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Domestic abuse is a global public health issue. The association between the development of central sensitivity syndromes (CSS) and previous exposure to domestic abuse has been poorly understood particularly within European populations.
Learn More >Migraine pathophysiology has been suggested to include dysregulation of the endocannabinoid system (ES). We simultaneously evaluated plasma anandamide (AEA) and palmitoylethanolamide (PEA) levels and spinal sensitization in a validated human model of migraine based on systemic nitroglycerin (NTG) administration.Twenty-four subjects with episodic migraine (MIG) and 19 healthy controls (HC) underwent blood sampling and investigation of nociceptive withdrawal reflex thresholds (RTh: single-stimulus threshold; TST: temporal summation threshold) before and 30 (T30), 60 (T60) and 120 (T120) minutes after sublingual NTG administration (0.9 mg).At baseline, the MIG and HC groups were comparable for plasma AEA (p=0.822) and PEA (p=0.182) levels, and for RTh (p=0.142) and TST values (p=0.150). AEA levels increased after NTG administration (p=0.022) in both groups, without differences between them (p=0.779). By contrast, after NTG administration, PEA levels increased in the MIG group at T120 (p=0.004), while remaining stable in the HC group.NTG administration induced central sensitization in the MIG group, which was recorded as reductions in RTh (p=0.046) at T30 and T120, and in TST (p=0.001) at all time points. In the HC group we observed increases in RTh (p=0.001) and TST (p=0.008), which suggests the occurrence of habituation. We found no significant correlations between the ES and neurophysiological parameters.Our findings suggest a role for PEA in the ictal phase of episodic migraine. The ES does not seem to be directly involved in the modulation of NTG-induced central sensitization, which suggests that the observed PEA increase and spinal sensitization are parallel, probably unrelated, phenomena.
Learn More >CACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming Caα subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.
Learn More >Chronic pruritus of unknown origin (CPUO) is a highly debilitating disease that lacks effective treatments. This study explores a new therapeutic strategy with dupilumab.
Learn More >Chronic pruritus of unknown origin (CPUO) is described as chronic itch lasting longer than 6 weeks in the absence of a defined skin rash and any known causative disease process. A retrospective study was performed on biopsy samples from patients with CPUO and normal controls to compare the immune profiles of these patients with healthy individuals. We used dual CD3/T-bet and CD3/GATA3 immunohistochemical staining to assess for T-cells expressing Th1 versus Th2 transcription factors, respectively. Our data showed that CD3+ cells of patients with CPUO co-express significantly more GATA3 compared with normal controls. Meanwhile, the normal control skin showed a much more balanced T-bet/GATA3 ratio of co-expression. Our data suggest an enrichment of Th2 cells in CPUO skin by T cell/GATA3 co-staining, supporting that CPUO is increasingly considered a type 2/Th2 cell-associated disease. We thus speculate that type 2 cytokine blockade-based therapies may represent effective treatments for CPUO.
Learn More >Peripheral sensory neurons are characterized by their size, molecular profiles, and physiological responses to specific stimuli. In mouse, the peptidergic and non-peptidergic subsets of nociceptors are distinct and innervate different lamina of the spinal dorsal horn. The unique molecular signature and neuroanatomical organization of these neurons supports a labeled line theory for certain types of nociceptive stimuli. However, long standing evidence supports the polymodal nature of nociceptors in many species. We have recently shown that the peptidergic marker, CGRP, and the non-peptidergic marker, P2X3R, show largely overlapping expression at the mRNA level in human dorsal root ganglion (DRG). Herein, our aim was to assess the protein distribution of nociceptor markers, including their central projections, in the human DRG and spinal cord. Using DRGs obtained from organ donors, we observed that CGRP and P2X3R were co-expressed by approximately 33% of human DRG neurons and TrpV1 was expressed in ~60% of human DRG neurons. In the dorsal spinal cord, CGRP, P2X3R, TrpV1 and Nav1.7 protein stained the entirety of lamina 1-2, with only P2XR3 showing a gradient of expression. This was confirmed by measuring the size of the substantia gelatinosa using Hematoxylin and Eosin staining of adjacent sections. Our findings are consistent with the known polymodal nature of most primate nociceptors and indicate that the central projection patterns of nociceptors are different between mice and humans. Elucidating how human nociceptors connect to subsets of dorsal horn neurons will be important for understanding the physiological consequences of these species differences. This article is protected by copyright. All rights reserved.
Learn More >Galcanezumab, a humanized monoclonal antibody that binds calcitonin gene-related peptide, has demonstrated a significant reduction in monthly migraine headache days compared with placebo. Here, we analyze data from 3 randomized clinical trials (2 episodic trials [EVOLVE-1, EVOLVE-2] and 1 chronic trial [REGAIN]), to examine if galcanezumab also alleviates the severity and symptoms of migraine.
Learn More >Little is known about the measurement properties of numeric rating scales (NRS) for pain in AD. We evaluated a novel NRS for skin-pain and existing NRS for average overall-pain in adults with AD. Self-administered questionnaires and skin-examination were performed in 463 AD patients (age 18-97 years) in a dermatology practice setting. Numeric rating scales skin-pain and average overall-pain had moderate correlations with each other, and multiple clinician-reported and patient-reported AD severity outcomes (Spearman correlations, P < 0.0001). There were significant and stepwise increases of NRS skin-pain and average overall-pain scores with patient-reported global severity (Wilcoxon rank-sum test, P < 0.0001). Floor-effects were observed for NRS skin-pain and average overall-pain. Changes from baseline in NRS skin-pain and average overall-pain showed weak-moderate correlations with changes of POEM, vIGA-AD*BSA, SCORAD, and DLQI. Using an anchoring approach, the optimal interpretability band for NRS skin-pain was clear = 0, mild = 1-3, moderate = 5-6, severe = 7-9, and very severe = 10 (weighted kappa = 0.4923). The thresholds for minimally clinically important difference for NRS skin-pain ranged from 2.2 to 2.9. NRS skin-pain and average overall-pain showed moderate-good reliability. Numeric rating scales skin-pain and average overall-pain had sufficient validity, reliability, responsiveness, and interpretability in adults with AD, and were inherently feasible as single-items for use in clinical trials and practice.
Learn More >Biopsychosocial, integrated pain care models are increasingly implemented in the Veterans Health Administration to improve chronic pain care and reduce opioid-related risks, but little is known about how well these models address women veterans' needs.
Learn More >To assess the real-world efficacy, tolerability, and safety of ubrogepant in a tertiary headache center.
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