Further evidence of emotional allodynia in unmedicated young adults with major depressive disorder.

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Alexander Ushinsky

Full Text Available Recent evidence suggests that sensitivity to the emotional sequela of experimental thermal pain(measured by emotional unpleasantness is heightened in individuals with major depressive disorder(MDD, a phenomenon we termed "emotional allodynia". The aim of this study was to examine whether acute happy and sad mood induction alters emotional allodynia in MDD. We hypothesized that emotional allodynia will be a robust characteristic of individuals with MDD compared to healthy controls. Thus, it would remain following acute mood induction, independent of valence.Twenty-one subjects with current MDD and 21 well-matched healthy subjects(HC received graded brief temperature stimuli following happy and sad mood inductions procedures(MIP. All subjects rated the intensity and affect(pleasantness/unpleasantness of each stimulus. Sensory(pain intensity and affective(pain unpleasantness thresholds were determined by methods of constant stimuli.The MIPs reliably induced happy and sad mood and the resulting induced mood and subjective arousal were not different between the groups at the time of temperature stimulation. Compared to HC, MDD individuals demonstrated emotional allodynia. We found significantly decreased affective pain thresholds whereby significantly lower temperatures became unpleasant in the MDD compared to the HC group. This was not observed for the sensory pain thresholds. Within the MDD, the affective pain thresholds were significantly lower than the corresponding pain intensity thresholds, whereby non-painful temperatures were already unpleasant for the MDD irrespective of the induced mood. This was not observed for the HC groups where the affective and pain intensity thresholds were comparable.These findings suggest that emotional allodynia may be a chronic characteristic of current MDD. Future studies should determine if emotional allodynia persists after psychological or pharmacological interventions. Finally, longitudinal work should

Spinal high-mobility group box 1 contributes to mechanical allodynia in a rat model of bone cancer pain

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Tong, Wei; Wang, Wei; Huang, Jing; Ren, Ning; Wu, Sheng-Xi; Li, Yong-Qi

2010-01-01

Mechanisms underlying bone cancer-induced pain are largely unknown. Previous studies indicate that neuroinflammation in the spinal dorsal horn is especially involved. Being first reported as a nonhistone chromosomal protein, high-mobility group box 1 (HMGB1) is now implicated as a mediator of inflammation. We hypothesized that HMGB1 could trigger the release of cytokines in the spinal dorsal horn and contribute to bone cancer pain. To test this hypothesis, we first built a bone cancer pain model induced by intratibal injection of Walker 256 mammary gland carcinoma cells. The structural damage to the tibia was monitored by radiological analysis. The mechanical allodynia was measured and the expression of spinal HMGB1 and IL-1β was evaluated. We observed that inoculation of cancer cells, but not heat-killed cells, induced progressive bone destruction from 9 d to 21 d post inoculation. Behavioral tests demonstrated that the significant nociceptive response in the cancer cells-injected rats emerged on day 9 and this kind of mechanical allodynia lasted at least 21 d following inoculation. Tumor cells inoculation significantly increased HMGB1 expression in the spinal dorsal horn, while intrathecal injecting a neutralizing antibody against HMGB1 showed an effective and reliable anti-allodynia effect with a dose-dependent manner. IL-1β was significantly increased in caner pain rats while intrathecally administration of anti-HMGB1 could decrease IL-1β. Together with previous reports, we predict that bone cancer induces HMGB1 production, enhancing spinal IL-1β expression and thus modulating spinal excitatory synaptic transmission and pain response.

Prevention of Paclitaxel-induced allodynia by Minocycline: Effect on loss of peripheral nerve fibers and infiltration of macrophages in rats

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Xin Wen-Jun

2010-11-01

Full Text Available Abstract Background Although paclitaxel is a frontline antineoplastic agent for treatment of solid tumors, the paclitaxel-evoked pain syndrome is a serious problem for patients. There is currently no valid drug to prevent or treat the paclitaxel-induced allodynia, partly due to lack of understanding regarding the cellular mechanism. Studies have shown that minocycline, an inhibitor of microglia/macrophage, prevented neuropathic pain and promoted neuronal survival in animal models of neurodegenerative disease. Recently, Cata et al also reported that minocycline inhibited allodynia induced by low-dose paclitaxel (2 mg/kg in rats, but the mechanism is still unclear. Results Here, we investigate by immunohistochemistry the change of intraepidermal nerve fiber (IENF in the hind paw glabrous skin, expression of macrophage and activating transcription factor 3 (ATF3 in DRG at different time points after moderate-dose paclitaxel treatment (cumulative dose 24 mg/kg; 3 × 8 mg/kg in rats. Moreover, we observe the effect of minocycline on the IENF, macrophages and ATF3. The results showed that moderate-dose paclitaxel induced a persisted, gradual mechanical allodynia, which was accompanied by the loss of IENF in the hind paw glabrous skin and up-regulation of macrophages and ATF3 in DRG in rats. The expressions of ATF3 mainly focus on the NF200-positive cells. More importantly, we observed that pretreatment of minocycline at dose of 30 mg/kg or 50 mg/kg, but not 5 mg/kg, prevented paclitaxel-evoked allodynia. The evidence from immunohistochemistry showed that 30 mg/kg minocycline rescued the degeneration of IENF, attenuated infiltration of macrophages and up-regulation of ATF3 induced by paclitaxel treatment in rats. Conclusions Minocycline prevents paclitaxel-evoked allodynia, likely due to its inhibition on loss of IENF, infiltration of macrophages and up-regulation of ATF3 in rats. The finding might provide potential target for preventing paclitaxel

Contribution of large-sized primary sensory neuronal sensitization to mechanical allodynia by upregulation of hyperpolarization-activated cyclic nucleotide gated channels via cyclooxygenase 1 cascade.

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Sun, Wei; Yang, Fei; Wang, Yan; Fu, Han; Yang, Yan; Li, Chun-Li; Wang, Xiao-Liang; Lin, Qing; Chen, Jun

2017-02-01

Under physiological state, small- and medium-sized dorsal root ganglia (DRG) neurons are believed to mediate nociceptive behavioral responses to painful stimuli. However, recently it has been found that a number of large-sized neurons are also involved in nociceptive transmission under neuropathic conditions. Nonetheless, the underlying mechanisms that large-sized DRG neurons mediate nociception are poorly understood. In the present study, the role of large-sized neurons in bee venom (BV)-induced mechanical allodynia and the underlying mechanisms were investigated. Behaviorally, it was found that mechanical allodynia was still evoked by BV injection in rats in which the transient receptor potential vanilloid 1-positive DRG neurons were chemically deleted. Electrophysiologically, in vitro patch clamp recordings of large-sized neurons showed hyperexcitability in these neurons. Interestingly, the firing pattern of these neurons was changed from phasic to tonic under BV-inflamed state. It has been suggested that hyperpolarization-activated cyclic nucleotide gated channels (HCN) expressed in large-sized DRG neurons contribute importantly to repeatedly firing. So we examined the roles of HCNs in BV-induced mechanical allodynia. Consistent with the overexpression of HCN1/2 detected by immunofluorescence, HCNs-mediated hyperpolarization activated cation current (I h ) was significantly increased in the BV treated samples. Pharmacological experiments demonstrated that the hyperexcitability and upregulation of I h in large-sized neurons were mediated by cyclooxygenase-1 (COX-1)-prostaglandin E2 pathway. This is evident by the fact that the COX-1 inhibitor significantly attenuated the BV-induced mechanical allodynia. These results suggest that BV can excite the large-sized DRG neurons at least in part by increasing I h through activation of COX-1. Copyright © 2016 Elsevier Ltd. All rights reserved.

Upregulation of EMMPRIN (OX47 in Rat Dorsal Root Ganglion Contributes to the Development of Mechanical Allodynia after Nerve Injury

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Qun Wang

2015-01-01

Full Text Available Matrix metalloproteinases (MMPs are widely implicated in inflammation and tissue remodeling associated with various neurodegenerative diseases and play an important role in nociception and allodynia. Extracellular Matrix Metalloproteinase Inducer (EMMPRIN plays a key regulatory role for MMP activities. However, the role of EMMPRIN in the development of neuropathic pain is not clear. Western blotting, real-time quantitative RT-PCR (qRT-PCR, and immunofluorescence were performed to determine the changes of messenger RNA and protein of EMMPRIN/OX47 and their cellular localization in the rat dorsal root ganglion (DRG after nerve injury. Paw withdrawal threshold test was examined to evaluate the pain behavior in spinal nerve ligation (SNL model. The lentivirus containing OX47 shRNA was injected into the DRG one day before SNL. The expression level of both mRNA and protein of OX47 was markedly upregulated in ipsilateral DRG after SNL. OX47 was mainly expressed in the extracellular matrix of DRG. Administration of shRNA targeted against OX47 in vivo remarkably attenuated mechanical allodynia induced by SNL. In conclusion, peripheral nerve injury induced upregulation of OX47 in the extracellular matrix of DRG. RNA interference against OX47 significantly suppressed the expression of OX47 mRNA and the development of mechanical allodynia. The altered expression of OX47 may contribute to the development of neuropathic pain after nerve injury.

Supradural inflammatory soup in awake and freely moving rats induces facial allodynia that is blocked by putative immune modulators.

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Wieseler, Julie; Ellis, Amanda; McFadden, Andrew; Stone, Kendra; Brown, Kimberley; Cady, Sara; Bastos, Leandro F; Sprunger, David; Rezvani, Niloofar; Johnson, Kirk; Rice, Kenner C; Maier, Steven F; Watkins, Linda R

2017-06-01

Facial allodynia is a migraine symptom that is generally considered to represent a pivotal point in migraine progression. Treatment before development of facial allodynia tends to be more successful than treatment afterwards. As such, understanding the underlying mechanisms of facial allodynia may lead to a better understanding of the mechanisms underlying migraine. Migraine facial allodynia is modeled by applying inflammatory soup (histamine, bradykinin, serotonin, prostaglandin E2) over the dura. Whether glial and/or immune activation contributes to such pain is unknown. Here we tested if trigeminal nucleus caudalis (Sp5C) glial and/or immune cells are activated following supradural inflammatory soup, and if putative glial/immune inhibitors suppress the consequent facial allodynia. Inflammatory soup was administered via bilateral indwelling supradural catheters in freely moving rats, inducing robust and reliable facial allodynia. Gene expression for microglial/macrophage activation markers, interleukin-1β, and tumor necrosis factor-α increased following inflammatory soup along with robust expression of facial allodynia. This provided the basis for pursuing studies of the behavioral effects of 3 diverse immunomodulatory drugs on facial allodynia. Pretreatment with either of two compounds broadly used as putative glial/immune inhibitors (minocycline, ibudilast) prevented the development of facial allodynia, as did treatment after supradural inflammatory soup but prior to the expression of facial allodynia. Lastly, the toll-like receptor 4 (TLR4) antagonist (+)-naltrexone likewise blocked development of facial allodynia after supradural inflammatory soup. Taken together, these exploratory data support that activated glia and/or immune cells may drive the development of facial allodynia in response to supradural inflammatory soup in unanesthetized male rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Involvement of spinal glutamate transporter-1 in the development of mechanical allodynia and hyperalgesia associated with type 2 diabetes

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Shi J

2016-11-01

Full Text Available Jinshan Shi,1,* Ke Jiang,2,* Zhaoduan Li,3 1Department of Anesthesiology, Guizhou Provincial People’s Hospital, 2Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, 3Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin, People’s Republic of China *These authors contributed equally to this work Abstract: Little is known about the effects of the development of type 2 diabetes on glutamate homeostasis in the spinal cord. Therefore, we quantified the extracellular levels of glutamate in the spinal cord of Zucker diabetic fatty (ZDF rats using in vivo microdialysis. In addition, protein levels of glutamate transporter-1 (GLT-1 in the spinal cord of ZDF rats were measured using Western blot. Finally, the effects of repeated intrathecal injections of ceftriaxone, which was previously shown to enhance GLT-1 expression, on the development of mechanical allodynia and hyperalgesia as well as on basal extracellular level of glutamate and the expression of GLT-1 in the spinal cord of ZDF rats were evaluated. It was found that ZDF rats developed mechanical hyperalgesia and allodynia, which were associated with increased basal extracellular levels of glutamate and attenuated levels of GLT-1 expression in the spinal cord, particularly in the dorsal horn. Furthermore, repeated intrathecal administrations of ceftriaxone dose-dependently prevented the development of mechanical hyperalgesia and allodynia in ZDF rats, which were correlated with enhanced GLT-1 expression without altering the basal glutamate levels in the spinal cord of ZDF rats. Overall, the results suggested that impaired glutamate reuptake in the spinal cord may contribute to the development of neuropathic pains in type 2 diabetes. Keywords: diabetes, peripheral neuropathy, spinal cord, Zucker diabetic fatty rats, glutamate, glutamate transporter-1

Presurgical ketoprofen, but not morphine, dipyrone, diclofenac or tenoxicam, preempts post-incisional mechanical allodynia in rats

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Prado W.A.

2002-01-01

Full Text Available The treatment of pain before it initiates may prevent the persistent pain-induced changes in the central nervous system that amplify pain long after the initial stimulus. The effects of pre- or postoperative intraperitoneal administration of morphine (2 to 8 mg/kg, dipyrone (40 and 80 mg/kg, diclofenac (2 to 8 mg/kg, ketoprofen (10 and 20 mg/kg, and tenoxicam (10 and 20 mg/kg were studied in a rat model of post-incisional pain. Groups of 5 to 8 male Wistar rats (140-160 g were used to test each drug dose. An incision was made on the plantar surface of a hind paw and the changes in the withdrawal threshold to mechanical stimulation were evaluated with Von Frey filaments at 1, 2, 6 and 24 h after the surgery. Tenoxicam was given 12 or 6 h preoperatively, whereas the remaining drugs were given 2 h or 30 min preoperatively. Postoperative drugs were all given 5 min after surgery. No drug abolished allodynia when injected before or after surgery, but thresholds were significantly higher than in control during up to 2 h following ketoprofen, 6 h following diclofenac, and 24 h following morphine, dipyrone or tenoxicam when drugs were injected postoperatively. Significant differences between pre- and postoperative treatments were obtained only with ketoprofen administered 30 min before surgery. Preoperative (2 h intraplantar, but not intrathecal, ketoprofen reduced the post-incisional pain for up to 24 h after surgery. It is concluded that stimuli generated in the inflamed tissue, rather than changes in the central nervous system are relevant for the persistence of pain in the model of post-incisional pain.

Nicotine Prevents and Reverses Paclitaxel-Induced Mechanical Allodynia in a Mouse Model of CIPN.

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Kyte, S Lauren; Toma, Wisam; Bagdas, Deniz; Meade, Julie A; Schurman, Lesley D; Lichtman, Aron H; Chen, Zhi-Jian; Del Fabbro, Egidio; Fang, Xianjun; Bigbee, John W; Damaj, M Imad; Gewirtz, David A

2018-01-01

Chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration, continues to be a dose-limiting and debilitating side effect during and/or after cancer chemotherapy. Paclitaxel, a taxane commonly used to treat breast, lung, and ovarian cancers, causes CIPN in 59-78% of cancer patients. Novel interventions are needed due to the current lack of effective CIPN treatments. Our studies were designed to investigate whether nicotine can prevent and/or reverse paclitaxel-induced peripheral neuropathy in a mouse model of CIPN, while ensuring that nicotine will not stimulate lung tumor cell proliferation or interfere with the antitumor properties of paclitaxel. Male C57BL/6J mice received paclitaxel every other day for a total of four injections (8 mg/kg, i.p.). Acute (0.3-0.9 mg/kg, i.p.) and chronic (24 mg/kg per day, s.c.) administration of nicotine respectively reversed and prevented paclitaxel-induced mechanical allodynia. Blockade of the antinociceptive effect of nicotine with mecamylamine and methyllycaconitine suggests that the reversal of paclitaxel-induced mechanical allodynia is primarily mediated by the α 7 nicotinic acetylcholine receptor subtype. Chronic nicotine treatment also prevented paclitaxel-induced intraepidermal nerve fiber loss. Notably, nicotine neither promoted proliferation of A549 and H460 non-small cell lung cancer cells nor interfered with paclitaxel-induced antitumor effects, including apoptosis. Most importantly, chronic nicotine administration did not enhance Lewis lung carcinoma tumor growth in C57BL/6J mice. These data suggest that the nicotinic acetylcholine receptor-mediated pathways may be promising drug targets for the prevention and treatment of CIPN. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Low Frequency Electroacupuncture Alleviated Spinal Nerve Ligation Induced Mechanical Allodynia by Inhibiting TRPV1 Upregulation in Ipsilateral Undamaged Dorsal Root Ganglia in Rats

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Yong-Liang Jiang

2013-01-01

Full Text Available Neuropathic pain is an intractable problem in clinical practice. Accumulating evidence shows that electroacupuncture (EA with low frequency can effectively relieve neuropathic pain. Transient receptor potential vanilloid type 1 (TRPV1 plays a key role in neuropathic pain. The study aimed to investigate whether neuropathic pain relieved by EA administration correlates with TRPV1 inhibition. Neuropathic pain was induced by right L5 spinal nerve ligation (SNL in rats. 2 Hz EA stimulation was administered. SNL induced mechanical allodynia in ipsilateral hind paw. SNL caused a significant reduction of TRPV1 expression in ipsilateral L5 dorsal root ganglia (DRG, but a significant up-regulation in ipsilateral L4 and L6 DRGs. Calcitonin gene-related peptide (CGRP change was consistent with that of TRPV1. EA alleviated mechanical allodynia, and inhibited TRPV1 and CGRP overexpressions in ipsilateral L4 and L6 DRGs. SNL did not decrease pain threshold of contralateral hind paw, and TRPV1 expression was not changed in contralateral L5 DRG. 0.001, 0.01 mg/kg TRPV1 agonist 6′-IRTX fully blocked EA analgesia in ipsilateral hind paw. 0.01 mg/kg 6′-IRTX also significantly decreased pain threshold of contralateral paw. These results indicated that inhibition of TRPV1 up-regulation in ipsilateral adjacent undamaged DRGs contributed to low frequency EA analgesia for mechanical allodynia induced by spinal nerve ligation.

Selective Cathepsin S Inhibition with MIV-247 Attenuates Mechanical Allodynia and Enhances the Antiallodynic Effects of Gabapentin and Pregabalin in a Mouse Model of Neuropathic Pain.

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Hewitt, Ellen; Pitcher, Thomas; Rizoska, Biljana; Tunblad, Karin; Henderson, Ian; Sahlberg, Britt-Louise; Grabowska, Urszula; Classon, Björn; Edenius, Charlotte; Malcangio, Marzia; Lindström, Erik

2016-09-01

Cathepsin S inhibitors attenuate mechanical allodynia in preclinical neuropathic pain models. The current study evaluated the effects when combining the selective cathepsin S inhibitor MIV-247 with gabapentin or pregabalin in a mouse model of neuropathic pain. Mice were rendered neuropathic by partial sciatic nerve ligation. MIV-247, gabapentin, or pregabalin were administered alone or in combination via oral gavage. Mechanical allodynia was assessed using von Frey hairs. Neurobehavioral side effects were evaluated by assessing beam walking. MIV-247, gabapentin, and pregabalin concentrations in various tissues were measured. Oral administration of MIV-247 (100-200 µmol/kg) dose-dependently attenuated mechanical allodynia by up to approximately 50% reversal when given as a single dose or when given twice daily for 5 days. No behavioral deficits were observed at any dose of MIV-247 tested. Gabapentin (58-350 µmol/kg) and pregabalin (63-377 µmol/kg) also inhibited mechanical allodynia with virtually complete reversal at the highest doses tested. The minimum effective dose of MIV-247 (100 µmol/kg) in combination with the minimum effective dose of pregabalin (75 µmol/kg) or gabapentin (146 µmol/kg) resulted in enhanced antiallodynic efficacy without augmenting side effects. A subeffective dose of MIV-247 (50 µmol/kg) in combination with a subeffective dose of pregabalin (38 µmol/kg) or gabapentin (73 µmol/kg) also resulted in substantial efficacy. Plasma levels of MIV-247, gabapentin, and pregabalin were similar when given in combination as to when given alone. Cathepsin S inhibition with MIV-247 exerts significant antiallodynic efficacy alone, and also enhances the effect of gabapentin and pregabalin without increasing side effects or inducing pharmacokinetic interactions. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

TRV0109101, a G Protein-Biased Agonist of the µ-Opioid Receptor, Does Not Promote Opioid-Induced Mechanical Allodynia following Chronic Administration.

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Koblish, Michael; Carr, Richard; Siuda, Edward R; Rominger, David H; Gowen-MacDonald, William; Cowan, Conrad L; Crombie, Aimee L; Violin, Jonathan D; Lark, Michael W

2017-08-01

Prescription opioids are a mainstay in the treatment of acute moderate to severe pain. However, chronic use leads to a host of adverse consequences including tolerance and opioid-induced hyperalgesia (OIH), leading to more complex treatment regimens and diminished patient compliance. Patients with OIH paradoxically experience exaggerated nociceptive responses instead of pain reduction after chronic opioid usage. The development of OIH and tolerance tend to occur simultaneously and, thus, present a challenge when studying the molecular mechanisms driving each phenomenon. We tested the hypothesis that a G protein-biased µ -opioid peptide receptor (MOPR) agonist would not induce symptoms of OIH, such as mechanical allodynia, following chronic administration. We observed that the development of opioid-induced mechanical allodynia (OIMA), a model of OIH, was absent in β -arrestin1 -/- and β -arrestin2 -/- mice in response to chronic administration of conventional opioids such as morphine, oxycodone and fentanyl, whereas tolerance developed independent of OIMA. In agreement with the β -arrestin knockout mouse studies, chronic administration of TRV0109101, a G protein-biased MOPR ligand and structural analog of oliceridine, did not promote the development of OIMA but did result in drug tolerance. Interestingly, following induction of OIMA by morphine or fentanyl, TRV0109101 was able to rapidly reverse allodynia. These observations establish a role for β -arrestins in the development of OIH, independent of tolerance, and suggest that the use of G protein-biased MOPR ligands, such as oliceridine and TRV0109101, may be an effective therapeutic avenue for managing chronic pain with reduced propensity for opioid-induced hyperalgesia. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Astrocyte sigma-1 receptors modulate connexin 43 expression leading to the induction of below-level mechanical allodynia in spinal cord injured mice.

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Choi, Sheu-Ran; Roh, Dae-Hyun; Yoon, Seo-Yeon; Kwon, Soon-Gu; Choi, Hoon-Seong; Han, Ho-Jae; Beitz, Alvin J; Lee, Jang-Hern

2016-12-01

We have previously shown using a spinal cord injury (SCI) model that gap junctions contribute to the early spread of astrocyte activation in the lumbar spinal cord and that this astrocyte communication plays critical role in the induction of central neuropathic pain. Sigma-1 receptors (Sig-1Rs) have been implicated in spinal astrocyte activation and the development of peripheral neuropathic pain, yet their contribution to central neuropathic pain remains unknown. Thus, we investigated whether SCI upregulates spinal Sig-1Rs, which in turn increase the expression of the astrocytic gap junction protein, connexin 43 (Cx43) leading to the induction of central neuropathic pain. A thoracic spinal cord hemisection significantly increased both astrocyte activation and Cx43 expression in lumbar dorsal horn. Sig-1Rs were also increased in lumbar dorsal horn astrocytes, but not neurons or microglia. Intrathecal injection of an astrocyte metabolic inhibitor (fluorocitrate); a gap junction/hemichannel blocker (carbenoxolone); or a Cx43 mimetic peptide ( 43 Gap26) significantly reduced SCI-induced bilateral below-level mechanical allodynia. Blockade of Sig-1Rs with BD1047 during the induction phase of pain significantly suppressed the SCI-induced development of mechanical allodynia, astrocyte activation, increased expression of Cx43 in both total and membrane levels, and increased association of Cx43 with Sig-1R. However, SCI did not change the expression of oligodendrocyte (Cx32) or neuronal (Cx36) gap junction proteins. These findings demonstrate that SCI activates astrocyte Sig-1Rs leading to increases in the expression of the gap junction protein, Cx43 and astrocyte activation in the lumbar dorsal horn, and ultimately contribute to the induction of bilateral below-level mechanical allodynia. Copyright © 2016 Elsevier Ltd. All rights reserved.

Accumulation of methylglyoxal increases the advanced glycation end-product levels in DRG and contributes to lumbar disk herniation-induced persistent pain.

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Liu, Cui-Cui; Zhang, Xin-Sheng; Ruan, Yu-Ting; Huang, Zhu-Xi; Zhang, Su-Bo; Liu, Meng; Luo, Hai-Jie; Wu, Shao-Ling; Ma, Chao

2017-08-01

Lumbar disk herniation (LDH) with discogenic low back pain and sciatica is a common and complicated musculoskeletal disorder. The underlying mechanisms are poorly understood, and there are no effective therapies for LDH-induced pain. In the present study, we found that the patients who suffered from LDH-induced pain had elevated plasma methylglyoxal (MG) levels. In rats, implantation of autologous nucleus pulposus (NP) to the left lumbar 5 spinal nerve root, which mimicked LDH, induced mechanical allodynia, increased MG level in plasma and dorsal root ganglion (DRG), and enhanced the excitability of small DRG neurons (DRG neurons ex vivo increased the number of action potentials evoked by depolarizing current pulses. Furthermore, inhibition of MG accumulation by aminoguanidine attenuated the enhanced excitability of small DRG neurons and the mechanical allodynia induced by NP implantation. In addition, NP implantation increased levels of advanced glycation end products (AGEs) in DRG, and intrathecal injection of MG-derived AGEs induced the mechanical allodynia and DRG neuronal hyperactivity. Intrathecal injection of MG also significantly increased the expression of AGEs in DRG. Importantly, scavenging of MG by aminoguanidine also attenuated the increase in AGEs induced by NP implantation. These results suggested that LDH-induced MG accumulation contributed to persistent pain by increasing AGE levels. Thus generation of AGEs from MG may represent a target for treatment of LDH-induced pain. NEW & NOTEWORTHY Our study demonstrates that methylglyoxal accumulation via increasing advanced glycation end-product levels in dorsal root ganglion contributes to the persistent pain induced by lumbar disk herniation, which proposed potential targets for the treatment of lumbar disk herniation-induced persistent pain. Copyright © 2017 the American Physiological Society.

Stat3 inhibition attenuates mechanical allodynia through transcriptional regulation of chemokine expression in spinal astrocytes.

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Xiaodong Liu

Full Text Available BACKGROUND: Signal transducer and activator of transcription 3 (Stat3 is known to induce cell proliferation and inflammation by regulating gene transcription. Recent studies showed that Stat3 modulates nociceptive transmission by reducing spinal astrocyte proliferation. However, it is unclear whether Stat3 also contributes to the modulation of nociceptive transmission by regulating inflammatory response in spinal astrocytes. This study aimed at investigating the role of Stat3 on neuroinflammation during development of pain in rats after intrathecal injection of lipopolysaccharide (LPS. METHODS: Stat3 specific siRNA oligo and synthetic selective inhibitor (Stattic were applied to block the activity of Stat3 in primary astrocytes or rat spinal cord, respectively. LPS was used to induce the expression of proinflammatory genes in all studies. Immunofluorescence staining of cells and slices of spinal cord was performed to monitor Stat3 activation. The impact of Stat3 inhibition on proinflammatory genes expression was determined by cytokine antibody array, enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Mechanical allodynia, as determined by the threshold pressure that could induce hind paw withdrawal after application of standardized von Frey filaments, was used to detect the effects of Stat3 inhibition after pain development with intrathecal LPS injection. RESULTS: Intrathecal injection of LPS activated Stat3 in reactive spinal astrocytes. Blockade of Stat3 activity attenuated mechanical allodynia significantly and was correlated with a lower number of reactive astrocytes in the spinal dorsal horn. In vitro study demonstrated that Stat3 modulated inflammatory response in primary astrocytes by transcriptional regulation of chemokine expression including Cx3cl1, Cxcl5, Cxcl10 and Ccl20. Similarly, inhibition of Stat3 reversed the expression of these chemokines in the spinal dorsal horn. CONCLUSIONS: Stat3 acted as a

Low-threshold mechanoreceptors play a frequency-dependent dual role in subjective ratings of mechanical allodynia.

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Löken, Line S; Duff, Eugene P; Tracey, Irene

2017-12-01

In the setting of injury, myelinated primary afferent fibers that normally signal light touch are thought to switch modality and instead signal pain. In the absence of injury, touch is perceived as more intense when firing rates of Aβ afferents increase. However, it is not known if varying the firing rates of Aβ afferents have any consequence to the perception of dynamic mechanical allodynia (DMA). We hypothesized that, in the setting of injury, the unpleasantness of DMA would be intensified as the firing rates of Aβ afferents increase. Using a stimulus-response protocol established in normal skin, where an increase in brush velocity results in an increase of Aβ afferent firing rates, we tested if brush velocity modulated the unpleasantness of capsaicin-induced DMA. We analyzed how changes in estimated low-threshold mechanoreceptor firing activity influenced perception and brain activity (functional MRI) of DMA. Brushing on normal skin was perceived as pleasant, but brushing on sensitized skin produced both painful and pleasant sensations. Surprisingly, there was an inverse relationship between Aβ firing rates and unpleasantness such that brush stimuli that produced low firing rates were most painful and those that elicited high firing rates were rated as pleasant. Concurrently to this, we found increased cortical activity in response to low Aβ firing rates in regions previously implicated in pain processing during brushing of sensitized skin, but not normal skin. We suggest that Aβ signals do not merely switch modality to signal pain during injury. Instead, they exert a high- and low-frequency-dependent dual role in the injured state, with respectively both pleasant and unpleasant consequences. NEW & NOTEWORTHY We suggest that Aβ signals do not simply switch modality to signal pain during injury but play a frequency-dependent and dual role in the injured state with both pleasant and unpleasant consequences. These results provide a framework to resolve the

Passiflora incarnata attenuation of neuropathic allodynia and vulvodynia apropos GABA-ergic and opioidergic antinociceptive and behavioural mechanisms.

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Aman, Urooj; Subhan, Fazal; Shahid, Muhammad; Akbar, Shehla; Ahmad, Nisar; Ali, Gowhar; Fawad, Khwaja; Sewell, Robert D E

2016-02-24

Passiflora incarnata is widely used as an anxiolytic and sedative due to its putative GABAergic properties. Passiflora incarnata L. methanolic extract (PI-ME) was evaluated in an animal model of streptozotocin-induced diabetic neuropathic allodynia and vulvodynia in rats along with antinociceptive, anxiolytic and sedative activities in mice in order to examine possible underlying mechanisms. PI-ME was tested preliminary for qualitative phytochemical analysis and then quantitatively by proximate and GC-MS analysis. The antinociceptive property was evaluated using the abdominal constriction assay and hot plate test. The anxiolytic activity was performed in a stair case model and sedative activity in an open field test. The antagonistic activities were evaluated using naloxone and/or pentylenetetrazole (PTZ). PI-ME was evaluated for prospective anti-allodynic and anti-vulvodynic properties in a rat model of streptozotocin induced neuropathic pain using the static and dynamic testing paradigms of mechanical allodynia and vulvodynia. GC-MS analysis revealed that PI-ME contained predominant quantities of oleamide (9-octadecenamide), palmitic acid (hexadecanoic acid) and 3-hydroxy-dodecanoic acid, among other active constituents. In the abdominal constriction assay and hot plate test, PI-ME produced dose dependant, naloxone and pentylenetetrazole reversible antinociception suggesting an involvement of opioidergic and GABAergic mechanisms. In the stair case test, PI-ME at 200 mg/kg increased the number of steps climbed while at 600 mg/kg a significant decrease was observed. The rearing incidence was diminished by PI-ME at all tested doses and in the open field test, PI-ME decreased locomotor activity to an extent that was analagous to diazepam. The effects of PI-ME were antagonized by PTZ in both the staircase and open field tests implicating GABAergic mechanisms in its anxiolytic and sedative activities. In the streptozotocin-induced neuropathic nociceptive model, PI

Contact lenses, migraine, and allodynia

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Ozgur Bulent Timucin

2016-01-01

Full Text Available Clinical trials and electrophysiologic studies demonstrated increased perceptual sensitivity in patients suffering from migraines. At least, one triggering factor is described in 85% of migraine patients. The aim of this report was to investigate the relationship between contact lens (CL usage and migraine attacks in two cases. Two patients who were diagnosed with migraine reported that the frequency of migraine attacks increased after they switched to using CL with different base curves (BCs. These two patients, who began using CL with different BCs experienced discomfort and dryness of the eye. The ocular complaints were followed by migraine attacks. CL intolerance was also developed during migraine attack in one of the cases. The frequency of migraine attacks decreased and allodynia relieved significantly when flatter BCs were selected. CL related stimulus could have triggered the migraine attack. CLs should be well fitted in migraine patients with allodynia.

Photochemically-induced ischemia of the rat sciatic nerve produces a dose-dependent and highly reproducible mechanical, heat and cold allodynia, and signs of spontaneous pain.

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Kupers, R; Yu, W; Persson, J K; Xu, X J; Wiesenfeld-Hallin, Z

1998-05-01

Sensory abnormalities and changes in spontaneous behavior were examined after a photochemically induced ischemic lesion of the rat sciatic nerve. Male adult rats were anesthetized and the sciatic nerve was exposed. After the intravenous injection of a photosensitizing dye, erythrosin B, the exposed nerve was irradiated just proximal to the nerve trifurcation with light from an argon laser. Three different irradiation times were used, 30 s, 1 and 2 min. In sham-operated rats, the exposed sciatic nerve was irradiated for 2 min without prior injection of the erythrosin B. Rats were tested for the presence of mechanical, cold and heat allodynia or hyperalgesia. All the animals in the 1- and 2-min irradiation groups developed mechanical, cold and heat allodynia after nerve irradiation. A significant dose-dependent effect of laser exposure time was observed for all modalities tested (2 min > 1 min > 30 s = sham). The maximum effects were observed at 3 and 7 days postirradiation and remained present for up to 10 weeks. No significant contralateral effects were observed in any of the groups. In three separate groups of rats (1, 2 and 4 min of laser exposure), the presence of possible signs of spontaneous pain (paw shaking, paw elevation and freezing behavior) was tested. A significant and exposure time-dependent increase in spontaneous paw elevation and paw shaking was observed which was maximal at week 1, but resolved at 4 weeks (4 min > 2 min > 1 min > sham). In addition, animals in all ischemic groups, but not in the sham group, showed a significant increase in freezing behavior up to 4 weeks after nerve irradiation. Light microscopic evaluation of nerves removed 7 days post-irradiation, i.e. when maximal allodynia was observed, showed clear evidence of demyelination of large myelinated fibers. These data indicate that photochemically-induced peripheral nerve ischemia is associated with abnormal pain-related behaviors, including mechanical, thermal and cold allodynia

Mild closed head traumatic brain injury-induced changes in monoamine neurotransmitters in the trigeminal subnuclei of a rat model: mechanisms underlying orofacial allodynias and headache

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Golam Mustafa

2017-01-01

Full Text Available Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias, a hypersensitive pain response induced by non-painful stimulation. These allodynias, tested using thermal hyperalgesia, correlated with changes in several known pain signaling receptors and molecules along the trigeminal pain pathway, especially in the trigeminal nucleus caudalis. This study focused to extend our previous work to investigate the changes in monoamine neurotransmitter immunoreactivity changes in spinal trigeminal nucleus oralis, pars interpolaris and nucleus tractus solitaries following mild to moderate closed head traumatic brain injury, which are related to tactile allodynia, touch-pressure sensitivity, and visceral pain. Our results exhibited significant alterations in the excitatory monoamine, serotonin, in spinal trigeminal nucleus oralis and pars interpolaris which usually modulate tactile and mechanical sensitivity in addition to the thermal sensitivity. Moreover, we also detected a robust alteration in the expression of serotonin, and inhibitory molecule norepinephrine in the nucleus tractus solitaries, which might indicate the possibility of an alteration in visceral pain, and existence of other morbidities related to solitary nucleus dysfunction in this rodent model of mild to moderate closed head traumatic brain injury. Collectively, widespread changes in monoamine neurotransmitter may be related to orofacial allodynhias and headache after traumatic brain injury.

Repetitive Acupuncture Point Treatment with Diluted Bee Venom Relieves Mechanical Allodynia and Restores Intraepidermal Nerve Fiber Loss in Oxaliplatin-Induced Neuropathic Mice.

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Yeo, Ji-Hee; Yoon, Seo-Yeon; Kwon, Soon-Keun; Kim, Sol-Ji; Lee, Jang-Hern; Beitz, Alvin J; Roh, Dae-Hyun

2016-03-01

The chemotherapeutic agent, oxaliplatin, produces a robust painful neuropathy that results in the loss of intraepidermal nerve fibers (IENFs). We have previously reported that an acupuncture point (acupoint) injection of diluted bee venom (DBV) produces a temporary antiallodynic effect in oxaliplatin-induced neuropathic mice. Herein we show a significant long-lasting antinociceptive effect of repetitive DBV acupoint treatment on oxaliplatin-induced mechanical allodynia and a significant reduction in the loss of IENFs. DBV (0.1 mg/kg, subcutaneous) was administered once a day for 18 days beginning on day 15 after oxaliplatin injection. Immunohistochemistry for IENF was performed on the glabrous skin of the hind paw footpad using the pan-neuronal marker, protein gene product 9.5. A temporary increase in mechanical threshold was observed 60 minutes after a single DBV injection into the Zusanli acupoint, and this effect was enhanced over time with repetitive DBV treatments. The basal mechanical threshold before daily DBV injection also increased from day 7 after DBV injections, and peaked at day 14 after DBV treatment. Moreover, the oxaliplatin-induced loss of IENFs was significantly reduced in mice treated repetitively with DBV. Repetitive pretreatment with the α-2 adrenoceptor antagonist, yohimbine, (5 mg/kg, subcutaneous) completely prevented the antiallodynic effects and the increase in IENFs observed in mice treated repetitively with DBV. We showed that repetitive acupoint stimulation with DBV gradually and significantly reduced oxaliplatin-induced mechanical allodynia and restored the loss of IENFs in neuropathic mice via an α-2 adrenoceptor mechanism. Collectively, results of this study suggest that repetitive acupoint treatment with DBV can be a potential strategy for the management of chemotherapy-induced neuropathy. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Herbal Medicine Goshajinkigan Prevents Paclitaxel-Induced Mechanical Allodynia without Impairing Antitumor Activity of Paclitaxel

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Bahar, Muh. Akbar; Andoh, Tsugunobu; Ogura, Keisuke; Hayakawa, Yoshihiro; Saiki, Ikuo; Kuraishi, Yasushi

2013-01-01

Chemotherapy-induced peripheral neuropathy is a major dose-limiting side effect of commonly used chemotherapeutic agents. However, there are no effective strategies to treat the neuropathy. We examined whether Goshajinkigan, a herbal medicine, would prevent paclitaxel-induced allodynia without affecting the anticancer action in mice. Murine breast cancer 4T1 cells were inoculated into the mammary fat pad. Paclitaxel (10 and 20 mg/kg, intraperitoneal, alternate day from day 7 postinoculation) ...

Activation of voltage-gated KCNQ/Kv7 channels by anticonvulsant retigabine attenuates mechanical allodynia of inflammatory temporomandibular joint in rats

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Xu Wen

2010-08-01

Full Text Available Abstract Background Temporomandibular disorders (TMDs are characterized by persistent orofacial pain and have diverse etiologic factors that are not well understood. It is thought that central sensitization leads to neuronal hyperexcitability and contributes to hyperalgesia and spontaneous pain. Nonsteroidal anti-inflammatory drugs (NSAIDs are currently the first choice of drug to relieve TMD pain. NSAIDS were shown to exhibit anticonvulsant properties and suppress cortical neuron activities by enhancing neuronal voltage-gated potassium KCNQ/Kv7 channels (M-current, suggesting that specific activation of M-current might be beneficial for TMD pain. Results In this study, we selected a new anticonvulsant drug retigabine that specifically activates M-current, and investigated the effect of retigabine on inflammation of the temporomandibular joint (TMJ induced by complete Freund's adjuvant (CFA in rats. The results show that the head withdrawal threshold for escape from mechanical stimulation applied to facial skin over the TMJ in inflamed rats was significantly lower than that in control rats. Administration of centrally acting M-channel opener retigabine (2.5 and 7.5 mg/kg can dose-dependently raise the head withdrawal threshold of mechanical allodynia, and this analgesic effect can be reversed by the specific KCNQ channel blocker XE991 (3 mg/kg. Food intake is known to be negatively associated with TMJ inflammation. Food intake was increased significantly by the administration of retigabine (2.5 and 7.5 mg/kg, and this effect was reversed by XE991 (3 mg/kg. Furthermore, intracerebralventricular injection of retigabine further confirmed the analgesic effect of central retigabine on inflammatory TMJ. Conclusions Our findings indicate that central sensitization is involved in inflammatory TMJ pain and pharmacological intervention for controlling central hyperexcitability by activation of neuronal KCNQ/M-channels may have therapeutic potential for

Detection of cold pain, cold allodynia and cold hyperalgesia in freely behaving rats

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Woolf Clifford J

2005-12-01

Full Text Available Abstract Background Pain is elicited by cold, and a major feature of many neuropathic pain states is that normally innocuous cool stimuli begin to produce pain (cold allodynia. To expand our understanding of cold induced pain states we have studied cold pain behaviors over a range of temperatures in several animal models of chronic pain. Results We demonstrate that a Peltier-cooled cold plate with ± 1°C sensitivity enables quantitative measurement of a detection withdrawal response to cold stimuli in unrestrained rats. In naïve rats the threshold for eliciting cold pain behavior is 5°C. The withdrawal threshold for cold allodynia is 15°C in both the spared nerve injury and spinal nerve ligation models of neuropathic pain. Cold hyperalgesia is present in the spared nerve injury model animals, manifesting as a reduced latency of withdrawal response threshold at temperatures that elicit cold pain in naïve rats. We also show that following the peripheral inflammation produced by intraplantar injection of complete Freund's adjuvant, a hypersensitivity to cold occurs. Conclusion The peltier-cooled provides an effective means of assaying cold sensitivity in unrestrained rats. Behavioral testing of cold allodynia, hyperalgesia and pain will greatly facilitate the study of the neurobiological mechanisms involved in cold/cool sensations and enable measurement of the efficacy of pharmacological treatments to reduce these symptoms.

Intervertebral Foramen Injection of Ozone Relieves Mechanical Allodynia and Enhances Analgesic Effect of Gabapentin in Animal Model of Neuropathic Pain.

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Luo, Wen-Jun; Yang, Fan; Yang, Fei; Sun, Wei; Zheng, Wei; Wang, Xiao-Liang; Wu, Fang-Fang; Wang, Jiang-Lin; Wang, Jia-Shuang; Guan, Su-Min; Chen, Jun

2017-07-01

In a 5-year follow-up study in a hospital in southern China, it was shown that intervertebral foramen (IVF) injection of ozone at the involved segmental levels could significantly alleviate paroxysmal spontaneous pain and mechanical allodynia in patients with chronic, intractable postherpetic neuralgia (PHN) and improve the quality of life. However, so far no proof-of-concept studies in animals have been available. This study was designed to investigate whether IVF ozone has an analgesic effect on animal models of neuropathic and inflammatory pain. Experimental trial in rats. Institute for Biomedical Sciences of Pain. By IVF injection, a volume of 50 µl containing 30 µg/mL ozone-oxygen mixture or 50 µl air was carried out on male Sprague-Dawley rats of naïve, inflammatory pain states produced by injections of either bee venom or complete Freud's adjuvant, and neuropathic pain state produced by spared nerve injury, respectively. The effects of IVF ozone on pain-related behaviors were evaluated for 2 weeks or one month. Then combined use of gabapentin (100 mg/1 kg body weight) with IVF ozone was evaluated in rats with neuropathic pain by intraperitoneal administration 5 days after the ozone treatment. Finally, the analgesic effects of another 4 drugs, AMD3100 (a CXCR4 antagonist), A-803467 (a selective Nav1.8 blocker), rapamycin (the mTOR inhibitor), and MGCD0103 (a selective histone deacetylase inhibitor) were evaluated for long term through IVF injection, respectively. (1) IVF injection of ozone at L4-5 was only effective in suppression of mechanical allodynia in rats with neuropathic pain but not with inflammatory pain; (2) the analgesic effects of IVF ozone lasted much longer (> 14 days) than other selective molecular target drugs (bee venom, complete Freud's adjuvant.

Depression-like behavior and mechanical allodynia are reduced by bis selenide treatment in mice with chronic constriction injury: a comparison with fluoxetine, amitriptyline, and bupropion.

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Jesse, Cristiano R; Wilhelm, Ethel A; Nogueira, Cristina W

2010-12-01

Neuropathic pain is associated with significant co-morbidities, including depression, which impact considerably on the overall patient experience. Pain co-morbidity symptoms are rarely assessed in animal models of neuropathic pain. Neuropathic pain is characterized by hyperexcitability within nociceptive pathways and remains difficult to treat with standard analgesics. The present study determined the effect of bis selenide and conventional antidepressants (fluoxetine, amitriptyline, and bupropion) on neuropathic pain using mechanical allodynic and on depressive-like behavior. Male mice were subjected to chronic constriction injury (CCI) or sham surgery and were assessed on day 14 after operation. Mice received oral treatment with bis selenide (1-5 mg/kg), fluoxetine, amitriptyline, or bupropion (10-30 mg/kg). The response frequency to mechanical allodynia in mice was measured with von Frey hairs. Mice were evaluated in the forced swimming test (FST) test for depression-like behavior. The CCI procedure produced mechanical allodynia and increased depressive-like behavior in the FST. All of the drugs produced antiallodynic effects in CCI mice and produced antidepressant effects in control mice without altering locomotor activity. In CCI animals, however, only the amitriptyline and bis selenide treatments significantly reduced immobility in the FST. These data demonstrate an important dissociation between the antiallodynic and antidepressant effects in mice when tested in a model of neuropathic pain. Depressive behavior in CCI mice was reversed by bis selenide and amitriptyline but not by the conventional antidepressants fluoxetine and buproprion. Bis selenide was more potent than the other drugs tested for antidepressant-like and antiallodynic effects in mice.

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

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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 minocycline-treated participants experienced a bilateral 70% alleviation in muscle soreness (P minocycline-treated participants showed cold allodynia. This study showed that repeated injections of HS can induce a hypersensitivity that outlasts the acute response, and the development of this hypersensitivity can be reliably attenuated with minocycline pretreatment. Four repeated injections of HS at 48-hour intervals induce a state of persistent hypersensitivity in

Persistence Mechanisms of Conjugative Plasmids

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Bahl, Martin Iain; Hansen, Lars H.; Sørensen, Søren Johannes

2009-01-01

Are plasmids selfish parasitic DNA molecules or an integrated part of the bacterial genome? This chapter reviews the current understanding of the persistence mechanisms of conjugative plasmids harbored by bacterial cells and populations. The diversity and intricacy of mechanisms affecting the suc...

Clinical evidence of parietal cortex dysfunction and correlation with extent of allodynia in CRPS type 1.

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Cohen, H; McCabe, C; Harris, N; Hall, J; Lewis, J; Blake, D R

2013-04-01

Unusual symptoms such as digit misidentification and neglect-like phenomena have been reported in complex regional pain syndrome (CRPS), which we hypothesized could be explained by parietal lobe dysfunction. Twenty-two patients with chronic CRPS attending an in-patient rehabilitation programme underwent standard neurological examination followed by clinical assessment of parietal lobe function and detailed sensory testing. Fifteen (68%) patients had evidence of parietal lobe dysfunction. Six (27%) subjects failed six or more test categories and demonstrated new clinical signs consistent with their parietal testing impairments, which were impacting significantly on activities of daily living. A higher incidence was noted in subjects with >1 limb involvement, CRPS affecting the dominant side and in left-handed subjects. Eighteen patients (82%) had mechanical allodynia covering 3-57.5% of the body surface area. Allochiria (unilateral tactile stimulation perceived only in the analogous location on the opposite limb), sensory extinction (concurrent bilateral tactile stimulation perceived only in one limb), referred sensations (unilateral tactile stimulation perceived concurrently in another discrete body area) and dysynchiria (unilateral non-noxious tactile stimulation perceived bilaterally as noxious) were present in some patients. Greater extent of body surface allodynia was correlated with worse parietal function (Spearman's rho = -0.674, p = 0.001). In patients with chronic CRPS, detailed clinical examination may reveal parietal dysfunction, with severity relating to the extent of allodynia. © 2012 European Federation of International Association for the Study of Pain Chapters.

Reactive oxygen species scavengers ameliorate mechanical allodynia in a rat model of cancer-induced bone pain

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Ya-Qun Zhou

2018-04-01

Full Text Available Cancer-induced bone pain (CIBP is a frequent complication in patients suffering from bone metastases. Previous studies have demonstrated a pivotal role of reactive oxygen species (ROS in inflammatory and neuropathic pain, and ROS scavengers exhibited potent antinociceptive effect. However, the role of spinal ROS remains unclear. In this study, we investigated the analgesic effect of two ROS scavengers in a well-established CIBP model. Our results found that intraperitoneal injection of N-tert-Butyl-α-phenylnitrone (PBN, 50 and 100 mg/kg and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol, 100 and 200 mg/kg significantly suppressed the established mechanical allodynia in CIBP rats. Moreover, repeated injection of PBN and Tempol showed cumulative analgesic effect without tolerance. However, early treatment with PBN and Tempol failed to prevent the development of CIBP. Naive rats received repetitive injection of PBN and Tempol showed no significant change regarding the nociceptive responses. Finally, PBN and Tempol treatment notably suppressed the activation of spinal microglia in CIBP rats. In conclusion, ROS scavengers attenuated established CIBP by suppressing the activation of microglia in the spinal cord. Keywords: Cancer-induced bone pain, Reactive oxygen species, PBN, Tempol

Activation of Spinal α2-Adrenoceptors Using Diluted Bee Venom Stimulation Reduces Cold Allodynia in Neuropathic Pain Rats

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Suk-Yun Kang

2012-01-01

Full Text Available Cold allodynia is an important distinctive feature of neuropathic pain. The present study examined whether single or repetitive treatment of diluted bee venom (DBV reduced cold allodynia in sciatic nerve chronic constriction injury (CCI rats and whether these effects were mediated by spinal adrenergic receptors. Single injection of DBV (0.25 or 2.5 mg/kg was performed into Zusanli acupoint 2 weeks post CCI, and repetitive DBV (0.25 mg/kg was injected for 2 weeks beginning on day 15 after CCI surgery. Single treatment of DBV at a low dose (0.25 mg/kg did not produce any anticold allodynic effect, while a high dose of DBV (2.5 mg/kg significantly reduced cold allodynia. Moreover, this effect of high-dose DBV was completely blocked by intrathecal pretreatment of idazoxan (α2-adrenoceptor antagonist, but not prazosin (α1-adrenoceptor antagonist or propranolol (nonselective β-adrenoceptor antagonist. In addition, coadministration of low-dose DBV (0.25 mg/kg and intrathecal clonidine (α2-adrenoceptor agonist synergically reduced cold allodynia. On the other hand, repetitive treatments of low-dose DBV showing no motor deficit remarkably suppressed cold allodynia from 7 days after DBV treatment. This effect was also reversed by intrathecal idazoxan injection. These findings demonstrated that single or repetitive stimulation of DBV could alleviate CCI-induced cold allodynia via activation of spinal α2-adrenoceptor.

Peripheral Neuropathic Pain: A mechanism-related organizing principle based on sensory profiles

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Baron, Ralf; Maier, Christoph; Attal, Nadine

2017-01-01

with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combination with pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed...

Role of PAF receptor in proinflammatory cytokine expression in the dorsal root ganglion and tactile allodynia in a rodent model of neuropathic pain.

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Shigeo Hasegawa

Full Text Available BACKGROUND: Neuropathic pain is a highly debilitating chronic pain following damage to peripheral sensory neurons and is often resistant to all treatments currently available, including opioids. We have previously shown that peripheral nerve injury induces activation of cytosolic phospholipase A(2 (cPLA(2 in injured dorsal root ganglion (DRG neurons that contribute to tactile allodynia, a hallmark of neuropathic pain. However, lipid mediators downstream of cPLA(2 activation to produce tactile allodynia remain to be determined. PRINCIPAL FINDINGS: Here we provide evidence that platelet-activating factor (PAF is a potential candidate. Pharmacological blockade of PAF receptors (PAFRs reduced the development and expression of tactile allodynia following nerve injury. The expression of PAFR mRNA was increased in the DRG ipsilateral to nerve injury, which was seen mainly in macrophages. Furthermore, mice lacking PAFRs showed a reduction of nerve injury-induced tactile allodynia and, interestingly, a marked suppression of upregulation of tumor necrosis factor alpha (TNFalpha and interleukin-1beta (IL-1beta expression in the injured DRG, crucial proinflammatory cytokines involved in pain hypersensitivity. Conversely, a single injection of PAF near the DRG of naïve rats caused a decrease in the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner and an increase in the expression of mRNAs for TNFalpha and IL-1beta, both of which were inhibited by pretreatment with a PAFR antagonist. CONCLUSIONS: Our results indicate that the PAF/PAFR system has an important role in production of TNFalpha and IL-1beta in the DRG and tactile allodynia following peripheral nerve injury and suggest that blocking PAFRs may be a viable therapeutic strategy for treating neuropathic pain.

Concomitant Migraine and Temporomandibular Disorders are Associated With Higher Heat Pain Hyperalgesia and Cephalic Cutaneous Allodynia.

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Chaves, Thais C; Dach, Fabíola; Florencio, Lidiane L; Carvalho, Gabriela F; Gonçalves, Maria C; Bigal, Marcelo E; Speciali, José G; Bevilaqua-Grossi, Débora

2016-10-01

The aim of this study was to assess differences in the levels of hyperalgesia and cutaneous allodynia (CA) among women with migraine, temporomandibular disorders (TMD), or both. Eighty women participated in the study. Mean ages for the control group, TMD group, migraine group, and migraine+TMD group were 26.15 (95% confidence interval [CI], 28.73 to 23.57), 31.65 (95% CI, 37.82 to 25.48), 35.05 (95% CI, 40.37 to 29.73), and 34.20 (95% CI, 37.99 to 30.41) years, respectively. The 12-item Allodynia Symptom Checklist was administered to assess CA. All participants underwent the Quantitative Sensory Test to determine the cold-pain and heat-pain thresholds. Mechanical pain thresholds were assessed using Semmes-Weinstein monofilaments. One-way analysis of variance and χ tests were used for statistical analysis. Alpha was set at 0.05 level for statistical significance. For all sites evaluated, the mean cold-pain threshold values were significantly lower in the TMD, migraine, and TMD+migraine groups compared with the control group. However, the mean heat-pain threshold values in the extracephalic region were significantly smaller only for the TMD+migraine group compared with the control group (41.94°C; 95% CI, 40.54 to 43.34 vs. 44.79°C; 95% CI, 43.45 to 46.12; P=0.03). Mechanical hyperalgesia in orofacial and neck sites was significantly lower in the TMD and TMD+migraine groups compared with the control group. Mean total 12-item Allodynia Symptom Checklist score in the TMD+migraine group was significantly higher than in the migraine group (9.53; 95% CI, 7.45 to 11.60 vs. 6.95; 95% CI, 5.35 to 8.55; P=0.02). More pronounced levels of hyperalgesia and CA were found in patients with both TMD and migraine. Thus, it is suggested that the concomitant presence of TMD and migraine may be related to intensification of central sensitization.

Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury

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Ellis, Amanda; Grace, Peter M.; Wieseler, Julie; Favret, Jacob; Springer, Kendra; Skarda, Bryce; Hutchinson, Mark R.; Falci, Scott; Rice, Kenner C.; Maier, Steven F.; Watkins, Linda R.

2016-01-01

Central neuropathic pain (CNP) is a pervasive, debilitating problem that impacts thousands of people living with central nervous system disorders, including spinal cord injury (SCI). Current therapies for treating this type of pain are ineffective and often have dose-limiting side effects. Although opioids are one of the most commonly used CNP treatments, recent animal literature has indicated that administering opioids shortly after a traumatic injury can actually have deleterious effects on long-term health and recovery. In order to study the deleterious effects of administering morphine shortly after trauma, we employed our low thoracic (T13) dorsal root avulsion model (Spinal Neuropathic Avulsion Pain, SNAP). Administering a weeklong course of 10 mg/kg/day morphine beginning 24 hr after SNAP resulted in amplified mechanical allodynia. Co-administering the non-opioid toll-like receptor 4 (TLR4) antagonist (+)-naltrexone throughout the morphine regimen prevented morphine-induced amplification of SNAP. Exploration of changes induced by early post-trauma morphine revealed that this elevated gene expression of TLR4, TNF, IL-1β, and NLRP3, as well as IL-1β protein at the site of spinal cord injury. These data suggest that a short course of morphine administered early after spinal trauma can exacerbate CNP in the long term. TLR4 initiates this phenomenon and, as such, may be potential therapeutic targets for preventing the deleterious effects of administering opioids after traumatic injury. PMID:27519154

Spinal cord transection-induced allodynia in rats--behavioral, physiopathological and pharmacological characterization.

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Saïd M'Dahoma

Full Text Available In humans, spinal cord lesions induce not only major motor and neurovegetative deficits but also severe neuropathic pain which is mostly resistant to classical analgesics. Better treatments can be expected from precise characterization of underlying physiopathological mechanisms. This led us to thoroughly investigate (i mechanical and thermal sensory alterations, (ii responses to acute treatments with drugs having patent or potential anti-allodynic properties and (iii the spinal/ganglion expression of transcripts encoding markers of neuronal injury, microglia and astrocyte activation in rats that underwent complete spinal cord transection (SCT. SCT was performed at thoracic T8-T9 level under deep isoflurane anaesthesia, and SCT rats were examined for up to two months post surgery. SCT induced a marked hyper-reflexia at hindpaws and strong mechanical and cold allodynia in a limited (6 cm2 cutaneous territory just rostral to the lesion site. At this level, pressure threshold value to trigger nocifensive reactions to locally applied von Frey filaments was 100-fold lower in SCT- versus sham-operated rats. A marked up-regulation of mRNAs encoding ATF3 (neuronal injury and glial activation markers (OX-42, GFAP, P2×4, P2×7, TLR4 was observed in spinal cord and/or dorsal root ganglia at T6-T11 levels from day 2 up to day 60 post surgery. Transcripts encoding the proinflammatory cytokines IL-1β, IL-6 and TNF-α were also markedly but differentially up-regulated at T6-T11 levels in SCT rats. Acute treatment with ketamine (50 mg/kg i.p., morphine (3-10 mg/kg s.c. and tapentadol (10-20 mg/kg i.p. significantly increased pressure threshold to trigger nocifensive reaction in the von Frey filaments test, whereas amitriptyline, pregabalin, gabapentin and clonazepam were ineffective. Because all SCT rats developed long lasting, reproducible and stable allodynia, which could be alleviated by drugs effective in humans, thoracic cord transection might be a

Allodynia Is Associated With Initial and Sustained Response to Acute Migraine Treatment: Results from the American Migraine Prevalence and Prevention Study.

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Lipton, Richard B; Munjal, Sagar; Buse, Dawn C; Bennett, Alix; Fanning, Kristina M; Burstein, Rami; Reed, Michael L

2017-07-01

In a population sample of persons with migraine treating with a single category of acute migraine medication, to identify rates and factors associated with acute treatment outcomes, including 2-hour pain freedom (2hPF), 24-hour pain response (24hPR), and 24-hour sustained pain response (24hSPR). Key predictors include acute treatment type (triptans and other medication categories), the influence of allodynia on response to medication, and the interaction between medication category and presence of allodynia in response to treatment among people with migraine. Cutaneous allodynia was previously associated with inadequate 2hPF, 24hPR, and 24hSPR (sustained response at 24 hours among those with adequate 2hPF) among people with migraine in the American Migraine Prevalence and Prevention (AMPP) Study. The AMPP Study obtained data from a representative US sample of persons with migraine by mailed questionnaire. The 2006 survey included 8233 people with migraine aged 18 or over who completed the Migraine Treatment Optimization Questionnaire (mTOQ). mTOQ was used to assess acute treatment outcomes including 2hPF, 24hPR, and 24hSPR. Eligible individuals used only a single category of acute prescription migraine treatments (n  =  5236, 63.6%). This sample was stratified into 5 categories of type of acute prescription headache medication used (triptans, nonsteroidal anti-inflammatory drugs, barbiturate-combinations, opioids, and opioid combinations and ergot alkaloids). Separate binary logistic regression models evaluated: (1) triptans vs other medication types; (2) presence of allodynia vs no allodynia; and (3) the interaction of medication category with allodynia. Sociodemographic variables, health insurance status, over-the-counter and preventive medication use were included as covariates. Odds ratios (OR) and 95% confidence intervals (CI) were generated for each acute treatment outcome. Among eligible participants, the mean age was 46 years, and 82.5% were women

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

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Deng Liting

2012-09-01

Full Text Available Abstract 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.

A ketogenic diet reduces metabolic syndrome-induced allodynia and promotes peripheral nerve growth in mice.

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Cooper, Michael A; Menta, Blaise W; Perez-Sanchez, Consuelo; Jack, Megan M; Khan, Zair W; Ryals, Janelle M; Winter, Michelle; Wright, Douglas E

2018-08-01

Current experiments investigated whether a ketogenic diet impacts neuropathy associated with obesity and prediabetes. Mice challenged with a ketogenic diet were compared to mice fed a high-fat diet or a high-fat diet plus exercise. Additionally, an intervention switching to a ketogenic diet following 8 weeks of high-fat diet was performed to compare how a control diet, exercise, or a ketogenic diet affects metabolic syndrome-induced neural complications. When challenged with a ketogenic diet, mice had reduced bodyweight and fat mass compared to high-fat-fed mice, and were similar to exercised, high-fat-fed mice. High-fat-fed, exercised and ketogenic-fed mice had mildly elevated blood glucose; conversely, ketogenic diet-fed mice were unique in having reduced serum insulin levels. Ketogenic diet-fed mice never developed mechanical allodynia contrary to mice fed a high-fat diet. Ketogenic diet fed mice also had increased epidermal axon density compared all other groups. When a ketogenic diet was used as an intervention, a ketogenic diet was unable to reverse high-fat fed-induced metabolic changes but was able to significantly reverse a high-fat diet-induced mechanical allodynia. As an intervention, a ketogenic diet also increased epidermal axon density. In vitro studies revealed increased neurite outgrowth in sensory neurons from mice fed a ketogenic diet and in neurons from normal diet-fed mice given ketone bodies in the culture medium. These results suggest a ketogenic diet can prevent certain complications of prediabetes and provides significant benefits to peripheral axons and sensory dysfunction. Published by Elsevier Inc.

Assessment of the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia and neuropathic pain. A pilot study

OpenAIRE

Keizer, D.; van Wijhe, M.; Post, W.J.; Uges, D.R.A.; Wierda, J.M.K.H.

2007-01-01

Background: Allodynia is a common and disabling symptom in many patients with neuropathic pain. Whereas quantification of pain mostly depends on subjective pain reports, allodynia can also be measured objectively with quantitative sensory testing. In this pilot study, we investigated the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia as a consequence of a neuropathic pain syndrome, by means of correlating subjective pain scores with p...

Assessment of the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia and neuropathic pain. A pilot study

NARCIS (Netherlands)

Keizer, D.; van Wijhe, M.; Post, W.J.; Uges, D.R.A.; Wierda, J.M.K.H.

Background: Allodynia is a common and disabling symptom in many patients with neuropathic pain. Whereas quantification of pain mostly depends on subjective pain reports, allodynia can also be measured objectively with quantitative sensory testing. In this pilot study, we investigated the clinical

N-hexane neuropathy with vertigo and cold allodynia in a silk screen printer: A case study

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Sunil Pradhan

2015-10-01

Full Text Available N-hexane neuropathy is an occupational disease caused by exposure to n-hexane, which is used as a solvent in silk screen printing. Here, we describe a 35-year-old man, a silk screen printer by profession, who presented with dizziness, distal swelling of both lower limbs for 10 months and tingling and burning sensation in both feet for 9.5 months along with cold allodynia. The patient had normal results of a motor and sensory system examination, apart from an impaired temperature sense. Nerve conduction tests showed a conduction block in bilateral common peroneal nerves and absence of conduction in bilateral sural nerves. These symptoms resolved when further exposure to n-hexane was ceased but cold allodynia remained. Thus, cold allodynia and impaired temperature sense can be a manifestation of n-hexane neuropathy. Hence, abnormalities on nerve conduction studies can be detected in n-hexane neuropathy patients, even before clinical examination detects any such abnormalities. In the case of the patients presenting with sensory motor neuropathy, history of occupational exposure to n-hexane becomes important, as the sooner the disease is detected, the better the chances of recovery.

Small-fibre neuropathy in female Fabry patients: reduced allodynia and skin blood flow after topical capsaicin

DEFF Research Database (Denmark)

Møller, Anette Torvin; Feldt-Rasmussen, Ulla; Rasmussen, Åse K.

2006-01-01

affected. Recently, attention has been drawn to female patients whether they also show signs of nerve involvement. An early sign of the disease is painful small-fibre neuropathy. The aim of this study was to evaluate a small-fibre dysfunction in female Fabry patients by using capsaicin applied topically......Fabry disease is a rare X-linked lysosomal storage disorder. The mutations result in a deficiency of the lysosomal enzyme α-galactosidase A causing accumulation of glycosphingolipids in the vascular endothelial cells and many other tissues. Given the X-linked inheritance, male patients are severely....... The response to capsaicin was evaluated by laser Doppler imaging. We found that the female Fabry patients had a significantly smaller increase in blood flow (p = 0.0003) after capsaicin application. The area of static mechanical allodynia and dynamic mechanical hyperalgesia was also significantly smaller (p...

N-hexane neuropathy with vertigo and cold allodynia in a silk screen printer: A case study.

Science.gov (United States)

Pradhan, Sunil; Tandon, Ruchika

2015-01-01

N-hexane neuropathy is an occupational disease caused by exposure to n-hexane, which is used as a solvent in silk screen printing. Here, we describe a 35-year-old man, a silk screen printer by profession, who presented with dizziness, distal swelling of both lower limbs for 10 months and tingling and burning sensation in both feet for 9.5 months along with cold allodynia. The patient had normal results of a motor and sensory system examination, apart from an impaired temperature sense. Nerve conduction tests showed a conduction block in bilateral common peroneal nerves and absence of conduction in bilateral sural nerves. These symptoms resolved when further exposure to n-hexane was ceased but cold allodynia remained. Thus, cold allodynia and impaired temperature sense can be a manifestation of n-hexane neuropathy. Hence, abnormalities on nerve conduction studies can be detected in n-hexane neuropathy patients, even before clinical examination detects any such abnormalities. In the case of the patients presenting with sensory motor neuropathy, history of occupational exposure to n-hexane becomes important, as the sooner the disease is detected, the better the chances of recovery. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

The contribution of TRPM8 and TRPA1 channels to cold allodynia and neuropathic pain.

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Caspani, Ombretta; Zurborg, Sandra; Labuz, Dominika; Heppenstall, Paul A

2009-10-08

Cold allodynia is a common feature of neuropathic pain however the underlying mechanisms of this enhanced sensitivity to cold are not known. Recently the transient receptor potential (TRP) channels TRPM8 and TRPA1 have been identified and proposed to be molecular sensors for cold. Here we have investigated the expression of TRPM8 and TRPA1 mRNA in the dorsal root ganglia (DRG) and examined the cold sensitivity of peripheral sensory neurons in the chronic construction injury (CCI) model of neuropathic pain in mice.In behavioral experiments, chronic constriction injury (CCI) of the sciatic nerve induced a hypersensitivity to both cold and the TRPM8 agonist menthol that developed 2 days post injury and remained stable for at least 2 weeks. Using quantitative RT-PCR and in situ hybridization we examined the expression of TRPM8 and TRPA1 in DRG. Both channels displayed significantly reduced expression levels after injury with no change in their distribution pattern in identified neuronal subpopulations. Furthermore, in calcium imaging experiments, we detected no alterations in the number of cold or menthol responsive neurons in the DRG, or in the functional properties of cold transduction following injury. Intriguingly however, responses to the TRPA1 agonist mustard oil were strongly reduced.Our results indicate that injured sensory neurons do not develop abnormal cold sensitivity after chronic constriction injury and that alterations in the expression of TRPM8 and TRPA1 are unlikely to contribute directly to the pathogenesis of cold allodynia in this neuropathic pain model.

The contribution of TRPM8 and TRPA1 channels to cold allodynia and neuropathic pain.

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Ombretta Caspani

Full Text Available Cold allodynia is a common feature of neuropathic pain however the underlying mechanisms of this enhanced sensitivity to cold are not known. Recently the transient receptor potential (TRP channels TRPM8 and TRPA1 have been identified and proposed to be molecular sensors for cold. Here we have investigated the expression of TRPM8 and TRPA1 mRNA in the dorsal root ganglia (DRG and examined the cold sensitivity of peripheral sensory neurons in the chronic construction injury (CCI model of neuropathic pain in mice.In behavioral experiments, chronic constriction injury (CCI of the sciatic nerve induced a hypersensitivity to both cold and the TRPM8 agonist menthol that developed 2 days post injury and remained stable for at least 2 weeks. Using quantitative RT-PCR and in situ hybridization we examined the expression of TRPM8 and TRPA1 in DRG. Both channels displayed significantly reduced expression levels after injury with no change in their distribution pattern in identified neuronal subpopulations. Furthermore, in calcium imaging experiments, we detected no alterations in the number of cold or menthol responsive neurons in the DRG, or in the functional properties of cold transduction following injury. Intriguingly however, responses to the TRPA1 agonist mustard oil were strongly reduced.Our results indicate that injured sensory neurons do not develop abnormal cold sensitivity after chronic constriction injury and that alterations in the expression of TRPM8 and TRPA1 are unlikely to contribute directly to the pathogenesis of cold allodynia in this neuropathic pain model.

Perineural pretreatment of bee venom attenuated the development of allodynia in the spinal nerve ligation injured neuropathic pain model; an experimental study.

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Koh, Won Uk; Choi, Seong Soo; Lee, Jong Hyuk; Lee, So Hee; Lee, Sun Kyung; Lee, Yoon Kyung; Leem, Jeong Gil; Song, Jun Gol; Shin, Jin Woo

2014-11-04

Diluted bee venom (BV) is known to have anti-nociceptive and anti-inflammatory effects. We therefore assessed whether perineural bee venom pretreatment could attenuate the development of neuropathic pain in the spinal nerve ligation injured animal model. Neuropathic pain was surgically induced in 30 male Sprague Dawley rats by ligation of the L5 and L6 spinal nerves, with 10 rats each treated with saline and 0.05 and 0.1 mg BV. Behavioral testing for mechanical, cold, and thermal allodynia was conducted on postoperative days 3 to 29. Three rats in each group and 9 sham operated rats were sacrificed on day 9, and the expression of transient receptor potential vanilloid type 1 (TRPV1), ankyrin type 1 (TRPA1), and melastatin type 8 (TRPM8) receptors in the ipsilateral L5 dorsal root ganglion was analyzed. The perineural administration of BV to the spinal nerves attenuated the development of mechanical, thermal, and cold allodynia, and the BV pretreatment reduced the expression of TRPV1, TRPA1, TRPM8 and c - Fos in the ipsilateral dorsal root ganglion. The current study demonstrates that the perineural pretreatment with diluted bee venom before the induction of spinal nerve ligation significantly suppresses the development of neuropathic pain. Furthermore, this bee venom induced suppression was strongly related with the involvement of transient receptor potential family members.

Stress-related psychological symptoms contribute to axial pain persistence after motor vehicle collision: path analysis results from a prospective longitudinal study.

Science.gov (United States)

Feinberg, Rose K; Hu, JunMei; Weaver, Mark A; Fillingim, Roger B; Swor, Robert A; Peak, David A; Jones, Jeffrey S; Rathlev, Niels K; Lee, David C; Domeier, Robert M; Hendry, Phyllis L; Liberzon, Israel; McLean, Samuel A

2017-04-01

Posttraumatic stress disorder (PTSD) symptoms and pain after traumatic events such as motor vehicle collision (MVC) have been proposed to be mutually promoting. We performed a prospective multicenter study that enrolled 948 individuals who presented to the emergency department within 24 hours of MVC and were discharged home after evaluation. Follow-up evaluations were completed 6 weeks, 6 months, and 1 year after MVC. Path analysis results supported the hypothesis that axial pain after MVC consistently promotes the maintenance of hyperarousal and intrusive symptoms, from the early weeks after injury through 1 year. In addition, path analysis results supported the hypothesis that one or more PTSD symptom clusters had an influence on axial pain outcomes throughout the year after MVC, with hyperarousal symptoms most influencing axial pain persistence in the initial months after MVC. The influence of hyperarousal symptoms on pain persistence was only present among individuals with genetic vulnerability to stress-induced pain, suggesting specific mechanisms by which hyperarousal symptoms may lead to hyperalgesia and allodynia. Further studies are needed to better understand the specific mechanisms by which pain and PTSD symptoms enhance one another after trauma, and how such mechanisms vary among specific patient subgroups, to better inform the development of secondary preventive interventions.

Orofacial neuropathic pain mouse model induced by Trigeminal Inflammatory Compression (TIC of the infraorbital nerve

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Ma Fei

2012-12-01

Full Text Available Abstract Background Trigeminal neuropathic pain attacks can be excruciating for patients, even after being lightly touched. Although there are rodent trigeminal nerve research models to study orofacial pain, few models have been applied to studies in mice. A mouse trigeminal inflammatory compression (TIC model is introduced here which successfully and reliably promotes vibrissal whisker pad hypersensitivity. Results The chronic orofacial neuropathic pain model is induced after surgical placement of chromic gut suture in the infraorbital nerve fissure in the maxillary bone. Slight compression and chemical effects of the chromic gut suture on the portion of the infraorbital nerve contacted cause mild nerve trauma. Nerve edema is observed in the contacting infraorbital nerve bundle as well as macrophage infiltration in the trigeminal ganglia. Centrally in the spinal trigeminal nucleus, increased immunoreactivity for an activated microglial marker is evident (OX42, postoperative day 70. Mechanical thresholds of the affected whisker pad are significantly decreased on day 3 after chromic gut suture placement, persisting at least 10 weeks. The mechanical allodynia is reversed by suppression of microglial activation. Cold allodynia was detected at 4 weeks. Conclusions A simple, effective, and reproducible chronic mouse model mimicking clinical orofacial neuropathic pain (Type 2 is induced by placing chromic gut suture between the infraorbital nerve and the maxillary bone. The method produces mild inflammatory compression with significant continuous mechanical allodynia persisting at least 10 weeks and cold allodynia measureable at 4 weeks.

Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration?

DEFF Research Database (Denmark)

Sjøgren, P; Thunedborg, L P; Christrup, Lona Louring

1998-01-01

Recently, clinical reports have suggested a relationship between the occurrence of hyperalgesia, allodynia and/or myoclonus and treatment with high doses of morphine in humans. Although few clinical descriptions of these phenomena are available, experimental work supports the notion that high dos...

Topical gabapentin gel alleviates allodynia and hyperalgesia in the chronic sciatic nerve constriction injury neuropathic pain model.

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Shahid, M; Subhan, F; Ahmad, N; Ali, G; Akbar, S; Fawad, K; Sewell, R D E

2017-04-01

Systemic gabapentin is a mainstay treatment for neuropathic pain though there are side-effects. Localized therapy may curtail such side-effects so a topical gabapentin dermal application was examined in the chronic constriction injury (CCI) model of neuropathic pain. Partial denervation CCI was achieved by rat sciatic nerve ligation. Gabapentin gel (10% w/w) was applied three times daily on the ipsilateral or contralateral plantar surface of the hind-paw, whereas in a concurrent systemic study, gabapentin was intraperitoneally administered daily (75 mg/kg) for 30 days. Tests for static- and dynamic-mechano-allodynia [paw withdrawal threshold (PWT) to von Frey filament application and latency (PWL) to light brushing], cold-allodynia [paw withdrawal duration (PWD) to acetone], heat- (PWL and PWD) and mechano-hyperalgesia (PWD to pin prick) were utilized to assess pain, whereas effects on locomotion (open field) and motor balance (rotarod and footprint analysis) were measured on days 5-30 post surgery. Topical application of gabapentin gel ipsilaterally but not contralaterally alleviated CCI-induced static- (days 10-30) and dynamic-allodynia (days 15-30), suppressed cold-allodynia (days 10-30), heat- (days 15-30) and mechano-hyperalgesia (days 5-30) indicating a local action. Systemic gabapentin exhibited similar pain profiles but was associated with motor impairment. The gabapentin gel formulation afforded desirable neuropathic pain alleviating effects devoid of unwanted systemic side-effects. These outcomes disclose an expedient pharmacological validation of the effectiveness of topical gabapentin gel against an extensive range of nociceptive stimulus modalities utilizing the CCI-induced neuropathic pain model. They also advocate further clinical studies on topical gabapentin with regard to certain neuropathic pain syndromes. Systemic gabapentin neuropathic pain management carries side-effects ostensibly preventable by localized therapy. This study validates the

Constriction of the buccal branch of the facial nerve produces unilateral craniofacial allodynia.

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Lewis, Susannah S; Grace, Peter M; Hutchinson, Mark R; Maier, Steven F; Watkins, Linda R

2017-08-01

Despite pain being a sensory experience, studies of spinal cord ventral root damage have demonstrated that motor neuron injury can induce neuropathic pain. Whether injury of cranial motor nerves can also produce nociceptive hypersensitivity has not been addressed. Herein, we demonstrate that chronic constriction injury (CCI) of the buccal branch of the facial nerve results in long-lasting, unilateral allodynia in the rat. An anterograde and retrograde tracer (3000MW tetramethylrhodamine-conjugated dextran) was not transported to the trigeminal ganglion when applied to the injury site, but was transported to the facial nucleus, indicating that this nerve branch is not composed of trigeminal sensory neurons. Finally, intracisterna magna injection of interleukin-1 (IL-1) receptor antagonist reversed allodynia, implicating the pro-inflammatory cytokine IL-1 in the maintenance of neuropathic pain induced by facial nerve CCI. These data extend the prior evidence that selective injury to motor axons can enhance pain to supraspinal circuits by demonstrating that injury of a facial nerve with predominantly motor axons is sufficient for neuropathic pain, and that the resultant pain has a neuroimmune component. Copyright © 2016 Elsevier Inc. All rights reserved.

Sleep Deprivation and Recovery Sleep Prior to a Noxious Inflammatory Insult Influence Characteristics and Duration of Pain.

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Vanini, Giancarlo

2016-01-01

Insufficient sleep and chronic pain are public health epidemics. Sleep loss worsens pain and predicts the development of chronic pain. Whether previous, acute sleep loss and recovery sleep determine pain levels and duration remains poorly understood. This study tested whether acute sleep deprivation and recovery sleep prior to formalin injection alter post-injection pain levels and duration. Male Sprague-Dawley rats (n = 48) underwent sleep deprivation or ad libitum sleep for 9 hours. Thereafter, rats received a subcutaneous injection of formalin or saline into a hind paw. In the recovery sleep group, rats were allowed 24 h between sleep deprivation and the injection of formalin. Mechanical and thermal nociception were assessed using the von Frey test and Hargreaves' method. Nociceptive measures were performed at 1, 3, 7, 10, 14, 17 and 21 days post-injection. Formalin caused bilateral mechanical hypersensitivity (allodynia) that persisted for up to 21 days post-injection. Sleep deprivation significantly enhanced bilateral allodynia. There was a synergistic interaction when sleep deprivation preceded a formalin injection. Rats allowed a recovery sleep period prior to formalin injection developed allodynia only in the injected limb, with higher mechanical thresholds (less allodynia) and a shorter recovery period. There were no persistent changes in thermal nociception. The data suggest that acute sleep loss preceding an inflammatory insult enhances pain and can contribute to chronic pain. The results encourage studies in a model of surgical pain to test whether enhancing sleep reduces pain levels and duration. © 2016 Associated Professional Sleep Societies, LLC.

Neuropathic pain and its treatment with ARA 290 and ketamine : overlapping pathways

NARCIS (Netherlands)

Swartjes, Maarten

2014-01-01

Neuropathic pain is a disabling disease with a mechanism consisting of several pathways that ultimately converge in the development and persistence tactile and cold allodynia. Pharmacological treatment is often inadequate and coincides with intolerable side effects. The spared nerve injury animal

Topical combinations aimed at treating microvascular dysfunction reduce allodynia in rat models of CRPS-I and neuropathic pain.

Science.gov (United States)

Ragavendran, J Vaigunda; Laferrière, André; Xiao, Wen Hua; Bennett, Gary J; Padi, Satyanarayana S V; Zhang, Ji; Coderre, Terence J

2013-01-01

Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α(2)-adrenergic (α(2)A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent antiallodynic effects in rats with chronic postischemia pain, and the antiallodynic dose-response curves of PDE and PA inhibitors were shifted 2.5- to 10-fold leftward when combined with nonanalgesic doses of α(2)A receptor agonists or NO donors. Topical combinations also produced significant antiallodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 hours after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α(2)A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain. This article presents the synergistic antiallodynic effects of combinations of α(2)A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest that effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected

Cultural mechanisms and the persistence of neighborhood violence.

Science.gov (United States)

Kirk, David S; Papachristos, Andrew V

2011-01-01

Sociologists have given considerable attention to identifying the neighborhood-level social-interactional mechanisms that influence outcomes such as crime, educational attainment, and health. Yet, cultural mechanisms are often overlooked in quantitative studies of neighborhood effects. This paper adds a cultural dimension to neighborhood effects research by exploring the consequences of legal cynicism. Legal cynicism refers to a cultural frame in which people perceive the law as illegitimate, unresponsive, and ill equipped to ensure public safety. The authors find that legal cynicism explains why homicide persisted in certain Chicago neighborhoods during the 1990s despite declines in poverty and declines in violence city-wide.

Rapid Elimination of the Persistent Synergid through a Cell Fusion Mechanism

KAUST Repository

Maruyama, Daisuke

2015-05-01

In flowering plants, fertilization-dependent degeneration of the persistent synergid cell ensures one-on-one pairings of male and female gametes. Here, we report that the fusion of the persistent synergid cell and the endosperm selectively inactivates the persistent synergid cell in Arabidopsis thaliana. The synergid-endosperm fusion causes rapid dilution of pre-secreted pollen tube attractant in the persistent synergid cell and selective disorganization of the synergid nucleus during the endosperm proliferation, preventing attractions of excess number of pollen tubes (polytubey). The synergid-endosperm fusion is induced by fertilization of the central cell, while the egg cell fertilization predominantly activates ethylene signaling, an inducer of the synergid nuclear disorganization. Therefore, two female gametes (the egg and the central cell) control independent pathways yet coordinately accomplish the elimination of the persistent synergid cell by double fertilization. Two female gametes (the egg cell and the central cell) in flowering plants coordinately prevent attractions of excess number of pollen tubes via two mechanisms to inactivate persistent synergid cell. © 2015 Elsevier Inc.

Virtual visual reminiscing pain stimulation of allodynia patients activates cortical representation of pain and emotions. fMRI study

International Nuclear Information System (INIS)

Ikemoto, Tatsunori; Ushida, Takahiro; Taniguchi, Shinichirou; Tania, Toshikazu; Zinchuk, V.; Morio, Kazuo; Sasaki, Toshikazu

2004-01-01

It is widely known that sensation of the pain is derived from sensory-discriminative factor and emotional factor. Especially in chronic pain, emotional factors and psychosocial backgrounds are more likely to contribute for the patients' discomfort. The aim of this study is to investigate how emotional factor of pain participates in intractable pain. We employed functional MRI (fMRI) to compare the brain activations occurring in the orthopaedic neuropathic pain patients with allodynia and normal individuals in response to the visual virtual painful experience. During fMRI scanning, a video demonstrating an actual tactile stimulation of the palm and its imitation were shown to participants. In contrast to normal individuals, allodynia patients also displayed activation of the areas reflecting emotions: frontal lobe and anterior cingulate. These findings suggest that brain have important role in the development and maintaining of peripheral originated chronic painful condition. (author)

Mechanisms of Acupuncture-Electroacupuncture on Persistent Pain

Science.gov (United States)

Zhang, Ruixin; Lao, Lixing; Ren, Ke; Berman, Brian M.

2014-01-01

In the last decade, preclinical investigations of electroacupuncture mechanisms on persistent tissue-injury (inflammatory), nerve-injury (neuropathic), cancer, and visceral pain have increased. These studies show that electroacupuncture activates the nervous system differently in health than in pain conditions, alleviates both sensory and affective inflammatory pain, and inhibits inflammatory and neuropathic pain more effectively at 2–10 Hz than at 100 Hz. Electroacupuncture blocks pain by activating a variety of bioactive chemicals through peripheral, spinal, and supraspinal mechanisms. These include opioids, which desensitize peripheral nociceptors and reduce pro-inflammatory cytokines peripherally and in the spinal cord, and serotonin and norepinephrine, which decrease spinal n-methyl-d-aspartate receptor subunit GluN1 phosphorylation. Additional studies suggest that electroacupuncture, when combined with low dosages of conventional analgesics, provides effective pain management that can forestall the side effects of often-debilitating pharmaceuticals. PMID:24322588

Specific involvement of atypical PKCζ/PKMζ in spinal persistent nociceptive processing following peripheral inflammation in rat

Directory of Open Access Journals (Sweden)

Marchand Fabien

2011-11-01

Full Text Available Abstract Background Central sensitization requires the activation of various intracellular signalling pathways within spinal dorsal horn neurons, leading to a lowering of activation threshold and enhanced responsiveness of these cells. Such plasticity contributes to the manifestation of chronic pain states and displays a number of features of long-term potentiation (LTP, a ubiquitous neuronal mechanism of increased synaptic strength. Here we describe the role of a novel pathway involving atypical PKCζ/PKMζ in persistent spinal nociceptive processing, previously implicated in the maintenance of late-phase LTP. Results Using both behavioral tests and in vivo electrophysiology in rats, we show that inhibition of this pathway, via spinal delivery of a myristoylated protein kinase C-ζ pseudo-substrate inhibitor, reduces both pain-related behaviors and the activity of deep dorsal horn wide dynamic range neurons (WDRs following formalin administration. In addition, Complete Freund's Adjuvant (CFA-induced mechanical and thermal hypersensitivity was also reduced by inhibition of PKCζ/PKMζ activity. Importantly, this inhibition did not affect acute pain or locomotor behavior in normal rats and interestingly, did not inhibited mechanical allodynia and hyperalgesia in neuropathic rats. Pain-related behaviors in both inflammatory models coincided with increased phosphorylation of PKCζ/PKMζ in dorsal horn neurons, specifically PKMζ phosphorylation in formalin rats. Finally, inhibition of PKCζ/PKMζ activity decreased the expression of Fos in response to formalin and CFA in both superficial and deep laminae of the dorsal horn. Conclusions These results suggest that PKCζ, especially PKMζ isoform, is a significant factor involved in spinal persistent nociceptive processing, specifically, the manifestation of chronic pain states following peripheral inflammation.

Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera.

Science.gov (United States)

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. © 2015 The Authors. European Journal of Neuroscience published by Federation of

Interbank funding as insurance mechanism for (persistent) liquidity shocks

OpenAIRE

Bluhm, Marcel

2015-01-01

The interbank market is important for the efficient functioning of the financial system, transmission of monetary policy and therefore ultimately the real economy. In particular, it facilitates banks' liquidity management. This paper aims at extending the literature which views interbank markets as mutual liquidity insurance mechanism by taking into account persistence of liquidity shocks. Following a theory of long-term interbank funding a financial system which is modeled as a micro-founded...

Acute versus chronic phase mechanisms in a rat model of CRPS.

Science.gov (United States)

Wei, Tzuping; Guo, Tian-Zhi; Li, Wen-Wu; Kingery, Wade S; Clark, John David

2016-01-19

Tibia fracture followed by cast immobilization in rats evokes nociceptive, vascular, epidermal, and bone changes resembling complex regional pain syndrome (CRPS). In most cases, CRPS has three stages. Over time, this acute picture, allodynia, warmth, and edema observed at 4 weeks, gives way to a cold, dystrophic but still painful limb. In the acute phase (at 4 weeks post fracture), cutaneous immunological and NK1-receptor signaling mechanisms underlying CRPS have been discovered; however, the mechanisms responsible for the chronic phase are still unknown. The purpose of this study is to understand the mechanisms responsible for the chronic phases of CRPS (at 16 weeks post fracture) at both the peripheral and central levels. We used rat tibial fracture/cast immobilization model of CRPS to study molecular, vascular, and nociceptive changes at 4 and 16 weeks post fracture. Immunoassays and Western blotting were carried out to monitor changes in inflammatory response and NK1-receptor signaling in the skin and spinal cord. Skin temperature and thickness were measured to elucidate vascular changes, whereas von Frey testing and unweighting were carried out to study nociceptive changes. All data were analyzed by one-way analysis of variance (ANOVA) followed by Neuman-Keuls multiple comparison test to compare among all cohorts. In the acute phase (at 4 weeks post fracture), hindpaw allodynia, unweighting, warmth, edema, and/or epidermal thickening were observed among 90 % fracture rats, though by 16 weeks (chronic phase), only the nociceptive changes persisted. The expression of the neuropeptide signaling molecule substance P (SP), NK1 receptor, inflammatory mediators TNFα, IL-1β, and IL-6 and nerve growth factor (NGF) were elevated at 4 weeks in sciatic nerve and/or skin, returning to normal levels by 16 weeks post fracture. The systemic administration of a peripherally restricted IL-1 receptor antagonist (anakinra) or of anti-NGF inhibited nociceptive behaviors at 4

Persistent visual impairment in multiple sclerosis: prevalence, mechanisms and resulting disability.

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Jasse, Laurence; Vukusic, Sandra; Durand-Dubief, Françoise; Vartin, Cristina; Piras, Carolina; Bernard, Martine; Pélisson, Denis; Confavreux, Christian; Vighetto, Alain; Tilikete, Caroline

2013-10-01

The objective of this article is to evaluate in multiple sclerosis (MS) patients the prevalence of persistent complaints of visual disturbances and the mechanisms and resulting functional disability of persistent visual complaints (PVCs). Firstly, the prevalence of PVCs was calculated in 303 MS patients. MS-related data of patients with or without PVCs were compared. Secondly, 70 patients with PVCs performed an extensive neuro-ophthalmologic assessment and a vision-related quality of life questionnaire, the National Eye Institute Visual Functionary Questionnaire (NEI-VFQ-25). PVCs were reported in 105 MS patients (34.6%). Patients with PVCs had more frequently primary progressive MS (30.5% vs 13.6%) and more neuro-ophthalmologic relapses (1.97 vs 1.36) than patients without PVCs. In the mechanisms/disability study, an afferent visual and an ocular-motor pathways dysfunction were respectively diagnosed in 41 and 59 patients, mostly related to bilateral optic neuropathy and bilateral internuclear ophthalmoplegia. The NEI-VFQ 25 score was poor and significantly correlated with the number of impaired neuro-ophthalmologic tests. Our study emphasizes the high prevalence of PVC in MS patients. Regarding the nature of neuro-ophthalmologic deficit, our results suggest that persistent optic neuropathy, as part of the progressive evolution of the disease, is not rare. We also demonstrate that isolated ocular motor dysfunctions induce visual disability in daily life.

How diagnostic tests help to disentangle the mechanisms underlying neuropathic pain symptoms in painful neuropathies.

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Truini, Andrea; Cruccu, Giorgio

2016-02-01

Neuropathic pain, ie, pain arising directly from a lesion or disease affecting the somatosensory afferent pathway, manifests with various symptoms, the commonest being ongoing burning pain, electrical shock-like sensations, and dynamic mechanical allodynia. Reliable insights into the mechanisms underlying neuropathic pain symptoms come from diagnostic tests documenting and quantifying somatosensory afferent pathway damage in patients with painful neuropathies. Neurophysiological investigation and skin biopsy studies suggest that ongoing burning pain primarily reflects spontaneous activity in nociceptive-fiber pathways. Electrical shock-like sensations presumably arise from high-frequency ectopic bursts generated in demyelinated, nonnociceptive, Aβ fibers. Although the mechanisms underlying dynamic mechanical allodynia remain debatable, normally innocuous stimuli might cause pain by activating spared and sensitized nociceptive afferents. Extending the mechanistic approach to neuropathic pain symptoms might advance targeted therapy for the individual patient and improve testing for new drugs.

Effects of intrathecal lidocaine on hyperalgesia and allodynia following chronic constriction injury in rats.

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Tian, Jie; Gu, Yiwen; Su, Diansan; Wu, Yichao; Wang, Xiangrui

2009-02-01

The present study investigated the effects of different doses of intrathecal lidocaine on established thermal hyperalgesia and tactile allodynia in the chronic constriction injury model of neuropathic pain, defined the effective drug dose range, the duration of pain-relief effects, and the influence of this treatment on the body and tissues. Male Sprague-Dawley rats were divided into five groups and received intrathecal saline or lidocaine (2, 6.5, 15, and 35 mg/kg) 7 days after loose sciatic ligation. Respiratory depression and hemodynamic instability were found to become more severe as doses of lidocaine increased during intrathecal therapy. Two animals in the group receiving 35 mg/kg lidocaine developed pulmonary oedema and died. Behavioral tests indicated that 6.5, 15, and 35 mg/kg intrathecal lidocaine showed different degrees of reversal of thermal hyperalgesia, and lasted for 2-8 days, while 2 mg/kg lidocaine did not. The inhibition of tactile allodynia was only observed in rats receiving 15 and 35 mg/kg lidocaine, and the anti-allodynic effects were identical in these two groups. Histopathologic examinations on the spinal cords revealed mild changes in rats receiving 2-15 mg/kg lidocaine. However, lesions were severe after administration of 35 mg/kg lidocaine. These findings indicate that intrathecal lidocaine has prolonged therapeutic effects on established neuropathic pain. The balance between sympathetic and parasympathetic nervous activities could be well preserved in most cases, except for 35 mg/kg. Considering the ratio between useful effects and side effects, doses of 15 mg/kg are suitable for intrathecal injection for relief of neuropathic pain.

Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice.

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Zhang, Qian; Cao, De-Li; Zhang, Zhi-Jun; Jiang, Bao-Chun; Gao, Yong-Jing

2016-07-11

Trigeminal nerve damage-induced neuropathic pain is a severely debilitating chronic orofacial pain syndrome. Spinal chemokine CXCL13 and its receptor CXCR5 were recently demonstrated to play a pivotal role in the pathogenesis of spinal nerve ligation-induced neuropathic pain. Whether and how CXCL13/CXCR5 in the trigeminal ganglion (TG) mediates orofacial pain are unknown. The partial infraorbital nerve ligation (pIONL) was used to induce trigeminal neuropathic pain in mice. The expression of ATF3, CXCL13, CXCR5, and phosphorylated extracellular signal-regulated kinase (pERK) in the TG was detected by immunofluorescence staining and western blot. The effect of shRNA targeting on CXCL13 or CXCR5 on pain hypersensitivity was checked by behavioral testing. pIONL induced persistent mechanical allodynia and increased the expression of ATF3, CXCL13, and CXCR5 in the TG. Inhibition of CXCL13 or CXCR5 by shRNA lentivirus attenuated pIONL-induced mechanical allodynia. Additionally, pIONL-induced neuropathic pain and the activation of ERK in the TG were reduced in Cxcr5 (-/-) mice. Furthermore, MEK inhibitor (PD98059) attenuated mechanical allodynia and reduced TNF-α and IL-1β upregulation induced by pIONL. TNF-α inhibitor (Etanercept) and IL-1β inhibitor (Diacerein) attenuated pIONL-induced orofacial pain. Finally, intra-TG injection of CXCL13 induced mechanical allodynia, increased the activation of ERK and the production of TNF-α and IL-1β in the TG of WT mice, but not in Cxcr5 (-/-) mice. Pretreatment with PD98059, Etanercept, or Diacerein partially blocked CXCL13-induced mechanical allodynia, and PD98059 also reduced CXCL13-induced TNF-α and IL-1β upregulation. CXCL13 and CXCR5 contribute to orofacial pain via ERK-mediated proinflammatory cytokines production. Targeting CXCL13/CXCR5/ERK/TNF-α and IL-1β pathway in the trigeminal ganglion may offer effective treatment for orofacial neuropathic pain.

Hippocampal activation of microglia may underlie the shared neurobiology of comorbid posttraumatic stress disorder and chronic pain.

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Sun, Rao; Zhang, Zuoxia; Lei, Yishan; Liu, Yue; Lu, Cui'e; Rong, Hui; Sun, Yu'e; Zhang, Wei; Ma, Zhengliang; Gu, Xiaoping

2016-01-01

The high comorbidity rates of posttraumatic stress disorder and chronic pain have been widely reported, but the underlying mechanisms remain unclear. Emerging evidence suggested that an excess of inflammatory immune activities in the hippocampus involved in the progression of both posttraumatic stress disorder and chronic pain. Considering that microglia are substrates underlying the initiation and propagation of the neuroimmune response, we hypothesized that stress-induced activation of hippocampal microglia may contribute to the pathogenesis of posttraumatic stress disorder-pain comorbidity. We showed that rats exposed to single prolonged stress, an established posttraumatic stress disorder model, exhibited persistent mechanical allodynia and anxiety-like behavior, which were accompanied by increased activation of microglia and secretion of pro-inflammatory cytokines in the hippocampus. Correlation analyses showed that hippocampal activation of microglia was significantly correlated with mechanical allodynia and anxiety-like behavior. Our data also showed that both intraperitoneal and intra-hippocampal injection of minocycline suppressed single prolonged stress-induced microglia activation and inflammatory cytokines accumulation in the hippocampus, and attenuated both single prolonged stress-induced mechanical allodynia and anxiety-like behavior. Taken together, the present study suggests that stress-induced microglia activation in the hippocampus may serve as a critical mechanistic link in the comorbid relationship between posttraumatic stress disorder and chronic pain. The novel concept introduces the possibility of cotreating chronic pain and posttraumatic stress disorder. © The Author(s) 2016.

Classical Conditioning Fails to Elicit Allodynia in an Experimental Study with Healthy Humans

NARCIS (Netherlands)

Madden, Victoria J; Russek, Leslie N; Harvie, Daniel S; Vlaeyen, Johan W S; Moseley, G Lorimer

2016-01-01

OBJECTIVE : Associative learning has been proposed as a mechanism behind the persistence of pain after tissue healing. The simultaneous occurrence of nociceptive and non-nociceptive input during acute injury mimics the pairings thought to drive classical conditioning effects. However, empirical

One-single physical exercise session after object recognition learning promotes memory persistence through hippocampal noradrenergic mechanisms.

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da Silva de Vargas, Liane; Neves, Ben-Hur Souto das; Roehrs, Rafael; Izquierdo, Iván; Mello-Carpes, Pâmela

2017-06-30

Previously we showed the involvement of the hippocampal noradrenergic system in the consolidation and persistence of object recognition (OR) memory. Here we show that one-single physical exercise session performed immediately after learning promotes OR memory persistence and increases norepinephrine levels in the hippocampus. Additionally, effects of exercise on memory are avoided by an intra-hippocampal beta-adrenergic antagonist infusion. Taken together, these results suggest that exercise effects on memory can be related to noradrenergic mechanisms and acute physical exercise can be a non-pharmacological intervention to assist memory consolidation and persistence, with few or no side effects. Copyright © 2017 Elsevier B.V. All rights reserved.

Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain

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Tillu Dipti V

2012-01-01

Full Text Available Abstract Background Despite advances in our understanding of basic mechanisms driving post-surgical pain, treating incision-induced pain remains a major clinical challenge. Moreover, surgery has been implicated as a major cause of chronic pain conditions. Hence, more efficacious treatments are needed to inhibit incision-induced pain and prevent the transition to chronic pain following surgery. We reasoned that activators of AMP-activated protein kinase (AMPK may represent a novel treatment avenue for the local treatment of incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors. Results To test this hypothesis we used a potent and efficacious activator of AMPK, resveratrol. Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity. Interleukin-6 (IL-6 is thought to play an important role in incision-induced pain and resveratrol potently inhibited IL-6-mediated signaling to ERK in sensory neurons and blocked IL-6-mediated allodynia in vivo through a local mechanism of action. Using a model of incision-induced allodynia in mice, we further demonstrate that local injection of resveratrol around the surgical wound strongly attenuates incision-induced allodynia. Intraplantar IL-6 injection and plantar incision induces persistent nociceptive sensitization to PGE2 injection into the affected paw after the resolution of allodynia to the initial stimulus. We further show that resveratrol treatment at the time of IL-6 injection or plantar incision completely blocks the development of persistent nociceptive sensitization consistent with the blockade of a transition to a chronic pain state by resveratrol treatment. Conclusions These results highlight the importance of signaling

Incidence of persistent postoperative pain after hepatectomies with 2 regimes of perioperative analgesia containing ketamine.

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Masgoret, Paula; Gomar, Carmen; Tena, Beatriz; Taurá, Pilar; Ríos, José; Coca, Miquel

2017-04-01

Studies designed to assess persistent postoperative pain (PPP) incidence after hepatectomies are lacking. Our aim was to assess PPP incidence 6 months after hepatectomies with intravenous (IV) or epidural (EPI) analgesia containing ketamine.Prospective observational comparative study between 2 cohorts of patients submitted to hepatectomy. Patients received 1 of 2 analgesic regimes containing ketamine: EPI group or IV group. Visual analog scale (VAS), Neuropathic Pain Symptom Inventory (NPSI), Pain Catastrophizing Scale (PCS), and quantitative sensorial testing (QST: to determine area of hyperalgesia/allodynia) were assessed preoperatively and postoperatively at 2 h, 24 h, 7 days, 1 month, and 6 months. VAS ≥ 1 at 1 and 6 months was considered indicative of PPP and VAS > 3 was considered as not controlled pain. Side effects and complications were registered.Forty-four patients were included: 23 in EPI group and 21 in IV group. Patients in IV group were older and had more comorbidities. No patient presented VAS > 3 at 1 or 6 months. VAS ≥ 1 at 1 and 6 months was 36.4% and 22.7%, respectively. No differences in VAS, NPSI, or PCS were found between groups. Allodynia/hyperalgesia area did not differ between groups and was infrequent and slight. Pain pressure threshold in the wound vertical component was significantly higher in EPI group after 7 days. IV group showed more cognitive side effects.Incidence of PPP at 6 months after open hepatectomies with EPI or IV analgesia containing ketamine was lower than previously reported for other abdominal surgeries.Ketamine influence on low PPP incidence and hyperalgesia cannot be discarded.

Persistent myalgia following whiplash.

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Dommerholt, Jan

2005-10-01

Persistent myalgia following whiplash is commonly considered the result of poor psychosocial status, illness behavior, or failing coping skills. However, there is much evidence that persistent myalgia may be due to neurophysiologic mechanisms involving peripheral and central sensitization. Myofascial trigger points may play a crucial role in maintaining sensitization. Recent research suggests that the chemical environment of myofascial trigger points is an important factor. Several consequences are reviewed when central pain mechanisms and myofascial trigger points are included in the differential diagnosis and in the management of patients with persistent pain following whiplash.

A behavioral and pharmacological validation of the acetone spray test in gerbils with a chronic constriction injury.

NARCIS (Netherlands)

Vissers, K.C.P.; Meert, T.F.

2005-01-01

Cold and mechanical allodynia are important symptoms in patients with neuropathic pain. The study of cold allodynia in animals can help us to understand the underlying pathophysiological mechanisms of neuropathic pain and to validate drugs. The evaluation of cold allodynia in gerbils with a chronic

Antinociceptive effects of fisetin against diabetic neuropathic pain in mice: Engagement of antioxidant mechanisms and spinal GABAA receptors.

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Zhao, Xin; Li, Xin-Lin; Liu, Xin; Wang, Chuang; Zhou, Dong-Sheng; Ma, Qing; Zhou, Wen-Hua; Hu, Zhen-Yu

2015-12-01

Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Fisetin, a naturally occurring flavonoid, has been reported to exert antidepressant-like effect in previous studies. As antidepressant drugs are employed clinically to treat neuropathic pain, this work aimed to investigate whether fisetin possess beneficial effect on diabetic neuropathic pain and explore the mechanism(s). We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (200mg/kg), and von Frey test or Hargreaves test was used to assess mechanical allodynia or thermal hyperalgesia, respectively. Chronic treatment of diabetic mice with fisetin not only ameliorated the established symptoms of thermal hyperalgesia and mechanical allodynia, but also arrested the development of neuropathic pain when given at low doses. Although chronic fisetin administration did not impact on the symptom of hyperglycemia in diabetic mice, it reduced exacerbated oxidative stress in tissues of spinal cord, dorsal root ganglion (DRG) and sciatic verve. Furthermore, the analgesic actions of fisetin were abolished by repetitive co-treatment with the reactive oxygen species (ROS) donor tert-butyl hydroperoxide (t-BOOH), but potentiated by the ROS scavenger phenyl-N-tert-butylnitrone (PBN). Finally, acute blockade of spinal GABAA receptors by bicuculline totally counteracted such fisetin analgesia. These findings indicate that chronic fisetin treatment can delay or correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the present fisetin analgesia may be associated with its antioxidant activity, and spinal GABAA receptors are likely rendered as downstream targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: Evidence for mitochondrial dysfunction

OpenAIRE

Flatters, Sarah J.L.; Bennett, Gary J.

2006-01-01

Paclitaxel chemotherapy frequently induces neuropathic pain during and often persisting after therapy. The mechanisms responsible for this pain are unknown. Using a rat model of paclitaxel-induced painful peripheral neuropathy, we have performed studies to search for peripheral nerve pathology. Paclitaxel-induced mechano-allodynia and mechano-hyperalgesia were evident after a short delay, peaked at day 27 and finally resolved on day 155. Paclitaxel- and vehicle-treated rats were perfused on d...

Gastrodin Inhibits Allodynia and Hyperalgesia in Painful Diabetic Neuropathy Rats by Decreasing Excitability of Nociceptive Primary Sensory Neurons

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Ye, Xin; Han, Wen-Juan; Wang, Wen-Ting; Luo, Ceng; Hu, San-Jue

2012-01-01

Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus and adversely affects the patients’ quality of life. Evidence has accumulated that PDN is associated with hyperexcitability of peripheral nociceptive primary sensory neurons. However, the precise cellular mechanism underlying PDN remains elusive. This may result in the lacking of effective therapies for the treatment of PDN. The phenolic glucoside, gastrodin, which is a main constituent of the Chinese herbal medicine Gastrodia elata Blume, has been widely used as an anticonvulsant, sedative, and analgesic since ancient times. However, the cellular mechanisms underlying its analgesic actions are not well understood. By utilizing a combination of behavioral surveys and electrophysiological recordings, the present study investigated the role of gastrodin in an experimental rat model of STZ-induced PDN and to further explore the underlying cellular mechanisms. Intraperitoneal administration of gastrodin effectively attenuated both the mechanical allodynia and thermal hyperalgesia induced by STZ injection. Whole-cell patch clamp recordings were obtained from nociceptive, capsaicin-sensitive small diameter neurons of the intact dorsal root ganglion (DRG). Recordings from diabetic rats revealed that the abnormal hyperexcitability of neurons was greatly abolished by application of GAS. To determine which currents were involved in the antinociceptive action of gastrodin, we examined the effects of gastrodin on transient sodium currents (I NaT) and potassium currents in diabetic small DRG neurons. Diabetes caused a prominent enhancement of I NaT and a decrease of potassium currents, especially slowly inactivating potassium currents (I AS); these effects were completely reversed by GAS in a dose-dependent manner. Furthermore, changes in activation and inactivation kinetics of I NaT and total potassium current as well as I AS currents induced by STZ were normalized by GAS. This study provides a

[Mechanism of tritium persistence in porous media like clay minerals].

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Wu, Dong-Jie; Wang, Jin-Sheng; Teng, Yan-Guo; Zhang, Ke-Ni

2011-03-01

To investigate the mechanisms of tritium persistence in clay minerals, three types of clay soils (montmorillonite, kaolinite and illite) and tritiated water were used in this study to conduct the tritium sorption tests and the other related tests. Firstly, the ingredients, metal elements and heat properties of clay minerals were studied with some instrumental analysis methods, such as ICP and TG. Secondly, with a specially designed fractionation and condensation experiment, the adsorbed water, the interlayer water and the structural water in the clay minerals separated from the tritium sorption tests were fractionated for investigating the tritium distributions in the different types of adsorptive waters. Thirdly, the location and configuration of tritium adsorbed into the structure of clay minerals were studied with infrared spectrometry (IR) tests. And finally, the forces and mechanisms for driving tritium into the clay minerals were analyzed on the basis of the isotope effect of tritium and the above tests. Following conclusions have been reached: (1) The main reason for tritium persistence in clay minerals is the entrance of tritium into the adsorbed water, the interlayer water and the structural water in clay minerals. The percentage of tritium distributed in these three types of adsorptive water are in the range of 13.65% - 38.71%, 0.32% - 5.96%, 1.28% - 4.37% of the total tritium used in the corresponding test, respectively. The percentages are different for different types of clay minerals. (2) Tritium adsorbed onto clay minerals are existed in the forms of the tritiated hydroxyl radical (OT) and the tritiated water molecule (HTO). Tritium mainly exists in tritiated water molecule for adsorbed water and interlayer water, and in tritiated hydroxyl radical for structural water. (3) The forces and effects driving tritium into the clay minerals may include molecular dispersion, electric charge sorption, isotope exchange and tritium isotope effect.

Physical trust-based persistent authentication

DEFF Research Database (Denmark)

Fujita, Masahiro; Jensen, Christian D.; Arimura, Shiori

2015-01-01

propose a new type of persistent authentication, called Persistent Authentication Based On physical Trust (PABOT). PABOT uses a context of “physical trust relationship” that is built by visual contact between users, and thus can offer a persistent authentication mechanism with better usability and higher...

Tumor Necrosis Factor Alpha Signaling in Trigeminal Ganglion Contributes to Mechanical Hypersensitivity in Masseter Muscle During Temporomandibular Joint Inflammation.

Science.gov (United States)

Ito, Reio; Shinoda, Masamichi; Honda, Kuniya; Urata, Kentaro; Lee, Jun; Maruno, Mitsuru; Soma, Kumi; Okada, Shinji; Gionhaku, Nobuhito; Iwata, Koichi

To determine the involvement of tumor necrosis factor alpha (TNFα) signaling in the trigeminal ganglion (TG) in the mechanical hypersensitivity of the masseter muscle during temporomandibular joint (TMJ) inflammation. A total of 55 male Sprague-Dawley rats were used. Following injection of Complete Freund's Adjuvant into the TMJ, the mechanical sensitivities of the masseter muscle and the overlying facial skin were measured. Satellite glial cell (SGC) activation and TNFα expression in the TG were investigated immunohistochemically, and the effects of their inhibition on the mechanical hypersensitivity of the masseter muscle were also examined. Student t test or two-way repeated-measures analysis of variance followed by Bonferroni multiple comparisons test were used for statistical analyses. P < .05 was considered to reflect statistical significance. Mechanical allodynia in the masseter muscle was induced without any inflammatory cell infiltration in the muscle after TMJ inflammation. SGC activation and an increased number of TNFα-immunoreactive cells were induced in the TG following TMJ inflammation. Intra-TG administration of an inhibitor of SGC activity or of TNFα-neutralizing antibody depressed both the increased number of TG cells encircled by activated SGCs and the mechanical hypersensitivity of the masseter following TMJ inflammation. These findings suggest that persistent masseter hypersensitivity associated with TMJ inflammation was mediated by SGC-TG neuron interactions via TNFα signaling in the TG.

Early life vincristine exposure evokes mechanical pain hypersensitivity in the developing rat.

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Schappacher, Katie A; Styczynski, Lauren; Baccei, Mark L

2017-09-01

Vincristine (VNC) is commonly used to treat pediatric cancers, including the most prevalent childhood malignancy, acute lymphoblastic leukemia. Although clinical evidence suggests that VNC causes peripheral neuropathy in children, the degree to which pediatric chemotherapeutic regimens influence pain sensitivity throughout life remains unclear, in part because of the lack of an established animal model of chemotherapy-induced neuropathic pain during early life. Therefore, this study investigated the effects of VNC exposure between postnatal days (P) 11 and 21 on mechanical and thermal pain sensitivity in the developing rat. Low doses of VNC (15 or 30 μg/kg) failed to alter nociceptive withdrawal reflexes at any age examined compared with vehicle-injected littermate controls. Meanwhile, high dose VNC (60 μg/kg) evoked mechanical hypersensitivity in both sexes beginning at P26 that persisted until adulthood and included both static and dynamic mechanical allodynia. Hind paw withdrawal latencies to noxious heat and cold were unaffected by high doses of VNC, suggesting a selective effect of neonatal VNC on mechanical pain sensitivity. Gross and fine motor function appeared normal after VNC treatment, although a small decrease in weight gain was observed. The VNC regimen also produced a significant decrease in intraepidermal nerve fiber density in the hind paw skin by P33. Overall, the present results demonstrate that high-dose administration of VNC during the early postnatal period selectively evokes a mechanical hypersensitivity that is slow to emerge during adolescence, providing further evidence that aberrant sensory input during early life can have prolonged consequences for pain processing.

Pathogen dynamics during invasion and establishment of white-nose syndrome explain mechanisms of host persistence.

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Frick, Winifred F; Cheng, Tina L; Langwig, Kate E; Hoyt, Joseph R; Janicki, Amanda F; Parise, Katy L; Foster, Jeffrey T; Kilpatrick, A Marm

2017-03-01

Disease dynamics during pathogen invasion and establishment determine the impacts of disease on host populations and determine the mechanisms of host persistence. Temporal progression of prevalence and infection intensity illustrate whether tolerance, resistance, reduced transmission, or demographic compensation allow initially declining populations to persist. We measured infection dynamics of the fungal pathogen Pseudogymnoascus destructans that causes white-nose syndrome in bats by estimating pathogen prevalence and load in seven bat species at 167 hibernacula over a decade as the pathogen invaded, became established, and some host populations stabilized. Fungal loads increased rapidly and prevalence rose to nearly 100% at most sites within 2 yr of invasion in six of seven species. Prevalence and loads did not decline over time despite huge reductions in colony sizes, likely due to an extensive environmental reservoir. However, there was substantial variation in fungal load among sites with persisting colonies, suggesting that both tolerance and resistance developed at different sites in the same species. In contrast, one species disappeared from hibernacula within 3 yr of pathogen invasion. Variable host responses to pathogen invasion require different management strategies to prevent disease-induced extinction and to facilitate evolution of tolerance or resistance in persisting populations. © 2016 by the Ecological Society of America.

Modeling the Mechanisms by Which HIV-Associated Immunosuppression Influences HPV Persistence at the Oral Mucosa.

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Verma, Meghna; Erwin, Samantha; Abedi, Vida; Hontecillas, Raquel; Hoops, Stefan; Leber, Andrew; Bassaganya-Riera, Josep; Ciupe, Stanca M

2017-01-01

Human immunodeficiency virus (HIV)-infected patients are at an increased risk of co-infection with human papilloma virus (HPV), and subsequent malignancies such as oral cancer. To determine the role of HIV-associated immune suppression on HPV persistence and pathogenesis, and to investigate the mechanisms underlying the modulation of HPV infection and oral cancer by HIV, we developed a mathematical model of HIV/HPV co-infection. Our model captures known immunological and molecular features such as impaired HPV-specific effector T helper 1 (Th1) cell responses, and enhanced HPV infection due to HIV. We used the model to determine HPV prognosis in the presence of HIV infection, and identified conditions under which HIV infection alters HPV persistence in the oral mucosa system. The model predicts that conditions leading to HPV persistence during HIV/HPV co-infection are the permissive immune environment created by HIV and molecular interactions between the two viruses. The model also determines when HPV infection continues to persist in the short run in a co-infected patient undergoing antiretroviral therapy. Lastly, the model predicts that, under efficacious antiretroviral treatment, HPV infections will decrease in the long run due to the restoration of CD4+ T cell numbers and protective immune responses.

Modeling the Mechanisms by Which HIV-Associated Immunosuppression Influences HPV Persistence at the Oral Mucosa.

Directory of Open Access Journals (Sweden)

Meghna Verma

Full Text Available Human immunodeficiency virus (HIV-infected patients are at an increased risk of co-infection with human papilloma virus (HPV, and subsequent malignancies such as oral cancer. To determine the role of HIV-associated immune suppression on HPV persistence and pathogenesis, and to investigate the mechanisms underlying the modulation of HPV infection and oral cancer by HIV, we developed a mathematical model of HIV/HPV co-infection. Our model captures known immunological and molecular features such as impaired HPV-specific effector T helper 1 (Th1 cell responses, and enhanced HPV infection due to HIV. We used the model to determine HPV prognosis in the presence of HIV infection, and identified conditions under which HIV infection alters HPV persistence in the oral mucosa system. The model predicts that conditions leading to HPV persistence during HIV/HPV co-infection are the permissive immune environment created by HIV and molecular interactions between the two viruses. The model also determines when HPV infection continues to persist in the short run in a co-infected patient undergoing antiretroviral therapy. Lastly, the model predicts that, under efficacious antiretroviral treatment, HPV infections will decrease in the long run due to the restoration of CD4+ T cell numbers and protective immune responses.

Interaction between Mu and Delta Opioid Receptor Agonists in an Assay of Capsaicin-Induced Thermal Allodynia in Rhesus Monkeys

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S. Stevens Negus

2012-01-01

Full Text Available Delta opioid agonists enhance antinociceptive effects of mu-opioid agonists in many preclinical assays of acute nociception, but delta/mu interactions in preclinical models of inflammation-associated pain have not been examined. This study examined interactions between the delta agonist SNC80 [(+-4-[(αR-α-((2S,5R-4-allyl-2,5-dimethyl-1-piperazinyl-3-methoxybenzyl]-N,N-diethylbenzamide] and the mu agonist analgesics methadone, morphine, and nalbuphine in an assay of capsaicin-induced thermal allodynia in rhesus monkeys. Thermal allodynia was produced by topical application of capsaicin to the tail. Antiallodynic effects of methadone, morphine, and nalbuphine were evaluated alone or in combination with fixed proportions of SNC80 identical to proportions previously shown to enhance acute thermal antinociceptive effects of these mu agonists in rhesus monkeys (0.9 : 1 SNC80/methadone; 0.29 : 1 SNC80/morphine; 3.6 : 1 SNC80/nalbuphine. Methadone, morphine, and nalbuphine each produced dose-dependent antiallodynia. SNC80 produced partial antiallodynia up to the highest dose tested (5.6 mg/kg. SNC80 produced a modest, enantioselective, and naltrindole-reversible enhancement of methadone-induced antiallodynia. However, SNC80 did not enhance morphine antiallodynia and only weakly enhanced nalbuphine antiallodynia. Overall, SNC80 produced modest or no enhancement of the antiallodynic effects of the three mu agonists evaluated. These results suggest that delta agonist-induced enhancement of mu agonist antiallodynia may be weaker and less reliable than previously demonstrated enhancement of mu agonist acute thermal nociception.

A Review of Neuropathic Pain: From Diagnostic Tests to Mechanisms

OpenAIRE

Truini, Andrea

2017-01-01

Neuropathic pain develops when the somatosensory nervous system is affected by a lesion or disease. Diagnostic tests aimed at assessing somatosensory afferent pathway damage are therefore useful for diagnosing neuropathic pain. Neuropathic pain manifests with a range of different symptoms such as ongoing burning pain, squeezing or pressure pain, paroxysmal electric shock-like sensations, stabbing pain, or mechanical dynamic allodynia. The various types of neuropathic pain are associated with ...

Ropivacaine and Bupivacaine prevent increased pain sensitivity without altering neuroimmune activation following repeated social defeat stress.

Science.gov (United States)

Sawicki, Caroline M; Kim, January K; Weber, Michael D; Jarrett, Brant L; Godbout, Jonathan P; Sheridan, John F; Humeidan, Michelle

2018-03-01

Mounting evidence indicates that stress influences the experience of pain. Exposure to psychosocial stress disrupts bi-directional communication pathways between the central nervous system and peripheral immune system, and can exacerbate the frequency and severity of pain experienced by stressed subjects. Repeated social defeat (RSD) is a murine model of psychosocial stress that recapitulates the immune and behavioral responses to stress observed in humans, including activation of stress-reactive neurocircuitry and increased pro-inflammatory cytokine production. It is unclear, however, how these stress-induced neuroimmune responses contribute to increased pain sensitivity in mice exposed to RSD. Here we used a technique of regional analgesia with local anesthetics in mice to block the development of mechanical allodynia during RSD. We next investigated the degree to which pain blockade altered stress-induced neuroimmune activation and depressive-like behavior. Following development of a mouse model of regional analgesia with discrete sensory blockade over the dorsal-caudal aspect of the spine, C57BL/6 mice were divided into experimental groups and treated with Ropivacaine (0.08%), Liposomal Bupivacaine (0.08%), or Vehicle (0.9% NaCl) prior to exposure to stress. This specific region was selected for analgesia because it is the most frequent location for aggression-associated pain due to biting during RSD. Mechanical allodynia was assessed 12 h after the first, third, and sixth day of RSD after resolution of the sensory blockade. In a separate experiment, social avoidance behavior was determined after the sixth day of RSD. Blood, bone marrow, brain, and spinal cord were collected for immunological analyses after the last day of RSD in both experiments following behavioral assessments. RSD increased mechanical allodynia in an exposure-dependent manner that persisted for at least one week following cessation of the stressor. Mice treated with either Ropivacaine or

Linking Cellular Mechanisms to Behavior: Entorhinal Persistent Spiking and Membrane Potential Oscillations May Underlie Path Integration, Grid Cell Firing, and Episodic Memory

Directory of Open Access Journals (Sweden)

Michael E. Hasselmo

2008-01-01

Full Text Available The entorhinal cortex plays an important role in spatial memory and episodic memory functions. These functions may result from cellular mechanisms for integration of the afferent input to entorhinal cortex. This article reviews physiological data on persistent spiking and membrane potential oscillations in entorhinal cortex then presents models showing how both these cellular mechanisms could contribute to properties observed during unit recording, including grid cell firing, and how they could underlie behavioural functions including path integration. The interaction of oscillations and persistent firing could contribute to encoding and retrieval of trajectories through space and time as a mechanism relevant to episodic memory.

Magnesium sulphate as a safe treatment for persistent pulmonary hypertension of newborn resistant to mechanical hyperventilation

International Nuclear Information System (INIS)

Dehdashtian, M.; Tebatebae, K.

2007-01-01

To see the effects of magnesium sulphate in newborn with persistent pulmonary hypertension of newborn (PPHN) who did not respond to mechanical hyperventilation and are candidate for Extra Corporeal Membrane Oxygenation (ECMO). Ten newborn who were admitted to Neonatal Intensive Care Unit (NICU) with profound hypoxia and respiratory failure due to PPHN were treated with conventional mechanical ventilation and then mechanical hyperventilation. The newborns who did not respond to mechanical Hyperventilation were treated with magnesium sulphate infusion. Nine out of ten babies survived and one of them died. The differences between the mean AaDo2, OI index, and PH after mechanical hyperventilation and magnesium sulphate administration was significant. Magnesium has a role in the treatment of PPHN patients who do not respond to hyperventilation or may be applied instead of hyperventilation. (author)

Upregulation of calcium channel alpha-2-delta-1 subunit in dorsal horn contributes to spinal cord injury-induced tactile allodynia.

Science.gov (United States)

Kusuyama, Kazuki; Tachibana, Toshiya; Yamanaka, Hiroki; Okubo, Masamichi; Yoshiya, Shinichi; Noguchi, Koichi

2018-01-31

Spinal cord injury (SCI) commonly results not only in motor paralysis but also in the emergence of neuropathic pain (NeuP), both of which can impair the quality of life for patients with SCI. In the clinical field, it is well known that pregabalin, which binds to the voltage-gated calcium channel alpha-2-delta-1 (α 2 δ-1) subunit has therapeutic effects on NeuP after SCI. A previous study has demonstrated that SCI increased α 2 δ-1 in the L4-L6 dorsal spinal cord of SCI rats by Western blot analysis and that the increase of α 2 δ-1 was correlated with tactile allodynia of the hind paw. However, the detailed feature of an increase in α 2 δ-1 protein in the spinal dorsal horn and the mechanism of pregabalin effect on SCI-induced NeuP have not been fully examined. This study aimed to examine the detailed distribution of α 2 δ-1 expression in the lumbar spinal cord after thoracic SCI in rats and the correlation of the therapeutic effect of pregabalin in SCI rats. Male Sprague-Dawley rats underwent thoracic (T10) spinal cord contusion injury using the IH impactor device. Spinal cord injury rats received pregabalin (30 mg/kg) once a day for 2 weeks over a 4-week period after SCI. The mechanical threshold in the rat hind paw was measured over 4 weeks. Alpha-2-delta-1 expression in the lumbar spinal cord and in the dorsal root ganglion (DRG) was analyzed using immunohistochemistry and in situ hybridization histochemistry. A significant reduction of the withdrawal threshold of mechanical stimuli to the hind paw was observed for 2 weeks and continued at least 4 weeks after SCI. In the control rats, expression of α 2 δ-1 immunoreactivity was detected mainly in laminae I and II in the lumbar dorsal horn. Thoracic SCI significantly increased α 2 δ-1 immunoreactivity in laminae I and II in the lumbar dorsal horn 4 weeks after SCI; however, thoracic SCI did not affect the expression of α 2 δ-1 mRNA in the L4 and L5 DRGs. Meanwhile, the signal intensity of α 2 �

The influence of ictal cutaneous allodynia on the response to occipital transcutaneous electrical stimulation in chronic migraine and chronic tension-type headache: a randomized, sham-controlled study.

Science.gov (United States)

Bono, F; Salvino, D; Mazza, M R; Curcio, M; Trimboli, M; Vescio, B; Quattrone, A

2015-04-01

The objective of this article is to determine whether cutaneous allodynia (CA) influences the response to treatment with occipital transcutaneous electrical stimulation (OTES) in chronic migraine (CM) and chronic tension-type headache (CTTH). One hundred and sixty consecutive patients with CM or CTTH were randomized to be treated with real or sham OTES stimulation three times a day for two consecutive weeks. All patients completed the validated 12-item allodynia symptom checklist for assessing the presence and the severity of CA during headache attack. Primary end-point was change (≥50%) in number of monthly headache-free days. There was a significant difference in the percentage of responders in the real OTES compared with sham OTES group (p headache-free days in the allodynic patients with CM and CTTH treated both with real and sham OTES, while the number of headache-free days per month was significantly reduced in the real (86%) but not in the sham group (7%) of non-allodynic patients with CTTH and CM. Severe CA is associated with decreased response to treatment with OTES in patients with CM and CTTH. © International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Etiopathogenetic mechanisms of fibromyalgia syndrome

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R.H. Gracely

2011-09-01

Full Text Available Fibromyalgia syndrome (FMS is a common chronic condition of widespread pain with causal mechanisms that are largely unknown. It is characterized by moderate to severe musculoskel - etal pain and allodynia, but its pathogenesis appears confined to the nociceptive structures of the central nervous system. From a pathogenetic point of view, indeed, no clear muscle pathology has been demonstrated in FMS (1, 2, while increasing evidence suggests a disturbance in pain perception that is genetically conditioned. In our review we will consider five “keypoints” that we think determine the origin and maintenance of the pain syndrome that we define as fibromyalgia...

Cortical dynamics of feature binding and reset: control of visual persistence.

Science.gov (United States)

Francis, G; Grossberg, S; Mingolla, E

1994-04-01

An analysis of the reset of visual cortical circuits responsible for the binding or segmentation of visual features into coherent visual forms yields a model that explains properties of visual persistence. The reset mechanisms prevent massive smearing of visual percepts in response to rapidly moving images. The model simulates relationships among psychophysical data showing inverse relations of persistence to flash luminance and duration, greater persistence of illusory contours than real contours, a U-shaped temporal function for persistence of illusory contours, a reduction of persistence due to adaptation with a stimulus of like orientation, an increase of persistence with spatial separation of a masking stimulus. The model suggests that a combination of habituative, opponent, and endstopping mechanisms prevent smearing and limit persistence. Earlier work with the model has analyzed data about boundary formation, texture segregation, shape-from-shading, and figure-ground separation. Thus, several types of data support each model mechanism and new predictions are made.

Persistence and drug tolerance in pathogenic yeast

DEFF Research Database (Denmark)

Bojsen, Rasmus Kenneth; Regenberg, Birgitte; Folkesson, Sven Anders

2017-01-01

In this review, we briefly summarize the current understanding of how fungal pathogens can persist antifungal treatment without heritable resistance mutations by forming tolerant persister cells. Fungal infections tolerant to antifungal treatment have become a major medical problem. One mechanism...

Insights into persistence mechanisms of a zoonotic virus in bat colonies using a multispecies metapopulation model.

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Margarita Pons-Salort

Full Text Available Rabies is a worldwide zoonosis resulting from Lyssavirus infection. In Europe, Eptesicus serotinus is the most frequently reported bat species infected with Lyssavirus, and thus considered to be the reservoir of European bat Lyssavirus type 1 (EBLV-1. To date, the role of other bat species in EBLV-1 epidemiology and persistence remains unknown. Here, we built an EBLV-1-transmission model based on local observations of a three-cave and four-bat species (Myotis capaccinii, Myotis myotis, Miniopterus schreibersii, Rhinolophus ferrumequinum system in the Balearic Islands, for which a 1995-2011 serological dataset indicated the continuous presence of EBLV-1. Eptesicus serotinus was never observed in the system during the 16-year follow-up and therefore was not included in the model. We used the model to explore virus persistence mechanisms and to assess the importance of each bat species in the transmission dynamics. We found that EBLV-1 could not be sustained if transmission between M. schreibersii and other bat species was eliminated, suggesting that this species serves as a regional reservoir. Global sensitivity analysis using Sobol's method revealed that following the rate of autumn-winter infectious contacts, M. schreibersii's incubation- and immune-period durations, but not the infectious period length, were the most relevant factors driving virus persistence.

Insights into Persistence Mechanisms of a Zoonotic Virus in Bat Colonies Using a Multispecies Metapopulation Model

Science.gov (United States)

Pons-Salort, Margarita; Serra-Cobo, Jordi; Jay, Flora; López-Roig, Marc; Lavenir, Rachel; Guillemot, Didier; Letort, Véronique; Bourhy, Hervé; Opatowski, Lulla

2014-01-01

Rabies is a worldwide zoonosis resulting from Lyssavirus infection. In Europe, Eptesicus serotinus is the most frequently reported bat species infected with Lyssavirus, and thus considered to be the reservoir of European bat Lyssavirus type 1 (EBLV-1). To date, the role of other bat species in EBLV-1 epidemiology and persistence remains unknown. Here, we built an EBLV-1−transmission model based on local observations of a three-cave and four-bat species (Myotis capaccinii, Myotis myotis, Miniopterus schreibersii, Rhinolophus ferrumequinum) system in the Balearic Islands, for which a 1995–2011 serological dataset indicated the continuous presence of EBLV-1. Eptesicus serotinus was never observed in the system during the 16-year follow-up and therefore was not included in the model. We used the model to explore virus persistence mechanisms and to assess the importance of each bat species in the transmission dynamics. We found that EBLV-1 could not be sustained if transmission between M. schreibersii and other bat species was eliminated, suggesting that this species serves as a regional reservoir. Global sensitivity analysis using Sobol's method revealed that following the rate of autumn−winter infectious contacts, M. schreibersii's incubation- and immune-period durations, but not the infectious period length, were the most relevant factors driving virus persistence. PMID:24755619

Analgesic Effects of Bee Venom Derived Phospholipase A(2) in a Mouse Model of Oxaliplatin-Induced Neuropathic Pain.

Science.gov (United States)

Li, Dongxing; Lee, Younju; Kim, Woojin; Lee, Kyungjin; Bae, Hyunsu; Kim, Sun Kwang

2015-06-29

A single infusion of oxaliplatin, which is widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs that are triggered or aggravated when exposed to cold or mechanical stimuli. Bee Venom (BV) has been traditionally used in Korea to treat various pain symptoms. Our recent study demonstrated that BV alleviates oxaliplatin-induced cold allodynia in rats, via noradrenergic and serotonergic analgesic pathways. In this study, we have further investigated whether BV derived phospholipase A2 (bvPLA2) attenuates oxaliplatin-induced cold and mechanical allodynia in mice and its mechanism. The behavioral signs of cold and mechanical allodynia were evaluated by acetone and a von Frey hair test on the hind paw, respectively. The significant allodynia signs were observed from one day after an oxaliplatin injection (6 mg/kg, i.p.). Daily administration of bvPLA2 (0.2 mg/kg, i.p.) for five consecutive days markedly attenuated cold and mechanical allodynia, which was more potent than the effect of BV (1 mg/kg, i.p.). The depletion of noradrenaline by an injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 50 mg/kg, i.p.) blocked the analgesic effect of bvPLA2, whereas the depletion of serotonin by injecting DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for three successive days did not. Furthermore, idazoxan (α2-adrenegic receptor antagonist, 1 mg/kg, i.p.) completely blocked bvPLA2-induced anti-allodynic action, whereas prazosin (α1-adrenegic antagonist, 10 mg/kg, i.p.) did not. These results suggest that bvPLA2 treatment strongly alleviates oxaliplatin-induced acute cold and mechanical allodynia in mice through the activation of the noradrenergic system, via α2-adrenegic receptors, but not via the serotonergic system.

Spinal activation of alpha7-nicotinic acetylcholine receptor attenuates posttraumatic stress disorder-related chronic pain via suppression of glial activation.

Science.gov (United States)

Sun, Rao; Zhang, Wei; Bo, Jinhua; Zhang, Zuoxia; Lei, Yishan; Huo, Wenwen; Liu, Yue; Ma, Zhengliang; Gu, Xiaoping

2017-03-06

The high prevalence of chronic pain in posttraumatic stress disorder (PTSD) individuals has been widely reported by clinical studies, which emphasized an urgent need to uncover the underlying mechanisms and identify potential therapeutic targets. Recent studies suggested that targeting activated glia and their pro-inflammatory products may provide a novel and effective therapy for the stress-related pain. In this study, we investigated whether activation of alpha-7 nicotinic acetylcholine receptor (α7 nAChR), a novel anti-inflammatory target, could attenuate PTSD-related chronic pain. The experiments were conducted in a rat model of single prolonged stress (SPS), an established model of PTSD-pain comorbidity. We found that SPS exposure produced persistent mechanical allodynia. Immunohistochemical and enzyme-linked immuno sorbent assay analysis showed that SPS also induced elevated activation of glia cells (including microglia and astrocytes) and accumulation of pro-inflammatory cytokines in spinal cord. In another experiment, we found that intrathecal injection of PHA-543613, a selective α7 nAchR agonist, attenuated the SPS-evoked allodynia in a dose dependent manner. However, this anti-hyperalgesic effect was blocked by pretreatment with methyllycaconitine (MLA), a selective α7 nAchR antagonist. Further analyses showed that PHA-543613 suppressed SPS-induced spinal glial activation and SPS-elevated spinal pro-inflammatory cytokines, and these were abolished by MLA. Taken together, the present study showed that spinal activation of α7 nAChR by PHA-543613 attenuated mechanical allodynia induced by PTSD-like stress, and the suppression of spinal glial activation may underlie this anti-hyperalgesic effect. Our study demonstrated the therapeutic potential of targeting α7 nAChR in the treatment of PTSD-related chronic pain. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Mechanisms underlying ectopic persistent tooth-pulp pain following pulpal inflammation.

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Shingo Matsuura

Full Text Available In order to clarify the peripheral mechanisms of ectopic persistent pain in a tooth pulp following pulpal inflammation of an adjacent tooth, masseter muscle activity, phosphorylated extracellular signal-regulated protein kinase (pERK and TRPV1 immunohistochemistries and satellite cell activation using glial fibrillary acidic protein (GFAP immunohistochemistry in the trigeminal ganglion (TG were studied in the rats with molar tooth-pulp inflammation. And, Fluorogold (FG and DiI were also used in a neuronal tracing study to analyze if some TG neurons innervate more than one tooth pulp. Complete Freund's adjuvant (CFA or saline was applied into the upper first molar tooth pulp (M1 in pentobarbital-anesthetized rats, and capsaicin was applied into the upper second molar tooth pulp (M2 on day 3 after the CFA or saline application. Mean EMG activity elicited in the masseter muscle by capsaicin application to M2 was significantly larger in M1 CFA-applied rats compared with M1 vehicle-applied rats. The mean number of pERK-immunoreactive (IR TG cells was significantly larger in M1 CFA-applied rats compared with M1 vehicle-applied rats. Application of the satellite cell inhibitor fluorocitrate (FC into TG caused a significant depression of capsaicin-induced masseter muscle activity and a significant reduction of satellite cell activation. The number of TRPV1-IR TG cells innervating M2 was significantly larger in M1 CFA-applied rats compared with M1 vehicle-applied rats, and that was decreased following FC injection into TG. Furthermore, 6% of TG neurons innervating M1 and/or M2 innervated both M1 and M2. These findings suggest that satellite cell activation following tooth pulp inflammation and innervation of multiple tooth pulps by single TG neurons may be involved in the enhancement of the activity of TG neurons innervating adjacent non-inflamed teeth that also show enhancement of TRPV1 expression in TG neurons, resulting in the ectopic persistent tooth

Bacterial persistence: some new insights into an old phenomenon

Indian Academy of Sciences (India)

PRAKASH KUMAR

the involvement of the alarmone (p) ppGpp in the generation of persisters. However, the precise mechanisms are ... Bigger noticed that treatment of cultures of Staphylococcus aureus with high concentrations of ...... Li Y and Zhang Y 2007 pho U is a persister switch involved in persister formation and tolerance to multiple ...

Variable Persister Gene Interactions with (pppGpp for Persister Formation in Escherichia coli

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Shuang Liu

2017-09-01

Full Text Available Persisters comprise a group of phenotypically heterogeneous metabolically quiescent bacteria with multidrug tolerance and contribute to the recalcitrance of chronic infections. Although recent work has shown that toxin-antitoxin (TA system HipAB depends on stringent response effector (pppGppin persister formation, whether other persister pathways are also dependent on stringent response has not been explored. Here we examined the relationship of (pppGpp with 15 common persister genes (dnaK, clpB, rpoS, pspF, tnaA, sucB, ssrA, smpB, recA, umuD, uvrA, hipA, mqsR, relE, dinJ using Escherichia coli as a model. By comparing the persister levels of wild type with their single gene knockout and double knockout mutants with relA, we divided their interactions into five types, namely A “dependent” (dnaK, recA, B “positive reinforcement” (rpoS, pspF, ssrA, recA, C “antagonistic” (clpB, sucB, umuD, uvrA, hipA, mqsR, relE, dinJ, D “epistasis” (clpB, rpoS, tnaA, ssrA, smpB, hipA, and E “irrelevant” (dnaK, clpB, rpoS, tnaA, sucB, smpB, umuD, uvrA, hipA, mqsR, relE, dinJ. We found that the persister gene interactions are intimately dependent on bacterial culture age, cell concentrations (diluted versus undiluted culture, and drug classifications, where the same gene may belong to different groups with varying antibiotics, culture age or cell concentrations. Together, this study represents the first attempt to systematically characterize the intricate relationships among the different mechanisms of persistence and as such provide new insights into the complexity of the persistence phenomenon at the level of persister gene network interactions.

Transposon mutagenesis identifies novel genes associated with Staphylococcus aureus persister formation

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Wang ewenjie

2015-12-01

Full Text Available Pathogenic bacterial persisters are responsible for the recalcitrance of chronic and persistent infections to antimicrobial therapy. Although the mechanisms of persister formation and survival have been widely studied in Escherichia coli, persistence mechanisms in S. aureus remain largely unknown. Here, we screened a transposon mutant library of a clinical methicillin-resistant Staphylococcus aureus（MRSA）strain, USA500 (ST8, under antibiotic pressure and identified 13 genes whose insertion mutations resulted in a defect in persistence. These candidate genes were further confirmed by evaluating the survival of the mutants upon exposure to levofloxacin and several other stress conditions. We found 13 insertion mutants with significantly lower persister numbers under several stress conditions, including sdhA, sdhB, ureG, mnhG1, fbaA, ctaB, clpX, parE, HOU_0223, HOU_0587, HOU_2091, HOU_2315 and HOU_2346, which mapped into pathways of oxidative phosphorylation, TCA cycle, glycolysis, cell cycle and ABC transporters, suggesting that these genes and pathways may play an important role in persister formation and survival. The newly constructed knockout strains of ureG, sdhA and sdhB and their complemented strains were also tested for defect in persisters following exposure to levofloxacin and several other stress conditions. The results from these experiments were consistent with the screening results, which indicated that deletion of these genes in MRSA USA500 leads to persister defect. These findings provide novel insights into the mechanisms of persister formation and survival in S. aureus and offer new targets for the development of persister-directed antibiotics for the improved treatment of chronic and persistent infections.

Persistent Authentication in Smart Environments

DEFF Research Database (Denmark)

Hansen, Mads Syska; Kirschmeyer, Martin; Jensen, Christian D.

2008-01-01

present a proof-of-concept implementation of the proposed mechanism, which employs camera based tracking with a single stationary 3D camera that uses the "time of flight" principle. A preliminary evaluation of the proposed mechanism indicates that persistent authentication is technically possible...... with the proposed hardware. The proposed model is sufficiently general to allow the addition of more cameras or supplemental tracking technologies, which will improve the robustness and scalability of the proposed mechanism....

Acidic pH facilitates peripheral αβmeATP-mediated nociception in rats: differential roles of P2X, P2Y, ASIC and TRPV1 receptors in ATP-induced mechanical allodynia and thermal hyperalgesia.

Science.gov (United States)

Seo, Hyoung-Sig; Roh, Dae-Hyun; Kwon, Soon-Gu; Yoon, Seo-Yeon; Kang, Suk-Yun; Moon, Ji-Young; Choi, Sheu-Ran; Beitz, Alvin J; Lee, Jang-Hern

2011-03-01

Peripheral ischemia is commonly associated with an increase in tissue ATP concentration and a decrease in tissue pH. Although in vitro data suggest that low tissue pH can affect ATP-binding affinities to P2 receptors, the mechanistic relationship between ATP and low pH on peripheral nociception has not been fully examined. This study was designed to investigate the potential role of an acidified environment on intraplantar αβmeATP-induced peripheral pain responses in rats. The mechanical allodynia (MA) produced by injection of αβmeATP was significantly increased in animals that received the drug diluted in pH 4.0 saline compared to those that received the drug diluted in pH 7.0 saline. Moreover, animals injected with αβmeATP (100 nmol) in pH 4.0 saline developed thermal hyperalgesia (TH), which did not occur in animals treated with αβmeATP diluted in pH 7.0 saline. To elucidate which receptors were involved in this pH-related facilitation of αβmeATP-induced MA and TH, rats were pretreated with PPADS (P2 antagonist), TNP-ATP (P2X antagonist), MRS2179 (P2Y1 antagonist), AMG9810 (TRPV1 antagonist) or amiloride (ASIC blocker). Both PPADS and TNP-ATP dose-dependently blocked pH-facilitated MA, while TH was significantly reduced by pre-treatment with MRS2179 or AMG9810. Moreover, amiloride injection significantly reduced low pH-induced facilitation of αβmeATP-mediated MA, but not TH. These results demonstrate that low tissue pH facilitates ATP-mediated MA via the activation of P2X receptors and ASICs, whereas TH induced by ATP under low pH conditions is mediated by the P2Y1 receptor and TRPV1, but not ASIC. Thus distinct mechanisms are responsible for the development of MA and TH under conditions of tissue acidosis and increased ATP. Copyright © 2010 Elsevier Ltd. All rights reserved.

Non-persistent pesticides removal in constructed wetlands

Science.gov (United States)

Tu, Yue; Jiang, Lei; Li, Haixiang

2018-03-01

The heavy use of non-persistent pesticides, resulting in the accumulation of environment and destroy the aquatic environment. This paper presents the research status of using CWs to treat non-persistent pesticides in water. The removal mechanisms are mainly physical deposition, chemical hydrolysis and plant absorption. Analysis of the factors that affect the removal effect are mainly the nature of pesticides, HRT, plants. Some scholars have proposed that secondary products of non-persistent pesticides may be more harmful to the environment, However, the relevant reports are scarce.

Bacterial biofilm mechanical properties persist upon antibiotic treatment and survive cell death

International Nuclear Information System (INIS)

Zrelli, K; Galy, O; Henry, N; Latour-Lambert, P; Ghigo, J M; Beloin, C; Kirwan, L

2013-01-01

Bacteria living on surfaces form heterogeneous three-dimensional consortia known as biofilms, where they exhibit many specific properties one of which is an increased tolerance to antibiotics. Biofilms are maintained by a polymeric network and display physical properties similar to that of complex fluids. In this work, we address the question of the impact of antibiotic treatment on the physical properties of biofilms based on recently developed tools enabling the in situ mapping of biofilm local mechanical properties at the micron scale. This approach takes into account the material heterogeneity and reveals the spatial distribution of all the small changes that may occur in the structure. With an Escherichia coli biofilm, we demonstrate using in situ fluorescent labeling that the two antibiotics ofloxacin and ticarcillin—targeting DNA replication and membrane assembly, respectively—induced no detectable alteration of the biofilm mechanical properties while they killed the vast majority of the cells. In parallel, we show that a proteolytic enzyme that cleaves extracellular proteins into short peptides, but does not alter bacterial viability in the biofilm, clearly affects the mechanical properties of the biofilm structure, inducing a significant increase of the material compliance. We conclude that conventional biofilm control strategy relying on the use of biocides targeting cells is missing a key target since biofilm structural integrity is preserved. This is expected to efficiently promote biofilm resilience, especially in the presence of persister cells. In contrast, the targeting of polymer network cross-links—among which extracellular proteins emerge as major players—offers a promising route for the development of rational multi-target strategies to fight against biofilms. (paper)

Bacterial biofilm mechanical properties persist upon antibiotic treatment and survive cell death

Science.gov (United States)

Zrelli, K.; Galy, O.; Latour-Lambert, P.; Kirwan, L.; Ghigo, J. M.; Beloin, C.; Henry, N.

2013-12-01

Bacteria living on surfaces form heterogeneous three-dimensional consortia known as biofilms, where they exhibit many specific properties one of which is an increased tolerance to antibiotics. Biofilms are maintained by a polymeric network and display physical properties similar to that of complex fluids. In this work, we address the question of the impact of antibiotic treatment on the physical properties of biofilms based on recently developed tools enabling the in situ mapping of biofilm local mechanical properties at the micron scale. This approach takes into account the material heterogeneity and reveals the spatial distribution of all the small changes that may occur in the structure. With an Escherichia coli biofilm, we demonstrate using in situ fluorescent labeling that the two antibiotics ofloxacin and ticarcillin—targeting DNA replication and membrane assembly, respectively—induced no detectable alteration of the biofilm mechanical properties while they killed the vast majority of the cells. In parallel, we show that a proteolytic enzyme that cleaves extracellular proteins into short peptides, but does not alter bacterial viability in the biofilm, clearly affects the mechanical properties of the biofilm structure, inducing a significant increase of the material compliance. We conclude that conventional biofilm control strategy relying on the use of biocides targeting cells is missing a key target since biofilm structural integrity is preserved. This is expected to efficiently promote biofilm resilience, especially in the presence of persister cells. In contrast, the targeting of polymer network cross-links—among which extracellular proteins emerge as major players—offers a promising route for the development of rational multi-target strategies to fight against biofilms.

Persistent physical symptoms as perceptual dysregulation

DEFF Research Database (Denmark)

Henningsen, Peter; Gündel, Harald; Kop, Willem J

2018-01-01

OBJECTIVE: The mechanisms underlying the perception and experience of persistent physical symptoms are not well understood, and in the models, the specific relevance of peripheral input versus central processing, or of neurobiological versus psychosocial factors in general, is not clear.In this a......OBJECTIVE: The mechanisms underlying the perception and experience of persistent physical symptoms are not well understood, and in the models, the specific relevance of peripheral input versus central processing, or of neurobiological versus psychosocial factors in general, is not clear.......In this article, we propose a model for this clinical phenomenon that is designed to be coherent with an underlying, relatively new model of the normal brain functions involved in the experience of bodily signals. METHODS: Based on a review of recent literature we describe central elements of this model and its...... of predictions and sensory input. Two possibilities exist: adaptation of the generative model underlying the predictions or alteration of the sensory input via autonomic nervous activation (in the case of interoception). Following this model, persistent physical symptoms can be described as "failures...

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse.

Science.gov (United States)

Korpi, Esa R; den Hollander, Bjørnar; Farooq, Usman; Vashchinkina, Elena; Rajkumar, Ramamoorthy; Nutt, David J; Hyytiä, Petri; Dawe, Gavin S

2015-10-01

Adaptation of the nervous system to different chemical and physiologic conditions is important for the homeostasis of brain processes and for learning and remembering appropriate responses to challenges. Although processes such as tolerance and dependence to various drugs of abuse have been known for a long time, it was recently discovered that even a single pharmacologically relevant dose of various drugs of abuse induces neuroplasticity in selected neuronal populations, such as the dopamine neurons of the ventral tegmental area, which persist long after the drug has been excreted. Prolonged (self-) administration of drugs induces gene expression, neurochemical, neurophysiological, and structural changes in many brain cell populations. These region-specific changes correlate with addiction, drug intake, and conditioned drugs effects, such as cue- or stress-induced reinstatement of drug seeking. In rodents, adolescent drug exposure often causes significantly more behavioral changes later in adulthood than a corresponding exposure in adults. Clinically the most impairing and devastating effects on the brain are produced by alcohol during fetal development. In adult recreational drug users or in medicated patients, it has been difficult to find persistent functional or behavioral changes, suggesting that heavy exposure to drugs of abuse is needed for neurotoxicity and for persistent emotional and cognitive alterations. This review describes recent advances in this important area of research, which harbors the aim of translating this knowledge to better treatments for addictions and related neuropsychiatric illnesses. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Pathological mechanism of musculoskeletal manifestations associated with CRPS type II: an animal study.

Science.gov (United States)

Ota, Hideyuki; Arai, Tetsuya; Iwatsuki, Katsuyuki; Urano, Hideki; Kurahashi, Toshikazu; Kato, Shuichi; Yamamoto, Michiro; Hirata, Hitoshi

2014-10-01

Patients with complex regional pain syndrome (CRPS) often complain of abnormal sensations beyond the affected body part, but causes of this spread of musculoskeletal manifestations into contiguous areas remain unclear. In addition, immobilization can predispose to the development of CRPS. We examined functional, biochemical, and histological alterations in affected parts, including contiguous zones, using an animal model. Ten-week-old male Wistar rats were assigned to 5 groups: a normal group receiving no treatment, a sham operation group with surgical exploration, an immobilization group with surgical exploration plus internal knee joint immobilization, a surgical neuropathy group prepared by spinal nerve ligation (SNL) of the left L5 nerve root, and a surgical neuropathy+immobilization group with simultaneous SNL and knee joint immobilization. Mechanical allodynia and knee contracture were compared between groups, and tissues were harvested for histological assessments and gene and protein expression analyses. Neither surgical procedures nor immobilization induced detectable mechanical sensitivity. However, the addition of nerve injury resulted in detectable mechanical allodynia, and immobilization not only accelerated hyperalgesia, but also resulted in muscle fibrosis. Nerve growth factor (NGF) and other mediators of neurogenic inflammation were highly expressed not only in denervated muscles, but also in innervated muscles in contiguous areas, suggesting the spread of NGF production beyond the myotome of the injured nerve. Transforming growth factor β was involved in the development of contracture in CRPS. These findings imply that neuroinflammatory components play major roles in the progression and dispersion of both sensory pathologies and pathologies that are exacerbated by immobilization. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Persistent increased PKMζ in long-term and remote spatial memory.

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Hsieh, Changchi; Tsokas, Panayiotis; Serrano, Peter; Hernández, A Iván; Tian, Dezhi; Cottrell, James E; Shouval, Harel Z; Fenton, André Antonio; Sacktor, Todd Charlton

2017-02-01

PKMζ is an autonomously active PKC isoform that is thought to maintain both LTP and long-term memory. Whereas persistent increases in PKMζ protein sustain the kinase's action in LTP, the molecular mechanism for the persistent action of PKMζ during long-term memory has not been characterized. PKMζ inhibitors disrupt spatial memory when introduced into the dorsal hippocampus from 1day to 1month after training. Therefore, if the mechanisms of PKMζ's persistent action in LTP maintenance and long-term memory were similar, persistent increases in PKMζ would last for the duration of the memory, far longer than most other learning-induced gene products. Here we find that spatial conditioning by aversive active place avoidance or appetitive radial arm maze induces PKMζ increases in dorsal hippocampus that persist from 1day to 1month, coinciding with the strength and duration of memory retention. Suppressing the increase by intrahippocampal injections of PKMζ-antisense oligodeoxynucleotides prevents the formation of long-term memory. Thus, similar to LTP maintenance, the persistent increase in the amount of autonomously active PKMζ sustains the kinase's action during long-term and remote spatial memory maintenance. Copyright © 2016. Published by Elsevier Inc.

DNA-crosslinker cisplatin eradicates bacterial persister cells.

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Chowdhury, Nityananda; Wood, Thammajun L; Martínez-Vázquez, Mariano; García-Contreras, Rodolfo; Wood, Thomas K

2016-09-01

For all bacteria, nearly every antimicrobial fails since a subpopulation of the bacteria enter a dormant state known as persistence, in which the antimicrobials are rendered ineffective due to the lack of metabolism. This tolerance to antibiotics makes microbial infections the leading cause of death worldwide and makes treating chronic infections, including those of wounds problematic. Here, we show that the FDA-approved anti-cancer drug cisplatin [cis-diamminodichloroplatinum(II)], which mainly forms intra-strand DNA crosslinks, eradicates Escherichia coli K-12 persister cells through a growth-independent mechanism. Additionally, cisplatin is more effective at killing Pseudomonas aeruginosa persister cells than mitomycin C, which forms inter-strand DNA crosslinks, and cisplatin eradicates the persister cells of several pathogens including enterohemorrhagic E. coli, Staphylococcus aureus, and P. aeruginosa. Cisplatin was also highly effective against clinical isolates of S. aureus and P. aeruginosa. Therefore, cisplatin has broad spectrum activity against persister cells. Biotechnol. Bioeng. 2016;113: 1984-1992. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Antinociceptive and antiallodynic effects of Momordica charantia L. in tibial and sural nerve transection-induced neuropathic pain in rats.

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Jain, Vivek; Pareek, Ashutosh; Paliwal, Nishant; Ratan, Yashumati; Jaggi, Amteshwar Singh; Singh, Nirmal

2014-02-01

This study was designed to investigate the ameliorative potential of Momordica charantia L. (MC) in tibial and sural nerve transection (TST)-induced neuropathic pain in rats. TST was performed by sectioning tibial and sural nerve portions (2 mm) of the sciatic nerve, and leaving the common peroneal nerve intact. Acetone drop, pin-prick, hot plate, paint-brush, and walking track tests were performed to assess cold allodynia, mechanical and heat hyperalgesia, and dynamic mechanical allodynia and tibial functional index, respectively. The levels of tumour necrosis factor (TNF)-alpha and thio-barbituric acid reactive substances (TBARS) were measured in the sciatic nerve as an index of inflammation and oxidative stress. MC (all doses, orally, once daily) was administered to the rats for 24 consecutive days. TST led to significant development of cold allodynia, mechanical and heat hyperalgesia, dynamic mechanical allodynia, and functional deficit in walking along with rise in the levels of TBARS and TNF-alpha. Administration of MC (200, 400, and 800 mg/kg) significantly attenuated TST-induced behavioural and biochemical changes. Furthermore, pretreatment of BADGE (120 mg/kg, intraperitoneally) abolished the protective effect of MC in TST-induced neuropathic pain. Collectively, it is speculated that PPAR-gamma agonistic activity, anti-inflammatory, and antioxidative potential is critical for antinociceptive effect of MC in neuropathic pain.

Genetic Screen Reveals the Role of Purine Metabolism in Staphylococcus aureus Persistence to Rifampicin

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Rebecca Yee

2015-12-01

Full Text Available Chronic infections with Staphylococcus aureus such as septicemia, osteomyelitis, endocarditis, and biofilm infections are difficult to treat because of persisters. Despite many efforts in understanding bacterial persistence, the mechanisms of persister formation in S. aureus remain elusive. Here, we performed a genome-wide screen of a transposon mutant library to study the molecular mechanisms involved in persistence of community-acquired S. aureus. Screening of the library for mutants defective in persistence or tolerance to rifampicin revealed many genes involved in metabolic pathways that are important for antibiotic persistence. In particular, the identified mutants belonged to metabolic pathways involved in carbohydrate, amino acid, lipid, vitamin and purine biosynthesis. Five mutants played a role in purine biosynthesis and two mutants, purB, an adenylosuccinate lyase, and purM, a phosphoribosylaminoimidazole synthetase, were selected for further confirmation. Mutants purB and purM showed defective persistence compared to the parental strain USA300 in multiple stress conditions including various antibiotics, low pH, and heat stress. The defect in persistence was restored by complementation with the wildtype purB and purM gene in the respective mutants. These findings provide new insights into the mechanisms of persistence in S. aureus and provide novel therapeutic targets for developing more effective treatment for persistent infections due to S. aureus.

Novel protocol for persister cells isolation.

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Silvia J Cañas-Duarte

Full Text Available Bacterial persistence, where a fraction of a population presents a transient resistance to bactericidal substances, has great medical importance due to its relation with the appearance of antibiotic resistances and untreatable bacterial chronic infections. The mechanisms behind this phenomenon remain largely unknown in spite of recent advances, in great part because of the difficulty in isolating the very small fraction of the population that is in this state at any given time. Current protocols for persister isolation have resulted in possible biases because of the induction of this state by the protocol itself. Here we present a novel protocol that allows rapid isolation of persister cells both from exponential and stationary phase. Moreover, it is capable of differentiating between type I and type II persister cells, which should allow the field to move beyond its current state of studying only one type. While this protocol prompts a revision of many of the current results, it should greatly facilitate further advances in the field.

Persistent facial pain conditions

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Forssell, Heli; Alstergren, Per; Bakke, Merete

2016-01-01

Persistent facial pains, especially temporomandibular disorders (TMD), are common conditions. As dentists are responsible for the treatment of most of these disorders, up-to date knowledge on the latest advances in the field is essential for successful diagnosis and management. The review covers...... TMD, and different neuropathic or putative neuropathic facial pains such as persistent idiopathic facial pain and atypical odontalgia, trigeminal neuralgia and painful posttraumatic trigeminal neuropathy. The article presents an overview of TMD pain as a biopsychosocial condition, its prevalence......, clinical features, consequences, central and peripheral mechanisms, diagnostic criteria (DC/TMD), and principles of management. For each of the neuropathic facial pain entities, the definitions, prevalence, clinical features, and diagnostics are described. The current understanding of the pathophysiology...

Reflex mechanisms in CRPS-related dystonia

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Mugge, W.

2011-01-01

Complex Regional Pain Syndrome (CRPS) is a disabling syndrome associated with sensory (e.g., burning pain, allodynia, hyperalgesia), autonomic (e.g., edema, skin color and temperature changes), and motor impairments (e.g., tremor, myoclonus, dystonia). Approximately 25% of the patients with CRPS

Mechanistic Differences in Neuropathic Pain Modalities Revealed by Correlating Behavior with Global Expression Profiling

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Enrique J. Cobos

2018-01-01

Full Text Available Chronic neuropathic pain is a major morbidity of neural injury, yet its mechanisms are incompletely understood. Hypersensitivity to previously non-noxious stimuli (allodynia is a common symptom. Here, we demonstrate that the onset of cold hypersensitivity precedes tactile allodynia in a model of partial nerve injury, and this temporal divergence was associated with major differences in global gene expression in innervating dorsal root ganglia. Transcripts whose expression change correlates with the onset of cold allodynia were nociceptor related, whereas those correlating with tactile hypersensitivity were immune cell centric. Ablation of TrpV1 lineage nociceptors resulted in mice that did not acquire cold allodynia but developed normal tactile hypersensitivity, whereas depletion of macrophages or T cells reduced neuropathic tactile allodynia but not cold hypersensitivity. We conclude that neuropathic pain incorporates reactive processes of sensory neurons and immune cells, each leading to distinct forms of hypersensitivity, potentially allowing drug development targeted to each pain type.

Extending and implementing the Persistent ID pillars

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Car, Nicholas; Golodoniuc, Pavel; Klump, Jens

2017-04-01

The recent double decade anniversary of scholarly persistent identifier use has triggered journal special editions such as "20 Years of Persistent Identifiers". For such a publication, it is apt to consider the longevity of some persistent identifier (PID) mechanisms (Digital Object Identifiers) and the partial disappearance of others (Life Sciences IDs). We have previously postulated a set of "PID Pillars" [1] which are design principles aimed at ensuring PIDs can survive technology and social change and thus persist for the long term that we have drawn from our observations of PIDs at work over many years. The principles: describe how to ensure identifiers' system and organisation independence; codify the delivery of essential PID system functions; mandate a separation of PID functions from data delivery mechanisms; and require generation of policies detailing how change is handled. In this presentation, first we extend on our previous work of introducing the pillars by refining their descriptions, giving specific suggestions for each and presenting some work that addresses them. Second, we propose a baseline data model for persistent identifiers that, if used, would assist the separation of PID metadata and PID system functioning. This would allow PID system function specifics to change over time (e.g. resolver services or even resolution protocols) and yet preserve the PIDs themselves. Third, we detail our existing PID system — the PID Service [2] — that partially implements the pillars and describe both its successes and shortcomings. Finally, we describe our planned next-generation system that will aim to use the baseline data model and fully implement the pillars.

Comparison of the effects of crocin, safranal and diclofenac on local inflammation and inflammatory pain responses induced by carrageenan in rats.

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Tamaddonfard, Esmaeal; Farshid, Amir-Abbas; Eghdami, Karim; Samadi, Farzad; Erfanparast, Amir

2013-01-01

Crocin and safranal are the active substances of saffron and have many biological properties. In the present study, we compared the effects of crocin, safranal and diclofenac on local inflammation and its induced pain in rats. Local inflammation was induced by intraplantar (ipl) injection of carrageenan (100 μl, 2%). Paw thickness was measured before and after carrageenan injection. Inflammatory pain responses including cold allodynia, mechanical allodynia and hyperalgesia were assessed using acetone spray and von Frey filament tests, respectively. The number of neutrophils in inflammatory zone was counted 6.5 h after injection of carrageenan. Carrageenan produced edema, cold allodynia, mechanical allodynia and hyperalgesia and caused neutrophil infiltration in paw tissues. Crocin at doses of 25, 50 and 100 mg/kg, safranal at doses of 0.5, 1 and 2 mg/kg and diclofenac (as a reference drug) at a dose of 10 mg/kg attenuated edema, suppressed inflammatory pain responses and decreased the number of neutrophils. The present study showed anti-inflammatory and antinociceptive activities for crocin, safranal and diclofenac in carrageenan model of local inflammation and inflammatory pain.

Real exchange rate persistence and the excess return puzzle

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Juselius, Katarina; Assenmacher, Katrin

2017-01-01

The PPP puzzle refers to the wide swings of nominal exchange rates around their long-run equilibrium values whereas the excess return puzzle represents the persistent deviation of the domestic-foreign interest rate differential from the expected change in the nominal exchange rate. Using the I(2......) cointegrated VAR model, much of the excess return puzzle disappears when an uncertainty premium in the foreign exchange market, proxied by the persistent PPP gap, is introduced. Self-reinforcing feedback mechanisms seem to cause the persistence in the Swiss-US parity conditions. These results support imperfect...

Neural processes underlying cultural differences in cognitive persistence.

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Telzer, Eva H; Qu, Yang; Lin, Lynda C

2017-08-01

Self-improvement motivation, which occurs when individuals seek to improve upon their competence by gaining new knowledge and improving upon their skills, is critical for cognitive, social, and educational adjustment. While many studies have delineated the neural mechanisms supporting extrinsic motivation induced by monetary rewards, less work has examined the neural processes that support intrinsically motivated behaviors, such as self-improvement motivation. Because cultural groups traditionally vary in terms of their self-improvement motivation, we examined cultural differences in the behavioral and neural processes underlying motivated behaviors during cognitive persistence in the absence of extrinsic rewards. In Study 1, 71 American (47 females, M=19.68 years) and 68 Chinese (38 females, M=19.37 years) students completed a behavioral cognitive control task that required cognitive persistence across time. In Study 2, 14 American and 15 Chinese students completed the same cognitive persistence task during an fMRI scan. Across both studies, American students showed significant declines in cognitive performance across time, whereas Chinese participants demonstrated effective cognitive persistence. These behavioral effects were explained by cultural differences in self-improvement motivation and paralleled by increasing activation and functional coupling between the inferior frontal gyrus (IFG) and ventral striatum (VS) across the task among Chinese participants, neural activation and coupling that remained low in American participants. These findings suggest a potential neural mechanism by which the VS and IFG work in concert to promote cognitive persistence in the absence of extrinsic rewards. Thus, frontostriatal circuitry may be a neurobiological signal representing intrinsic motivation for self-improvement that serves an adaptive function, increasing Chinese students' motivation to engage in cognitive persistence. Copyright © 2017 Elsevier Inc. All rights

Persistent influence of maternal obesity on offspring health: Mechanisms from animal models and clinical studies.

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Wankhade, Umesh D; Thakali, Keshari M; Shankar, Kartik

2016-11-05

The consequences of excessive maternal weight and adiposity at conception for the offspring are now well recognized. Maternal obesity increases the risk of overweight and obesity even in children born with appropriate-for-gestational age (AGA) birth weights. Studies in animal models have employed both caloric excess and manipulation of macronutrients (especially high-fat) to mimic hypercaloric intake present in obesity. Findings from these studies show transmission of susceptibility to obesity, metabolic dysfunction, alterations in glucose homeostasis, hepatic steatosis, skeletal muscle metabolism and neuroendocrine changes in the offspring. This review summarizes the essential literature in this area in both experimental and clinical domains and focuses on the translatable aspects of these experimental studies. Moreover this review highlights emerging mechanisms broadly explaining maternal obesity-associated developmental programming. The roles of early developmental alterations and placental adaptations are also reviewed. Increasing evidence also points to changes in the epigenome and other emerging mechanisms such as alterations in the microbiome that may contribute to persistent changes in the offspring. Finally, we examine potential interventions that have been employed in clinical cohorts. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Combined inhibition of monoacylglycerol lipase and cyclooxygenases synergistically reduces neuropathic pain in mice

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Crowe, Molly S; Leishman, Emma; Banks, Matthew L; Gujjar, Ramesh; Mahadevan, Anu; Bradshaw, Heather B; Kinsey, Steven G

2015-01-01

Background and Purpose Neuropathic pain is commonly treated with GABA analogues, steroids or non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit one or more COX isozymes but chronic COX inhibition paradoxically increases gastrointestinal inflammation and risk of unwanted cardiovascular events. The cannabinoids also have analgesic and anti-inflammatory properties and reduce neuropathic pain in animal models. The present study investigated the analgesic effects of inhibiting both monoacylglycerol lipase (MAGL) and COX enzymes, using low doses of both inhibitors. Experimental Approach Mice subjected to chronic constriction injury (CCI) were tested for mechanical and cold allodynia after administration of the MAGL inhibitor, JZL184, or the non-selective COX inhibitor diclofenac. Then, both drugs were co-administered at fixed dose proportions of 1:3, 1:1 and 3:1, based on their ED50 values. PGs, endocannabinoids and related lipids were quantified in lumbar spinal cord. Key Results Combining low doses of JZL184 and diclofenac synergistically attenuated mechanical allodynia and additively reduced cold allodynia. The cannabinoid CB1 receptor antagonist, rimonabant, but not the CB2 receptor antagonist, SR144528, blocked the analgesic effects of the JZL184 and diclofenac combination on mechanical allodynia, implying that CB1 receptors were primarily responsible for the anti-allodynia. Diclofenac alone and with JZL184 significantly reduced PGE2 and PGF2α in lumbar spinal cord tissue, whereas JZL184 alone caused significant increases in the endocannabinoid metabolite, N-arachidonoyl glycine. Conclusions and Implications Combining COX and MAGL inhibition is a promising therapeutic approach for reducing neuropathic pain with minimal side effects. PMID:25393148

Differential roles of galanin on mechanical and cooling responses at the primary afferent nociceptor

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Hulse Richard P

2012-06-01

Full Text Available Abstract Background Galanin is expressed in a small percentage of intact small diameter sensory neurons of the dorsal root ganglia and in the afferent terminals of the superficial lamina of the dorsal horn of the spinal cord. The neuropeptide modulates nociception demonstrating dose-dependent pro- and anti-nociceptive actions in the naïve animal. Galanin also plays an important role in chronic pain, with the anti-nociceptive actions enhanced in rodent neuropathic pain models. In this study we compared the role played by galanin and its receptors in mechanical and cold allodynia by identifying individual rat C-fibre nociceptors and characterising their responses to mechanical or acetone stimulation. Results Mechanically evoked responses in C-fibre nociceptors from naive rats were sensitised after close intra-arterial infusion of galanin or Gal2-11 (a galanin receptor-2/3 agonist confirming previous data that galanin modulates nociception via activation of GalR2. In contrast, the same dose and route of administration of galanin, but not Gal2-11, inhibited acetone and menthol cooling evoked responses, demonstrating that this inhibitory mechanism is not mediated by activation of GalR2. We then used the partial saphenous nerve ligation injury model of neuropathic pain (PSNI and the complete Freund’s adjuvant model of inflammation in the rat and demonstrated that close intra-arterial infusion of galanin, but not Gal2-11, reduced cooling evoked nociceptor activity and cooling allodynia in both paradigms, whilst galanin and Gal2-11 both decreased mechanical activation thresholds. A previously described transgenic mouse line which inducibly over-expresses galanin (Gal-OE after nerve injury was then used to investigate whether manipulating the levels of endogenous galanin also modulates cooling evoked nociceptive behaviours after PSNI. Acetone withdrawal behaviours in naive mice showed no differences between Gal-OE and wildtype (WT mice. 7-days after

Constructing dual-defense mechanisms on membrane surfaces by synergy of PFSA and SiO2 nanoparticles for persistent antifouling performance

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Zhou, Linjie; Gao, Kang; Jiao, Zhiwei; Wu, Mengyuan; He, Mingrui; Su, Yanlei; Jiang, Zhongyi

2018-05-01

Synthetic antifouling membrane surfaces with dual-defense mechanisms (fouling-resistant and fouling-release mechanism) were constructed through the synergy of perfluorosulfonic acid (PFSA) and SiO2 nanoparticles. During the nonsolvent induced phase separation (NIPS) process, the amphiphilic PFSA polymers spontaneously segregated to membrane surfaces and catalyzed the hydrolysis-polycondensation of tetraethyl orthosilicate (TEOS) to generate hydrophilic SiO2 nanoparticles (NPs). The resulting PVDF/PFSA/SiO2 hybrid membranes were characterized by contact angle measurements, FTIR, XPS, SEM, AFM, TGA, and TEM. The hydrophilic microdomains and low surface energy microdomains of amphiphilic PFSA polymers respectively endowed membrane surfaces with fouling-resistant mechanism and fouling-release mechanism, while the hydrophilic SiO2 NPs intensified the fouling-resistant mechanism. When the addition of TEOS reached 3 wt%, the hybrid membrane with optimal synergy of PFSA and SiO2 NPs displayed low flux decline (17.4% DRt) and high flux recovery (99.8% FRR) during the filtration of oil-in-water emulsion. Meanwhile, the long-time stability test verified that the hybrid membrane possessed persistent antifouling performance.

Analgesic Effect of Photobiomodulation on Bothrops Moojeni Venom-Induced Hyperalgesia: A Mechanism Dependent on Neuronal Inhibition, Cytokines and Kinin Receptors Modulation.

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Nikele Nadur-Andrade

2016-10-01

Full Text Available Envenoming induced by Bothrops snakebites is characterized by drastic local tissue damage that involves an intense inflammatory reaction and local hyperalgesia which are not neutralized by conventional antivenom treatment. Herein, the effectiveness of photobiomodulation to reduce inflammatory hyperalgesia induced by Bothrops moojeni venom (Bmv, as well as the mechanisms involved was investigated.Bmv (1 μg was injected through the intraplantar route in the right hind paw of mice. Mechanical hyperalgesia and allodynia were evaluated by von Frey filaments at different time points after venom injection. Low level laser therapy (LLLT was applied at the site of Bmv injection at wavelength of red 685 nm with energy density of 2.2 J/cm2 at 30 min and 3 h after venom inoculation. Neuronal activation in the dorsal horn spinal cord was determined by immunohistochemistry of Fos protein and the mRNA expression of IL-6, TNF-α, IL-10, B1 and B2 kinin receptors were evaluated by Real time-PCR 6 h after venom injection. Photobiomodulation reversed Bmv-induced mechanical hyperalgesia and allodynia and decreased Fos expression, induced by Bmv as well as the mRNA levels of IL-6, TNF-α and B1 and B2 kinin receptors. Finally, an increase on IL-10, was observed following LLLT.These data demonstrate that LLLT interferes with mechanisms involved in nociception and hyperalgesia and modulates Bmv-induced nociceptive signal. The use of photobiomodulation in reducing local pain induced by Bothropic venoms should be considered as a novel therapeutic tool for the treatment of local symptoms induced after bothropic snakebites.

Amnestically Induced Persistence in Random Walks

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Cressoni, J. C.; da Silva, Marco Antonio Alves; Viswanathan, G. M.

2007-02-01

We study how the Hurst exponent α depends on the fraction f of the total time t remembered by non-Markovian random walkers that recall only the distant past. We find that otherwise nonpersistent random walkers switch to persistent behavior when inflicted with significant memory loss. Such memory losses induce the probability density function of the walker’s position to undergo a transition from Gaussian to non-Gaussian. We interpret these findings of persistence in terms of a breakdown of self-regulation mechanisms and discuss their possible relevance to some of the burdensome behavioral and psychological symptoms of Alzheimer’s disease and other dementias.

TNF α is involved in neuropathic pain induced by nucleoside reverse transcriptase inhibitor in rats

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Zheng, Xuexing; Ouyang, Handong; Liu, Shue; Mata, Marina; Fink, David J.; Hao, Shuanglin

2011-01-01

In patients with HIV/AIDS, neuropathic pain is a common neurological complication. Infection with the HIV itself may lead to neuropathic pain, and painful symptoms are enhanced when patients are treated with nucleoside reverse transcriptase inhibitors (NRTI). The mechanisms by which NRTIs contribute to the development of neuropathic pain are not known. In the current studies, we tested the role of TNFα in antiretroviral drug-induced neuropathic pain. We administered 2′,3′-dideoxycytidine (ddC, one of the NRTIs) systemically to induce mechanical allodynia. We found that ddC induced overexpression of both mRNA and proteins of GFAP and TNFα in the spinal dorsal horn. TNFα was colocalized with GFAP in the spinal dorsal horn and with NeuN in the DRG. Knockdown of TNFα with siRNA blocked the mechanical allodynia induced by ddC. Intrathecal administration of glial inhibitor or recombinant TNF soluble receptor, reversed mechanical allodynia induced by ddC. These results suggest that TNFα is involved in NRTI-induced neuropathic pain. PMID:21741472

Persistence drives gene clustering in bacterial genomes

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Rocha Eduardo PC

2008-01-01

Full Text Available Abstract Background Gene clustering plays an important role in the organization of the bacterial chromosome and several mechanisms have been proposed to explain its extent. However, the controversies raised about the validity of each of these mechanisms remind us that the cause of this gene organization remains an open question. Models proposed to explain clustering did not take into account the function of the gene products nor the likely presence or absence of a given gene in a genome. However, genomes harbor two very different categories of genes: those genes present in a majority of organisms – persistent genes – and those present in very few organisms – rare genes. Results We show that two classes of genes are significantly clustered in bacterial genomes: the highly persistent and the rare genes. The clustering of rare genes is readily explained by the selfish operon theory. Yet, genes persistently present in bacterial genomes are also clustered and we try to understand why. We propose a model accounting specifically for such clustering, and show that indispensability in a genome with frequent gene deletion and insertion leads to the transient clustering of these genes. The model describes how clusters are created via the gene flux that continuously introduces new genes while deleting others. We then test if known selective processes, such as co-transcription, physical interaction or functional neighborhood, account for the stabilization of these clusters. Conclusion We show that the strong selective pressure acting on the function of persistent genes, in a permanent state of flux of genes in bacterial genomes, maintaining their size fairly constant, that drives persistent genes clustering. A further selective stabilization process might contribute to maintaining the clustering.

A COMBINED EFFECT OF DEXTROMETHORPHAN AND MELATONIN ON NEUROPATHIC PAIN BEHAVIOR IN RATS

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Wang, Shuxing; Zhang, Lin; Lim, Grewo; Sung, Backil; Tian, Yinghong; Chou, Chiu-Wen; Hernstadt, Hayley; Rusanescu, Gabriel; Ma, Yuxin; Mao, Jianren

2009-01-01

Previous study has shown that administration of melatonin into the anterior cingulate cortex contralateral to peripheral nerve injury prevented exacerbation of mechanical allodynia with a concurrent improvement of depression-like behavior in Wistar-Kyoto (WKY) rats, a genetic variation of Wistar rats. In the present study, we examined the effect of the individual versus combined treatment of melatonin and/or dextromethorphan (DM), a clinically available N-methyl-D-aspartate (NMDA) receptor antagonist, on pain behaviors in WKY rats with chronic constriction sciatic nerve injury (CCI). Pain behaviors (thermal hyperalgesia and mechanical allodynia) were established at one week after CCI. WKY rats were then treated intraperitoneally with various doses of melatonin, DM or their combination once daily for the following week. At the end of this one-week treatment, behavioral tests were repeated in these same rats. While DM alone was effective in reducing thermal hyperalgesia at three tested doses (15, 30 or 60 mg/kg), it reduced mechanical allodynia only at high doses (30 or 60 mg/kg). By comparison, administration of melatonin alone was effective in reducing thermal hyperalgesia only at the highest dose (120 mg/kg, but not 30 or 60 mg/kg) tested in this experiment. Melatonin alone failed to reverse allodynia at all three tested doses (30, 60 and 120 mg/kg). However, the combined intraperitoneal administration of melatonin (30 mg/kg) and DM (15 mg/kg) effectively reversed both thermal hyperalgesia and mechanical allodynia although each individual dose alone did not reduce pain behaviors. These results suggest that a combination of melatonin with a clinically available NMDA receptor antagonist might be more effective than either drug alone for the treatment of neuropathic pain. PMID:19595681

Distinct Analgesic Actions of DHA and DHA-Derived Specialized Pro-Resolving Mediators on Post-operative Pain After Bone Fracture in Mice.

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Zhang, Linlin; Terrando, Niccolò; Xu, Zhen-Zhong; Bang, Sangsu; Jordt, Sven-Eric; Maixner, William; Serhan, Charles N; Ji, Ru-Rong

2018-01-01

Mechanisms of pain resolution are largely unclear. Increasing evidence suggests that specialized pro-resolving mediators (SPMs), derived from fish oil docosahexaenoic acid (DHA), promote the resolution of acute inflammation and potently inhibit inflammatory and neuropathic pain. In this study, we examined the analgesic impact of DHA and DHA-derived SPMs in a mouse model of post-operative pain induced by tibial bone fracture (fPOP). Intravenous perioperative treatment with DHA (500 μg), resolvin D1 (RvD1, 500 ng) and maresin 1 (MaR1, 500 ng), 10 min and 24 h after the surgery, delayed the development of fPOP (mechanical allodynia and cold allodynia). In contrast, post-operative intrathecal (IT) administration of DHA (500 μg) 2 weeks after the surgery had no effects on established mechanical and cold allodynia. However, by direct comparison, IT post-operative treatment (500 ng) with neuroprotectin D1 (NPD1), MaR1, and D-resolvins, RvD1 and RvD5, but not RvD3 and RvD4, effectively reduced mechanical and cold allodynia. ELISA analysis showed that perioperative DHA treatment increased RvD1 levels in serum and spinal cord samples after bone fracture. Interestingly, sham surgery resulted in transient allodynia and increased RvD1 levels, suggesting a correlation of enhanced SPM levels with acute pain resolution after sham surgery. Our findings suggest that (1) perioperative treatment with DHA is effective in preventing and delaying the development of fPOP and (2) post-treatment with some SPMs can attenuate established fPOP. Our data also indicate that orthopedic surgery impairs SPM production. Thus, DHA and DHA-derived SPMs should be differentially supplemented for treating fPOP and improving recovery.

Distinct Analgesic Actions of DHA and DHA-Derived Specialized Pro-Resolving Mediators on Post-operative Pain After Bone Fracture in Mice

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Linlin Zhang

2018-05-01

Full Text Available Mechanisms of pain resolution are largely unclear. Increasing evidence suggests that specialized pro-resolving mediators (SPMs, derived from fish oil docosahexaenoic acid (DHA, promote the resolution of acute inflammation and potently inhibit inflammatory and neuropathic pain. In this study, we examined the analgesic impact of DHA and DHA-derived SPMs in a mouse model of post-operative pain induced by tibial bone fracture (fPOP. Intravenous perioperative treatment with DHA (500 μg, resolvin D1 (RvD1, 500 ng and maresin 1 (MaR1, 500 ng, 10 min and 24 h after the surgery, delayed the development of fPOP (mechanical allodynia and cold allodynia. In contrast, post-operative intrathecal (IT administration of DHA (500 μg 2 weeks after the surgery had no effects on established mechanical and cold allodynia. However, by direct comparison, IT post-operative treatment (500 ng with neuroprotectin D1 (NPD1, MaR1, and D-resolvins, RvD1 and RvD5, but not RvD3 and RvD4, effectively reduced mechanical and cold allodynia. ELISA analysis showed that perioperative DHA treatment increased RvD1 levels in serum and spinal cord samples after bone fracture. Interestingly, sham surgery resulted in transient allodynia and increased RvD1 levels, suggesting a correlation of enhanced SPM levels with acute pain resolution after sham surgery. Our findings suggest that (1 perioperative treatment with DHA is effective in preventing and delaying the development of fPOP and (2 post-treatment with some SPMs can attenuate established fPOP. Our data also indicate that orthopedic surgery impairs SPM production. Thus, DHA and DHA-derived SPMs should be differentially supplemented for treating fPOP and improving recovery.

Post-Retrieval Late Process Contributes to Persistence of Reactivated Fear Memory

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Nakayama, Daisuke; Yamasaki, Yoshiko; Matsuki, Norio; Nomura, Hiroshi

2013-01-01

Several studies have demonstrated the mechanisms involved in memory persistence after learning. However, little is known about memory persistence after retrieval. In this study, a protein synthesis inhibitor, anisomycin, was infused into the basolateral amygdala of mice 9.5 h after retrieval of contextual conditioned fear. Anisomycin attenuated…

Anti-allodynic effects of N-demethylsinomenine, an active metabolite of sinomenine, in a mouse model of postoperative pain.

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Ou, Yuntao; Su, Man; Ling, Yong; Wei, Qianqian; Pan, Fei; Li, Jiejia; Li, Jun-Xu; Zhu, Qing

2018-03-15

Sinomenine, a major bioactive ingredient isolated from traditional Chinese medicine Sinomenium acutum, has been reported to have analgesic effects in various pain animal models. N-demethylsinomenine, the N-demethylated product of sinomenine, has been identified to be the major metabolite of sinomenine and is also a natural component extracted from Sinomenium acutum. This study examined the anti-allodynic effects of N-demethylsinomenine in a mouse model of postoperative pain. A significant and sustained mechanical allodynia that lasted for 4 days was induced by making a surgical incision on the right hind paw in mice. Acute treatment with N-demethylsinomenine (10-40 mg/kg, s.c.) relieved the mechanical allodynia in a dose-dependent manner. Although there was no difference in maximal analgesic effect between N-demethylsinomenine (40 mg/kg, s.c.) and sinomenine (40 mg/kg, s.c.), the onset of action of N-demethylsinomenine was quicker than sinomenine. Repeated treatment with N-demethylsinomenine (10-40 mg/kg/day, s.c.) also dose-dependently exerted sustained antinociception against postoperative allodynia and did not produce analgesic tolerance and carry-over effect. The anti-allodynia induced by N-demethylsinomenine (40 mg/kg, s.c.) was attenuated by bicuculline, a selective γ-aminobutyric acid type A (GABA A ) receptor antagonist. In addition, the doses of N-demethylsinomenine used here did not alter the locomotor activity in mice. Our findings demonstrated that N-demethylsinomenine exerts behaviorally-specific anti-allodynia against postoperative allodynia mediated through the GABA A receptors, suggesting it may be a useful novel pharmacotherapy for the control of postoperative pain. Copyright © 2018 Elsevier B.V. All rights reserved.

Immunodominant fragments of myelin basic protein initiate T cell-dependent pain

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Liu Huaqing

2012-06-01

Full Text Available Abstract Background The myelin sheath provides electrical insulation of mechanosensory Aβ-afferent fibers. Myelin-degrading matrix metalloproteinases (MMPs damage the myelin sheath. The resulting electrical instability of Aβ-fibers is believed to activate the nociceptive circuitry in Aβ-fibers and initiate pain from innocuous tactile stimulation (mechanical allodynia. The precise molecular mechanisms, responsible for the development of this neuropathic pain state after nerve injury (for example, chronic constriction injury, CCI, are not well understood. Methods and results Using mass spectrometry of the whole sciatic nerve proteome followed by bioinformatics analyses, we determined that the pathways, which are classified as the Infectious Disease and T-helper cell signaling, are readily activated in the nerves post-CCI. Inhibition of MMP-9/MMP-2 suppressed CCI-induced mechanical allodynia and concomitant TNF-α and IL-17A expression in nerves. MMP-9 proteolysis of myelin basic protein (MBP generated the MBP84-104 and MBP68-86 digest peptides, which are prominent immunogenic epitopes. In agreement, the endogenous MBP69-86 epitope co-localized with MHCII and MMP-9 in Schwann cells and along the nodes of Ranvier. Administration of either the MBP84-104 or MBP68-86 peptides into the naïve nerve rapidly produced robust mechanical allodynia with a concomitant increase in T cells and MHCII-reactive cell populations at the injection site. As shown by the genome-wide expression profiling, a single intraneural MBP84-104 injection stimulated the inflammatory, immune cell trafficking, and antigen presentation pathways in the injected naïve nerves and the associated spinal cords. Both MBP84-104-induced mechanical allodynia and characteristic pathway activation were remarkably less prominent in the T cell-deficient athymic nude rats. Conclusions These data implicate MBP as a novel mediator of pain. Furthermore, the action of MMPs expressed within 1�

Immunodominant fragments of myelin basic protein initiate T cell-dependent pain.

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Liu, Huaqing; Shiryaev, Sergey A; Chernov, Andrei V; Kim, Youngsoon; Shubayev, Igor; Remacle, Albert G; Baranovskaya, Svetlana; Golubkov, Vladislav S; Strongin, Alex Y; Shubayev, Veronica I

2012-06-07

The myelin sheath provides electrical insulation of mechanosensory Aβ-afferent fibers. Myelin-degrading matrix metalloproteinases (MMPs) damage the myelin sheath. The resulting electrical instability of Aβ-fibers is believed to activate the nociceptive circuitry in Aβ-fibers and initiate pain from innocuous tactile stimulation (mechanical allodynia). The precise molecular mechanisms, responsible for the development of this neuropathic pain state after nerve injury (for example, chronic constriction injury, CCI), are not well understood. Using mass spectrometry of the whole sciatic nerve proteome followed by bioinformatics analyses, we determined that the pathways, which are classified as the Infectious Disease and T-helper cell signaling, are readily activated in the nerves post-CCI. Inhibition of MMP-9/MMP-2 suppressed CCI-induced mechanical allodynia and concomitant TNF-α and IL-17A expression in nerves. MMP-9 proteolysis of myelin basic protein (MBP) generated the MBP84-104 and MBP68-86 digest peptides, which are prominent immunogenic epitopes. In agreement, the endogenous MBP69-86 epitope co-localized with MHCII and MMP-9 in Schwann cells and along the nodes of Ranvier. Administration of either the MBP84-104 or MBP68-86 peptides into the naïve nerve rapidly produced robust mechanical allodynia with a concomitant increase in T cells and MHCII-reactive cell populations at the injection site. As shown by the genome-wide expression profiling, a single intraneural MBP84-104 injection stimulated the inflammatory, immune cell trafficking, and antigen presentation pathways in the injected naïve nerves and the associated spinal cords. Both MBP84-104-induced mechanical allodynia and characteristic pathway activation were remarkably less prominent in the T cell-deficient athymic nude rats. These data implicate MBP as a novel mediator of pain. Furthermore, the action of MMPs expressed within 1 day post-injury is critical to the generation of tactile allodynia

A novel and selective poly (ADP-ribose polymerase inhibitor ameliorates chemotherapy-induced painful neuropathy.

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Lauren E Ta

Full Text Available Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose polymerase (PARP inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888 would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice.An established chemotherapy-induced painful neuropathy model of two weekly cycles of 10 intraperitoneal (i.p. injections separated by 5 days rest was used to examine the therapeutic potential of the PARP inhibitor compound 4a. Behavioral testing using von Frey, paw radiant heat, cold plate, and exploratory behaviors were taken at baseline, and followed by testing at 3, 6, and 8 weeks from the beginning of drug treatment.Cisplatin-treated mice developed heat hyperalgesia and mechanical allodynia while oxaliplatin-treated mice exhibited cold hyperalgesia and mechanical allodynia. Co-administration of 50 mg/kg or 25 mg/kg compound 4a with platinum regimen, attenuated cisplatin-induced heat hyperalgesia and mechanical allodynia in a dose dependent manner. Similarly, co-administration of 50 mg/kg compound 4a attenuated oxaliplatin-induced cold hyperalgesia and mechanical allodynia. These data indicate that administration of a novel PARP inhibitor may have important applications as a therapeutic agent for human chemotherapy-induced painful neuropathy.

A novel and selective poly (ADP-ribose) polymerase inhibitor ameliorates chemotherapy-induced painful neuropathy.

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Ta, Lauren E; Schmelzer, James D; Bieber, Allan J; Loprinzi, Charles L; Sieck, Gary C; Brederson, Jill D; Low, Philip A; Windebank, Anthony J

2013-01-01

Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose) polymerase (PARP) inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888) would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice. An established chemotherapy-induced painful neuropathy model of two weekly cycles of 10 intraperitoneal (i.p.) injections separated by 5 days rest was used to examine the therapeutic potential of the PARP inhibitor compound 4a. Behavioral testing using von Frey, paw radiant heat, cold plate, and exploratory behaviors were taken at baseline, and followed by testing at 3, 6, and 8 weeks from the beginning of drug treatment. Cisplatin-treated mice developed heat hyperalgesia and mechanical allodynia while oxaliplatin-treated mice exhibited cold hyperalgesia and mechanical allodynia. Co-administration of 50 mg/kg or 25 mg/kg compound 4a with platinum regimen, attenuated cisplatin-induced heat hyperalgesia and mechanical allodynia in a dose dependent manner. Similarly, co-administration of 50 mg/kg compound 4a attenuated oxaliplatin-induced cold hyperalgesia and mechanical allodynia. These data indicate that administration of a novel PARP inhibitor may have important applications as a therapeutic agent for human chemotherapy-induced painful neuropathy.

The social transmission of metacontrol policies: Mechanisms underlying the interpersonal transfer of persistence and flexibility.

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Hommel, Bernhard; Colzato, Lorenza S

2017-10-01

Humans often face binary cognitive-control dilemmas, with the choice between persistence and flexibility being a crucial one. Tackling these dilemmas requires metacontrol, i.e., the control of the current cognitive-control policy. As predicted from functional, psychometric, neuroscientific, and modeling approaches, interindividual variability in metacontrol biases towards persistence or flexibility could be demonstrated in metacontrol-sensitive tasks. These biases covary systematically with genetic predispositions regarding mesofrontal and nigrostriatal dopaminergic functioning and the individualistic or collectivistic nature of the cultural background. However, there is also evidence for mood- and meditation-induced intraindividual variability (with negative mood and focused-attention meditation being associated with a bias towards persistence, and positive mood and open-monitoring meditation being associated with a bias towards flexibility), suggesting that genetic and cultural factors do not determine metacontrol settings entirely. We suggest a theoretical framework that explains how genetic predisposition and cultural learning can lead to the implementation of metacontrol defaults, which however can be shifted towards persistence or flexibility by situational factors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Saffold Virus Type 3 (SAFV-3) Persists in HeLa Cells

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Himeda, Toshiki; Hosomi, Takushi; Okuwa, Takako; Muraki, Yasushi; Ohara, Yoshiro

2013-01-01

Saffold virus (SAFV) was identified as a human cardiovirus in 2007. Although several epidemiological studies have been reported, they have failed to provide a clear picture of the relationship between SAFV and human diseases. SAFV genotype 3 has been isolated from the cerebrospinal fluid specimen of patient with aseptic meningitis. This finding is of interest since Theiler’s murine encephalomyelitis virus (TMEV), which is the closely related virus, is known to cause a multiple sclerosis-like syndrome in mice. TMEV persistently infects in mouse macrophage cells in vivo and in vitro, and the viral persistence is essential in TMEV-induced demyelinating disease. The precise mechanism(s) of SAFV infection still remain unclear. In order to clarify the SAFV pathogenicity, in the present study, we studied the possibilities of the in vitro persistent infection of SAFV. The two distinct phenotypes of HeLa cells, HeLa-N and HeLa-R, were identified. In these cells, the type of SAFV-3 infection was clearly different. HeLa-N cells were lyticly infected with SAFV-3 and the host suitable for the efficient growth. On the other hand, HeLa-R cells were persistently infected with SAFV-3. In addition, the SAFV persistence in HeLa-R cells is independent of type I IFN response of host cells although the TMEV persistence in mouse macrophage cells depends on the response. Furthermore, it was suggested that SAFV persistence may be influenced by the expression of receptor(s) for SAFV infection on the host cells. The present findings on SAFV persistence will provide the important information to encourage the research of SAFV pathogenicity. PMID:23308162

Allergic Inflammation Leads to Neuropathic Pain via Glial Cell Activation.

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Yamasaki, Ryo; Fujii, Takayuki; Wang, Bing; Masaki, Katsuhisa; Kido, Mizuho A; Yoshida, Mari; Matsushita, Takuya; Kira, Jun-Ichi

2016-11-23

and CNS complications is unknown. A peculiar myelitis presenting with persistent neuropathic pain has been reported in patients with allergic disorders. We studied how atopy exerts substantial influence on the nociceptive system. We found that mice with allergic disorders had severe allodynia with activated astroglia and microglia, and showed marked upregulation of endothelin-1 (ET-1) receptor type B (EDNRB) in the spinal cord. A selective EDNRB antagonist prevented allodynia and glial activation. Our findings suggest a novel mechanism whereby atopy induces glial activation and neuropathic pain via an ET-1/EDNRB pathway. Copyright © 2016 the authors 0270-6474/16/3611929-17$15.00/0.

The analgesic effect of orexin-A in a murine model of chemotherapy-induced neuropathic pain.

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Toyama, Satoshi; Shimoyama, Naohito; Shimoyama, Megumi

2017-02-01

Orexins are neuropeptides that are localized to neurons in the lateral and dorsal hypothalamus but its receptors are distributed to many different regions of the central nervous system. Orexins are implicated in a variety of physiological functions including sleep regulation, energy homeostats, and stress reactions. Furthermore, orexins administered exogenously have been shown to have analgesic effects in animal models. A type of intractable pain in patients is pain due to chemotherapy-induced peripheral neuropathy (CIPN). Several chemotherapeutic agents used for the treatment of malignant diseases induce dose-limiting neuropathic pain that compromises patients' quality of life. Here, we examined the analgesic effect of orexin-A in a murine model of CIPN, and compared it with the effect of duloxetine, the only drug recommended for the treatment of CIPN pain in patients. CIPN was induced in male BALB/c mice by repeated intraperitoneal injection of oxaliplatin, a platinum chemotherapeutic agent used for the treatment of advanced colorectal cancer. Neuropathic mechanical allodynia was assessed by the von Frey test, and the effect on acute thermal pain was assessed by the tail flick test. Intracerebroventricularly administered orexin-A dose-dependently attenuated oxaliplatin-induced mechanical allodynia and increased tail flick latencies. Oxaliplatin-induced mechanical allodynia was completely reversed by orexin-A at a low dose that did not increase tail flick latency. Duloxetine only partially reversed mechanical allodynia and had no effect on tail flick latency. The analgesic effect of orexin-A on oxaliplatin-induced mechanical allodynia was completely antagonized by prior intraperitoneal injection of SB-408124 (orexin type-1 receptor antagonist), but not by prior intraperitoneal injection of TCS-OX2-29 (orexin type-2 receptor antagonist). Our findings suggest that orexin-A is more potent than duloxetine in relieving pain CIPN pain and its analgesic effect is

Burning Eye Syndrome: Do Neuropathic Pain Mechanisms Underlie Chronic Dry Eye?

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Kalangara, Jerry P; Galor, Anat; Levitt, Roy C; Felix, Elizabeth R; Alegret, Ramon; Sarantopoulos, Constantine D

2016-04-01

Dry eye is a multi-factorial disorder that manifests with painful ocular symptoms and visual disturbances, which can only be partly attributed to tear dysfunction. This disorder may also involve neuroplasticity in response to neuronal injury. This review will emphasize the key characteristics of dry eye pain and its pathologic mechanisms, making the argument that a subset of dry eye represents a neuropathic pain disorder of the eye, more appropriately called "burning eye syndrome." A literature review was conducted using a PubMed search focusing on dry eye, corneal nociception, and neuropathic pain. Articles were reviewed and those discussing clinical course, pathophysiology, and neuronal regulation of chronic ocular pain as related to dry eye were summarized. We found that there is a discordance between ocular pain and dryness on the ocular surface. Although tear dysfunction may be one of the initial insults, its persistence may be associated with repeated ocular sensory nerve injury leading to an acute-to-chronic pain transition associated with neuropathologic changes (peripheral and central sensitization), neuronal dysfunction, and spontaneous ocular pain. Dry eye is becoming a major health concern due to its increasing incidence, significant morbidity, and economic burden. Recent evidence suggests that a subset of dry eye may be better represented as a chronic neuropathic pain disorder due to its features of dysesthesia, spontaneous pain, allodynia, and hyperalgesia. Future therapies targeted at the underlying neuroplasticity may yield improved efficacy for patients with this subset of dry eye, which we term "burning eye syndrome." © 2015 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Getting the phenotypes right: an essential ingredient for understanding aetiological mechanisms underlying persistent violence and developing effective treatments

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Sheilagh Hodgins

2009-11-01

Full Text Available In order to reduce societal levels of violence, it is essential to advance understanding of the neurobiological mechanisms involved in initiating and maintaining individual patterns of physical aggression. New technologies such as Magnetic Resonance Imagining and analyses of DNA provide tools for identifying these mechanisms. The reliability and validity of the results of studies using these tools depend not only on aspects of the technology, but also on the methodological rigour with which the studies are conducted, particularly with respect to characterizing the phenotype. The present article discusses five challenges confronting scientists who aim to advance understanding of the neurobiological mechanisms associated with persistent violence. These challenges are: (1 to develop evidence-based hypotheses and to design studies that test alternate hypotheses; (2 to recruit samples that are homogeneous with respect to variables that may be linked to neurobiological mechanisms underpinning violent behaviour; (3 to use reliable and valid measures in order to fully characterize participants so that the external validity of the results is evident; (4 to restrict the range of age of participants so as not to confuse developmental change with group differences; and (5 to take account of sex. Our goal is to contribute to elevating methodological standards in this new field of research and to thereby improve the validity of results and move closer to finding effective ways to reduce violence

Behavioral and pharmacological characteristics of bortezomib-induced peripheral neuropathy in rats

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Shota Yamamoto

2015-09-01

Full Text Available Bortezomib, an effective anticancer drug for multiple myeloma, often causes peripheral neuropathy which is mainly characterized by numbness and painful paresthesia. Nevertheless, there is no effective strategy to escape or treat bortezomib-induced peripheral neuropathy (BIPN, because we have understood few mechanism of this side effect. In this study, we evaluated behavioral and pathological characteristics of BIPN, and investigated pharmacological efficacy of various analgesic drugs and adjuvants on mechanical allodynia induced by bortezomib treatment in rats. The repeated administration of bortezomib induced mechanical and cold allodynia. There was axonal degeneration of sciatic nerve behind these neuropathic symptoms. Furthermore, the exposure to bortezomib shortened neurite length in PC12 cells. Finally, the result of evaluation of anti-allodynic potency, oral administration of tramadol (10 mg/kg, pregabalin (3 mg/kg, duloxetine (30 mg/kg or mexiletine (100 mg/kg, but not amitriptyline or diclofenac, transiently relieved the mechanical allodynia induced by bortezomib. These results suggest that axonal degeneration of the sciatic nerve is involved in BIPN and that some analgesic drugs and adjuvants are effective in the relief of painful neuropathy.

Suppression of Pax2 attenuates allodynia and hyperalgesia through ET-1-ETAR-NFAT5 signaling in a rat model of neuropathic pain.

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Tai, Lydia Wai; Pan, Zhiqiang; Sun, Liting; Li, Haobo; Gu, Pan; Wong, Stanley Sau Ching; Chung, Sookja K; Cheung, Chi Wai

2018-05-27

Endothelin-1 (ET-1) and its receptors (ETAR/ETBR) emerge to be a key signaling axis in neuropathic pain processing and are recognized as new therapeutic targets. Yet, little is known on the functional regulation of ET-1 axis during neuropathic pain. Bioinformatics analysis indicated that paired box gene 2 (Pax2) or nuclear factor of activated T-cells 5 (NFAT5), two transcription factors involved in the modulation of neurotransmission, may regulate ET-1. Therefore, we hypothesized that ET-1 axis may be regulated by Pax2 or NFAT5 in the development of neuropathic pain. After partial sciatic nerve ligation (pSNL), rats displayed allodynia and hyperalgesia, which was associated with increased mRNA and protein expressions of spinal Pax2, NFAT5, and mRNA levels of ET-1 and ETAR, but not ETBR. Knockdown of Pax2 or NFAT5 with siRNA, or inhibition of ETAR with BQ-123 attenuated pSNL-induced pain-like behaviors. At molecular level, Pax2 siRNA, but not NFAT5 siRNA, downregulated ET-1 and ETAR, while ETAR inhibitor reduced NFAT5, indicating Pax2 in the upstream of ET-1 axis with NFAT5 in the downstream. Further, suppression of Pax2 (inhibiting ET-1) or impairment of ET-1 signaling (inhibition of ETAR and/or decrease of NFAT5) deactivated mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, supporting the significance of functional regulation of ET-1 axis in neuropathic pain signaling. These findings demonstrate that Pax2 targeting ET-1-ETAR-NFAT5 is a novel regulatory mechanism underlying neuropathic pain. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Analysis of inflammation-induced depression of home cage wheel running in rats reveals the difference between opioid antinociception and restoration of function

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Kandasamy, Ram; Calsbeek, Jonas J.; Morgan, Michael M.

2016-01-01

Opioids are effective at inhibiting responses to noxious stimuli in rodents, but have limited efficacy and many side effects in chronic pain patients. One reason for this disconnect is that nociception is typically assessed using withdrawal from noxious stimuli in animals, whereas chronic pain patients suffer from abnormal pain that disrupts normal activity. We hypothesized that assessment of home cage wheel running in rats would provide a much more clinically relevant method to assess opioid efficacy to restore normal behavior. Intraplantar injection of Complete Freund’s Adjuvant (CFA) into the right hindpaw depressed wheel running and caused mechanical allodynia measured with the von Frey test in both male and female rats. Administration of an ED50 dose of morphine (3.2 mg/kg) reversed mechanical allodynia, but did not reverse CFA-induced depression of wheel running. In contrast, administration of a low dose of morphine (1.0 mg/kg) restored running for one hour in both sexes, but had no effect on mechanical allodynia. Administration of the atypical opioid buprenorphine had no effect on inflammation-induced depression of wheel running in male or female rats, but attenuated mechanical allodynia in male rats. Administration of buprenorphine and higher doses of morphine depressed wheel running in non-inflamed rats, suggesting that the side effects of opioids interfere with restoration of function. These data indicate that restoration of pain-depressed function requires antinociception in the absence of disruptive side effects. The disruptive side effects of opioids are consistent with the major limitation of opioid use in human pain patients. PMID:27746208

Immune Evasion Strategies and Persistence of Helicobacter pylori.

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Mejías-Luque, Raquel; Gerhard, Markus

Helicobacter pylori infection is commonly acquired during childhood, can persist lifelong if not treated, and can cause different gastric pathologies, including chronic gastritis, peptic ulcer disease, and eventually gastric cancer. H. pylori has developed a number of strategies in order to cope with the hostile conditions found in the human stomach as well as successful mechanisms to evade the strong innate and adaptive immune responses elicited upon infection. Thus, by manipulating innate immune receptors and related signaling pathways, inducing tolerogenic dendritic cells and inhibiting effector T cell responses, H. pylori ensures low recognition by the host immune system as well as its persistence in the gastric epithelium. Bacterial virulence factors such as cytotoxin-associated gene A, vacuolating cytotoxin A, or gamma-glutamyltranspeptidase have been extensively studied in the context of bacterial immune escape and persistence. Further, the bacterium possesses other factors that contribute to immune evasion. In this chapter, we discuss in detail the main evasion and persistence strategies evolved by the bacterium as well as the specific bacterial virulence factors involved.

Persistent villi hypoperfusion explains intramucosal acidosis in sheep endotoxemia

NARCIS (Netherlands)

Dubin, Arnaldo; Edul, Vanina Siham Kanoore; Pozo, Mario Omar; Murias, Gastón; Canullán, Carlos Manuel; Martins, Enrique Francisco; Ferrara, Gonzalo; Canales, Héctor Saul; Laporte, Mercedes; Estenssoro, Elisa; Ince, Can

2008-01-01

OBJECTIVE: To test the hypothesis that persistent villi hypoperfusion explains intramucosal acidosis after endotoxemic shock resuscitation. DESIGN: Controlled experimental study. SETTING: University-based research laboratory. SUBJECTS: A total of 14 anesthetized, mechanically ventilated sheep.

Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats

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Karina Genaro

2017-06-01

Full Text Available Background: Pain involves different brain regions and is critically determined by emotional processing. Among other areas, the rostral anterior cingulate cortex (rACC is implicated in the processing of affective pain. Drugs that interfere with the endocannabinoid system are alternatives for the management of clinical pain. Cannabidiol (CBD, a phytocannabinoid found in Cannabis sativa, has been utilized in preclinical and clinical studies for the treatment of pain. Herein, we evaluate the effects of CBD, injected either systemically or locally into the rACC, on mechanical allodynia in a postoperative pain model and on the negative reinforcement produced by relief of spontaneous incision pain. Additionally, we explored whether CBD underlies the reward of pain relief after systemic or rACC injection.Methods and Results: Male Wistar rats were submitted to a model of incision pain. All rats had mechanical allodynia, which was less intense after intraperitoneal CBD (3 and 10 mg/kg. Conditioned place preference (CPP paradigm was used to assess negative reinforcement. Intraperitoneal CBD (1 and 3 mg/kg inverted the CPP produced by peripheral nerve block even at doses that do not change mechanical allodynia. CBD (10 to 40 nmol/0.25 μL injected into the rACC reduced mechanical allodynia in a dose-dependent manner. CBD (5 nmol/0.25 μL did not change mechanical allodynia, but reduced peripheral nerve block-induced CPP, and the higher doses inverted the CPP. Additionally, CBD injected systemically or into the rACC at doses that did not change the incision pain evoked by mechanical stimulation significantly produced CPP by itself. Therefore, a non-rewarding dose of CBD in sham-incised rats becomes rewarding in incised rats, presumably because of pain relief or reduction of pain aversiveness.Conclusion: The study provides evidence that CBD influences different dimensions of the response of rats to a surgical incision, and the results establish the rACC as a

Nutrient transitions are a source of persisters in Escherichia coli biofilms.

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Stephanie M Amato

Full Text Available Chronic and recurrent infections have been attributed to persisters in biofilms, and despite this importance, the mechanisms of persister formation in biofilms remain unclear. The plethora of biofilm characteristics that could give rise to persisters, including slower growth, quorum signaling, oxidative stress, and nutrient heterogeneity, have complicated efforts to delineate formation pathways that generate persisters during biofilm development. Here we sought to specifically determine whether nutrient transitions, which are a common metabolic stress encountered within surface-attached communities, stimulate persister formation in biofilms and if so, to then identify the pathway. To accomplish this, we established an experimental methodology where nutrient availability to biofilm cells could be controlled exogenously, and then used that method to discover that diauxic carbon source transitions stimulated persister formation in Escherichia coli biofilms. Previously, we found that carbon source transitions stimulate persister formation in planktonic E. coli cultures, through a pathway that involved ppGpp and nucleoid-associated proteins, and therefore, tested the functionality of that pathway in biofilms. Biofilm persister formation was also found to be dependent on ppGpp and nucleoid-associated proteins, but the importance of specific proteins and enzymes between biofilm and planktonic lifestyles was significantly different. Data presented here support the increasingly appreciated role of ppGpp as a central mediator of bacterial persistence and demonstrate that nutrient transitions can be a source of persisters in biofilms.

Nutrient transitions are a source of persisters in Escherichia coli biofilms.

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Amato, Stephanie M; Brynildsen, Mark P

2014-01-01

Chronic and recurrent infections have been attributed to persisters in biofilms, and despite this importance, the mechanisms of persister formation in biofilms remain unclear. The plethora of biofilm characteristics that could give rise to persisters, including slower growth, quorum signaling, oxidative stress, and nutrient heterogeneity, have complicated efforts to delineate formation pathways that generate persisters during biofilm development. Here we sought to specifically determine whether nutrient transitions, which are a common metabolic stress encountered within surface-attached communities, stimulate persister formation in biofilms and if so, to then identify the pathway. To accomplish this, we established an experimental methodology where nutrient availability to biofilm cells could be controlled exogenously, and then used that method to discover that diauxic carbon source transitions stimulated persister formation in Escherichia coli biofilms. Previously, we found that carbon source transitions stimulate persister formation in planktonic E. coli cultures, through a pathway that involved ppGpp and nucleoid-associated proteins, and therefore, tested the functionality of that pathway in biofilms. Biofilm persister formation was also found to be dependent on ppGpp and nucleoid-associated proteins, but the importance of specific proteins and enzymes between biofilm and planktonic lifestyles was significantly different. Data presented here support the increasingly appreciated role of ppGpp as a central mediator of bacterial persistence and demonstrate that nutrient transitions can be a source of persisters in biofilms.

THE MOLECULAR MECHANISMS OF EPSTEINBARR VIRUS PERSISTENCE IN THE HUMAN ORGANISM

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Volyanskiy A.Yu.

2014-12-01

Full Text Available This review describes advances in molecular aspects of EBV infection and disease. We discuss the spectrum of clinical illness due to EBV persistent infection. The main characteristic of Epstein-Barr virus (EBV is that initial infection results in lifelong persistence. EBV infects nearly all humans by the time they reach adulthood. Healthy humans have approximately 1 to 50 infected cells per million leukocytes. EBV is one of the eight known human herpesviruses. EBV virions have a doublestranded linear DNA and 100 genes had been described in virus genome. Initial infection is thought to occur in the oral compartment. The host cells of EBV are mainly lymphocytes and epithelial cells. EBV attaches to B cells via binding of the viral gp350 protein to CD21 receptor. The consequence of EBV infection is cells proliferation and differentiation into memory B lymphocyte in the germinal center. Infected memory B cells are released into the peripheral circulation. EBV persists mostly in the memory B cell. Latency is the state of persistent viral infection without active viral production. In latently infected B cells EBV virus exist as episomes. During the latent phase episomal replication occurs via host DNA polymerase. Genes of the nuclear antigens (EBNA and latent membrane proteins (LMP are transcribed during latency. These include EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C, EBNA leader protein (EBNALP, LMP1 and LMP2 genes. All nuclear antigens are transcription transactivators which bind to cis-regulatory DNA elements of cell or virus genomes directly or in complex with other proteins. LMP2A and LMP1 can function to coordinately mimic B-cell receptor and CD40 coreceptor signaling in latently infected B cells. LMP proteins activate cell signaling systems and as the consequence different gene expression programs. Characterization of gene expression patterns in different cell lines and pathologic conditions has revealed that there are at least three different

[Persistent diarrhea

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Andrade, J A; Moreira, C; Fagundes Neto, U

2000-07-01

INTRODUCTION: Persistent diarrhea has high impact on infantile morbidity and mortality rates in developing countries. Several studies have shown that 3 to 20% of acute diarrheal episodes in children under 5 years of age become persistent. DEFINITION: Persistent diarrhea is defined as an episode that lasts more than 14 days. ETIOLOGY: The most important agents isolated in persistent diarrhea are: Enteropathogenic E. coli (EPEC), Salmonella, Enteroaggregative E. coli (EAEC), Klebisiella and Cryptosporidium. CLINICAL ASPECTS: In general, the clinical characteristics of patients with persistent diarrhea do not change with the pathogenic agent. Persistent diarrhea seems to represent the final result of a several insults a infant suffers that predisposes to a more severe episode of diarrhea due to a combination of host factors and high rates of enviromental contamination. Therefore, efforts should be made to promptly treat all episodes of diarrhea with apropriate follow-up. THERAPY: The aim of the treatment is to restore hydroelectrolytic deficits and to replace losses until the diarrheal ceases. It is possible in the majority of the cases, using oral rehydration therapy and erly an appropriate type of diet. PREVENTION: It is imperative that management strategies also focus on preventive aspects. The most effective diarrheal prevention strategy in young infants worldwide is promotion of exclusive breast feeding.

Impact of persistent cytomegalovirus infection on human neuroblastoma cell gene expression

International Nuclear Information System (INIS)

Hoever, Gerold; Vogel, Jens-Uwe; Lukashenko, Polina; Hofmann, Wolf-Karsten; Komor, Martina; Doerr, Hans Wilhelm; Cinatl, Jindrich

2005-01-01

In a model of human neuroblastoma (NB) cell lines persistently infected with human cytomegalovirus (HCMV) we previously showed that persistent HCMV infection is associated with an increased malignant phenotype, enhanced drug resistance, and invasive properties. To gain insights into the mechanisms of increased malignancy we analyzed the global changes in cellular gene expression induced by persistent HCMV infection of human neuroblastoma cells by use of high-density oligonucleotide microarrays (HG-U133A, Affymetrix) and RT-PCR. Comparing the gene expression of different NB cell lines with persistently infected cell sub-lines revealed 11 host cell genes regulated in a similar manner throughout all infected samples. Nine of these 11 genes may contribute to the previously observed changes in malignant phenotype of persistently HCMV infected NB cells by influencing invasive growth, apoptosis, angiogenesis, and proliferation. Thus, this work provides the basis for further functional studies

Persister formation in Staphylococcus aureus is associated with ATP depletion

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Conlon, Brian P.; Rowe, Sarah E.; Gandt, Autumn Brown; Nuxoll, Austin S.; Donegan, Niles P.; Zalis, Eliza A.; Clair, Geremy; Adkins, Joshua N.; Cheung, Ambrose L.; Lewis, Kim

2016-04-18

Persisters are dormant phenotypic variants of bacterial cells that are tolerant to killing by antibiotics1. Persisters are associated with chronic bacterial infection and antibiotic treatment failure. In Escherichia coli, toxin/antitoxin (TA) modules are responsible for persister formation. The mechanism of persister formation in Gram positive bacteria is unknown. Staphylococcus aureus is a major human pathogen, responsible for a variety of chronic and relapsing infections such as osteomyelitis, endocarditis and infections of implanted devices. Deleting TA modules in S. aureus did not affect the level of persisters. Here we show that S. aureus persisters are produced due to a stochastic entrance to stationary phase accompanied by a drop in intracellular ATP. Cells expressing stationary state markers are present throughout the growth phase, increasing in frequency with cell density. Cell sorting revealed that expression of stationary markers was associated with a 100-1000 fold increased likelihood of survival to antibiotic challenge. We find that the antibiotic tolerance of these cells is due to a drop in intracellular ATP. The ATP level of the cell is predictive of bactericidal antibiotic efficacy and explains bacterial tolerance to antibiotic treatment.

Afterglow luminescence in sol-gel/Pechini grown oxide materials: persistence or phosphorescence process? (Conference Presentation)

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Sontakke, Atul; Ferrier, Alban; Viana, Bruno

2017-03-01

Persistent luminescence and phosphorescence, both yields afterglow luminescence, but are completely different mechanisms. Persistent luminescence involves a slow thermal release of trapped electrons stored in defect states, whereas the phosphorescence is caused due to triplet to singlet transition [1,2]. Many persistent luminescence phosphors are based on oxide inorganic hosts, and exhibit long afterglow luminescence after ceasing the excitation. We observed intense and long afterglow luminescence in sol-gel/pechini grown inorganic oxides, and as a first interpretation thought to be due to persistence mechanism. However, some of these materials do not exhibit defect trap centers, and a detailed investigation suggested it is due to phosphorescence, but not the persistence. Phosphorescence is not common in inorganic solids, and that too at room temperature, and therefore usually misinterpreted as persistence luminescence [3]. Here we present a detailed methodology to distinguish phosphorescence from persistence luminescence in inorganic solids, and the process to harvest highly efficient long phosphorescence afterglow at room temperature. 1. Jian Xu, Setsuhisa Tanabe, Atul D. Sontakke, Jumpei Ueda, Appl. Phys. Lett. 107, 081903 (2015) 2. Sebastian Reineke, Marc A. Baldo, Scientific Reports, 4, 3797 (2014) 3. Pengchong Xue, Panpan Wang, Peng Chen, Boqi Yao, Peng Gong, Jiabao Sun, Zhenqi Zhang, Ran Lu, Chem. Sci. (2016) DOI: 10.1039/C5SC03739E

Zika Virus Persistently Infects and Is Basolaterally Released from Primary Human Brain Microvascular Endothelial Cells

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Megan C. Mladinich

2017-07-01

Full Text Available Zika virus (ZIKV is a mosquito-borne Flavivirus that has emerged as the cause of encephalitis and fetal microencephaly in the Americas. ZIKV uniquely persists in human bodily fluids for up to 6 months, is sexually transmitted, and traverses the placenta and the blood-brain barrier (BBB to damage neurons. Cells that support persistent ZIKV replication and mechanisms by which ZIKV establishes persistence remain enigmatic but central to ZIKV entry into protected neuronal compartments. The endothelial cell (EC lining of capillaries normally constrains transplacental transmission and forms the BBB, which selectively restricts access of blood constituents to neurons. We found that ZIKV (strain PRVABC59 persistently infects and continuously replicates in primary human brain microvascular ECs (hBMECs, without cytopathology, for >9 days and following hBMEC passage. ZIKV did not permeabilize hBMECs but was released basolaterally from polarized hBMECs, suggesting a direct mechanism for ZIKV to cross the BBB. ZIKV-infected hBMECs were rapidly resistant to alpha interferon (IFN-α and transiently induced, but failed to secrete, IFN-β and IFN-λ. Global transcriptome analysis determined that ZIKV constitutively induced IFN regulatory factor 7 (IRF7, IRF9, and IFN-stimulated genes (ISGs 1 to 9 days postinfection, despite persistently replicating in hBMECs. ZIKV constitutively induced ISG15, HERC5, and USP18, which are linked to hepatitis C virus (HCV persistence and IFN regulation, chemokine CCL5, which is associated with immunopathogenesis, as well as cell survival factors. Our results reveal that hBMECs act as a reservoir of persistent ZIKV replication, suggest routes for ZIKV to cross hBMECs into neuronal compartments, and define novel mechanisms of ZIKV persistence that can be targeted to restrict ZIKV spread.

The exploration and characterization of an orange emitting long persistent luminescence phosphor LiSr4(BO3)3:Eu2+

International Nuclear Information System (INIS)

Jin, Yahong; Hu, Yihua; Wu, Haoyi; Chen, Li; Wang, Xiaojuan

2016-01-01

An orange emitting long persistent phosphor LiSr 4 (BO 3 ) 3 :Eu 2+ was prepared successfully using a conventional solid state reaction method. The luminescent and persistent luminescence properties were studied using fluorescence spectra, decay curves, persistent luminescence spectra and thermoluminescence (TL) glow curves. The effects on the fluorescence and persistent luminescence properties by the dosage of Li 2 CO 3 were explored. The relationship between the Eu 2+ contents and persistent luminescence properties were studied. The optimal doping concentration of Eu 2+ was experimentally to be 1 mol%. The detailed processes and a possible mechanism were also discussed. - Highlights: • Li 2 CO 3 plays a critical role in producing persistent luminescence. • 40 % excess of Li 2 CO 3 makes the largest enhancement on persistent luminescence. • The optimal doping concentration of Eu 2+ was experimentally to be 1mol %. • Possible mechanism for persistent luminescence was discussed.

A proof-of-concept implementation of persistence in a hierarchical storage system

International Nuclear Information System (INIS)

Grossman, R.; Qin, Xiao; Lifka, D.

1992-01-01

The concept of providing transparent access to a collection of files in a mass storage system is a familiar one. The goal of this project was to investigate the feasibility of providing similar access to a collection of persistent, complex objects. We describe an architecture for interfacing a persistent store of complex objects to a hierarchical storage system. Persistent object stores support the uniform creation, storage, and access of complex objects, regardless of their lifetimes. In other words, a mechanism is provided so that persistent objects outlive the processes which create them and can be accessed in a uniform manner by other processes. We validated this architecture by implementing a proof-of-concept system and testing the system on two stores of data. These tests indicate that this architecture supports the creation. storage and access of very large persistent object stores

Mobility-induced persistent chimera states

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Petrungaro, Gabriela; Uriu, Koichiro; Morelli, Luis G.

2017-12-01

We study the dynamics of mobile, locally coupled identical oscillators in the presence of coupling delays. We find different kinds of chimera states in which coherent in-phase and antiphase domains coexist with incoherent domains. These chimera states are dynamic and can persist for long times for intermediate mobility values. We discuss the mechanisms leading to the formation of these chimera states in different mobility regimes. This finding could be relevant for natural and technological systems composed of mobile communicating agents.

Overview of persistent pain in older adults.

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Molton, Ivan R; Terrill, Alexandra L

2014-01-01

With the shifting age demographics of the U.S. population, more psychologists will be asked to provide clinical services to older adults. Given the high prevalence of persistent pain in aging, in many cases this will mean providing empirically supported interventions for pain and the interference it creates. The purpose of this review is to provide a broad overview of the scope and impact of persistent pain in older people and to discuss mechanisms by which persistent geriatric pain can lead to suffering and disability. We consider the unique context of pain in older adulthood and review differences between older and younger people in terms of pain perception, the social network, beliefs about pain, pain-related coping, and adherence to pain medication. Finally, we discuss special issues affecting pain management in older adults, including dementia, polypharmacy, and barriers to accessing adequate pain care. This review also highlights a need for greater provider training in pain management to meet the needs of a changing U.S. population. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Viral (hepatitis C virus, hepatitis B virus, HIV) persistence and immune homeostasis

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Zhou, Yun; Zhang, Ying; Moorman, Jonathan P; Yao, Zhi Q; Jia, Zhan S

2014-01-01

Immune homeostasis is a host characteristic that maintains biological balance within a host. Humans have evolved many host defence mechanisms that ensure the survival of individuals upon encountering a pathogenic infection, with recovery or persistence from a viral infection being determined by both viral factors and host immunity. Chronic viral infections, such as hepatitis B virus, hepatitis C virus and HIV, often result in chronic fluctuating viraemia in the face of host cellular and humoral immune responses, which are dysregulated by multi-faceted mechanisms that are incompletely understood. This review attempts to illuminate the mechanisms involved in this process, focusing on immune homeostasis in the setting of persistent viral infection from the aspects of host defence mechanism, including interferon-stimulated genes, apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3), autophagy and interactions of various immune cells, cytokines and regulatory molecules. PMID:24965611

Role of TRPM8 in dorsal root ganglion in nerve injury-induced chronic pain

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Su Lin

2011-11-01

Full Text Available Abstract Background Chronic neuropathic pain is an intractable pain with few effective treatments. Moderate cold stimulation can relieve pain, and this may be a novel train of thought for exploring new methods of analgesia. Transient receptor potential melastatin 8 (TRPM8 ion channel has been proposed to be an important molecular sensor for cold. Here we investigate the role of TRPM8 in the mechanism of chronic neuropathic pain using a rat model of chronic constriction injury (CCI to the sciatic nerve. Results Mechanical allodynia, cold and thermal hyperalgesia of CCI rats began on the 4th day following surgery and maintained at the peak during the period from the 10th to 14th day after operation. The level of TRPM8 protein in L5 dorsal root ganglion (DRG ipsilateral to nerve injury was significantly increased on the 4th day after CCI, and reached the peak on the 10th day, and remained elevated on the 14th day following CCI. This time course of the alteration of TRPM8 expression was consistent with that of CCI-induced hyperalgesic response of the operated hind paw. Besides, activation of cold receptor TRPM8 of CCI rats by intrathecal application of menthol resulted in the inhibition of mechanical allodynia and thermal hyperalgesia and the enhancement of cold hyperalgesia. In contrast, downregulation of TRPM8 protein in ipsilateral L5 DRG of CCI rats by intrathecal TRPM8 antisense oligonucleotide attenuated cold hyperalgesia, but it had no effect on CCI-induced mechanical allodynia and thermal hyperalgesia. Conclusions TRPM8 may play different roles in mechanical allodynia, cold and thermal hyperalgesia that develop after nerve injury, and it is a very promising research direction for the development of new therapies for chronic neuroapthic pain.

Predictive features of persistent activity emergence in regular spiking and intrinsic bursting model neurons.

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Kyriaki Sidiropoulou

Full Text Available Proper functioning of working memory involves the expression of stimulus-selective persistent activity in pyramidal neurons of the prefrontal cortex (PFC, which refers to neural activity that persists for seconds beyond the end of the stimulus. The mechanisms which PFC pyramidal neurons use to discriminate between preferred vs. neutral inputs at the cellular level are largely unknown. Moreover, the presence of pyramidal cell subtypes with different firing patterns, such as regular spiking and intrinsic bursting, raises the question as to what their distinct role might be in persistent firing in the PFC. Here, we use a compartmental modeling approach to search for discriminatory features in the properties of incoming stimuli to a PFC pyramidal neuron and/or its response that signal which of these stimuli will result in persistent activity emergence. Furthermore, we use our modeling approach to study cell-type specific differences in persistent activity properties, via implementing a regular spiking (RS and an intrinsic bursting (IB model neuron. We identify synaptic location within the basal dendrites as a feature of stimulus selectivity. Specifically, persistent activity-inducing stimuli consist of activated synapses that are located more distally from the soma compared to non-inducing stimuli, in both model cells. In addition, the action potential (AP latency and the first few inter-spike-intervals of the neuronal response can be used to reliably detect inducing vs. non-inducing inputs, suggesting a potential mechanism by which downstream neurons can rapidly decode the upcoming emergence of persistent activity. While the two model neurons did not differ in the coding features of persistent activity emergence, the properties of persistent activity, such as the firing pattern and the duration of temporally-restricted persistent activity were distinct. Collectively, our results pinpoint to specific features of the neuronal response to a given

A meme propagation model to combine social affirmation with meme attractiveness and persistence

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Zheng, Aiguo; Luo, Shuangling; Xia, Haoxiang

2016-06-01

The propagation of memes on online social networks often depends on the mechanism of social affirmation. Centola termed such social-affirmation-driven diffusion as complex contagion and partly validated it through an online experiment. However, for actual online meme propagation, the mechanism of social affirmation often takes effect in combination with various other factors and mechanisms. In this paper, we examine the combinatorial effects of social affirmation and the attractiveness and persistence of the meme by proposing and analyzing a UACI model, where an agent’s activities to receive and transfer a meme is associated with the transition between its four possible states of “Uninformed”, “Attended”,“Convinced” and “Immune”. The numerical simulations illustrate nontrivial patterns of propagation. Especially, it is revealed that the effects of simple and complex contagions co-exist and equilibrate in accordance with the joint functions of meme attractiveness and social affirmation. Furthermore, the low-persistence of the meme hinders the propagation-scale more remarkably on the regular network than on the random one, indicating that the persistence may be critical for retaining complex contagion.

The Inhibitory Effect of Somatostatin Receptor Activation on Bee Venom-Evoked Nociceptive Behavior and pCREB Expression in Rats

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Li Li

2014-01-01

Full Text Available The present study examined nociceptive behaviors and the expression of phosphorylated cAMP response element-binding protein (pCREB in the dorsal horn of the lumbar spinal cord and the dorsal root ganglion (DRG evoked by bee venom (BV. The effect of intraplantar preapplication of the somatostatin analog octreotide on nociceptive behaviors and pCREB expression was also examined. Subcutaneous injection of BV into the rat unilateral hindpaw pad induced significant spontaneous nociceptive behaviors, primary mechanical allodynia, primary thermal hyperalgesia, and mirror-thermal hyperalgesia, as well as an increase in pCREB expression in the lumbar spinal dorsal horn and DRG. Octreotide pretreatment significantly attenuated the BV-induced lifting/licking response and mechanical allodynia. Local injection of octreotide also significantly reduced pCREB expression in the lumbar spinal dorsal horn and DRG. Furthermore, pretreatment with cyclosomatostatin, a somatostatin receptor antagonist, reversed the octreotide-induced inhibition of the lifting/licking response, mechanical allodynia, and the expression of pCREB. These results suggest that BV can induce nociceptive responses and somatostatin receptors are involved in mediating the antinociception, which provides new evidence for peripheral analgesic action of somatostatin in an inflammatory pain state.

Preventive Effects of Bee Venom Derived Phospholipase A₂ on Oxaliplatin-Induced Neuropathic Pain in Mice.

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Li, Dongxing; Kim, Woojin; Shin, Dasom; Jung, Yongjae; Bae, Hyunsu; Kim, Sun Kwang

2016-01-19

Oxaliplatin, a chemotherapy drug used to treat colorectal cancer, induces specific sensory neurotoxicity signs that are aggravated by cold and mechanical stimuli. Here we examined the preventive effects of Bee Venom (BV) derived phospholipase A₂ (bvPLA₂) on oxaliplatin-induced neuropathic pain in mice and its immunological mechanism. The cold and mechanical allodynia signs were evaluated by acetone and von Frey hair test on the hind paw, respectively. The most significant allodynia signs were observed at three days after an injection of oxaliplatin (6 mg/kg, i.p.) and then decreased gradually to a normal level on days 7-9. The oxaliplatin injection also induced infiltration of macrophages and upregulated levels of the pro-inflammatory cytokine interleukin (IL)-1β in the lumbar dorsal root ganglia (DRG). Daily treatment with bvPLA₂ (0.2 mg/kg, i.p.) for five consecutive days prior to the oxaliplatin injection markedly inhibited the development of cold and mechanical allodynia, and suppressed infiltration of macrophages and the increase of IL-1β level in the DRG. Such preventive effects of bvPLA₂ were completely blocked by depleting regulatory T cells (Tregs) with CD25 antibody pre-treatments. These results suggest that bvPLA₂ may prevent oxaliplatin-induced neuropathic pain by suppressing immune responses in the DRG by Tregs.

Viral Interference and Persistence in Mosquito-Borne Flaviviruses

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Juan Santiago Salas-Benito

2015-01-01

Full Text Available Mosquito-borne flaviviruses are important pathogens for humans, and the detection of two or more flaviviruses cocirculating in the same geographic area has often been reported. However, the epidemiological impact remains to be determined. Mosquito-borne flaviviruses are primarily transmitted through Aedes and Culex mosquitoes; these viruses establish a life-long or persistent infection without apparent pathological effects. This establishment requires a balance between virus replication and the antiviral host response. Viral interference is a phenomenon whereby one virus inhibits the replication of other viruses, and this condition is frequently associated with persistent infections. Viral interference and persistent infection are determined by several factors, such as defective interfering particles, competition for cellular factors required for translation/replication, and the host antiviral response. The interaction between two flaviviruses typically results in viral interference, indicating that these viruses share common features during the replicative cycle in the vector. The potential mechanisms involved in these processes are reviewed here.

Does stress remove the HDAC brakes for the formation and persistence of long-term memory?

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White, André O.; Wood, Marcelo A.

2013-01-01

It has been known for numerous decades that gene expression is required for long-lasting forms of memory. In the past decade, the study of epigenetic mechanisms in memory processes has revealed yet another layer of complexity in the regulation of gene expression. Epigenetic mechanisms do not only provide complexity in the protein regulatory complexes that control coordinate transcription for specific cell function, but the epigenome encodes critical information that integrates experience and cellular history for specific cell functions as well. Thus, epigenetic mechanisms provide a unique mechanism of gene expression regulation for memory processes. This may be why critical negative regulators of gene expression, such as histone deacetylases (HDACs), have powerful effects on the formation and persistence of memory. For example, HDAC inhibition has been shown to transform a subthreshold learning event into robust long-term memory and also generate a form of long-term memory that persists beyond the point at which normal long-term memory fails. A key question that is explored in this review, from a learning and memory perspective, is whether stress-dependent signaling drives the formation and persistence of long-term memory via HDAC-dependent mechanisms. PMID:24149059

MiR-19a targets suppressor of cytokine signaling 1 to modulate the progression of neuropathic pain.

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Wang, Conghui; Jiang, Qi; Wang, Min; Li, Dong

2015-01-01

We aimed to investigate whether miR-19a is associated with neuropathic pain and elucidate the underlying regulatory mechanism. We established a neuropathic pain model of bilateral chronic constriction injury (bCCI). Then bCCI rats were injected with mo-miR-19a, siR-SOCS1 or blank expression vector through a microinjection syringe via an intrathecal catheter on 3 day before surgery and after surgery. Behavioral tests, such as mechanical allodynia, thermal hyperalgesia and acetone induced cold allodynia, were performed to evaluate the pain threshold. Besides, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine the expression of miR-19a and western blotting was carried out to measure the expression of SOCS1. miR-19a expression levels were markedly increased in neuropathic pain models. Moreover, miR-19a significantly attenuated mechanical allodynia and thermal hyperalgesia, and similar results were obtained after knockdown of SOCS1 expression. However, miR-19a markedly increased the times that the rats appeared a sign of cold allodynia, and knockdown of SOCS1 expression had similar effects. Besides, the results of bioinformatics analysis and western blotting analysis were all confirmed that SOCS1 was a direct target of miR-19a in neuropathic pain models. Our finding indicate that SOCS1 is a direct target of miR-19a in neuropathic pain rats and miR-19a may play a critical role in regulating of neuropathic pain via targeting SOCS1.

BXD recombinant inbred strains participate in social preference, anxiety and depression behaviors along sex-differences in cytokines and tactile allodynia.

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López-Granero, Caridad; Antunes Dos Santos, Alessandra; Ferrer, Beatriz; Culbreth, Megan; Chakraborty, Sudipta; Barrasa, Angel; Gulinello, Maria; Bowman, Aaron B; Aschner, Michael

2017-06-01

Depression and anxiety are the most common psychiatric disorders, representing a major public health concern. Dysregulation of oxidative and inflammatory systems may be associated with psychiatric disorders, such as depression and anxiety. Due to the need to find appropriate animal models to the understanding of such disorders, we queried whether 2 BXD recombinant inbred (RI) mice strains (BXD21/TyJ RI and BXD84/RwwJ RI mice) and C57BL/6 wild-type mice show differential performance in depression and anxiety related behaviors and biomarkers. Specifically, we assessed social preference, elevated plus maze, forced swim, and Von Frey tests at 3-4 months-of-age, as well as activation of cytokines and antioxidant mRNA levels in the cortex at 7 months-of-age. We report that (1) the BXD84/RwwJ RI strain exhibits anxiety disorder and social avoidance-like behavior (2) BXD21/TyJ RI strain shows a resistance to depression illness, and (3) sex-dependent cytokine profiles and allodynia with elevated inflammatory activity were inherent to male BXD21/TyJ RI mice. In conclusion, we provide novel data in favor of the use of BXD recombinant inbred mice to further understand anxiety and depression disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Botulinum toxin type A for cephalic cutaneous allodynia in chronic migraine: a randomized, double-blinded, placebo-controlled trial

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Luciano Hollanda

2014-12-01

Full Text Available Cephalic allodynia (CA can be observed in 50-70% of patients with chronic migraine (CM. The aim of this trial was to assess the efficacy of botulinum toxin type A (Botx-A in the treatment of CA associated with CM. In this placebo-controlled trial, patients were randomized either into Botx-A or 0.9% saline injections and efficacy measures were assessed every 4 weeks for 3 months. Efficacy endpoints were number of migraine episodes associated with CA, changes from baseline in visual analogical scale scores for pain (VAS and frequency of common analgesics use for migraine. A total of 38 subjects were randomized to saline (n=18 or Botx-A (n=20. There were no significant differences in baseline between active intervention or placebo groups regarding mean age, number of headache episodes [mean 12.1 (9.22 and 17.00 (9.69 respectively; P=0.12], pain severity as measured by the VAS or frequency of analgesic use for headache episodes. Efficacy analysis showed that Botx-A injections led to an important decrease from baseline in the mean migraine episodes associated with CA after 12 weeks (5.20 versus 11.17; P=0.01. Also, VAS scores and frequency of analgesics use for headache were significantly reduced in the Botx-A group. This study suggests that Botx-A injections are superior to saline in the treatment of CA associated with CM, with mild self limited side effects.

Screening for pain-persistence and pain-avoidance patterns in fibromyalgia.

NARCIS (Netherlands)

Koulil, S. van; Kraaimaat, F.W.; Lankveld, W.G.J.M. van; Helmond, T. van; Vedder, A.; Hoorn, H. van; Cats, H.; Riel, P.L.C.M. van; Evers, A.W.M.

2008-01-01

BACKGROUND: The heterogeneity of patients regarding pain-related cognitive-behavioral mechanisms, such as pain-avoidance and pain-persistence patterns, has been proposed to underlie varying treatment outcomes in patients with fibromyalgia (FM). PURPOSE: To investigate the validity of a screening

TRPV1 and the MCP-1/CCR2 Axis Modulate Post-UTI Chronic Pain.

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Rosen, John M; Yaggie, Ryan E; Woida, Patrick J; Miller, Richard J; Schaeffer, Anthony J; Klumpp, David J

2018-05-08

The etiology of chronic pelvic pain syndromes remains unknown. In a murine urinary tract infection (UTI) model, lipopolysaccharide of uropathogenic E. coli and its receptor TLR4 are required for post-UTI chronic pain development. However, downstream mechanisms of post-UTI chronic pelvic pain remain unclear. Because the TRPV1 and MCP-1/CCR2 pathways are implicated in chronic neuropathic pain, we explored their role in post-UTI chronic pain. Mice were infected with the E. coli strain SΦ874, known to produce chronic allodynia, and treated with the TRPV1 antagonist capsazepine. Mice treated with capsazepine at the time of SΦ874 infection failed to develop chronic allodynia, whereas capsazepine treatment of mice at two weeks following SΦ874 infection did not reduce chronic allodynia. TRPV1-deficient mice did not develop chronic allodynia either. Similar results were found using novelty-suppressed feeding (NSF) to assess depressive behavior associated with neuropathic pain. Imaging of reporter mice also revealed induction of MCP-1 and CCR2 expression in sacral dorsal root ganglia following SΦ874 infection. Treatment with a CCR2 receptor antagonist at two weeks post-infection reduced chronic allodynia. Taken together, these results suggest that TRPV1 has a role in the establishment of post-UTI chronic pain, and CCR2 has a role in maintenance of post-UTI chronic pain.

Persistência inflacionária e curva de Phillips novo-keynesiana para o Brasil

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Fernando de Aquino Fonseca Neto

2010-06-01

Full Text Available Inflation persistence and new Keynesian Phillips curves for Brazil. In this paper is shown that sustainable inflation persistence has theoretical support not only due price indexation, but also because of micro-foundations based on assumptions of Simon's bounded rationality and because of persistent mark-up shocks. the new keynesian phillips curve, estimated for brazil for the period 2000/2008, and the partial coefficients of determination for moving sub-periods of 36 months identifies inflation persistence as the main determinant of inflation, with the capacity gap presenting larger importance only in the end of the sample period. Inflation persistence requires harder monetary policy when neither accommodation is acceptable nor complementary policies in order to reduce it, such as the minimization of indexation mechanisms and control of the market power, are adopted.

Persistence of uranium groundwater plumes: Contrasting mechanisms at two DOE sites in the groundwater-river interaction zone

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Zachara, John M.; Long, Philip E.; Bargar, John; Davis, James A.; Fox, Patricia; Fredrickson, Jim K.; Freshley, Mark D.; Konopka, Allan E.; Liu, Chongxuan; McKinley, James P.; Rockhold, Mark L.; Williams, Kenneth H.; Yabusaki, Steve B.

2013-04-01

We examine subsurface uranium (U) plumes at two U.S. Department of Energy sites that are located near large river systems and are influenced by groundwater-river hydrologic interaction. Following surface excavation of contaminated materials, both sites were projected to naturally flush remnant uranium contamination to levels below regulatory limits (e.g., 30 μg/L or 0.126 μmol/L; U.S. EPA drinking water standard), with 10 years projected for the Hanford 300 Area (Columbia River) and 12 years for the Rifle site (Colorado River). The rate of observed uranium decrease was much lower than expected at both sites. While uncertainty remains, a comparison of current understanding suggests that the two sites have common, but also different mechanisms controlling plume persistence. At the Hanford 300 A, the persistent source is adsorbed U(VI) in the vadose zone that is released to the aquifer during spring water table excursions. The release of U(VI) from the vadose zone and its transport within the oxic, coarse-textured aquifer sediments is dominated by kinetically-limited surface complexation. Modeling implies that annual plume discharge volumes to the Columbia River are small (oxidation of naturally reduced, contaminant U(IV) in the saturated zone and a continuous influx of U(VI) from natural, up-gradient sources influence plume persistence. Rate-limited mass transfer and surface complexation also control U(VI) migration velocity in the sub-oxic Rifle groundwater. Flux of U(VI) from the vadose zone at the Rifle site may be locally important, but it is not the dominant process that sustains the plume. A wide range in microbiologic functional diversity exists at both sites. Strains of Geobacter and other metal reducing bacteria are present at low natural abundance that are capable of enzymatic U(VI) reduction in localized zones of accumulated detrital organic carbon or after organic carbon amendment. Major differences between the sites include the geochemical nature of

Does stress remove the HDAC brakes for the formation and persistence of long-term memory?

Science.gov (United States)

White, André O; Wood, Marcelo A

2014-07-01

It has been known for numerous decades that gene expression is required for long-lasting forms of memory. In the past decade, the study of epigenetic mechanisms in memory processes has revealed yet another layer of complexity in the regulation of gene expression. Epigenetic mechanisms do not only provide complexity in the protein regulatory complexes that control coordinate transcription for specific cell function, but the epigenome encodes critical information that integrates experience and cellular history for specific cell functions as well. Thus, epigenetic mechanisms provide a unique mechanism of gene expression regulation for memory processes. This may be why critical negative regulators of gene expression, such as histone deacetylases (HDACs), have powerful effects on the formation and persistence of memory. For example, HDAC inhibition has been shown to transform a subthreshold learning event into robust long-term memory and also generate a form of long-term memory that persists beyond the point at which normal long-term memory fails. A key question that is explored in this review, from a learning and memory perspective, is whether stress-dependent signaling drives the formation and persistence of long-term memory via HDAC-dependent mechanisms. Copyright © 2013 Elsevier Inc. All rights reserved.

Persistence motives in irrational decisions to complete a boring task.

Science.gov (United States)

Halkjelsvik, Torleif; Rise, Jostein

2015-01-01

We explored a novel task paradigm where participants from the online work marketplace Amazon Mechanical Turk were given the choice to quit or continue an unfinished boring task for identical economic rewards. In Studies 1a and 1b, about half the participants chose to continue (corresponding to an average of 55 and 35 cents in foregone earnings). Participants' self-reported reasons for continuing involved various types of persistence motives, reflecting a desire to persist or complete per se. Studies 2, 3a, 3b, and 3c ruled out the possibility that people continued because they enjoyed the task or believed there were additional rewards for continuing. Study 4 showed that the choice to quit/continue was associated with the manner in which the choice was presented (persistence test vs. decision-making test) and individual differences in dispositional persistence motives. The present data indicate that motivational forces independent of the focal reward may affect intertemporal decisions. © 2014 by the Society for Personality and Social Psychology, Inc.

Persistent organic pollutants alter DNA methylation during human adipocyte differentiation

NARCIS (Netherlands)

Dungen, van den Myrthe W.; Murk, Albertinka J.; Gils-Kok, van Dieuwertje; Steegenga, Wilma T.

2017-01-01

Ubiquitous persistent organic pollutants (POPs) can accumulate in humans where they might influence differentiation of adipocytes. The aim of this study was to investigate whether DNA methylation is one of the underlying mechanisms by which POPs affect adipocyte differentiation, and to what

The energetic and chemical signatures of persistent soil organic matter

DEFF Research Database (Denmark)

Barré, Pierre; Plante, Alain F.; Cecillon, Lauric

2016-01-01

A large fraction of soil organic matter (OM) resists decomposition over decades to centuries as indicated by long radiocarbon residence times, but the mechanisms responsible for the long-term (multi-decadal) persistence are debated. The current lack of mechanistic understanding limits our ability...

Information persistence using XML database technology

Science.gov (United States)

Clark, Thomas A.; Lipa, Brian E. G.; Macera, Anthony R.; Staskevich, Gennady R.

2005-05-01

The Joint Battlespace Infosphere (JBI) Information Management (IM) services provide information exchange and persistence capabilities that support tailored, dynamic, and timely access to required information, enabling near real-time planning, control, and execution for DoD decision making. JBI IM services will be built on a substrate of network centric core enterprise services and when transitioned, will establish an interoperable information space that aggregates, integrates, fuses, and intelligently disseminates relevant information to support effective warfighter business processes. This virtual information space provides individual users with information tailored to their specific functional responsibilities and provides a highly tailored repository of, or access to, information that is designed to support a specific Community of Interest (COI), geographic area or mission. Critical to effective operation of JBI IM services is the implementation of repositories, where data, represented as information, is represented and persisted for quick and easy retrieval. This paper will address information representation, persistence and retrieval using existing database technologies to manage structured data in Extensible Markup Language (XML) format as well as unstructured data in an IM services-oriented environment. Three basic categories of database technologies will be compared and contrasted: Relational, XML-Enabled, and Native XML. These technologies have diverse properties such as maturity, performance, query language specifications, indexing, and retrieval methods. We will describe our application of these evolving technologies within the context of a JBI Reference Implementation (RI) by providing some hopefully insightful anecdotes and lessons learned along the way. This paper will also outline future directions, promising technologies and emerging COTS products that can offer more powerful information management representations, better persistence mechanisms and

Dynamics of West Nile virus persistence in House Sparrows (Passer domesticus.

Directory of Open Access Journals (Sweden)

Sarah S Wheeler

Full Text Available West Nile Virus (WNV is now endemic throughout North America, with annual recurrence dependent upon successful overwintering when cold temperatures drive mosquito vectors into inactivity and halt transmission. To investigate whether avian hosts may serve as an overwintering mechanism, groups of eight to ten House Sparrows were experimentally infected with a WN02 genotype of WNV and then held until necropsy at 3, 5, 7, 9, 12, 15, or 18 weeks post-infection (pi when they were assessed for the presence of persistent infection. Blood was collected from all remaining birds every two weeks pi, and sera tested for WNV RNA and WNV neutralizing antibodies. West Nile virus RNA was present in the sera of some birds up to 7 weeks pi and all birds retained neutralizing antibodies throughout the experiment. The detection of persistently infected birds decreased with time, from 100% (n = 13 positive at 3 weeks post-infection (pi to 12.5% (n = 8 at 18 weeks pi. Infectious virus was isolated from the spleens of birds necropsied at 3, 5, 7 and 12 weeks pi. The current study confirmed previous reports of infectious WNV persistence in avian hosts, and further characterized the temporal nature of these infections. Although these persistent infections supported the hypothesis that infected birds may serve as an overwintering mechanism, mosquito-infectious recrudescent viremias have yet to be demonstrated thereby providing proof of principle.

Activated ClpP kills persisters and eradicates a chronic biofilm infection.

Energy Technology Data Exchange (ETDEWEB)

Conlon, Brian P.; Nakayasu, Ernesto S.; Fleck, Laura E.; LaFleur, Michael D.; Isabella, Vincent M.; Coleman, K.; Leonard, Steve N.; Smith, Richard D.; Adkins, Joshua N.; Lewis, Kim

2013-11-21

The current antibiotic crisis stems from two distinct phenomena-drug resistance, and drug tolerance. Resistance mechanisms such as drug efflux or modification prevent antibiotics from binding to their targets 1, allowing pathogens to grow. Antibiotic tolerance is the property of persister cells, phenotypic variants of regular bacteria 2. Antibiotics kill by corrupting targets, but these are inactive in dormant persisters, leading to tolerance. Persisters were first identified by Joseph Bigger in 1944, when he discovered a surviving sub-population of Staphylococcus following treatment with penicillin3. Persisters are largely responsible for recalcitrance of chronic diseases such as tuberculosis, and various infections associated with biofilms - endocarditis, osteomyelitis, infections of catheters and indwelling devices, and deep-seated infections of soft tissues 4. There are a number of redundant pathways involved in persister formation5,6 precluding development of drugs inhibiting their formation. The acyldepsipeptide antibiotic (ADEP 4) has been shown to activate the ClpP protease resulting in death of growing cells 7. Here we show that ADEP4 activated ClpP becomes a fairly non-specific protease and kills persister cells by degradation of over 400 intracellular targets. clpP mutants are resistant to ADEP4 7, but we find that they display increased susceptibility to killing by a range of conventional antibiotics. Combining ADEP4 with rifampicin leads to eradication of persisters, stationary and biofilm populations of Staphylococcus aureus in vitro and in a deep-seated murine infection. Target corruption/activation provides an approach to killing persisters and eradicating chronic infections.

Involvement of TRPM2 in a wide range of inflammatory and neuropathic pain mouse models

Directory of Open Access Journals (Sweden)

Kanako So

2015-03-01

Full Text Available Recent evidence suggests a role of transient receptor potential melastatin 2 (TRPM2 in immune and inflammatory responses. We previously reported that TRPM2 deficiency attenuated inflammatory and neuropathic pain in some pain mouse models, including formalin- or carrageenan-induced inflammatory pain, and peripheral nerve injury-induced neuropathic pain models, while it had no effect on the basal mechanical and thermal nociceptive sensitivities. In this study, we further explored the involvement of TRPM2 in various pain models using TRPM2-knockout mice. There were no differences in the chemonociceptive behaviors evoked by intraplantar injection of capsaicin or hydrogen peroxide between wildtype and TRPM2-knockout mice, while acetic acid-induced writhing behavior was significantly attenuated in TRPM2-knockout mice. In the postoperative incisional pain model, no difference in mechanical allodynia was observed between the two genotypes. By contrast, mechanical allodynia in the monosodium iodoacetate-induced osteoarthritis pain model and the experimental autoimmune encephalomyelitis model were significantly attenuated in TRPM2-knockout mice. Furthermore, mechanical allodynia in paclitaxel-induced peripheral neuropathy and streptozotocin-induced painful diabetic neuropathy models were significantly attenuated in TRPM2-knockout mice. Taken together, these results suggest that TRPM2 plays roles in a wide range of pathological pain models based on peripheral and central neuroinflammation, rather than physiological nociceptive pain.

Molecular Hydrogen Attenuates Neuropathic Pain in Mice

Science.gov (United States)

Kawaguchi, Masanori; Satoh, Yasushi; Otsubo, Yukiko; Kazama, Tomiei

2014-01-01

Neuropathic pain remains intractable and the development of new therapeutic strategies are urgently required. Accumulating evidence indicates that overproduction of oxidative stress is a key event in the pathogenesis of neuropathic pain. However, repeated intra-peritoneal or intrathecal injections of antioxidants are unsuitable for continuous use in therapy. Here we show a novel therapeutic method against neuropathic pain: drinking water containing molecular hydrogen (H2) as antioxidant. The effect of hydrogen on neuropathic pain was investigated using a partial sciatic nerve ligation model in mice. As indicators of neuropathic pain, temporal aspects of mechanical allodynia and thermal hyperalgesia were analysed for 3 weeks after ligation. Mechanical allodynia and thermal hyperalgesia were measured using the von Frey test and the plantar test, respectively. When mice were allowed to drink water containing hydrogen at a saturated level ad libitum after ligation, both allodynia and hyperalgesia were alleviated. These symptoms were also alleviated when hydrogen was administered only for the induction phase (from day 0 to 4 after ligation). When hydrogen was administered only for the maintenance phase (from day 4 to 21 after ligation), hyperalgesia but not allodynia was alleviated. Immunohistochemical staining for the oxidative stress marker, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine, showed that hydrogen administration suppressed oxidative stress induced by ligation in the spinal cord and the dorsal root ganglion. In conclusion, oral administration of hydrogen water may be useful for alleviating neuropathic pain in a clinical setting. PMID:24941001

Security Evaluation of the Cyber Networks under Advanced Persistent Threats

NARCIS (Netherlands)

Yang, L.; Li, Pengdeng; Yang, Xiaofan; Tang, Yuan Yan

2017-01-01

Advanced persistent threats (APTs) pose a grave threat to cyberspace, because they deactivate all the conventional cyber defense mechanisms. This paper addresses the issue of evaluating the security of the cyber networks under APTs. For this purpose, a dynamic model capturing the APT-based

Persistence of Caliciviruses in Artificially Contaminated Oysters during Depuration▿

OpenAIRE

Ueki, You; Shoji, Mika; Suto, Atsushi; Tanabe, Toru; Okimura, Yoko; Kikuchi, Yoshihiko; Saito, Noriyuki; Sano, Daisuke; Omura, Tatsuo

2007-01-01

The fate of calicivirus in oysters in a 10-day depuration was assessed. The norovirus gene was persistently detected from artificially contaminated oysters during the depuration, whereas feline calicivirus in oysters was promptly eliminated. The prolonged observation of norovirus in oysters implies the existence of a selective retention mechanism for norovirus within oysters.

Grip strength in mice with joint inflammation: A rheumatology function test sensitive to pain and analgesia.

Science.gov (United States)

Montilla-García, Ángeles; Tejada, Miguel Á; Perazzoli, Gloria; Entrena, José M; Portillo-Salido, Enrique; Fernández-Segura, Eduardo; Cañizares, Francisco J; Cobos, Enrique J

2017-10-01

Grip strength deficit is a measure of pain-induced functional disability in rheumatic disease. We tested whether this parameter and tactile allodynia, the standard pain measure in preclinical studies, show parallels in their response to analgesics and basic mechanisms. Mice with periarticular injections of complete Freund's adjuvant (CFA) in the ankles showed periarticular immune infiltration and synovial membrane alterations, together with pronounced grip strength deficits and tactile allodynia measured with von Frey hairs. However, inflammation-induced tactile allodynia lasted longer than grip strength alterations, and therefore did not drive the functional deficits. Oral administration of the opioid drugs oxycodone (1-8 mg/kg) and tramadol (10-80 mg/kg) induced a better recovery of grip strength than acetaminophen (40-320 mg/kg) or the nonsteroidal antiinflammatory drugs ibuprofen (10-80 mg/kg) or celecoxib (40-160 mg/kg); these results are consistent with their analgesic efficacy in humans. Functional impairment was generally a more sensitive indicator of drug-induced analgesia than tactile allodynia, as drug doses that attenuated grip strength deficits showed little or no effect on von Frey thresholds. Finally, ruthenium red (a nonselective TRP antagonist) or the in vivo ablation of TRPV1-expressing neurons with resiniferatoxin abolished tactile allodynia without altering grip strength deficits, indicating that the neurobiology of tactile allodynia and grip strength deficits differ. In conclusion, grip strength deficits are due to a distinct type of pain that reflects an important aspect of the human pain experience, and therefore merits further exploration in preclinical studies to improve the translation of new analgesics from bench to bedside. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Positive emotions from social company in women with persisting subclinical psychosis: lessons from daily life.

Science.gov (United States)

Collip, D; Wigman, J T W; van Os, J; Oorschot, M; Jacobs, N; Derom, C; Thiery, E; Peeters, F; Wichers, M; Myin-Germeys, I

2014-03-01

Altered social reward functioning is associated with psychosis irrespective of stage and severity. Examining the role of social reward functioning prospectively in relation to psychotic experiences before these become persistent and potentially disabling can aid in elucidating social mechanisms that induce shifts toward more severe psychotic states, without the confounding effects of clinical disorder. In a longitudinal general population sample (N = 566), the experience sampling method (repetitive random sampling of momentary emotions and social context) was used to assess daily life social functioning at baseline. Persistence of subclinical psychotic experiences was based on the Community Assessment of Psychic Experiences assessed three times over 14 months. Analyses examined to what degree i) social context and ii) appreciation thereof differentiated between those who did and did not develop persistent psychotic experiences. Although individuals with persistent psychotic experiences did not differ in overall level of positive effect, the amount of time spent alone or the level of social satisfaction compared to individuals without persistent psychotic experiences, they were more sensitive to the rewarding effects of social company. Alterations in social reward experience may form one of the mechanisms that precede the development of the extended psychosis phenotype over time. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Asymptomatic bacteriuria Escherichia coli are live biotherapeutics for UTI.

Science.gov (United States)

Rudick, Charles N; Taylor, Aisha K; Yaggie, Ryan E; Schaeffer, Anthony J; Klumpp, David J

2014-01-01

Urinary tract infections (UTI) account for approximately 8 million clinic visits annually with symptoms that include acute pelvic pain, dysuria, and irritative voiding. Empiric UTI management with antimicrobials is complicated by increasing antimicrobial resistance among uropathogens, but live biotherapeutics products (LBPs), such as asymptomatic bacteriuria (ASB) strains of E. coli, offer the potential to circumvent antimicrobial resistance. Here we evaluated ASB E. coli as LBPs, relative to ciprofloxacin, for efficacy against infection and visceral pain in a murine UTI model. Visceral pain was quantified as tactile allodynia of the pelvic region in response to mechanical stimulation with von Frey filaments. Whereas ciprofloxacin promoted clearance of uropathogenic E. coli (UPEC), it did not reduce pelvic tactile allodynia, a measure of visceral pain. In contrast, ASB E. coli administered intravesically or intravaginally provided comparable reduction of allodynia similar to intravesical lidocaine. Moreover, ASB E. coli were similarly effective against UTI allodynia induced by Proteus mirabilis, Enterococccus faecalis and Klebsiella pneumoniae. Therefore, ASB E. coli have anti-infective activity comparable to the current standard of care yet also provide superior analgesia. These studies suggest that ASB E. coli represent novel LBPs for UTI symptoms.

Penguin colonies as secondary sources of contamination with persistent organic pollutants

NARCIS (Netherlands)

Roosens, L.; Brink, van den N.W.; Riddle, M.; Blust, R.; Neels, H.; Covaci, A.

2007-01-01

Although long-range atmospheric transport has been described as the predominant mechanism for exposing polar regions to persistent organic pollutants (POPs), recent studies have suggested that bird activity can also contribute substantially to contaminant levels in some environments. However,

Decreased Cerebellar-Orbitofrontal Connectivity Correlates with Stuttering Severity: Whole-Brain Functional and Structural Connectivity Associations with Persistent Developmental Stuttering

OpenAIRE

Sitek, Kevin R.; Cai, Shanqing; Beal, Deryk S.; Perkell, Joseph S.; Guenther, Frank H.; Ghosh, Satrajit S.

2016-01-01

Persistent developmental stuttering is characterized by speech production disfluency and affects 1% of adults. The degree of impairment varies widely across individuals and the neural mechanisms underlying the disorder and this variability remain poorly understood. Here we elucidate compensatory mechanisms related to this variability in impairment using whole-brain functional and white matter connectivity analyses in persistent developmental stuttering. We found that people who stutter had st...

Decreased cerebellar-orbitofrontal connectivity correlates with stuttering severity: Whole-brain functional and structural connectivity associations with persistent developmental stuttering

OpenAIRE

Kevin Richard Sitek; Kevin Richard Sitek; Shanqing eCai; Shanqing eCai; Deryk Scott Beal; Deryk Scott Beal; Deryk Scott Beal; Deryk Scott Beal; Deryk Scott Beal; Joseph S Perkell; Joseph S Perkell; Frank eGuenther; Satrajit S Ghosh; Satrajit S Ghosh

2016-01-01

Persistent developmental stuttering is characterized by speech production disfluency and affects 1% of adults. The degree of impairment varies widely across individuals and the neural mechanisms underlying the disorder and this variability remain poorly understood. Here, we elucidate compensatory mechanisms related to this variability in impairment using whole-brain functional and white matter connectivity analyses in persistent developmental stuttering. We found that people who stutter had ...

Numeric invariants from multidimensional persistence

Energy Technology Data Exchange (ETDEWEB)

Skryzalin, Jacek [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Carlsson, Gunnar [Stanford Univ., Stanford, CA (United States)

2017-05-19

In this paper, we analyze the space of multidimensional persistence modules from the perspectives of algebraic geometry. We first build a moduli space of a certain subclass of easily analyzed multidimensional persistence modules, which we construct specifically to capture much of the information which can be gained by using multidimensional persistence over one-dimensional persistence. We argue that the global sections of this space provide interesting numeric invariants when evaluated against our subclass of multidimensional persistence modules. Lastly, we extend these global sections to the space of all multidimensional persistence modules and discuss how the resulting numeric invariants might be used to study data.

Persistent Aerial Tracking

KAUST Repository

Mueller, Matthias

2016-01-01

persistent, robust and autonomous object tracking system for unmanned aerial vehicles (UAVs) called Persistent Aerial Tracking (PAT). A computer vision and control strategy is applied to a diverse set of moving objects (e.g. humans, animals, cars, boats, etc

Postnatal persistent infection with classical Swine Fever virus and its immunological implications.

Directory of Open Access Journals (Sweden)

Sara Muñoz-González

might go unnoticed. In addition to the epidemiological and economic significance of persistent CSFV infection, this model could be useful for understanding the mechanisms of viral persistence.

Persistently obese youth: interactions between parenting styles and feeding practices with child temperament.

Science.gov (United States)

Boles, Richard E; Reiter-Purtill, Jennifer; Zeller, Meg H

2013-12-01

To assess the interaction of parent and child characteristics with feeding practices and mealtime functioning. Longitudinal, predictive study comparing baseline characteristics with follow-up assessments. The caregivers of 52 persistently obese youth and 32 nonoverweight comparison youth completed measurements of child temperament, parental feeding practices, parenting styles, and interactions during mealtimes. Adolescents with persistent obesity were significantly more likely to be parented using problematic feeding practices when parents also reported difficult child temperaments. Additionally, adolescents with persistent obesity and difficult temperaments were significantly more likely to have lower levels of positive mealtime interactions. Persistently obese youth are at increased risk for problematic parental feeding practices and mealtime functioning, particularly when youth are described as having difficult temperaments. These results indicate that further investigations are needed to better understand the mechanisms linking parent and child characteristics with health-related behaviors for adolescents with obesity.

Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli.

Directory of Open Access Journals (Sweden)

Tobias Dörr

2010-02-01

Full Text Available Bacteria induce stress responses that protect the cell from lethal factors such as DNA-damaging agents. Bacterial populations also form persisters, dormant cells that are highly tolerant to antibiotics and play an important role in recalcitrance of biofilm infections. Stress response and dormancy appear to represent alternative strategies of cell survival. The mechanism of persister formation is unknown, but isolated persisters show increased levels of toxin/antitoxin (TA transcripts. We have found previously that one or more components of the SOS response induce persister formation after exposure to a DNA-damaging antibiotic. The SOS response induces several TA genes in Escherichia coli. Here, we show that a knockout of a particular SOS-TA locus, tisAB/istR, had a sharply decreased level of persisters tolerant to ciprofloxacin, an antibiotic that causes DNA damage. Step-wise administration of ciprofloxacin induced persister formation in a tisAB-dependent manner, and cells producing TisB toxin were tolerant to multiple antibiotics. TisB is a membrane peptide that was shown to decrease proton motive force and ATP levels, consistent with its role in forming dormant cells. These results suggest that a DNA damage-induced toxin controls production of multidrug tolerant cells and thus provide a model of persister formation.

Persistent angina

DEFF Research Database (Denmark)

Jespersen, L.; Abildstrom, S. Z.; Hvelplund, Anders

2013-01-01

To evaluate persistent angina in stable angina pectoris with no obstructive coronary artery disease (CAD) compared to obstructive CAD and its relation to long-term anxiety, depression, quality of life (QOL), and physical functioning. We invited 357 patients (men = 191; women = 166; response rate 83......-obstructive CAD or normal coronary arteries than in patients with obstructive CAD. Persistent angina symptoms were associated with long-term anxiety, depression, impaired physical functioning, and QOL irrespective of the degree of CAD. Contrary to common perception, excluding obstructive CAD in stable angina does...... %) with no prior cardiovascular disease who had a first-time coronary angiography (CAG) in 2008-2009 due to suspected stable angina to participate in a questionnaire survey in 2011 with the Seattle Angina Questionnaire and the Hospital Anxiety and Depression Scale as key elements. Long-term persistent angina (i...

Persistence of uranium groundwater plumes: contrasting mechanisms at two DOE sites in the groundwater-river interaction zone.

Science.gov (United States)

Zachara, John M; Long, Philip E; Bargar, John; Davis, James A; Fox, Patricia; Fredrickson, Jim K; Freshley, Mark D; Konopka, Allan E; Liu, Chongxuan; McKinley, James P; Rockhold, Mark L; Williams, Kenneth H; Yabusaki, Steve B

2013-04-01

We examine subsurface uranium (U) plumes at two U.S. Department of Energy sites that are located near large river systems and are influenced by groundwater-river hydrologic interaction. Following surface excavation of contaminated materials, both sites were projected to naturally flush remnant uranium contamination to levels below regulatory limits (e.g., 30 μg/L or 0.126 μmol/L; U.S. EPA drinking water standard), with 10 years projected for the Hanford 300 Area (Columbia River) and 12 years for the Rifle site (Colorado River). The rate of observed uranium decrease was much lower than expected at both sites. While uncertainty remains, a comparison of current understanding suggests that the two sites have common, but also different mechanisms controlling plume persistence. At the Hanford 300 A, the persistent source is adsorbed U(VI) in the vadose zone that is released to the aquifer during spring water table excursions. The release of U(VI) from the vadose zone and its transport within the oxic, coarse-textured aquifer sediments is dominated by kinetically-limited surface complexation. Modeling implies that annual plume discharge volumes to the Columbia River are small (oxidation of naturally reduced, contaminant U(IV) in the saturated zone and a continuous influx of U(VI) from natural, up-gradient sources influence plume persistence. Rate-limited mass transfer and surface complexation also control U(VI) migration velocity in the sub-oxic Rifle groundwater. Flux of U(VI) from the vadose zone at the Rifle site may be locally important, but it is not the dominant process that sustains the plume. A wide range in microbiologic functional diversity exists at both sites. Strains of Geobacter and other metal reducing bacteria are present at low natural abundance that are capable of enzymatic U(VI) reduction in localized zones of accumulated detrital organic carbon or after organic carbon amendment. Major differences between the sites include the geochemical nature of

Persistent colonization of Helicobacter pylori in human gut induces gastroduodenal diseases

Directory of Open Access Journals (Sweden)

Animesh Sarker

2014-12-01

Full Text Available Helicobacter pylori are gut bacteria colonize in the epithelial cell lining of the stomach and persist there for long du­ration. Around two-thirds of the world’s populations are infected with H. pylori and cause more than 90 percent of ulcers. The development of persistent inflammation is the main cause of chronic gastritis that finally results in a severe consequence known as stomach cancer. Two major virulence factors cytotoxin-associated gene product (cagA and the vacuolating toxin (vacA are mostly investigated as their close association with gastric carcinoma. In this review, host im­munity against H. pylori infection and their evasion mechanism are intensely explored. It is the fact, that understanding pin point molecular mechanisms of any infection is critical to develop novel strategies to prevent pertinent diseases. .J Microbiol Infect Dis 2014; 4(4: 170-176

Early life innate immune signatures of persistent food allergy.

Science.gov (United States)

Neeland, Melanie R; Koplin, Jennifer J; Dang, Thanh D; Dharmage, Shyamali C; Tang, Mimi L; Prescott, Susan L; Saffery, Richard; Martino, David J; Allen, Katrina J

2017-11-14

Food allergy naturally resolves in a proportion of food-allergic children without intervention; however the underlying mechanisms governing the persistence or resolution of food allergy in childhood are not understood. This study aimed to define the innate immune profiles associated with egg allergy at age 1 year, determine the phenotypic changes that occur with the development of natural tolerance in childhood, and explore the relationship between early life innate immune function and serum vitamin D. This study used longitudinally collected PBMC samples from a population-based cohort of challenge-confirmed egg-allergic infants with either persistent or transient egg allergy outcomes in childhood to phenotype and quantify the functional innate immune response associated with clinical phenotypes of egg allergy. We show that infants with persistent egg allergy exhibit a unique innate immune signature, characterized by increased numbers of circulating monocytes and dendritic cells that produce more inflammatory cytokines both at baseline and following endotoxin exposure when compared with infants with transient egg allergy. Follow-up analysis revealed that this unique innate immune signature continues into childhood in those with persistent egg allergy and that increased serum vitamin D levels correlate with changes in innate immune profiles observed in children who developed natural tolerance to egg. Early life innate immune dysfunction may represent a key immunological driver and predictor of persistent food allergy in childhood. Serum vitamin D may play an immune-modulatory role in the development of natural tolerance. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

FeO "Orange Arc" Emission Detected in Optical Spectrum of Leonid Persistent Trains

Science.gov (United States)

Jenniskens, Peter; Lacey, Matt; Allan, Beverly J.; Self, Daniel E.; Plane, John M. C.; DeVincenzi, Donald L. (Technical Monitor)

2000-01-01

We report the detection of a broad continuum emission dominating the visual spectrum of a Leonid persistent train. A comparison with laboratory spectra of FeO 1 "orange arc" emission at I mbar shows a general agreement of the band position and shape. The detection of FeO confirms the classical mechanism of metal atom catalyzed recombination of ozone and oxygen atoms as the driving force behind optical emission from persistent trains. Sodium and iron atoms are now confirmed catalysts.

Persistent and progressive long-term lung disease in survivors of preterm birth.

Science.gov (United States)

Urs, Rhea; Kotecha, Sailesh; Hall, Graham L; Simpson, Shannon J

2018-04-13

Preterm birth accounts for approximately 11% of births globally, with rates increasing across many countries. Concurrent advances in neonatal care have led to increased survival of infants of lower gestational age (GA). However, infants born poor respiratory outcomes throughout childhood, into adolescence and adulthood. Indeed, survivors of preterm birth have shown increased respiratory symptoms, altered lung structure, persistent and even declining lung function throughout childhood. The mechanisms behind this persistent and sometimes progressive lung disease are unclear, and the implications place those born preterm at increased risk of respiratory morbidity into adulthood. This review aims to summarise what is known about the long-term pulmonary outcomes of contemporary preterm birth, examine the possible mechanisms of long-term respiratory morbidity in those born preterm and discuss addressing the unknowns and potentials for targeted treatments. Copyright © 2018 Elsevier Ltd. All rights reserved.

Persistent postsurgical pain: risk factors and prevention

DEFF Research Database (Denmark)

Kehlet, Henrik; Jensen, Troels Staehelin; Woolf, Clifford J.

2006-01-01

therapy for postoperative pain should be investigated, since the intensity of acute postoperative pain correlates with the risk of developing a persistent pain state. Finally, the role of genetic factors should be studied, since only a proportion of patients with intraoperative nerve damage develop...... chronic pain. Based on information about the molecular mechanisms that affect changes to the peripheral and central nervous system in neuropathic pain, several opportunities exist for multimodal pharmacological intervention. Here, we outline strategies for identification of patients at risk...

Association of Dioxin and Other Persistent Organic Pollutants (POPs) with Diabetes: Epidemiological Evidence and New Mechanisms of Beta Cell Dysfunction

Science.gov (United States)

De Tata, Vincenzo

2014-01-01

The worldwide explosion of the rates of diabetes and other metabolic diseases in the last few decades cannot be fully explained only by changes in the prevalence of classical lifestyle-related risk factors, such as physical inactivity and poor diet. For this reason, it has been recently proposed that other “nontraditional” risk factors could contribute to the diabetes epidemics. In particular, an increasing number of reports indicate that chronic exposure to and accumulation of a low concentration of environmental pollutants (especially the so-called persistent organic pollutants (POPs)) within the body might be associated with diabetogenesis. In this review, the epidemiological evidence suggesting a relationship between dioxin and other POPs exposure and diabetes incidence will be summarized, and some recent developments on the possible underlying mechanisms, with particular reference to dioxin, will be presented and discussed. PMID:24802877

The role of glia in the spinal cord in neuropathic and inflammatory pain.

Science.gov (United States)

Old, Elizabeth Amy; Clark, Anna K; Malcangio, Marzia

2015-01-01

Chronic pain, both inflammatory and neuropathic, is a debilitating condition in which the pain experience persists after the painful stimulus has resolved. The efficacy of current treatment strategies using opioids, NSAIDS and anticonvulsants is limited by the extensive side effects observed in patients, underlining the necessity for novel therapeutic targets. Preclinical models of chronic pain have recently provided evidence for a critical role played by glial cells in the mechanisms underlying the chronicity of pain, both at the site of damage in the periphery and in the dorsal horn of the spinal cord. Here microglia and astrocytes respond to the increased input from the periphery and change morphology, increase in number and release pro-nociceptive mediators such as ATP, cytokines and chemokines. These gliotransmitters can sensitise neurons by activation of their cognate receptors thereby contributing to central sensitization which is fundamental for the generation of allodynia, hyperalgesia and spontaneous pain.

Nutmeg oil alleviates chronic inflammatory pain through inhibition of COX-2 expression and substance P release in vivo

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Wei Kevin Zhang

2016-04-01

Full Text Available Background: Chronic pain, or sometimes referred to as persistent pain, reduces the life quality of patients who are suffering from chronic diseases such as inflammatory diseases, cancer and diabetes. Hence, herbal medicines draw many attentions and have been shown effective in the treatment or relief of pain. Methods and Results: Here in this study, we used the CFA-injected rats as a sustainable pain model to test the anti-inflammatory and analgesic effect of nutmeg oil, a spice flavor additive to beverages and baked goods produced from the seed of Myristica fragrans tree. Conclusions: We have demonstrated that nutmeg oil could potentially alleviate the CFA-injection induced joint swelling, mechanical allodynia and heat hyperanalgesia of rats through inhibition of COX-2 expression and blood substance P level, which made it possible for nutmeg oil to be a potential chronic pain reliever.

Inflation persistence and flexible prices

OpenAIRE

Robert Dittmar; William T. Gavin; Finn E. Kydland

2004-01-01

If the central bank follows an interest rate rule, then inflation is likely to be persistence, even when prices are fully flexible. Any shock, whether persistent or not, may lead to inflation persistence. In equilibrium, the dynamics of inflation are determined by the evolution of the spread between the real interest rate and the central bank’s target. Inflation persistence in U.S. data can be characterized by a vector autocorrelation function relating inflation and deviations of output from ...

Effects of Persistent Atrial Fibrillation-Induced Electrical Remodeling on Atrial Electro-Mechanics - Insights from a 3D Model of the Human Atria.

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Adeniran, Ismail; MacIver, David H; Garratt, Clifford J; Ye, Jianqiao; Hancox, Jules C; Zhang, Henggui

2015-01-01

Atrial stunning, a loss of atrial mechanical contraction, can occur following a successful cardioversion. It is hypothesized that persistent atrial fibrillation-induced electrical remodeling (AFER) on atrial electrophysiology may be responsible for such impaired atrial mechanics. This simulation study aimed to investigate the effects of AFER on atrial electro-mechanics. A 3D electromechanical model of the human atria was developed to investigate the effects of AFER on atrial electro-mechanics. Simulations were carried out in 3 conditions for 4 states: (i) the control condition, representing the normal tissue (state 1) and the tissue 2-3 months after cardioversion (state 2) when the atrial tissue recovers its electrophysiological properties after completion of reverse electrophysiological remodelling; (ii) AFER-SR condition for AF-remodeled tissue with normal sinus rhythm (SR) (state 3); and (iii) AFER-AF condition for AF-remodeled tissue with re-entrant excitation waves (state 4). Our results indicate that at the cellular level, AFER (states 3 & 4) abbreviated action potentials and reduced the Ca2+ content in the sarcoplasmic reticulum, resulting in a reduced amplitude of the intracellular Ca2+ transient leading to decreased cell active force and cell shortening as compared to the control condition (states 1 & 2). Consequently at the whole organ level, atrial contraction in AFER-SR condition (state 3) was dramatically reduced. In the AFER-AF condition (state 4) atrial contraction was almost abolished. This study provides novel insights into understanding atrial electro-mechanics illustrating that AFER impairs atrial contraction due to reduced intracellular Ca2+ transients.

Differential Persistence of Foot-and-Mouth Disease Virus in African Buffalo Is Related to Virus Virulence.

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Maree, Francois; de Klerk-Lorist, Lin-Mari; Gubbins, Simon; Zhang, Fuquan; Seago, Julian; Pérez-Martín, Eva; Reid, Liz; Scott, Katherine; van Schalkwyk, Louis; Bengis, Roy; Charleston, Bryan; Juleff, Nicholas

2016-05-15

Foot-and-mouth disease (FMD) virus (FMDV) circulates as multiple serotypes and strains in many regions of endemicity. In particular, the three Southern African Territories (SAT) serotypes are maintained effectively in their wildlife reservoir, the African buffalo, and individuals may harbor multiple SAT serotypes for extended periods in the pharyngeal region. However, the exact site and mechanism for persistence remain unclear. FMD in buffaloes offers a unique opportunity to study FMDV persistence, as transmission from carrier ruminants has convincingly been demonstrated for only this species. Following coinfection of naive African buffaloes with isolates of three SAT serotypes from field buffaloes, palatine tonsil swabs were the sample of choice for recovering infectious FMDV up to 400 days postinfection (dpi). Postmortem examination identified infectious virus for up to 185 dpi and viral genomes for up to 400 dpi in lymphoid tissues of the head and neck, focused mainly in germinal centers. Interestingly, viral persistence in vivo was not homogenous, and the SAT-1 isolate persisted longer than the SAT-2 and SAT-3 isolates. Coinfection and passage of these SAT isolates in goat and buffalo cell lines demonstrated a direct correlation between persistence and cell-killing capacity. These data suggest that FMDV persistence occurs in the germinal centers of lymphoid tissue but that the duration of persistence is related to virus replication and cell-killing capacity. Foot-and-mouth disease virus (FMDV) causes a highly contagious acute vesicular disease in domestic livestock and wildlife species. African buffaloes (Syncerus caffer) are the primary carrier hosts of FMDV in African savannah ecosystems, where the disease is endemic. We have shown that the virus persists for up to 400 days in buffaloes and that there is competition between viruses during mixed infections. There was similar competition in cell culture: viruses that killed cells quickly persisted more

The persistence of hepatitis B antigen in the bloodmeal of the ...

African Journals Online (AJOL)

The results are compared with reports on other arthropods which indicate increasing antigen persistence with increasing body size. The findings implicate medicinal leeches as mechanical vectors of HBV and possibly of other medically important viruses, and argue against using leeches of suspect or unknown origin in the ...

Distributed Persistent Identifiers System Design

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Pavel Golodoniuc

2017-06-01

Full Text Available The need to identify both digital and physical objects is ubiquitous in our society. Past and present persistent identifier (PID systems, of which there is a great variety in terms of technical and social implementation, have evolved with the advent of the Internet, which has allowed for globally unique and globally resolvable identifiers. PID systems have, by in large, catered for identifier uniqueness, integrity, and persistence, regardless of the identifier’s application domain. Trustworthiness of these systems has been measured by the criteria first defined by Bütikofer (2009 and further elaborated by Golodoniuc 'et al'. (2016 and Car 'et al'. (2017. Since many PID systems have been largely conceived and developed by a single organisation they faced challenges for widespread adoption and, most importantly, the ability to survive change of technology. We believe that a cause of PID systems that were once successful fading away is the centralisation of support infrastructure – both organisational and computing and data storage systems. In this paper, we propose a PID system design that implements the pillars of a trustworthy system – ensuring identifiers’ independence of any particular technology or organisation, implementation of core PID system functions, separation from data delivery, and enabling the system to adapt for future change. We propose decentralisation at all levels — persistent identifiers and information objects registration, resolution, and data delivery — using Distributed Hash Tables and traditional peer-to-peer networks with information replication and caching mechanisms, thus eliminating the need for a central PID data store. This will increase overall system fault tolerance thus ensuring its trustworthiness. We also discuss important aspects of the distributed system’s governance, such as the notion of the authoritative source and data integrity

Transgenerational plasticity is sex-dependent and persistent in yellow monkeyflower (Mimulus guttatus).

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Akkerman, Kayla C; Sattarin, Arash; Kelly, John K; Scoville, Alison G

2016-04-01

Transgenerational phenotypic plasticity, whereby environmental cues experienced by parents alter the phenotype of their progeny, has now been documented in diverse organisms. Transmission of environmentally determined responses is known to occur through both maternal and paternal gametes, but the underlying mechanisms have rarely been compared. In addition, the persistence of induction over multiple generations appears to vary widely, but has been characterized for relatively few systems. Yellow monkeyflower ( Mimulus guttatus ) is known to exhibit transgenerational induction of increased glandular trichome production in response to simulated insect damage. Here, we test for differences between maternal and paternal transmission of this response and examine its persistence over five generations following damage. Maternal and paternal damage resulted in similar and apparently additive increases in progeny trichome production. Treatment of germinating seeds with the genome-wide demethylating agent 5-azacytidine erased the effect of maternal but not paternal damage. The number of glandular trichomes remained elevated for three generations following damage. These results indicate that transgenerational transmission occurs through both maternal and paternal germ lines, but that they differ in the proximate mechanism of epigenetic inheritance. Our results also indicate that a wounding response can persist for multiple generations in the absence of subsequent damage.

The Effect of Intrathecal Administration of Muscimol on Modulation of Neuropathic Pain Symptoms Resulting from Spinal Cord Injury; an Experimental Study

Directory of Open Access Journals (Sweden)

Marjan Hosseini

2014-09-01

Full Text Available Introduction: Neuropathic pain can be very difficult to treat and it is one of the important medical challenging about pain treatments. Muscimol as a new agonist of gamma-Aminobutyric acid receptor type A (GABAA have been introduced for pain management. Thus, the present study was performed to evaluate the pain alleviating effect of intrathecal injection of different doses of muscimol as GABAA receptor agonist in spinal cord injury (SCI model of neuropathic pain. Methods: In the present experimental study male Wistar rats were treated by muscimol 0.01, 0.1 or 1 µg/10ul, intrathecally (i.t. three weeks after induction of spinal cord injury using compression injury model. Neuropathic pain symptoms were assessed at before treatment, 15 minutes, one hour and three hours after muscimol administration. The time of peak effect and optimum dosage was assessed by repeated measures analysis of variance and analysis of covariance, respectively. Results: Muscimol with the dose of 0.01 µg in 15 minutes caused to improve the thermal hyperalgesia (df: 24, 5; F= 6.6; p<0.001, mechanical hyperalgesia (df: 24, 5; F= 7.8; p<0.001, cold allodynia (df: 24, 5; F= 6.96; p<0.001, and mechanical allodynia (df: 24, 5; F= 15.7; p<0.001. The effect of doses of 0.1 µg and 1 µg were also significant. In addition, the efficacy of different doses of muscimol didn't have difference on thermal hyperalgesia (df: 24, 5; F= 1.52; p= 0.24, mechanical hyperalgesia (df: 24, 5; F= 0.3; p= -0.75, cold allodynia (df: 24, 5; F= 0.8; p= -0.56, and mechanical allodynia (df: 24, 5; F= 1.75; p= 0.86. Conclusion: The finding of the present study revealed that using muscimol with doses of 0.01µg, 0.1µg, and 1 µg reduces the symptoms of neuropathic pain. Also the effect of GABAA agonist is short term and its effectiveness gradually decreases by time.

Thermal and mechanical pain sensitization in patients with osteoarthritis of the knee.

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Bevilaqua-Grossi, Debora; Zanin, Marilia; Benedetti, Camila; Florencio, Lidiane; Oliveira, Anamaria

2018-02-26

The aim was to assess sensitization using quantitative sensory testing in mechanical and thermal modes in individuals with and without osteoarthritis (OA) of the knee. Pain thresholds were correlated with functionality, symptoms of depression and intensity of pain. Thirty control volunteers and 30 patients with OA of the knee were assessed. Punctate pain thresholds using Von Frey filaments and thermal pain thresholds using a Thermal Sensory Analyzer were evaluated in the periarticular region of the knee and forearm. Using a digital pressure algometer, pressure pain thresholds were assessed in the periarticular region of the knee and on the root exit zone on the lumbar and sacral spine. Punctate, pressure, and thermal pain thresholds differed significantly between participants with and without OA (p pain sensitization. Pressure pain thresholds also showed moderate and negative correlations with data on functionality, symptoms of depression and intensity of pain (-0.36  -0.56), contributing up to 30% of their variability. Allodynia and hyperalgesia were demonstrated in the OA group, suggesting central sensitization in patients with mild to moderate severity of joint damage. Correlation between mechanical hypersensitivity and psychosocial factors seems to be small, despite of its significance.

New-found fundamentals of bacterial persistence.

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Kint, Cyrielle I; Verstraeten, Natalie; Fauvart, Maarten; Michiels, Jan

2012-12-01

Persister cells display tolerance to high doses of bactericidal antibiotics and typically comprise a small fraction of a bacterial population. Recently, evidence was provided for a causal link between therapy failure and the presence of persister cells in chronic infections, underscoring the need for research on bacterial persistence. A series of recent breakthroughs have shed light on the multiplicity of persister genes, the contribution of gene expression noise to persister formation, the importance of active responses to antibiotic tolerance and heterogeneity among persister cells. Moreover, the development of in vivo model systems has highlighted the clinical relevance of persistence. This review discusses these recent advances and how this knowledge fundamentally changes the way in which we will perceive the problem of antibiotic tolerance in years to come. Copyright © 2012 Elsevier Ltd. All rights reserved.

Black lung persistent pulmonary hypertension of the newborn

Science.gov (United States)

Alnemri, AbdulRahman M.

2017-01-01

Objectives: To determine the clinical presentation, risk factors, diagnosis, and treatment outcome of Saudi infants with black lung persistent pulmonary hypertension of the newborn (PPHN). Methods: This is a retrospective review of all neonates with PPHN presented to the Armed Force Hospital Southern Region, Kingdom of Saudi Arabia from January 2012 to December 2014. Results: Ten term and near term infants presented with PPHN were included. Maternal diabetes and Down syndrome were the most common identified risk factors for PPHN in the study group. Nine infants were treated with oral sildenafil and did not require mechanical ventilation. Only one infant required mechanical ventilation and inhaled nitric oxide in addition to oral sildenafil. Conclusion: Most of the patients in this cohort with PPHN had risk factors, they did not require mechanical ventilation and responded well to oral sildenafil. PMID:28042638

Persistent homology of complex networks

International Nuclear Information System (INIS)

Horak, Danijela; Maletić, Slobodan; Rajković, Milan

2009-01-01

Long-lived topological features are distinguished from short-lived ones (considered as topological noise) in simplicial complexes constructed from complex networks. A new topological invariant, persistent homology, is determined and presented as a parameterized version of a Betti number. Complex networks with distinct degree distributions exhibit distinct persistent topological features. Persistent topological attributes, shown to be related to the robust quality of networks, also reflect the deficiency in certain connectivity properties of networks. Random networks, networks with exponential connectivity distribution and scale-free networks were considered for homological persistency analysis

Mechanism of Chronic Pain in Rodent Brain Imaging

Science.gov (United States)

Chang, Pei-Ching

Chronic pain is a significant health problem that greatly impacts the quality of life of individuals and imparts high costs to society. Despite intense research effort in understanding of the mechanism of pain, chronic pain remains a clinical problem that has few effective therapies. The advent of human brain imaging research in recent years has changed the way that chronic pain is viewed. To further extend the use of human brain imaging techniques for better therapies, the adoption of imaging technique onto the animal pain models is essential, in which underlying brain mechanisms can be systematically studied using various combination of imaging and invasive techniques. The general goal of this thesis is to addresses how brain develops and maintains chronic pain in an animal model using fMRI. We demonstrate that nucleus accumbens, the central component of mesolimbic circuitry, is essential in development of chronic pain. To advance our imaging technique, we develop an innovative methodology to carry out fMRI in awake, conscious rat. Using this cutting-edge technique, we show that allodynia is assoicated with shift brain response toward neural circuits associated nucleus accumbens and prefrontal cortex that regulate affective and cognitive component of pain. Taken together, this thesis provides a deeper understanding of how brain mediates pain. It builds on the existing body of knowledge through maximizing the depth of insight into brain imaging of chronic pain.

Autocatalytic polymerization generates persistent random walk of crawling cells.

Science.gov (United States)

Sambeth, R; Baumgaertner, A

2001-05-28

The autocatalytic polymerization kinetics of the cytoskeletal actin network provides the basic mechanism for a persistent random walk of a crawling cell. It is shown that network remodeling by branching processes near the cell membrane is essential for the bimodal spatial stability of the network which induces a spontaneous breaking of isotropic cell motion. Details of the phenomena are analyzed using a simple polymerization model studied by analytical and simulation methods.

Persistent luminescence nanothermometers

Science.gov (United States)

Martín Rodríguez, Emma; López-Peña, Gabriel; Montes, Eduardo; Lifante, Ginés; García Solé, José; Jaque, Daniel; Diaz-Torres, Luis Armando; Salas, Pedro

2017-08-01

Persistent phosphorescence nanoparticles emitting in the red and near-infrared spectral regions are strongly demanded as contrast nanoprobes for autofluorescence free bioimaging and biosensing. In this work, we have developed Sr4Al14O25:Eu2+, Cr3+, Nd3+ nanopowders that produce persistent red phosphorescence peaking at 694 nm generated by Cr3+ ions. This emission displays temperature sensitivity in the physiological temperature range (20-60 °C), which makes these nanoparticles potentially useful as fluorescence (contactless) nanothermometers operating without requiring optical excitation. Nd3+ ions, which act as shallow electron traps for the red Cr3+ persistent emission, also display infrared emission bands, extending the fluorescence imaging capability to the second biological window. This unique combination of properties makes these nanoparticles multifunctional luminescent probes with great potential applications in nanomedicine.

Incentive Processing in Persistent Disruptive Behavior and Psychopathic Traits: A Functional Magnetic Resonance Imaging Study in Adolescents.

Science.gov (United States)

Cohn, Moran D; Veltman, Dick J; Pape, Louise E; van Lith, Koen; Vermeiren, Robert R J M; van den Brink, Wim; Doreleijers, Theo A H; Popma, Arne

2015-11-01

Children with early-onset disruptive behavior disorder (DBD), especially those with callous-unemotional traits, are at risk of developing persistent and severe adult antisocial behavior. One possible underlying mechanism for persistence is deficient reward and loss sensitivity, i.e., deficient incentive processing. However, little is known about the relation between deficient incentive processing and persistence of antisocial behavior into adulthood or its relation with callous-unemotional and other psychopathic traits. In this study, we investigate the relationship between the neural correlates of incentive processing and both DBD persistence and psychopathic traits. In a sample of 128 adolescents (mean age 17.7) with a history of criminal offending before age 12, functional magnetic resonance imaging was performed during a monetary incentive delay task designed to assess neural responses during incentive processing. Neural activation during incentive processing was then associated with DBD persistence and psychopathic traits, measured with the Youth Psychopathic Traits Inventory. Compared with both healthy control subjects and youths who had desisted from DBD, persistent DBD subjects showed lower neural responses in the ventral striatum during reward outcomes and higher neural responses in the amygdala during loss outcomes. Callous-unemotional traits were related to lower neural responses in the amygdala during reward outcomes, while other psychopathic traits were not related to incentive processing. In the current study, aberrant incentive processing is related to persistence of childhood antisocial behavior into late adolescence and to callous-unemotional traits. This mechanism may underlie treatment resistance in a subgroup of antisocial youth and provide a target for intervention. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Aberrant TRPV1 expression in heat hyperalgesia associated with trigeminal neuropathic pain.

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Urano, Hiroko; Ara, Toshiaki; Fujinami, Yoshiaki; Hiraoka, B Yukihiro

2012-01-01

Trigeminal neuropathic pain is a facial pain syndrome associated with trigeminal nerve injury. However, the mechanism of trigeminal neuropathic pain is poorly understood. This study aimed to determine the role of transient receptor potential vanilloid 1 (TRPV1) in heat hyperalgesia in a trigeminal neuropathic pain model. We evaluated nociceptive responses to mechanical and heat stimuli using a partial infraorbital nerve ligation (pIONL) model. Withdrawal responses to mechanical and heat stimuli to vibrissal pads (VP) were assessed using von Frey filaments and a thermal stimulator equipped with a heat probe, respectively. Changes in withdrawal responses were measured after subcutaneous injection of the TRP channel antagonist capsazepine. In addition, the expression of TRPV1 in the trigeminal ganglia was examined. Mechanical allodynia and heat hyperalgesia were observed in VP by pIONL. Capsazepine suppressed heat hyperalgesia but not mechanical allodynia. The number of TRPV1-positive neurons in the trigeminal ganglia was significantly increased in the large-diameter-cell group. These results suggest that TRPV1 plays an important role in the heat hyperalgesia observed in the pIONL model.

The shape of early persistent slip markings in fatigued 316L steel

Czech Academy of Sciences Publication Activity Database

Polák, Jaroslav; Kuběna, Ivo; Man, Jiří

2013-01-01

Roč. 564, MARCH (2013), s. 8-12 ISSN 0921-5093 R&D Projects: GA ČR GAP108/10/2371 Institutional support: RVO:68081723 Keywords : Persistent slip marking * Extrusion * Intrusion * fatigue * crack Subject RIV: JL - Materials Fatigue, Friction Mechanics Impact factor: 2.409, year: 2013

Perioperative epidural or intravenous ketamine does not improve the effectiveness of thoracic epidural analgesia for acute and chronic pain after thoracotomy.

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Tena, Beatriz; Gomar, Carmen; Rios, Jose

2014-06-01

Persistent postsurgical pain (PPP) after thoracotomy effect 50% to 80%. Nerve damage and central sensitization involving NDMDAr activation may play an important role. This study evaluates the efficacy of adding intravenous (IV) or epidural ketamine to thoracic epidural analgesia (TEA) after thoracotomy. Double-blind randomized study on patients undergoing thoracotomy allocated to one of the following: group Kiv (IV racemic ketamine 0.5 mg/kg preincisional +0.25 mg/kg/h for 48 h), group Kep (epidural racemic ketamine 0.5 mg/kg preincisional +0.25 mg/kg/h for 48 h), or group S (saline). Postoperative analgesia was ensured by TEA with ropivacaine and fentanyl. Pain visual analog scales (VAS), Neuropathic Pain Symptom Inventory, Catastrophizing Scale, and Quantitative Sensory Testing, measuring both the peri-incisional and distant hyperalgesia area, were conducted preoperatively and postoperatively until 6 months. Plasma ketamine levels and stability of the analgesic solutions were analyzed. A total of 104 patients were included. PPP incidence was 20% at 6 months. Pain scores on coughing were significantly lower in Kiv and Kep than in S at 24 and 72 hours, but there were no differences afterwards. There were no significant differences in pain at rest, Neuropathic Pain Symptom Inventory, and Catastrophizing Scale, or in the area of mechanical allodynia at any time. Adverse effects were mild. Plasma ketamine levels did not differ significantly between groups. Analgesic solutions were stable. Adding epidural or IV racemic ketamine to TEA after thoracotomy did not lead to any reduction in PPP or allodynia. Epidural administration produced similar plasma ketamine levels to the IV route.

Persistent drought monitoring using a microfluidic-printed electro-mechanical sensor of stomata in planta.

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Koman, Volodymyr B; Lew, Tedrick T S; Wong, Min Hao; Kwak, Seon-Yeong; Giraldo, Juan P; Strano, Michael S

2017-11-21

Stomatal function can be used effectively to monitor plant hydraulics, photosensitivity, and gas exchange. Current approaches to measure single stomatal aperture, such as mold casting or fluorometric techniques, do not allow real time or persistent monitoring of the stomatal function over timescales relevant for long term plant physiological processes, including vegetative growth and abiotic stress. Herein, we utilize a nanoparticle-based conducting ink that preserves stomatal function to print a highly stable, electrical conductometric sensor actuated by the stomata pore itself, repeatedly and reversibly for over 1 week. This stomatal electro-mechanical pore size sensor (SEMPSS) allows for real-time tracking of the latency of single stomatal opening and closing times in planta, which we show vary from 7.0 ± 0.5 to 25.0 ± 0.5 min for the former and from 53.0 ± 0.5 to 45.0 ± 0.5 min for the latter in Spathiphyllum wallisii. These values are shown to correlate with the soil water potential and the onset of the wilting response, in quantitative agreement with a dynamic mathematical model of stomatal function. A single stoma of Spathiphyllum wallisii is shown to distinguish between incident light intensities (up to 12 mW cm -2 ) with temporal latency slow as 7.0 ± 0.5 min. Over a seven day period, the latency in opening and closing times are stable throughout the plant diurnal cycle and increase gradually with the onset of drought. The monitoring of stomatal function over long term timescales at single stoma level will improve our understanding of plant physiological responses to environmental factors.

Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway.

Science.gov (United States)

Fineran, Paul; Lloyd-Evans, Emyr; Lack, Nathan A; Platt, Nick; Davis, Lianne C; Morgan, Anthony J; Höglinger, Doris; Tatituri, Raju Venkata V; Clark, Simon; Williams, Ian M; Tynan, Patricia; Al Eisa, Nada; Nazarova, Evgeniya; Williams, Ann; Galione, Antony; Ory, Daniel S; Besra, Gurdyal S; Russell, David G; Brenner, Michael B; Sim, Edith; Platt, Frances M

2016-11-18

Tuberculosis remains a major global health concern. The ability to prevent phagosome-lysosome fusion is a key mechanism by which intracellular mycobacteria, including Mycobacterium tuberculosis , achieve long-term persistence within host cells. The mechanisms underpinning this key intracellular pro-survival strategy remain incompletely understood. Host macrophages infected with persistent mycobacteria share phenotypic similarities with cells taken from patients suffering from Niemann-Pick Disease Type C (NPC), a rare lysosomal storage disease in which endocytic trafficking defects and lipid accumulation within the lysosome lead to cell dysfunction and cell death. We investigated whether these shared phenotypes reflected an underlying mechanistic connection between mycobacterial intracellular persistence and the host cell pathway dysfunctional in NPC. The induction of NPC phenotypes in macrophages from wild-type mice or obtained from healthy human donors was assessed via infection with mycobacteria and subsequent measurement of lipid levels and intracellular calcium homeostasis. The effect of NPC therapeutics on intracellular mycobacterial load was also assessed. Macrophages infected with persistent intracellular mycobacteria phenocopied NPC cells, exhibiting accumulation of multiple lipid types, reduced lysosomal Ca 2+ levels, and defects in intracellular trafficking. These NPC phenotypes could also be induced using only lipids/glycomycolates from the mycobacterial cell wall. These data suggest that persistent intracellular mycobacteria inhibit the NPC pathway, likely via inhibition of the NPC1 protein, and subsequently induce altered acidic store Ca 2+ homeostasis. Reduced lysosomal calcium levels may provide a mechanistic explanation for the reduced levels of phagosome-lysosome fusion in mycobacterial infection. Treatments capable of correcting defects in NPC mutant cells via modulation of host cell calcium were of benefit in promoting clearance of mycobacteria

Is bacterial persistence a social trait?

Directory of Open Access Journals (Sweden)

Andy Gardner

Full Text Available The ability of bacteria to evolve resistance to antibiotics has been much reported in recent years. It is less well-known that within populations of bacteria there are cells which are resistant due to a non-inherited phenotypic switch to a slow-growing state. Although such 'persister' cells are receiving increasing attention, the evolutionary forces involved have been relatively ignored. Persistence has a direct benefit to cells because it allows survival during catastrophes-a form of bet-hedging. However, persistence can also provide an indirect benefit to other individuals, because the reduced growth rate can reduce competition for limiting resources. This raises the possibility that persistence is a social trait, which can be influenced by kin selection. We develop a theoretical model to investigate the social consequences of persistence. We predict that selection for persistence is increased when: (a cells are related (e.g. a single, clonal lineage; and (b resources are scarce. Our model allows us to predict how the level of persistence should vary with time, across populations, in response to intervention strategies and the level of competition. More generally, our results clarify the links between persistence and other bet-hedging or social behaviours.

Persistence of canine distemper virus in the Greater Yellowstone Ecosystem's carnivore community

Science.gov (United States)

Almberg, E.S.; Cross, P.C.; Smith, D.W.

2010-01-01

Canine distemper virus (CDV) is an acute, highly immunizing pathogen that should require high densities and large populations of hosts for long-term persistence, yet CDV persists among terrestrial carnivores with small, patchily distributed groups. We used CDV in the Greater Yellowstone ecosystem's (GYE) wolves (Canis lupus) and coyotes (Canis latrans) as a case study for exploring how metapopulation structure, host demographics, and multi-host transmission affect the critical community size and spatial scale required for CDV persistence. We illustrate how host spatial connectivity and demographic turnover interact to affect both local epidemic dynamics, such as the length and variation in inter-epidemic periods, and pathogen persistence using stochastic, spatially explicit susceptible-exposed-infectious-recovered simulation models. Given the apparent absence of other known persistence mechanisms (e.g., a carrier or environmental state, densely populated host, chronic infection, or a vector), we suggest that CDV requires either large spatial scales or multi-host transmission for persistence. Current GYE wolf populations are probably too small to support endemic CDV. Coyotes are a plausible reservoir host, but CDV would still require 50 000-100 000 individuals for moderate persistence (>50% over 10 years), which would equate to an area of 1-3 times the size of the GYE (60000-200000 km2). Coyotes, and carnivores in general, are not uniformly distributed; therefore, this is probably a gross underestimate of the spatial scale of CDV persistence. However, the presence of a second competent host species can greatly increase the probability of long-term CDV persistence at much smaller spatial scales. Although no management of CDV is currently recommended for the GYE, wolf managers in the region should expect periodic but unpredictable CDV-related population declines as often as every 2-5 years. Awareness and monitoring of such outbreaks will allow corresponding

Persistence of canine distemper virus in the Greater Yellowstone ecosystem's carnivore community.

Science.gov (United States)

Almberg, Emily S; Cross, Paul C; Smith, Douglas W

2010-10-01

Canine distemper virus (CDV) is an acute, highly immunizing pathogen that should require high densities and large populations of hosts for long-term persistence, yet CDV persists among terrestrial carnivores with small, patchily distributed groups. We used CDV in the Greater Yellowstone ecosystem's (GYE) wolves (Canis lupus) and coyotes (Canis latrans) as a case study for exploring how metapopulation structure, host demographics, and multi-host transmission affect the critical community size and spatial scale required for CDV persistence. We illustrate how host spatial connectivity and demographic turnover interact to affect both local epidemic dynamics, such as the length and variation in inter-epidemic periods, and pathogen persistence using stochastic, spatially explicit susceptible-exposed-infectious-recovered simulation models. Given the apparent absence of other known persistence mechanisms (e.g., a carrier or environmental state, densely populated host, chronic infection, or a vector), we suggest that CDV requires either large spatial scales or multi-host transmission for persistence. Current GYE wolf populations are probably too small to support endemic CDV. Coyotes are a plausible reservoir host, but CDV would still require 50000-100000 individuals for moderate persistence (> 50% over 10 years), which would equate to an area of 1-3 times the size of the GYE (60000-200000 km2). Coyotes, and carnivores in general, are not uniformly distributed; therefore, this is probably a gross underestimate of the spatial scale of CDV persistence. However, the presence of a second competent host species can greatly increase the probability of long-term CDV persistence at much smaller spatial scales. Although no management of CDV is currently recommended for the GYE, wolf managers in the region should expect periodic but unpredictable CDV-related population declines as often as every 2-5 years. Awareness and monitoring of such outbreaks will allow corresponding adjustments

Effects of Persistent Atrial Fibrillation-Induced Electrical Remodeling on Atrial Electro-Mechanics – Insights from a 3D Model of the Human Atria

Science.gov (United States)

Adeniran, Ismail; MacIver, David H.; Garratt, Clifford J.; Ye, Jianqiao; Hancox, Jules C.; Zhang, Henggui

2015-01-01

Aims Atrial stunning, a loss of atrial mechanical contraction, can occur following a successful cardioversion. It is hypothesized that persistent atrial fibrillation-induced electrical remodeling (AFER) on atrial electrophysiology may be responsible for such impaired atrial mechanics. This simulation study aimed to investigate the effects of AFER on atrial electro-mechanics. Methods and Results A 3D electromechanical model of the human atria was developed to investigate the effects of AFER on atrial electro-mechanics. Simulations were carried out in 3 conditions for 4 states: (i) the control condition, representing the normal tissue (state 1) and the tissue 2–3 months after cardioversion (state 2) when the atrial tissue recovers its electrophysiological properties after completion of reverse electrophysiological remodelling; (ii) AFER-SR condition for AF-remodeled tissue with normal sinus rhythm (SR) (state 3); and (iii) AFER-AF condition for AF-remodeled tissue with re-entrant excitation waves (state 4). Our results indicate that at the cellular level, AFER (states 3 & 4) abbreviated action potentials and reduced the Ca2+ content in the sarcoplasmic reticulum, resulting in a reduced amplitude of the intracellular Ca2+ transient leading to decreased cell active force and cell shortening as compared to the control condition (states 1 & 2). Consequently at the whole organ level, atrial contraction in AFER-SR condition (state 3) was dramatically reduced. In the AFER-AF condition (state 4) atrial contraction was almost abolished. Conclusions This study provides novel insights into understanding atrial electro-mechanics illustrating that AFER impairs atrial contraction due to reduced intracellular Ca2+ transients. PMID:26606047

Role of NFkappaB in an animal model of complex regional pain syndrome-type I (CRPS-I).

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de Mos, Marissa; Laferrière, André; Millecamps, Magali; Pilkington, Mercedes; Sturkenboom, Miriam C J M; Huygen, Frank J P M; Coderre, Terence J

2009-11-01

NFkappaB is involved in several pathogenic mechanisms that are believed to underlie the complex regional pain syndrome (CRPS), including ischemia, inflammation and sensitization. Chronic postischemia pain (CPIP) has been developed as an animal model that mimics the symptoms of CRPS-I. The possible involvement of NFkappaB in CRPS-I was studied using CPIP rats. Under sodium pentobarbital anesthesia, a tourniquet was placed around the rat left ankle joint, producing 3 hours of ischemia, followed by rapid reperfusion (IR injury). NFkappaB was measured in nuclear extracts of muscle and spinal cord tissue using ELISA. Moreover, the anti-allodynic (mechanical and cold) effect was tested for systemic, intrathecal, or intraplantar treatment with the NFkappaB inhibitor pyrrolidine dithiocarbamate (PDTC). At 2 and 48 hours after IR injury, NFkappaB was elevated in muscle and spinal cord of CPIP rats compared to shams. At 7 days, NFkappaB levels were normalized in muscle, but still elevated in spinal cord tissue. Systemic PDTC treatment relieved mechanical and cold allodynia in a dose-dependent manner, lasting for at least 3 hours. Intrathecal-but not intraplantar-administration also relieved mechanical allodynia. The results suggest that muscle and spinal NFkappaB plays a role in the pathogenesis of CPIP and potentially of human CRPS. Using the CPIP model, we demonstrate that NFkappaB is involved in the development of allodynia after a physical injury (ischemia and reperfusion) without direct nerve trauma. Since CPIP animals exhibit many features of human CRPS-I, this observation indicates a potential role for NFkappaB in human CRPS.

The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors

DEFF Research Database (Denmark)

Wieskopf, Jeffrey S; Mathur, Jayanti; Limapichat, Walrati

2015-01-01

expression levels of Chrna6, which encodes the α6 subunit of the nicotinic acetylcholine receptor (nAChR), as highly associated with allodynia. We confirmed the importance of α6* (α6-containing) nAChRs by analyzing both gain- and loss-of-function mutants. We find that mechanical allodynia associated...... with neuropathic and inflammatory injuries is significantly altered in α6* mutants, and that α6* but not α4* nicotinic receptors are absolutely required for peripheral and/or spinal nicotine analgesia. Furthermore, we show that Chrna6's role in analgesia is at least partially due to direct interaction and cross...

Focus: the peculiar persistence of the naturalistic fallacy. Introduction.

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Milam, Erika Lorraine

2014-09-01

Although "naturalistic fallacy" is a term coined in the twentieth century, scholars have long voiced myriad anxieties over the mechanisms by which their contemporaries have derived moral, social, and political lessons from natural phenomena--often as gambits for advancing their own alternative explanations. The essays in this Focus section explore five episodes in the history of such concerns with naturalistic reasoning in order to shed new light on the persistence of naturalism itself.

Cyclic AMP Regulates Bacterial Persistence through Repression of the Oxidative Stress Response and SOS-Dependent DNA Repair in Uropathogenic Escherichia coli.

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Molina-Quiroz, Roberto C; Silva-Valenzuela, Cecilia; Brewster, Jennifer; Castro-Nallar, Eduardo; Levy, Stuart B; Camilli, Andrew

2018-01-09

Bacterial persistence is a transient, nonheritable physiological state that provides tolerance to bactericidal antibiotics. The stringent response, toxin-antitoxin modules, and stochastic processes, among other mechanisms, play roles in this phenomenon. How persistence is regulated is relatively ill defined. Here we show that cyclic AMP, a global regulator of carbon catabolism and other core processes, is a negative regulator of bacterial persistence in uropathogenic Escherichia coli , as measured by survival after exposure to a β-lactam antibiotic. This phenotype is regulated by a set of genes leading to an oxidative stress response and SOS-dependent DNA repair. Thus, persister cells tolerant to cell wall-acting antibiotics must cope with oxidative stress and DNA damage and these processes are regulated by cyclic AMP in uropathogenic E. coli IMPORTANCE Bacterial persister cells are important in relapsing infections in patients treated with antibiotics and also in the emergence of antibiotic resistance. Our results show that in uropathogenic E. coli , the second messenger cyclic AMP negatively regulates persister cell formation, since in its absence much more persister cells form that are tolerant to β-lactams antibiotics. We reveal the mechanism to be decreased levels of reactive oxygen species, specifically hydroxyl radicals, and SOS-dependent DNA repair. Our findings suggest that the oxidative stress response and DNA repair are relevant pathways to target in the design of persister-specific antibiotic compounds. Copyright © 2018 Molina-Quiroz et al.

Diagnostic Accuracy of Quantitative Sensory Testing to Discriminate Inflammatory Toothache and Intraoral Neuropathic Pain.

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Porporatti, André Luís; Costa, Yuri Martins; Stuginski-Barbosa, Juliana; Bonjardim, Leonardo Rigoldi; Duarte, Marco Antônio Hungaro; Conti, Paulo César Rodrigues

2015-10-01

A differential diagnosis between inflammatory toothache (IT) and intraoral neuropathic pain is challenging. The aim of this diagnostic study was to quantify somatosensory function of subjects with IT (acute pulpitis) and atypical odontalgia (AO, intraoral neuropathic pain) and healthy volunteers and to quantify how accurately quantitative sensory testing (QST) discriminates an IT or AO diagnosis. The sample consisted of 60 subjects equally divided (n = 20) into 3 groups: (1) IT, (2) AO, and (3) control. A sequence of 4 QST methods was performed over the dentoalveolar mucosa in the apical maxillar or mandibular area: mechanical detection threshold, pain detection threshold (PDT), dynamic mechanical allodynia, and temporal summation. One-way analysis of variance, Tukey post hoc analyses, and z score transformation were applied to the data. In addition, the receiver operating characteristic curve analysis, diagnostic accuracy, sensitivity, specificity, likelihood ratios, and diagnostic odds ratio of the QST methods were calculated (α = 5%). Somatosensory abnormalities were found for the AO group, which is consistent with a low detection threshold to touch and pain and the presence of mechanical allodynia. For the IT group, no somatosensory abnormality was observed when compared with the control group. The most accurate QST to discriminate the diagnostic differences between IT and healthy individuals is the PDT. The diagnostic differences between AO and healthy individuals and between IT and AO are best discriminated with the mechanical detection threshold, PDT, and dynamic mechanical allodynia. The proposed QST methods may aid in the differential diagnosis between IT and AO with strong accuracy and may be used as complementary diagnostic tests. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Persistence of urinary excretion products of benzo(a)pyrene

International Nuclear Information System (INIS)

Uziel, M.; Haglund, R.; White, D.A.

1988-01-01

Persistence of DNA-adducts has been observed in a variety of experimental circumstances and has been suggested as one potential mechanism for explaining the long-term delay before expression of proliferative disease. In this concept, a stable DNA-adduct, which is a remnant of a prior exposure in a nondividing cell, would not express the genotoxic effect until the cells were stimulated to divide, and thus explain the long-term delay in expression of cancer. An alternative view of the observation of persistent DNA-adducts, described in this communication, is the continuing replenishment of DNA adducts by formation and turnover of these adducts from exposure to a constant supply of the ultimate carcinogenic species derived from a prior exposure. It is of interest to note that virtually all experiments where ''persistent'' adducts have been observed have been high dose exposures. During the course of experiments designed to develop improved methods for detection of DNA adducts and related derivatives derived from polynuclear aromatic hydrocarbons (PAH), we observed that there was a continuous excretion of urinary derivatives of the injected benzo(a)pyrene (BaP) beyond the initial burst of detoxification. This report describes the time dependent distribution of those derivatives in blood, urine, feces, and at the site of injection. 11 refs., 5 figs., 4 tabs

Persistent hole-burning of perylene microcrystallites dispersed in PVA

International Nuclear Information System (INIS)

Mizuno, K.; Matsubara, T.; Sugahara, K.; Aoki-Matsumoto, T.; Ichida, M.; Ando, H.; Itoh, T.

2011-01-01

A persistent hole-burning is observed in β-perylene microcrystallites, which were embedded in poly-vinyl alcohol. By laser light excitation at 22,535 cm -1 and at 10 K, the hole is found at the excitation photon energy. The mechanism of the persistent hole-burning is interpreted in terms of the resolution of microcrystallites into smaller microcrystallites. This is a novel observation of the persistent hole-burning in aromatic microcrystallites. When the specimen, which includes a hole, is annealed at high temperatures, the resolved microcrystallites restore back to the old position as had been. The β-perylene microcrystallite specimen that we have grown was as small as 1.5 nm in average diameter. They are one order smaller in number of molecules included, compared to those that have been reported on aromatic microcrystallites, anthracene for example. Due to this, we were able to observe the 0-0 transition energy, which varied according as the number of molecules involved in the microcrystallites. We also observed the 0-0 absorption (excitation) spectrum, which depends on the molecular arrays in the microcrystallites. The 0-0 transition of a single molecule in poly-vinyl alcohol matrix is anticipated to be located at 22,885 cm -1 .

What is the mechanism for persistent coexistence of drug-susceptible and drug-resistant strains of Streptococcus pneumoniae?

Science.gov (United States)

Colijn, Caroline; Cohen, Ted; Fraser, Christophe; Hanage, William; Goldstein, Edward; Givon-Lavi, Noga; Dagan, Ron; Lipsitch, Marc

2010-01-01

The rise of antimicrobial resistance in many pathogens presents a major challenge to the treatment and control of infectious diseases. Furthermore, the observation that drug-resistant strains have risen to substantial prevalence but have not replaced drug-susceptible strains despite continuing (and even growing) selective pressure by antimicrobial use presents an important problem for those who study the dynamics of infectious diseases. While simple competition models predict the exclusion of one strain in favour of whichever is ‘fitter’, or has a higher reproduction number, we argue that in the case of Streptococcus pneumoniae there has been persistent coexistence of drug-sensitive and drug-resistant strains, with neither approaching 100 per cent prevalence. We have previously proposed that models seeking to understand the origins of coexistence should not incorporate implicit mechanisms that build in stable coexistence ‘for free’. Here, we construct a series of such ‘structurally neutral’ models that incorporate various features of bacterial spread and host heterogeneity that have been proposed as mechanisms that may promote coexistence. We ask to what extent coexistence is a typical outcome in each. We find that while coexistence is possible in each of the models we consider, it is relatively rare, with two exceptions: (i) allowing simultaneous dual transmission of sensitive and resistant strains lets coexistence become a typical outcome, as does (ii) modelling each strain as competing more strongly with itself than with the other strain, i.e. self-immunity greater than cross-immunity. We conclude that while treatment and contact heterogeneity can promote coexistence to some extent, the in-host interactions between strains, particularly the interplay between coinfection, multiple infection and immunity, play a crucial role in the long-term population dynamics of pathogens with drug resistance. PMID:19940002

Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease.

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Pettigrew, Melinda M; Ahearn, Christian P; Gent, Janneane F; Kong, Yong; Gallo, Mary C; Munro, James B; D'Mello, Adonis; Sethi, Sanjay; Tettelin, Hervé; Murphy, Timothy F

2018-04-03

Nontypeable Haemophilus influenzae (NTHi) exclusively colonize and infect humans and are critical to the pathogenesis of chronic obstructive pulmonary disease (COPD). In vitro and animal models do not accurately capture the complex environments encountered by NTHi during human infection. We conducted whole-genome sequencing of 269 longitudinally collected cleared and persistent NTHi from a 15-y prospective study of adults with COPD. Genome sequences were used to elucidate the phylogeny of NTHi isolates, identify genomic changes that occur with persistence in the human airways, and evaluate the effect of selective pressure on 12 candidate vaccine antigens. Strains persisted in individuals with COPD for as long as 1,422 d. Slipped-strand mispairing, mediated by changes in simple sequence repeats in multiple genes during persistence, regulates expression of critical virulence functions, including adherence, nutrient uptake, and modification of surface molecules, and is a major mechanism for survival in the hostile environment of the human airways. A subset of strains underwent a large 400-kb inversion during persistence. NTHi does not undergo significant gene gain or loss during persistence, in contrast to other persistent respiratory tract pathogens. Amino acid sequence changes occurred in 8 of 12 candidate vaccine antigens during persistence, an observation with important implications for vaccine development. These results indicate that NTHi alters its genome during persistence by regulation of critical virulence functions primarily by slipped-strand mispairing, advancing our understanding of how a bacterial pathogen that plays a critical role in COPD adapts to survival in the human respiratory tract.

Persistent luminescence of Eu, Mn, Dy doped calcium phosphates for in-vivo optical imaging

Energy Technology Data Exchange (ETDEWEB)

Rosticher, Céline [UPMC Univ Paris 06, CNRS, UMR 7574, Chimie de la Matière Condensée de Paris, Collège de France, 11 place Marcelin Berthelot, 75231 Paris Cedex 05 (France); Viana, Bruno, E-mail: bruno.viana@chimie-paristech.fr [PSL Research University, Chimie ParisTech-CNRS, Institut de Recherche de Chimie Paris, 11 rue Pierre et Marie Curie, 75005 Paris (France); Maldiney, Thomas; Richard, Cyrille [Unité de Technologies Chimiques et Biologiques pour la Santé, CNRS, UMR 8258, Paris Cedex F-75270 (France); Inserm U1022, Paris Cedex F-75270 (France); Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Sorbonne Paris Cité, Paris Cedex F-75270 (France); Chanéac, Corinne, E-mail: corinne.chaneac@upmc.fr [UPMC Univ Paris 06, CNRS, UMR 7574, Chimie de la Matière Condensée de Paris, Collège de France, 11 place Marcelin Berthelot, 75231 Paris Cedex 05 (France)

2016-02-15

Biocompatible nanoparticles possessing persistent luminescence properties offer attractive possibilities for in vivo imaging applications as it allows an excitation of the sensors outside the animal before injection and a long-lasting emission of light. Here we report the development of highly biocompatible calcium phosphate nanoparticles doped with europium, Mn{sup 2+} and Ln{sup 3+} (Ln{sup 3+}=Dy{sup 3+}, Pr{sup 3+}) ions synthesized by hydrothermal route and tailored to present red-near infrared persistent luminescence after UV excitation. Nanosize biphasic HAp/β-TCP compounds with sphere and rod-shaped were obtained. Two emission bands in the red-near infrared range were observed and attributed to {sup 4}T{sub 1}→{sup 6}A{sub 1} transitions of Mn{sup 2+} ions in HAp/β-TCP. An annealing treatment in reductive atmosphere post-synthesis was essential to reveal persistent luminescence properties. Indeed, such thermal treatment allows reducing Eu{sup 3+} ions in Eu{sup 2+} ions and generating required defaults as oxygen vacancies in the crystal necessary for red emission in accordance with persistent luminescence mechanism. These nanoparticles have been tested for the first time for in vivo imaging on small animal as proof of concept of prospective highly biocompatible nanoprobes. - Highlights: • Biocompatible HAp/b-TCP nanoparticles with persistent luminescence are investigated. • Reducing step induced persistent luminescence. • Nanoparticles have been tested for the first time for in vivo imaging. • Persistent luminescence is observed after 10 min in vivo.

Segmental neuropathic pain does not develop in male rats with complete spinal transections.

Science.gov (United States)

Hubscher, Charles H; Kaddumi, Ezidin G; Johnson, Richard D

2008-10-01

In a previous study using male rats, a correlation was found between the development of "at-level" allodynia in T6-7 dermatomes following severe T8 spinal contusion injury and the sparing of some myelinated axons within the core of the lesion epicenter. To further test our hypothesis that this sparing is important for the expression of allodynia and the supraspinal plasticity that ensues, an injury that severs all axons (i.e., a complete spinal cord transection) was made in 15 male rats. Behavioral assessments were done at level throughout the 30-day recovery period followed by terminal electrophysiological recordings (urethane anesthesia) from single medullary reticular formation (MRF) neurons receiving convergent nociceptive inputs from receptive fields above, at, and below the lesion level. None of the rats developed signs of at-level allodynia (versus 18 of 26 male rats following severe contusion). However, the terminal recording (206 MRF neurons) data resembled those obtained previously post-contusion. That is, there was evidence of neuronal hyper-excitability (relative to previous data from intact controls) to high- and low-threshold mechanical stimulation for "at-level" (dorsal trunk) and "above-level" (eyelids and face) cutaneous territories. These results, when combined with prior data on intact controls and severe/moderate contusions, indicate that (1) an anatomically incomplete injury (some lesion epicenter axonal sparing) following severe contusion is likely important for the development of allodynia and (2) the neuronal hyper-excitability at the level of the medulla is likely involved in nociceptive processes that are not directly related to the conscious expression of pain-like avoidance behaviors that are being used as evidence of allodynia.

Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain

Directory of Open Access Journals (Sweden)

Elphick Maurice R

2009-07-01

Full Text Available Abstract Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG, and the related compound N-palmitoylethanolamine (PEA, in neuropathic spinal cord. Selective spinal nerve ligation (SNL in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord. Chronic daily treatment with minocycline (30 mg/kg, ip for 14 days significantly reduced the development of mechanical allodynia at days 5, 10 and 14 post-SNL surgery, compared to vehicle-treated SNL rats (P P P P P

Dualities in persistent (co)homology

International Nuclear Information System (INIS)

De Silva, Vin; Morozov, Dmitriy; Vejdemo-Johansson, Mikael

2011-01-01

We consider sequences of absolute and relative homology and cohomology groups that arise naturally for a filtered cell complex. We establish algebraic relationships between their persistence modules, and show that they contain equivalent information. We explain how one can use the existing algorithm for persistent homology to process any of the four modules, and relate it to a recently introduced persistent cohomology algorithm. We present experimental evidence for the practical efficiency of the latter algorithm

The role of metabolism in bacterial persistence

Directory of Open Access Journals (Sweden)

Stephanie M. Amato

2014-03-01

Full Text Available Bacterial persisters are phenotypic variants with extraordinary tolerances toward antibiotics. Persister survival has been attributed to inhibition of essential cell functions during antibiotic stress, followed by reversal of the process and resumption of growth upon removal of the antibiotic. Metabolism plays a critical role in this process, since it participates in the entry, maintenance, and exit from the persister phenotype. Here, we review the experimental evidence that demonstrates the importance of metabolism to persistence, highlight the successes and potential for targeting metabolism in the search for anti-persister therapies, and discuss the current methods and challenges to understand persister physiology.

Introduction: Persistent Modelling

DEFF Research Database (Denmark)

Ayres, Phil

2012-01-01

This introduction to 'Persistent Modelling – an extended role for architectural representation' identifies how the book probes the relationship between representation and the represented, in an architectural context. It discusses how the book presents an examination and discussion of historical......, familiar contemporary and, perhaps, not so familiar emerging manifestations of this relation. What persists from this probing, fully intact, is that representation and the represented remain inextricably related in our contemporary and emerging practices. What comes into focus is that the nature...

Objective sensory evaluation of the spread of complex regional pain syndrome.

Science.gov (United States)

Edinger, Lara; Schwartzman, Robert J; Ahmad, Ayesha; Erwin, Kirsten; Alexander, Guillermo M

2013-01-01

The spread of complex regional pain syndrome (CRPS) has been well documented. Many severe refractory long-standing patients have total body pain (TBP) that evolved from a single extremity injury. The purpose of this study was to document by objective sensory threshold testing the extent of body area involvement in 20 long-standing patients with CRPS who have TBP. A comparison of sensory threshold testing parameters between 20 long-standing refractory patients with CRPS who have TBP versus 10 healthy participants. Twenty patients with CRPS who stated that they suffered from total body pain were chosen from the Drexel University College of Medicine CRPS database. They were compared to 10 healthy participants that were age and gender matched to the patients with CRPS. The sensory parameters tested were: skin temperature; static and mechanical allodynia; thermal allodynia; mechanical hyperalgesia; after sensations following all sensory tests. The sites chosen for testing in the patients with CRPS were the most painful area in each of 8 body regions that comprised the total body area. Five patients with CRPS had signs of CRPS over 100% of their body (20%). One patient had pain over 87% and another had pain over 90% of their body area. The average percentage of body involvement was 62% (range 37% - 100%). All patients with CRPS had at least one sensory parameter abnormality in all body regions. All patients with CRPS had lower pain thresholds for static allodynia in all body areas, while 50% demonstrated a lower threshold for dynamic allodynia in all body regions compared to the healthy participants. Cold allodynia had a higher median pain rating on the Likert pain scale in all body areas versus healthy participants except for the chest, abdomen, and back. Eighty-five percent of the patients with CRPS had a significantly lower pain threshold for mechanical hyperalgesia in all body areas compared to the healthy participants. After sensations occurred after all sensory

Mycobacterium Lysine ε-aminotransferase is a novel alarmone metabolism related persister gene via dysregulating the intracellular amino acid level.

Science.gov (United States)

Duan, Xiangke; Li, Yunsong; Du, Qinglin; Huang, Qinqin; Guo, Siyao; Xu, Mengmeng; Lin, Yanping; Liu, Zhidong; Xie, Jianping

2016-01-25

Bacterial persisters, usually slow-growing, non-replicating cells highly tolerant to antibiotics, play a crucial role contributing to the recalcitrance of chronic infections and treatment failure. Understanding the molecular mechanism of persister cells formation and maintenance would obviously inspire the discovery of new antibiotics. The significant upregulation of Mycobacterium tuberculosis Rv3290c, a highly conserved mycobacterial lysine ε-aminotransferase (LAT) during hypoxia persistent model, suggested a role of LAT in persistence. To test this, a lat deleted Mycobacterium smegmatis was constructed. The expression of transcriptional regulator leucine-responsive regulatory protein (LrpA) and the amino acids abundance in M. smegmatis lat deletion mutants were lowered. Thus, the persistence capacity of the deletion mutant was impaired upon norfloxacin exposure under nutrient starvation. In summary, our study firstly reported the involvement of mycobacterium LAT in persister formation, and possibly through altering the intracellular amino acid metabolism balance.

Ranolazine attenuation of CFA-induced mechanical hyperalgesia.

Science.gov (United States)

Casey, Gregory P; Roberts, Jomar S; Paul, Dennis; Diamond, Ivan; Gould, Harry J

2010-01-01

To determine whether ranolazine, a new anti-angina medication, could be an effective analgesic agent in complete Freund's adjuvant-induced inflammatory pain. Plantar injection of complete Freund's adjuvant (CFA) produces an extended period of hyperalgesia that is associated with a dramatic up-regulation of Na(v) 1.7 sodium channels in populations of large and small dorsal root ganglion neurons related to the injection site. Ranolazine appears to produce its anti-angina effect through blocking the late sodium current associated with the voltage-gated sodium channel, Na(v) 1.5. Because ranolazine also inhibits Na(v) 1.7, and 1.8, we sought to determine whether it could be an effective analgesic agent in CFA-induced inflammatory pain. Baseline determinations of withdrawal from thermal and mechanical stimulation were made in Sprague-Dawley rats ( approximately 300-350 x g). Following determination of baseline, one hindpaw in each group was injected with 0.1 mL of CFA. The contralateral paw received saline. Thermal and mechanical stimulation was repeated on the third day post-injection. Vehicle (0.9% isotonic saline; pH 3.0) or ranolazine was then administered in randomized and blinded doses either by intraperitoneal (ip) injection (0, 10, 20, and 50 mg/kg) or by oral gavage (po; 0, 20, 50, 100, and 200 mg/kg). Animals were again tested 30 minutes (ip) and 1 hour (po) after drug administration. Ranolazine produced dose-dependant analgesia on mechanical allodynia induced by CFA injection, but had no effect on thermal hyperalgesia. Ranolazine's potential as a new option for managing both angina and chronic inflammatory pain warrants further study.

Persistence of Coxsackievirus B4 in pancreatic ductal-like cells results in cellular and viral changes.

Science.gov (United States)

Alidjinou, E K; Engelmann, I; Bossu, J; Villenet, C; Figeac, M; Romond, M-B; Sané, F; Hober, D

2017-10-03

Although known as cytolytic viruses, group B coxackieviruses (CVB) are able to establish a persistent infection in vitro and in vivo. Viral persistence has been reported as a key mechanism in the pathogenesis of CVB-associated chronic diseases such as type 1 diabetes (T1D). The impact of CVB4 persistence on human pancreas ductal-like cells was investigated. A persistent CVB4 infection was established in ductal-like cells. PDX-1 expression, resistance to CVB4-induced lysis and CAR expression were evaluated. The profile of cellular microRNAs (miRNAs) was investigated through miRNA-sequencing. Viral phenotypic changes were examined, and genomic modifications were assessed by sequencing of the viral genome. The CVB4 persistence in ductal-like cells was productive, with continuous release of infectious particles. Persistently infected cells displayed a resistance to CVB4-induced lysis upon superinfection and expression of PDX-1 and CAR was decreased. These changes were maintained even after virus clearance. The patterns of cellular miRNA expression in mock-infected and in CVB4-persistently infected ductal-like cells were clearly different. The persistent infection-derived virus (PIDV) was still able to induce cytopathic effect but its plaques were smaller than the parental virus. Several mutations appeared in various PIDV genome regions, but amino acid substitutions did not affect the predicted site of interaction with CAR. Cellular and viral changes occur during persistent infection of human pancreas ductal-like cells with CVB4. The persistence of cellular changes even after virus clearance supports the hypothesis of a long-lasting impact of persistent CVB infection on the cells.

Forensic Excavation of Rock Masses: A Technique to Investigate Discontinuity Persistence

Science.gov (United States)

Shang, J.; Hencher, S. R.; West, L. J.; Handley, K.

2017-11-01

True persistence of rock discontinuities (areas with insignificant tensile strength) is an important factor controlling the engineering behaviour of fractured rock masses, but is extremely difficult to quantify using current geological survey methodologies, even where there is good rock exposure. Trace length as measured in the field or using remote measurement devices is actually only broadly indicative of persistence for rock engineering practice and numerical modelling. Visible traces of discontinuities are treated as if they were open fractures within rock mass classifications, despite many such traces being non-persistent and actually retaining considerable strength. The common assumption of 100% persistence, based on trace length, is generally extremely conservative in terms of strength and stiffness, but not always so and may lead to a wrong prediction of failure mechanism or of excavatability. Assuming full persistence would give hopelessly incorrect predictions of hydraulic conductivity. A new technique termed forensic excavation of rock masses is introduced, as a procedure for directly investigating discontinuity persistence. This technique involves non-explosive excavation of rock masses by injecting an expansive chemical splitter along incipient discontinuities. On expansion, the splitter causes the incipient traces to open as true joints. Experiments are described in which near-planar rock discontinuities, through siltstone and sandstone, were opened up by injecting the splitter into holes drilled along the lines of visible traces of the discontinuities in the laboratory and in the field. Once exposed the surfaces were examined to investigate the pre-existing persistence characteristics of the incipient discontinuities. One conclusion from this study is that visible trace length of a discontinuity can be a poor indicator of true persistence (defined for a fracture area with negligible tensile strength). An observation from this series of experiments

Exoproteome analysis reveals higher abundance of proteins linked to alkaline stress in persistent Listeria monocytogenes strains.

Science.gov (United States)

Rychli, Kathrin; Grunert, Tom; Ciolacu, Luminita; Zaiser, Andreas; Razzazi-Fazeli, Ebrahim; Schmitz-Esser, Stephan; Ehling-Schulz, Monika; Wagner, Martin

2016-02-02

The foodborne pathogen Listeria monocytogenes, responsible for listeriosis a rare but severe infection disease, can survive in the food processing environment for month or even years. So-called persistent L. monocytogenes strains greatly increase the risk of (re)contamination of food products, and are therefore a great challenge for food safety. However, our understanding of the mechanism underlying persistence is still fragmented. In this study we compared the exoproteome of three persistent strains with the reference strain EGDe under mild stress conditions using 2D differential gel electrophoresis. Principal component analysis including all differentially abundant protein spots showed that the exoproteome of strain EGDe (sequence type (ST) 35) is distinct from that of the persistent strain R479a (ST8) and the two closely related ST121 strains 4423 and 6179. Phylogenetic analyses based on multilocus ST genes showed similar grouping of the strains. Comparing the exoproteome of strain EGDe and the three persistent strains resulted in identification of 22 differentially expressed protein spots corresponding to 16 proteins. Six proteins were significantly increased in the persistent L. monocytogenes exoproteomes, among them proteins involved in alkaline stress response (e.g. the membrane anchored lipoprotein Lmo2637 and the NADPH dehydrogenase NamA). In parallel the persistent strains showed increased survival under alkaline stress, which is often provided during cleaning and disinfection in the food processing environments. In addition, gene expression of the proteins linked to stress response (Lmo2637, NamA, Fhs and QoxA) was higher in the persistent strain not only at 37 °C but also at 10 °C. Invasion efficiency of EGDe was higher in intestinal epithelial Caco2 and macrophage-like THP1 cells compared to the persistent strains. Concurrently we found higher expression of proteins involved in virulence in EGDe e.g. the actin-assembly-inducing protein ActA and the

From acute to persistent low back pain: a longitudinal investigation of somatosensory changes using quantitative sensory testing—an exploratory study

Directory of Open Access Journals (Sweden)

Anna Marcuzzi

2018-04-01

Conclusion:. Changes in mechanical pain sensitivity occurring in the subacute stage warrant further longitudinal evaluation to better understand the role of somatosensory changes in the development of persistent LBP. Pain-related cognitions at baseline distinguished persistent from the recovered LBP groups, emphasizing the importance of concurrent evaluation of psychological contributors in acute LBP.

Effects of constant immigration on the dynamics and persistence of stable and unstable Drosophila populations

Science.gov (United States)

Dey, Snigdhadip; Joshi, Amitabh

2013-01-01

Constant immigration can stabilize population size fluctuations but its effects on extinction remain unexplored. We show that constant immigration significantly reduced extinction in fruitfly populations with relatively stable or unstable dynamics. In unstable populations with oscillations of amplitude around 1.5 times the mean population size, persistence and constancy were unrelated. Low immigration enhanced persistence without affecting constancy whereas high immigration increased constancy without enhancing persistence. In relatively stable populations with erratic fluctuations of amplitude close to the mean population size, both low and high immigration enhanced persistence. In these populations, the amplitude of fluctuations relative to mean population size went down due to immigration, and their dynamics were altered to low-period cycles. The effects of immigration on the population size distribution and intrinsic dynamics of stable versus unstable populations differed considerably, suggesting that the mechanisms by which immigration reduced extinction risk depended on underlying dynamics in complex ways. PMID:23470546

Spatial patterns of persistent neural activity vary with the behavioral context of short-term memory.

Science.gov (United States)

Daie, Kayvon; Goldman, Mark S; Aksay, Emre R F

2015-02-18

A short-term memory can be evoked by different inputs and control separate targets in different behavioral contexts. To address the circuit mechanisms underlying context-dependent memory function, we determined through optical imaging how memory is encoded at the whole-network level in two behavioral settings. Persistent neural activity maintaining a memory of desired eye position was imaged throughout the oculomotor integrator after saccadic or optokinetic stimulation. While eye position was encoded by the amplitude of network activity, the spatial patterns of firing were context dependent: cells located caudally generally were most persistent following saccadic input, whereas cells located rostrally were most persistent following optokinetic input. To explain these data, we computationally identified four independent modes of network activity and found these were differentially accessed by saccadic and optokinetic inputs. These results show how a circuit can simultaneously encode memory value and behavioral context, respectively, in its amplitude and spatial pattern of persistent firing. Copyright © 2015 Elsevier Inc. All rights reserved.

Persistent and recurrent hyperparathyroidism.

Science.gov (United States)

Guerin, Carole; Paladino, Nunzia Cinzia; Lowery, Aoife; Castinetti, Fréderic; Taieb, David; Sebag, Fréderic

2017-06-01

Despite remarkable progress in imaging modalities and surgical management, persistence or recurrence of primary hyperparathyroidism (PHPT) still occurs in 2.5-5% of cases of PHPT. The aim of this review is to expose the management of persistent and recurrent hyperparathyroidism. A literature search was performed on MEDLINE using the search terms "recurrent" or "persistent" and "hyperparathyroidism" within the past 10 years. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. Before considering reoperation, the surgeon must confirm the diagnosis of PHPT. Then, the patient must be evaluated with new imaging modalities. A single adenoma is found in 68% of cases, multiglandular disease in 28%, and parathyroid carcinoma in 3%. Others causes (<1%) include parathyromatosis and graft recurrence. The surgeon must balance the benefits against the risks of a reoperation (permanent hypocalcemia and recurrent laryngeal nerve palsy). If surgery is necessary, a focused approach can be considered in cases of significant imaging foci, but in the case of multiglandular disease, a bilateral neck exploration could be necessary. Patients with multiple endocrine neoplasia syndromes are at high risk of recurrence and should be managed regarding their hereditary pathology. The cure rate of persistent-PHPT or recurrent-PHPT in expert centers is estimated from 93 to 97%. After confirming the diagnosis of PHPT, patients with persistent-PHPT and recurrent-PHPT should be managed in an expert center with all dedicated competencies.

Persistence of interest in science, technology, engineering and mathematics: An analysis of persisting and non-persisting students

Science.gov (United States)

White, Jeffry L.

While there has been an increase in enrollment, interest in science, technology, engineering, and mathematics (STEM) has been declining on college campuses since 1967. Higher enrollment does not transfer to an increase in the number of minorities in the STEM fields. The majority-minority enrollment ratio is nearly 2:1 but the gap widens to 4:1 when it comes to graduation. In fact, underrepresented minorities (URM) earned only 12% of the STEM degrees awarded in 1998. When the higher attrition and lower graduation rates of URM are scrutinized, upwards of 60% changed majors or dropped out of STEM. Further investigation reveals the most frequently cited reasons for departure were loss of initial interest, developed a greater interest in another field, or were turned off by the STEM disciplines. A primarily exploratory study was conducted into the conditions necessary for academic interest in the STEM fields to persist. A model based on student engagement (Astin, 1977) and interest operations (Prenzel, 1988a) theories was used with a random sample of URM at universities participating in the Ohio Science and Engineering Alliance. Survey research was employed to investigate interest development and the effect of student retention programs and activities on such interest. The latter part of the study could not be fully examined when 95% reported not utilizing retention services. For the section on interest, an online survey using a 5-point Likert scale was validated using principal components analysis. A binominal logistic regression was used to predict membership in one of two possible groups: persisters and students at-risk for not persisting. The major conclusions are: (1) While 3 variables (feelings, learning and difficulty) were statistically significant only one, feelings was substantively significant. (2) Persistence increased 80.9% for each 1-unit increase in feelings and 9.9% for learning. (3) Persistence decreased 19.8% for each one-unit increase in difficulty

Specific non-monotonous interactions increase persistence of ecological networks.

Science.gov (United States)

Yan, Chuan; Zhang, Zhibin

2014-03-22

The relationship between stability and biodiversity has long been debated in ecology due to opposing empirical observations and theoretical predictions. Species interaction strength is often assumed to be monotonically related to population density, but the effects on stability of ecological networks of non-monotonous interactions that change signs have not been investigated previously. We demonstrate that for four kinds of non-monotonous interactions, shifting signs to negative or neutral interactions at high population density increases persistence (a measure of stability) of ecological networks, while for the other two kinds of non-monotonous interactions shifting signs to positive interactions at high population density decreases persistence of networks. Our results reveal a novel mechanism of network stabilization caused by specific non-monotonous interaction types through either increasing stable equilibrium points or reducing unstable equilibrium points (or both). These specific non-monotonous interactions may be important in maintaining stable and complex ecological networks, as well as other networks such as genes, neurons, the internet and human societies.

Colossal X-Ray-Induced Persistent Photoconductivity in Current-Perpendicular-to-Plane Ferroelectric/Semiconductor Junctions

KAUST Repository

Hu, Weijin

2017-12-07

Persistent photoconductivity (PPC) is an intriguing physical phenomenon, where electric conduction is retained after the termination of electromagnetic radiation, which makes it appealing for applications in a wide range of optoelectronic devices. So far, PPC has been observed in bulk materials and thin-film structures, where the current flows in the plane, limiting the magnitude of the effect. Here using epitaxial Nb:SrTiO3/Sm0.1Bi0.9FeO3/Pt junctions with a current-perpendicular-to-plane geometry, a colossal X-ray-induced PPC (XPPC) is achieved with a magnitude of six orders. This PPC persists for days with negligible decay. Furthermore, the pristine insulating state could be fully recovered by thermal annealing for a few minutes. Based on the electric transport and microstructure analysis, this colossal XPPC effect is attributed to the X-ray-induced formation and ionization of oxygen vacancies, which drives nonvolatile modification of atomic configurations and results in the reduction of interfacial Schottky barriers. This mechanism differs from the conventional mechanism of photon-enhanced carrier density/mobility in the current-in-plane structures. With their persistent nature, such ferroelectric/semiconductor heterojunctions open a new route toward X-ray sensing and imaging applications.

Persistence Characteristics of Australian Rainfall Anomalies

Science.gov (United States)

Simmonds, Ian; Hope, Pandora

1997-05-01

Using 79 years (1913-1991) of Australian monthly precipitation data we examined the nature of the persistence of rainfall anomalies. Analyses were performed for four climate regions covering the country, as well as for the entire Australian continent. We show that rainfall over these regions has high temporal variability and that annual rainfall amounts over all five sectors vary in phase and are, with the exception of the north-west region, significantly correlated with the Southern Oscillation Index (SOI). These relationships were particularly strong during the spring season.It is demonstrated that Australian rainfall exhibits statistically significant persistence on monthly, seasonal, and (to a limited extent) annual time-scales, up to lags of 3 months and one season and 1 year. The persistence showed strong seasonal dependence, with each of the five regions showing memory out to 4 or 5 months from winter and spring. Many aspects of climate in the Australasian region are known to have undergone considerable changes about 1950. We show this to be true for persistence also; its characteristics identified for the entire record were present during the 1951--1980 period, but virtually disappeared in the previous 30-year period.Much of the seasonal distribution of rainfall persistence on monthly time-scales, particularly in the east, is due to the influence of the SOI. However, most of the persistence identified in winter and spring in the north-west is independent of the ENSO phenomenon.Rainfall anomalies following extreme dry and wet months, seasons and years (lowest and highest two deciles) persisted more than would be expected by chance. For monthly extreme events this was more marked in the winter semester for the wet events, except in the south-east region. In general, less persistence was found for the extreme seasons. Although the persistence of dry years was less than would have been expected by chance, the wet years appear to display persistence.

Phytotherapeutic activity of curcumol: Isolation, GC-MS identification, and assessing potentials against acute and subchronic hyperglycemia, tactile allodynia, and hyperalgesia.

Science.gov (United States)

Raafat, Karim M; Omar, Amal G

2016-08-01

Curcumol has recently attracted special attention due to its potential activities in many chronic disorders. Moreover, the traditional role of turmeric [Curcuma longa L. (Zingiberaceae)] in suppression of hyperglycemia is of great interest. The present work explores the potential acute and subchronic antihyperglycemic, antinociceptive, and in vivo antioxidant effects of curcumol in alloxan-diabetic mice. Bio-guided fractionation, column-chromatography, and GC-MS were utilized to identify the most active compound of turmeric (curcumol). Turmeric (25, 50, and 100 mg/kg), the curcumol rich fraction (CRF) (7 mg/kg), and curcumol (20, 30, and 40 mg/kg) were assessed for their acute (6 h) and subchronic (8 d) antihyperglycemic potentials and antinociceptive effects (8 weeks) were measured, using hot-plate and tail-flick latencies and von-Frey filaments method and in vivo antioxidant effects in alloxan-diabetic mice. The most-active turmeric fraction was found to be rich in curcumol (45.5%) using GC-MS analysis method. The results proved that the highest dose levels of turmeric extract and curcumol exerted remarkable hypoglycemic activity with 41.4 and 39.3% drop in the mice glucose levels after 6 h, respectively. Curcumol (40 mg/kg) was found to be 9.4% more potent than turmeric extract (100 mg/kg) in subchronic management of diabetes. Curcumol also showed a significant improvement of peripheral nerve function as observed from the latency and tactile tests. The antioxidant potential of curcumol may cause its ability to ameliorate diabetes and diabetes-related complications. Curcumol, a natural metabolite with a good safety-profile, showed results comparable with tramadol in reversing diabetes-induced tactile allodynia and hyperalgesia.

Keratinocyte expression of inflammatory mediators plays a crucial role in substance P-induced acute and chronic pain

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Wei Tzuping

2012-07-01

Full Text Available Abstract Tibia fracture in rats followed by cast immobilization leads to nociceptive, trophic, vascular and bone-related changes similar to those seen in Complex Regional Pain Syndrome (CRPS. Substance P (SP mediated neurogenic inflammation may be responsible for some of the signs of CRPS in humans. We therefore hypothesized that SP acting through the SP receptor (NK1 leads to the CRPS-like changes found in the rat model. In the present study, we intradermally injected rats with SP and monitored hindpaw mechanical allodynia, temperature, and thickness as well as tissue levels of tumor necrosis factor-α (TNF-α, interleukin 1β (IL-1β, interleukin 6 (IL-6, and nerve growth factor-β (NGF for 72 h. Anti-NGF antibody was utilized to block the effects of SP-induced NGF up-regulation. Fracture rats treated with the selective NK1 receptor antagonist LY303870 prior to cast removal were assessed for BrdU, a DNA synthesis marker, incorporation in skin cells to examine cellular proliferation. Bone microarchitecture was measured using micro computed tomography (μCT. We observed that: (1 SP intraplantar injection induced mechanical allodynia, warmth and edema as well as the expression of nociceptive mediators in the hindpaw skin of normal rats, (2 LY303870 administered intraperitoneally after fracture attenuated allodynia, hindpaw unweighting, warmth, and edema, as well as cytokine and NGF expression, (3 LY303870 blocked fracture-induced epidermal thickening and BrdU incorporation after fracture, (4 anti-NGF antibody blocked SP-induced allodynia but not warmth or edema, and (5 LY303870 had no effect on bone microarchitecture. Collectively our data indicate that SP acting through NK1 receptors supports the nociceptive and vascular components of CRPS, but not the bone-related changes.

Influence of dosing times on cisplatin-induced peripheral neuropathy in rats

International Nuclear Information System (INIS)

Seto, Yoshihiro; Okazaki, Fumiyasu; Horikawa, Keiji; Zhang, Jing; Sasaki, Hitoshi; To, Hideto

2016-01-01

Although cis-diamminedichloro-platinum (CDDP) exhibits strong therapeutic effects in cancer chemotherapy, its adverse effects such as peripheral neuropathy, nephropathy, and vomiting are dose-limiting factors. Previous studies reported that chronotherapy decreased CDDP-induced nephropathy and vomiting. In the present study, we investigated the influence of dosing times on CDDP-induced peripheral neuropathy in rats. CDDP (4 mg/kg) was administered intravenously at 5:00 or 17:00 every 7 days for 4 weeks to male Sprague–Dawley rats, and saline was given to the control group. To assess the dosing time dependency of peripheral neuropathy, von-Frey test and hot-plate test were performed. In order to estimate hypoalgesia, the hot-plate test was performed in rats administered CDDP weekly for 4 weeks. On day 28, the withdrawal latency to thermal stimulation was significantly prolonged in the 17:00-treated group than in the control and 5:00-treated groups. When the von-Frey test was performed to assess mechanical allodynia, the withdrawal threshold was significantly lower in the 5:00 and 17:00-treated groups than in the control group on day 6 after the first CDDP dose. The 5:00-treated group maintained allodynia throughout the experiment with the repeated administration of CDDP, whereas the 17:00-treated group deteriorated from allodynia to hypoalgesia. It was revealed that the severe of CDDP-induced peripheral neuropathy was inhibited in the 5:00-treated group, whereas CDDP-treated groups exhibited mechanical allodynia. These results suggested that the selection of an optimal dosing time ameliorated CDDP-induced peripheral neuropathy. The online version of this article (doi:10.1186/s12885-016-2777-0) contains supplementary material, which is available to authorized users

Neuroendocrine Associations Underlying the Persistent Therapeutic Effects of Classic Serotonergic Psychedelics

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Emmanuelle A. D. Schindler

2018-03-01

Full Text Available Recent reports on the effects of psychedelic-assisted therapies for mood disorders and addiction, as well as the effects of psychedelics in the treatment of cluster headache, have demonstrated promising therapeutic results. In addition, the beneficial effects appear to persist well after limited exposure to the drugs, making them particularly appealing as treatments for chronic neuropsychiatric and headache disorders. Understanding the basis of the long-lasting effects, however, will be critical for the continued use and development of this drug class. Several mechanisms, including biological and psychological ones, have been suggested to explain the long-lasting effects of psychedelics. Actions on the neuroendocrine system are some such mechanisms that warrant further investigation in the study of persisting psychedelic effects. In this report, we review certain structural and functional neuroendocrinological pathologies associated with neuropsychiatric disorders and cluster headache. We then review the effects that psychedelic drugs have on those systems and provide preliminary support for potential long-term effects. The circadian biology of cluster headache is of particular relevance in this area. We also discuss methodologic considerations for future investigations of neuroendocrine system involvement in the therapeutic benefits of psychedelic drugs.

Cognitive-behavioral mechanisms in a pain-avoidance and a pain-persistence treatment for high-risk fibromyalgia patients

NARCIS (Netherlands)

Koulil, S. van; Kraaimaat, F.W.; Lankveld, W.G.J.M. van; Helmond, T. van; Vedder, A.; Hoorn, H. van; Donders, A.R.T.; Thieme, K.; Cats, H.; Riel, P.L. van; Evers, A.W.M.

2011-01-01

OBJECTIVE: The heterogeneity of cognitive-behavioral patterns in patients with fibromyalgia (FM) has been proposed to underlie the variability in treatment outcomes. It has previously been shown that pain-avoidance and pain-persistence treatments tailored to the patient's pattern are effective in

Contributions to Persistence Theory

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Du Dong

2014-12-01

Full Text Available Persistence theory discussed in this paper is an application of algebraic topology (Morse Theory [29] to Data Analysis, precisely to qualitative understanding of point cloud data, or PCD for short. PCD can be geometrized as a filtration of simplicial complexes (Vietoris-Rips complex [25] [36] and the homology changes of these complexes provide qualitative information about the data. Bar codes describe the changes in homology with coefficients in a fixed field. When the coefficient field is ℤ2, the calculation of bar codes is done by ELZ algorithm (named after H. Edelsbrunner, D. Letscher, and A. Zomorodian [20]. When the coefficient field is ℝ, we propose an algorithm based on the Hodge decomposition [17]. With Dan Burghelea and Tamal K. Dey we developed a persistence theory which involves level sets discussed in Section 4. We introduce and discuss new computable invariants, the “relevant level persistence numbers” and the “positive and negative bar codes”, and explain how they are related to the bar codes for level persistence. We provide enhancements and modifications of ELZ algorithm to calculate such invariants and illustrate them by examples.

Traumatic osteoarthritis-induced persistent mechanical hyperalgesia in a rat model of anterior cruciate ligament transection plus a medial meniscectomy

Directory of Open Access Journals (Sweden)

Tsai HC

2017-12-01

after 5 weeks but persisted. There were no differences in thermal hyperalgesia or motor coordination. Conclusion: Traumatic OA induced mechanical hyperalgesia but did not cause thermal hyperalgesia or influence motor coordination. Furthermore, to investigate chronic pain induced by OA, the observational period should be at least 5 weeks after the intervention. These findings may help in further research and improve our understanding of traumatic OA-induced pain mechanisms. Keywords: traumatic osteoarthritis, acute and chronic pain, mechanical hyperalgesia, thermal hyperalgesia, motor coordination

Gate-controlled switching between persistent and inverse persistent spin helix states

International Nuclear Information System (INIS)

Yoshizumi, K.; Sasaki, A.; Kohda, M.; Nitta, J.

2016-01-01

We demonstrate gate-controlled switching between persistent spin helix (PSH) state and inverse PSH state, which are detected by quantum interference effect on magneto-conductance. These special symmetric spin states showing weak localization effect give rise to a long spin coherence when the strength of Rashba spin-orbit interaction (SOI) is close to that of Dresselhaus SOI. Furthermore, in the middle of two persistent spin helix states, where the Rashba SOI can be negligible, the bulk Dresselhaus SOI parameter in a modulation doped InGaAs/InAlAs quantum well is determined.

Gate-controlled switching between persistent and inverse persistent spin helix states

Energy Technology Data Exchange (ETDEWEB)

Yoshizumi, K.; Sasaki, A.; Kohda, M.; Nitta, J. [Department of Materials Science, Tohoku University, Sendai 980-8579 (Japan)

2016-03-28

We demonstrate gate-controlled switching between persistent spin helix (PSH) state and inverse PSH state, which are detected by quantum interference effect on magneto-conductance. These special symmetric spin states showing weak localization effect give rise to a long spin coherence when the strength of Rashba spin-orbit interaction (SOI) is close to that of Dresselhaus SOI. Furthermore, in the middle of two persistent spin helix states, where the Rashba SOI can be negligible, the bulk Dresselhaus SOI parameter in a modulation doped InGaAs/InAlAs quantum well is determined.

Demographics of antibiotic persistence

DEFF Research Database (Denmark)

Kollerova, Silvia; Jouvet, Lionel; Steiner, Ulrich

Persister cells, cells that can survive antibiotic exposure but lack heritable antibiotic resistance, are assumed to play a crucial role for the evolution of antibiotic resistance. Persistence is a stage associated with reduced metabolic activity. Most previous studies have been done on batch...... even play a more prominent role for the evolution of resistance and failures of medical treatment by antibiotics as currently assumed....

Genomic and transcriptomic analysis of Escherichia coli strains associated with persistent and transient bovine mastitis and the role of colanic acid

Science.gov (United States)

Escherichia coli is a leading cause of bacterial mastitis in dairy cattle. This infection is most often transient in nature, causing an infection that lasts 2–3 days. However, E. coli has been shown to cause a persistent infection in a minority of cases. The mechanisms that allow for a persistent E....

Emergence and fate of cyclic volatile polydimethylsiloxanes (D4, D5) in municipal waste streams: release mechanisms, partitioning and persistence in air, water, soil and sediments.

Science.gov (United States)

Surita, Sharon C; Tansel, Berrin

2014-01-15

Siloxane use in consumer products (i.e., fabrics, paper, concrete, wood, adhesive surfaces) has significantly increased in recent years due to their excellent water repelling and antimicrobial characteristics. The objectives of this study were to evaluate the release mechanisms of two siloxane compounds, octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5), which have been detected both at landfills and wastewater treatment plants, estimate persistence times in different media, and project release quantities over time in relation to their increasing use. Analyses were conducted based on fate and transport mechanisms after siloxanes enter waste streams. Due to their high volatility, the majority of D4 and D5 end up in the biogas during decomposition. D5 is about ten times more likely to partition into the solid phase (i.e., soil, biosolids). D5 concentrations in the wastewater influent and biogas are about 16 times and 18 times higher respectively, in comparison to the detected levels of D4. © 2013 Elsevier B.V. All rights reserved.

Using Benchmarking To Strengthen the Assessment of Persistence.

Science.gov (United States)

McLachlan, Michael S; Zou, Hongyan; Gouin, Todd

2017-01-03

Chemical persistence is a key property for assessing chemical risk and chemical hazard. Current methods for evaluating persistence are based on laboratory tests. The relationship between the laboratory based estimates and persistence in the environment is often unclear, in which case the current methods for evaluating persistence can be questioned. Chemical benchmarking opens new possibilities to measure persistence in the field. In this paper we explore how the benchmarking approach can be applied in both the laboratory and the field to deepen our understanding of chemical persistence in the environment and create a firmer scientific basis for laboratory to field extrapolation of persistence test results.

A novel behavioral assay for measuring cold sensation in mice.

Science.gov (United States)

Brenner, Daniel S; Golden, Judith P; Gereau, Robert W

2012-01-01

Behavioral models of cold responses are important tools for exploring the molecular mechanisms of cold sensation. To complement the currently cold behavioral assays and allow further studies of these mechanisms, we have developed a new technique to measure the cold response threshold, the cold plantar assay. In this assay, animals are acclimated on a glass plate and a cold stimulus is applied to the hindpaw through the glass using a pellet of compressed dry ice. The latency to withdrawal from the cooled glass is used as a measure of the cold response threshold of the rodents, and the dry ice pellet provides a ramping cold stimulus on the glass that allows the correlation of withdrawal latency values to rough estimates of the cold response threshold temperature. The assay is highly sensitive to manipulations including morphine-induced analgesia, Complete Freund's Adjuvant-induced inflammatory allodynia, and Spinal Nerve Ligation-induced neuropathic allodynia.

The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model.

Directory of Open Access Journals (Sweden)

Qi-Liang Mao-Ying

Full Text Available Chemotherapy-induced peripheral neuropathy (CIPN characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co-administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra-epidermal nerve fibers (IENFs in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved.

Persistent Organic Pollutants as Risk Factors for Obesity and Diabetes.

Science.gov (United States)

Yang, Chunxue; Kong, Alice Pik Shan; Cai, Zongwei; Chung, Arthur C K

2017-11-02

The rising prevalence of obesity and diabetes cannot be fully explained by known risk factors, such as unhealthy diet, a sedentary lifestyle, and family history. This review summarizes the available studies linking persistent organic pollutants (POPs) to obesity and diabetes and discusses plausible underlying mechanisms. Increasing evidence suggest that POPs may act as obesogens and diabetogens to promote the development of obesity and diabetes and induce metabolic dysfunction. POPs are synthesized chemicals and are used widely in our daily life. These chemicals are resistant to degradation in chemical or biological processes, which enable them to exist in the environment persistently and to be bio-accumulated in animal and human tissue through the food chain. Increasingly, epidemiologic studies suggest a positive association between POPs and risk of developing diabetes. Understanding the relationship of POPs with obesity and diabetes may shed light on preventive strategies for obesity and diabetes.

Mastering NServiceBus and persistence

CERN Document Server

Helton, Rich

2014-01-01

This book is intended for developers, designers, and architects alike who wish to build C# NServiceBus enterprise architectures and learn how ESB persists data and messages to help them attain their goals. No prior knowledge of persistence in NServiceBus is required.

Zika Virus Persistently and Productively Infects Primary Adult Sensory Neurons In Vitro

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Brianna K. Swartwout

2017-10-01

Full Text Available Zika virus (ZIKV has recently surged in human populations, causing an increase in congenital and Guillain-Barré syndromes. While sexual transmission and presence of ZIKV in urine, semen, vaginal secretions, and saliva have been established, the origin of persistent virus shedding into biological secretions is not clear. Using a primary adult murine neuronal culture model, we have determined that ZIKV persistently and productively infects sensory neurons of the trigeminal and dorsal root ganglia, which innervate glands and mucosa of the face and the genitourinary tract, respectively, without apparent injury. Autonomic neurons that innervate these regions are not permissive for infection. However, productive ZIKV infection of satellite glial cells that surround and support sensory and autonomic neurons in peripheral ganglia results in their destruction. Persistent infection of sensory neurons, without affecting their viability, provides a potential reservoir for viral shedding in biological secretions for extended periods of time after infection. Furthermore, viral destruction of satellite glial cells may contribute to the development of Guillain-Barré Syndrome via an alternative mechanism to the established autoimmune response.

Zika Virus Persistently and Productively Infects Primary Adult Sensory Neurons In Vitro.

Science.gov (United States)

Swartwout, Brianna K; Zlotnick, Marta G; Saver, Ashley E; McKenna, Caroline M; Bertke, Andrea S

2017-10-13

Zika virus (ZIKV) has recently surged in human populations, causing an increase in congenital and Guillain-Barré syndromes. While sexual transmission and presence of ZIKV in urine, semen, vaginal secretions, and saliva have been established, the origin of persistent virus shedding into biological secretions is not clear. Using a primary adult murine neuronal culture model, we have determined that ZIKV persistently and productively infects sensory neurons of the trigeminal and dorsal root ganglia, which innervate glands and mucosa of the face and the genitourinary tract, respectively, without apparent injury. Autonomic neurons that innervate these regions are not permissive for infection. However, productive ZIKV infection of satellite glial cells that surround and support sensory and autonomic neurons in peripheral ganglia results in their destruction. Persistent infection of sensory neurons, without affecting their viability, provides a potential reservoir for viral shedding in biological secretions for extended periods of time after infection. Furthermore, viral destruction of satellite glial cells may contribute to the development of Guillain-Barré Syndrome via an alternative mechanism to the established autoimmune response.

Reliable and Persistent Identification of Linked Data Elements

Science.gov (United States)

Wood, David

Linked Data techniques rely upon common terminology in a manner similar to a relational database'vs reliance on a schema. Linked Data terminology anchors metadata descriptions and facilitates navigation of information. Common vocabularies ease the human, social tasks of understanding datasets sufficiently to construct queries and help to relate otherwise disparate datasets. Vocabulary terms must, when using the Resource Description Framework, be grounded in URIs. A current bestpractice on the World Wide Web is to serve vocabulary terms as Uniform Resource Locators (URLs) and present both human-readable and machine-readable representations to the public. Linked Data terminology published to theWorldWideWeb may be used by others without reference or notification to the publishing party. That presents a problem: Vocabulary publishers take on an implicit responsibility to maintain and publish their terms via the URLs originally assigned, regardless of the inconvenience such a responsibility may cause. Over the course of years, people change jobs, publishing organizations change Internet domain names, computers change IP addresses,systems administrators publish old material in new ways. Clearly, a mechanism is required to manageWeb-based vocabularies over a long term. This chapter places Linked Data vocabularies in context with the wider concepts of metadata in general and specifically metadata on the Web. Persistent identifier mechanisms are reviewed, with a particular emphasis on Persistent URLs, or PURLs. PURLs and PURL services are discussed in the context of Linked Data. Finally, historic weaknesses of PURLs are resolved by the introduction of a federation of PURL services to address needs specific to Linked Data.

Exploring acute-to-chronic neuropathic pain in rats after contusion spinal cord injury.

Science.gov (United States)

Gaudet, Andrew D; Ayala, Monica T; Schleicher, Wolfgang E; Smith, Elana J; Bateman, Emily M; Maier, Steven F; Watkins, Linda R

2017-09-01

Spinal cord injury (SCI) causes chronic pain in 65% of individuals. Unfortunately, current pain management is inadequate for many SCI patients. Rodent models could help identify how SCI pain develops, explore new treatment strategies, and reveal whether acute post-SCI morphine worsens chronic pain. However, few studies explore or compare SCI-elicited neuropathic pain in rats. Here, we sought to determine how different clinically relevant contusion SCIs in male and female rats affect neuropathic pain, and whether acute morphine worsens later chronic SCI pain. First, female rats received sham surgery, or 150kDyn or 200kDyn midline T9 contusion SCI. These rats displayed modest mechanical allodynia and long-lasting thermal hyperalgesia. Next, a 150kDyn (1s dwell) midline contusion SCI was performed in male and female rats. Interestingly, males, but not females showed SCI-elicited mechanical allodynia; rats of both sexes had thermal hyperalgesia. In this model, acute morphine treatment had no significant effect on chronic neuropathic pain symptoms. Unilateral SCIs can also elicit neuropathic pain that could be exacerbated by morphine, so male rats received unilateral T13 contusion SCI (100kDyn). These rats exhibited significant, transient mechanical allodynia, but not thermal hyperalgesia. Acute morphine did not exacerbate chronic pain. Our data show that specific rat contusion SCI models cause neuropathic pain. Further, chronic neuropathic pain elicited by these contusion SCIs was not amplified by our course of early post-trauma morphine. Using clinically relevant rat models of SCI could help identify novel pain management strategies. Copyright © 2017 Elsevier Inc. All rights reserved.

Assessment of paclitaxel induced sensory polyneuropathy with "Catwalk" automated gait analysis in mice.

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Petra Huehnchen

Full Text Available Neuropathic pain as a symptom of sensory nerve damage is a frequent side effect of chemotherapy. The most common behavioral observation in animal models of chemotherapy induced polyneuropathy is the development of mechanical allodynia, which is quantified with von Frey filaments. The data from one study, however, cannot be easily compared with other studies owing to influences of environmental factors, inter-rater variability and differences in test paradigms. To overcome these limitations, automated quantitative gait analysis was proposed as an alternative, but its usefulness for assessing animals suffering from polyneuropathy has remained unclear. In the present study, we used a novel mouse model of paclitaxel induced polyneuropathy to compare results from electrophysiology and the von Frey method to gait alterations measured with the Catwalk test. To mimic recently improved clinical treatment strategies of gynecological malignancies, we established a mouse model of dose-dense paclitaxel therapy on the common C57Bl/6 background. In this model paclitaxel treated animals developed mechanical allodynia as well as reduced caudal sensory nerve action potential amplitudes indicative of a sensory polyneuropathy. Gait analysis with the Catwalk method detected distinct alterations of gait parameters in animals suffering from sensory neuropathy, revealing a minimized contact of the hind paws with the floor. Treatment of mechanical allodynia with gabapentin improved altered dynamic gait parameters. This study establishes a novel mouse model for investigating the side effects of dose-dense paclitaxel therapy and underlines the usefulness of automated gait analysis as an additional easy-to-use objective test for evaluating painful sensory polyneuropathy.

The persistence of depression score

NARCIS (Netherlands)

Spijker, J.; de Graaf, R.; Ormel, J.; Nolen, W. A.; Grobbee, D. E.; Burger, H.

2006-01-01

Objective: To construct a score that allows prediction of major depressive episode (MDE) persistence in individuals with MDE using determinants of persistence identified in previous research. Method: Data were derived from 250 subjects from the general population with new MDE according to DSM-III-R.

Drought Persistence Errors in Global Climate Models

Science.gov (United States)

Moon, H.; Gudmundsson, L.; Seneviratne, S. I.

2018-04-01

The persistence of drought events largely determines the severity of socioeconomic and ecological impacts, but the capability of current global climate models (GCMs) to simulate such events is subject to large uncertainties. In this study, the representation of drought persistence in GCMs is assessed by comparing state-of-the-art GCM model simulations to observation-based data sets. For doing so, we consider dry-to-dry transition probabilities at monthly and annual scales as estimates for drought persistence, where a dry status is defined as negative precipitation anomaly. Though there is a substantial spread in the drought persistence bias, most of the simulations show systematic underestimation of drought persistence at global scale. Subsequently, we analyzed to which degree (i) inaccurate observations, (ii) differences among models, (iii) internal climate variability, and (iv) uncertainty of the employed statistical methods contribute to the spread in drought persistence errors using an analysis of variance approach. The results show that at monthly scale, model uncertainty and observational uncertainty dominate, while the contribution from internal variability is small in most cases. At annual scale, the spread of the drought persistence error is dominated by the statistical estimation error of drought persistence, indicating that the partitioning of the error is impaired by the limited number of considered time steps. These findings reveal systematic errors in the representation of drought persistence in current GCMs and suggest directions for further model improvement.

Postoperative persistent chronic pain: what do we know about prevention, risk factors, and treatment

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Durval Campos Kraychete

Full Text Available Abstract Background and objectives: Postoperative persistent chronic pain (POCP is a serious health problem, disabling, undermining the quality of life of affected patients. Although more studies and research have addressed the possible mechanisms of the evolution from acute pain to chronic postoperatively, there are still no consistent data about the risk factors and prevention. This article aims to bring what is in the panorama of the current literature available. Content: This review describes the definition, risk factors, and mechanisms of POCD, its prevention and treatment. The main drugs and techniques are exposed comprehensively. Conclusion: Postoperative persistent chronic pain is a complex and still unclear etiology entity, which interferes heavily in the life of the subject. Neuropathic pain resulting from surgical trauma is still the most common expression of this entity. Techniques to prevent nerve injury are recommended and should be used whenever possible. Despite efforts to understand and select risk patients, the management and prevention of this syndrome remain challenging and inappropriate.

Stochastic convergence of persistence landscapes and silhouettes

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Frédéric Chazal

2015-03-01

Full Text Available Persistent homology is a widely used tool in Topological Data Analysis that encodes multi-scale topological information as a multiset of points in the plane called a persistence diagram. It is difficult to apply statistical theory directly to a random sample of diagrams. Instead, we summarize persistent homology with a persistence landscape, introduced by Bubenik, which converts a diagram into a well-behaved real-valued function. We investigate the statistical properties of landscapes, such as weak convergence of the average landscapes and convergence of the bootstrap. In addition, we introduce an alternate functional summary of persistent homology, which we call the silhouette, and derive an analogous statistical theory.

A preconditioning nerve lesion inhibits mechanical pain hypersensitivity following subsequent neuropathic injury

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Wu Ann

2011-01-01

Full Text Available Abstract Background A preconditioning stimulus can trigger a neuroprotective phenotype in the nervous system - a preconditioning nerve lesion causes a significant increase in axonal regeneration, and cerebral preconditioning protects against subsequent ischemia. We hypothesized that a preconditioning nerve lesion induces gene/protein modifications, neuronal changes, and immune activation that may affect pain sensation following subsequent nerve injury. We examined whether a preconditioning lesion affects neuropathic pain and neuroinflammation after peripheral nerve injury. Results We found that a preconditioning crush injury to a terminal branch of the sciatic nerve seven days before partial ligation of the sciatic nerve (PSNL; a model of neuropathic pain induced a significant attenuation of pain hypersensitivity, particularly mechanical allodynia. A preconditioning lesion of the tibial nerve induced a long-term significant increase in paw-withdrawal threshold to mechanical stimuli and paw-withdrawal latency to thermal stimuli, after PSNL. A preconditioning lesion of the common peroneal induced a smaller but significant short-term increase in paw-withdrawal threshold to mechanical stimuli, after PSNL. There was no difference between preconditioned and unconditioned animals in neuronal damage and macrophage and T-cell infiltration into the dorsal root ganglia (DRGs or in astrocyte and microglia activation in the spinal dorsal and ventral horns. Conclusions These results suggest that prior exposure to a mild nerve lesion protects against adverse effects of subsequent neuropathic injury, and that this conditioning-induced inhibition of pain hypersensitivity is not dependent on neuroinflammation in DRGs and spinal cord. Identifying the underlying mechanisms may have important implications for the understanding of neuropathic pain due to nerve injury.

Comment on “Emergence and fate of cyclic volatile polydimethylsiloxanes (D4, D5) in municipal waste streams: Release mechanisms, partitioning and persistence in air, water, soil and sediments”

Energy Technology Data Exchange (ETDEWEB)

Buser, Andreas M., E-mail: andreas.buser@alumni.ethz.ch; Bogdal, Christian; Scheringer, Martin

2015-02-01

The review article “Emergence and fate of cyclic volatile polydimethylsiloxanes (D4, D5) in municipal waste streams: Release mechanisms, partitioning and persistence in air, water, soil and sediments” by Surita and Tansel covers a relevant topic, but there are several serious issues with this paper. The inappropriate handling of data gathered from various sources has resulted in a flawed dataset. In addition, the authors performed several erroneous or meaningless calculations with the data. Their dataset leads to incorrect and misleading interpretations and should not be used.

Missed diagnosis-persistent delirium

Directory of Open Access Journals (Sweden)

Aseem Mehra

2014-01-01

Full Text Available Delirium is in general considered as an acute short lasting reversible neuropsychiatric syndrome. However, there is some evidence to suggest that in a small proportion of cases delirium may be a chronic or persistent condition. However, making this diagnosis requires clinical suspicion and ruling other differential diagnosis. In this report, we present a case of a 55-year-old man who had cognitive symptoms, psychotic symptoms and depressive symptoms along with persistent hypokalemia and glucose intolerance. He was seen by 3 psychiatrists with these symptoms and was initially diagnosed as having depressive disorder and later diagnosis of bipolar affective disorder (current episode mania, and psychosis were considered by the third psychiatrist. However, despite the presence of persistent neurocognitive deficits, evening worsening of symptoms, hypokalemia and glucose intolerance diagnosis of delirium was not suspected.

Bacterial persistence

Indian Academy of Sciences (India)

PRAKASH KUMAR

Drug indifference versus persistence. Studies on the mode of ... is a special case of drug indifference, restricted to a small ... to his model (outlined in detail in Lewis 2008), treatment .... belong to the heat and cold shock response family; many.

The mechanism of persistent photoconductivity induced by minority carrier trapping effect in ultraviolet photo-detector made of polycrystalline diamond film

International Nuclear Information System (INIS)

Wang Lanxi; Chen Xuekang; Wu Gan; Guo Wantu; Cao Shengzhu; Shang Kaiwen; Han Weihua

2011-01-01

Performances of long persistent photoconductivity, high responsivity and high photoconductive gain were observed in a metal–semiconductor–metal ultraviolet photo-detector fabricated on a microcrystalline diamond film. Charge-based deep level transient spectroscopy measurement confirmed that a shallow level with activation energy of 0.21 eV and capture cross section of 9.9 × 10 −20 cm 2 is presented in the band gap of the diamond film. The shallow level may not act as effective recombination center due to the so small activation energy according to Schockly-Read-Hall statistics. The persistent photoconductivity relaxation fits in with the so called “barrier-limited recombination” model, which may be a minority carrier trapping effect related recombination process. The photo-induced minority carriers (electrons in this paper) may be trapped by the shallow level during light irradiation process and then de-trap slowly via thermal excitation or tunneling effect after removing the light source, which contributes to the persistent photoconductivity. The trapping effect can also reduce the probability of carrier recombination, resulting in the high responsivity and the high gain.

Ranking of persister genes in the same Escherichia coli genetic background demonstrates varying importance of individual persister genes in tolerance to different antibiotics

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Nan eWu

2015-09-01

Full Text Available Despite the identification of many genes and pathways involved in the persistence phenomenon of bacteria, the relative importance of these genes in a single organism remains unclear. Here, using Escherichia coli as a model, we generated mutants of 21 known candidate persister genes and compared the relative importance of these mutants in persistence to various antibiotics (ampicillin, gentamicin, norfloxacin, and trimethoprim at different times. We found that oxyR, dnaK, sucB, relA, rpoS, clpB, mqsR, and recA were prominent persister genes involved in persistence to multiple antibiotics. These genes map to the following pathways: antioxidative defense pathway (oxyR, global regulators (dnaK, clpB, and rpoS, energy production (sucB, stringent response (relA, toxin–antitoxin (TA module (mqsR, and SOS response (recA. Among the TA modules, the ranking order was mqsR, lon, relE, tisAB, hipA, and dinJ. Intriguingly, rpoS deletion caused a defect in persistence to gentamicin but increased persistence to ampicillin and norfloxacin. Mutants demonstrated dramatic differences in persistence to different antibiotics at different time points: some mutants (oxyR, dnaK, phoU, lon, recA, mqsR, and tisAB displayed defect in persistence from early time points, while other mutants (relE, smpB, glpD, umuD, and tnaA showed defect only at later time points. These results indicate that varying hierarchy and importance of persister genes exist and that persister genes can be divided into those involved in shallow persistence and those involved in deep persistence. Our findings suggest that the persistence phenomenon is a dynamic process with different persister genes playing roles of variable significance at different times. These findings have implications for improved understanding of persistence phenomenon and developing new drugs targeting persisters for more effective cure of persistent infections.

Clearance of a persistent Picornavirus infection is associated with enhanced pro-apoptotic and cellular immune responses

Science.gov (United States)

Immunomodulatory mechanisms associated with clearance versus persistence of foot-and-mouth disease virus (FMDV) in distinct microanatomic compartments of the bovine nasopharynx were investigated using quantitative RT-PCR and whole transcriptome microarray. Analysis of tissue samples obtained during ...

Irregular persistent activity induced by synaptic excitatory feedback

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Francesca Barbieri

2007-11-01

Full Text Available Neurophysiological experiments on monkeys have reported highly irregular persistent activity during the performance of an oculomotor delayed-response task. These experiments show that during the delay period the coefficient of variation (CV of interspike intervals (ISI of prefrontal neurons is above 1, on average, and larger than during the fixation period. In the present paper, we show that this feature can be reproduced in a network in which persistent activity is induced by excitatory feedback, provided that (i the post-spike reset is close enough to threshold , (ii synaptic efficacies are a non-linear function of the pre-synaptic firing rate. Non-linearity between presynaptic rate and effective synaptic strength is implemented by a standard short-term depression mechanism (STD. First, we consider the simplest possible network with excitatory feedback: a fully connected homogeneous network of excitatory leaky integrate-and-fire neurons, using both numerical simulations and analytical techniques. The results are then confirmed in a network with selective excitatory neurons and inhibition. In both the cases there is a large range of values of the synaptic efficacies for which the statistics of firing of single cells is similar to experimental data.

How to decode Unemployment Persistence: An econometric framework for identifying and comparing the sources of persistence

DEFF Research Database (Denmark)

Møller, Niels Framroze

2016-01-01

Most econometric analyses of persistence focus on the existence of non-stationary unemployment but not the origin of this. The present research contains a multivariate econometric framework for identifying and comparing different sources of unemployment persistence (e.g. hysteresis versus a slowly...... moving equilibrium rate). A small example, considering historical data (1988-2006) for the UK, demonstrates how the method can be applied in practice. Although this primarily serves as an illustration, the evidence clearly suggests that persistence was due to a slowly moving equilibrium (driven...

Persistent polar depletion of stratospheric ozone and emergent mechanisms of ultraviolet radiation-mediated health dysregulation.

Science.gov (United States)

Dugo, Mark A; Han, Fengxiang; Tchounwou, Paul B

2012-01-01

Year 2011 noted the first definable ozone "hole" in the Arctic region, serving as an indicator to the continued threat of dangerous ultraviolet radiation (UVR) exposure caused by the deterioration of stratospheric ozone in the northern hemisphere. Despite mandates of the Montreal Protocol to phase out the production of ozone-depleting chemicals (ODCs), the relative stability of ODCs validates popular notions of persistent stratospheric ozone for several decades. Moreover, increased UVR exposure through stratospheric ozone depletion is occurring within a larger context of physiologic stress and climate change across the biosphere. In this review, we provide commentaries on stratospheric ozone depletion with relative comparisons between the well-known Antarctic ozone hole and the newly defined ozone hole in the Arctic. Compared with the Antarctic region, the increased UVR exposure in the Northern Hemisphere poses a threat to denser human populations across North America, Europe, and Asia. In this context, we discuss emerging targets of UVR exposure that can potentially offset normal biologic rhythms in terms of taxonomically conserved photoperiod-dependent seasonal signaling and entrainment of circadian clocks. Consequences of seasonal shifts during critical life history stages can alter fitness and condition, whereas circadian disruption is increasingly becoming associated as a causal link to increased carcinogenesis. We further review the significance of genomic alterations via UVR-induced modulations of phase I and II transcription factors located in skin cells, the aryl hydrocarbon receptor (AhR), and the nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2), with emphasis on mechanism that can lead to metabolic shifts and cancer. Although concern for adverse health consequences due to increased UVR exposure are longstanding, recent advances in biochemical research suggest that AhR and Nrf2 transcriptional regulators are likely targets for UVR

Proteomic Identification of an Upregulated Isoform of Annexin A3 in the Spinal Cords of Rats in a Neuropathic Pain Model

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Wangyuan Zou

2017-09-01

Full Text Available Neuropathic pain (NP is induced by nerve damage or a disturbance in the peripheral or central nervous systems. Nerve damage causes the activation of sensitizing mechanisms in the peripheral and central nervous systems, which induces transcriptional and post-transcriptional alterations in sensory nerves. However, the underlying mechanisms of NP remain elusive. In the study, Two-dimensional gel electrophoresis (2DGE-based comparative proteomics identified 38 differential gel spots, and 15 differentially expressed proteins (DEPs between the sham and the chronic constriction injury (CCI-induced neuropathic pain rats. Of them, Annexin A3 (ANXA3 was significantly increased after CCI with Western blot analysis and immunofluorescence imaging. A lentivirus delivering ANXA3 shRNA (LV-shANXA3 was administered intrathecally to determine the analgesic effects of ANXA3 on allodynia and hyperalgesia in a CCI-induced neuropathic pain model in rats. Further study showed that LV-shANXA3 reversed the upregulation of ANXA3, alleviated CCI-induced mechanical allodynia and thermal hyperalgesia. The study indicated that ANXA3 may play an important role in neuropathic pain.

Persistent hyperdopaminergia decreases the peak frequency of hippocampal theta oscillations during quiet waking and REM sleep.

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Kafui Dzirasa

Full Text Available Long-term changes in dopaminergic signaling are thought to underlie the pathophysiology of a number of psychiatric disorders. Several conditions are associated with cognitive deficits such as disturbances in attention processes and learning and memory, suggesting that persistent changes in dopaminergic signaling may alter neural mechanisms underlying these processes. Dopamine transporter knockout (DAT-KO mice exhibit a persistent five-fold increase in extracellular dopamine levels. Here, we demonstrate that DAT-KO mice display lower hippocampal theta oscillation frequencies during baseline periods of waking and rapid-eye movement sleep. These altered theta oscillations are not reversed via treatment with the antidopaminergic agent haloperidol. Thus, we propose that persistent hyperdopaminergia, together with secondary alterations in other neuromodulatory systems, results in lower frequency activity in neural systems responsible for various cognitive processes.

TRPV1 antagonist attenuates postoperative hypersensitivity by central and peripheral mechanisms

Czech Academy of Sciences Publication Activity Database

Uchytilová, Eva; Špicarová, Diana; Paleček, Jiří

2014-01-01

Roč. 10, č. 2014 (2014), s. 67 ISSN 1744-8069 R&D Projects: GA MŠk(CZ) EE2.3.30.0025; GA MŠk(CZ) ED1.1.00/02.0109; GA ČR(CZ) GBP304/12/G069; GA MŠk(CZ) LH12058; GA ČR(CZ) GPP303/12/P510 Institutional support: RVO:67985823 Keywords : SB366791 * TRPV1 * allodynia * hyperalgesia * surgical pain * spinal cord Subject RIV: FH - Neurology Impact factor: 3.654, year: 2014

Persistence of Women in Online Degree-Completion Programs

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Terry Müller

2008-06-01

Full Text Available Although online courses at postsecondary institutions promise adults access, flexibility, and convenience, many barriers to online learning remain. This article presents findings from a qualitative case study, which explored the phenomenon of undergraduate and graduate women learners’ persistence in online degree-completion programs at a college in the Northeast of the United States. Research questions asked why women learners persisted or failed to persist, and how factors supporting or hindering persistence influenced learners. Interviews with a purposeful sample of 20 participants revealed the complexity of variables affecting learners’ persistence to graduation. Findings suggested that multiple responsibilities, insufficient interaction with faculty, technology, and coursework ranked highest as barriers to women’s persistence. Strong motivation to complete degrees, engagement in the learning community, and appreciation for the convenience of an online degree-completion option facilitated persistence.

An FMRI Study of Olfactory Cues to Perception of Conspecific Stress

Science.gov (United States)

2010-04-01

Petrovic P, Ingvar M, Stone-Elander S, Petersson KM, Hansson P (1999) A PET activation study of dynamic mechanical allodynia in patients with...state on olfactory sensitivity suggest odor specificity. Biol Psychol 71: 244-247. 67. Mair RG, Bouffard JA, Engen T, Morton TH (1978) Olfactory

Risk factors predicting onset and persistence of subthreshold expression of bipolar psychopathology among youth from the community.

Science.gov (United States)

Tijssen, M J A; Van Os, J; Wittchen, H U; Lieb, R; Beesdo, K; Wichers, Marieke

2010-09-01

To examine factors increasing the risk for onset and persistence of subthreshold mania and depression. In a prospective cohort community study, the association between risk factors [a family history of mood disorders, trauma, substance use, attention-deficit/hyperactivity disorder (ADHD) and temperamental/personality traits] and onset of manic/depressive symptoms was determined in 705 adolescents. The interaction between baseline risk factors and baseline symptoms in predicting 8-year follow-up symptoms was used to model the impact of risk factors on persistence. Onset of manic symptoms was associated with cannabis use and novelty seeking (NS), but NS predicted a transitory course. Onset of depressive symptoms was associated with a family history of depression. ADHD and harm avoidance (HA) were associated with persistence of depressive symptoms, while trauma and a family history of depression predicted a transitory course. Different risk factors may operate during onset and persistence of subthreshold mania and depression. The differential associations found for mania and depression dimensions suggest partly different underlying mechanisms.

Laboratory diagnosis of persistent human chlamydial infection

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Mirja ePuolakkainen

2013-12-01

Full Text Available Diagnostic assays for persistent chlamydial infection are much needed to conduct high-quality, large-scale studies investigating the persistent state in vivo, its disease associations and the response to therapy. Yet in most studies the distinction between acute and persistent infection is based on the interpretation of the data obtained by the assays developed to diagnose acute infections or on complex assays available for research only and/or difficult to establish for clinical use. Novel biomarkers for detection of persistent chlamydial infection are urgently needed. Chlamydial whole genome proteome arrays are now available and they can identify chlamydial antigens that are differentially expressed between acute infection and persistent infection. Utilizing these data will lead to the development of novel diagnostic assays. Carefully selected specimens from well-studied patient populations are clearly needed in the process of translating the proteomic data into assays useful for clinical practice. Before such antigens are identified and validated assays become available, we face a challenge of deciding whether the persistent infection truly induced appearance of the proposed marker or do we just base our diagnosis of persistent infection on the presence of the suggested markers. Consequently, we must bear this in mind when interpreting the available data.

A novel behavioral assay for measuring cold sensation in mice.

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Daniel S Brenner

Full Text Available Behavioral models of cold responses are important tools for exploring the molecular mechanisms of cold sensation. To complement the currently cold behavioral assays and allow further studies of these mechanisms, we have developed a new technique to measure the cold response threshold, the cold plantar assay. In this assay, animals are acclimated on a glass plate and a cold stimulus is applied to the hindpaw through the glass using a pellet of compressed dry ice. The latency to withdrawal from the cooled glass is used as a measure of the cold response threshold of the rodents, and the dry ice pellet provides a ramping cold stimulus on the glass that allows the correlation of withdrawal latency values to rough estimates of the cold response threshold temperature. The assay is highly sensitive to manipulations including morphine-induced analgesia, Complete Freund's Adjuvant-induced inflammatory allodynia, and Spinal Nerve Ligation-induced neuropathic allodynia.

Frequency, Impact, and Predictors of Persistent Pain Following Root Canal Treatment: A National Dental PBRN Study

Science.gov (United States)

Nixdorf, Donald R.; Law, Alan S.; Lindquist, Kimberly; Reams, Gregory J.; Cole, Emery; Kanter, Keith; Nguyen, Ruby H.N.; Harris, D. Robert

2015-01-01

Root canal treatment (RCT) is commonly performed surgery and persistent pain is known to occur, but little is known about how these patients are affected by this pain. While biopsychosocial mechanisms are thought to be associated with the development of such pain, similar to persistent pain following surgery in other body sites, little is known about the baseline predictors for persistent pain. We assessed the frequency of persistent pain 6 months following RCT, measured the impact this pain had on patients, and determined predictive factors for persistent tooth pain in a multi-center prospective cohort study conducted within the National Dental Practice-Based Research Network. Of 708 patients enrolled, 651 (91.9%) provided follow-up data, with 65 (10.0%) meeting criteria for pain 6 months following RCT. On average, these patients reported their pain as mild to moderate in intensity, present for about 10 days in the preceding month, and minimally interfered with daily activities. After adjusting for type of dental practitioner and patient age, gender and household income, pain duration over the week prior to RCT significantly increased the risk of developing persistent pain (odds ratio [OR]=1.19 per 1 day increase in pain duration, 95% confidence interval [CI]: 1.07–1.33), whereas optimism about the procedure reduced the risk (OR=0.39, 95% CI: 0.22–0.67). Our data suggest that persistent pain following RCT is fairly common, but generally does not have a large impact on those experiencing it. Furthermore, patient age and gender did not predict persistent pain, while pre-operative pain duration and the patient’s expectation did. PMID:26335907

Exploring Non-Traditional Adult Undergraduate Student Persistence and Non-Persistence in Higher Education: A Stress and Coping Model Approach

Science.gov (United States)

Maroney, Barbara R.

2010-01-01

This study explores persistence and non-persistence among adult undergraduate students with particular focus on these students' lives, their stressors, their coping resources including academic supports, and their styles of coping. The study approaches the issue of non-persistence not as a personal failure but rather as a consequence of multiple…

Surviving colorectal cancer: long-term, persistent ostomy-specific concerns and adaptations.

Science.gov (United States)

Sun, Virginia; Grant, Marcia; McMullen, Carmit K; Altschuler, Andrea; Mohler, M Jane; Hornbrook, Mark C; Herrinton, Lisa J; Baldwin, Carol M; Krouse, Robert S

2013-01-01

The purpose of this article was to describe persistent ostomy-specific concerns and adaptations in long-term (>5 years) colorectal cancer survivors with ostomies. Thirty-three colorectal cancer survivors who participated in 8 gender- and health-related quality of life stratified focus groups and 130 colorectal cancer survivors who provided written comments to 2 open-ended questions on ostomy location and pouch problems participated in the study. Data were collected on health maintenance organization members in Oregon, southwestern Washington, and northern California. Qualitative data were analyzed for the 8 focus groups and written comments from 2 open-ended survey questions. Discussions from the focu s groups were recorded, transcribed, and analyzed using content analysis. Written content from the open-ended questions was derived from a mailed questionnaire on health-related quality of life in survivors with ostomies and analyzed using content analysis. Discussions related to persistent ostomy-related issues more than 5 years after formation were common. Persistent ostomy-related issues were focused on clothing restrictions and adaptations, dietary concerns, issues related to ostomy equipment and self-care, and the constant need to find solutions to adjust and readjust to living with an ostomy. Ostomy-specific concerns persist 5 years and more for long-term colorectal cancer survivors after initial ostomy formation. Adaptations tend to be individualized and based on trial and error. Findings underscore the need to develop long-term support mechanisms that survivors can access to promote better coping and adjustment to living with an ostomy.

Sensory-motor responses to mechanical stimulation of the esophagus after sensitization with acid.

Science.gov (United States)

Drewes, Asbjørn-Mohr; Reddy, Hariprasad; Staahl, Camilla; Pedersen, Jan; Funch-Jensen, Peter; Arendt-Nielsen, Lars; Gregersen, Hans

2005-07-28

Sensitization most likely plays an important role in chronic pain disorders, and such sensitization can be mimicked by experimental acid perfusion of the esophagus. The current study systematically investigated the sensory and motor responses of the esophagus to controlled mechanical stimuli before and after sensitization. Thirty healthy subjects were included. Distension of the distal esophagus with a balloon was performed before and after perfusion with 0.1 mol/L hydrochloric acid for 30 min. An impedance planimetry system was used to measure cross-sectional area, volume, pressure, and tension during the distensions. A new model allowed evaluation of the phasic contractions by the tension during contractions as a function of the initial muscle length before the contraction (comparable to the Frank-Starling law for the heart). Length-tension diagrams were used to evaluate the muscle tone before and after relaxation of the smooth muscle with butylscopolamine. The sensitization resulted in allodynia and hyperalgesia to the distension volumes, and the degree of sensitization was related to the infused volume of acid. Furthermore, a nearly 50% increase in the evoked referred pain was seen after sensitization. The mechanical analysis demonstrated hyper-reactivity of the esophagus following acid perfusion, with an increased number and force of the phasic contractions, but the muscle tone did not change. Acid perfusion of the esophagus sensitizes the sensory pathways and facilitates secondary contractions. The new model can be used to study abnormal sensory-motor mechanisms in visceral organs.

Persistent insomnia is associated with mortality risk.

Science.gov (United States)

Parthasarathy, Sairam; Vasquez, Monica M; Halonen, Marilyn; Bootzin, Richard; Quan, Stuart F; Martinez, Fernando D; Guerra, Stefano

2015-03-01

Insomnia has been associated with mortality risk, but whether this association is different in subjects with persistent vs intermittent insomnia is unclear. Additionally, the role of systemic inflammation in such an association is unknown. We used data from a community-based cohort to determine whether persistent or intermittent insomnia, defined based on persistence of symptoms over a 6-year period, was associated with death during the following 20 years of follow-up. We also determined whether changes in serum C-reactive protein (CRP) levels measured over 2 decades between study initiation and insomnia determination were different for the persistent, intermittent, and never insomnia groups. The results were adjusted for confounders such as age, sex, body mass index, smoking, physical activity, alcohol, and sedatives. Of the 1409 adult participants, 249 (18%) had intermittent and 128 (9%) had persistent insomnia. During a 20-year follow-up period, 318 participants died (118 due to cardiopulmonary disease). In adjusted Cox proportional-hazards models, participants with persistent insomnia (adjusted hazards ratio [HR] 1.58; 95% confidence interval [CI], 1.02-2.45) but not intermittent insomnia (HR 1.22; 95% CI, 0.86-1.74) were more likely to die than participants without insomnia. Serum CRP levels were higher and increased at a steeper rate in subjects with persistent insomnia as compared with intermittent (P = .04) or never (P = .004) insomnia. Although CRP levels were themselves associated with increased mortality (adjusted HR 1.36; 95% CI, 1.01-1.82; P = .04), adjustment for CRP levels did not notably change the association between persistent insomnia and mortality. In a population-based cohort, persistent, and not intermittent, insomnia was associated with increased risk for all-cause and cardiopulmonary mortality and was associated with a steeper increase in inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

MOOCs and Persistence: Definitions and Predictors

Science.gov (United States)

Evans, Brent J.; Baker, Rachel B.

2016-01-01

The chapter argues for redefining the term "persistence" as it relates to MOOCs and considers how different measures produce different results in the research; it closes with a review of research on persistence in MOOCs.

Modulation of network excitability by persistent activity: how working memory affects the response to incoming stimuli.

Directory of Open Access Journals (Sweden)

Elisa M Tartaglia

2015-02-01

Full Text Available Persistent activity and match effects are widely regarded as neuronal correlates of short-term storage and manipulation of information, with the first serving active maintenance and the latter supporting the comparison between memory contents and incoming sensory information. The mechanistic and functional relationship between these two basic neurophysiological signatures of working memory remains elusive. We propose that match signals are generated as a result of transient changes in local network excitability brought about by persistent activity. Neurons more active will be more excitable, and thus more responsive to external inputs. Accordingly, network responses are jointly determined by the incoming stimulus and the ongoing pattern of persistent activity. Using a spiking model network, we show that this mechanism is able to reproduce most of the experimental phenomenology of match effects as exposed by single-cell recordings during delayed-response tasks. The model provides a unified, parsimonious mechanistic account of the main neuronal correlates of working memory, makes several experimentally testable predictions, and demonstrates a new functional role for persistent activity.

Habit persistence

DEFF Research Database (Denmark)

Vinther Møller, Stig

2009-01-01

This paper uses an iterated GMM approach to estimate and test the consumption based habit persistence model of Campbell and Cochrane (1999) on the US stock market. The empirical evidence shows that the model is able to explain the size premium, but fails to explain the value premium. Further...

CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy.

Science.gov (United States)

Huang, Zhen-Zhen; Li, Dai; Liu, Cui-Cui; Cui, Yu; Zhu, He-Quan; Zhang, Wen-Wen; Li, Yong-Yong; Xin, Wen-Jun

2014-08-01

Painful peripheral neuropathy is a dose-limiting side effect of paclitaxel therapy, which hampers the optimal clinical management of chemotherapy in cancer patients. Currently the underlying mechanisms remain largely unknown. Here we showed that the clinically relevant dose of paclitaxel (3×8mg/kg, cumulative dose 24mg/kg) induced significant upregulation of the chemokine CX3CL1 in the A-fiber primary sensory neurons in vivo and in vitro and infiltration of macrophages into the dorsal root ganglion (DRG) in rats. Paclitaxel treatment also increased cleaved caspase-3 expression, induced the loss of primary afferent terminal fibers and decreased sciatic-evoked A-fiber responses in the spinal dorsal horn, indicating DRG neuronal apoptosis induced by paclitaxel. In addition, the paclitaxel-induced DRG neuronal apoptosis occurred exclusively in the presence of macrophage in vitro study. Intrathecal or systemic injection of CX3CL1 neutralizing antibody blocked paclitaxel-induced macrophage recruitment and neuronal apoptosis in the DRG, and also attenuated paclitaxel-induced allodynia. Furthermore, depletion of macrophage by systemic administration of clodronate inhibited paclitaxel-induced allodynia. Blocking CX3CL1 decreased activation of p38 MAPK in the macrophage, and inhibition of p38 MAPK activity blocked the neuronal apoptosis and development of mechanical allodynia induced by paclitaxel. These findings provide novel evidence that CX3CL1-recruited macrophage contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy. Copyright © 2014 Elsevier Inc. All rights reserved.

Sensory symptom profiles and co-morbidities in painful radiculopathy.

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Friederike Mahn

Full Text Available Painful radiculopathies (RAD and classical neuropathic pain syndromes (painful diabetic polyneuropathy, postherpetic neuralgia show differences how the patients express their sensory perceptions. Furthermore, several clinical trials with neuropathic pain medications failed in painful radiculopathy. Epidemiological and clinical data of 2094 patients with painful radiculopathy were collected within a cross sectional survey (painDETECT to describe demographic data and co-morbidities and to detect characteristic sensory abnormalities in patients with RAD and compare them with other neuropathic pain syndromes. Common co-morbidities in neuropathic pain (depression, sleep disturbance, anxiety do not differ considerably between the three conditions. Compared to other neuropathic pain syndromes touch-evoked allodynia and thermal hyperalgesia are relatively uncommon in RAD. One distinct sensory symptom pattern (sensory profile, i.e., severe painful attacks and pressure induced pain in combination with mild spontaneous pain, mild mechanical allodynia and thermal hyperalgesia, was found to be characteristic for RAD. Despite similarities in sensory symptoms there are two important differences between RAD and other neuropathic pain disorders: (1 The paucity of mechanical allodynia and thermal hyperalgesia might be explained by the fact that the site of the nerve lesion in RAD is often located proximal to the dorsal root ganglion. (2 The distinct sensory profile found in RAD might be explained by compression-induced ectopic discharges from a dorsal root and not necessarily by nerve damage. These differences in pathogenesis might explain why medications effective in DPN and PHN failed to demonstrate efficacy in RAD.

Aberrant cellular immune responses in humans infected persistently with parvovirus B19

DEFF Research Database (Denmark)

Isa, Adiba; Norbeck, Oscar; Hirbod, Taha

2006-01-01

A subset of parvovirus B19 (B19) infected patients retains the infection for years, as defined by detection of B19 DNA in bone marrow. Thus far, analysis of B19-specific humoral immune responses and viral genome variations has not revealed a mechanism for the absent viral clearance. In this study......, ex-vivo cellular immune responses were assessed by enzyme linked immunospot assay mounted against the majority of the translated viral genome. Compared to seropositive healthy individuals, individuals with B19 persistence (2-8 years) showed larger number of responses to the structural proteins (P = 0.......0022), whereas responses to the non-structural protein were of lower magnitude (P = 0.012). These observations provide the first findings of immunological discrepancies between individuals with B19 persistence and healthy individuals, findings that may reflect both failed immunity and antigenic exhaustion....

[Effects of intrathecal administration of AM22-52 on mechanical allodynia and CCL2 expression in DRG in bone cancer rats].

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Chen, Ya-Juan; Huo, Yuan-Hui; Hong, Yanguo

2017-02-25

The pain peptide adrenomedullin (AM) plays a pivotal role in pathological pain. The present study was designed to investigate the effect of blockade of AM receptor on bone cancer pain (BCP) and its mechanism. BCP was developed by inoculation of Walker 256 mammary gland carcinoma cells in the tibia medullary cavity of Sprague Dawley rats. The selective AM receptor antagonist AM 22-52 was administered intrathecally on 15 d after the inoculation. Quantitative real-time PCR was used to detect mRNA level of CC chemokine ligand 2 (CCL2) in dorsal root ganglion (DRG). Double immunofluorescence staining was used to analyze the localizations of CCL2 and AM in DRG of normal rats. The results showed that, from 6 to15 d after the inoculation, the animals showed significant reduction in the mechanical pain threshold in the ipsilateral hindpaw, companied by the decline in bone density of tibia bone. The expression of CCL2 mRNA in DRG of BCP rats was increased by 3 folds (P DRG neurons. These results suggest that AM may play a role in the pathogenesis of BCP. The increased AM bioactivity up-regulates CCL2 expression in DRG, which may contribute to the induction of pain hypersensitivity in bone cancer.

[Management of severe or persistent postpartum hemorrhage after vaginal delivery].

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Morel, O; Perdriolle-Galet, E; Mézan de Malartic, C; Gauchotte, E; Moncollin, M; Patte, C; Chabot-Lecoanet, A-C

2014-12-01

This chapter is an update of the 2004 recommendations for the management of persistent or severe postpartum hemorrhage (PPH) after natural childbirth. Severe PPH is defined by estimated blood loss greater than 1000mL (gradeC). Persistent bleeding within 15 to 30minutes after diagnosis and initial treatment (gradeC) or abundant immediately (professional consensus) should lead to a further management. A systematic review of the literature concerning the management of persistent or severe PPH was conducted on Medline and Cochrane Database, with no specified time period. The initial clinical evaluation is the same whatever initial severity. Each possible cause of bleeding must be evaluated: uterine vacuity must be checked and birth canal lesions must be researched and repaired (gradeC). Sulprostone is effective for the treatment of severe or persistent PPH (EL4) and its use is recommended for the management of PPH resistant to oxytocin administration (grade B). In the current state of the literature, there is no argument for replacing sulprostone in France by dinoprostone or prostaglandins F2α (professional consensus). If oxytocin has been administered, it is not recommended to use misoprostol (EL1) as adjuvant treatment because there is no evidence of benefit in this indication (grade A). Balloon intra-uterine tamponade appears to be an efficient mechanical treatment of uterine atony in case of failure of the initial management by sulprostone. Tamponade allows avoiding the need for further interventional radiology or surgery in most cases (EL4). Intra-uterine tamponade may be offered in case of failure of sulprostone and prior to surgical management or interventional radiology (professional consensus). Its use is left to the discretion of the practitioner. Tamponade should not delay the implementation of further invasive procedures. Copyright © 2014. Published by Elsevier Masson SAS.

Face-to-face comparison of the predictive validity of two models of neuropathic pain in the rat: analgesic activity of pregabalin, tramadol and duloxetine.

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Le Cudennec, Camille; Castagné, Vincent

2014-07-15

We compared the preclinical analgesic activity of three marketed drugs with different pharmacological properties, pregabalin, tramadol and duloxetine, described as effective against neuropathic pain in the clinic. These drugs were tested against evoked pain in two different neuropathic models in the rat, the Bennett (CCI) and the Chung (SNL) models. The selected endpoints were tactile allodynia, tactile hyperalgesia, heat hyperalgesia and cold allodynia. Although all three drugs displayed analgesic activity, the effects observed varied according to the behavioral evaluation. Pregabalin showed clear analgesic effects against cold allodynia and tactile hyperalgesia in both the CCI and Chung models. Tramadol was active against all four endpoints in the Chung model with similar effects in the CCI model, apart from tactile allodynia. Duloxetine inhibited tactile allodynia and heat hyperalgesia in both neuropathic pain models. It also displayed efficacy against tactile hyperalgesia in the CCI model and against cold allodynia in the Chung model. These data confirm that the CCI and the Chung models of neuropathic pain do not detect the activity of analgesics with the same sensitivity. Furthermore, the mode of stimulation (tactile or thermal) and the type of endpoint (allodynia or hyperalgesia) can further influence the observed efficacy of gold standards as well as novel compounds developed for treating neuropathic pain symptoms. Copyright © 2014. Published by Elsevier B.V.

Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury

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Decosterd Isabelle

2009-09-01

Full Text Available Abstract Background After peripheral nerve injury, spontaneous ectopic activity arising from the peripheral axons plays an important role in inducing central sensitization and neuropathic pain. Recent evidence indicates that activation of spinal cord microglia also contributes to the development of neuropathic pain. In particular, activation of p38 mitogen-activated protein kinase (MAPK in spinal microglia is required for the development of mechanical allodynia. However, activity-dependent activation of microglia after nerve injury has not been fully addressed. To determine whether spontaneous activity from C- or A-fibers is required for microglial activation, we used resiniferatoxin (RTX to block the conduction of transient receptor potential vanilloid subtype 1 (TRPV1 positive fibers (mostly C- and Aδ-fibers and bupivacaine microspheres to block all fibers of the sciatic nerve in rats before spared nerve injury (SNI, and observed spinal microglial changes 2 days later. Results SNI induced robust mechanical allodynia and p38 activation in spinal microglia. SNI also induced marked cell proliferation in the spinal cord, and all the proliferating cells (BrdU+ were microglia (Iba1+. Bupivacaine induced a complete sensory and motor blockade and also significantly inhibited p38 activation and microglial proliferation in the spinal cord. In contrast, and although it produced an efficient nociceptive block, RTX failed to inhibit p38 activation and microglial proliferation in the spinal cord. Conclusion (1 Blocking peripheral input in TRPV1-positive fibers (presumably C-fibers is not enough to prevent nerve injury-induced spinal microglial activation. (2 Peripheral input from large myelinated fibers is important for microglial activation. (3 Microglial activation is associated with mechanical allodynia.

Distributed design approach in persistent identifiers systems

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Golodoniuc, Pavel; Car, Nicholas; Klump, Jens

2017-04-01

The need to identify both digital and physical objects is ubiquitous in our society. Past and present persistent identifier (PID) systems, of which there is a great variety in terms of technical and social implementations, have evolved with the advent of the Internet, which has allowed for globally unique and globally resolvable identifiers. PID systems have catered for identifier uniqueness, integrity, persistence, and trustworthiness, regardless of the identifier's application domain, the scope of which has expanded significantly in the past two decades. Since many PID systems have been largely conceived and developed by small communities, or even a single organisation, they have faced challenges in gaining widespread adoption and, most importantly, the ability to survive change of technology. This has left a legacy of identifiers that still exist and are being used but which have lost their resolution service. We believe that one of the causes of once successful PID systems fading is their reliance on a centralised technical infrastructure or a governing authority. Golodoniuc et al. (2016) proposed an approach to the development of PID systems that combines the use of (a) the Handle system, as a distributed system for the registration and first-degree resolution of persistent identifiers, and (b) the PID Service (Golodoniuc et al., 2015), to enable fine-grained resolution to different information object representations. The proposed approach solved the problem of guaranteed first-degree resolution of identifiers, but left fine-grained resolution and information delivery under the control of a single authoritative source, posing risk to the long-term availability of information resources. Herein, we develop these approaches further and explore the potential of large-scale decentralisation at all levels: (i) persistent identifiers and information resources registration; (ii) identifier resolution; and (iii) data delivery. To achieve large-scale decentralisation

Persistent airflow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection

NARCIS (Netherlands)

ten Brinke, A.; van Dissel, J. T.; Sterk, P. J.; Zwinderman, A. H.; Rabe, K. F.; Bel, E. H.

2001-01-01

Persistent airflow limitation may develop in patients with asthma, particularly in adults with nonatopic (intrinsic) disease. Although the underlying mechanisms are still unknown, respiratory infections might be involved. We investigated the annual loss of lung function in relation to seropositivity

Photoluminescence, reddish orange long persistent luminescence and photostimulated luminescence properties of praseodymium doped CdGeO3 phosphor

International Nuclear Information System (INIS)

Jin, Yahong; Hu, Yihua; Chen, Li; Fu, Yinrong; Mu, Zhongfei; Wang, Tao; Lin, Jun

2014-01-01

Highlights: • A novel phosphor CdGeO 3 :Pr 3+ was synthesized successfully. • The persistent luminescence properties of CdGeO 3 :Pr 3+ were studied. • The photostimulated luminescence properties of CdGeO 3 :Pr 3+ were investigated. • The persistent and photostimulated luminescence mechanisms were discussed in detail. - Abstract: Praseodymium doped CdGeO 3 phosphors were prepared successfully by a conventional high temperature solid-state reaction method. It showed reddish orange long persistent luminescence (LPL) after the short UV-irradiation. The reddish orange photostimulated luminescence (PSL) was also observed upon near infrared stimulation at 980 nm after per-exposure into UV light. The origin of LPL and PSL was identified with the emission from Pr 3+ ions with the aid of traps in host lattice. The optimal concentration of Pr 3+ ions for the brightest photoluminescence (PL) emission and the best LPL characteristic were experimentally to be about 3% and 0.5 mol%, respectively. The trapping and de-trapping processes of charge carriers between shallower and deep traps were illustrated. A model was proposed on the basis of experimental results to study the mechanisms of LPL and PSL

Zika Virus RNA Replication and Persistence in Brain and Placental Tissue

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Rabeneck, Demi B.; Martines, Roosecelis B.; Reagan-Steiner, Sarah; Ermias, Yokabed; Estetter, Lindsey B.C.; Suzuki, Tadaki; Ritter, Jana; Keating, M. Kelly; Hale, Gillian; Gary, Joy; Muehlenbachs, Atis; Lambert, Amy; Lanciotti, Robert; Oduyebo, Titilope; Meaney-Delman, Dana; Bolaños, Fernando; Saad, Edgar Alberto Parra; Shieh, Wun-Ju; Zaki, Sherif R.

2017-01-01

Zika virus is causally linked with congenital microcephaly and may be associated with pregnancy loss. However, the mechanisms of Zika virus intrauterine transmission and replication and its tropism and persistence in tissues are poorly understood. We tested tissues from 52 case-patients: 8 infants with microcephaly who died and 44 women suspected of being infected with Zika virus during pregnancy. By reverse transcription PCR, tissues from 32 (62%) case-patients (brains from 8 infants with microcephaly and placental/fetal tissues from 24 women) were positive for Zika virus. In situ hybridization localized replicative Zika virus RNA in brains of 7 infants and in placentas of 9 women who had pregnancy losses during the first or second trimester. These findings demonstrate that Zika virus replicates and persists in fetal brains and placentas, providing direct evidence of its association with microcephaly. Tissue-based reverse transcription PCR extends the time frame of Zika virus detection in congenital and pregnancy-associated infections. PMID:27959260

Providing the Persistent Data Storage in a Software Engineering Environment Using Java/COBRA and a DBMS

Science.gov (United States)

Dhaliwal, Swarn S.

1997-01-01

An investigation was undertaken to build the software foundation for the WHERE (Web-based Hyper-text Environment for Requirements Engineering) project. The TCM (Toolkit for Conceptual Modeling) was chosen as the foundation software for the WHERE project which aims to provide an environment for facilitating collaboration among geographically distributed people involved in the Requirements Engineering process. The TCM is a collection of diagram and table editors and has been implemented in the C++ programming language. The C++ implementation of the TCM was translated into Java in order to allow the editors to be used for building various functionality of the WHERE project; the WHERE project intends to use the Web as its communication back- bone. One of the limitations of the translated software (TcmJava), which militated against its use in the WHERE project, was persistent data management mechanisms which it inherited from the original TCM; it was designed to be used in standalone applications. Before TcmJava editors could be used as a part of the multi-user, geographically distributed applications of the WHERE project, a persistent storage mechanism must be built which would allow data communication over the Internet, using the capabilities of the Web. An approach involving features of Java, CORBA (Common Object Request Broker), the Web, a middle-ware (Java Relational Binding (JRB)), and a database server was used to build the persistent data management infrastructure for the WHERE project. The developed infrastructure allows a TcmJava editor to be downloaded and run from a network host by using a JDK 1.1 (Java Developer's Kit) compatible Web-browser. The aforementioned editor establishes connection with a server by using the ORB (Object Request Broker) software and stores/retrieves data in/from the server. The server consists of a CORBA object or objects depending upon whether the data is to be made persistent on a single server or multiple servers. The CORBA

On persistence interfaces for scientific data stores

International Nuclear Information System (INIS)

Malon, D.M.; May, E.N.

1996-01-01

A common dilemma among builders of large scientific data stores is whether to use a lightweight object persistence manager or a genuine object-oriented database. There are often good reasons to consider each of these strategies; a few are described in this paper. Too often, however, electing to use a lightweight approach has meant programming to an interface that is entirely different than that expected by commercial object-oriented databases. With the emergence of object database standards, it is possible to provide an interface to persistence managers that does not needlessly inhibit coexistence with (and, perhaps, eventual migration to) object-oriented databases. This paper describes an implementation of a substantial subset of the ODMG-93[1]C++ specification that allows clients to use many of today's lightweight object persistence managers through an interface that conforms to the ODMG standard. We also describe a minimal interface that persistence software should support in order to provide persistence services for ODMG implementations

Persistence of stapedial artery: a case report

International Nuclear Information System (INIS)

Carvalho, Bruna Vilaca de; Gaiotti, Juliana Oggioni; Diniz, Renata Lopes Furletti Caldeira; Ribeiro, Marcelo Almeida; Motta, Emilia Guerra Pinto Coelho; Moreira, Wanderval

2013-01-01

Persistent stapedial artery is a rare congenital anomaly that occurs by a failure in the involution of such artery. Most patients with persistent stapedial artery are asymptomatic. The imaging diagnosis is made principally by means of multidetector computed tomography. In the present case, persistent stapedial artery was an incidental computed tomography finding. The authors discuss the embryogenesis, computed tomography findings and the importance of an early diagnosis of such anomaly. (author)

Teriparatide Induced Delayed Persistent Hypercalcemia

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Nirosshan Thiruchelvam

2014-01-01

Full Text Available Teriparatide, a recombinant PTH, is an anabolic treatment for osteoporosis that increases bone density. Transient hypercalcemia is a reported side effect of teriparatide that is seen few hours following administration of teriparatide and resolves usually within 16 hours of drug administration. Persistent hypercalcemia, although not observed in clinical trials, is rarely reported. The current case describes a rare complication of teriparatide induced delayed persistent hypercalcemia.

Experimental and numerical study of the failure process and energy mechanisms of rock-like materials containing cross un-persistent joints under uniaxial compression.

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Rihong Cao

Full Text Available Joints and fissures in natural rocks have a significant influence on the stability of the rock mass, and it is often necessary to evaluate strength failure and crack evolution behavior. In this paper, based on experimental tests and numerical simulation (PFC2D, the macro-mechanical behavior and energy mechanism of jointed rock-like specimens with cross non-persistent joints under uniaxial loading were investigated. The focus was to study the effect of joint dip angle α and intersection angle γ on the characteristic stress, the coalescence modes and the energy release of jointed rock-like specimens. For specimens with γ = 30° and 45°, the UCS (uniaxial compression strength, CIS (crack initiation stress and CDiS (critical dilatancy stress increase as α increases from 0° to 75°. When γ = 60° and 75°, the UCS, CIS and CDiS increase as α increases from 0° to 60° and decrease when α is over 60°. Both the inclination angle α and intersection angle γ have great influence on the failure pattern of pre-cracked specimens. With different α and γ, specimens exhibit 4 kinds of failure patterns. Both the experimental and numerical results show that the energy of a specimen has similar trends with characteristic stress as α increases.

Low-Grade Persistent Hyperparathyroidism After Pediatric Renal Transplant.

Science.gov (United States)

Gulleroglu, Kaan; Baskin, Esra; Moray, Gokhan; Haberal, Mehmet

2016-06-01

Hyperparathyroidism, a frequent complication of chronic kidney disease, persists after renal transplant. Our aims were to examine the status of parathyroid hormone levels and to determine the clinical and biochemical risk factors of persistent hyperparathyroidism after transplant. Our study included 44 pediatric renal transplant recipients with stable graft function. Median follow-up after transplant was 17.5 months (range, 12-126 mo). Patients did not receive routine vitamin D or calcium supplements after transplant, and none had undergone previous parathyroidectomy. Bone mineral densitometry of the lumbar spine was measured. Fifteen patients (34%) had parathyroid hormone levels greater than 70 pg/mL (normal range, 10-70 pg/mL). Duration of dialysis before transplant was longer in patients with persistent hyperparathyroidism. Mean serum bicarbonate levels were significantly lower in patients with persistent hyperparathyroidism than in patients without persistent hyperparathyroidism after transplant. A significant negative correlation was noted between parathyroid hormone level and serum bicarbonate level. Another significant negative correlation was shown between parathyroid hormone level and z score. We found that persistent hyperparathyroidism is related to longer dialysis duration, lower serum bicarbonate level, and lower z score. Pretransplant dialysis duration is an important predictor of persistent hyperparathyroidism. Early identification of factors that contribute to persistent hyperparathyroidism after transplant could lead to treatment strategies to minimize or prevent its detrimental effects on bone health and growth in pediatric transplant recipients.

The role of temporal synchrony as a binding cue for visual persistence in early visual areas: an fMRI study.

Science.gov (United States)

Wong, Yvonne J; Aldcroft, Adrian J; Large, Mary-Ellen; Culham, Jody C; Vilis, Tutis

2009-12-01

We examined the role of temporal synchrony-the simultaneous appearance of visual features-in the perceptual and neural processes underlying object persistence. When a binding cue (such as color or motion) momentarily exposes an object from a background of similar elements, viewers remain aware of the object for several seconds before it perceptually fades into the background, a phenomenon known as object persistence. We showed that persistence from temporal stimulus synchrony, like that arising from motion and color, is associated with activation in the lateral occipital (LO) area, as measured by functional magnetic resonance imaging. We also compared the distribution of occipital cortex activity related to persistence to that of iconic visual memory. Although activation related to iconic memory was largely confined to LO, activation related to object persistence was present across V1 to LO, peaking in V3 and V4, regardless of the binding cue (temporal synchrony, motion, or color). Although persistence from motion cues was not associated with higher activation in the MT+ motion complex, persistence from color cues was associated with increased activation in V4. Taken together, these results demonstrate that although persistence is a form of visual memory, it relies on neural mechanisms different from those of iconic memory. That is, persistence not only activates LO in a cue-independent manner, it also recruits visual areas that may be necessary to maintain binding between object elements.

Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling.

Science.gov (United States)

Vetter, Irina; Touska, Filip; Hess, Andreas; Hinsbey, Rachel; Sattler, Simon; Lampert, Angelika; Sergejeva, Marina; Sharov, Anastasia; Collins, Lindon S; Eberhardt, Mirjam; Engel, Matthias; Cabot, Peter J; Wood, John N; Vlachová, Viktorie; Reeh, Peter W; Lewis, Richard J; Zimmermann, Katharina

2012-10-03

Ciguatoxins are sodium channel activator toxins that cause ciguatera, the most common form of ichthyosarcotoxism, which presents with peripheral sensory disturbances, including the pathognomonic symptom of cold allodynia which is characterized by intense stabbing and burning pain in response to mild cooling. We show that intraplantar injection of P-CTX-1 elicits cold allodynia in mice by targeting specific unmyelinated and myelinated primary sensory neurons. These include both tetrodotoxin-resistant, TRPA1-expressing peptidergic C-fibres and tetrodotoxin-sensitive A-fibres. P-CTX-1 does not directly open heterologously expressed TRPA1, but when co-expressed with Na(v) channels, sodium channel activation by P-CTX-1 is sufficient to drive TRPA1-dependent calcium influx that is responsible for the development of cold allodynia, as evidenced by a large reduction of excitatory effect of P-CTX-1 on TRPA1-deficient nociceptive C-fibres and of ciguatoxin-induced cold allodynia in TRPA1-null mutant mice. Functional MRI studies revealed that ciguatoxin-induced cold allodynia enhanced the BOLD (Blood Oxygenation Level Dependent) signal, an effect that was blunted in TRPA1-deficient mice, confirming an important role for TRPA1 in the pathogenesis of cold allodynia.

Fundamental bound on the persistence and capacity of short-term memory stored as graded persistent activity.

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Koyluoglu, Onur Ozan; Pertzov, Yoni; Manohar, Sanjay; Husain, Masud; Fiete, Ila R

2017-09-07

It is widely believed that persistent neural activity underlies short-term memory. Yet, as we show, the degradation of information stored directly in such networks behaves differently from human short-term memory performance. We build a more general framework where memory is viewed as a problem of passing information through noisy channels whose degradation characteristics resemble those of persistent activity networks. If the brain first encoded the information appropriately before passing the information into such networks, the information can be stored substantially more faithfully. Within this framework, we derive a fundamental lower-bound on recall precision, which declines with storage duration and number of stored items. We show that human performance, though inconsistent with models involving direct (uncoded) storage in persistent activity networks, can be well-fit by the theoretical bound. This finding is consistent with the view that if the brain stores information in patterns of persistent activity, it might use codes that minimize the effects of noise, motivating the search for such codes in the brain.

Genetic evidence for an essential role of neuronally expressed IL-6 signal transducer gp130 in the induction and maintenance of experimentally induced mechanical hypersensitivity in vivo and in vitro

Directory of Open Access Journals (Sweden)

Constantin Cristina E

2011-09-01

Full Text Available Abstract Tenderness and mechanical allodynia are key symptoms of malignant tumor, inflammation and neuropathy. The proinflammatory cytokine interleukin-6 (IL-6 is causally involved in all three pathologies. IL-6 not only regulates innate immunity and inflammation but also causes nociceptor sensitization and hyperalgesia. In general and in most cell types including immune cells and sensory neurons, IL-6 binds soluble μ receptor subunits which heteromerizes with membrane bound IL-6 signal transducer gp130. In the present study, we used a conditional knock-out strategy to investigate the importance of signal transducer gp130 expressed in C nociceptors for the generation and maintenance of mechanical hypersensitivity. Nociceptors were sensitized to mechanical stimuli by experimental tumor and this nociceptor sensitization was preserved at later stages of the pathology in control mice. However, in mice with a conditional deletion of gp130 in Nav1.8 expressing nociceptors mechanical hypersensitivity by experimental tumor, nerve injury or inflammation recovery was not preserved in the maintenance phase and nociceptors exhibited normal mechanical thresholds comparable to untreated mice. Together, the results argue for IL-6 signal transducer gp130 as an essential prerequisite in nociceptors for long-term mechanical hypersensitivity associated with cancer, inflammation and nerve injury.

Herbicide Persistence in Seawater Simulation Experiments.

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Philip Mercurio

Full Text Available Herbicides are detected year-round in marine waters, including those of the World Heritage listed Great Barrier Reef (GBR. The few previous studies that have investigated herbicide persistence in seawater generally reported half-lives in the order of months, and several studies were too short to detect significant degradation. Here we investigated the persistence of eight herbicides commonly detected in the GBR or its catchments in standard OECD simulation flask experiments, but with the aim to mimic natural conditions similar to those found on the GBR (i.e., relatively low herbicide concentrations, typical temperatures, light and microbial communities. Very little degradation was recorded over the standard 60 d period (Experiment 1 so a second experiment was extended to 365 d. Half-lives of PSII herbicides ametryn, atrazine, diuron, hexazinone and tebuthiuron were consistently greater than a year, indicating high persistence. The detection of atrazine and diuron metabolites and longer persistence in mercuric chloride-treated seawater confirmed that biodegradation contributed to the breakdown of herbicides. The shortest half-life recorded was 88 d for growth-regulating herbicide 2,4-D at 31°C in the dark, while the fatty acid-inhibitor metolachlor exhibited a minimum half-life of 281 d. The presence of moderate light and elevated temperatures affected the persistence of most of the herbicides; however, the scale and direction of the differences were not predictable and were likely due to changes in microbial community composition. The persistence estimates here represent some of the first appropriate data for application in risk assessments for herbicide exposure in tropical marine systems. The long persistence of herbicides identified in the present study helps explain detection of herbicides in nearshore waters of the GBR year round. Little degradation of these herbicides would be expected during the wet season with runoff and associated

Herbicide Persistence in Seawater Simulation Experiments

Science.gov (United States)

Mercurio, Philip; Mueller, Jochen F.; Eaglesham, Geoff; Flores, Florita; Negri, Andrew P.

2015-01-01

Herbicides are detected year-round in marine waters, including those of the World Heritage listed Great Barrier Reef (GBR). The few previous studies that have investigated herbicide persistence in seawater generally reported half-lives in the order of months, and several studies were too short to detect significant degradation. Here we investigated the persistence of eight herbicides commonly detected in the GBR or its catchments in standard OECD simulation flask experiments, but with the aim to mimic natural conditions similar to those found on the GBR (i.e., relatively low herbicide concentrations, typical temperatures, light and microbial communities). Very little degradation was recorded over the standard 60 d period (Experiment 1) so a second experiment was extended to 365 d. Half-lives of PSII herbicides ametryn, atrazine, diuron, hexazinone and tebuthiuron were consistently greater than a year, indicating high persistence. The detection of atrazine and diuron metabolites and longer persistence in mercuric chloride-treated seawater confirmed that biodegradation contributed to the breakdown of herbicides. The shortest half-life recorded was 88 d for growth-regulating herbicide 2,4-D at 31°C in the dark, while the fatty acid-inhibitor metolachlor exhibited a minimum half-life of 281 d. The presence of moderate light and elevated temperatures affected the persistence of most of the herbicides; however, the scale and direction of the differences were not predictable and were likely due to changes in microbial community composition. The persistence estimates here represent some of the first appropriate data for application in risk assessments for herbicide exposure in tropical marine systems. The long persistence of herbicides identified in the present study helps explain detection of herbicides in nearshore waters of the GBR year round. Little degradation of these herbicides would be expected during the wet season with runoff and associated flood plumes

CaMKII Requirement for in Vivo Insular Cortex LTP Maintenance and CTA Memory Persistence

Directory of Open Access Journals (Sweden)

Yectivani Juárez-Muñoz

2017-11-01

Full Text Available Calcium-calmodulin/dependent protein kinase II (CaMKII plays an essential role in LTP induction, but since it has the capacity to remain persistently activated even after the decay of external stimuli it has been proposed that it can also be necessary for LTP maintenance and therefore for memory persistence. It has been shown that basolateral amygdaloid nucleus (Bla stimulation induces long-term potentiation (LTP in the insular cortex (IC, a neocortical region implicated in the acquisition and retention of conditioned taste aversion (CTA. Our previous studies have demonstrated that induction of LTP in the Bla-IC pathway before CTA training increased the retention of this task. Although it is known that IC-LTP induction and CTA consolidation share similar molecular mechanisms, little is known about the molecular actors that underlie their maintenance. The purpose of the present study was to evaluate the role of CaMKII in the maintenance of in vivo Bla-IC LTP as well as in the persistence of CTA long-term memory (LTM. Our results show that acute microinfusion of myr-CaMKIINtide, a selective inhibitor of CaMKII, in the IC of adult rats during the late-phase of in vivo Bla-IC LTP blocked its maintenance. Moreover, the intracortical inhibition of CaMKII 24 h after CTA acquisition impairs CTA-LTM persistence. Together these results indicate that CaMKII is a central key component for the maintenance of neocortical synaptic plasticity as well as for persistence of CTA-LTM.

Hippocampal subfield and medial temporal cortical persistent activity during working memory reflects ongoing encoding

Directory of Open Access Journals (Sweden)

Rachel K Nauer

2015-03-01

Full Text Available Previous neuroimaging studies support a role for the medial temporal lobes (MTL in maintaining novel stimuli over brief working memory (WM delays, and suggest delay period activity predicts subsequent memory. Additionally, slice recording studies have demonstrated neuronal persistent spiking in entorhinal cortex (EC, perirhinal cortex (PrC, and hippocampus (CA1, CA3, subiculum. These data have led to computational models that suggest persistent spiking in parahippocampal regions could sustain neuronal representations of sensory information over many seconds. This mechanism may support both WM maintenance and encoding of information into long term episodic memory. The goal of the current study was to use high-resolution fMRI to elucidate the contributions of the MTL cortices and hippocampal subfields to WM maintenance as it relates to later episodic recognition memory. We scanned participants while they performed a delayed match to sample task with novel scene stimuli, and assessed their memory for these scenes post-scan. We hypothesized stimulus-driven activation that persists into the delay period—a putative correlate of persistent spiking—would predict later recognition memory. Our results suggest sample and delay period activation in the parahippocampal cortex (PHC, PrC, and subiculum (extending into DG/CA3 and CA1 was linearly related to increases in subsequent memory strength. These data extend previous neuroimaging studies that have constrained their analysis to either the sample or delay period by modeling these together as one continuous ongoing encoding process, and support computational frameworks that predict persistent activity underlies both WM and episodic encoding.

New and Persistent Gender Equality Challenges in Academia

DEFF Research Database (Denmark)

Nielsen, Mathias Wullum

This dissertation is about the cumulative disadvantages slowing down women academics’ advancement and keeping them from gaining the same organizational status as their male colleagues. It is also about understanding and explaining how gender relations are reconstituted in a rapidly changing...... academic context characterized by increasing demands for international competitiveness, innovation, flexibility and accountability. The thesis employs a case study approach, adopting a critical realist meta- theoretical framework and a pluralist methodology to investigate the new and persistent gender...... equality challenges at Aarhus University in Denmark. The overall research objective has been divided into four analytically distinct potential explanatory components, each drawing attention to a number of social mechanisms, which under certain circumstances, can be expected to be instrumental...

On the persistence of unstable bump-on-tail electron velocity distributions in the earth's foreshock

International Nuclear Information System (INIS)

Klimas, A.J.; Fitzenreiter, R.J.

1988-01-01

Further evidence for the persistence of bump-on-tail unstable reduced velocity distribution in the Earth's electron foreshock is presented. This persistence contradicts our understanding of quasi-linear saturation of the bump-on-tail instability; the distributions should be stabilized through velocity space diffusion too quickly to allow an observation of their unstable form. A modified theory for the saturation of the bump-on-tail instability in the Earth's foreshock is proposed and examined using numerical simulation and quasi-linear theoretical techniques. It is argued the mechanism due to Filbert and Kellogg and to Cairns which is responsible for the creation of the bump-on-tail velocity distribution in the foreshock is still operative during the evolution of the bump-on-tail instability. The saturated state of the plasma must represent a balance between this creation mechanism and velocity space diffusion; the saturated state is not determined by velocity space diffusion alone. Thus the velocity distribution of the saturated stat may still appear bump-on-tail unstable to standard linear analysis which does not take the creation mechanism into account. The bump-on-tail velocity distributions in the foreshock would then represent the state of the plasma after saturation of the bump-on-tail instability, not before

Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states.

Science.gov (United States)

Boroujerdi, Amin; Zeng, Jun; Sharp, Kelli; Kim, Donghyun; Steward, Oswald; Luo, Z David

2011-03-01

Spinal cord injury (SCI) commonly results in the development of neuropathic pain, which can dramatically impair the quality of life for SCI patients. SCI-induced neuropathic pain can be manifested as both tactile allodynia (a painful sensation to a non-noxious stimulus) and hyperalgesia (an enhanced sensation to a painful stimulus). The mechanisms underlying these pain states are poorly understood. Clinical studies have shown that gabapentin, a drug that binds to the voltage-gated calcium channel alpha-2-delta-1 subunit (Ca(v)α2δ-1) proteins is effective in the management of SCI-induced neuropathic pain. Accordingly, we hypothesized that tactile allodynia post SCI is mediated by an upregulation of Ca(v)α2δ-1 in dorsal spinal cord. To test this hypothesis, we examined whether SCI-induced dysregulation of spinal Ca(v)α2δ-1 plays a contributory role in below-level allodynia development in a rat spinal T9 contusion injury model. We found that Ca(v)α2δ-1 expression levels were significantly increased in L4-6 dorsal, but not ventral, spinal cord of SCI rats that correlated with tactile allodynia development in the hind paw plantar surface. Furthermore, both intrathecal gabapentin treatment and blocking SCI-induced Ca(v)α2δ-1 protein upregulation by intrathecal Ca(v)α2δ-1 antisense oligodeoxynucleotides could reverse tactile allodynia in SCI rats. These findings support that SCI-induced Ca(v)α2δ-1 upregulation in spinal dorsal horn is a key component in mediating below-level neuropathic pain states, and selectively targeting this pathway may provide effective pain relief for SCI patients. Spinal cord contusion injury caused increased calcium channel Ca(v)α2δ-1 subunit expression in dorsal spinal cord that contributes to neuropathic pain states. Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Relationship of left ventricular systolic function to persistence or development of electrocardiographic left ventricular hypertrophy in hypertensive patients

DEFF Research Database (Denmark)

Okin, Peter M; Wachtell, Kristian; Gerdts, Eva

2014-01-01

left ventricular systolic function in patients with new or persistent ECG LVH. METHODS: Baseline and year-3 ECG LVH and left ventricular midwall shortening (MWS) were examined in 725 hypertensive patients in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiographic...... 1.03-3.50, P = 0.040) at year 3. CONCLUSION: Persistence or development of new ECG LVH during antihypertensive therapy is associated with an increased risk of left ventricular systolic dysfunction after 3 years' follow-up. These findings provide insight into a possible mechanism by which changes......BACKGROUND: Persistence or development of ECG left ventricular hypertrophy (LVH) by Cornell product criteria is associated with an increased risk of developing heart failure compared with regression or continued absence of LVH. We postulated that this association might be in part mediated via worse...

Performance Persistence of Equity Funds in Hungary

Directory of Open Access Journals (Sweden)

Dariusz Filip

2011-03-01

Full Text Available This study examines the phenomenon of performance persistence of equity funds in Hungary in two time perspectives: 1-year and 6-month perspectives. The empirical results confirm the occurrence of performance dependence in consecutive periods. There is also a strong evidence of short-term persistence in the total horizon of the study (from the beginning of 2000 to the end of 2009, and in several sub-periods. The 1-year persistence was also found in the tested sample and, in general, depended on the measure applied. Furthermore, I observed performance reversal, which can be partly explained by trend changes in the financial markets. The persistence of equity funds performance in Hungary is shaped by market factors rather than the diversity of managerial characteristics.

Low doses of dextromethorphan have a beneficial effect in the treatment of neuropathic pain.

Science.gov (United States)

Morel, Véronique; Pickering, Gisèle; Etienne, Monique; Dupuis, Amandine; Privat, Anne-Marie; Chalus, Maryse; Eschalier, Alain; Daulhac, Laurence

2014-12-01

N-methyl-D-aspartate receptor (NMDAR) antagonists may be given in persistent neuropathic pain, but adverse events especially with ketamine may limit their clinical use. Less central and cognitive adverse events are described with dextromethorphan and memantine. These molecules have been explored in many preclinical and clinical studies, but data are conflicting as regards neuropathic pain alleviation. Dextromethorphan and memantine have been administered to animals after spinal nerve ligation (SNL) to evaluate their antinociceptive/cognitive effects and associated molecular events, including the phosphorylation of several tyrosine (pTyr(1336), pTyr(1472)) residues in the NR2B NMDAR subunit. Spinal nerve ligation and sham animals received dextromethorphan (10 mg/kg, i.p.), memantine (20 mg/kg, i.p.) or saline (1 mL/kg, i.p.). These drugs were administered once symptoms of allodynia and hyperalgesia had developed. Tests were carried out before and after surgery. Tactile allodynia, mechanical hyperalgesia and spatial memory were, respectively, evaluated by von Frey, Randall & Selitto and Y-maze tests and molecular events by Western blot analysis. Spinal nerve-ligated animals displayed nociception and impaired spatial memory. Dextromethorphan, but not memantine, reversed neuropathic pain (NP) symptoms, restored spatial memory integrity and decreased the expression of pTyr(1336)NR2B. Following postoperative administration of dextromethorphan, this study has demonstrated for the first time a concordance between behaviour, cognitive function and molecular events via pTyr(1336)NR2B for neuropathic pain alleviation. Confirmation of these findings in patients would constitute a major step forward in the treatment of neuropathic pain and in the improvement of cognitive function and quality of life. © 2014 Société Française de Pharmacologie et de Thérapeutique.

Support for viral persistence in bats from age-specific serology and models of maternal immunity.

Science.gov (United States)

Peel, Alison J; Baker, Kate S; Hayman, David T S; Broder, Christopher C; Cunningham, Andrew A; Fooks, Anthony R; Garnier, Romain; Wood, James L N; Restif, Olivier

2018-03-01

Spatiotemporally-localised prediction of virus emergence from wildlife requires focused studies on the ecology and immunology of reservoir hosts in their native habitat. Reliable predictions from mathematical models remain difficult in most systems due to a dearth of appropriate empirical data. Our goal was to study the circulation and immune dynamics of zoonotic viruses in bat populations and investigate the effects of maternally-derived and acquired immunity on viral persistence. Using rare age-specific serological data from wild-caught Eidolon helvum fruit bats as a case study, we estimated viral transmission parameters for a stochastic infection model. We estimated mean durations of around 6 months for maternally-derived immunity to Lagos bat virus and African henipavirus, whereas acquired immunity was long-lasting (Lagos bat virus: mean 12 years, henipavirus: mean 4 years). In the presence of a seasonal birth pulse, the effect of maternally-derived immunity on virus persistence within modelled bat populations was highly dependent on transmission characteristics. To explain previous reports of viral persistence within small natural and captive E. helvum populations, we hypothesise that some bats must experience prolonged infectious periods or within-host latency. By further elucidating plausible mechanisms of virus persistence in bat populations, we contribute to guidance of future field studies.

Persistent agents in Axelrod's social dynamics model

Science.gov (United States)

Reia, Sandro M.; Neves, Ubiraci P. C.

2016-01-01

Axelrod's model of social dynamics has been studied under the effect of external media. Here we study the formation of cultural domains in the model by introducing persistent agents. These are agents whose cultural traits are not allowed to change but may be spread through local neighborhood. In the absence of persistent agents, the system is known to present a transition from a monocultural to a multicultural regime at some critical Q (number of traits). Our results reveal a dependence of critical Q on the occupation probability p of persistent agents and we obtain the phase diagram of the model in the (p,Q) -plane. The critical locus is explained by the competition of two opposite forces named here barrier and bonding effects. Such forces are verified to be caused by non-persistent agents which adhere (adherent agents) to the set of traits of persistent ones. The adherence (concentration of adherent agents) as a function of p is found to decay for constant Q. Furthermore, adherence as a function of Q is found to decay as a power law with constant p.

Persistence in the Cryptocurrency Market

OpenAIRE

Caporale, Guglielmo Maria; Gil-Alaña, Luis A.; Plastun, Alex

2017-01-01

This paper examines persistence in the cryptocurrency market. Two different long-memory methods (R/S analysis and fractional integration) are used to analyse it in the case of the four main cryptocurrencies (BitCoin, LiteCoin, Ripple, Dash) over the sample period 2013-2017. The findings indicate that this market exhibits persistence (there is a positive correlation between its past and future values), and that its degree changes over time. Such predictability represents evidence of market ine...

Reverting antibiotic tolerance of Pseudomonas aeruginosa PAO1 persister cells by (Z-4-bromo-5-(bromomethylene-3-methylfuran-2(5H-one.

Directory of Open Access Journals (Sweden)

Jiachuan Pan

Full Text Available BACKGROUND: Bacteria are well known to form dormant persister cells that are tolerant to most antibiotics. Such intrinsic tolerance also facilitates the development of multidrug resistance through acquired mechanisms. Thus persister cells are a promising target for developing more effective methods to control chronic infections and help prevent the development of multidrug-resistant bacteria. However, control of persister cells is still an unmet challenge. METHODOLOGY/PRINCIPAL FINDINGS: We show in this report that (Z-4-bromo-5-(bromomethylene-3-methylfuran-2(5H-one (BF8 can restore the antibiotic susceptibility of Pseudomonas aeruginosa PAO1 persister cells at growth non-inhibitory concentrations. Persister control by BF8 was found to be effective against both planktonic and biofilm cells of P. aeruginosa PAO1. Interestingly, although BF8 is an inhibitor of quorum sensing (QS in Gram-negative bacteria, the data in this study suggest that the activities of BF8 to revert antibiotic tolerance of P. aeruginosa PAO1 persister cells is not through QS inhibition and may involve other targets. CONCLUSION: BF8 can sensitize P. aeruginosa persister cells to antibiotics.

Treatment of acral persistent papular mucinosis with electrocoagulation.

Science.gov (United States)

André Jorge, Flávia; Mimura Cortez, Tatiana; Guadalini Mendes, Fabiana; Esther Alencar Marques, Mariângela; Amante Miot, Hélio

2011-01-01

Acral persistent papular mucinosis is a rare localized form of lichen myxedematosus with few case reports and no documented therapeutic options. To report full resolution of acral persistent papular mucinosis after electrocoagulation. Case report of a 51-year-old white female diagnosed with an acral persistent papular mucinosis. The clinical and histopathologic features, treatment provided, and response to treatment are detailed. Acral persistent papular mucinosis presented as multiple asymptomatic normochromic papules on the wrists. Treatment with topical and intralesional steroids was unsatisfactory. Gentle electrocoagulation led to complete resolution of the lesions and negligible scarring. The favorable results remained for 6 months of follow-up, and no new lesions have emerged. Our case of acral persistent papular mucinosis was successfully treated with electrocoagulation and long-lasting, excellent cosmetic results.

IB4(+) nociceptors mediate persistent muscle pain induced by GDNF.

Science.gov (United States)

Alvarez, Pedro; Chen, Xiaojie; Bogen, Oliver; Green, Paul G; Levine, Jon D

2012-11-01

Skeletal muscle is a well-known source of glial cell line-derived neurotrophic factor (GDNF), which can produce mechanical hyperalgesia. Since some neuromuscular diseases are associated with both increased release of GDNF and intense muscle pain, we explored the role of GDNF as an endogenous mediator in muscle pain. Intramuscularly injected GDNF induced a dose-dependent (0.1-10 ng/20 μl) persistent (up to 3 wk) mechanical hyperalgesia in the rat. Once hyperalgesia subsided, injection of prostaglandin E(2) at the site induced a prolonged mechanical hyperalgesia (>72 h) compared with naïve rats (vibration increased muscle GDNF levels at 24 h, a time point where rats also exhibited marked muscle hyperalgesia. Intrathecal antisense oligodeoxynucleotides to mRNA encoding GFRα1, the canonical binding receptor for GDNF, reversibly inhibited eccentric exercise- and mechanical vibration-induced muscle hyperalgesia. Finally, electrophysiological recordings from nociceptors innervating the gastrocnemius muscle in anesthetized rats, revealed significant increase in response to sustained mechanical stimulation after local GDNF injection. In conclusion, these data indicate that GDNF plays a role as an endogenous mediator in acute and induction of chronic muscle pain, an effect likely to be produced by GDNF action at GFRα1 receptors located in IB4(+) nociceptors.

Spatial patterns of drought persistence in East China

Science.gov (United States)

Meng, L.; Ford, T.

2017-12-01

East China has experienced a number of severe droughts in recent decades. Understanding the characteristics of droughts and their persistence will provide operational guidelines for water resource management and agricultural production. This study uses a logistic regression model to measure the probability of drought occurrence in the current season given the previous season's Standardized Precipitation Index (SPI) and Southern Oscillation Index (SOI) as well as drought persistence. Results reveal large spatial and seasonal variations in the relationship between the previous season's SPI and the drought occurrence probability in a given season. The drought persistence averaged over the entire study area for all the four seasons is approximately 34% with large variations from season to season and from region to region. The East and Northeast regions have the largest summer drought persistence ( 40%) and lowest fall drought persistence ( 28%). The spatial pattern in winter and spring drought persistence is dissimilar with stronger winter and weaker spring drought persistence in the Southwest and Northeast relative to other regions. Logistic regression analysis indicates a stronger negative relationship in summer-to-fall (or between fall drought occurrence and summer SPI) than other inter-season relationships. This study demonstrates that the impact of previous season SPI and SOI on current season drought varies substantially from region to region and from season to season. This study also shows stronger drought persistence in summer than in other seasons. In other words, the probability of fall drought occurrence is closely related to summer moisture conditions in the East China.

Persistence in the WFC3 IR Detector: Intrinsic Variability

Science.gov (United States)

Long, Knox S.; Baggett, Sylvia M.

2018-03-01

When the WFC3 IR detector is exposed to a bright source or sources, the sources can appear as afterimages in subsequent exposures, a phenomenon known as persistence. This can affect the science obtained with the IR channel. We have been involved in an effort to predict the brightness of the afterimages so that users can (at a minimum) flag the affected pixels and remove them from their analysis or (even better) subtract the afterimages from their science images to salvage the data. The ability of any model to remove afterimages depends on the degree to which persistence is the same for identical sets of exposures. We investigate possible time variability of persistence in the WFC3 detector using sets of (almost) identical visits comprised of single exposures of Omega Cen followed by a series of darks in which persistence is measured. We analyze 8 data sets, each consisting of two or three identical visits, with stimulus exposures between 49 and 1199 s, and find clear evidence of variability in several of the datasets in darks taken within 1000 s of the stimulus exposure. In most of the datasets, the difference in persistence for saturated pixels in the stimulus exposure is a power law decay; the visit with higher persistence has a higher power law amplitude. There was nothing unusual about the observing conditions preceding and during each of these visits that can explain the discrepancy in persistence levels. Variation in persistence implies that: (1) Unless and until the source of the variability is understood, any persistence model for the WFC3 array will be limited in its ability to predict persistence in a single observation, and, (2) as a consequence, users should always carefully inspect the results of any attempt to subtract persistence from WFC3 IR data based on a model prediction.

Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation

Energy Technology Data Exchange (ETDEWEB)

Musah, Sadiatu; Schlueter, Connie F.; Humphrey, David M. [Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (United States); Powell, Karen S. [Research Resource Facilities, University of Louisville, Louisville, KY (United States); Roberts, Andrew M. [Department of Physiology, University of Louisville, Louisville, KY (United States); Hoyle, Gary W., E-mail: Gary.Hoyle@louisville.edu [Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (United States)

2017-01-15

Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24 h after exposure to 800 ppm chlorine for 4 min to study acute effects or up to 7 days after exposure to 400 ppm for 8 min to study longer term effects. Acute effects observed 6 or 24 h after inhalation of 800 ppm chlorine for 4 min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400 ppm chlorine for 8 min, rabbits exhibited mild hypoxemia, increased area of pressure–volume loops, and airway hyperreactivity. Lung histology 7 days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. - Highlights: • A novel rabbit model of chlorine-induced lung disease was developed. �

Involvement of the chemokine CCL3 and the purinoceptor P2X7 in the spinal cord in paclitaxel-induced mechanical allodynia

OpenAIRE

Ochi-ishi, Ryutaro; Nagata, Kenichiro; Inoue, Tomoyuki; Tozaki-Saitoh, Hidetoshi; Tsuda, Makoto; Inoue, Kazuhide

2014-01-01

Background Paclitaxel is an effective chemotherapeutic agent widely used for the treatment of solid tumors. The major dose-limiting toxicity of paclitaxel is peripheral neuropathy. The mechanisms underlying the development and maintenance of paclitaxel-induced peripheral neuropathy are still unclear, and there are no currently established effective treatments. Accumulating evidence in models of neuropathic pain in which peripheral nerves are lesioned has implicated spinal microglia and chemok...

Near-Infrared Quantum Cutting Long Persistent Luminescence

OpenAIRE

Zou, Zehua; Feng, Lin; Cao, Cheng; Zhang, Jiachi; Wang, Yuhua

2016-01-01

By combining the unique features of the quantum cutting luminescence and long persistent luminescence, we design a new concept called ?near-infrared quantum cutting long persistent luminescence (NQPL)?, which makes it possible for us to obtain highly efficient (>100%) near-infrared long persistent luminescence in theory. Guided by the NQPL concept, we fabricate the first NQPL phosphor Ca2Ga2GeO7:Pr3+,Yb3+. It reveals that both the two-step energy transfer of model (I) and the one-step energy ...

p38 phosphorylation in medullary microglia mediates ectopic orofacial inflammatory pain in rats.

Science.gov (United States)

Kiyomoto, Masaaki; Shinoda, Masamichi; Honda, Kuniya; Nakaya, Yuka; Dezawa, Ko; Katagiri, Ayano; Kamakura, Satoshi; Inoue, Tomio; Iwata, Koichi

2015-08-12

Orofacial inflammatory pain is likely to accompany referred pain in uninflamed orofacial structures. The ectopic pain precludes precise diagnosis and makes treatment problematic, because the underlying mechanism is not well understood. Using the established ectopic orofacial pain model induced by complete Freund's adjuvant (CFA) injection into trapezius muscle, we analyzed the possible role of p38 phosphorylation in activated microglia in ectopic orofacial pain. Mechanical allodynia in the lateral facial skin was induced following trapezius muscle inflammation, which accompanied microglial activation with p38 phosphorylation and hyperexcitability of wide dynamic range (WDR) neurons in the trigeminal spinal subnucleus caudalis (Vc). Intra-cisterna successive administration of a p38 mitogen-activated protein kinase selective inhibitor, SB203580, suppressed microglial activation and its phosphorylation of p38. Moreover, SB203580 administration completely suppressed mechanical allodynia in the lateral facial skin and enhanced WDR neuronal excitability in Vc. Microglial interleukin-1β over-expression in Vc was induced by trapezius muscle inflammation, which was significantly suppressed by SB203580 administration. These findings indicate that microglia, activated via p38 phosphorylation, play a pivotal role in WDR neuronal hyperexcitability, which accounts for the mechanical hypersensitivity in the lateral facial skin associated with trapezius muscle inflammation.

Early Postoperative Nociceptive Threshold and Production of Brain-Derived Neurotrophic Factor Induced by Plantar Incision Are Not Influenced with Minocycline in a Rat: Role of Spinal Microglia

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Eiji Masaki

2016-03-01

Full Text Available Background: Brain-derived neurotrophic factor (BDNF from spinal microglia is crucial for aberrant nociceptive signaling in several pathological pain conditions, including postoperative pain. We assess the contribution of spinal microglial activation and associated BDNF overexpression to the early post-incisional nociceptive threshold. Methods: Male Sprague-Dawley rats were implanted with an intrathecal catheter. A postoperative pain model was established by plantar incision. Thermal and mechanical nociceptive responses were assessed by infrared radiant heat and von Frey filaments before and after plantar incision. Rats were injected intrathecally the microglial activation inhibitor minocycline before incision, 24 h after incision, or both. Other groups were subjected to the same treatments and the L4-L5 spinal cord segment removed for immunohistochemical analysis of microglia activation and BNDF expression. Results: Plantar incision reduced both thermal latency and mechanical threshold, indicating thermal hypersensitivity and mechanical allodynia. Minocycline temporally reduced thermal withdrawal latency but had no effect on mechanical withdrawal threshold, spinal microglial activity, or dorsal horn BDNF overexpression during the early post-incision period. Conclusion: These results suggest that spinal microglia does not contribute substantially to post-incisional nociceptive threshold. The BDNF overexpression response that may contribute to postoperative hyperalgesia and allodynia is likely derived from other sources.

Prediction of antibody persistency from antibody titres to natalizumab

DEFF Research Database (Denmark)

Jensen, Poul Erik H; Koch-Henriksen, Nils; Sellebjerg, Finn

2012-01-01

In a subgroup of patients with multiple sclerosis natalizumab therapy causes generation of anti-natalizumab antibodies that may be transient or persistent. It is recommended to discontinue natalizumab therapy in persistently antibody-positive patients.......In a subgroup of patients with multiple sclerosis natalizumab therapy causes generation of anti-natalizumab antibodies that may be transient or persistent. It is recommended to discontinue natalizumab therapy in persistently antibody-positive patients....

Persistent and transient Listeria monocytogenes strains from retail deli environments vary in their ability to adhere and form biofilms and rarely have inlA premature stop codons.

Science.gov (United States)

Wang, Jingjin; Ray, Andrea J; Hammons, Susan R; Oliver, Haley F

2015-02-01

Based on recent risk assessments, up to 83% of listeriosis cases from deli meat in the United States are predicted to be from ready-to-eat deli meats contaminated during processing at retail grocery stores. Listeria monocytogenes is known to use sanitizer tolerance and biofilm formation to survive, but interplay of these mechanisms along with virulence potential and persistence mechanisms specific to deli environments had yet to be elucidated. In this study, 442 isolates from food and nonfood contact surfaces in 30 retail delis over 9 months were tested for inlA premature stop codons (PMSCs); inlA encodes InlA, which is necessary to cause listeriosis. A total of 96 isolates, composed of 23 persistent and 73 transient strains, were tested for adhesion and biofilm-forming ability and sanitizer tolerance. Only 10/442 isolates had inlA PMSCs (pdelis with other persistent strains. Most (7/10) PMSC-containing isolates were collected from food contact surfaces (pdelis (p<0.05). Persistent strains had enhanced adhesion on day 1 of a 5-day adhesion-biofilm formation assay. However, there was no significant difference in sanitizer tolerance between persistent and transient strains. Results suggest that foods contaminated with persistent L. monocytogenes strains from the retail environment are (1) likely to have wild-type virulence potential and (2) may persist due to increased adhesion and biofilm formation capacity rather than sanitizer tolerance, thus posing a significant public health risk.

Persistent vs. Permanent Income Shocks in the Buffer-Stock Model

DEFF Research Database (Denmark)

Druedahl, Jeppe; Jørgensen, Thomas Høgholm

2017-01-01

relative risk aversion (CRRA) coefficient. If used for calibration, misspecified preferences could, for example, lead to a serious misjudgment in the value of social insurance mechanisms. Economic behavior, such as the marginal propensity to consume (MPC), of households simulated from the estimated......We investigate the effects of assuming a fully permanent income shock in a standard buffer-stock consumption model, when the true income process is only highly persistent. This assumption is computationally very advantageous, and thus often used, but might be problematic due to the implied...... (misspecified) model is, on the other hand, rather close to that from the correctly specified model....

Persistent Hiccups Following Stapedectomy

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Aidonis I

2010-10-01

Full Text Available Objective: We report a case of a 37 year-old man who developed persistent hiccups after elective stapedectomy. Method and Results: The diagnostic approach is discussed as well as the non-pharmacologic and pharmacologic treatments and overall management. The aim is to stress that there is a variety of potential factors that can induce hiccups perioperatively and in cases like this a step by step approach must be taken. Conclusion: Persistent hiccups are very rare following stapedectomy, control of them is crucial for the successful outcome. The trigger may be more than one factors and the good response to treatment may be due to dealing successfully with more than one thing.

DNA-cisplatin binding mechanism peculiarities studied with single molecule stretching experiments

Science.gov (United States)

Crisafuli, F. A. P.; Cesconetto, E. C.; Ramos, E. B.; Rocha, M. S.

2012-02-01

We propose a method to determine the DNA-cisplatin binding mechanism peculiarities by monitoring the mechanical properties of these complexes. To accomplish this task, we have performed single molecule stretching experiments by using optical tweezers, from which the persistence and contour lengths of the complexes can be promptly measured. The persistence length of the complexes as a function of the drug total concentration in the sample was used to deduce the binding data, from which we show that cisplatin binds cooperatively to the DNA molecule, a point which so far has not been stressed in binding equilibrium studies of this ligand.

On the persistence of unstable bump-on-tail electron velocity distributions in the earth's foreshock

Science.gov (United States)

Klimas, Alexander J.; Fitzenreiter, Richard J.

1988-01-01

This paper presents further evidence for the persistence of bump-on-tail unstable reduced velocity distributions in the earth's electron foreshock, which contradicts the understanding of quasi-linear saturation of the bump-on-tail instability. A modified theory for the saturation of the bump-on-tail instability in the earth's foreshock is proposed to explain the mechanism of this persistence, and the predictions are compared to the results of a numerical simulation of the electron plasma in the foreshock. The results support the thesis that quasi-linear saturation of the bump-on-tail instability is modified in the foreshock, due to the driven nature of the region, so that at saturation the stabilized velocity distribution still appears bump-on-tail unstable to linear plasma analysis.

Anti-allodynic Effect of Nefopam and Morphine in a Rat Model of Neuropathic Pain

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Taraneh Moini Zanjani

2013-05-01

Full Text Available Please cite this article as: Moini Zanjani T, Saghaei E, Ameli H, Sabetkasaei M. Anti-allodynic Effect of Nefopam and Morphine in a Rat Model of Neuropathic Pain. Novel Biomed 2013;1:16-22.Background: Neuropathic pain is a chronic pain due to a disorder in the peripheral or central nervous system with different pathophysiological mechanisms. Current treatments are not effective. Here we compared the analgesic effect of nefopam, and morphine in chronic constriction injury (CCI model of neuropathic pain.Methods: Male wistar rat (150-200g, n=8 were divided into 3 different groups: 1- Saline-treated CCI group, 2- Saline-treated sham group, and 3- Drug-treated CCI groups. In CCI model of neuropathic pain, the left sciatic nerve was exposed and 4 loose chromic gut ligatures were placed around the nerve proximal to the trifurcation. Ketamine 60mg/kg and xylazine 10 mg/kg were used for anesthesia. Nefopam (10, 20, 30mg/kg, and morphine (1, 3, 5mg/kg were injected 30 minutes before surgery and continued daily to day 14 post-ligation. Von Frey filaments for mechanical allodynia and acetone test for cold allodynia were respectively used as pain behavioral tests. Experiments were performed on day 0 (before surgery and days 1, 3, 5,7,10 and 14 post injury. Behavioral studies were performed in a quiet room between 9:00 to 11:00 AM. All experiments followed the IASP guidelines on ethical standards for investigation of experimental pain in animals.Results: Nefopam (20 and 30mg/kg blocked mechanical and cold allodynia during the experimental period, but the analgesic effects of morphine (5mg/kg lasted for 7 days.Conclusions: It seems that nefopam could effectively reduce pain behavior compared to morphine with reduced adverse effects.

D-Aspartate drinking solution alleviates pain and cognitive impairment in neuropathic mice.

Science.gov (United States)

Palazzo, Enza; Luongo, Livio; Guida, Francesca; Marabese, Ida; Romano, Rosaria; Iannotta, Monica; Rossi, Francesca; D'Aniello, Antimo; Stella, Luigi; Marmo, Federica; Usiello, Alessandro; de Bartolomeis, Andrea; Maione, Sabatino; de Novellis, Vito

2016-07-01

D-Aspartate (D-Asp) is a free D-amino acid detected in multiple brain regions and putative precursor of endogenous N-methyl-D-aspartate (NMDA) acting as agonist at NMDA receptors. In this study, we investigated whether D-Asp (20 mM) in drinking solution for 1 month affects pain responses and pain-related emotional, and cognitive behaviour in a model of neuropathic pain induced by the spared nerve injury (SNI) of the sciatic nerve in mice. SNI mice developed mechanical allodynia and motor coordination impairment 30 days after SNI surgery. SNI mice showed cognitive impairment, anxiety and depression-like behaviour, reduced sociability in the three chamber sociability paradigm, increased expression of NR2B subunit of NMDA receptor and Homer 1a in the medial prefrontal cortex (mPFC). The expression of (post synaptic density) PSD-95 and Shank 1was instead unaffected in the mPFC of the SNI mice. Treatment with D-Asp drinking solution, started right after the SNI (day 0), alleviated mechanical allodynia, improved cognition and motor coordination and increased social interaction. D-Asp also restored the levels of extracellular D-Asp, Homer 1a and NR2B subunit of the NMDA receptor to physiological levels and reduced Shank1 and PSD-95 protein levels in the mPFC. Amitriptyline, a tricyclic antidepressant used also to alleviate neuropathic pain in humans, reverted mechanical allodynia and cognitive impairment, and unlike D-Asp, was effective in reducing depression and anxiety-like behaviour in the SNI mice and increased PSD protein level. Altogether these findings demonstrate that D-Asp improves sensorial, motor and cognitive-like symptoms related to chronic pain possibly through glutamate neurotransmission normalization in neuropathic mice.

The Key Role of Epigenetics in the Persistence of Asexual Lineages

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Emilie Castonguay

2012-01-01

Full Text Available Asexual organisms, often perceived as evolutionary dead ends, can be long-lived and geographically widespread. We propose that epigenetic mechanisms could play a crucial role in the evolutionary persistence of these lineages. Genetically identical organisms could rely on phenotypic plasticity to face environmental variation. Epigenetic modifications could be the molecular mechanism enabling such phenotypic plasticity; they can be influenced by the environment and act at shorter timescales than mutation. Recent work on the asexual vertebrate Chrosomus eos-neogaeus (Pisces: Cyprinidae provides broad insights into the contribution of epigenetics in genetically identical individuals. We discuss the extension of these results to other asexual organisms, in particular those resulting from interspecific hybridizations. We finally develop on the evolutionary relevance of epigenetic variation in the context of heritability.

Persistence and origin of the lunar core dynamo

Science.gov (United States)

Suavet, Clément; Weiss, Benjamin P.; Cassata, William S.; Shuster, David L.; Gattacceca, Jérôme; Chan, Lindsey; Garrick-Bethell, Ian; Head, James W.; Grove, Timothy L.; Fuller, Michael D.

2013-01-01

The lifetime of the ancient lunar core dynamo has implications for its power source and the mechanism of field generation. Here, we report analyses of two 3.56-Gy-old mare basalts demonstrating that they were magnetized in a stable and surprisingly intense dynamo magnetic field of at least ∼13 μT. These data extend the known lifetime of the lunar dynamo by ∼160 My and indicate that the field was likely continuously active until well after the final large basin-forming impact. This likely excludes impact-driven changes in rotation rate as the source of the dynamo at this time in lunar history. Rather, our results require a persistent power source like precession of the lunar mantle or a compositional convection dynamo. PMID:23650386

Transcriptional and physiological changes during Mycobacterium tuberculosis reactivation from non-replicating persistence

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Peicheng Du

2016-08-01

Full Text Available Mycobacterium tuberculosis can persist for years in the hostile environment of the host in a non-replicating or slowly replicating state. While active disease predominantly results from reactivation of a latent infection, the molecular mechanisms of M. tuberculosis reactivation are still poorly understood. We characterized the physiology and global transcriptomic profiles of M. tuberculosis during reactivation from hypoxia-induced non-replicating persistence. We found that M. tuberculosis reactivation upon reaeration was associated with a lag phase, in which the recovery of cellular physiological and metabolic functions preceded the resumption of cell replication. Enrichment analysis of the transcriptomic dynamics revealed changes to many metabolic pathways and transcription regulons/subnetworks that orchestrated the metabolic and physiological transformation in preparation for cell division. In particular, we found that M. tuberculosis reaeration lag phase is associated with down-regulation of persistence-associated regulons/subnetworks, including DosR, MprA, SigH, SigE and ClgR, as well as metabolic pathways including those involved in the uptake of lipids and their catabolism. More importantly, we identified a number of up-regulated transcription regulons and metabolic pathways, including those involved in metal transport and remobilization, second messenger-mediated responses, DNA repair and recombination, and synthesis of major cell wall components. We also found that inactivation of the major alternative sigma factors SigE or SigH disrupted exit from persistence, underscoring the importance of the global transcriptional reprogramming during M. tuberculosis reactivation. Our observations suggest that M. tuberculosis lag phase is associated with a global gene expression reprogramming that defines the initiation of a reactivation process.

White matter developmental trajectories associated with persistence and recovery of childhood stuttering.

Science.gov (United States)

Chow, Ho Ming; Chang, Soo-Eun

2017-04-08

Stuttering affects the fundamental human ability of fluent speech production, and can have a significant negative impact on an individual's psychosocial development. While the disorder affects about 5% of all preschool children, approximately 80% of them recover naturally within a few years of stuttering onset. The pathophysiology and neuroanatomical development trajectories associated with persistence and recovery of stuttering are still largely unknown. Here, the first mixed longitudinal diffusion tensor imaging (DTI) study of childhood stuttering has been reported. A total of 195 high quality DTI scans from 35 children who stutter (CWS) and 43 controls between 3 and 12 years of age were acquired, with an average of three scans per child, each collected approximately a year apart. Fractional anisotropy (FA), a measure reflecting white matter structural coherence, was analyzed voxel-wise to examine group and age-related differences using a linear mixed-effects (LME) model. Results showed that CWS exhibited decreased FA relative to controls in the left arcuate fasciculus, underlying the inferior parietal and posterior temporal areas, and the mid body of corpus callosum. Further, white matter developmental trajectories reflecting growth rate of these tract regions differentiated children with persistent stuttering from those who recovered from stuttering. Specifically, a reduction in FA growth rate (i.e., slower FA growth with age) in persistent children relative to fluent controls in the left arcuate fasciculus and corpus callosum was found, which was not evident in recovered children. These findings provide first glimpses into the possible neural mechanisms of onset, persistence, and recovery of childhood stuttering. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Observation of time-varying photoconductivity and persistent photoconductivity in porous silicon

DEFF Research Database (Denmark)

Frello, T.; Veje, E.; Leistiko, Otto

1996-01-01

We have observed time-varying photoconductivity and persistent photoconductivity in porous silicon, both with time-evolution scales of the order of several minutes or hours. The time evolutions depend on the wavelength and the intensity of the illuminating light. The data indicate the presence...... of at least two competing mechanisms, one is tentatively related to photoinduced creation of charge carriers in the silicon substrate followed by diffusion into the porous silicon layer, and the other is tentatively related to desorption of hydrogen from the porous silicon. ©1996 American Institute of Physics....

Bilateral Neuropathy of Primary Sensory Neurons by the Chronic Compression of Multiple Unilateral DRGs

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Ya-Bin Xie

2016-01-01

Full Text Available To mimic multilevel nerve root compression and intervertebral foramina stenosis in human, we established a new animal model of the chronic compression of unilateral multiple lumbar DRGs (mCCD in the rat. A higher occurrence of signs of spontaneous pain behaviors, such as wet-dog shaking and spontaneous hind paw shrinking behaviors, was firstly observed from day 1 onward. In the meantime, the unilateral mCCD rat exhibited significant bilateral hind paw mechanical and cold allodynia and hyperalgesia, as well as a thermal preference to 30°C plate between 30 and 35°C. The expression of activating transcription factor 3 (ATF3 was significantly increased in the ipsilateral and contralateral all-sized DRG neurons after the mCCD. And the expression of CGRP was significantly increased in the ipsilateral and contralateral large- and medium-sized DRG neurons. ATF3 and CGRP expressions correlated to evoked pain hypersensitivities such as mechanical and cold allodynia on postoperative day 1. The results suggested that bilateral neuropathy of primary sensory neurons might contribute to bilateral hypersensitivity in the mCCD rat.

The antihistamine diphenhydramine is extremely persistent in agricultural soil

International Nuclear Information System (INIS)

Topp, Edward; Sumarah, Mark W.; Sabourin, Lyne

2012-01-01

The widely used antihistamine diphenhydramine is present in municipal biosolids, and is detected in runoff from agricultural land fertilized with biosolids. In the present study the kinetics and major pathways of diphenhydramine dissipation in a loam, sandy loam, and clay loam soil were determined in laboratory incubations. The time to dissipate 50% (DT 50 ) of 14 C-diphenhydramine residues at 30 °C ranged from 88 ± 28 days in the clay loam to 335 ± 145 days in the loam soil. Mineralization of 14 C was insignificant, and diphenhydramine-N-oxide was the only detected extractable transformation product elucidated by radioisotope and HPLC-MS methods. There were no significant effects of municipal biosolids on the kinetics or pathways of removal. Overall, diphenhydramine is quite persistent in soils, and formation of non-extractable soil-bound residues is the major mechanism of diphenhydramine dissipation. -- Highlights: ► Diphenhydramine is a widely used antihistamine drug, is found in biosolids, and in runoff from biosolids-fertilized fields. ► The persistence of 14 C-diphenhydramine was evaluated in soils. ► Half lives ranged from 88 to 335 days. Diphenhydramine-N-oxide was the only detected transformation product. ► Soil-bound residues was a major sink.

The antihistamine diphenhydramine is extremely persistent in agricultural soil

Energy Technology Data Exchange (ETDEWEB)

Topp, Edward, E-mail: ed.topp@agr.gc.ca; Sumarah, Mark W.; Sabourin, Lyne

2012-11-15

The widely used antihistamine diphenhydramine is present in municipal biosolids, and is detected in runoff from agricultural land fertilized with biosolids. In the present study the kinetics and major pathways of diphenhydramine dissipation in a loam, sandy loam, and clay loam soil were determined in laboratory incubations. The time to dissipate 50% (DT{sub 50}) of {sup 14}C-diphenhydramine residues at 30 Degree-Sign C ranged from 88 {+-} 28 days in the clay loam to 335 {+-} 145 days in the loam soil. Mineralization of {sup 14}C was insignificant, and diphenhydramine-N-oxide was the only detected extractable transformation product elucidated by radioisotope and HPLC-MS methods. There were no significant effects of municipal biosolids on the kinetics or pathways of removal. Overall, diphenhydramine is quite persistent in soils, and formation of non-extractable soil-bound residues is the major mechanism of diphenhydramine dissipation. -- Highlights: Black-Right-Pointing-Pointer Diphenhydramine is a widely used antihistamine drug, is found in biosolids, and in runoff from biosolids-fertilized fields. Black-Right-Pointing-Pointer The persistence of {sup 14}C-diphenhydramine was evaluated in soils. Black-Right-Pointing-Pointer Half lives ranged from 88 to 335 days. Diphenhydramine-N-oxide was the only detected transformation product. Black-Right-Pointing-Pointer Soil-bound residues was a major sink.

Empirical evidence of the game-based learning advantages for online students persistence

OpenAIRE

A. Imbellone; G. Marinensi; C.M. Medaglia

2015-01-01

The paper presents the empirical results obtained from a study conducted on a game-based online course that took place in 2014 with 47 participants. The study evidenced the benefits of the learning games mechanics on learners’ willingness to continue the course. Assuming the interest for the subject of the course as a fundamental condition for student persistence within the course, it is shown how it can be significantly enhanced by the presence of both ludic and narrative game-based elements.

Persistent and non-persistent strains of Listeria monocytogenes: A focus on growth kinetics under different temperature, salt, and pH conditions and their sensitivity to sanitizers.

Science.gov (United States)

Magalhães, R; Ferreira, V; Brandão, T R S; Palencia, R Casquete; Almeida, G; Teixeira, P

2016-08-01

This study aimed to investigate the effect of different conditions, including temperature (37 °C, 22 °C, and 4 °C), NaCl concentrations (2.5%, 4%, and 8%), and acidity (pH = 5), on the growth response of persistent and non-persistent isolates of Listeria monocytogenes. The resistance to two common sanitizers (benzalkonium chloride and hydrogen peroxide) was also investigated. A selected group of 41 persistent and non-persistent L. monocytogenes isolates recovered from three cheese processing plants during a previous longitudinal study was assembled. Average lag time was similar for persistent and non-persistent isolates grown at 37 °C, 22 °C and 4 °C but significantly shorter (p < 0.05) for persistent isolates grown at 2.5%, 4% and 8% NaCl, and at pH 5. Average growth rates were significantly higher (p < 0.05) for persistent than for non-persistent isolates when grown at 22 °C, 2.5%, 4% and 8% NaCl, and at pH 5. These results suggest that persistent strains may be better adapted to grow under stressful conditions frequently encountered in food processing environments than non-persistent strains. No relation between persistence and resistance to the tested sanitizers was found. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antagonism of the melanocortin system reduces cold and mechanical allodynia in mononeuropathic rats

NARCIS (Netherlands)

Gispen, W.H.; Vrinten, D.H.; Groen, G.J.; Adan, R.A.H.

2000-01-01

The presence of both pro-opiomelanocortin-derived peptides and melanocortin (MC) receptors in nociception-associated areas in the spinal cord suggests that, at the spinal level, the MC system might be involved in nociceptive transmission. In the present study, we demonstrate that a chronic

Temporal dynamics of 'HoBi'-like pestivirus quasispecies in persistently infected calves generated under experimental conditions.

Science.gov (United States)

Weber, Matheus N; Bauermann, Fernando V; Canal, Cláudio W; Bayles, Darrell O; Neill, John D; Ridpath, Julia F

2017-01-02

'HoBi'-like virus is an atypical group within the Pestivirus genus that is implicated in economic losses for cattle producers due to both acute and persistent infections. Pestivirus strains exist as quasispecies (swarms of individual viruses) in infected animals and the viral populations making up the quasispecies differ widely in size and diversity in each animal. In the present study the viral quasispecies circulating in persistently infected (PI) calves, generated and maintained under experimental conditions using two different 'HoBi'-like strains, was observed over time. An increase in genetic variability and the development of certain mutations was observed over time. Mutations observed included the loss of a putative N-linked glycosylation site in the E2 region and the change of specific residues in E1/E2. It is hypothesized that these changes may be the results on continued adaption of the pestivirus to individual hosts. This is the first study characterizing variation in the viral swarms of animals persistently infected with HoBi-like viruses over time. Studies of the shifts in PI viral swarms will contribute to our understanding of the host and viral mechanisms that function in the maintenance of pestivirus persistent infections. Published by Elsevier B.V.

Combined effects of PEG hydrogel elasticity and cell-adhesive coating on fibroblast adhesion and persistent migration.

Science.gov (United States)

Missirlis, Dimitris; Spatz, Joachim P

2014-01-13

The development and use of synthetic, cross-linked, macromolecular substrates with tunable elasticity has been instrumental in revealing the mechanisms by which cells sense and respond to their mechanical microenvironment. We here describe a hydrogel based on radical-free, cross-linked poly(ethylene glycol) to study the effects of both substrate elasticity and type of adhesive coating on fibroblast adhesion and migration. Hydrogel elasticity was controlled through the structure and concentration of branched precursors, which efficiently react via Michael-type addition to produce the polymer network. We found that cell spreading and focal adhesion characteristics are dependent on elasticity for all types of coatings (RGD peptide, fibronectin, vitronectin), albeit with significant differences in magnitude. Importantly, fibroblasts migrated slower but more persistently on stiffer hydrogels, with the effects being more pronounced on fibronectin-coated substrates. Therefore, our results validate the hydrogels presented in this study as suitable for future mechanosensing studies and indicate that cell adhesion, polarity, and associated migration persistence are tuned by substrate elasticity and biochemical properties.

The Persistence of Mutual Fund Performance.

OpenAIRE

Grinblatt, Mark; Titman, Sheridan

1992-01-01

This paper analyzes how mutual fund performance relates to past performance. These tests are based on a multiple portfolio benchmark that was formed on the basis of securities characteristics. The authors find evidence that differences in performance between funds persist over time and that this persistence is consistent with the ability of fund managers to earn abnormal returns. Copyright 1992 by American Finance Association.

Statistical Inference for Porous Materials using Persistent Homology.

Energy Technology Data Exchange (ETDEWEB)

Moon, Chul [Univ. of Georgia, Athens, GA (United States); Heath, Jason E. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Mitchell, Scott A. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

2017-12-01

We propose a porous materials analysis pipeline using persistent homology. We rst compute persistent homology of binarized 3D images of sampled material subvolumes. For each image we compute sets of homology intervals, which are represented as summary graphics called persistence diagrams. We convert persistence diagrams into image vectors in order to analyze the similarity of the homology of the material images using the mature tools for image analysis. Each image is treated as a vector and we compute its principal components to extract features. We t a statistical model using the loadings of principal components to estimate material porosity, permeability, anisotropy, and tortuosity. We also propose an adaptive version of the structural similarity index (SSIM), a similarity metric for images, as a measure to determine the statistical representative elementary volumes (sREV) for persistence homology. Thus we provide a capability for making a statistical inference of the uid ow and transport properties of porous materials based on their geometry and connectivity.

Research on the Pathological Mechanism and Drug Treatment Mechanism of Depression.

Science.gov (United States)

Peng, Guo-jiang; Tian, Jun-sheng; Gao, Xiao-xia; Zhou, Yu-zhi; Qin, Xue-mei

2015-01-01

Depression is one of the prevalent and persistent psychiatric illnesses. It brings heavy socioeconomic burden such as healthcare expenditures and even higher suicide rates. Despite many hypotheses about its mechanism have been put forward, so far it is still unclear, not to mention the precise and effective diagnostic or therapeutic methods. In this paper, the current conditions of pathological and pharmacological mechanism of depression were reviewed systematically. Firstly, the most recent hypotheses and metabolomics based research including hereditary, neurotransmitter systems, brain derived neurotrophic factor (BDNF), hyperactivity of the hypothalamic pituitary adrenal (HPA) axis and inflammatory as well as metabolomics were summarized. Secondly, the present situation and development on antidepressant drugs at home and abroad were reviewed. Finally, a conclusion and prospect on the pathological and pharmacological mechanism of depression were provided primarily.

Modelling asymmetric persistence over the business cycle

NARCIS (Netherlands)

Ph.H.B.F. Franses (Philip Hans); R. Paap (Richard)

1998-01-01

textabstractWe address the issue of time varying persistence of shocks to macroeconomic time series variables by proposing a new and parsimonious time series model. Our model assumes that this time varying persistence depends on a linear combination of lagged explanatory variables, where this

Understanding mild persistent asthma in children

DEFF Research Database (Denmark)

Bisgaard, Hans; Szefler, Stanley J

2005-01-01

Limitations in asthma prevalence studies and difficulties in diagnosing pediatric asthma lead to uncertainty over the full extent of mild persistent asthma in children and adolescents. Although recent surveys have reported that the majority of pediatric patients with asthma in the United States...... and Europe have symptoms consistent with mild disease, these surveys have limitations in design. Thus, the true prevalence of mild asthma remains unknown. It is unclear whether children with mild persistent asthma progress to more severe asthma, but the risk of severe asthma exacerbations seems...... to be unrelated to the symptom severity. Clinical studies restricted to pediatric patients with mild asthma are limited, but available data do suggest substantial morbidity of mild persistent asthma in this population and support inhaled corticosteroid intervention. There is a need for further investigation...

International perspectives on retention and persistence

Directory of Open Access Journals (Sweden)

Gary Burkholder

2014-06-01

Full Text Available Access to higher education globally is increasing dramatically; attainment of tertiary degrees is a high priority, as educational attainment is associated with increased personal incomes as well as growth of the middle class in developing countries. The purpose of this essay is to briefly examine retention and persistence issues from a global perspective, review some retention strategies that have been employed at schools outside the United States, and to identify several key factors that related to retention and persistence globally, including access, infrastructure, financial consideration, and readiness for tertiary education.  There exists an opportunity to utilize knowledge gained in the evolution of the higher education system in the United States to help address the problems associated with retention and persistence.   DOI: 10.18870/hlrc.v4i2.208

Persistent Structural Priming from Language Comprehension to Language Production

Science.gov (United States)

Bock, Kathryn; Dell, Gary S.; Chang, Franklin; Onishi, Kristine H.

2007-01-01

To examine the relationship between syntactic processes in language comprehension and language production, we compared structural persistence from sentence primes that speakers heard to persistence from primes that speakers produced. [Bock, J. K., & Griffin, Z. M. (2000). The persistence of structural priming: transient activation or implicit…

THE ROLE OF PERSISTENCE IN STUDENTS’ SELF-REALIZATION

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Sergey I. Kudinov

2017-12-01

Full Text Available The paper analyzes the results of an empirical research obtained with the help of a sample of students. The research of persistence was carried out within the framework of the dispositional concept of personality traits and individuality by A. I. Krupnov. The techniques developed by A. I. Krupnov as well as the author’s test of persistence were used in the study. After allocating the levels of persistence, the features of self-realization were analyzed in each group of the respondents. The specificity of self-realization was revealed in the context of the author’s polysystemic concept, the author’s multidimensional questionnaire on personality’s self-realization (MQPSR was used as a diagnostic tool. The empirical study revealed statistically significant differences in the specifics of self-realization of the students with different levels of persistence manifestation. The respondents with a high level of persistence realize themselves more successfully in different spheres of life due to the obvious active behaviour, optimistic attitude, high motivation, creative methods and techniques of self-expression, internal self-regulation and constructive behavior. The students with low persistence lack successful self-realization because of passivity, pessimism, external locus of self-control, a high level of barriers and standard simple schemes of self-expression.

Inefficiency persistence and heterogeneity in Colombian electricity utilities

International Nuclear Information System (INIS)

Galán, Jorge E.; Pollitt, Michael G.

2014-01-01

The electricity reform in Colombia has exhibited gains in terms of reliability but its effects on firm efficiency and service quality have not been clear. Previous studies evaluating the performance of distribution companies after the reform have not found evidence of improvements, although large differences in efficiency have been found among firms. This suggests high inefficiency persistence and heterogeneity in the Colombian distribution sector. In this paper, we propose an extension of dynamic stochastic frontier models that accounts for unobserved heterogeneity in the inefficiency persistence and in the technology. The model incorporates total expenses, service quality and energy losses in an efficiency analysis of Colombian distributors over fifteen years after the reform. We identify the presence of high inefficiency persistence in the sector, and important differences between firms. In particular, rural companies and firms with small customers present low persistence and evidence the largest gains in efficiency during the period. However, increases in efficiency are only manifested during thelast five years when the main improvements in service quality and energy losses are presented. Overall, inefficiency persistence, customer density and consumption density are found to be important criteria to be considered for regulatory purposes. - Highlights: • We evaluate efficiency of Colombian electricity distributors after the reform. • We use a stochastic frontier model with dynamic effects and heterogeneity. • We find high inefficiency persistence but important differences among firms. • High persistent and low efficient firms should draw the attention of the regulator. • Recent regulation in quality has increased not only efficiency but also tariffs

Persistence among Minority STEM Majors: A Phenomenological Study

Science.gov (United States)

Williams-Watson, Stacey

The United States needs to increase the number of science, technology, engineering, and math (STEM) graduates to remain competitive in the global market and maintain national security. Minority students, specifically African-American and Hispanic, are underrepresented in STEM fields. As the minority population continues to grow it is essential that higher education institutions improve minority students' persistence in STEM education. This study examined the problem of minority students' lack of persistence in STEM programs. The purpose of this qualitative transcendental phenomenological study was to describe the lived experiences that minority students perceived as contributing to their persistence in STEM. The central research question was: What are the lived experiences of minority STEM students that have contributed to their persistence in a STEM program? The sub-questions were: a) What led participants to majors in STEM?; b) What contributed to students' success and persistence in STEM?; and c) What advice do students have to offer? The researcher interviewed 12 minority STEM students and uncovered 10 themes that described the lived experiences of minority students' persistence in STEM programs. The themes were 1) Childhood experiences and interests; 2) Positive educational experiences in secondary school; 3) Self- motivation; 4) Positive experiences with professors; 5) Family encouragement and values; 6) Lack of minorities; 7) Lack of educational preparation; 8) The need for financial assistance; 9) Clubs and organizations; and 10) Friends within the major. The significance of these findings is the potential to produce changes in curricula, programs, and retention methods that may improve the persistence of minority students in STEM programs.

Persistence of Mycoplasma genitalium following azithromycin therapy.

Directory of Open Access Journals (Sweden)

Catriona S Bradshaw

Full Text Available BACKGROUND: To determine clinical outcomes and cure rates for M.genitalium genital infection in men and women following azithromycin 1 g. METHODOLOGY: Patients attending Melbourne Sexual Health Centre between March 2005 and November 2007 with urethritis/epididymitis, cervicitis/pelvic inflammatory disease and sexual contacts of M.genitalium were tested for M.genitalium by polymerase chain reaction (PCR. M.genitalium-infection was treated with 1 g of azithromycin and a test-of-cure (toc was performed one month post-azithromycin. Response to azithromycin, and response to moxifloxacin (400 mg daily for 10 days in individuals with persistent infection post-azithromycin, was determined. PRINCIPAL FINDINGS: Of 1538 males and 313 females tested, 161 males (11% and 30 females (10% were infected with M.genitalium. A toc was available on 131 (69% infected individuals (median = 36 days [range 12-373]. Of 120 individuals prescribed azithromycin only pre-toc, M.genitalium was eradicated in 101 (84%, 95% confidence intervals [CI]: 77-90% and persisted in 19 (16%, 95% CI: 10-23%. Eleven individuals with persistent infection (9%, 95% CI: 5-15% had no risk of reinfection from untreated-partners, while eight (7%, 95% CI: 3-12% may have been at risk of reinfection from doxycycline-treated or untreated-partners. Moxifloxacin was effective in eradicating persistent infection in all cases not responding to azithromycin. Patients with persistent-M.genitalium were more likely to experience persistent symptoms (91%, compared to patients in whom M.genitalium was eradicated (17%, p<0.0001. CONCLUSION: Use of azithromycin 1 g in M.genitalium-infected patients was associated with unacceptable rates of persistent infection, which was eradicated with moxifloxacin. These findings highlight the importance of follow-up in M.genitalium-infected patients prescribed azithromycin, and the need to monitor for the development of resistance. Research to determine optimal first and

Persistence of undergraduate women in STEM fields

Science.gov (United States)

Pedone, Maggie Helene

The underrepresentation of women in science, technology, engineering, and mathematics (STEM) is a complex problem that continues to persist at the postsecondary level, particularly in computer science and engineering fields. This dissertation explored the pre-college and college level factors that influenced undergraduate women's persistence in STEM. This study also examined and compared the characteristics of undergraduate women who entered STEM fields and non-STEM fields in 2003-2004. The nationally representative Beginning Postsecondary Students Longitudinal Study (BPS:04/09) data set was used for analysis. BPS:04/09 study respondents were surveyed three times (NPSAS:04, BPS:04/06, BPS:04/09) over a six-year period, which enabled me to explore factors related to long-term persistence. Astin's Input-Environment-Output (I-E-O) model was used as the framework to examine student inputs and college environmental factors that predict female student persistence (output) in STEM. Chi-square tests revealed significant differences between undergraduate women who entered STEM and non-STEM fields in 2003-2004. Differences in student demographics, prior academic achievement, high school course-taking patterns, and student involvement in college such as participation in study groups and school clubs were found. Notably, inferential statistics showed that a significantly higher proportion of female minority students entered STEM fields than non-STEM fields. These findings challenge the myth that underrepresented female minorities are less inclined to enter STEM fields. Logistic regression analyses revealed thirteen significant predictors of persistence for undergraduate women in STEM. Findings showed that undergraduate women who were younger, more academically prepared, and academically and socially involved in college (e.g., lived on campus, interacted with faculty, participated in study groups, fine arts activities, and school sports) were more likely to persist in STEM

Demonstration of persistent contamination of a cooked egg product production facility with Salmonella enterica serovar Tennessee and characterization of the persistent strain

DEFF Research Database (Denmark)

Jakociune, D.; Bisgaard, M.; Pedersen, Karl

2014-01-01

Aims: The aim of this study was to investigate whether continuous contamination of light pasteurized egg products with Salmonella enterica serovar Tennessee (S. Tennessee) at a large European producer of industrial egg products was caused by persistent contamination of the production facility......, members of the persistent clone were weak producers of H2S in laboratory medium. S. Tennessee isolated from the case was able to grow better in pasteurized egg product compared with other serovars investigated. Conclusions: It was concluded that the contamination was caused by a persistent strain...... in the production facility and that this strain apparently had adapted to grow in the relevant egg product. Significance and Impact of the Study: S. Tennessee has previously been associated with persistence in hatching facilities. This is the first report of persistent contamination of an egg production facility...

A model for persistency of egg production

NARCIS (Netherlands)

Grossman, M.; Gossman, T.N.; Koops, W.J.

2000-01-01

The objectives of our study were to propose a new definition for persistency of egg production and to develop a mathematical model to describe the egg production curve, one that includes a new measure for persistency, based on the proposed definition, for use as a selection criterion to improve

Empirical evidence of the game-based learning advantages for online students persistence

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A. Imbellone

2015-07-01

Full Text Available The paper presents the empirical results obtained from a study conducted on a game-based online course that took place in 2014 with 47 participants. The study evidenced the benefits of the learning games mechanics on learners’ willingness to continue the course. Assuming the interest for the subject of the course as a fundamental condition for student persistence within the course, it is shown how it can be significantly enhanced by the presence of both ludic and narrative game-based elements.

The origins of lactase persistence in Europe.

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Yuval Itan

2009-08-01

Full Text Available Lactase persistence (LP is common among people of European ancestry, but with the exception of some African, Middle Eastern and southern Asian groups, is rare or absent elsewhere in the world. Lactase gene haplotype conservation around a polymorphism strongly associated with LP in Europeans (-13,910 C/T indicates that the derived allele is recent in origin and has been subject to strong positive selection. Furthermore, ancient DNA work has shown that the--13,910*T (derived allele was very rare or absent in early Neolithic central Europeans. It is unlikely that LP would provide a selective advantage without a supply of fresh milk, and this has lead to a gene-culture coevolutionary model where lactase persistence is only favoured in cultures practicing dairying, and dairying is more favoured in lactase persistent populations. We have developed a flexible demic computer simulation model to explore the spread of lactase persistence, dairying, other subsistence practices and unlinked genetic markers in Europe and western Asia's geographic space. Using data on--13,910*T allele frequency and farming arrival dates across Europe, and approximate Bayesian computation to estimate parameters of interest, we infer that the--13,910*T allele first underwent selection among dairying farmers around 7,500 years ago in a region between the central Balkans and central Europe, possibly in association with the dissemination of the Neolithic Linearbandkeramik culture over Central Europe. Furthermore, our results suggest that natural selection favouring a lactase persistence allele was not higher in northern latitudes through an increased requirement for dietary vitamin D. Our results provide a coherent and spatially explicit picture of the coevolution of lactase persistence and dairying in Europe.

The origins of lactase persistence in Europe.

Science.gov (United States)

Itan, Yuval; Powell, Adam; Beaumont, Mark A; Burger, Joachim; Thomas, Mark G

2009-08-01

Lactase persistence (LP) is common among people of European ancestry, but with the exception of some African, Middle Eastern and southern Asian groups, is rare or absent elsewhere in the world. Lactase gene haplotype conservation around a polymorphism strongly associated with LP in Europeans (-13,910 C/T) indicates that the derived allele is recent in origin and has been subject to strong positive selection. Furthermore, ancient DNA work has shown that the--13,910*T (derived) allele was very rare or absent in early Neolithic central Europeans. It is unlikely that LP would provide a selective advantage without a supply of fresh milk, and this has lead to a gene-culture coevolutionary model where lactase persistence is only favoured in cultures practicing dairying, and dairying is more favoured in lactase persistent populations. We have developed a flexible demic computer simulation model to explore the spread of lactase persistence, dairying, other subsistence practices and unlinked genetic markers in Europe and western Asia's geographic space. Using data on--13,910*T allele frequency and farming arrival dates across Europe, and approximate Bayesian computation to estimate parameters of interest, we infer that the--13,910*T allele first underwent selection among dairying farmers around 7,500 years ago in a region between the central Balkans and central Europe, possibly in association with the dissemination of the Neolithic Linearbandkeramik culture over Central Europe. Furthermore, our results suggest that natural selection favouring a lactase persistence allele was not higher in northern latitudes through an increased requirement for dietary vitamin D. Our results provide a coherent and spatially explicit picture of the coevolution of lactase persistence and dairying in Europe.

Rotenone persistence model for montane streams

Science.gov (United States)

Brown, Peter J.; Zale, Alexander V.

2012-01-01

The efficient and effective use of rotenone is hindered by its unknown persistence in streams. Environmental conditions degrade rotenone, but current label instructions suggest fortifying the chemical along a stream based on linear distance or travel time rather than environmental conditions. Our objective was to develop models that use measurements of environmental conditions to predict rotenone persistence in streams. Detailed measurements of ultraviolet radiation, water temperature, dissolved oxygen, total dissolved solids (TDS), conductivity, pH, oxidation–reduction potential (ORP), substrate composition, amount of organic matter, channel slope, and travel time were made along stream segments located between rotenone treatment stations and cages containing bioassay fish in six streams. The amount of fine organic matter, biofilm, sand, gravel, cobble, rubble, small boulders, slope, pH, TDS, ORP, light reaching the stream, energy dissipated, discharge, and cumulative travel time were each significantly correlated with fish death. By using logistic regression, measurements of environmental conditions were paired with the responses of bioassay fish to develop a model that predicted the persistence of rotenone toxicity in streams. This model was validated with data from two additional stream treatment reaches. Rotenone persistence was predicted by a model that used travel time, rubble, and ORP. When this model predicts a probability of less than 0.95, those who apply rotenone can expect incomplete eradication and should plan on fortifying rotenone concentrations. The significance of travel time has been previously identified and is currently used to predict rotenone persistence. However, rubble substrate, which may be associated with the degradation of rotenone by adsorption and volatilization in turbulent environments, was not previously considered.

Persistent organic pollutants

NARCIS (Netherlands)

Dungen, van den M.W.

2016-01-01

Wild caught fish, especially marine fish, can contain high levels of persistent organic pollutants (POPs). In the Netherlands, especially eel from the main rivers have high POP levels. This led to a ban in 2011 on eel fishing due to health concerns. Many of the marine POPs have been related to

Enhanced pre-synaptic glutamate release in deep-dorsal horn contributes to calcium channel alpha-2-delta-1 protein-mediated spinal sensitization and behavioral hypersensitivity

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Dickenson Anthony H

2009-02-01

Full Text Available Abstract Nerve injury-induced expression of the spinal calcium channel alpha-2-delta-1 subunit (Cavα2δ1 has been shown to mediate behavioral hypersensitivity through a yet identified mechanism. We examined if this neuroplasticity modulates behavioral hypersensitivity by regulating spinal glutamatergic neurotransmission in injury-free transgenic mice overexpressing the Cavα2δ1 proteins in neuronal tissues. The transgenic mice exhibited hypersensitivity to mechanical stimulation (allodynia similar to the spinal nerve ligation injury model. Intrathecally delivered antagonists for N-methyl-D-aspartate (NMDA and α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA/kainate receptors, but not for the metabotropic glutamate receptors, caused a dose-dependent allodynia reversal in the transgenic mice without changing the behavioral sensitivity in wild-type mice. This suggests that elevated spinal Cavα2δ1 mediates allodynia through a pathway involving activation of selective glutamate receptors. To determine if this is mediated by enhanced spinal neuronal excitability or pre-synaptic glutamate release in deep-dorsal horn, we examined wide-dynamic-range (WDR neuron excitability with extracellular recording and glutamate-mediated excitatory postsynaptic currents with whole-cell patch recording in deep-dorsal horn of the Cavα2δ1 transgenic mice. Our data indicated that overexpression of Cavα2δ1 in neuronal tissues led to increased frequency, but not amplitude, of miniature excitatory post synaptic currents mediated mainly by AMPA/kainate receptors at physiological membrane potentials, and also by NMDA receptors upon depolarization, without changing the excitability of WDR neurons to high intensity stimulation. Together, these findings support a mechanism of Cavα2δ1-mediated spinal sensitization in which elevated Cavα2δ1 causes increased pre-synaptic glutamate release that leads to reduced excitation thresholds of post-synaptic dorsal

Enhanced pre-synaptic glutamate release in deep-dorsal horn contributes to calcium channel alpha-2-delta-1 protein-mediated spinal sensitization and behavioral hypersensitivity

Science.gov (United States)

Nguyen, David; Deng, Ping; Matthews, Elizabeth A; Kim, Doo-Sik; Feng, Guoping; Dickenson, Anthony H; Xu, Zao C; Luo, Z David

2009-01-01

Nerve injury-induced expression of the spinal calcium channel alpha-2-delta-1 subunit (Cavα2δ1) has been shown to mediate behavioral hypersensitivity through a yet identified mechanism. We examined if this neuroplasticity modulates behavioral hypersensitivity by regulating spinal glutamatergic neurotransmission in injury-free transgenic mice overexpressing the Cavα2δ1 proteins in neuronal tissues. The transgenic mice exhibited hypersensitivity to mechanical stimulation (allodynia) similar to the spinal nerve ligation injury model. Intrathecally delivered antagonists for N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, but not for the metabotropic glutamate receptors, caused a dose-dependent allodynia reversal in the transgenic mice without changing the behavioral sensitivity in wild-type mice. This suggests that elevated spinal Cavα2δ1 mediates allodynia through a pathway involving activation of selective glutamate receptors. To determine if this is mediated by enhanced spinal neuronal excitability or pre-synaptic glutamate release in deep-dorsal horn, we examined wide-dynamic-range (WDR) neuron excitability with extracellular recording and glutamate-mediated excitatory postsynaptic currents with whole-cell patch recording in deep-dorsal horn of the Cavα2δ1 transgenic mice. Our data indicated that overexpression of Cavα2δ1 in neuronal tissues led to increased frequency, but not amplitude, of miniature excitatory post synaptic currents mediated mainly by AMPA/kainate receptors at physiological membrane potentials, and also by NMDA receptors upon depolarization, without changing the excitability of WDR neurons to high intensity stimulation. Together, these findings support a mechanism of Cavα2δ1-mediated spinal sensitization in which elevated Cavα2δ1 causes increased pre-synaptic glutamate release that leads to reduced excitation thresholds of post-synaptic dorsal horn neurons to innocuous

Persistent infection caused by Hobi-like pestivirus.

Science.gov (United States)

Decaro, Nicola; Losurdo, Michele; Lucente, Maria Stella; Sciarretta, Rossana; Mari, Viviana; Larocca, Vittorio; Elia, Gabriella; Cavaliere, Nicola; Martella, Vito; Fasanella, Antonio; Buonavoglia, Canio

2013-04-01

A calf persistently infected by Hobi-like pestivirus was monitored for about 6 months, displaying clinical signs typical of bovine viral diarrhea virus persistent infection and shedding the virus through all body secretions, with maximal titers detected in urine. This report provides new insights into the pathogenesis of the emerging pestivirus.

Host persistence or extinction from emerging infectious disease: insights from white-nose syndrome in endemic and invading regions.

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Hoyt, Joseph R; Langwig, Kate E; Sun, Keping; Lu, Guanjun; Parise, Katy L; Jiang, Tinglei; Frick, Winifred F; Foster, Jeffrey T; Feng, Jiang; Kilpatrick, A Marm

2016-03-16

Predicting species' fates following the introduction of a novel pathogen is a significant and growing problem in conservation. Comparing disease dynamics between introduced and endemic regions can offer insight into which naive hosts will persist or go extinct, with disease acting as a filter on host communities. We examined four hypothesized mechanisms for host-pathogen persistence by comparing host infection patterns and environmental reservoirs for Pseudogymnoascus destructans (the causative agent of white-nose syndrome) in Asia, an endemic region, and North America, where the pathogen has recently invaded. Although colony sizes of bats and hibernacula temperatures were very similar, both infection prevalence and fungal loads were much lower on bats and in the environment in Asia than North America. These results indicate that transmission intensity and pathogen growth are lower in Asia, likely due to higher host resistance to pathogen growth in this endemic region, and not due to host tolerance, lower transmission due to smaller populations, or lower environmentally driven pathogen growth rate. Disease filtering also appears to be favouring initially resistant species in North America. More broadly, determining the mechanisms allowing species persistence in endemic regions can help identify species at greater risk of extinction in introduced regions, and determine the consequences for disease dynamics and host-pathogen coevolution. © 2016 The Author(s).

Presynaptic learning and memory with a persistent firing neuron and a habituating synapse: a model of short term persistent habituation.

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Ramanathan, Kiruthika; Ning, Ning; Dhanasekar, Dhiviya; Li, Guoqi; Shi, Luping; Vadakkepat, Prahlad

2012-08-01

Our paper explores the interaction of persistent firing axonal and presynaptic processes in the generation of short term memory for habituation. We first propose a model of a sensory neuron whose axon is able to switch between passive conduction and persistent firing states, thereby triggering short term retention to the stimulus. Then we propose a model of a habituating synapse and explore all nine of the behavioral characteristics of short term habituation in a two neuron circuit. We couple the persistent firing neuron to the habituation synapse and investigate the behavior of short term retention of habituating response. Simulations show that, depending on the amount of synaptic resources, persistent firing either results in continued habituation or maintains the response, both leading to longer recovery times. The effectiveness of the model as an element in a bio-inspired memory system is discussed.

Impact of persistence and non-persistence in leisure time physical activity on coronary heart disease and all-cause mortality

DEFF Research Database (Denmark)

Schnohr, Peter; O'Keefe, James H.; Lange, Peter

2017-01-01

Aims: The aim of this study was to investigate the impact of persistence and non-persistence in leisure time physical activity on coronary heart disease and all-cause mortality. Methods and results: In the Copenhagen City Heart Study, we prospectively followed 12,314 healthy subjects for 33 years...

Generating Dynamic Persistence in the Time Domain

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Guerrero, A.; Smith, L. A.; Smith, L. A.; Kaplan, D. T.

2001-12-01

Many dynamical systems present long-range correlations. Physically, these systems vary from biological to economical, including geological or urban systems. Important geophysical candidates for this type of behaviour include weather (or climate) and earthquake sequences. Persistence is characterised by slowly decaying correlation function; that, in theory, never dies out. The Persistence exponent reflects the degree of memory in the system and much effort has been expended creating and analysing methods that successfully estimate this parameter and model data that exhibits persistence. The most widely used methods for generating long correlated time series are not dynamical systems in the time domain, but instead are derived from a given spectral density. Little attention has been drawn to modelling persistence in the time domain. The time domain approach has the advantage that an observation at certain time can be calculated using previous observations which is particularly suitable when investigating the predictability of a long memory process. We will describe two of these methods in the time domain. One is a traditional approach using fractional ARIMA (autoregressive and moving average) models; the second uses a novel approach to extending a given series using random Fourier basis functions. The statistical quality of the two methods is compared, and they are contrasted with weather data which shows, reportedly, persistence. The suitability of this approach both for estimating predictability and for making predictions is discussed.

BEAM-BASED MEASUREMENTS OF PERSISTENT CURRENT DECAY IN RHIC

International Nuclear Information System (INIS)

FISCHER, W.; JAIN, A.; TEPIKIAN, S.

2001-01-01

The two RHIC rings are equipped with superconducting dipole magnets. At injection, induced persistent currents in these magnets lead to a sextupole component. As the persistent currents decay with time, the horizontal and vertical chromaticities change. From magnet measurements of persistent current decays, chromaticity changes in the machine are estimated and compared with chromaticity measurements

Mib1 contributes to persistent directional cell migration by regulating the Ctnnd1-Rac1 pathway.

Science.gov (United States)

Mizoguchi, Takamasa; Ikeda, Shoko; Watanabe, Saori; Sugawara, Michiko; Itoh, Motoyuki

2017-10-31

Persistent directional cell migration is involved in animal development and diseases. The small GTPase Rac1 is involved in F-actin and focal adhesion dynamics. Local Rac1 activity is required for persistent directional migration, whereas global, hyperactivated Rac1 enhances random cell migration. Therefore, precise control of Rac1 activity is important for proper directional cell migration. However, the molecular mechanism underlying the regulation of Rac1 activity in persistent directional cell migration is not fully understood. Here, we show that the ubiquitin ligase mind bomb 1 (Mib1) is involved in persistent directional cell migration. We found that knockdown of MIB1 led to an increase in random cell migration in HeLa cells in a wound-closure assay. Furthermore, we explored novel Mib1 substrates for cell migration and found that Mib1 ubiquitinates Ctnnd1. Mib1-mediated ubiquitination of Ctnnd1 K547 attenuated Rac1 activation in cultured cells. In addition, we found that posterior lateral line primordium cells in the zebrafish mib1 ta52b mutant showed increased random migration and loss of directional F-actin-based protrusion formation. Knockdown of Ctnnd1 partially rescued posterior lateral line primordium cell migration defects in the mib1 ta52b mutant. Taken together, our data suggest that Mib1 plays an important role in cell migration and that persistent directional cell migration is regulated, at least in part, by the Mib1-Ctnnd1-Rac1 pathway. Published under the PNAS license.

Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues.

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Alec J Hirsch

2017-03-01

Full Text Available Zika virus (ZIKV, an emerging flavivirus, has recently spread explosively through the Western hemisphere. In addition to symptoms including fever, rash, arthralgia, and conjunctivitis, ZIKV infection of pregnant women can cause microcephaly and other developmental abnormalities in the fetus. We report herein the results of ZIKV infection of adult rhesus macaques. Following subcutaneous infection, animals developed transient plasma viremia and viruria from 1-7 days post infection (dpi that was accompanied by the development of a rash, fever and conjunctivitis. Animals produced a robust adaptive immune response to ZIKV, although systemic cytokine response was minimal. At 7 dpi, virus was detected in peripheral nervous tissue, multiple lymphoid tissues, joints, and the uterus of the necropsied animals. Notably, viral RNA persisted in neuronal, lymphoid and joint/muscle tissues and the male and female reproductive tissues through 28 to 35 dpi. The tropism and persistence of ZIKV in the peripheral nerves and reproductive tract may provide a mechanism of subsequent neuropathogenesis and sexual transmission.

Using latent selection difference to model persistence in a declining population.

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Mara E Erickson

Full Text Available Population persistence is a direct measure of the viability of a population. Monitoring the distribution of declining populations or subpopulations over time can yield estimates of persistence, which we show can be modeled as a latent selection difference (LSD contrasting attributes of sites where populations have persisted versus those that have not. Predicted persistence can be modeled with predictor covariates to identify factors correlated with species persistence. We demonstrate how to model persistence based on changes in occupancy that can include adjustments for detection probability. Using a known historical distribution of the western grebe (Aechmophorus occidentalis, we adapted methods originally developed for occupancy modeling to evaluate how environmental covariates including emergent vegetation and human developments have affected western grebe persistence in Alberta. The relative probability of persistence was correlated with the extent of shoreline bulrush (Scirpus lacustris, which is important vegetation for nesting cover. We also documented that western grebe populations were less likely to persist on lakes in the boreal forest, primarily located on the northern boundary of the species' range. Factors influencing occupancy were different than those determining persistence by western grebes; persistence and occupancy were not correlated. Persistence was more likely on lakes with recreational development, reflecting reliance by grebes on the larger, fish-bearing waterbodies that also are attractive for lakeshore development. Unfortunately, the correlation with recreational development on Alberta's lakes puts grebes at risk for loss of brood-rearing habitats--primary threats to altricial birds--if steps are not taken to prevent disturbance to bulrush stands. Identifying factors related to the persistence of a species--especially one in decline--is a fundamental step in conservation management.

Neuropathic pain mechanisms in patients with chronic sports injuries: a diagnostic model useful in sports medicine?

Science.gov (United States)

van Wilgen, Cornelis P; Keizer, Doeke

2011-01-01

The pathophysiology of chronic sports injuries such as overuse or tendinopathy remains largely unknown. With this exploratory study, we aim to detect signs of sensitization of the nervous system. Sensitization is an indication of the involvement of neuropathic mechanisms in patients with chronic sports injuries. Sensory descriptors were assessed by means of a neuropathic pain questionnaire (DN4-interview) and by three methods of sensory testing. The test results were integrated in a scoring system. Patients were recruited from an outpatient clinic of a University Medical Centre and at primary care physical therapy practices. Fifteen athletes with a unilateral chronic sports injury were included. All subjects filled out the seven-items of the DN4-interview to assess sensory descriptors. Next, the presence of brush-evoked allodynia was assessed and pain thresholds with Von Frey monofilaments and a pressure algometer were measured in all patients to determine signs of sensitization. Based on the scoring system, in 4 out of 15 patients (27%) the presence of sensitization could be detected. In two other patients, signs of hypoalgesia were observed. The involvement of sensitization as an explanation for the pain in chronic sports injuries is credible in a considerable proportion of patients. With respect to treatment, the establishment of such neuropathic pain mechanisms is of clinical significance. Wiley Periodicals, Inc.

Quantification of image persistence in a digital angiography system

International Nuclear Information System (INIS)

Okkalides, D.P.; Raptou, P.D.

1993-01-01

Image persistence, as a characteristic of video imaging systems affecting the quality of fast moving fluoroscopic images, is shown to vary considerably. A simple quantitative method for measuring image persistence in a digital angiography system is presented, together with a series of image intensifier exposure-response curves. For the Saticon tube, used with the Siemens 3VA Digitron, it was found that persistence increased for low exposure rates and may increase to 31% at a 120 ms interval. In addition, a sharp increase in image persistence, from 8.3% to 33%, was observed within 18 months from installation of the system. (author)

Persistent Depressive Symptoms are Independent Predictors of Low-Grade Inflammation Onset Among Healthy Individuals

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Fábio Gazelato de Mello Franco

Full Text Available Abstract Background: Depressive symptoms are independently associated with an increased risk of cardiovascular disease (CVD among individuals with non-diagnosed CVD. The mechanisms underlying this association, however, remain unclear. Inflammation has been indicated as a possible mechanistic link between depression and CVD. Objectives: This study evaluated the association between persistent depressive symptoms and the onset of low-grade inflammation. Methods: From a database of 1,508 young (mean age: 41 years individuals with no CVD diagnosis who underwent at least two routine health evaluations, 134 had persistent depressive symptoms (Beck Depression Inventory - BDI ≥ 10, BDI+ and 1,374 had negative symptoms at both time points (BDI-. All participants had been submitted to repeated clinical and laboratory evaluations at a regular follow-up with an average of 26 months from baseline. Low-grade inflammation was defined as plasma high-sensitivity C-Reactive Protein (CRP concentrations > 3 mg/L. The outcome was the incidence of low-grade inflammation evaluated by the time of the second clinical evaluation. Results: The incidence of low-grade inflammation was more frequently observed in the BDI+ group compared to the BDI- group (20.9% vs. 11.4%; p = 0.001. After adjusting for sex, age, waist circumference, body mass index, levels of physical activity, smoking, and prevalence of metabolic syndrome, persistent depressive symptoms remained an independent predictor of low-grade inflammation onset (OR = 1.76; 95% CI: 1.03-3.02; p = 0.04. Conclusions: Persistent depressive symptoms were independently associated with low-grade inflammation onset among healthy individuals.

Persistence of pollination mutualisms in the presence of ants.

Science.gov (United States)

Wang, Yuanshi; Wang, Shikun

2015-01-01

This paper considers plant-pollinator-ant systems in which the plant-pollinator interaction is mutualistic but ants have both positive and negative effects on plants. The ants also interfere with pollinators by preventing them from accessing plants. While a Beddington-DeAngelis (BD) formula can describe the plant-pollinator interaction, the formula is extended in this paper to characterize the pollination mutualism under the ant interference. Then, a plant-pollinator-ant system with the extended BD functional response is discussed, and global dynamics of the model demonstrate the mechanisms by which pollination mutualism can persist in the presence of ants. When the ant interference is strong, it can result in extinction of pollinators. Moreover, if the ants depend on pollination mutualism for survival, the strong interference could drive pollinators into extinction, which consequently lead to extinction of the ants themselves. When the ant interference is weak, a cooperation between plant-ant and plant-pollinator mutualisms could occur, which promotes survival of both ants and pollinators, especially in the case that ants (respectively, pollinators) cannot survive in the absence of pollinators (respectively, ants). Even when the level of ant interference remains invariant, varying ants' negative effect on plants can result in survival/extinction of both ants and pollinators. Therefore, our results provide an explanation for the persistence of pollination mutualism when there exist ants.

Astrocytes play a key role in activation of microglia by persistent Borna disease virus infection

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Sauder Christian

2008-11-01

Full Text Available Abstract Neonatal Borna disease virus (BDV infection of the rat brain is associated with microglial activation and damage to certain neuronal populations. Since persistent BDV infection of neurons is nonlytic in vitro, activated microglia have been suggested to be responsible for neuronal cell death in vivo. However, the mechanisms of activation of microglia in neonatally BDV-infected rat brains remain unclear. Our previous studies have shown that activation of microglia by BDV in culture requires the presence of astrocytes as neither the virus nor BDV-infected neurons alone activate microglia. Here, we evaluated the mechanisms whereby astrocytes can contribute to activation of microglia in neuron-glia-microglia mixed cultures. We found that persistent infection of neuronal cells leads to activation of uninfected astrocytes as measured by elevated expression of RANTES. Activation of astrocytes then produces activation of microglia as evidenced by increased formation of round-shaped, MHCI-, MHCII- and IL-6-positive microglia cells. Our analysis of possible molecular mechanisms of activation of astrocytes and/or microglia in culture indicates that the mediators of activation may be soluble heat-resistant, low molecular weight factors. The findings indicate that astrocytes may mediate activation of microglia by BDV-infected neurons. The data are consistent with the hypothesis that microglia activation in the absence of neuronal damage may represent initial steps in the gradual neurodegeneration observed in brains of neonatally BDV-infected rats.

Inferring differential evolutionary processes of plant persistence traits in Northern Hemisphere Mediterranean fire-prone ecosystems

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Pausas, J.G.; Keeley, J.E.; Verdu, M.

2006-01-01

1 Resprouting capacity (R) and propagule-persistence (P) are traits that are often considered to have evolved where there are predictable crown fires. Because several indicators suggest a stronger selective pressure for such traits in California than in the Mediterranean Basin, we hypothesize that plant species should have evolved to become R+ and P+ more frequently in California than in the Mediterranean Basin. 2 To test this hypothesis we studied the phylogenetic association between R and P states in both California and the Mediterranean Basin using published molecular phylogenies. 3 The results suggest that R and P evolved differently in the two regions. The occurrence of the states differs significantly between regions for trait P, but not for trait R. The different patterns (towards R+ and P+ in California and towards R+ and P- in the Mediterranean Basin) are reflected in the higher abundance and the wider taxonomic distribution of species with both persistence traits (R+P+ species) in California. 4 The differential acquisition of fire persistence mechanisms at the propagule level (P+) supports the idea that fire selective pressures has been higher in California than in the Mediterranean Basin. 5 Our comparative phylogenetic-informed analysis contributes to an understanding of the differential role of the Quaternary climate in determining fire persistence traits in different Mediterranean-type ecosystems and, thus, to the debate on the evolutionary convergence of traits. ?? 2006 British Ecological Society.

Persistent Mullerian Duct Syndrome with Transverse Testicular ...

African Journals Online (AJOL)

Eastham JA, McEvoy K, Sullivan R, Chandrasoma P. A case of simultaneous bilateral nonseminomatous testicular tumors in persistent müllerian duct syndrome. J Urol 1992;148:407-8. 8. Shinmura Y, Yokoi T, Tsutsui Y. A case of clear cell adenocarcinoma of the müllerian duct in persistent müllerian duct syndrome: The first ...

Lymphogranuloma venereum causing a persistent genital ulcer.

Science.gov (United States)

Marcotte, Terrence; Lee, Yer; Pandori, Mark; Jain, Vivek; Cohen, Stephanie Elise

2014-04-01

Lymphogranuloma venereum (LGV) is a sexually transmitted cause of inguinal lymphadenopathy and proctocolitis. We report a patient with a persistent genital ulcer due to LGV (serovar L2b), an unusual presentation among US men who have sex with men. Lymphogranuloma venereum should be considered when evaluating persistent genital ulcers, and LGV-specific testing should be sought.

Persistent ovarian masses and pregnancy outcomes.

Science.gov (United States)

Goh, William A; Rincon, Monica; Bohrer, Justin; Tolosa, Jorge E; Sohaey, Roya; Riaño, Rene; Davis, James; Zalud, Ivica

2013-07-01

To determine if persistent ovarian masses in pregnancy are associated with increased adverse outcomes. This is a retrospective cohort of 126 pregnant women with a persistent ovarian mass measuring 5 cm or greater who delivered at two university hospitals between 2001 and 2009. Maternal outcomes included gestational age (GA) at diagnosis, delivery and surgery as well as miscarriage, preterm birth (PTB), ovarian torsion and hospital admission for pain. Neonatal outcomes included birth weight, respiratory distress syndrome (RDS), intra-ventricular hemorrhage (IVH), death and sepsis. A total of 1225 ovarian masses were identified (4.9%) in 24,868 patients. A persistent ovarian mass was found in 0.7%. Average GA at diagnosis was 17.8 weeks. Miscarriage rate was 3.3%. Average GA at delivery was 37.9 weeks. Of the patients, 8.5% had ovarian torsion, 10.3% had admission for pain and 9.3% had PTBs. The mean cesarean delivery rate was 46.3%. The average neonatal weight was 3273 g. There was one neonatal death in this cohort. The rate of RDS was 2.8%, IVH 0.9% and neonatal sepsis 1.9%. The most common surgical pathologic diagnosis was dermoids (37.6%). No overt malignancies were seen. A persistent ovarian mass in pregnancy does not confer an increased risk of adverse pregnancy outcomes.

Decreased Cerebellar-Orbitofrontal Connectivity Correlates with Stuttering Severity: Whole-Brain Functional and Structural Connectivity Associations with Persistent Developmental Stuttering.

Science.gov (United States)

Sitek, Kevin R; Cai, Shanqing; Beal, Deryk S; Perkell, Joseph S; Guenther, Frank H; Ghosh, Satrajit S

2016-01-01

Persistent developmental stuttering is characterized by speech production disfluency and affects 1% of adults. The degree of impairment varies widely across individuals and the neural mechanisms underlying the disorder and this variability remain poorly understood. Here we elucidate compensatory mechanisms related to this variability in impairment using whole-brain functional and white matter connectivity analyses in persistent developmental stuttering. We found that people who stutter had stronger functional connectivity between cerebellum and thalamus than people with fluent speech, while stutterers with the least severe symptoms had greater functional connectivity between left cerebellum and left orbitofrontal cortex (OFC). Additionally, people who stutter had decreased functional and white matter connectivity among the perisylvian auditory, motor, and speech planning regions compared to typical speakers, but greater functional connectivity between the right basal ganglia and bilateral temporal auditory regions. Structurally, disfluency ratings were negatively correlated with white matter connections to left perisylvian regions and to the brain stem. Overall, we found increased connectivity among subcortical and reward network structures in people who stutter compared to controls. These connections were negatively correlated with stuttering severity, suggesting the involvement of cerebellum and OFC may underlie successful compensatory mechanisms by more fluent stutterers.

Decreased Cerebellar-Orbitofrontal Connectivity Correlates with Stuttering Severity: Whole-Brain Functional and Structural Connectivity Associations with Persistent Developmental Stuttering

Science.gov (United States)

Sitek, Kevin R.; Cai, Shanqing; Beal, Deryk S.; Perkell, Joseph S.; Guenther, Frank H.; Ghosh, Satrajit S.

2016-01-01

Persistent developmental stuttering is characterized by speech production disfluency and affects 1% of adults. The degree of impairment varies widely across individuals and the neural mechanisms underlying the disorder and this variability remain poorly understood. Here we elucidate compensatory mechanisms related to this variability in impairment using whole-brain functional and white matter connectivity analyses in persistent developmental stuttering. We found that people who stutter had stronger functional connectivity between cerebellum and thalamus than people with fluent speech, while stutterers with the least severe symptoms had greater functional connectivity between left cerebellum and left orbitofrontal cortex (OFC). Additionally, people who stutter had decreased functional and white matter connectivity among the perisylvian auditory, motor, and speech planning regions compared to typical speakers, but greater functional connectivity between the right basal ganglia and bilateral temporal auditory regions. Structurally, disfluency ratings were negatively correlated with white matter connections to left perisylvian regions and to the brain stem. Overall, we found increased connectivity among subcortical and reward network structures in people who stutter compared to controls. These connections were negatively correlated with stuttering severity, suggesting the involvement of cerebellum and OFC may underlie successful compensatory mechanisms by more fluent stutterers. PMID:27199712

Decreased cerebellar-orbitofrontal connectivity correlates with stuttering severity: Whole-brain functional and structural connectivity associations with persistent developmental stuttering

Directory of Open Access Journals (Sweden)

Kevin Richard Sitek

2016-05-01

Full Text Available Persistent developmental stuttering is characterized by speech production disfluency and affects 1% of adults. The degree of impairment varies widely across individuals and the neural mechanisms underlying the disorder and this variability remain poorly understood. Here, we elucidate compensatory mechanisms related to this variability in impairment using whole-brain functional and white matter connectivity analyses in persistent developmental stuttering. We found that people who stutter had stronger functional connectivity between cerebellum and thalamus than people with fluent speech, while stutterers with the least severe symptoms had greater functional connectivity between left cerebellum and left orbitofrontal cortex. Additionally, people who stutter had decreased functional and white matter connectivity among the perisylvian auditory, motor, and speech planning regions compared to typical speakers, but greater functional connectivity between the right basal ganglia and bilateral temporal auditory regions. Structurally, disfluency ratings were negatively correlated with white matter connections to left perisylvian regions and to the brain stem. Overall, we found increased connectivity among subcortical and reward network structures in people who stutter compared to controls. These connections were negatively correlated with stuttering severity, suggesting the involvement of cerebellum and orbitofrontal cortex may underlie successful compensatory mechanisms by more fluent stutterers.

Lesion progression in post-treatment persistent endodontic lesions.

Science.gov (United States)

Yu, Victoria Soo Hoon; Messer, Harold Henry; Shen, Liang; Yee, Robert; Hsu, Chin-ying Stephen

2012-10-01

Radiographic lesions related to root-filled teeth may persist for long periods after treatment and are considered to indicate failure of initial treatment. Persistent lesions are found in a proportion of cases, but information on lesion progression is lacking. This study examined the incidence of lesion improvement, remaining unchanged, and deterioration among persistent lesions in a group of patients recruited from a university-based clinic and identified potential predictors for lesion progression. Patients of a university clinic with persistent endodontic lesions at least 4 years since treatment and with original treatment radiographs available were recruited with informed consent. Data were obtained by interview and from dental records and clinical and radiographic examinations. Univariate and multivariate statistical analyses were carried out by using SPSS (version 19). One hundred fifty-one persistent lesions were identified in 114 patients. A majority of the lesions (107, 70.9%) received treatment between 4 and 5 years prior. Eighty-six lesions (57.0%) improved, 18 (11.9%) remained unchanged, and 47 (31.1%) deteriorated since treatment. Potential predictors for lesions that did not improve included recall lesion size, pain on biting at recall examination, history of a postobturation flare-up, and a non-ideal root-filling length (P < .05). Lesions that had persisted for a longer period appeared less likely to be improving (relative risk, 1.038; 95% confidence interval, 1.000-1.077). A specific time interval alone should not be used to conclude that a lesion will not resolve without intervention. This study identified several clinical factors that are associated with deteriorating persistent lesions, which should aid in identifying lesions that require further intervention. Copyright © 2012 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Living with persistent rheumatoid arthritis: a BARFOT study.

Science.gov (United States)

Bala, Sidona-Valentina; Samuelson, Karin; Hagell, Peter; Fridlund, Bengt; Forslind, Kristina; Svensson, Björn; Thomé, Bibbi

2017-09-01

To describe and understand the meaning of living with persistent rheumatoid arthritis. A considerable number of patients with rheumatoid arthritis live with an ongoing active and symptomatic illness despite access to potent antirheumatic treatment. There is, however, a lack of knowledge about the meaning of living with this severe long-term illness, defined as persistent rheumatoid arthritis. A descriptive design based on a hermeneutic phenomenological method was used. Ten adults with persistent rheumatoid arthritis and at least five years disease duration were interviewed. The interviews were analysed according to van Manen's method. Living with persistent rheumatoid arthritis revealed four overall themes: an existence dominated by painful symptoms and treatment, radical changes and limitations in one's life, a continual struggle to cope with one's life and to master the illness, and a dependency on those who are close by and the world around. The lifeworld was affected to a varying extent and in various ways by the illness but also by the dependence on its treatment and care that was not experienced as sufficiently meeting needs in terms of security, access to and coordination of care as well as team and rehabilitation services. Persistent rheumatoid arthritis and its treatment entail a radical effect on the person's life and quality of life. Current ordinary rheumatology care does not seem to meet the individual needs of the person with persistent rheumatoid arthritis in an optimal way. A greater knowledge about and understanding of the person who lives with persistent rheumatoid arthritis is important for facilitating the development of care and the relief of suffering. A holistic alternative to conventional clinical practice, such as person-centred care, could be tested as an innovative model of care. Our findings might serve as material for educational and counselling purposes for healthcare professionals. © 2016 John Wiley & Sons Ltd.

Key role for spinal dorsal horn microglial kinin B1 receptor in early diabetic pain neuropathy

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Couture Réjean

2010-06-01

Full Text Available Abstract Background The pro-nociceptive kinin B1 receptor (B1R is upregulated on sensory C-fibres, astrocytes and microglia in the spinal cord of streptozotocin (STZ-diabetic rat. This study aims at defining the role of microglial kinin B1R in diabetic pain neuropathy. Methods Sprague-Dawley rats were made diabetic with STZ (65 mg/kg, i.p., and 4 days later, two specific inhibitors of microglial cells (fluorocitrate, 1 nmol, i.t.; minocycline, 10 mg/kg, i.p. were administered to assess the impact on thermal hyperalgesia, allodynia and mRNA expression (qRT-PCR of B1R and pro-inflammatory markers. Spinal B1R binding sites ((125I-HPP-desArg10-Hoe 140 were also measured by quantitative autoradiography. Inhibition of microglia was confirmed by confocal microscopy with the specific marker Iba-1. Effects of intrathecal and/or systemic administration of B1R agonist (des-Arg9-BK and antagonists (SSR240612 and R-715 were measured on neuropathic pain manifestations. Results STZ-diabetic rats displayed significant tactile and cold allodynia compared with control rats. Intrathecal or peripheral blockade of B1R or inhibition of microglia reversed time-dependently tactile and cold allodynia in diabetic rats without affecting basal values in control rats. Microglia inhibition also abolished thermal hyperalgesia and the enhanced allodynia induced by intrathecal des-Arg9-BK without affecting hyperglycemia in STZ rats. The enhanced mRNA expression (B1R, IL-1β, TNF-α, TRPV1 and Iba-1 immunoreactivity in the STZ spinal cord were normalized by fluorocitrate or minocycline, yet B1R binding sites were reduced by 38%. Conclusion The upregulation of kinin B1R in spinal dorsal horn microglia by pro-inflammatory cytokines is proposed as a crucial mechanism in early pain neuropathy in STZ-diabetic rats.

The Persistence of Long Work Hours

OpenAIRE

Robert Drago; David Black; Mark Wooden

2005-01-01

Previous research hypothesizes that long working hours are related to consumerism, the ideal worker norm, high levels of human capital, and a high cost-of-job-loss. The authors test these hypotheses using panel data on working hours for an Australian sample of full-time employed workers. Analyses include a static cross-sectional model and a persistence model for long hours over time. The results suggest that long hours (50 or more hours in a usual week) are often persistent, and provide stron...

The Persistence of Profits in Azerbaijan's Banking System

Directory of Open Access Journals (Sweden)

K. Batu TUNAY

2015-06-01

Full Text Available In this research, the persistence of profits in Azerbaijan's banking sector in the short-run and the long-run is investigated. Although there are a lot of researches done in the case of different countries, enough study has been implemented for the case of Azerbaijan despite of its high speed economic growth. This research analysis continuity of profits by using system panel data method. Obtained results indicate that profits demonstrate no persistence or a little persistence. In this context, existence of competitive powers in the sector can be stated.

Preventive Treatment with Ketamine Attenuates the Ischaemia-Reperfusion Response in a Chronic Postischaemia Pain Model

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Suryamin Liman

2015-01-01

Full Text Available Ischemia and inflammation may be pathophysiological mechanisms of complex regional pain syndrome (CRPS. Ketamine has proposed anti-inflammatory effects and has been used for treating CRPS. This study aimed to evaluate anti-inflammatory and analgesic effects of ketamine after ischaemia-reperfusion injury in a chronic postischaemia pain (CPIP model of CRPS-I. Using this model, ischemia was induced in the hindlimbs of male Sprague-Dawley rats. Ketamine, methylprednisolone, or saline was administered immediately after reperfusion. Physical effects, (oedema, temperature, and mechanical and cold allodynia in the bilateral hindpaws, were assessed from 48 hours after reperfusion. Fewer (56% rats in the ketamine group developed CPIP at the 48th hour after reperfusion (nonsignificant. Ketamine treated rats showed a significantly lower temperature in the ischaemic hindpaw compared to saline (P<0.01 and methylprednisolone (P<0.05 groups. Mechanical and cold allodynia were significantly lower in the ischaemic side in the ketamine group (P<0.05. Proinflammatory cytokines TNF-α and IL-2 were significantly lower at the 48th hour after reperfusion in ketamine and methylprednisolone groups, compared to saline (all P<0.05. In conclusion, immediate administration of ketamine after an ischaemia-reperfusion injury can alleviate pain and inflammation in the CPIP model and has potential to treat postischaemic pain.

A Combined Water Extract of Frankincense and Myrrh Alleviates Neuropathic Pain in Mice via Modulation of TRPV1

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Danyou Hu

2017-01-01

Full Text Available Frankincense and myrrh are widely used in clinics as a pair of herbs to obtain a synergistic effect for relieving pain. To illuminate the analgesia mechanism of frankincense and myrrh, we assessed its effect in a neuropathic pain mouse model. Transient receptor potential vanilloid 1 (TRPV1 plays a crucial role in neuropathic pain and influences the plasticity of neuronal connectivity. We hypothesized that the water extraction of frankincense and myrrh (WFM exerted its analgesia effect by modulating the neuronal function of TRPV1. In our study, WFM was verified by UHPLC-TQ/MS assay. In vivo study showed that nociceptive response in mouse by heat and capsaicin induced were relieved by WFM treatment. Furthermore, thermal hypersensitivity and mechanical allodynia were also alleviated by WFM treatment in a chronic constriction injury (CCI mouse model. CCI resulted in increased TRPV1 expression at both the mRNA and protein levels in predominantly small-to-medium neurons. However, after WFM treatment, TRPV1 expression was reverted in real-time PCR, Western blot, and immunofluorescence experiments. Calcium response to capsaicin was also decreased in cultured DRG neurons from CCI model mouse after WFM treatment. In conclusion, WFM alleviated CCI-induced mechanical allodynia and thermal hypersensitivity via modulating TRPV1.

Persistent genital arousal disorder

DEFF Research Database (Denmark)

Eibye, Simone; Jensen, Hans Mørch

2014-01-01

We report a case of a woman suffering from persistent genital arousal disorder (PGAD) after paroxetine cessation. She was admitted to a psychiatric department and diagnosed with agitated depression. Physical investigation showed no gynaecological or neurological explanation; however, a pelvic MRI...

[Persistent pulmonary hypertension in a neonate caused by blood aspiration following vaginal blood loss].

Science.gov (United States)

Krüse-Ruijter, M F; Zimmermann, L J I

2007-07-14

A preterm neonate, with a gestational age of 30 1/7 weeks, was born after a period of prolonged rupture of the membranes and a retroplacental haematoma causing vaginal bleeding. During admission to the neonatal intensive-care unit, mechanical ventilation was indicated because of acute respiratory failure following blood aspiration, which was causing oxygenation and ventilation problems. Endotracheal surfactant was administered and, because of persistent pulmonary hypertension of the newborn (PPHN), NO-inhalation therapy was started. A quick recovery was seen and two days post partum the patient could be extubated. Blood aspiration may cause acute respiratory problems and PPHN, with quick recovery after effective mechanical ventilation, surfactant and NO-inhalation therapy.

"Nurse's cramp"

DEFF Research Database (Denmark)

Jepsen, Jørgen Riis

2015-01-01

. The physical examination revealed minor pareses of median nerve-innervated muscles, mild sensory deviations in the median nerve territories and mechanical allodynia with palpation of the median nerve trunk at the proximal forearm. The physical findings are in accordance with a median nerve entrapment...... on forearm level. The symptoms in all three patients were relieved by nerve mobilization and reduced exposure....

Persistent Identifiers in Earth science data management environments

Science.gov (United States)

Weigel, Tobias; Stockhause, Martina; Lautenschlager, Michael

2014-05-01

Globally resolvable Persistent Identifiers (PIDs) that carry additional context information (which can be any form of metadata) are increasingly used by data management infrastructures for fundamental tasks. The notion of a Persistent Identifier is originally an abstract concept that aims to provide identifiers that are quality-controlled and maintained beyond the life time of the original issuer, for example through the use of redirection mechanisms. Popular implementations of the PID concept are for example the Handle System and the DOI System based on it. These systems also move beyond the simple identification concept by providing facilities that can hold additional context information. Not only in the Earth sciences, data managers are increasingly attracted to PIDs because of the opportunities these facilities provide; however, long-term viable principles and mechanisms for efficient organization of PIDs and context information are not yet available or well established. In this respect, promising techniques are to type the information that is associated with PIDs and to construct actionable collections of PIDs. There are two main drivers for extended PID usage: Earth science data management middleware use cases and applications geared towards scientific end-users. Motivating scenarios from data management include hierarchical data and metadata management, consistent data tracking and improvements in the accountability of processes. If PIDs are consistently assigned to data objects, context information can be carried over to subsequent data life cycle stages much easier. This can also ease data migration from one major curation domain to another, e.g. from early dissemination within research communities to formal publication and long-term archival stages, and it can help to document processes across technical and organizational boundaries. For scientific end users, application scenarios include for example more personalized data citation and improvements in the

Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system

Science.gov (United States)

Zhao, Xin; Wang, Chuang; Cui, Wu-Geng; Ma, Qing; Zhou, Wen-Hua

2015-01-01

Fisetin, a natural flavonoid, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential antinociceptive efficacies of fisetin against neuropathic pain and explore mechanism(s). We subjected mice to chronic constriction injury (CCI) by loosely ligating the sciatic nerves, and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic fisetin treatment (5, 15 or 45 mg/kg, p.o.) ameliorated thermal hyperalgesia (but not mechanical allodynia) in CCI mice, concomitant with escalated levels of spinal monoamines and suppressed monoamine oxidase (MAO)-A activity. The antihyperalgesic action of fisetin was abolished by chemical depletion of spinal serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. Moreover, intraperitoneal (i.p.) or intrathecal (i.t.) co-treatment with 5-HT7 receptor antagonist SB-258719 completely abrogated fisetin's antihyperalgesia. These findings confirm that chronic fisetin treatment exerts antinociceptive effect on thermal hyperalgesia in neuropathic mice, with spinal serotonergic system (coupled with 5-HT7) being critically involved. Of special benefit, fisetin attenuated co-morbidly behavioral symptoms of depression and anxiety (evaluated in forced swim test, novelty suppressed feeding test and light-dark test) evoked by neuropathic pain. PMID:25761874

On the causes of persistent apical periodontitis: a review.

Science.gov (United States)

Nair, P N R

2006-04-01

Apical periodontitis is a chronic inflammatory disorder of periradicular tissues caused by aetiological agents of endodontic origin. Persistent apical periodontitis occurs when root canal treatment of apical periodontitis has not adequately eliminated intraradicular infection. Problems that lead to persistent apical periodontitis include: inadequate aseptic control, poor access cavity design, missed canals, inadequate instrumentation, debridement and leaking temporary or permanent restorations. Even when the most stringent procedures are followed, apical periodontitis may still persist as asymptomatic radiolucencies, because of the complexity of the root canal system formed by the main and accessory canals, their ramifications and anastomoses where residual infection can persist. Further, there are extraradicular factors -- located within the inflamed periapical tissue -- that can interfere with post-treatment healing of apical periodontitis. The causes of apical periodontitis persisting after root canal treatment have not been well characterized. During the 1990s, a series of investigations have shown that there are six biological factors that lead to asymptomatic radiolucencies persisting after root canal treatment. These are: (i) intraradicular infection persisting in the complex apical root canal system; (ii) extraradicular infection, generally in the form of periapical actinomycosis; (iii) extruded root canal filling or other exogenous materials that cause a foreign body reaction; (iv) accumulation of endogenous cholesterol crystals that irritate periapical tissues; (v) true cystic lesions, and (vi) scar tissue healing of the lesion. This article provides a comprehensive overview of the causative factors of non-resolving periapical lesions that are seen as asymptomatic radiolucencies post-treatment.

Modeling Real Exchange Rate Persistence in Chile

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Leonardo Salazar

2017-07-01

Full Text Available The long and persistent swings in the real exchange rate have for a long time puzzled economists. Recent models built on imperfect knowledge economics seem to provide a theoretical explanation for this persistence. Empirical results, based on a cointegrated vector autoregressive (CVAR model, provide evidence of error-increasing behavior in prices and interest rates, which is consistent with the persistence observed in the data. The movements in the real exchange rate are compensated by movements in the interest rate spread, which restores the equilibrium in the product market when the real exchange rate moves away from its long-run benchmark value. Fluctuations in the copper price also explain the deviations of the real exchange rate from its long-run equilibrium value.

A role for the non-canonical Wnt-ß-Catenin and TGF-ß signaling pathways in the induction of tolerance during the establishment of a Salmonella enterica serovar Enteritidis persistent cecal infection in chickens

Science.gov (United States)

Non-typhoidal Salmonella enterica induce an early pro-inflammatory response in chickens. However, the response is short-lived, asymptomatic of disease, resulting in a persistent colonization of the ceca, and fecal shedding of bacteria. The underlying mechanisms that control this persistent infecti...

Thalamo-cortical activation and connectivity during response preparation in adults with persistent and remitted ADHD.

Science.gov (United States)

Clerkin, Suzanne M; Schulz, Kurt P; Berwid, Olga G; Fan, Jin; Newcorn, Jeffrey H; Tang, Cheuk Y; Halperin, Jeffrey M

2013-09-01

The neural correlates of stimulus-driven processes, such as response preparation, have been posited to be associated with the onset of attention deficit hyperactivity disorder (ADHD) while being distinct from the neural mechanisms associated with recovery. The authors tested this hypothesis in adults with remitted and persistent ADHD. Thirty-eight young adults who were diagnosed with combined-type ADHD in childhood (probands) and 32 carefully matched comparison subjects were followed longitudinally and scanned with functional MRI while performing an event-related cued reaction time task. Probands were characterized as individuals with persistent or remitted ADHD. Differences in thalamo-cortical activation and functional connectivity during response preparation between comparison subjects and probands and between individuals with persistent ADHD and those with remitted ADHD were assessed by contrasting neural activation and functional connectivity during cue or noncue events. Probands exhibited less cue-related activation than comparison subjects in the thalamus, anterior cingulate cortex, supplementary motor area, inferior parietal lobe, and dorsolateral prefrontal cortex despite similar overall patterns of activation. There were no differences in activation between individuals in the remitted ADHD group and those in the persistent ADHD group in any hypothesized regions. However, cue-related functional connectivity between the right thalamus and brainstem was greater in comparison subjects relative to probands, and cue-related connectivity was greater between the right thalamus and prefrontal regions in individuals with remitted ADHD relative to those with persistent ADHD. Decreased thalamo-cortical activation during response preparation was present in adults diagnosed with ADHD in childhood regardless of symptom remission in adulthood, and may be partly driven by less functional coordination between the brainstem and thalamus. Greater functional integration of the

Inflation persistence in African countries: Does inflation targeting matter?

OpenAIRE

Phiri, Andrew

2016-01-01

This study investigates inflation persistence in annual CPI inflation collected between 1994 and 2014 for 46 African countries. We group these countries into panels according to whether they are inflation targeters or not and conduct estimations for pre and post inflation targeting periods. Interestingly enough, we find that inflation persistence was much higher for inflation targeters in periods before adopting their inflation targeting regimes and inflation persistence dropped by 40 percent...

Salt stress-induced transcription of σB- and CtsR-regulated genes in persistent and non-persistent Listeria monocytogenes strains from food processing plants.

Science.gov (United States)

Ringus, Daina L; Ivy, Reid A; Wiedmann, Martin; Boor, Kathryn J

2012-03-01

Listeria monocytogenes is a foodborne pathogen that can persist in food processing environments. Six persistent and six non-persistent strains from fish processing plants and one persistent strain from a meat plant were selected to determine if expression of genes in the regulons of two stress response regulators, σ(B) and CtsR, under salt stress conditions is associated with the ability of L. monocytogenes to persist in food processing environments. Subtype data were also used to categorize the strains into genetic lineages I or II. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to measure transcript levels for two σ(B)-regulated genes, inlA and gadD3, and two CtsR-regulated genes, lmo1138 and clpB, before and after (t=10 min) salt shock (i.e., exposure of exponential phase cells to BHI+6% NaCl for 10 min at 37°C). Exposure to salt stress induced higher transcript levels relative to levels under non-stress conditions for all four stress and virulence genes across all wildtype strains tested. Analysis of variance (ANOVA) of induction data revealed that transcript levels for one gene (clpB) were induced at significantly higher levels in non-persistent strains compared to persistent strains (p=0.020; two-way ANOVA). Significantly higher transcript levels of gadD3 (p=0.024; two-way ANOVA) and clpB (p=0.053; two-way ANOVA) were observed after salt shock in lineage I strains compared to lineage II strains. No clear association between stress gene transcript levels and persistence was detected. Our data are consistent with an emerging model that proposes that establishment of L. monocytogenes persistence in a specific environment occurs as a random, stochastic event, rather than as a consequence of specific bacterial strain characteristics.

Is corruption really persistent?

NARCIS (Netherlands)

Seldadyo, H.; de Haan, J.

Theoretical and empirical research on corruption generally concludes that corruption is persistent. However, using International Country Risk Guide data for the period 1984-2008 for 101 countries, we find strong evidence that corruption changes over time. In the present study, corruption levels of

Persistence of environmental DNA in freshwater ecosystems.

Directory of Open Access Journals (Sweden)

Tony Dejean

Full Text Available The precise knowledge of species distribution is a key step in conservation biology. However, species detection can be extremely difficult in many environments, specific life stages and in populations at very low density. The aim of this study was to improve the knowledge on DNA persistence in water in order to confirm the presence of the focus species in freshwater ecosystems. Aquatic vertebrates (fish: Siberian sturgeon and amphibian: Bullfrog tadpoles were used as target species. In control conditions (tanks and in the field (ponds, the DNA detectability decreases with time after the removal of the species source of DNA. DNA was detectable for less than one month in both conditions. The density of individuals also influences the dynamics of DNA detectability in water samples. The dynamics of detectability reflects the persistence of DNA fragments in freshwater ecosystems. The short time persistence of detectable amounts of DNA opens perspectives in conservation biology, by allowing access to the presence or absence of species e.g. rare, secretive, potentially invasive, or at low density. This knowledge of DNA persistence will greatly influence planning of biodiversity inventories and biosecurity surveys.

Energy Savings Lifetimes and Persistence

Energy Technology Data Exchange (ETDEWEB)

Hoffman, Ian M. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Schiller, Steven R. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Todd, Annika [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Billingsley, Megan A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Goldman, Charles A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Schwartz, Lisa C. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

2016-02-01

This technical brief explains the concepts of energy savings lifetimes and savings persistence and discusses how program administrators use these factors to calculate savings for efficiency measures, programs and portfolios. Savings lifetime is the length of time that one or more energy efficiency measures or activities save energy, and savings persistence is the change in savings throughout the functional life of a given efficiency measure or activity. Savings lifetimes are essential for assessing the lifecycle benefits and cost effectiveness of efficiency activities and for forecasting loads in resource planning. The brief also provides estimates of savings lifetimes derived from a national collection of costs and savings for electric efficiency programs and portfolios.

Search along persistent random walks

International Nuclear Information System (INIS)

Friedrich, Benjamin M

2008-01-01

Optimal search strategies and their implementations in biological systems are a subject of active research. Here we study a search problem which is motivated by the hunt of sperm cells for the egg. We ask for the probability for an active swimmer to find a target under the condition that the swimmer starts at a certain distance from the target. We find that success probability is maximal for a certain level of fluctuations characterized by the persistence length of the swimming path of the swimmer. We derive a scaling law for the optimal persistence length as a function of the initial target distance and search time by mapping the search on a polymer physics problem

The Enigmatic Persistence of Anorexia Nervosa

Science.gov (United States)

Walsh, B. Timothy

2014-01-01

Objective In this review, based on recent advances in cognitive neuroscience, the author presents a formulation in which the marked persistence of anorexia nervosa can be usefully understood as a well-ingrained maladaptive habit. Method The author reviewed the relevant literature on the development and course of anorexia nervosa and interpreted critical features in light of developments in cognitive neuroscience. Results Anorexia nervosa is a well characterized disorder with remarkable persistence both across history and among affected individuals. Food restriction, the salient behavioral feature of the disorder, often begins innocently but gradually takes on a life of its own. Over time, it becomes highly entrenched and resistant to change through either psychological or pharmacological treatment. Cognitive neuroscience has described two related but distinct processes that underlie the acquisition of new patterns of behavior, namely, action-outcome and stimulus-response learning. It is likely that both processes are engaged in the development of anorexia nervosa and that stimulus-response learning (that is, habit formation) is critical to the persistence of the dieting behavior. Conclusions The formulation of the dieting behavior characteristic of anorexia nervosa as a well-entrenched habit provides a basis for understanding the striking persistence of this disorder. This model helps explain the resistance of anorexia nervosa to interventions that have established efficacy in related disorders and implies that addressing the dieting behavior is critical, especially early in the course of the illness, before it has become ingrained. PMID:23429750

Reflections on Student Persistence

Directory of Open Access Journals (Sweden)

Vincent Tinto

2017-07-01

Full Text Available The Feature for this issue Reflections on Student Persistence has been prepared by Professor Vincent Tinto, Distinguished University Professor Emeritus at Syracuse University, United States of America (USA and a longtime friend and supporter of STARS. Vincent explores the case for motivation to be considered as a significant aspect of the tertiary student psyche by drawing on theoretical frameworks, research and practical experiences related to the issue. He synthesises this extensive, detailed, rich but often somewhat impenetrable data into a trilogy of clear and credible key dimensions of the motivation construct student self efficacy, sense of belonging and perceived value of the curriculum. This interpretation of the literature is a personal but informed reflection and is a timely piece which highlights the breadth and profundity of the presentations at this year's conference in Adelaide, Australia where students in all their diversity are central to our focus on enhancing the student experience. In this opening article, Vincent refers directly to the STARS papers selected for this Conference issue of the Journal which also address the importance of student persistence, self-efficacy and building the sense of belonging within their own institutional communities (Fernandes, Ford, Rayner & Pretorius; Kahu, Nelson, & Picton; McFarlane, Spes-Skrbis & Taib; Naylor; Smallhorn. Echoing his position on social justice and his advocacy for underserved students, Vincent reminds us that educational equity gaps still exist, and he encourages us to see the issue of persistence through the eyes of the students to support their perseverance and completion and thereby help reduce educational disadvantage.

Entropy measurements in paroxysmal and persistent atrial fibrillation

International Nuclear Information System (INIS)

Cervigón, R; Moreno, J; Pérez-Villacastín, J; Reilly, R B; Millet, J; Castells, F

2010-01-01

Recent studies on atrial fibrillation (AF) have identified different activation patterns in paroxysmal and persistent AF. In this study, bipolar intra-atrial registers from 28 patients (14 paroxysmal AF and 14 persistent AF) were analyzed in order to find out regional differences in the organization in both types of arrhythmias. The organization of atrial electrical activity was assessed in terms of nonlinear parameters, such as entropy measurements. Results showed differences between the atrial chambers with a higher disorganization in the left atrium in paroxysmal AF patients and a more homogenous behavior along the atria in persistent AF patients