 Malay patients and 1 Chinese patient that developed a skin rash after CBZ administration who were not positive for the allele, indicating that there might be more that one allele associated with CBZ-induced hypersensitivity. Another 2 patients were suspected of having phenytoin-induced rash, instead of CBZ, and these patients did not have HLA-B*1502. In conclusion, this study confirmed the association of HLA-B*1502 with CBZ-SJS among Malaysian epilepsy patients, however there might be other genes that could be responsible for the CBZ-induced rash.

  16. Is the drug-induced hypersensitivity syndrome (DIHS) due to human herpesvirus 6 infection or to allergy-mediated viral reactivation? Report of a case and literature review

    PubMed Central

    2010-01-01

    Background Drug-Induced Hypersensitivity Syndrome (DIHS) is a severe and rare systemic reaction triggered by a drug (usually an antiepileptic drug). We present a case of DISH and we review studies on the clinical features and treatment of DIHS, and on its pathogenesis in which two elements (Herpesvirus infection and the drug) interact with the immune system to trigger such a syndrome that can lead to death in about 20% of cases. Case presentation We report the case of a 26-year old woman with fever, systemic maculopapular rash, lymphadenopathy, hepatitis and eosinophilic leukocytosis. She had been treated with antibiotics that gave no benefit. She was taking escitalopram and lamotrigine for a bipolar disease 30 days before fever onset. Because the patient's general condition deteriorated, betamethasone and acyclovir were started. This treatment resulted in a mild improvement of symptoms. Steroids were rapidly tapered and this was followed with a relapse of fever and a worsening of laboratory parameters. Human herpesvirus 6 (HHV-6) DNA was positive as shown by PCR. Drug-Induced Hypersensitivity Syndrome (DIHS) was diagnosed. Symptoms regressed on prednisone (at a dose of 50 mg/die) that was tapered very slowly. The patient recovered completely. Conclusions The search for rare causes of fever led to complete resolution of a very difficult case. As DIHS is a rare disease the most relevant issue is to suspect and include it in differential diagnosis of fevers of unknown origin. Once diagnosed, the therapy is easy (steroidal administration) and often successful. However our case strongly confirms that attention should be paid on the steroidal tapering that should be very slow to avoid a relapse. PMID:20205923

  17. Is the drug-induced hypersensitivity syndrome (DIHS) due to human herpesvirus 6 infection or to allergy-mediated viral reactivation? Report of a case and literature review.

    PubMed

    Gentile, Ivan; Talamo, Maria; Borgia, Guglielmo

    2010-03-06

    Drug-Induced Hypersensitivity Syndrome (DIHS) is a severe and rare systemic reaction triggered by a drug (usually an antiepileptic drug). We present a case of DISH and we review studies on the clinical features and treatment of DIHS, and on its pathogenesis in which two elements (Herpesvirus infection and the drug) interact with the immune system to trigger such a syndrome that can lead to death in about 20% of cases. We report the case of a 26-year old woman with fever, systemic maculopapular rash, lymphadenopathy, hepatitis and eosinophilic leukocytosis. She had been treated with antibiotics that gave no benefit. She was taking escitalopram and lamotrigine for a bipolar disease 30 days before fever onset. Because the patient's general condition deteriorated, betamethasone and acyclovir were started. This treatment resulted in a mild improvement of symptoms. Steroids were rapidly tapered and this was followed with a relapse of fever and a worsening of laboratory parameters. Human herpesvirus 6 (HHV-6) DNA was positive as shown by PCR. Drug-Induced Hypersensitivity Syndrome (DIHS) was diagnosed. Symptoms regressed on prednisone (at a dose of 50 mg/die) that was tapered very slowly. The patient recovered completely. The search for rare causes of fever led to complete resolution of a very difficult case. As DIHS is a rare disease the most relevant issue is to suspect and include it in differential diagnosis of fevers of unknown origin. Once diagnosed, the therapy is easy (steroidal administration) and often successful. However our case strongly confirms that attention should be paid on the steroidal tapering that should be very slow to avoid a relapse.

  18. Inhibition of common cold-induced aggravation of childhood asthma by leukotriene receptor antagonists.

    PubMed

    Yoshihara, Shigemi; Fukuda, Hironobu; Abe, Toshio; Nishida, Mitsuhiro; Yamada, Yumi; Kanno, Noriko; Arisaka, Osamu

    2012-09-01

    Virus infection is an important risk factor for aggravation of childhood asthma. The objective of this study was to examine the effect of drugs on aggravation of asthma induced by a common cold. Asthma control was examined in a survey of 1,014 Japanese pediatric patients with bronchial asthma. The occurrence of common cold, asthma control, and drugs used for asthma control were investigated using a modified Childhood Asthma Control Test (C-ACT) for patients aged <4 years old and 4 to 11 years old, and an Asthma Control Test (ACT) for patients aged 12 to 15 years old. The status of asthma control did not differ among the age groups. The prevalence of common cold and aggravation of asthma were significantly higher in patients aged <4 years old. Control of asthma following common cold-induced aggravation was significantly less effective in patients aged <4 years old compared to those aged ≥4 years old. In patients aged <4 years old with a common cold, asthma control was significantly more effective for those treated with leukotriene receptor antagonists (LTRAs) compared to treatment without LTRAs. Asthma control did not differ between patients who did or did not take inhaled corticosteroids or long-acting β2 stimulants. These findings showed a high prevalence of common cold in younger patients with childhood asthma and indicated that common cold can induce aggravation of asthma. LTRAs are useful for long-term asthma control in very young patients who develop an asthma attack due to a common cold.

  19. Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions.

    PubMed

    Amstutz, Ursula; Shear, Neil H; Rieder, Michael J; Hwang, Soomi; Fung, Vincent; Nakamura, Hidefumi; Connolly, Mary B; Ito, Shinya; Carleton, Bruce C

    2014-04-01

    To systematically review evidence on genetic risk factors for carbamazepine (CBZ)-induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA-B*15:02 and HLA-A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ-induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA-B*15:02 or HLA-A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results? A systematic literature search was performed for HLA-B*15:02 and HLA-A*31:01 and their association with CBZ-induced HSRs. Evidence was critically appraised and clinical practice recommendations were developed based on expert group consensus. Patients carrying HLA-B*15:02 are at strongly increased risk for CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in populations where HLA-B*15:02 is common, but not CBZ-induced hypersensitivity syndrome (HSS) or maculopapular exanthema (MPE). HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported from Asian countries only, including China, Thailand, Malaysia, and India. HLA-B*15:02 is rare among Caucasians or Japanese; no HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported so far in these groups. HLA-A*31:01-positive patients are at increased risk for CBZ-induced HSS and MPE, and possibly SJS/TEN and acute generalized exanthematous pustulosis (AGEP). This association has been shown in Caucasian, Japanese, Korean, Chinese, and patients of mixed origin; however, HLA-A*31:01 is common in most ethnic groups. Not all patients carrying either risk variant develop an HSR, resulting in a relatively low positive predictive value of the genetic tests. This review provides the latest update on genetic markers for CBZ HSRs, clinical practice recommendations as a basis for informed decision making regarding

  20. Mitofusin-2 protects against cold stress-induced cell injury in HEK293 cells

    SciTech Connect

    Zhang, Wenbin; Chen, Yaomin; Yang, Qun; Che, Honglei; Chen, Xiangjun; Yao, Ting; Zhao, Fang; Liu, Mingchao; Ke, Tao; Chen, Jingyuan; Luo, Wenjing

    2010-06-25

    Mitochondrial impairment is hypothesized to contribute to cell injury during cold stress. Mitochondria fission and fusion are closely related in the function of the mitochondria, but the precise mechanisms whereby these processes regulate cell injury during cold stress remain to be determined. HEK293 cells were cultured in a cold environment (4.0 {+-} 0.1 {sup o}C) for 2, 4, 8, or 12 h. Western blot analyses showed that these cells expressed decreased fission-related protein Drp1 and increased fusion-related protein Mfn2 at 4 h; meanwhile, electron microscopy analysis revealed large and long mitochondrial morphology within these cells, indicating increased mitochondrial fusion. With silencing of Mfn2 but not of Mfn1 by siRNA promoted cold-stress-induced cell death with decreased ATP production in HEK293 cells. Our results show that increased expression of Mfn2 and mitochondrial fusion are important for mitochondrial function as well as cell survival during cold stress. These findings have important implications for understanding the mechanisms of mitochondrial fusion and fission in cold-stress-induced cell injury.

  1. Mitofusin-2 protects against cold stress-induced cell injury in HEK293 cells.

    PubMed

    Zhang, Wenbin; Chen, Yaomin; Yang, Qun; Che, Honglei; Chen, Xiangjun; Yao, Ting; Zhao, Fang; Liu, Mingchao; Ke, Tao; Chen, Jingyuan; Luo, Wenjing

    2010-06-25

    Mitochondrial impairment is hypothesized to contribute to cell injury during cold stress. Mitochondria fission and fusion are closely related in the function of the mitochondria, but the precise mechanisms whereby these processes regulate cell injury during cold stress remain to be determined. HEK293 cells were cultured in a cold environment (4.0+/-0.1 degrees C) for 2, 4, 8, or 12h. Western blot analyses showed that these cells expressed decreased fission-related protein Drp1 and increased fusion-related protein Mfn2 at 4h; meanwhile, electron microscopy analysis revealed large and long mitochondrial morphology within these cells, indicating increased mitochondrial fusion. With silencing of Mfn2 but not of Mfn1 by siRNA promoted cold-stress-induced cell death with decreased ATP production in HEK293 cells. Our results show that increased expression of Mfn2 and mitochondrial fusion are important for mitochondrial function as well as cell survival during cold stress. These findings have important implications for understanding the mechanisms of mitochondrial fusion and fission in cold-stress-induced cell injury.

  2. Study on the storm surges induced by cold waves in the Northern East China Sea

    NASA Astrophysics Data System (ADS)

    Mo, Dongxue; Hou, Yijun; Li, Jian; Liu, Yahao

    2016-08-01

    Cold wave, a kind of severe weather system, can bring strong wind and induce significant sea level rise to the Northern East China Sea. Based on CFSR data, the study shows the monthly distributions of invaded days and the spatiotemporal distributions of cold-wave wind direction and wind speed. A three-dimensional numerical model (ROMS) was developed to study storm surges induced by cold waves. The role of wind direction, wind speed, wind duration, extratropical cyclone and tide-surge interaction is investigated by conducting different sensitivity experiments. The results indicate that storm surges mainly happen at the coasts perpendicular to the wind directions. Surge range and time lag are related to the geometry of the basin and the continental shelf. The response of the sea-level fluctuations to cold wave indicates that there is a positive correlation between crests and wind speed, a negative correlation between troughs and wind speed, but no obvious correlations to wind duration. Coupled weather cold waves, which yield a larger range and a multi-peak structure of surges, can be classified according to cold wave tracks and extratropical cyclones. The tide-surge interaction has an obvious and different effect on the magnitudes and phases of storm surges for different tidal stages.

  3. Genotyping for Severe Drug Hypersensitivity

    PubMed Central

    Karlin, Eric; Phillips, Elizabeth

    2014-01-01

    Over the past decade, there have been significant advances in our understanding of the immunopathogenesis and pharmacogenomics of severe immunologically-mediated adverse drug reactions. Such T-cell-mediated adverse drug reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug-induced liver disease (DILI) and other drug hypersensitivity syndromes have more recently been shown to be mediated through interactions with various class I and II HLA alleles. Key examples have included the associations of HLA-B*15:02 and carbamazepine induced SJS/TEN in Southeast Asian populations and HLA-B*57:01 and abacavir hypersensitivity. HLA-B*57:01 screening to prevent abacavir hypersensitivity exemplifies a successful translational roadmap from pharmacogenomic discovery through to widespread clinical implementation. Ultimately, our increased understanding of the interaction between drugs and the MHC could be used to inform drug design and drive pre-clinical toxicity programs to improve drug safety. PMID:24429903

  4. [Induced sputum supernatant prostaglandin E2 during oral aspirin challenge of asthmatic patients with and without aspirin hypersensitivity and healthy controls--pilot study].

    PubMed

    Ignacak, Maria; Celejewska-Wójcik, Natalia; Wójcik, Krzysztof; Sałapa, Kinga; Konduracka, Ewa; Sanak, Marek; Tyrak, Katarzyna; Sładek, Krzysztof; Musiał, Jacek; Mastalerz, Lucyna

    2016-01-01

    The aim of this pilot study was to evaluate changes in the concentration of prostaglandin E2 (PGE2) in induced sputum supernatant in 3 groups: sub- jects with NSAID-exacerbated respira- tory disease (NERD), aspirin tolerant asthma (ATA) and healthy controls (HC), before and after oral aspirin chal- lenge test. The study was conducted in the years 2014-2015 at the Clinical Department of the Pulmonology Clinic at the University Hospital in Cracow. 43 patients were enrolled in the study (NERD - n = 15, ATA - n = 15 and HC - n = 13). All of them underwent a placebo-controlled oral aspirin challenge. Sputum was induced 24 hours before the challenge and immediately after the test. Induced sputum was processed in order to obtain cystospin slides to depict inflammatory cell patterns and supernatants, in which PGE2 was measured. The concentration of PGE2 was determined using mass spectrometry coupled with gas chromatography (gas chromatography/mass spectrometry - GC/MS). After aspirin challenge, the concentration of PGE2 in induced sputum supernatant decreased in both asthmatics hypersensitive to aspirin (p = 0.01) and those who tolerated aspirin well (p = 0.17). The change in the healthy control group was not statistically significant. These results support the cyclooxygenase theory of PGE2 inhibition by aspirin. However, the mechanism of bronchoconstriction after aspirin administration alone in patients with NSAID-exacerbated respiratory disease remains unclear.

  5. Effects of baicalin cream in two mouse models: 2,4-dinitrofluorobenzene-induced contact hypersensitivity and mouse tail test for psoriasis

    PubMed Central

    Wu, Jie; Li, Hong; Li, Ming

    2015-01-01

    Background:Scutellaria baicalensis is a Chinese herbal medicine that has been used for centuries to treat psoriasis. Baicalin is one of the major flavonoids and bioactive components of S. baicalensis and is responsible for the pharmacologic actions of the plant. Objective: This study aimed to investigate the anti-inflammatory effect and keratinocyte differentiation-inducing activity of baicalin in vivo. Methods: Baicalin was formulated into topical creams at concentrations of 1%, 3%, and 5%. The anti-inflammatory effect of baicalin cream was evaluated in 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS) mice, and its keratinocyte-modulating action was assessed using the mouse tail model for psoriasis. Results: During the topical application of baicalin cream, no evidence of irritant effect was observed in both tests. In the inflammation model, mice exposed to baicalin cream displayed a reduction in DNFB-induced CHS responses compared with vehicle-treated animals, showing that the topical application of baicalin cream exerted an anti-inflammatory effect. In the second model, baicalin cream dose-dependently increased the orthokeratosis of granular layers and the relative epidermal thickness of mouse tail skin, indicative of the keratinocyte differentiation-inducing activity of this topical preparation. Conclusions: Taking the in vivo findings together, the present study indicated that baicalin cream may be a promising antipsoriatic agent worthy of further investigation for psoriasis treatment. PMID:25932143

  6. Effects of baicalin cream in two mouse models: 2,4-dinitrofluorobenzene-induced contact hypersensitivity and mouse tail test for psoriasis.

    PubMed

    Wu, Jie; Li, Hong; Li, Ming

    2015-01-01

    Scutellaria baicalensis is a Chinese herbal medicine that has been used for centuries to treat psoriasis. Baicalin is one of the major flavonoids and bioactive components of S. baicalensis and is responsible for the pharmacologic actions of the plant. This study aimed to investigate the anti-inflammatory effect and keratinocyte differentiation-inducing activity of baicalin in vivo. Baicalin was formulated into topical creams at concentrations of 1%, 3%, and 5%. The anti-inflammatory effect of baicalin cream was evaluated in 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS) mice, and its keratinocyte-modulating action was assessed using the mouse tail model for psoriasis. During the topical application of baicalin cream, no evidence of irritant effect was observed in both tests. In the inflammation model, mice exposed to baicalin cream displayed a reduction in DNFB-induced CHS responses compared with vehicle-treated animals, showing that the topical application of baicalin cream exerted an anti-inflammatory effect. In the second model, baicalin cream dose-dependently increased the orthokeratosis of granular layers and the relative epidermal thickness of mouse tail skin, indicative of the keratinocyte differentiation-inducing activity of this topical preparation. Taking the in vivo findings together, the present study indicated that baicalin cream may be a promising antipsoriatic agent worthy of further investigation for psoriasis treatment.

  7. Molecular characterization of the cold- and heat-induced Arabidopsis PXL1 gene and its potential role in transduction pathways under temperature fluctuations.

    PubMed

    Jung, Chang Gyo; Hwang, Sun-Goo; Park, Yong Chan; Park, Hyeon Mi; Kim, Dong Sub; Park, Duck Hwan; Jang, Cheol Seong

    2015-03-15

    LRR-RLK (Leucine-Rich Repeat Receptor-Like Kinase) proteins are believed to play essential roles in cell-to-cell communication during various cellular processes including development, hormone perception, and abiotic stress responses. We isolated an LRR-RLK gene previously named Arabidopsis PHLOEM INTERCALATED WITH XYLEM-LIKE 1 (AtPXL1) and examined its expression patterns. AtPXL1 was highly induced by cold and heat stress, but not by drought. The fluorescence signal of 35S::AtPXL1-EGFP was closely localized to the plasma membrane. A yeast two-hybrid and bimolecular fluorescence complementation assay exhibited that AtPXL1 interacts with both proteins, A. thaliana histidine-rich dehydrin1 (AtHIRD1) and A. thaliana light-harvesting protein complex I (AtLHCA1). We found that AtPXL1 possesses autophosphorylation activity and phosphorylates AtHIRD1 and AtLHCA1 in an in vitro assay. Subsequently, we found that the knockout line (atpxl1) showed hypersensitive phenotypes when subjected to cold and heat during the germination stage, while the AtPXL1 overexpressing line as well as wild type plants showed high germination rates compared to the knockout plants. These results provide an insight into the molecular function of AtPXL1 in the regulation of signal transduction pathways under temperature fluctuations. Copyright © 2015 Elsevier GmbH. All rights reserved.

  8. Salidroside reduces cold-induced mucin production by inhibiting TRPM8 activation.

    PubMed

    Li, Qi; Zhou, Xiang-Dong; Kolosov, Victor P; Perelman, Juliy M

    2013-09-01

    Salidroside is an effective component of the traditional Chinese herb, Rhodiola rosea, that is known to have the ability to protect individuals from cold attacks. In the present study, we investigated the effects of salidroside on respiratory epithelial cells exposed to cold temperatures. We wished to determine whether salidroside exerts any effect on cold-induced mucin (MUC) production and the possible mechanisms involved in this process. We incubated HBE16 cells with salidroside, exposed them to a cold stimulus (18˚C), and assayed the following endpoints: MUC production (the expression of MUC5AC), concentration intracellular of free calcium ([Ca2+]i), the activation of the transient receptor potential melastatin 8 (TRPM8) channel and the cAMP response element-binding protein (CREB). Our results revealed a significant increase in the [Ca2+]i concentration, as well as in TRPM8 and CREB expression in the cold-stimulated cells. MUC5AC expression was also increased. Treatment of the cells with salidroside at concentrations of 50 and 100 µM decreased the [Ca2+]i concentration, with a maximal effect detected in the cells treated with 100 µM salidroside. The expression of TRPM8 and TRPM8 channel conductivity were also repressed by salidroside; salidroside decreased the high levels of CREB activity and phosphorylation observed in the cold-stimulated cells. Furthermore, we transfected the cold-stimulated cells with CREB small interfering RNA (siRNA) to analyze TRPM8 gene expression in the absence of CREB activity. The results revealed that the cells treated with either CREB siRNA or salidroside expressed low levels of TRPM8 mRNA and protein. These results indicate that salidroside reduces MUC overproduction induced by cold stimuli and that salidroside exerts its protective effects by inhibiting TRPM8 activation, mainly by decreasing CREB activity.

  9. [Evaluation of short-time premedication with d-chlorpheniramine maleate injection for paclitaxel-induced hypersensitivity reaction].

    PubMed

    Harada, Tomohiko; Doi, Masakazu; Yamada, Yasuhiko; Akase, Tomohide

    2008-08-01

    Paclitaxel(referred to hereinafter as PTX )is used in ovarian cancer, non-small cell lung cancer, breast cancer, gastric cancer, and endometrial cancer with positive treatment result reports. However, severe allergic reactions such as decreases in blood pressure and impaired breathing occur with relatively high frequency. For the prevention of such allergic reactions, administration of a premedication composed of the three components, dexamethasone sodium phosphate injection, diphenhydramine hydrochloride tablet, and ranitidine hydrochloride injection solution(or injectable famodine), is advised in the appended documentation. Administration is difficult because, among these three components, only diphenhydramine hydrochloride is administered orally and thus must be provided through the internal medicine department. Particularly when this combined dosage is administered as outpatient chemotherapy, the doctor must prescribe diphenhydramine hydrochloride tablets, and the patient must not forget to bring them on the day in which chemotherapy is administered. Also, checks by the medical staff such as pharmacists and nurses are required, complicating the administration of this therapy further. Taking this situation into consideration, our hospital uses a short-time premedication method wherein d-Chlorpheniramine Maleate injections are substituted for diphenhydramine hydrochloride tablets, and the time required for premedication is reduced to 15 minutes. This study investigated the allergic reaction ratio to consider the safety and usefulness of the short-time premedication method used at our hospital. The chemotherapy regimens conducted for the subject patients were 9 cases of PTX+CBDCA, 6 cases of biweekly- PTX, and 5 cases of weekly-PTX. A total of 67 PTX injections were given, 15 of them being first-time administrations. The ratio of allergic/hypersensitivity reactions was 10.0%(2 cases in 20). The short-time premedication method using d-Chlorpheniramine Maleate

  10. Chronic mitochondrial uncoupling treatment prevents acute cold-induced oxidative stress in birds.

    PubMed

    Stier, Antoine; Massemin, Sylvie; Criscuolo, François

    2014-12-01

    Endotherms have evolved two major types of thermogenesis that allow them to actively produce heat in response to cold exposure, either through muscular activity (i.e. shivering thermogenesis) or through futile electro-chemical cycles (i.e. non-shivering thermogenesis). Amongst the latter, mitochondrial uncoupling is of key importance because it is suggested to drive heat production at a low cost in terms of oxidative stress. While this has been experimentally shown in mammals, the oxidative stress consequences of cold exposure and mitochondrial uncoupling are clearly less understood in the other class of endotherms, the birds. We compared metabolic and oxidative stress responses of zebra finches chronically treated with or without a chemical mitochondrial uncoupler (2,4-dinitrophenol: DNP), undergoing an acute (24 h) and a chronic (4 weeks) cold exposure (12 °C). We predicted that control birds should present at least a transient elevation of oxidative stress levels in response to cold exposure. This oxidative stress cost should be more pronounced in control birds than in DNP-treated birds, due to their lower basal uncoupling state. Despite similar increase in metabolism, control birds presented elevated levels of DNA oxidative damage in response to acute (but not chronic) cold exposure, while DNP-treated birds did not. Plasma antioxidant capacity decreased overall in response to chronic cold exposure. These results show that acute cold exposure increases oxidative stress in birds. However, uncoupling mitochondrial functioning appears as a putative compensatory mechanism preventing cold-induced oxidative stress. This result confirms previous observations in mice and underlines non-shivering thermogenesis as a putative key mechanism for endotherms in mounting a response to cold at a low oxidative cost.

  11. Role of the sympathetic nervous system in cold-induced hypertension in rats.

    PubMed

    Papanek, P E; Wood, C E; Fregly, M J

    1991-07-01

    Hypertension develops in rats exposed chronically to cold [6 +/- 2 degrees C (SE)] and includes both an elevation of mean arterial pressure and cardiac hypertrophy. Previous studies suggest that cold-exposed animals, at least initially, have a large sustained increase in the activity of their sympathetic nervous system, suggesting a failure of the baroreceptor system to provide sufficient negative feedback to the central nervous system. The present study was designed to investigate whether alterations in the activity of the sympathetic nervous system, including the baroreceptor reflex, occur during exposure to cold and whether they contribute to cold-induced hypertension. Twenty male rats were prepared with indwelling catheters in the femoral artery and vein. Ten of the rats were exposed to cold (6 +/- 2 degrees C) chronically, while the remaining 10 were kept at 26 +/- 2 degrees C. Withdrawal of arterial blood samples (less than 5 ml/kg), measurement of direct arterial pressures, and measurement of baroreflex function were carried out at 0800 h at intervals throughout the experiment. Norepinephrine and epinephrine concentrations in plasma were also determined at intervals throughout the experiment. Systolic, diastolic, and mean blood pressures of cold-exposed rats were increased to levels significantly above those of controls. The sensitivity of the baroreflex (delta heart period/delta mean arterial pressure) was decreased in the cold-treated group. The concentration of norepinephrine in plasma increased after 24 h of exposure to cold and remained elevated throughout the experiment, whereas the concentration of epinephrine in plasma increased initially but returned to control levels after 19 days of exposure to cold.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Cold-induced limb pain decreases sensitivity to pressure-pain sensations in the ipsilateral forehead.

    PubMed

    Knudsen, Lone; Drummond, Peter D

    2009-11-01

    The aim of this study was to investigate the effect of unilateral limb pain on sensitivity to pain on each side of the forehead. In the first experiment, pressure-pain thresholds and sharpness sensations were assessed on each side of the forehead in 45 healthy volunteers before and after a 10 degrees C cold pressor of the hand and in 18 controls who were not subjected to the cold pressor. In a second experiment, forehead sensitivity was assessed in 32 healthy volunteers before and after a 2 degrees C cold pressor. The assessments were repeated without the cold pressor, and before and after six successive 4 degrees C cold pressor tests. The 10 degrees C cold pressor did not influence forehead sensitivity, whereas the 2 degrees C cold pressor and the 4 degrees C cold pressor tests resulted in bilateral analgesia to sharpness and pressure. The analgesia to pressure was greater in the ipsilateral forehead. Stress-induced analgesia and diffuse noxious inhibitory controls may have contributed to the analgesia to pressure-pain and sharpness sensations bilaterally after the most painful cold pressor tests. The locus coeruleus inhibits ipsilateral nociceptive activity in dorsal horn neurons during limb inflammation, and thus may have mediated the ipsilateral component of analgesia. Pain-evoked changes in forehead sensitivity differed for sharpness and pressure, possibly due to separate thalamic or cortical representations of cutaneous and deep tissue sensibility. These findings suggest that several mechanisms act concurrently to influence pain sensitivity at sites distant from a primary site of painful stimulation.

  13. Mechanism of sand slide - cold lahar induced by extreme rainfall

    NASA Astrophysics Data System (ADS)

    Fukuoka, Hiroshi; Yamada, Masumi; Dok, Atitkagna

    2014-05-01

    Along with the increasing frequencies of extreme rainfall events in almost every where on the earth, shallow slide - debris flow, i.e. cold lahars running long distance often occurs and claims downslope residents lives. In the midnight of 15 October 2013, Typhoon Wilpha attacked the Izu-Oshima, a active volcanic Island and the extreme rainfall of more than 800 mm / 24 hours was recorded. This downpour of more than 80 mm/hr lasted 4 hours at its peak and caused a number of cold lahars. The initial stage of those lahars was shallow slides of surface black volcanic ash deposits, containing mostly fine sands. The thickness was only 50 cm - 1 m. In the reconnaissance investigation, author found that the sliding surface was the boundary of two separate volcanic ash layers between the black and yellow colored and apparently showing contrast of permeability and hardness. Permeability contrast may have contributed to generation of excess pore pressure on the border and trigger the slide. Then, the unconsolidated, unpacked mass was easily fluidized and transformed into mud flows, that which volcanologists call cold lahars. Seismometers installed for monitoring the active volcano's activities, succeeded to detect many tremors events. Many are spikes but 5 larger and longer events were extracted. They lasted 2 -3 minutes and if we assume that this tremors reflects the runout movement, then we can calculate the mean velocity of the lahars. Estimated velocity was 45 - 60 km/h, which is much higher than the average speed 30 - 40 km/h of debris flows observed in Japan. Flume tests of volcanic ash flows by the Forestry and Forest Products Research Institute showed the wet volcanic ash can run at higher speed than other materials. The two tremor records were compare d with the local residents witnessed and confirmed by newspaper reported that the reach of the lahar was observed at the exact time when tremor ends. We took the black volcanic ash and conducted ring shear tests to

  14. Curcumin reduces cold storage-induced damage in human cardiac myoblasts.

    PubMed

    Abuarqoub, Hadil; Green, Colin J; Foresti, Roberta; Motterlini, Roberto

    2007-04-30

    Curcumin is a polyphenolic compound possessing interesting anti-inflammatory and antioxidant properties and has the ability to induce the defensive protein heme oxygenase-1 (HO-1). The objective of this study was to investigate whether curcumin protects against cold storage-mediated damage of human adult atrial myoblast cells (Girardi cells) and to assess the potential involvement of HO-1 in this process. Girardi cells were exposed to either normothermic or hypothermic conditions in Celsior preservation solution in the presence or absence of curcumin. HO-1 protein expression and heme oxygenase activity as well as cellular damage were assessed after cold storage or cold storage followed by re-warming. In additional experiments, an inhibitor of heme oxygenase activity (tin protoporphyrin IX, 10 microM) or siRNA for HO-1 were used to investigate the participation of HO-1 as a mediator of curcumin-induced effects. Treatment with curcumin produced a marked induction of cardiac HO-1 in normothermic condition but cells were less responsive to the polyphenolic compound at low temperature. Cold storage-induced damage was markedly reduced in the presence of curcumin and HO-1 contributed to some extent to this effect. Thus, curcumin added to Celsior preservation solution effectively prevents the damage caused by cold-storage; this effect involves the protective enzyme HO-1 but also other not yet identified mechanisms.

  15. Tuberculin-induced delayed-type hypersensitivity reaction in a model of hu-PBMC-SCID mice grafted with autologous skin.

    PubMed Central

    Tsicopoulos, A.; Pestel, J.; Fahy, O.; Vorng, H.; Vandenbusche, F.; Porte, H.; Eraldi, L.; Wurtz, A.; Akoum, H.; Hamid, Q.; Wallaert, B.; Tonnel, A. B.

    1998-01-01

    We have developed an animal model to study human delayed-type hypersensitivity reactions. Previous studies in humans have shown after tuberculin injection the presence of a mononuclear cell infiltration, with almost no eosinophils, associated with a preferential Th-1-type cytokine profile. Human skin graft obtained from tuberculin-reactive donors was grafted onto the back of severe combined immunodeficient mice. After healing, mice were reconstituted intraperitoneally with peripheral mononuclear cells. Tuberculin and diluent were injected intradermally, and skin biopsies were performed 72 hours later. Skin grafts were divided into two parts, one for immunohistochemistry and one for in situ hybridization studies. Immunohistochemistry was performed on cryostat sections using the alkaline phosphatase anti-alkaline phosphatase technique. In the tuberculin-injected sites as compared with the diluent-injected sites, there were significant increases in the number of CD45+ pan leukocytes and CD4+, CD8+, CD45RO+ T cells but not in CD68+ monocytes/macrophages and EG2 or MBP+ eosinophils. The activation markers CD25 and HLA-DR were up-regulated in the tuberculin-injected sites. In situ hybridization was performed using 35S-labeled riboprobes for interleukin (IL)-2, interferon (IFN)-gamma, IL-4, and IL-5. After tuberculin injection, a preferential Th-1-type cytokine profile was observed with significant increases in the numbers of IL-2 and IFN-gamma mRNA-expressing cells. These results are similar to those reported after tuberculin-induced delayed-type hypersensitivity in humans, suggesting that this model might be useful to study cutaneous inflammatory reaction. Images Figure 4 PMID:9626072

  16. The prevalence of widespread central hypersensitivity in chronic pain patients.

    PubMed

    Schliessbach, J; Siegenthaler, A; Streitberger, K; Eichenberger, U; Nüesch, E; Jüni, P; Arendt-Nielsen, L; Curatolo, M

    2013-11-01

    Chronic pain is associated with generalized hypersensitivity and impaired endogenous pain modulation (conditioned pain modulation; CPM). Despite extensive research, their prevalence in chronic pain patients is unknown. This study investigated the prevalence and potential determinants of widespread central hypersensitivity and described the distribution of CPM in chronic pain patients. We examined 464 consecutive chronic pain patients for generalized hypersensitivity and CPM using pressure algometry at the second toe and cold pressor test. Potential determinants of generalized central hypersensitivity were studied using uni- and multivariate regression analyses. Prevalence of generalized central hypersensitivity was calculated for the 5th, 10th and 25th percentile of normative values for pressure algometry obtained by a previous large study on healthy volunteers. CPM was addressed on a descriptive basis, since normative values are not available. Depending on the percentile of normative values considered, generalized central hypersensitivity affected 17.5-35.3% of patients. 23.7% of patients showed no increase in pressure pain threshold after cold pressor test. Generalized central hypersensitivity was more frequent and CPM less effective in women than in men. Unclearly classifiable pain syndromes showed higher frequencies of generalized central hypersensitivity than other pain syndromes. Although prevalent in chronic pain, generalized central hypersensitivity is not present in every patient. An individual assessment is therefore required in order to detect altered pain processing. The broad basic knowledge about central hypersensitivity now needs to be translated into concrete clinical consequences, so that patients can be offered an individually tailored mechanism-based treatment. © 2013 European Federation of International Association for the Study of Pain Chapters.

  17. VAMP7 regulates constitutive membrane incorporation of the cold-activated channel TRPM8.

    PubMed

    Ghosh, Debapriya; Pinto, Silvia; Danglot, Lydia; Vandewauw, Ine; Segal, Andrei; Van Ranst, Nele; Benoit, Melissa; Janssens, Annelies; Vennekens, Rudi; Vanden Berghe, Pieter; Galli, Thierry; Vriens, Joris; Voets, Thomas

    2016-02-04

    The cation channel TRPM8 plays a central role in the somatosensory system, as a key sensor of innocuously cold temperatures and cooling agents. Although increased functional expression of TRPM8 has been implicated in various forms of pathological cold hypersensitivity, little is known about the cellular and molecular mechanisms that determine TRPM8 abundance at the plasma membrane. Here we demonstrate constitutive transport of TRPM8 towards the plasma membrane in atypical, non-acidic transport vesicles that contain lysosomal-associated membrane protein 1 (LAMP1), and provide evidence that vesicle-associated membrane protein 7 (VAMP7) mediates fusion of these vesicles with the plasma membrane. In line herewith, VAMP7-deficient mice exhibit reduced functional expression of TRPM8 in sensory neurons and concomitant deficits in cold avoidance and icilin-induced cold hypersensitivity. Our results uncover a cellular pathway that controls functional plasma membrane incorporation of a temperature-sensitive TRP channel, and thus regulates thermosensitivity in vivo.

  18. Constitutively active Pto induces a Prf-dependent hypersensitive response in the absence of avrPto.

    PubMed Central

    Rathjen, J P; Chang, J H; Staskawicz, B J; Michelmore, R W

    1999-01-01

    Resistance in tomato to Pseudomonas syringae pv tomato (avrPto) is conferred by the gene Pto in a gene-for-gene relationship. A hypersensitive disease resistance response (HR) is elicited when Pto and avrPto are expressed experimentally within the same plant cell. The kinase capability of Pto was required for AvrPto-dependent HR induction. Systematic mutagenesis of the activation segment of Pto kinase confirmed the homologous P+1 loop as an AvrPto-binding determinant. Specific amino acid substitutions in this region led to constitutive induction of HR upon expression in the plant cell in the absence of AvrPto. Constitutively active Pto mutants required kinase capability for activity, and were unable to interact with proteins previously shown to bind to wild-type Pto. The constitutive gain-of-function phenotype was dependent on a functional Prf gene, demonstrating activation of the cognate disease resistance pathway and precluding a role for Prf upstream of Pto. PMID:10369664

  19. Targeting the transient receptor potential vanilloid type 1 (TRPV1) assembly domain attenuates inflammation-induced hypersensitivity.

    PubMed

    Flynn, Robyn; Chapman, Kevin; Iftinca, Mircea; Aboushousha, Reem; Varela, Diego; Altier, Christophe

    2014-06-13

    The transient receptor potential channel vanilloid type 1 (TRPV1) is a non-selective cation channel expressed in sensory neurons of the dorsal root and trigeminal ganglia. TRPV1 is a polymodal channel activated by noxious heat, capsaicin, and protons. As a sensor for noxious stimuli, TRPV1 channel has been described as a key contributor to pain signaling. To form a functional channel, TRPV1 subunits must assemble into tetramers, and several studies have identified the TRPV1 C terminus as an essential element in subunit association. Here we combined biochemical assays with electrophysiology and imaging-based bimolecular fluorescence complementation (BiFC) and bioluminescence resonance energy transfer (BRET) in live cells to identify a short motif in the C-terminal tail of the TRPV1 subunit that governs channel assembly. Removing this region through early truncation or targeted deletion results in loss of subunit association and channel function. Importantly, we found that interfering with TRPV1 subunit association using a plasma membrane-tethered peptide attenuated mechanical and thermal hypersensitivity in two mouse models of inflammatory hyperalgesia. This represents a novel mechanism to disrupt TRPV1 subunit assembly and hence may offer a new analgesic tool for pain relief. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Targeting the Transient Receptor Potential Vanilloid Type 1 (TRPV1) Assembly Domain Attenuates Inflammation-induced Hypersensitivity*

    PubMed Central

    Flynn, Robyn; Chapman, Kevin; Iftinca, Mircea; Aboushousha, Reem; Varela, Diego; Altier, Christophe

    2014-01-01

    The transient receptor potential channel vanilloid type 1 (TRPV1) is a non-selective cation channel expressed in sensory neurons of the dorsal root and trigeminal ganglia. TRPV1 is a polymodal channel activated by noxious heat, capsaicin, and protons. As a sensor for noxious stimuli, TRPV1 channel has been described as a key contributor to pain signaling. To form a functional channel, TRPV1 subunits must assemble into tetramers, and several studies have identified the TRPV1 C terminus as an essential element in subunit association. Here we combined biochemical assays with electrophysiology and imaging-based bimolecular fluorescence complementation (BiFC) and bioluminescence resonance energy transfer (BRET) in live cells to identify a short motif in the C-terminal tail of the TRPV1 subunit that governs channel assembly. Removing this region through early truncation or targeted deletion results in loss of subunit association and channel function. Importantly, we found that interfering with TRPV1 subunit association using a plasma membrane-tethered peptide attenuated mechanical and thermal hypersensitivity in two mouse models of inflammatory hyperalgesia. This represents a novel mechanism to disrupt TRPV1 subunit assembly and hence may offer a new analgesic tool for pain relief. PMID:24808184

  1. The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB2 receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy

    PubMed Central

    2012-01-01

    Background Chemotherapeutic agents produce dose-limiting peripheral neuropathy through mechanisms that remain poorly understood. We previously showed that AM1710, a cannabilactone CB2 agonist, produces antinociception without producing central nervous system (CNS)-associated side effects. The present study was conducted to examine the antinociceptive effect of AM1710 in rodent models of neuropathic pain evoked by diverse chemotherapeutic agents (cisplatin and paclitaxel). A secondary objective was to investigate the potential contribution of alpha-chemokine receptor (CXCR4) signaling to both chemotherapy-induced neuropathy and CB2 agonist efficacy. Results AM1710 (0.1, 1 or 5 mg/kg i.p.) suppressed the maintenance of mechanical and cold allodynia in the cisplatin and paclitaxel models. Anti-allodynic effects of AM1710 were blocked by the CB2 antagonist AM630 (3 mg/kg i.p.), but not the CB1 antagonist AM251 (3 mg/kg i.p.), consistent with a CB2-mediated effect. By contrast, blockade of CXCR4 signaling with its receptor antagonist AMD3100 (10 mg/kg i.p.) failed to attenuate mechanical or cold hypersensitivity induced by either cisplatin or paclitaxel. Moreover, blockade of CXCR4 signaling failed to alter the anti-allodynic effects of AM1710 in the paclitaxel model, further suggesting distinct mechanisms of action. Conclusions Our results indicate that activation of cannabinoid CB2 receptors by AM1710 suppresses both mechanical and cold allodynia in two distinct models of chemotherapy-induced neuropathic pain. By contrast, CXCR4 signaling does not contribute to the maintenance of chemotherapy-induced established neuropathy or efficacy of AM1710. Our studies suggest that CB2 receptors represent a promising therapeutic target for the treatment of toxic neuropathies produced by cisplatin and paclitaxel chemotherapeutic agents. PMID:22998838

  2. Hypersensitivity reaction to azathioprine.

    PubMed

    Fields, C L; Robinson, J W; Roy, T M; Ossorio, M A; Byrd, R P

    1998-05-01

    Adverse drug reactions can vary from a simple rash to anaphylactic shock. While certain medications including the penicillins are well known to cause such reactions, other drugs are not as commonly recognized. Azathioprine hypersensitivity reactions tend to be benign and self-limiting with cessation of drug ingestion. We report a patient who had a hypersensitivity reaction to azathioprine, which manifested as distributive shock that mimicked sepsis. We also reviewed the English language literature for risk factors for a hypersensitivity reaction to azathioprine and its possible mechanism.

  3. 5,6-EET Is Released upon Neuronal Activity and Induces Mechanical Pain Hypersensitivity via TRPA1 on Central Afferent Terminals

    PubMed Central

    Sisignano, Marco; Park, Chul-Kyu; Angioni, Carlo; Zhang, Dong Dong; von Hehn, Christian; Cobos, Enrique J.; Ghasemlou, Nader; Xu, Zhen-Zhong; Kumaran, Vigneswara; Lu, Ruirui; Grant, Andrew; Fischer, Michael J. M.; Schmidtko, Achim; Reeh, Peter; Ji, Ru-Rong; Woolf, Clifford J.; Geisslinger, Gerd; Scholich, Klaus; Brenneis, Christian

    2012-01-01

    Epoxyeicosatrienoic acids (EETs) are cytochrome P450-epoxygenase-derived metabolites of arachidonic acid that act as endogenous signaling molecules in multiple biological systems. Here we have investigated the specific contribution of 5,6-EET to transient receptor potential (TRP) channel activation in nociceptor neurons and its consequence for nociceptive processing. We found that, during capsaicin-induced nociception, 5,6-EET levels increased in dorsal root ganglia (DRGs) and the dorsal spinal cord, and 5,6-EET is released from activated sensory neurons in vitro. 5,6-EET potently induced a calcium flux (100 nm) in cultured DRG neurons that was completely abolished when TRPA1 was deleted or inhibited. In spinal cord slices, 5,6-EET dose dependently enhanced the frequency, but not the amplitude, of spontaneous EPSCs (sEPSCs) in lamina II neurons that also responded to mustard oil (allyl isothiocyanate), indicating a presynaptic action. Furthermore, 5,6-EET-induced enhancement of sEPSC frequency was abolished in TRPA1-null mice, suggesting that 5,6-EET presynaptically facilitated spinal cord synaptic transmission by TRPA1. Finally, in vivo intrathecal injection of 5,6-EET caused mechanical allodynia in wild-type but not TRPA1-null mice. We conclude that 5,6-EET is synthesized on the acute activation of nociceptors and can produce mechanical hypersensitivity via TRPA1 at central afferent terminals in the spinal cord. PMID:22553041

  4. Cold Atmospheric Plasma Induces a Predominantly Necrotic Cell Death via the Microenvironment

    PubMed Central

    Cousty, Sarah; Cambus, Jean-Pierre; Valentin, Alexis

    2015-01-01

    Introduction Cold plasma is a partially ionized gas generated by an electric field at atmospheric pressure that was initially used in medicine for decontamination and sterilization of inert surfaces. There is currently growing interest in using cold plasma for more direct medical applications, mainly due to the possibility of tuning it to obtain selective biological effects in absence of toxicity for surrounding normal tissues,. While the therapeutic potential of cold plasma in chronic wound, blood coagulation, and cancer treatment is beginning to be documented, information on plasma/cell interaction is so far limited and controversial. Methods and Results Using normal primary human fibroblast cultures isolated from oral tissue, we sought to decipher the effects on cell behavior of a proprietary cold plasma device generating guided ionization waves carried by helium. In this model, cold plasma treatment induces a predominantly necrotic cell death. Interestingly, death is not triggered by a direct interaction of the cold plasma with cells, but rather via a transient modification in the microenvironment. We show that modification of the microenvironment redox status suppresses treatment toxicity and protects cells from death. Moreover, necrosis is not accidental and seems to be an active response to an environmental cue, as its execution can be inhibited to rescue cells. Conclusion These observations will need to be taken into account when studying in vitro plasma/cell interaction and may have implications for the design and future evaluation of the efficacy and safety of this new treatment strategy. PMID:26275141

  5. A specific glycerol kinase induces rapid cold hardening of the diamondback moth, Plutella xylostella.

    PubMed

    Park, Youngjin; Kim, Yonggyun

    2014-08-01

    Insects in temperate zones survive low temperatures by migrating or tolerating the cold. The diamondback moth, Plutella xylostella, is a serious insect pest on cabbage and other cruciferous crops worldwide. We showed that P. xylostella became cold-tolerant by expressing rapid cold hardiness (RCH) in response to a brief exposure to moderately low temperature (4°C) for 7h along with glycerol accumulation in hemolymph. Glycerol played a crucial role in the cold-hardening process because exogenously supplying glycerol significantly increased the cold tolerance of P. xylostella larvae without cold acclimation. To determine the genetic factor(s) responsible for RCH and the increase of glycerol, four glycerol kinases (GKs), and glycerol-3-phosphate dehydrogenase (PxGPDH) were predicted from the whole P. xylostella genome and analyzed for their function associated with glycerol biosynthesis. All predicted genes were expressed, but differed in their expression during different developmental stages and in different tissues. Expression of the predicted genes was individually suppressed by RNA interference (RNAi) using double-stranded RNAs specific to target genes. RNAi of PxGPDH expression significantly suppressed RCH and glycerol accumulation. Only PxGK1 among the four GKs was responsible for RCH and glycerol accumulation. Furthermore, PxGK1 expression was significantly enhanced during RCH. These results indicate that a specific GK, the terminal enzyme to produce glycerol, is specifically inducible during RCH to accumulate the main cryoprotectant.

  6. Cold-induced bradycardia in man during sleep in Arctic winter nights

    NASA Astrophysics Data System (ADS)

    Buguet, A. G. C.

    1987-03-01

    Two young male Caucasians volunteered for a study on the effects of cold exposure during night sleep in winter in the Arctic. The 14-day experiment was divided in three consecutive periods, baseline (2 nights), cold exposure (10 night) and recovery (2 nights). Both baseline and recovery data were obtained in neutral thermal conditions in a laboratory. The subjects slept in a sleeping bag under an unheated tent during the cold exposure. Apart from polysomnographic and body temperature recordings, electrocardiograms were taken through a telemetric system for safety purposes. Heart rates were noted at 5-min intervals and averaged hourly. In both environmental conditions, heart rate decreased within the first two hours of sleep. Comparison of the data obtained during cold exposure vs. thermal neutrality revealed lower values of heart rate in the cold, while body temperatures remained within normal range. This cold-induced bradycardia supervening during night sleep is discussed in terms of the occurrence of a vagal reflex preventing central blood pressure to rise.

  7. Serotonin signalling is crucial in the induction of PUVA-induced systemic suppression of delayed-type hypersensitivity but not local apoptosis or inflammation of the skin.

    PubMed

    Wolf, Peter; Byrne, Scott N; Limon-Flores, Alberto Y; Hoefler, Gerald; Ullrich, Stephen E

    2016-07-01

    Psoralen and UVA (PUVA) has immunosuppressive and proapoptotic effects, which are thought to be responsible alone or in combination for its therapeutic efficacy. However, the molecular mechanism by which PUVA mediates its effects is not well understood. Activation of the serotonin (5-hydroxytryptamine, 5-HT) pathway has been suggested to be involved in the modulation of T-cell responses and found to mediate UVB-induced immune suppression. In particular, the activation of the 5-HT2A receptor has been proposed as one mechanism responsible for UV-induced immune suppression. We therefore hypothesized that 5-HT may play a role in PUVA-induced effects. The model of systemic suppression of delayed-type hypersensitivity (DTH) to Candida albicans was used to study immune function after exposure of C3H and KIT(W) (-Sh/W-Sh) mice to a minimal inflammatory dose of topical PUVA. The intra-peritoneal injection of the 5-HT2 receptor antagonist ketanserin or cyproheptadine or an anti-5-HT antibody immediately before PUVA exposure entirely abrogated suppression of DTH but had no significant effect on inflammation, as measured by swelling and cellular infiltration of the skin, and apoptosis as determined by the number of sunburn cells in C3H mice. Importantly, the systemic injection of 5-HT recapitulated PUVA immune suppression of DTH but did not induce inflammation or apoptosis in the skin. KIT(W) (-Sh/W-Sh) mice (exhibiting myelopoietic abnormalities, including lack of 5-HT-containing mast cells) were resistant to PUVA-induced suppression of DTH but not local skin swelling. Thus, this points towards a crucial role of 5-HT signalling in PUVA-induced immune suppression but not inflammation or apoptosis in situ in the skin.

  8. Classification and pathophysiology of radiocontrast media hypersensitivity.

    PubMed

    Brockow, Knut; Ring, Johannes

    2010-01-01

    Hypersensitivity reactions to radiocontrast media (RCM) are unpredictable and are a concern for radiologists and cardiologists. Immediate hypersensitivity reactions manifest as anaphylaxis, and an allergic IgE-mediated mechanism has been continuously discussed for decades. Non-immediate reactions clinically are exanthemas resembling other drug-induced non-immediate hypersensitivities. During the past years, evidence is increasing that some of these reactions may be immunological. Repeated reactions after re-exposure, positive skin tests, and presence of specific IgE antibodies as well as positive basophil activation tests in some cases, and positive lymphocyte transformation or lymphocyte activation tests in others, indicate that a subgroup of both immediate and non-immediate reactions are of an allergic origin, although many questions remain unanswered. Recently reported cases highlight that pharmacological premedication is not safe to prevent RCM hypersensitivity in patients with previous severe reactions. These insights may have important consequences. A large multicenter study on the value of skin tests in RCM hypersensitivity concluded that skin testing is a useful tool for diagnosis of RCM allergy. It may have a role for the selection of a safe product in previous reactors, although confirmatory validation data is still scarce. In vitro tests to search for RCM-specific cell activation still are in development. In conclusion, recent data indicate that RCM hypersensitivity may have an allergic mechanism and that allergological testing is useful and may indicate tolerability. Copyright 2010 S. Karger AG, Basel.

  9. Oral Hypersensitivity Reactions

    MedlinePlus

    ... of substances. The most common causes are food, food additives, drugs, oral hygiene products, and dental materials. Q: Are there any specific foods that are more commonly implicated in intraoral hypersensitivity ...

  10. Platinum hypersensitivity and desensitization.

    PubMed

    Miyamoto, Shingo; Okada, Rika; Ando, Kazumichi

    2015-09-01

    Platinum agents are drugs used for various types of cancer. With increased frequency of administration of platinum agents, hypersensitivity reactions appear more frequently, occurring in over 25% of cases from the seventh cycle or second line onward. It then becomes difficult to conduct treatment using these agents. Various approaches have been investigated to address hypersensitivity reactions to platinum agents. Desensitization, which gradually increases the concentration of the anticancer drug considered to be the antigen until the target dosage, has been reported as being particularly effective, with a success rate of 80-100%. The aims of this paper are to present the current findings regarding hypersensitivity reactions to platinum agents and to discuss attempts of using desensitization against hypersensitivity reactions worldwide. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Quantitative trait loci for resistance to common scab and cold-induced sweetening in diploid potato

    USDA-ARS?s Scientific Manuscript database

    The development of germplasm with resistance to common scab and cold-induced sweetening is a high priority for the potato industry. A mapping population was developed from mating two individuals from a diploid family generated by crossing the susceptible cultivated potato (Solanum tuberosum) clone U...

  12. Processed aconite root prevents cold-stress-induced hypothermia and immuno-suppression in mice.

    PubMed

    Makino, Toshiaki; Kato, Keita; Mizukami, Hajime

    2009-10-01

    Processed aconite root (PA) is a crude drug used in traditional Chinese or Japanese medicine to generate heat in interior body and dispel cold. We evaluated the effects of PA on hypothermia and reduction in the activity of natural killer (NK) cells in mice exposed to chronic cold stress. Male mice were reared at 4 degrees C, and powdered PA was administered for 10 d as a food additive. Core body temperature of mice significantly decreased by approximately 1 degrees C after rearing in a cold environment, and PA administration significantly restored the reduction in core body temperature in a dose-dependent manner. After 10 d, splenic NK-cell activity of cold-stressed mice was significantly reduced, and the reduction was dose-dependently recovered by PA administration. An aconitine-type alkaloid fraction prepared from PA was ineffective when administered to cold-stressed mice, and the thermogenic effect on hypothermic mice was present in the fraction containing low-molecular-weight compounds without alkaloids. In cold-stressed mice, the weight of brown adipose tissue (BAT) and uncoupling protein (UCP)-1 level in BAT increased, whereas the weight of white adipose tissue decreased. The increase in UCP-1 level in BAT of cold-stressed mice was further augmented by PA treatment. These results indicate that PA exhibited a thermogenic effect on hypothermia induced by cold stress in mice by additional upregulation of UCP-1 level in BAT, which was already enhanced by hypothermia, and that the active ingredients present in PA are non-alkaloidal low-molecular-weight compounds.

  13. Reactive oxygen species induced by cold stratification promote germination of Hedysarum scoparium seeds.

    PubMed

    Su, Liqiang; Lan, Qinying; Pritchard, Hugh W; Xue, Hua; Wang, Xiaofeng

    2016-12-01

    Seed germination is comprehensively regulated by multiple intrinsic and extrinsic factors, and reactive oxygen species (ROS) are relatively new among these factors. However, the role and underlying mechanisms of ROS in germination regulation remain largely unknown. In this study, we initially found that cold stratification could promote germination and respiration of Hedysarum scoparium seeds, especially at low temperature. We then noted that a ROS environment change induced by hydrogen peroxide (H2O2) or methylviologen (MV) could similarly promote seed germination. On the other hand, the ROS scavenger N-acetyl-L-cysteine (NAC) suppressed germination of cold-stratified H. scoparium seeds, indicating a stimulatory role of ROS upon seed germination. An increased accumulation of O2(-) was detected in embryonic axes of cold-stratified seeds, and stratification-induced ROS generation as well as progressive accumulation of ROS during germination was further confirmed at the cellular level by confocal microscopy. Moreover, protein carbonylation in cold-stratified seeds was enhanced during germination, which was reversed by NAC treatment. Finally, the relationship between ROS and abscisic acid (ABA) or gibberellin (GA) in germination regulation was investigated. ABA treatment significantly inhibited germination and reduced the H2O2 content in both cold-stratified and non-cold-stratified seeds. Furthermore, we found that cold stratification mediates the down-regulation of the ABA content and increase of GA, suggesting an interaction between ROS and ABA/GA. These results in H. scoparium shed new light on the positive role of ROS and their cross-talk between plant hormones in seed germination.

  14. Comparison of free radicals formation induced by cold atmospheric plasma, ultrasound, and ionizing radiation.

    PubMed

    Rehman, Mati Ur; Jawaid, Paras; Uchiyama, Hidefumi; Kondo, Takashi

    2016-09-01

    Plasma medicine is increasingly recognized interdisciplinary field combining engineering, physics, biochemistry and life sciences. Plasma is classified into two categories based on the temperature applied, namely "thermal" and "non-thermal" (i.e., cold atmospheric plasma). Non-thermal or cold atmospheric plasma (CAP) is produced by applying high voltage electric field at low pressures and power. The chemical effects of cold atmospheric plasma in aqueous solution are attributed to high voltage discharge and gas flow, which is transported rapidly on the liquid surface. The argon-cold atmospheric plasma (Ar-CAP) induces efficient reactive oxygen species (ROS) in aqueous solutions without thermal decomposition. Their formation has been confirmed by electron paramagnetic resonance (EPR) spin trapping, which is reviewed here. The similarities and differences between the plasma chemistry, sonochemistry, and radiation chemistry are explained. Further, the evidence for free radical formation in the liquid phase and their role in the biological effects induced by cold atmospheric plasma, ultrasound and ionizing radiation are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Mild cold induced thermogenesis: Are BAT and skeletal muscle synergistic partners?

    PubMed

    Bal, Naresh C; Maurya, Santosh K; Pani, Sunil; Sethy, Chinmayee; Banerjee, Ananya; Das, Sarita; Patanaik, Srinivas; Kundu, Chanakya N

    2017-08-22

    There are two well-described thermogenic sites; brown adipose tissue (BAT) and skeletal muscle, which utilize distinct mechanisms of heat production. In BAT, mitochondrial metabolism is the molecular basis of heat generation, while it serves only a minor role in supplying  energy for thermogenesis in muscle. Here, we wanted to document changes in mitochondrial ultrastructure in these two tissue types upon adaptation to mild (16°C) and severe (4°C) cold in mice. When reared at thermoneutrality (29°C), mitochondria in both tissues were loosely packed with irregular cristae. Interestingly, adaptation to even mild cold initiated ultrastructural remodeling of mitochondria including acquisition of more elaborate cristae structure in both thermogenic sites. The shape of mitochondria in the BAT remained mostly circular, whereas the intermyofibrilar mitochondria in the skeletal muscle became more elongated and tubular. The most dramatic remodeling of mitochondrial architecture was observed upon adaptation to severe cold. In addition, we report cold-induced alteration in levels of humoral factors: FGF21, IL1α, PYY, TNFα, and IL6 were all induced whereas both insulin and leptin were downregulated. In summary, adaptation to cold leads to enhanced cristae formation in mitochondria in the skeletal muscle and BAT. Further, this study indicates that circulating cytokines might play an important role in the synergistic recruitment of the thermogenic program including crosstalk between muscle and BAT. ©2017 The Author(s).

  16. Drug hypersensitivity syndrome.

    PubMed

    Bonnetblanc, J M

    1993-01-01

    Some types of hypersensitivity to drugs are defined either by the generic name of the drug or descriptive terms. They are sometimes assimilated to pseudolymphoma because the causative drugs are often the same, although the eruption lacks clinical and histopathological criteria of pseudolymphoma. It is then suggested to use 'idiosyncratic drug hypersensitivity syndrome' to define this type of drug reaction. As the skin and other organs may be involved, a generic name would help to determine a better definition and a surveillance program.

  17. Opposite regulation of brain angiotensin type 1 and type 2 receptors in cold-induced hypertension.

    PubMed

    Peng, J F; Phillips, M I

    2001-03-02

    Rats exposed chronically to mild cold (5 degrees C/41 degrees F) develop hypertension. This cold-induced hypertension (CIH) is an environmentally induced, non-surgical, non-pharmacological and non-genetic model for studying hypertension in rats. The blood renin angiotensin system (RAS) appears to play a role in both initiating and maintaining the high blood pressure in CIH. The goal of the present study was to evaluate the role of brain angiotensin type 1 and type 2 receptors (AT1R and AT2R) in CIH. Sprague-Dawley adult male rats were used. Thirty-six rats were kept in a cold room at 5 degrees C and the other 36 were kept at 24 degrees C as controls. Systolic blood pressure (SBP) was recorded by tail cuff. The SBP was elevated in rats exposed to cold within 1 week (n=12, P>0.05), significantly increased at 3 weeks (P<0.05) and reached a maximum (125%) at 5 weeks (P<0.01). Three subgroups of the cold-treated and the controls were sacrificed at 1, 3 and 5 weeks. Specific brain sections were removed, either for reverse transcription polymerase chain reaction (RT-PCR) to measure mRNA, or for autoradiography to measure receptor binding for AT1R and AT2R. The AT1R mRNA was increased significantly in hypothalamus and brainstem after the first week in cold-treated rats and was maintained throughout the time of exposure to cold (n=6, P<0.01). AT1R binding significantly increased initially in hypothalamus and thereafter in brainstem. The mRNA and the receptor binding for AT2R decreased significantly (P<0.01, n=6) in nucleus of inferior olive and locus coeruleus of brainstem in cold-treated rats after exposure to cold. The experiments show differential regulation of RAS components, AT1R and AT2R, in different brain areas in cold-exposed rats and provide evidence that up-regulated AT1R and down-regulated AT2R in different brain areas are involved in CIH. The opposing directions of expression of AT1R and AT2R suggest that they play counterbalancing roles in brain function.

  18. Brine induced low-Magnesium calcite formation at cold seeps

    NASA Astrophysics Data System (ADS)

    Feng, Dong; Roberts, Harry; Joye, Samantha; Heydari, Ezat

    2013-04-01

    Low-Mg calcite (LMC; < 5 mol% Mg), commonly observed during time intervals of "calcite seas," since the beginning of the Paleozoic Era, is a good indicator of low Mg/Ca ratio (< 2) in seawater. Calcite seas were coincident with times of active seawater-basalt interactions along mid-ocean ridges at high temperatures, which extract Mg from seawater and release Ca to it. In the modern aragonite sea, most carbonate minerals precipitate at the seafloor, including deposits from cold seep environments are primarily either aragonite or high-Mg calcite (HMC). Here, we report the finding of non-skeletal LMC from cold seeps in Alaminos Canyon block 601 (AC 601), 2200 m below the sea surface on northern Gulf of Mexico (GOM) continental slope. Low-Mg calcite usually represents the only carbonate mineral in the studied samples. Dominant allochems in these seep carbonates are peloids, grain aggregates, pelagic forams, and fragments of mollusks and echinoids. The limestone is heavily cemented. The observed cements include micrite, microspar, mosaic, bladed, fan, and needle cements. The dissolution of grains and cements was observed. Not only originally aragonitic mollusks shells, but also carbonate cement have been dissolved. The aerobic oxidation of reduced chemical species such as methane and H2S is responsible for an increase in pCO2 and a decrease of pH, leading to local carbonate dissolution. The occurrence of oxic conditions is confirmed by the presence of negative Ce anomalies of the carbonates. Further, we report on analyses showing that the ambient porewater Mg/Ca ratio actually governs the carbonate mineralogy. The occurrence of LMC may be attributed to the brine fluids, which is relatively Mg-depleted (Mg/Ca mole ratio is below 0.7) compared to pore fluid of the subsurface sediments from the reference site (Mg/Ca mole ratio is above 4.1) that usually produce HMC. The 87Sr/86Sr values of LMC (mean = 0.708001, sd = 0.000034, n=2) are significantly lower than that of the

  19. Thermoregulation in peripheral nerve injury-induced cold-intolerant rats.

    PubMed

    Duraku, L S; Smits, E S; Niehof, S P; Hovius, S E R; Walbeehm, E T; Selles, R W

    2012-06-01

    Cold intolerance is defined as pain after exposure to non-painful cold. It is suggested that cold intolerance may be related to dysfunctional thermoregulation in upper extremity nerve injury patients. The purpose of this study was to examine if the re-warming of a rat hind paw is altered in different peripheral nerve injury models and if these patterns are related to severity of cold intolerance. In the spared nerve injury (SNI) and complete sciatic lesion (CSL) model, the re-warming patterns after cold stress exposure were investigated preoperatively and at 3, 6 and 9 weeks postoperatively with a device to induce cooling of the hind paws. Thermocouples were attached on the dorsal side of the hind paw to monitor re-warming patterns. The Von Frey test and cold plate test indicated a significantly lower paw-withdrawal threshold and latency in the SNI compared to the Sham model. The CSL group, however, had only significantly lower paw-withdrawal latency on the cold plate test compared to the Sham group. While we found no significantly different re-warming patterns in the SNI and CSL group compared to Sham group, we did find a tendency in temperature increase in the CSL group 3 weeks postoperatively. Overall, our findings indicate that re-warming patterns are not altered after peripheral nerve injury in these rat models despite the fact that these animals did develop cold intolerance. This suggests that disturbed thermoregulation may not be the prime mechanism for cold intolerance and that, other, most likely, neurological mechanisms may play a more important role. There is no direct correlation between cold intolerance and re-warming patterns in different peripheral nerve injury rat models. This is an important finding for future developing treatments for this common problem, since treatment focussing on vaso-regulation may not help diminish symptoms of cold-intolerant patients. Copyright © 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons

  20. AAV Delivery of TNF-α shRNA Attenuates Cold-induced Pulmonary Hypertension and Pulmonary Arterial Remodeling

    PubMed Central

    Crosswhite, Patrick; Chen, Kai; Sun, Zhongjie

    2014-01-01

    Cold temperatures are associated with increased mortality and morbidity of cardiovascular and pulmonary disease. Cold exposure causes lung inflammation, pulmonary hypertension (PH) and right ventricle (RV) hypertrophy, but there is no effective therapy due to unknown mechanism. Here we investigated if RNAi silencing of TNF-α decreases cold-induced macrophage infiltration, PH, and pulmonary arterial (PA) remodeling. We found for the first time that continuous cold exposure (5.0°C) increased TNF-α expression and macrophage infiltration in the lungs and pulmonary arteries (PAs) right before elevation of RV systolic pressure. The in vivo RNAi silencing of TNF-α was achieved by IV delivery of recombinant AAV-2 carrying TNFα short hairpin siRNA (TNFshRNA) 24 hours prior to cold exposure. Cold exposure for eight weeks significantly increased RV pressure compared to the warm controls (40.19±4.9 vs. 22.9±1.1 mmHg), indicating that cold exposure caused PH. Cold exposure increased TNF-α, IL-6 and phosphodierterase-1C (PDE-1C) protein expression in the lungs and PAs and increased lung macrophage infiltration. Notably, TNFshRNA prevented the cold-induced increases in TNF-α, IL-6 and PDE-1C protein expression, abolished lung macrophage infiltration, and attenuated PH (26.28±1.6 mmHg), PA remodeling, and RV hypertrophy. PA SMCs isolated from cold-exposed animals showed increased intracellular superoxide levels and cell proliferation along with decreased intracellular cGMP. These cold-induced changes were prevented by TNFshRNA. Conclusions Upregulation of TNF-α played a critical role in the pathogenesis of cold-induced PH by promoting pulmonary macrophage infiltration and inflammation. AAV delivery of TNFshRNA may be an effective therapeutic approach for cold-induced PH and PA remodeling. PMID:25185133

  1. Phα1β toxin prevents capsaicin-induced nociceptive behavior and mechanical hypersensitivity without acting on TRPV1 channels.

    PubMed

    Castro-Junior, Celio J; Milano, Julie; Souza, Alessandra H; Silva, Juliana F; Rigo, Flávia K; Dalmolin, Geruza; Cordeiro, Marta N; Richardson, Michael; Barros, Alexandre G A; Gomez, Renato S; Silva, Marco A R; Kushmerick, Christopher; Ferreira, Juliano; Gomez, Marcus V

    2013-08-01

    Phα1β toxin is a peptide purified from the venom of the armed spider Phoneutria nigriventer, with markedly antinociceptive action in models of acute and persistent pain in rats. Similarly to ziconotide, its analgesic action is related to inhibition of high voltage activated calcium channels with more selectivity for N-type. In this study we evaluated the effect of Phα1β when injected peripherally or intrathecally in a rat model of spontaneous pain induced by capsaicin. We also investigated the effect of Phα1β on Ca²⁺ transients in cultured dorsal root ganglia (DRG) neurons and HEK293 cells expressing the TRPV1 receptor. Intraplantar or intrathecal administered Phα1β reduced both nocifensive behavior and mechanical hypersensitivity induced by capsaicin similarly to that observed with SB366791, a specific TRPV1 antagonist. Peripheral nifedipine and mibefradil did also decrease nociceptive behavior induced by intraplantar capsaicin. In contrast, ω-conotoxin MVIIA (a selective N-type Ca²⁺ channel blocker) was effective only when administered intrathecally. Phα1β, MVIIA and SB366791 inhibited, with similar potency, the capsaicin-induced Ca²⁺ transients in DRG neurons. The simultaneous administration of Phα1β and SB366791 inhibited the capsaicin-induced Ca²⁺ transients that were additive suggesting that they act through different targets. Moreover, Phα1β did not inhibit capsaicin-activated currents in patch-clamp recordings of HEK293 cells that expressed TRPV1 receptors. Our results show that Phα1β may be effective as a therapeutic strategy for pain and this effect is not related to the inhibition of TRPV1 receptors.

  2. Intra-articular nerve growth factor regulates development, but not maintenance, of injury-induced facet joint pain & spinal neuronal hypersensitivity.

    PubMed

    Kras, J V; Kartha, S; Winkelstein, B A

    2015-11-01

    The objective of the current study is to define whether intra-articular nerve growth factor (NGF), an inflammatory mediator that contributes to osteoarthritic pain, is necessary and sufficient for the development or maintenance of injury-induced facet joint pain and its concomitant spinal neuronal hyperexcitability. Male Holtzman rats underwent painful cervical facet joint distraction (FJD) or sham procedures. Mechanical hyperalgesia was assessed in the forepaws, and NGF expression was quantified in the C6/C7 facet joint. An anti-NGF antibody was administered intra-articularly in additional rats immediately or 1 day following facet distraction or sham procedures to block intra-articular NGF and test its contribution to initiation and/or maintenance of facet joint pain and spinal neuronal hyperexcitability. NGF was injected into the bilateral C6/C7 facet joints in separate rats to determine if NGF alone is sufficient to induce these behavioral and neuronal responses. NGF expression increases in the cervical facet joint in association with behavioral sensitivity after that joint's mechanical injury. Intra-articular application of anti-NGF immediately after a joint distraction prevents the development of both injury-induced pain and hyperexcitability of spinal neurons. Yet, intra-articular anti-NGF applied after pain has developed does not attenuate either behavioral or neuronal hyperexcitability. Intra-articular NGF administered to the facet in naïve rats also induces behavioral hypersensitivity and spinal neuronal hyperexcitability. Findings demonstrate that NGF in the facet joint contributes to the development of injury-induced joint pain. Localized blocking of NGF signaling in the joint may provide potential treatment for joint pain. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  3. INTRA-ARTICULAR NERVE GROWTH FACTOR REGULATES DEVELOPMENT, BUT NOT MAINTENANCE, OF INJURY-INDUCED FACET JOINT PAIN & SPINAL NEURONAL HYPERSENSITIVITY

    PubMed Central

    Kras, Jeffrey V.; Kartha, Sonia; Winkelstein, Beth A.

    2015-01-01

    Objective The objective of the current study is to define whether intra-articular nerve growth factor (NGF), an inflammatory mediator that contributes to osteoarthritic pain, is necessary and sufficient for the development or maintenance of injury-induced facet joint pain and its concomitant spinal neuronal hyperexcitability. Method Male Holtzman rats underwent painful cervical facet joint distraction or sham procedures. Mechanical hyperalgesia was assessed in the forepaws, and NGF expression was quantified in the C6/C7 facet joint. An anti-NGF antibody was administered intra-articularly in additional rats immediately or 1 day following facet distraction or sham procedures to block intra-articular NGF and test its contribution to initiation and/or maintenance of facet joint pain and spinal neuronal hyperexcitability. NGF was injected into the bilateral C6/C7 facet joints in separate rats to determine if NGF alone is sufficient to induce these behavioral and neuronal responses. Results NGF expression increases in the cervical facet joint in association with behavioral sensitivity after that joint’s mechanical injury. Intra-articular application of anti-NGF immediately after a joint distraction prevents the development of both injury-induced pain and hyperexcitability of spinal neurons. Yet, intra-articular anti-NGF applied after pain has developed does not attenuate either behavioral or neuronal hyperexcitability. Intra-articular NGF administered to the facet in naïve rats also induces behavioral hypersensitivity and spinal neuronal hyperexcitability. Conclusion Findings demonstrate that NGF in the facet joint contributes to the development of injury-induced joint pain. Localized blocking of NGF signaling in the joint may provide potential treatment for joint pain. PMID:26521746

  4. Mosquito salivary gland extracts induce EBV-infected NK cell oncogenesis via CD4 T cells in patients with hypersensitivity to mosquito bites.

    PubMed

    Asada, Hideo; Saito-Katsuragi, Mamiko; Niizeki, Hironori; Yoshioka, Akira; Suguri, Setsuo; Isonokami, Masaaki; Aoki, Toshiyuki; Ishihara, Shigehiko; Tokura, Yoshiki; Iwatsuki, Keiji; Miyagawa, Sachiko

    2005-11-01

    Severe hypersensitivity to mosquito bites (HMB) is characterized by intense local skin reactions and systemic symptoms such as high fever, lymphadenopathy, and hepatosplenomegaly. Patients with HMB often have natural killer (NK) cell lymphocytosis associated with Epstein-Barr virus (EBV) infection. Here we investigated whether mosquito bites have any influence on the oncogenesis of EBV-infected NK cells. We examined six HMB patients with EBV-infected NK cell lymphocytosis. We first demonstrated that CD4+ T cells, but not NK cells, proliferated well in response to mosquito salivary gland extracts (SGE), especially to SGE of Aedes albopictus. When NK cells were cocultured with autologous CD4+ T cells stimulated by mosquito SGE, the expression of viral oncogene latent membrane protein 1 (LMP1) was remarkably enhanced. Next, we stimulated mononuclear cells of the patients with mosquito SGE, and NK cell counts were monitored for 28 d. The counts changed little from initial levels in the culture with mosquito SGE, whereas they decreased steadily in the culture without the extracts. Furthermore, we detected LMP1 mRNA in the skin lesion induced by mosquito SGE. These results suggest that mosquito bites can induce expression of the viral oncogene LMP1 in NK cells via mosquito antigen-specific CD4+ T cells, which is involved in the oncogenesis of NK cells in vivo.

  5. Hypersensitivity reactions to fluoroquinolones: analysis of the factors involved.

    PubMed

    Blanca-López, N; Ariza, A; Doña, I; Mayorga, C; Montañez, M I; Garcia-Campos, J; Gomez, F; Rondón, C; Blanca, M; Torres, M J

    2013-05-01

    Hypersensitivity reactions to fluoroquinolones seem to be on the increase, especially immediate type reactions. The aim of this study was to determine whether several conditions, including gender, age, type of reaction, time interval between the reaction and the study, type of symptoms, the specific fluoroquinolone involved in the reaction and previous confirmed hypersensitivity to betalactams or to other drugs were factors contributing to the development of hypersensitivity to fluoroquinolones. We analysed retrospectively all patients attending our allergy department between January 2005 and December 2010 because of a reaction associated with fluoroquinolone administration. The diagnosis was confirmed by basophil activation test or drug provocation tests. In accordance with the results, patients were then classified as having hypersensitivity or non-hypersensitivity to fluoroquinolones. A group of 218 patients was evaluated; 69 were confirmed as having hypersensitivity, 146 as non-hypersensitivity and 3 were excluded. Comparisons between groups showed that the allergic patients more often had a previous confirmed hypersensitivity to betalactams (P = 0.029), immediate reactions (P = 0.001) and anaphylaxis (P = 0.000), and moxifloxacin was the fluoroquinolone most frequently involved (P = 0.027). The logistic regression analysis showed three factors associated with the diagnosis of hypersensitivity reactions to fluoroquinolones: previous hypersensitivity to betalactams (OR: 4.571; 95% CI: 0.987-21.171; adjusted OR: 23.654; 95% CI: 1.529-365.853), immediate reactions (OR: 17.333; 95% CI: 4.374-68.691; adjusted OR: 52.493; 95% CI: 6.621-416.200) and reactions induced by moxifloxacin (OR: 3.091; 95% CI: 1.160-8.239; adjusted OR: 13.610; 95% CI: 2.419-76.565). In patients who develop reactions to fluoroquinolones, hypersensitivity is more often confirmed in those with immediate reactions and when moxifloxacin is involved. Moreover, patients with hypersensitivity to

  6. A physiologic differentiation between delayed and immediate hypersensitivity

    PubMed Central

    Apicella, Michael A.; Allen, James C.

    1969-01-01

    Studies have been made of movement of various macromolecules into and out of the pleural space of guinea pigs during the course of a delayed hypersensitivity reaction to purified protein derivative (PPD), and a passively transferred immediate hypersensitivity reaction to ovalbumin. While the immediate hypersensitivity reaction transiently alters vascular permeability as shown by increased movement of macromolecules into the chest, the delayed hypersensitivity reaction is marked by a decreased capacity to resorb macromolecules from the pleural space. The data suggest that the two hypersensitivity reactions may be distinguished by these physiologic differences. Additional data from studies of a chemically induced pleural effusion in these animals suggest that some type of outflow obstruction is necessary for the development of effusion, but that the outflow defect caused by the irritating chemical is based on a different mechanism than that seen during the delayed hypersensitivity reaction. PMID:4179171

  7. [HLA-B*5701 and abacavir hypersensitivity reaction].

    PubMed

    Servonnet, A; Leclercq, E; Delacour, H; Ceppa, F

    2010-12-01

    A potentially life-threatening hypersensitive reaction occurs in association with initiation of HIV nucleoside analogue abacavir therapy in 4 to 8% of patients. Preliminary studies appear to confirm the role of the immune system in abacavir hypersensitivity. The reaction is possibly the result of presentation of drug peptides onto HLA, that may induce a pathogenic T-cell response. Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele and prospective HLA-B*5701 genetic screening has now been instituted in clinical practice to reduce the risk of hypersensitivity reaction. Copyright © 2009 Elsevier Masson SAS. All rights reserved.

  8. Possibility of phase transitions inducing cold fusion in palladium/deuterium systems

    SciTech Connect

    Zhang, W.X. )

    1992-01-01

    In this paper a tentative theory is presented in which {beta}-phase PdD{sub x} containing supersaturated deuterium transits into {beta}-phase PdD{sub x} containing less deuterium and {alpha}-phase PdD{sub x}. High-pressure ({approx}10 GPa) deuterium bubbles form at the same time. As the bubbles release energy, cracks are created in the PdD{sub x} crystal, and charge separation of deuterium occurs. Thus would cold fusion be induced. This proposal supports the fracture mechanism for cold fusion.

  9. Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm in humans: relationship between FGF21 levels, lipolysis, and cold-induced thermogenesis.

    PubMed

    Lee, Paul; Brychta, Robert J; Linderman, Joyce; Smith, Sheila; Chen, Kong Y; Celi, Francesco S

    2013-01-01

    Cold exposure stimulates fibroblast growth factor 21 (FGF21) secretion in animals, enhancing the cold-induced thermogenesis (CIT) response through browning of white adipose tissue. In humans, the effects of cold exposure on circulating FGF21 levels are unknown. Our objective was to evaluate the effects of mild cold exposure on circulating FGF21 and its relationship with CIT and lipolysis in humans. We conducted a randomized, single-blind, crossover intervention study at the National Institutes of Health Clinical Center. Participants were healthy adults. Subjects were exposed to a 12-h exposure to 24 or 19 C in a whole-room indirect calorimeter. Energy expenditure, plasma FGF 21, nonesterified fatty acid, and adipose tissue microdialysis glycerol concentrations were evaluated. At 24 C, plasma FGF21 exhibited a diurnal rhythm, peaking at 0800 h [110 (59-178) pg/ml], and progressively dropped to a nadir at 1700 h [41 (21-71) pg/ml, P < 0.0001] before rising at 1900 h [60 (11-81) pg/ml, P < 0.0001]. Exposure at 19 C lessened the diurnal reduction of FGF21 observed at 24 C from 0800-1700 h and augmented overall FGF21 levels by 37 ± 45% (P = 0.01). The change in area under the curve plasma FGF21 between 19 and 24 C correlated positively with the change in area under the curve adipose microdialysate glycerol (R(2) = 0.35, P = 0.04) but not with nonesterified fatty acid. Cold-induced increase in FGF21 predicted greater rise in energy expenditure during cold exposure (β = 0.66, P = 0.027), independent of age, gender, fat mass, and lean mass. Mild cold exposure increased circulating FGF21 levels, predicting greater lipolysis and CIT. A small reduction in environmental temperature is sufficient to modulate FGF21 diurnal rhythm in humans, which may mediate cold-induced metabolic changes similar to those in animals.

  10. Role of voltage gated Ca2+ channels in rat visceral hypersensitivity change induced by 2,4,6-trinitrobenzene sulfonic acid

    PubMed Central

    2013-01-01

    Background Visceral pain is common symptom involved in many gastrointestinal disorders such as inflammatory bowel disease. The underlying molecular mechanisms remain elusive. We investigated the molecular mechanisms and the role for voltage gated calcium channel (VGCC) in the pathogenesis in a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced visceral inflammatory hypersensitivity. Results Using Agilent cDNA arrays, we found 172 genes changed significantly in dorsal root ganglia (DRG) of TNBS treated rats. Among these changed genes, Cav1.2 and Cav2.3 were significantly up-regulated. Then the RT-PCR and Western blot further confirmed the up-regulation of Cav1.2 and Cav2.3. The whole cell patch clamp recording of acutely dissociated colonic specific DRG neurons showed that the peak IBa density was significantly increased in colonic neurons of TNBS treated rats compared with control rats (−127.82 ± 20.82 pA/pF Vs −91.67 ± 19.02 pA/pF, n = 9, *P < 0.05). To distinguish the different type of calcium currents with the corresponding selective channel blockers, we found that L-type (−38.56 ± 3.97 pA/pF Vs −25.75 ± 3.35 pA/pF, n = 9, * P < 0.05) and R-type (−13.31 ± 1.36 pA/pF Vs −8.60 ± 1.25 pA/pF, n = 9, * P < 0.05) calcium current density were significantly increased in colonic DRG neurons of TNBS treated rats compared with control rats. In addition, pharmacological blockade with L-type antagonist (nimodipine) and R-type antagonist (SNX-482) with intrathecal injection attenuates visceral pain in TNBS induced inflammatory visceral hypersensitivity. Conclusion Cav1.2 and Cav2.3 in colonic primary sensory neurons play an important role in visceral inflammatory hyperalgesia, which maybe the potential therapeutic targets. PMID:23537331

  11. Involvement of WRKY Transcription Factors in Abscisic-Acid-Induced Cold Tolerance of Banana Fruit.

    PubMed

    Luo, Dong-Lan; Ba, Liang-Jie; Shan, Wei; Kuang, Jian-Fei; Lu, Wang-Jin; Chen, Jian-Ye

    2017-05-10

    Phytohormone abscisic acid (ABA) and plant-specific WRKY transcription factors (TFs) have been implicated to play important roles in various stress responses. The involvement of WRKY TFs in ABA-mediated cold tolerance of economical fruits, such as banana fruit, however remains largely unknown. Here, we reported that ABA application could induce expressions of ABA biosynthesis-related genes MaNCED1 and MaNCED2, increase endogenous ABA contents, and thereby enhance cold tolerance in banana fruit. Four banana fruit WRKY TFs, designated as MaWRKY31, MaWRKY33, MaWRKY60, and MaWRKY71, were identified and characterized. All four of these MaWRKYs were nuclear-localized and displayed transactivation activities. Their expressions were induced by ABA treatment during cold storage. More importantly, the gel mobility shift assay and transient expression analysis revealed that MaWRKY31, MaWRKY33, MaWRKY60, and MaWRKY71 directly bound to the W-box elements in MaNCED1 and MaNCED2 promoters and activated their expressions. Taken together, our findings demonstrate that banana fruit WRKY TFs are involved in ABA-induced cold tolerance by, at least in part, increasing ABA levels via directly activating NECD expressions.

  12. Rice-induced enterocolitis in an infant: TH1/TH2 cellular hypersensitivity and absent IgE reactivity.

    PubMed

    Gray, Heather C; Foy, Thomas M; Becker, Bradley A; Knutsen, Alan P

    2004-12-01

    . Patch testing for gastrointestinal food allergies may be useful when the food specific IgE antibody is negative. Probiotic therapy in this patient did not ameliorate her sensitivity to rice, and food elimination remains the only reliable treatment for TH1/TH2-mediated food hypersensitivity.

  13. Cladosporium fulvum CfHNNI1 induces hypersensitive necrosis, defence gene expression and disease resistance in both host and nonhost plants.

    PubMed

    Cai, Xin-Zhong; Zhou, Xin; Xu, You-Ping; Joosten, Matthieu H A J; de Wit, Pierre J G M

    2007-05-01

    Nonhost resistance as a durable and broad-spectrum defence strategy is of great potential for agricultural applications. We have previously isolated a cDNA showing homology with genes encoding bZIP transcription factors from tomato leaf mould pathogen Cladosporium fulvum. Upon expression, the cDNA results in necrosis in C. fulvum host tomato and nonhost tobacco plants and is thus named CfHNNI1 (for C . f ulvum host and nonhost plant necrosis inducer 1). In the present study we report the induction of necrosis in a variety of nonhost plant species belonging to three families by the transient in planta expression of CfHNNI1 using virus-based vectors. Additionally, transient expression of CfHNNI1 also induced expression of the HR marker gene LeHSR203 and greatly reduced the accumulation of recombinant Potato virus X. Stable CfHNNI1 transgenic tobacco plants were generated in which the expression of CfHNNI1 is under the control of the pathogen-inducible hsr203J promoter. When infected with the oomycetes pathogen Phytophthora parasitica var. nicotianae, these transgenic plants manifested enhanced expression of CfHNNI1 and subsequent accumulation of CfHNNI1 protein, resulting in high expression of the HSR203J and PR genes, and strong resistance to the pathogen. The CfHNNI1 transgenic plants also exhibited induced resistance to Pseudomonas syringae pv. tabaci and Tobacco mosaic virus. Furthermore, CfHNNI1 was highly expressed and the protein was translocated into plant cells during the incompatible interactions between C. fulvum and host and nonhost plants. Our results demonstrate that CfHNNI1 is a potential general elicitor of hypersensitive response and nonhost resistance.

  14. CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs-mediated neuroinflammation in bone cancer rats.

    PubMed

    Hu, Xue-Ming; Liu, Yan-Nan; Zhang, Hai-Long; Cao, Shou-Bin; Zhang, Ting; Chen, Li-Ping; Shen, Wen

    2015-02-01

    The activation of