Oral ibuprofen versus oral ketorolac for children with moderate and severe acute traumatic pain: a randomized comparative study.

This study is to compare ibuprofen and ketorolac for children with trauma-related acute pain. We conducted a multicentre randomized, double-blind, controlled trial in the Paediatric Emergency Department setting. We enrolled patients aged 8 to 17 who accessed the emergency department for pain related to a limb trauma that occurred in the previous 48 h. At the admission, patients were classified based on numeric rating scale-11 (NRS-11) in moderate (NRS 4-6) and severe (NRS 7-10) pain groups. Each patient was randomized to receive either ibuprofen (10 mg/kg) or ketorolac (0.5 mg/kg) and the placebo of the not given drug in a double dummies design. NRS-11 was asked every 30 min until 2 h after drug and placebo administration. The primary outcome was NRS-11 reduction at 60 min. Among 125 patients with severe pain, NRS-11 reduction after 60 min from drug administration was 2.0 (IQR 1.0-4.0) for ibuprofen and 1.0 (IQR 1.0-3.0) for ketorolac (p = 0.36). Ibuprofen was significantly better, considering secondary outcomes, at 90 min with a lower median of NRS-11 (p 0.008), more patients with NRS-11 less than 4 (p 0.01) and a reduction of pain score of more than 3 NRS-11 points (p 0.01). Among 87 patients with moderate pain, the NRS-11 reduction after 60 min from drug administration was 1.63 (± 1.8) for ibuprofen and 1.8 (± 1.6) for ketorolac, with no statistically significant difference.Conclusions: Oral ibuprofen and ketorolac are similarly effective in children and adolescents with acute traumatic musculoskeletal pain.Trial registration: ClinicalTrial.gov registration number: NCT04133623.

Deep brain stimulation of the dentato-rubro-thalamic tract in a case of Holmes tremor: a constrained spherical deconvolution (CSD)-guided procedure.

Deep brain stimulation (DBS) is an established treatment for movement disorders, including Holmes tremor (HT). HT is a rest and action tremor that occurs as a late symptom of brainstem lesions such as stroke. Unfortunately, it is frequently refractory to medical treatment, hence DBS surgery may be a good option. Due to variable results, the ideal target for DBS in HT still remains to be established, ranging from the thalamus to the globus pallidus internus, to the subthalamic nucleus. Pre-operative imaging also is very challenging, as the complexity of brain fiber architecture may prevent the correct positioning of the directional lead. Herein, we describe the case of a patient affected by a rubral tremor secondary to a brain hemorrhage, who had advanced pre-operative neuroimaging with constrained spherical deconvolution (CSD)-based tractography obtained from diffusion-weighted imaging (DWI) to identify the dentato-rubro-thalamic tract, involved in the pathophysiology of HT. The patient was then addressed to an awake DBS surgery, and with the help of intraoperative microelectrode recordings, a tailored DRTT-targeted procedure was performed. The stimulation determined an almost complete tremor suppression, with no significant side effects at a follow-up of 6 months, paving the way towards new effective techniques for the planning, i.e., CSD-based tractography and the treatment of refractory tremors.

Modified percutaneous biopsy of the spine: improvement of the technique.

PURPOSE: Biopsy of the spine can be performed by open surgery or percutaneous needle sampling. The first has the highest diagnostic yield while the second is a less invasive procedure with lower rate of complications and shorter hospitalization time. We described a modified technique of percutaneous biopsy using semi-rigid grasping forceps that may offer the advantages of both, open and minimally invasive surgery. METHODS: Thirty consecutive patients with spinal lesions requiring biopsy were admitted to Neurosurgical Unit of Belcolle Hospital (Viterbo, Italy) from January 2017 to September 2021. There was a suspicion of spondylodiscitis in 25 cases and of tumor in 5 cases. Percutanous trans-pedicular spine biopsy has been performed using this new semi-rigid grasping forceps. Combining the opening width, jaw length and full 360° rotation, the device allows a wide and precise sampling. RESULTS: Sampling was sufficient in all cases (100%); tumors was observed in 5 cases (16.7%%) with a percentage of definitive histopathologic diagnosis of 100% (n = 5); among the remaining patients histological examination yielded a diagnosis of spinal infection in 25 cases (100%), and microbiologic culture provided an aetiologic diagnosis in 23 cases (92%). All procedures were well tolerated, and no postoperative complications were observed. Levels involved included: thoracic (T5-T9) in 8 cases, thoracolumbar junction (T10-L2) in 12 cases and lumbar (L3-L5) in 10 cases. CONCLUSIONS: Percutaneous biopsy with the semi-rigid grasping forceps is a safe and effective procedure that can be used for diagnosis of both infectious and tumor lesions of the spine. It allows to obtain a larger specimen volume and to use a multidirectional trajectory for sampling, resulting in a minimally invasive technique with strong ability to yield etiologic diagnosis.

Isolated intracranial myeloid sarcoma: report of a case and review of the literature.

Myeloid sarcoma is a rare malignant tumor of primitive myeloid cell origin often associated with hematologic disorders. The central nervous system is rarely involved and differentiating between myeloid sarcoma and other tumors is not possible on imaging. Here we present the rare case of an isolated intracranial myeloid sarcoma, initially misdiagnosed radiologically as a meningioma, treated with surgical total resection and subsequent chemotherapy, with no signs of any hematological disorder at follow up. Differential diagnosis and management strategies, as well as follow-up implications are discussed along with literature review, which pointed out that only five cases with no further signs of hematological disorders at follow up have been described in the literature so far and this case has the longest follow up of them at 9 years.

Acute Abdominal Pain: Recognition and Management of Constipation in the Emergency Department.

OBJECTIVE: The main aim of the study was to investigate the incidence and the clinically relevant features of functional constipation in patients evaluated for acute abdominal pain in a tertiary care pediatric emergency department. METHODS: This is a retrospective study. We analyzed 4394 medical records and recorded the information (demographics, triage code, symptoms, medical history, physical evaluation, laboratory tests, radiological studies, procedures, and treatments) of all patients admitted for acute abdominal pain to the emergency department of the IRCCS Burlo Garofolo, Trieste, during 2010 to 2013. RESULTS: In this study, a quarter of patients (1020) presenting in the emergency department with acute abdominal pain were affected by functional constipation. Acute pain associated with functional constipation is generally rated from moderate to severe, and the location of the pain on physical evaluation was not a sufficient criterion to guide diagnosis. Isolated vomiting may be present in a minority of cases. Digital rectal exploration was never performed; the majority of patients were treated by means of an enema with prompt relief. Six percent of patients with constipation underwent radiological studies. CONCLUSIONS: This study confirms that the medical history provides a pivotal role in the diagnosis of functional constipation. Digital rectal exploration and x-rays should be avoided in this setting, whereas an enema plays a useful diagnostic and therapeutic role in our study patients.

An induced folding process characterizes the partial-loss of function mutant LptAI36D in its interactions with ligands.

Lipopolysaccharide (LPS) is an essential glycolipid of the outer membrane (OM) of Gram-negative bacteria with a tripartite structure: lipid A, oligosaccharide core and O antigen. Seven essential LPS-transport proteins (LptABCDEFG) move LPS to the cell surface. Lpt proteins are linked by structural homology, featuring a ß-jellyroll domain that mediates protein-protein interactions and LPS binding. Analysis of LptA-LPS interaction by fluorescence spectroscopy is used here to evaluate the contribution of each LPS moiety in protein-ligand interactions, comparing the wild-type (wt) protein to the I36D mutant. In addition to a crucial role of lipid A, an unexpected contribution emerges for the core region in recognition and binding of Lpt proteins.

"Safety and utility of percutaneous liver biopsy in hematopoietic stem cell transplant pediatric recipients: a retrospective study".

BACKGROUND: Liver biopsies in pediatric hematopoietic stem cell transplantation (HSCT) patients are as and effective when performed at bedside in the Bone Marrow Transplant Unit (BMTU) than in the Day Surgery Unit (DSU), with better patient compliance and lower emotional distress for these children. METHODS: The study group consisted of 45 children who underwent allogeneic HSCT. We reviewed 68 liver biopsies performed between April 2006 and September 2015. 12 (17.6 %) biopsies were performed in the DSU and 56 (82.3 %) in the BMTU; nine (13.2 %) prior to HSCT and 59 (86.7 %) after HSCT. Pre-procedural behavioral status (subjective score) was evaluated by pediatric transplant physicians by filling in a questionnaire employing a three-point scale: "calm and cooperative", "agitated and non-cooperative" or "frightened and suffering". Objective score was obtained measuring patient's heart rate before the procedure and comparing it with mean heart rate. RESULTS: Patients who underwent the procedure at the BMTU experienced less emotional distress than those who underwent it in the DSU: 58.3 % of patients treated at the DSU were agitated as compared with 16.1 % of those treated at the BMTU (p < 0.01). Among the 59 biopsies performed after HSCT, 41 (69.5 %) were taken from symptomatic patients for a diagnostic purpose and 18 (30.5 %) in asymptomatic ones in order to rule out hepatic GVHD. Among these 18 procedures, GVHD was diagnosed in 16 (88.9 %) cases. Minor complications occurred in about 17 % of procedures (12 biopsies), at a rate of 25 % for the DSU location compared with 16 % for the BMTU location. Only two major complications were reported, one in the DSU and one in the BMTU. CONCLUSION: Liver biopsy performed at bedside in HSCT patients does not carry a higher risk of adverse events than the same procedure performed in the DSU and has lower emotional distress associated with better patient compliance, thus contributing significantly to a higher standard of care.

Ankylosis of the wrist bones in patients with rheumatoid arthritis: a study with extremity-dedicated MRI.

OBJECTIVES: Ankylosis, or spontaneous bone fusion, of the small joints of the hand is a rare event in patients with rheumatoid arthritis (RA), being observed in 0.8% of them on conventional radiographs. It is associated with long-lasting and severe disease. In other settings, such as fracture healing, bone fusion is a reparative process. The aim of this paper is the study of the frequency of wrist ankylosis in patients with RA in comparison with other arthritides; to correlate ankylosis with disease activity. METHODS: A total of 94 patients affected by RA, 71 patients with different rheumatic conditions and 42 controls with no joint disease or with slight hand osteoarthritis were studied. DAS-28 CRP was calculated in patients with RA and psoriatic arthritis. MRI of the clinically most involved wrist was performed with a 0.2 T, extremity-dedicated MRI system. RESULTS: Of RA patients, 10/94 (10.6%) showed ankylosis in comparison with 2/113 (1.8%) controls (p=0.015). RA patients with ankylosis had longer disease duration (p=0.019) but similar disease activity. CONCLUSIONS: MRI-defined bone ankylosis is frequent in RA. It is not limited to seronegative spondyloarthritides and may be part of the bone damage observed in RA.

Stimulus dependence of local field potential spectra: experiment versus theory.

The local field potential (LFP) captures different neural processes, including integrative synaptic dynamics that cannot be observed by measuring only the spiking activity of small populations. Therefore, investigating how LFP power is modulated by external stimuli can offer important insights into sensory neural representations. However, gaining such insight requires developing data-driven computational models that can identify and disambiguate the neural contributions to the LFP. Here, we investigated how networks of excitatory and inhibitory integrate-and-fire neurons responding to time-dependent inputs can be used to interpret sensory modulations of LFP spectra. We computed analytically from such models the LFP spectra and the information that they convey about input and used these analytical expressions to fit the model to LFPs recorded in V1 of anesthetized macaques (Macaca mulatta) during the presentation of color movies. Our expressions explain 60%-98% of the variance of the LFP spectrum shape and its dependency upon movie scenes and we achieved this with realistic values for the best-fit parameters. In particular, synaptic best-fit parameters were compatible with experimental measurements and the predictions of firing rates, based only on the fit of LFP data, correlated with the multiunit spike rate recorded from the same location. Moreover, the parameters characterizing the input to the network across different movie scenes correlated with cross-scene changes of several image features. Our findings suggest that analytical descriptions of spiking neuron networks may become a crucial tool for the interpretation of field recordings.

T helper 9 cells induced by plasmacytoid dendritic cells regulate interleukin-17 in multiple sclerosis.

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by persistent inflammation orchestrated by cluster of differentiation (CD) 4 T helper (Th) cells. In particular, Th1 and Th17 cells amplify, whereas T regulatory (Treg) cells moderate inflammation. The role of other Th subsets in MS is not clear. In the present study, we investigated the generation of different Th responses by human dendritic cells (DCs) in MS. We compared the production of several Th cytokines by naive CD4+ T-cells polarized with myeloid and plasmacytoid DCs (mDCs and pDCs) in healthy donors (HD) and relapsing-remitting (RR)-MS patients. We found that resiquimod-stimulated mDCs were able to activate Th17 differentiation, whereas pDCs induced interleukin (IL)-10-producing Th cells. Surprisingly, resiquimod-stimulated pDCs from MS patients also significantly induced the differentiation of Th9 cells, which produce IL-9 and are known to be involved in allergic diseases. We investigated the potential role of IL-9 in MS. We found that IL-9 activated signal transducer and activator of transcription (STAT) 1 and STAT5 phosphorylation and interfered with IL-17 and interferon (IFN) regulatory transcription factor (IRF)-4 expression in Th17-polarized cells. Moreover, in the cerebrospinal fluid (CSF) of 107 RR-MS patients, IL-9 inversely correlated with indexes of inflammatory activity, neurodegeneration and disability progression of MS. High levels of IL-9 were associated with the absence of IL-17 in the CSF of RR-MS patients. Our results demonstrate a Th9-inducing potential of pDCs in MS, suggesting an immunoregulatory role leading to attenuation of the exaggerated Th17 inflammatory response.

Imaging Techniques in Psoriatic Arthritis: Update 2012-2014 on Current Status and Future Prospects.

By providing additional and more sensitive information over clinical examination, imaging techniques are useful in the assessment of patients with psoriatic arthritis (PsA) and have been increasingly used to obtain additional clues to its pathogenesis. This review describes the current status and future development of conventional radiography, computed tomography, magnetic resonance imaging, positron emission tomography, and other novel techniques in the evaluation of PsA, with a focus on their use in diagnosing, monitoring, and predicting disease course and followup treatment response. The role and applications of ultrasonography are outside the scope and are reviewed elsewhere in these proceedings.

Synaptic plasticity and PDGF signaling defects underlie clinical progression in multiple sclerosis.

Neuroplasticity is essential to prevent clinical worsening despite continuing neuronal loss in several brain diseases, including multiple sclerosis (MS). The precise nature of the adaptation mechanisms taking place in MS brains, ensuring protection from disability appearance and accumulation, is however unknown. Here, we explored the hypothesis that long-term synaptic potentiation (LTP), potentially able to minimize the effects of neuronal loss by providing extra excitation of denervated neurons, is the most relevant form of adaptive plasticity in stable MS patients, and it is disrupted in progressing MS patients. We found that LTP, explored by means of transcranial magnetic theta burst stimulation over the primary motor cortex, was still possible, and even favored, in stable relapsing-remitting (RR-MS) patients, whereas it was absent in individuals with primary progressive MS (PP-MS). We also provided evidence that platelet-derived growth factor (PDGF) plays a substantial role in favoring both LTP and brain reserve in MS patients, as this molecule: (1) was reduced in the CSF of PP-MS patients, (2) enhanced LTP emergence in hippocampal mouse brain slices, (3) was associated with more pronounced LTP in RR-MS patients, and (4) was associated with the clinical compensation of new brain lesion formation in RR-MS. Our results show that brain plasticity reserve, in the form of LTP, is crucial to contrast clinical deterioration in MS. Enhancing PDGF signaling might represent a valuable treatment option to maintain brain reserve and to attenuate the clinical consequences of neuronal damage in the progressive phases of MS and in other neurodegenerative disorders.

Tumor necrosis factor is elevated in progressive multiple sclerosis and causes excitotoxic neurodegeneration.

BACKGROUND: Chronic inflammation leads to gray matter damage in progressive multiple sclerosis (MS), but the mechanism linking inflammation and neurodegeneration is unclear. OBJECTIVE: The objective of this paper is to investigate the synaptic mechanism of inflammatory neurodegeneration in progressive forms of MS. METHODS: Cytokine and neurofilament-light were determined in cerebrospinal fluid (CSF) of MS patients. In vitro electrophysiology and cell swelling experiments were performed to measure the effects of inflammatory cytokines in the CSF of MS patients on synaptic transmission and neuronal integrity. RESULTS: Tumor necrosis factor-α (TNF) was higher in CSF of progressive MS subjects, and caused excitotoxic neuronal death in vitro. In murine brain slices incubated in the presence of CSF from progressive MS, in fact, we observed increased spontaneous excitatory postsynaptic currents (sEPSCs) and glutamate-mediated neuronal swelling through a mechanism dependent on enhanced TNF signaling. We also suggested a pathogenic role of B cells in TNF CSF increase, exacerbation of glutamatergic transmission and neuronal damage, since CNS depletion of B cells with intrathecal rituximab caused a dramatic reduction of TNF levels, of TNF-induced sEPSC alterations, and of neurofilament CSF concentrations in a patient with progressive MS. CONCLUSION: Our results point to TNF as a primary neurotoxic molecule in progressive forms of MS.

Ultrasound versus low-field magnetic resonance imaging in rheumatic diseases: a systematic literature review.

OBJECTIVES: US and MRI play a significant role in the diagnosis of rheumatic diseases and in monitoring treatment response. This systematic review summarises and evaluates available evidence on the value of low-field MRI compared to US in rheumatic diseases. METHODS: A computerised literature search was conducted by a single reviewer to identify relevant published articles on the diagnostic accuracy of low-field MRI compared to US in rheumatic diseases. The literature search comprised the period from January 1998 to September 2013. RESULTS: The search yielded a total of 1055 articles that were reviewed by title or abstract; finally, 23 articles fulfilling all inclusion criteria were included in the analysis. Our results show that low-field MRI is probably more sensitive than US in the detection of erosions, due to its higher multiplanar capacity. In OA there was a good correlation between US and MRI measurements for cartilage thickness and for effusion in the superior and in the lateral recesses. CONCLUSIONS: There are still few studies comparing US and low-field MRI for their diagnostic and prognostic value in rheumatology and it is currently difficult to draw any firm conclusions on the preferred imaging technique to answer specific clinical questions.

Dynamic contrast-enhanced, extremity-dedicated MRI identifies synovitis changes in the follow-up of rheumatoid arthritis patients treated with rituximab.

OBJECTIVES: The aim of this study is to assess prospectively the effect of rituximab (RTX) on MRI features of wrist joint disease in patients affected by rheumatoid arthritis (RA). METHODS: Ten patients (6F/4M, mean age 52.9±15.5 years) diagnosed with IgM rheumatoid factor, anti-CCP positive, RA according to the 1987 ACR criteria were treated with a single course of RTX (2 infusions of 1000 mg, 15 days apart). MRI of the dominant hand was performed with a 0.2T extremity-dedicated machine using pre and post contrast T1 weighted SE, turbo 3D, and STIR sequences at baseline, and after 4 and 24 weeks. MRI was analysed using the OMERACT-RAMRIS score and the dynamic contrast-enhanced (DCE-MRI) technique for wrist synovitis, which calculates the enhancement ratio as both rate of early enhancement (REE) and relative enhancement (RE). The corresponding ME and IRE parameters were calculated also through a computer-aided semi-automated method on the mean of three MRI slices and on a small ROI positioned in the area of maximum enhancement. RESULTS: DAS significantly decreased during the study period (ANOVA for repeated measures, p=0.005). The RAMRIS score did not change along the study, whereas the dynamic MRI values RE, IRE and ME on the small ROI significantly decreased. RE, but not the RAMRIS synovitis score, significantly correlated with DAS at baseline, 1 and 6 months (p=0.005, 0.04, and 0.0007, respectively). CONCLUSIONS: RTX confirmed good clinical efficacy, which was paralleled by a significant decrease in dynamic MRI results for wrist synovitis. On the contrary, the traditional RAMRIS measures did not change.

Hemophagocytic lymphohistiocytosis in total parenteral nutrition dependent children: description of 5 cases and practical tips for management.

Although total parenteral nutrition (TPN) is mandatory in children with intestinal failure, this treatment is not risk free. The main complications of TPN include catheter-related sepsis, thrombosis, hepatic cholestasis and cirrhosis, metabolic bone disease, and, rarely, reactive hemophagocytic lymphohistiocytosis (HLH). The pathogenesis of HLH in patients with TPN is not known, although some authors hypothesized that it can result from the activation of macrophages because of "fat overload." We reported 5 cases of HLH that occurred in patients with 4 different underlying disorders, all requiring TPN for a long term. In our series, an underlying immunological defect or a serious infection (sepsis) can have triggered HLH. Therefore, it could be reasonable to hypothesize that besides TPN in itself, minor immune defects and infections may act together by overcoming a threshold of immune stimulation, which ultimately leads to HLH.

Current Evidence for a New Surgical Technique for Scleral Fixation: The Implantation of a Carlevale Lens, a Systematic Review.

Background: The Carlevale lens (FIL SSF, Soleko IOL Division, Italy) is a new lens for suture-less scleral fixation. This paper aimed to systematically review articles on this lens, the surgical techniques used for its implantation, complications and outcomes. Methods: This systematic review was performed following the PRISMA guidelines. The search string used was "Carlevale" AND "scleral fixation" from inception until March 2024. For completeness, either case-control studies, case reports or case series written in English were included. The authors used the Newcastle-Ottawa scale for the case-control studies and the JBI Critical Appraisal Checklist for case reports and case series. Results: Twenty-nine articles were included. Scleral fixation with Carlevale lens can be performed by creating scleral flaps or, alternatively, by using scleral pockets. The two sclerotomies must be diametrically opposed, and are preferably created by 25-gauge trocars. A pars plana vitrectomy should be performed every time, and the design of the lens should be suitable for self-anchoring to the sclera; the most accredited strategy to achieve this is to avoid scleral sutures. There were only a few intraoperative and postoperative complications reported; vitreous hemorrhages were the most frequent intraoperative events, while the most relevant postoperative complications were vitreous hemorrhages, cystoid macular oedema and transient variations in the intraocular pressure. Excellent results have been obtained in terms of BCVA, IOL centration and stability, mean intraocular pressure, postoperative spherical equivalent, separation between anterior and posterior chamber and the distance of the IOL from anterior chamber structures. Conclusions: The foldable hydrophilic design of the Carlevale lens has shown good effectiveness, IOL stability and few intra and post-operative complications.

Benzofuran-2-Carboxamide Derivatives as Immunomodulatory Agents Blocking the CCL20-Induced Chemotaxis and Colon Cancer Growth.

The correlation between the CCL20/CCR6 axis and autoimmune and non-autoimmune disorders is widely recognized. Inhibition of the CCL20-dependent cell migration represents therefore a promising approach for the treatment of many diseases, such as inflammatory bowel diseases and colorectal cancer. We report herein our efforts to explore the biologically relevant chemical space around the benzofuran scaffold of MR120, a modulator of the CCL20/CCR6 axis previously discovered by our group. A functional screening allowed us to identify C4 and C5-substituted derivatives as the most effective inhibitors of the CCL20-induced chemotaxis of human peripheral blood mononuclear cells (PBMC). Moreover, selected compounds (16 e and 24 b) also proved to potently inhibit the growth of different colon cancer cell lines, with cytotoxic/cytostatic and antiproliferative activity.

4-Trifluoromethyl bithiazoles as broad-spectrum antimicrobial agents for virus-related bacterial infections or co-infections.

Respiratory tract infections involving a variety of microorganisms such as viruses, bacteria, and fungi are a prominent cause of morbidity and mortality globally, exacerbating various pre-existing respiratory and non-respiratory conditions. Moreover, the ability of bacteria and viruses to coexist might impact the development and severity of lung infections, promoting bacterial colonization and subsequent disease exacerbation. Secondary bacterial infections following viral infections represent a complex challenge to be overcome from a therapeutic point of view. We report herein our efforts in the development of new bithiazole derivatives showing broad-spectrum antimicrobial activity against both viruses and bacteria. A series of 4-trifluoromethyl bithiazole analogues was synthesized and screened against selected viruses (hRVA16, EVD68, and ZIKV) and a panel of Gram-positive and Gram-negative bacteria. Among them, two promising broad-spectrum antimicrobial compounds (8a and 8j) have been identified: both compounds showed low micromolar activity against all tested viruses, 8a showed synergistic activity against E. coli and A. baumannii in the presence of a subinhibitory concentration of colistin, while 8j showed a broader spectrum of activity against Gram-positive and Gram-negative bacteria. Activity against antibiotic-resistant clinical isolates is also reported. Given the ever-increasing need to adequately address viral and bacterial infections or co-infections, this study paves the way for the development of new agents with broad antimicrobial properties and synergistic activity with common antivirals and antibacterials.

Interleukin-1ß causes anxiety by interacting with the endocannabinoid system.

Interleukin-1ß (IL-1ß) is involved in mood alterations associated with inflammatory illnesses and with stress. The synaptic basis of IL-1ß-induced emotional disturbances is still unknown. To address the possible involvement of the endocannabinoid system in IL-1ß-induced anxiety, we performed behavioral and neurophysiological studies in mice exposed to stress or to intracerebroventricular injections of this inflammatory cytokine or of its antagonist. We found that a single intracerebroventricular injection of IL-1ß caused anxiety in mice, and abrogated the sensitivity of cannabinoid CB1 receptors (CB1Rs) controlling GABA synapses in the striatum. Identical behavioral and synaptic results were obtained following social defeat stress, and intracerebroventricular injection of IL-1 receptor antagonist reverted both effects. IL-1ß-mediated inhibition of CB1R function was secondary to altered cholesterol composition within membrane lipid rafts, and required intact function of the transient receptor potential vanilloid 1 (TRPV1) channel, another element of the endocannabinoid system. Membrane lipid raft disruption and inhibition of cholesterol synthesis, in fact, abrogated IL-1ß-CB1R coupling, and TRPV1-/- mice were indeed insensitive to the synaptic and behavioral effects of both IL-1ß and stress. On the other hand, cholesterol enrichment of striatal slices mimicked the synaptic effects of IL-1ß on CB1Rs only in control mice, while the same treatment was ineffective in slices prepared from TRPV1-/- mice. The present investigation identifies a previously unrecognized interaction between a major proinflammatory cytokine and the endocannabinoid system in the pathophysiology of anxiety.