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A significant proportion of patients with short-lasting unilateral neuralgiform headache attacks (SUNHA) are refractory to medical treatments. Neuroimaging studies have suggested a role for ipsilateral trigeminal neurovascular conflict with morphological changes in the pathophysiology of this disorder. We present the outcome of an uncontrolled open-label prospective single centre study conducted between 2012 and 2020, to evaluate the efficacy and safety of trigeminal microvascular decompression in refractory chronic SUNHA with magnetic resonance imaging evidence of trigeminal neurovascular conflict ipsilateral to the pain side. Primary endpoint was the proportion of patients who achieved an "excellent response", defined as 90-100% weekly reduction in attack frequency, or "good response", defined as a reduction in weekly headache attack frequency between 75% and 89% at final follow-up, compared to baseline. These patients were defined as responders. The study group consisted of 47 patients of whom 31 had SUNCT and 16 had SUNA (25 females, mean age ± SD 55.2 years ± 14.8). Participants failed to respond or tolerate a mean of 8.1 (±2.7) preventive treatments pre-surgery. Magnetic resonance imaging of the trigeminal nerves (n = 47 patients, n = 50 symptomatic trigeminal nerves) demonstrated ipsilateral neurovascular conflict with morphological changes in 39/50 (78.0%) symptomatic nerves and without morphological changes in 11/50 (22.0%) symptomatic nerves. Post-operatively, 37/47 (78.7%) patients obtained either an excellent or a good response. Ten patients (21.3%, SUNCT = 7 and SUNA = 3) reported no post-operative improvement. The mean post-surgery follow-up was 57.4 ± 24.3 months (range 11-96 months). At final follow-up, 31 patients (66.0%) were excellent/good responders. Six patients experienced a recurrence of headache symptoms. There was no statistically significant difference between SUNCT and SUNA in the response to surgery (p = 0.463). Responders at the last follow-up were however more likely not to have interictal pain (77.42% vs 22.58%, p = 0.021) and to show morphological changes on the magnetic resonance imaging (78.38% vs 21.62%, p = 0.001). The latter outcome was confirmed in the Kaplan Meyer analysis, where patients with no morphological changes were more likely to relapse overtime compared to those with morphological changes (p = 0.0001). All but one patient who obtained an excellent response without relapse, discontinued their preventive medications. Twenty-two post-surgery adverse events occurred in 18 patients (46.8%) but no mortality or severe neurological deficit was seen. Trigeminal microvascular decompression may be a safe and effective long-term treatment for short-lasting unilateral neuralgiform headache attacks patients with magnetic resonance evidence of neurovascular conflict with morphological changes.
Learn More >The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn, direct investigations using rodent and human preclinical pain models have been lacking. Here, we discovered that in the Freund's adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal horn neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in superficial dorsal horn neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDAR potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females. This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.
Learn More >Epidermal growth factors (EGF) play a wide range of roles in embryogenesis, skin development, immune response homeostasis. They are involved in several pathologies as well, including several cancer types, psoriasis, chronic pain and chronic kidney disease. All members share the structural EGF domain, which is responsible for receptor interaction, thereby initiating transduction of signals. EGF growth factors have intense use in fundamental research and high potential for biotechnological applications. However, due to their structural organization with three disulfide bonds, recombinant production of these factors in prokaryotic systems is not straightforward. A significant fraction usually forms inclusion bodies. For the fraction remaining soluble, misfolding and incomplete disulfide bond formation may affect the amount of active factor in solution, which can compromise experimental conclusions and biotechnological applications. In this work, we describe a reliable procedure to produce seven human growth factors of the EGF family in Escherichia coli. Biophysical and stability analyses using limited proteolysis, light scattering, circular dichroism and nanoDSF show that the recombinant factors present folded and stable conformation. Cell proliferation and scratch healing assays confirmed that the recombinant factors are highly active at concentrations as low as 5 ng/ml.
Learn More >The ion channel TRPA1 is a promiscuous chemosensor, with reported response to a wide spectrum of noxious electrophilic irritants, as well as cold, heat, and mechanosensation. It is also implicated in the inception of itch and pain and has hence been investigated as a drug target for novel analgesics. The mechanism of electrophilic activation for TRPA1 is therefore of broad interest. TRPA1 structures with the pore in both open and closed states have recently been published as well as covalent binding modes for electrophile agonists. However, the detailed mechanism of coupling between electrophile binding sites and the pore remains speculative. In addition, while two different cysteine residues (C621 and C665) have been identified as critical for electrophile bonding and activation, the bound geometry has only been resolved at C621. Here, we use molecular dynamics simulations of TRPA1 in both pore-open and pore-closed states to explore the allosteric link between the electrophile binding sites and pore stability. Our simulations reveal that an open pore is structurally stable in the presence of open 'pockets' in the C621/C665 region, but rapidly collapses and closes when these pockets are shut. Binding of electrophiles at either C621 or C665 provides stabilisation of the pore-open state, but molecules bound at C665 are shown to be able to rotate in and out of the pocket, allowing for immediate stabilisation of transient open states. Finally, mutual information analysis of trajectories reveals an informational path linking the electrophile binding site pocket to the pore via the voltage-sensing-like domain, giving a detailed insight into the how the pore is stabilized in the open state.
Learn More >Dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL) are techniques used to evaluate brain perfusion using MRI. DSC requires dynamic image acquisition with a rapid administration of gadolinium-based contrast agent. In contrast, ASL obtains brain perfusion information using magnetically labeled blood water as an endogenous tracer. For the evaluation of brain perfusion in pediatric neurological diseases, ASL has a significant advantage compared to DSC, CT, and single-photon emission CT/positron emission tomography because of the lack of radiation exposure and contrast agent administration. However, in ASL, optimization of several parameters, including the type of labeling, image acquisition, background suppression, and postlabeling delay, is required, because they have a significant effect on the quantification of cerebral blood flow (CBF).In this article, we first review recent technical developments of ASL and age-dependent physiological characteristics in pediatric brain perfusion. We then review the clinical implementation of ASL in pediatric neurological diseases, including vascular diseases, brain tumors, acute encephalopathy with biphasic seizure and late reduced diffusion (AESD), and migraine. In moyamoya disease, ASL can be used for brain perfusion and vessel assessment in pre- and post-treatment. In arteriovenous malformations, ASL is sensitive to detect small degrees of shunt. Furthermore, in vascular diseases, the implementation of ASL-based time-resolved MR angiography is described. In neoplasms, ASL-derived CBF has a high diagnostic accuracy for differentiation between low- and high-grade pediatric brain tumors. In AESD and migraine, ASL may allow for accurate early diagnosis and provide pathophysiological information.
Learn More >This study was performed amongst trigeminal neuralgia (TN) patients with neurovascular contact (NVC) to 1) investigate the association of the demographic and radiologic factors/variables with TN occurrence, and 2) develop a screening tool for TN/TN-affected nerves based on the factors/variables associated with it.
Learn More >Response to analgesic therapy is influenced by several factors including genetics and drug-drug interactions. Pharmacogenetic (PGx) variants in the CYP2D6 gene modify response to opioids by altering drug metabolism. We sought to determine the potential impact of PGx testing on the care of Veterans with noncancer pain prescribed opioids metabolized by CYP2D6 (codeine, hydrocodone, or tramadol). A retrospective analysis was performed within the Veterans Health Administration (VHA) evaluating prescription records for pain medications metabolized by CYP2D6 and interacting drugs from 2012-2017. Among 2,436,654 VHA pharmacy users with at least one opioid prescription, 34% met the definition of chronic use (longer than 90 days with more than 10 prescriptions or 120 days- supply). Opioids were commonly co-prescribed with antidepressants interacting with CYP2D6 (28%). An estimated 21.6% (n=526,905) of these patients are at elevated risk of an undesirable response to their opioid medication based on predicted phenotypes and drug-drug interactions: 3.5% are predicted CYP2D6 ultrarapid metabolizers and at increased risk for toxicity, 5.4% are poor metabolizer at higher risk for nonresponse, and 12.8% are normal or intermediate metabolizers co-prescribed a CYP2D6 inhibitor leading to phenoconversion into poor metabolizer. Despite the high rate of co-prescription of opioids and interacting drugs, CYP2D6 testing was infrequent in the sample (0.02%) and chart review suggest that test results were used to optimize antidepressant treatments rather than pain medications. Using pharmacogenetic testing combined with consideration of phenoconversion may allow for an enhanced precision medicine approach to pain management in Veterans.
Learn More >Persistent postsurgical neuropathic pain (PPSNP) can occur after intraoperative damage to somatosensory nerves, with a prevalence of 29-57% in breast cancer surgery. Proteomics is an active research field in neuropathic pain and the first results support its utility for establishing diagnoses or finding therapy strategies.
Learn More >Nociceptin and the nociceptin receptor (NOP) have been described as targets for treatment of pain and inflammation, whereas toll-like receptors (TLRs) play key roles in inflammation and impact opioid receptors and endogenous opioids expression. In this study, interactions between the nociceptin and TLR systems were investigated. Human THP-1 cells were cultured with or without phorbol myristate acetate (PMA 5 ng/mL), agonists specific for TLR2 (lipoteichoic acid, LTA 10 µg/mL), TLR4 (lipopolysaccharide, LPS 100 ng/mL), TLR7 (imiquimod, IMQ 10 µg/mL), TLR9 (oligonucleotide (ODN) 2216 1 µM), PMA+TLR agonists, or nociceptin (0.01-100 nM). Prepronociceptin (), , and mRNAs were quantified by RT-qPCR. Proteins were measured using flow cytometry. PMA upregulated mRNA, intracellular nociceptin, and cell membrane NOP proteins (all < 0.05). LTA and LPS prevented PMA's upregulating effects on mRNA and nociceptin protein (both < 0.05). IMQ and ODN 2216 attenuated PMA's effects on mRNA. PMA, LPS, IMQ, and ODN 2216 increased NOP protein levels (all < 0.05). PMA+TLR agonists had no effects on NOP compared to PMA controls. Nociceptin dose-dependently suppressed TLR2, TLR4, TLR7, and TLR9 proteins (all < 0.01). Antagonistic effects observed between the nociceptin and TLR systems suggest that the nociceptin system plays an anti-inflammatory role in monocytes under inflammatory conditions.
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