TNF alpha-Induced p38MAPK Activation Regulates TRPA1 and TRPV4 Activity in Odontoblast-Like Cells

The transient receptor potential (TRP) channels are unique cellular sensors that are widely expressed in many neuronal and nonneuronal cells. Among the TRP family members, TRPA1 and TRPV4 are emerging as candidate mechanosensitive channels that play a pivotal role in inflammatory pain and mechanical hyperalgesia. Odontoblasts are nonneuronal cells that possess many of the features of mechanosensitive cells and mediate important defense and sensory functions. However, the effect of inflammation on the activity of the odontoblast's mechanosensitive channels remains unknown. By using immunohistochemistry and calcium microfluorimetry, we showed that odontoblast-like cells express TRPA1 and TRPV4 and that these channels were activated by hypotonicity-induced membrane stretch. Short treatment of odontoblast-like cells with tumor necrosis factor (TNF)-α enhanced TRPA1 and TRPV4 responses to their chemical agonists and membrane stretch. This enhanced channel activity was accompanied by phospho-p38 mitogen-activated protein kinase (MAPK) expression. Treatment of cells with the p38 inhibitor SB202190 reduced TNF-α effects, suggesting modulation of channel activity via p38 MAPK. In addition, TNF-α treatment also resulted in an up-regulation of TRPA1 expression but down-regulation of TRPV4. Unlike TRPV4, enhanced TRPA1 expression was also evident in dental pulp of carious compared with noncarious teeth. SB202190 treatment significantly reduced TNF-α-induced TRPA1 expression, suggesting a role for p38 MAPK signaling in modulating both the transcriptional and non-transcriptional regulation of TRP channels in odontoblasts.

Apparent tolerance of turkey vultures (Cathartes aura) to the non-steroidal anti-inflammatory drug diclofenac

The nonsteroidal anti-inflammatory drug diclofenac is extremely toxic to Old World Gyps vultures (median lethal dose -0.1-0.2 mg/kg), evoking visceral gout, renal necrosis, and mortality within a few days of exposure. Unintentional secondary poisoning of vultures that fed upon carcasses of diclofenac-treated livestock decimated populations in the Indian subcontinent. Because of the widespread use of diclofenac and other cyclooxygenase-2 inhibiting drugs, a toxicological study was undertaken in turkey vultures (Cathartes aura) as an initial step in examining sensitivity of New World scavenging birds. Two trials were conducted entailing oral gavage of diclofenac at doses ranging from 0.08 to 25 mg/kg body weight. Birds were observed for 7 d, blood samples were collected for plasma chemistry (predose and 12, 24, and 48 h and 7 d postdose), and select individuals were necropsied. Diclofenac failed to evoke overt signs of toxicity, visceral gout, renal necrosis, or elevate plasma uric acid at concentrations greater than 100 times the estimated median lethal dose reported for Gyps vultures. For turkey vultures receiving 8 or 25 mg/kg, the plasma half-life of diclofenac was estimated to be 6 h, and it was apparently cleared after several days as no residues were detectable in liver or kidney at necropsy. Differential sensitivity among avian species is a hallmark of cyclooxygenase-2 inhibitors, and despite the tolerance of turkey vultures to diclofenac, additional studies in related scavenging species seem warranted.

Neonatal Pain-Related Stress and NFKBIA Genotype Are Associated with Altered Cortisol Levels in Preterm Boys at School Age

Neonatal pain-related stress is associated with elevated salivary cortisol levels to age 18 months in children born very preterm, compared to full-term, suggesting early programming effects. Importantly, interactions between immune/inflammatory and neuroendocrine systems may underlie programming effects. We examined whether cortisol changes persist to school age, and if common genetic variants in the promoter region of the NFKBIA gene involved in regulation of immune and inflammatory responses, modify the association between early experience and later life stress as indexed by hair cortisol levels, which provide an integrated index of endogenous HPA axis activity. Cortisol was assayed in hair samples from 128 children (83 born preterm =32 weeks gestation and 45 born full-term) without major sensory, motor or cognitive impairments at age 7 years. We found that hair cortisol levels were lower in preterm compared to term-born children. Downregulation of the HPA axis in preterm children without major impairment, seen years after neonatal stress terminated, suggests persistent alteration of stress system programming. Importantly, the etiology was gender-specific such that in preterm boys but not girls, specifically those with the minor allele for NFKBIA rs2233409, lower hair cortisol was associated with greater neonatal pain (number of skin-breaking procedures from birth to term), independent of medical confounders. Moreover, the minor allele (CT or TT) of NFKBIA rs2233409 was associated with higher secretion of inflammatory cytokines, supporting the hypothesis that neonatal pain-related stress may act as a proinflammatory stimulus that induces long-term immune cell activation. These findings are the first evidence that a long-term association between early pain-related stress and cortisol may be mediated by a genetic variants that regulate the activity of NF-?B, suggesting possible involvement of stress/inflammatory mechanisms in HPA programming in boys born very preterm. © 2013 Grunau et al.

Islands of pain in a sea of change: Behaviour analysis and bereavement,

The paper Bereavement: A behavioural process (Dillenburger & Keenan, 1994) was first published within a vacuum of behaviour analytic thinking or research in this field. The paper was meant to be a first step in stimulating others to contribute to the understanding of one of the most complex, yet most universal, human behavioural processes. The only behaviour analyst addressing the issues directly was Calkin (1990). Recently, after reading our original 1994 paper, Beth Sulzer-Azaroff suggested that we should solicit comments directly from the behaviour analytic community. This we did with the help of Erik Arntzen and now the reprint and the commentaries in this edition of the European Journal of Behaviour Analysis (EJBA) fully embrace and extend the contribution of behaviour analysis to the understanding of the behavioural process that is bereavement.

Enhanced inflammatory responses in alpha-tocopherol transfer protein null mice

The liver preferentially secretes alpha-tocopherol into plasma under the control of the hepatic alpha-tocopherol transfer protein (alpha-TTP). alpha-TTP-null mice (Ttpa(-/-) mice) are vitamin E deficient, therefore were used for investigations of in vivo responses to sub-normal tissue alpha-tocopherol concentrations during inflammation. Increased basal oxidative stress in Ttpa(-/-) mice was documented by increased plasma lipid peroxidation, and superoxide production by bone marrow-derived neutrophils stimulated in vitro with phorbol 12-myristate 13-acetate. Lipopolysaccharide (LPS) injected intraperitoneally induced increases in lung and liver HO-1 and iNOS, as well as plasma NO(x) in Ttpa(+/+) mice. LPS induced more modest increases in these markers in Ttpa(-/-) mice, while more marked increases in plasma IL-10 and lung lavage TNF alpha were observed. Taken together, these results demonstrate that alpha-tocopherol is important for proper modulation of inflammatory responses and that sub-optimal alpha-tocopherol concentrations may derange inflammatory-immune responses.

Randomized controlled trial of interferential therapy and manipulative therapy for acute low back pain.

Study Design. A multi-center assessor-blinded randomized clinical trial was conducted. Objectives. To investigate the relative effectiveness of interferential therapy and manipulative therapy for patients with acute low back pain when used as sole treatments and in combination. Summary of Background Data. Both manipulative therapy and interferential therapy are commonly used treatments for low back pain. Evidence for the effectiveness of manipulative therapy is available only for the short term. There is no evidence for interferential therapy and no study has investigated the effectiveness of interferential therapy combined with manipulative therapy. Methods. Consenting subjects (n=240) were randomly assigned to receive a copy of the Back Book and either manipulative therapy (MT; n=80), interferential therapy (IFT; n=80) or combined manipulative therapy and interferential therapy (CT; n=80). Follow-up outcome questionnaires were posted at discharge, 6 and 12 months. Results. The groups were balanced at baseline for low back pain and demographic characteristics. All interventions were found to significantly reduce functional disability and pain and increase quality of life at discharge and to maintain these improvements at 6 and 12 months. No significant differences were found between groups for reported LBP recurrence, work absenteeism, medication consumption, exercise participation and healthcare use at 12 months. Conclusions. For acute low back pain, interferential therapy whether used in isolation or in combination with manipulative therapy was as effective as manipulative therapy alone (in addition to the Back Book).

A descriptive study of the usage of spinal manipulative therapy techniques within a randomised clinical trial in acute low back pain

The majority of randomized clinical trials (RCTs) of spinal manipulative therapy have not adequately de?ned the terms ‘mobilization’ and ‘manipulation’, nor distinguished between these terms in reporting the trial interventions. The purpose of this study was to describe the spinal manipulative therapy techniques utilized within a RCT of manipulative therapy (MT; n=80), interferential therapy (IFT; n=80), and a combination of both (CT; n=80) for people with acute low back pain (LBP). Spinal manipulative therapy was de?ned as any ‘mobilization’ (low velocity manual force without a thrust) or ‘manipulation’ (high velocity
thrust) techniques of the spine described by Maitland and Cyriax.
The 16 physiotherapists, all members of the Society of Orthopaedic Medicine, utilized three spinal manipulative therapy patterns in the RCT: Maitland Mobilization (40.4%, n=59), Maitland Mobilization/Cyriax Manipulation (40.4%, n=59) and Cyriax Manipulation (19.1%, n=28). There was a signi?cant difference between the MT and CT groups in their usage of spinal manipulative therapy techniques (w2=9.178; df=2;P=0.01); subjects randomized to the CT group received three times more Cyriax Manipulation (29.2%, n=21/72) than those randomized to the MT group (9.5%, n=7/74; df=1; P=0.003).
The use of mobilization techniques within the trial was comparable with their usage by the general population of physiotherapists in Britain and Ireland for LBP management. However, the usage of manipulation techniques was considerably higher than reported in physiotherapy surveys and may re?ect the postgraduate training of trial therapists.

Fate of inflammatory neutrophils within the joint

OBJECTIVE: Impaired flow-mediated dilation (FMD) occurs in disease states associated with atherosclerosis, including SLE. The primary hemodynamic determinant of FMD is wall shear stress, which is critically dependent on the forearm microcirculation. We explored the relationship between FMD, diastolic shear stress (DSS), and the forearm microcirculation in 32 patients with SLE and 19 controls. METHODS AND RESULTS: DSS was calculated using (mean diastolic velocity x 8 x blood viscosity)/baseline brachial artery diameter. Doppler velocity envelopes from the first 15 seconds of reactive hyperemia were analyzed for resistive index (RI), and interrogated in the frequency domain to assess forearm microvascular hemodynamics. FMD was significantly impaired in SLE patients (median, 2.4%; range, -2.1% to 10.7% versus median 5.8%; range, 1.9% to 14%; P