Glial Tumor Necrosis Factor Alpha (TNFα) Generates Metaplastic Inhibition of Spinal Learning

Injury-induced overexpression of tumor necrosis factor alpha (TNFα) in the spinal cord can induce chronic neuroinflammation and excitotoxicity that ultimately undermines functional recovery. Here we investigate how TNFα might also act to upset spinal function by modulating spinal plasticity. Using a model of instrumental learning in the injured spinal cord, we have previously shown that peripheral intermittent stimulation can produce a plastic change in spinal plasticity (metaplasticity), resulting in the prolonged inhibition of spinal learning. We hypothesized that spinal metaplasticity may be mediated by TNFα. We found that intermittent stimulation increased protein levels in the spinal cord. Using intrathecal pharmacological manipulations, we showed TNFα to be both necessary and sufficient for the long-term inhibition of a spinal instrumental learning task. These effects were found to be dependent on glial production of TNFα and involved downstream alterations in calcium-permeable AMPA receptors. These findings suggest a crucial role for glial TNFα in undermining spinal learning, and demonstrate the therapeutic potential of inhibiting TNFα activity to rescue and restore adaptive spinal plasticity to the injured spinal cord. TNFα modulation represents a novel therapeutic target for improving rehabilitation after spinal cord injury

The role of flavor and fragrance chemicals in TRPA1 (transient receptor potential cation channel, member A1) activity associated with allergies

TRPA1 has been proposed to be associated with diverse sensory allergic reactions, including thermal (cold) nociception, hearing and allergic inflammatory conditions. Some naturally occurring compounds are known to activate TRPA1 by forming a Michael addition product with a cysteine residue of TRPA1 through covalent protein modification and, in consequence, to cause allergic reactions. The anti-allergic property of TRPA1 agonists may be due to the activation and subsequent desensitization of TRPA1 expressed in sensory neurons. In this review, naturally occurring TRPA1 antagonists, such as camphor, 1,8-cineole, menthol, borneol, fenchyl alcohol and 2-methylisoborneol, and TRPA1 agonists, including thymol, carvacrol, 1’S-1’- acetoxychavicol acetate, cinnamaldehyde, α-n-hexyl cinnamic aldehyde and thymoquinone as well as isothiocyanates and sulfides are discussed

Discordant GH and IGF-1 Results in Treated Acromegaly: Impact of GH Cutoffs and Mean Values Assessment

CONTEXT: Discordant growth hormone (GH) and insulin-like growth factor-1 (IGF-1) values are frequent in acromegaly.OBJECTIVE: To evaluate the impact of different GH cutoffs on discordance rate. To investigate whether the mean of consecutive GH measurements impacts discordance rate when matched to the last available IGF-1 value.DESIGN: Retrospective study.SETTING: Referral center for pituitary diseases.PATIENTS: Ninety acromegaly patients with at least 3 consecutive evaluations for GH and IGF-1 using the same assay in the same laboratory (median follow-up 13 years).INTERVENTIONS: Multimodal treatment of acromegaly.MAIN OUTCOME MEASURES: Single fasting GH (GHf) and IGF-1 (IGF-1f). Mean of 3 GH measurements (GHm), collected during consecutive routine patients' evaluations.RESULTS: At last evaluation GHf values were 1.99 \ub1 2.79 g/L and age-adjusted IGF-1f was 0.86 \ub1 0.44 * upper limit of normality (mean \ub1 SD). The discordance rate using GHf was 52.2% (cutoff 1 g/L) and 35.6% (cutoff 2.5 g/L) (P = 0.025). "High GH" discordance was more common for GHf <1.0 g/L, while "high IGF-1" was predominant for GHf <2.5 g/L (P < 0.0001). Using GHm mitigated the impact of GH cutoffs on discordance (GHm <1.0 g/L: 43.3%; GHm <2.5 g/L: 38.9%; P = 0.265). At receiver-operator characteristic curve (ROC) analysis, both GHf and GHm were poor predictors of IGF-1f normalization (area under the curve [AUC] = 0.611 and AUC = 0.645, respectively). The prevalence of disease-related comorbidities did not significantly differ between controlled, discordant, and active disease patients.DISCUSSION: GH/IGF-1 discordance strongly depends on GH cutoffs. The use of GHm lessen the impact of GH cutoffs. Measurement of fasting GH levels (both GHf and GHm) is a poor predictor of IGF-1f normalization in our cohort