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Costello syndrome (CS) is a rare genetic syndrome affecting multiple organs, generally caused by mutations of theHRASgene, belonging to theRAS/MAPKgenes family.A male patient with CS developed a painful pulsatile mass on the lateral side of the wrist. An initial ultrasonographic investigation confirmed the presence of a radial artery lesion, possibly an arterial aneurysm. On surgical resection, histological evaluation showed a tangle of vascular structures with variable calibre and abnormal wall histology. Immunohistochemical stainings revealed a very poor endothelial contribution to the central vascular wall structure. These histological observations led us to conclude we had managed an acute vascular malformation (VM) rupture, rather than a common arterial aneurysmal condition. Considering the molecular mechanisms regulated byRAS/MAPKgenes, CS patients might have a higher risk of developing VMs and, in the presence of a pulsatile mass with acute onset, VM rupture should be considered.

Objectives. We adopted the near-infrared spectroscopy (NIRS) technology to monitor the spinal oxygen supply through the paraspinous muscles oxygenation in agreement with the concept of “collateral network” circulation. We retrospectively investigated our database of subjects who underwent thoraco-abdominal aorta open repair assessing for the reliability of this monitoring to predict spinal cord injury. Methods. Consecutive patients who underwent elective thoraco-abdominal aorta open repair between March 2019 and September 2021. In addition to standard monitoring, patients received the monitoring of the paraspinous muscles oxygenation by NIRS. Results. In one patient a significant drop of the mean arterial pressure (49 mmHg) and the spinal-cord perfusion pressure (31 mmHg) occurred after the aortic clamping, with a contemporary lowering of the left-side oxygenation of paraspinous muscles (

Purpose: Compare ibuprofen and ketorolac for children with trauma-related acute pain. Methods: 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 hours. 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 minutes until 2 hours after drug and placebo administration. The primary outcome was NRS-11 reduction at 60 minutes. Results: Among 125 patients with severe pain, NRS-11 reduction after 60 minutes 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 minutes 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 minutes 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. ClinicalTrial.gov registration number: NCT04133623

Cystic fibrosis (CF) is a genetic disease caused by loss-of-function mutations in the CFTR gene, which codes for a defective ion channel. This causes an electrolyte imbalance and results in a spiral of negative effects on multiple organs, most notably the accumulation of thick mucus in the lungs, chronic respiratory tract infections and inflammation leading to pulmonary exacerbation and premature death. Progressive decline of lung function is mainly linked to persistent or recurring infections, mostly caused by bacteria, which require treatments with antibiotics and represent one of the major life-limiting factors in subjects with CF. Treatment of such a complex disease require multiple drugs with a consequent therapeutic burden and complications caused by drug-drug interactions and rapid emergence of bacterial drug resistance. We report herein our recent efforts in developing innovative multifunctional antibiotics specifically tailored to CF by a direct action on bacterial topoisomerases and a potential indirect effect on the pulmonary mucociliary clearance mediated by ΔF508-CFTR correction. The obtained results may pave the way for the development of a simplified therapeutic approach with a single agent acting as multifunctional Antibacterial-Corrector.

Objective To characterize patients with acute ischemic stroke related to SARS-CoV-2 infection and assess the classification performance of clinical and laboratory parameters in predicting in-hospital outcome of these patients. Methods In the setting of the STROKOVID study including patients with acute ischemic stroke consecutively admitted to the ten hub hospitals in Lombardy, Italy, between March 8 and April 30, 2020, we compared clinical features of patients with confirmed infection and non-infected patients by logistic regression models and survival analysis. Then, we trained and tested a random forest (RF) binary classifier for the prediction of in-hospital death among patients with COVID-19. Results Among 1013 patients, 160 (15.8%) had SARS-CoV-2 infection. Male sex (OR 1.53; 95% CI 1.06–2.27) and atrial fibrillation (OR 1.60; 95% CI 1.05–2.43) were independently associated with COVID-19 status. Patients with COVID-19 had increased stroke severity at admission [median NIHSS score, 9 (25th to75th percentile, 13) vs 6 (25th to75th percentile, 9)] and increased risk of in-hospital death (38.1% deaths vs 7.2%; HR 3.30; 95% CI 2.17–5.02). The RF model based on six clinical and laboratory parameters exhibited high cross-validated classification accuracy (0.86) and precision (0.87), good recall (0.72) and F1-score (0.79) in predicting in-hospital death. Conclusions Ischemic strokes in COVID-19 patients have distinctive risk factor profile and etiology, increased clinical severity and higher in-hospital mortality rate compared to non-COVID-19 patients. A simple model based on clinical and routine laboratory parameters may be useful in identifying ischemic stroke patients with SARS-CoV-2 infection who are unlikely to survive the acute phase.

BackgroundHome chemotherapy programs for children with cancer are safe and feasible, and their impact on the quality of life has been reported in different countries. A home chemotherapy program was implemented between 2011 and 2019 in an Italian region. This pilot study investigates its safety and feasibility, along with parental satisfaction.MethodsPatients between 0 and 18 years diagnosed with malignancy were included. Deceased patients and patients whose families moved abroad or interrupted contact with the service were excluded. Adverse events comprised immediate deterioration of the patient’s condition, equipment failure, errors in drug storage, dose or patient identification and personnel safety issues. Parental satisfaction was explored through an email survey of 32 Likert-type and short open questions.ResultsThirty-five patients received 419 doses of intravenous chemotherapy at home (cytarabine, vincristine, vinblastine). No adverse events were reported. Twenty-three families out of 25 eligible completed the survey. Most reported being “very satisfied” with the possibility of maintaining a work/domestic routine and reducing time and financial burden of hospital access. Most were “very satisfied” with the opportunity for their child of being less troubled by the treatment. Besides, most reported being “very satisfied” with the chance for healthy siblings of maintaining their routine and coping with their brother/sister’s disease. Most perceived the program as safe. All families recommended extending the program to all children in the region.ConclusionsThis first Italian study supports home chemotherapy as safe and effective, positively influencing the quality of life for children and their families.

Sleep disturbance is a crucial issue in pediatric palliative care, with a dramatic impact on the quality of life of children and families. Dexmedetomidine (DEX) is a selective α-2 agonist, with anxiolytic, hypnotic, and analgesic properties, that could play a role in the management of refractory sleep disturbances. We describe the use of intranasal DEX as a sleep inductor in a 10-year-old female with dystrophic epidermolysis bullosa and a severe sleep disorder. After treatment with melatonin, benzodiazepines, and niaprazine had failed, she was admitted to the hospital where 3 mcg/kg/day of intranasal DEX was administered before bedtime. She received 0.7 mL of the IV formulation at a concentration of 100 mcg/mL with half the dose given in each nostril via a Mucosal Atomization Device. During this time, she was also monitored for potential side effects (e.g., bradycardia, blood pressure derangements). After 2 weeks of hospitalization, she was discharged with ready-to-use doses of DEX for home treatment. The child's heart rate and blood oxygen saturation were monitored at home. There was a definite improvement in sleep quality and duration, daytime alertness, pain control, and quality of life. No side effects were reported and the drug retained its effect over time (the patient is currently taking the drug). Intranasal DEX could be a safe and effective strategy to manage refractory sleep disturbances in children in pediatric palliative care.

Marco A Cimmino,1 Massimiliano Parodi,1 Francesca Barbieri,1 Stefano Bombardieri,2 Giuseppe Zampogna,1 Annamaria Iagnocco,3 Alberto Batticciotto,4 Luca Maria Sconfienza,5,6 Luigi Sinigaglia,7 Fabrizio De Benedetti,8 Fabiola Atzeni,9 Piercarlo Sarzi-Puttini10 1Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, Genoa, Italy; 2Rheumatology Unit, Santa Chiara Hospital, University of Pisa, Pisa, Italy; 3Academic Rheumatology Centre, Università degli Studi di Torino, Turin, Italy; 4Rheumatology Unit ASST-Settelaghi, Ospedale di Circolo – Fondazione Macchi, Varese, Varese, Italy; 5IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; 6Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy; 7Rheumatology Unit, G. Pini Hospital, Milan, Italy; 8Division of Rheumatology, IRCCS, Bambin Gesù Paediatric Hospital, Rome, Italy; 9Rheumatology Unit, University of Messina, Messina, Italy; 10Rheumatology Unit, L. Sacco University Hospital, Milan, ItalyCorrespondence: Piercarlo Sarzi-PuttiniReumatology Department, L. Sacco University Hospital, ASST Fatebenefratelli – Sacco, Via G.B. Grassi, 74, Milan 20157, ItalyTel +39 02 39042208Email piercarlo.sarziputtini@gmail.comObjective: This open-label study evaluated the effects of combined tocilizumab (TCZ) and disease-modifying antirheumatic drugs (DMARDs) on magnetic resonance imaging (MRI) changes in synovial membrane enhancement, bone marrow edema (BME), and erosions in the wrist and hand joints of rheumatoid arthritis (RA) patients inadequately responding to DMARDs alone.Methods: The efficacy of intravenous TCZ 8 mg/kg administered every four weeks for 48 weeks was evaluated on six occasions. The primary endpoints were the changes in the extent and degree of wrist synovitis as measured using the RA MRI Score (RAMRIS) and dynamic, gadolinium-enhanced 0.2T MRI (DCE-MRI). A number of different parameters of DCE-MRI were evaluated.Results: Fifty-eight patients were treated, eight of whom (13.8%) discontinued the study prematurely. The mean RAMRIS significantly decreased after two weeks and the decrease was maintained for up to 48 weeks. By week 4, the mean RAMRIS synovitis score had significantly decreased from baseline (− 0.804± 1.575; p=0.018), but not the mean early enhancement (REE) or relative enhancement (RE). However, there were significant decreases in RE at week 24, in REE and Ntotal (total number of enhancing voxels)*IRE (initial rate of enhancement) at weeks 12, 24 and 48, and in Ntotal*ME (maximal enhancement) at weeks 24 and 48. Mean BME decreased from baseline to week 48, and bone erosions did not progress. The patients’ clinical parameters significantly improved from baseline until week 48.Conclusion: TCZ in combination with DMARDs improved wrist synovitis, BME and clinical parameters, without any progression in bone erosions. The RAMRIS for synovitis rapidly improved from as early as two weeks after the first TCZ infusion. (Funded by F. Hoffmann–La Roche; ACTRACE EudraCT No. 2009 012185-32).Keywords: tocilizumab, rheumatoid arthritis, wrist, synovitis, low-field MRI, dedicated MRI

Myeloablative conditioning is a well‐established procedure that precedes hematopoietic stem cell transplantation (HSCT), particularly in pediatric patients. In the period directly following transplantation, several factors may contribute to complications that lead to the activation or damage of endothelial cells, involved in the pathogenesis of vascular endothelial syndromes (VES). However, to date, sufficiently specific and sensitive diagnostic markers for the various forms of VES have not been identified. This was a retrospective single‐center study of patients who underwent allogeneic HSCT. For this cohort of patients, parameters including type of engraftment, donor characteristics, and cytokine production were measured and correlated with a high prevalence of short‐term complications after HSCT. The aim of this study was to identify specific parameters useful for improving diagnostics and predicting adverse effects in VES. We confirmed that monocyte‐predominant engraftment was related to a higher risk for an early transplant‐related complication termed sinusoidal obstruction syndrome (SOS). The increased production of specific cytokines, in particular RANTES, represents a marker associated with prevalent engraftment. In addition, patients undergoing prophylaxis with defibrotide had “classical” engraftment, a common cytokine profile and a lower incidence of life‐threatening transplant‐related complications. The beneficial effect of defibrotide might be a starting point for developing selective prophylaxis for patients with monocyte engraftment to prevent severe early transplant‐related complications., The onset of vascular endothelial syndromes after hematopoietic stem cell transplantation is significantly associated with monocyte‐predominant engraftment (P

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.

Background MRI is increasingly used to objectively assess disease activity and damage in patients with rheumatoid arthritis (RA), especially in clinical trials. The preferred scoring method is the RAMRIS, which implies the use of gadolinium, an intravenous contrast agent, to assess synovitis. Objectives We evaluated in a small preliminary study if the fusion of MRI and US Power Doppler (PD) images could avoid gadolinium. Methods 12 patients (10 women) affected by RA, with at least one involved wrist, were studied. Mean age was 58.8±9.1 years and mean disease duration was 54.5±56.1 months. Disease activity (DAS 28-CRP) was evaluated on the day of the examinations. MRI was performed on a extremity-dedicated machine (Oscan 0.3 T, Esaote, Genova Italy) and US by MyLab Twice ultrasound scanner with a virtual navigator software (Esaote, Genova, Italy). T3Dt1 sequences were used in the fusion images (parameters: TR/TE/NEX 38/16/1, matrix 192*192*39, FOV 160*160*60, thickness 0.6 mm). US scans were performed sagittally on the radio-lunate joint and axially on the proximal carpal bones of the dorsal wrist with B-mode and PD (PRF 500–750Hz; WF: 3; maximum gain with probe9s calibration in air). Magnetic position sensor linked to the US transducer (13 MHz) and low magnetic field transmitters were used to allowed fusion images. MRI synovitis was scored by the RAMRIS and with the contrast-enhanced dynamic method resulting in rate of early enhancement (REE) and relative enhancement, (RE). The US score was the Global OMERACT-EULAR Synovitis Score (GLOESS) and its individual parts. Results Inter-reader agreement for PD by weighted kappa was 0.75 (75%CI 0.53–0.96) for the sagittal and 1 (75%CI 1–1) for the axial view. It was 0.85 (75%CI 0.69–0.98) for MRI synovitis. There was a correlation between DAS28 and the MRI synovits score (r=0.59, p=0.04), REE (r=0.60, p=0.04), and RE (r=0.58, p=0.05), US Doppler in the long (r=0.75, p=0.005) and in the axial axes (r=0.86, p=0.01), but not with B-mode synovial effusion (r=0.56, p=0.056). The GLOESS correlated with DAS28 (r=0.66, p=0.019), but not with RAMRIS synovitis, erosions or BME nor with REE. The MRI wrist synovitis score did not correlate with the Doppler score on the sagittal and axial views, nor with US B mode score. This was true also for the three individual MRI slices of the wrist, the REE and the RE. The figure shows from the left the pre-contrast axial MRI image, the post-contrast and the fusion images. Conclusions Although both MRI and Doppler are good indicators of disease activity in RA, they seem not to be interchangeable. This may be due to the fact that MRI and US show different features of synovitis or, alternatively, that MRI comprised the whole wrist whereas US visualized only its dorsal area. Although our preliminary data do not support the use of fusion images, these should be investigated on larger number of patients with a more extended PD approach. Disclosure of Interest None declared

Background Sympathovagal imbalance has been associated with poor prognosis in chronic diseases, but there is conflicting evidence in multiple sclerosis. Objectives The objective of this study was to investigate the autonomic nervous system dysfunction correlation with inflammation and progression in multiple sclerosis. Methods Heart rate variability was analysed in 120 multiple sclerosis patients and 60 healthy controls during supine rest and head-up tilt test; the normalised units of low frequency and high frequency power were considered to assess sympathetic and vagal components, respectively. Correlation analyses with clinical and radiological markers of disease activity and progression were performed. Results Sympathetic dysfunction was closely related to the progression of disability in multiple sclerosis: progressive patients showed altered heart rate variability with respect to healthy controls and relapsing–remitting patients, with higher rest low frequency power and lacking the expected low frequency power increase during the head-up tilt test. In relapsing–remitting patients, disease activity, even subclinical, was associated with lower rest low frequency power, whereas stable relapsing–remitting patients did not differ from healthy controls. Less sympathetic reactivity and higher low frequency power at rest were associated with incomplete recovery from relapse. Conclusions Autonomic balance appears to be intimately linked with both the inflammatory activity of multiple sclerosis, which is featured by an overall hypoactivity of the sympathetic nervous system, and its compensatory plastic processes, which appear inefficient in case of worsening and progressive multiple sclerosis.

During multiple sclerosis (MS) inflammatory attacks, and in subsequent clinical recovery phases, immune cells contribute to neuronal and oligodendroglial cell survival and tissue repair by secreting growth factors. Animal studies showed that growth factors also play a substantial role in regulating synaptic plasticity, and namely in long-term potentiation (LTP). LTP could drive clinical recovery in relapsing patients by restoring the excitability of denervated neurons. We recently reported that maintenance of synaptic plasticity reserve is crucial to contrast clinical deterioration in MS and that the platelet-derived growth factor (PDGF) may play a key role in its regulation. We also reported that a Hebbian form of LTP-like cortical plasticity, explored by paired associative stimulation (PAS), correlates with clinical recovery from a relapse in MS. Here, we explored the role of PDGF in clinical recovery and in adaptive neuroplasticity in relapsing-remitting MS (RR-MS) patients. We found a correlation between the cerebrospinal fluid (CSF) PDGF concentrations and the extent of clinical recovery after a relapse, as full recovery was more likely observed in patients with high PDGF concentrations and poor recovery in subjects with low PDGF levels. Consistently with the idea that PDGF-driven synaptic plasticity contributes to attenuate the clinical consequences of tissue damage in RR-MS, we also found a striking correlation between CSF levels of PDGF and the amplitude of LTP-like cortical plasticity explored by PAS. CSF levels of fibroblast growth factor, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor did not correlate with clinical recovery nor with measures of synaptic transmission and plasticity.

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.

Summary Background Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1 G93A mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS. Methods This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18–80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01753076, and with GSK-ClinicalStudyRegister.com, NOG112264, and is completed. Findings Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was −14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of −30·0 (95% CI −67·9 to 7·9; p=0·12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten [7%] in the ozanezumab group vs four [3%] in the placebo group), depression (11 [7%] vs five [3%]), and diarrhoea (25 [16%] vs 12 [8%]). Respiratory failure was the most common serious adverse event (12 [8%] vs seven [5%]). At week 60, the number of deaths was higher in the ozanezumab group (20 [13%]) than in the placebo group (16 [11%]), mainly as a result of respiratory failure (ten [7%] vs five [3%]). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group). Interpretation Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS. Funding GlaxoSmithKline.

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.

The case is described of a patient with chronic plantar pain, diagnosed as fasciitis, which was not improved by conventional treatment. Magnetic resonance imaging revealed flexor hallucis longus tenosynovitis, which improved after local glucocorticoid injection.

2D-immunomics may be useful in the identification of autoantigens in neurological autoimmune diseases, but its application may be limited by denaturation of target proteins. Here we compared the capacity of a single or multiple antigens to elicit autoantibodies targeting multiple neural autoantigens by ELISA and 2D-immunomics. We induced experimental autoimmune encephalomyelitis (EAE) with MBP peptide 89–104 , total MBP or spinal cord homogenate. Both techniques showed anti-MBP IgG only after immunization with total MBP. In addition, 2D-immunomics revealed the presence in EAE mice of autoantibodies targeting other neural proteins, some displaying partial sequence homology with MBP. The present finding by 2D-immunomics of multiple neural proteins targeted by autoantibodies generated by a single antigen may help to explain the complex autoimmune response observed in multiple sclerosis.

Objectives To study with MRI the hands of consecutive PMR patients, who were not selected on the basis of peripheral arthritis, with a correlation to clinical and laboratory findings. Methods Twenty-six hands of 15 PMR patients and 26 hands of 13 healthy controls were studied by extremity-dedicated MRI for the presence of synovitis, tenosynovitis, soft-tissue oedema, bone marrow oedema and erosions. Results Sixteen (61.6%) of the 26 PMR hands and 4 (15.4%) of the 26 control hands showed tenosynovitis (P = 0.001). Extensor tendon tenosynovitis was seen in 9 (34.6%) of the 26 PMR hands, but in only 1 (3.8%) control hand (P = 0.002) and flexor tenosynovitis was seen in 12 (46.1%) of the 26 PMR hands and in 4 (15.4%) of the 26 control hands (P = 0.03). All other features were similar in the two groups. Conclusions Our data support the view that tenosynovitis, especially of the extensor tendons, is a frequent event in PMR, unrelated to clinical involvement of the hand. This finding is in agreement with the concept of PMR as a disease of extra-articular structures.

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.

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 β-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.

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.

Summary Aim Natalizumab (NTZ) discontinuation leads to multiple sclerosis (MS) recurrence, but represents the only known strategy to limit the risk of progressive multifocal leukoencephalopathy (PML) in JCV seropositive patients. Here, we compared the clinical and imaging features of three groups of patients who discontinued NTZ treatment. Methods We treated 25 patients with subcutaneous INFβ-1b (INF group), 40 patients with glatiramer acetate (GA group), and 40 patients with GA plus pulse steroid (GA+CS group). Results Six of 25 patients (24%) of the INF group were relapse-free 6 months after NTZ suspension. In GA group, a significant higher proportion of patients (26 of 40 patients, 65%) were relapse-free (P

Neurons generate magnetic fields which can be recorded with macroscopic techniques such as magneto-encephalography. The theory that accounts for the genesis of neuronal magnetic fields involves macroscopic dipole structures in homogeneous resistive extracellular media. Here, we study this problem at the microscopic level using a variant of cable theory which accounts for the genesis of magnetic fields, in extracellular media with arbitrarily complex electric properties. The cable formalism, initially introduced by Rall [1], has been recently generalized to include the influence of the extracellular medium [2]. We use here this generalized cable formalism to calculate the magnetic field generated by neurons. We show that the magnetic induction generally depends on the impedance of the extracellular and intracellular media. Therefore, like the electric field, the electric properties of these media can influence the magnetic field, contrary to what is usually assumed. Next, we use this formalism to calculate the "magnetic signature" of different neuronal morphologies, such as pyramidal cells and basket cells. We show that the strongest magnetic fields correspond to media which are non-resistive, such as diffusive media, although they exert low-pass filtering properties. Recent measurements (see companion poster by Bedard et al.) suggest that the extracellular medium is best described by a diffusive impedance. We therefore predict that this will also affect neuronal magnetic fields. In conclusion, we show here that the generalized cable formalism is an important tool to calculate the extracellular electric and magnetic fields generated by neurons. The nature of the medium influences both types of fields, and should be measurable by appropriate measurements. Given the fact that the nature of the medium influences the magnetic field, inverse methods should consider this important parameter.

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.

The crystal growth of biological macromolecules is a very complicated process involving numerous parameters, such as pressure, pH, micro-gravity, photochemical and mechanical induction of nucleation. The utilization of Langmuir–Blodgett (LB) thin film as a template plays an important role in order to produce well-diffracting, stable and radiation-resistant protein crystals. LB nanotemplate crystallization method is a modification of the classical hanging drop vapor diffusion method. We tested four standard proteins, changing different parameters such as protein and salt concentration, number of LB layers etc., in order to verify the real role of LB template. Our results suggest that LB template essentially acts in two way on crystallization: in nucleation and in crystal growth. The possible explanation of these effects is also discussed.

Background Understanding how inflammation causes neuronal damage is of paramount importance in multiple sclerosis (MS) and in other neurodegenerative diseases. Here we addressed the role of the apoptotic cascade in the synaptic abnormalities and neuronal loss caused by the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α) in brain tissues, and disease progression caused by inflammation in relapsing-remitting MS (RRMS) patients. Results The effect of IL-1β, but not of TNF-α, on glutamate-mediated excitatory postsynaptic currents was blocked by pifithrin-α (PFT), inhibitor of p53. The protein kinase C (PKC)/transient receptor potential vanilloid 1 (TRPV1) pathway was involved in IL-1β-p53 interaction at glutamatergic synapses, as pharmacological modulation of this inflammation-relevant molecular pathway affected PFT effects on the synaptic action of IL-1β. IL-1β-induced neuronal swelling was also blocked by PFT, and IL-1β increased the expression of p21, a canonical downstream target of activated p53. Consistent with these in vitro results, the Pro/Pro genotype of p53, associated with low efficiency of transcription of p53-regulated genes, abrogated the association between IL-1β cerebrospinal fluid (CSF) levels and disability progression in RRMS patients. The interaction between p53 and CSF IL-1β was also evaluated at the optical coherence tomography (OCT), showing that IL-1β-driven neurodegenerative damage, causing alterations of macular volume and of retinal nerve fibre layer thickness, was modulated by the p53 genotype. Conclusions Inflammatory synaptopathy and neurodegeneration caused by IL-1β in RRMS patients involve the apoptotic cascade. Targeting IL-1β-p53 interaction might result in significant neuroprotection in MS.

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.

Synaptic transmission and plasticity mediated by NMDA receptors (NMDARs) could modulate the severity of multiple sclerosis (MS). Here the role of NMDARs in MS was first explored in 691 subjects carrying specific allelic variants of the NR1 subunit gene or of the NR2B subunit gene of this glutamate receptor. The analysis was replicated for significant SNPs in an independent sample of 1548 MS subjects. The C allele of rs4880213 was found to be associated with reduced NMDAR-mediated cortical excitability, and with increased probability of having more disability than the CT/TT MS subjects. MS severity was higher in the CC group among relapsing-remitting MS (RR-MS) patients, while primary progressive MS (PP-MS) subjects homozygous for the T allele had more pronounced clinical worsening. Mean time to first relapse, but not to an active MRI scan, was lower in the CC group of RR-MS patients, and the number of subjects with two or more clinical relapses in the first two years of the disease was higher in CC compared to CT/TT group. Furthermore, the percentage of relapses associated with residual disability was lower in subjects carrying the T allele. Lesion load at the MRI was conversely unaffected by the C or T allele of this SNP in RR-MS patients. Axonal and neuronal degeneration at the optical coherence tomography was more severe in the TT group of PP-MS patients, while reduced retinal nerve fiber thickness had less consequences on visual acuity in RR-MS patients bearing the T allele. Finally, the T allele was associated with preserved cognitive abilities at the Rao's brief repeatable neuropsychological battery in RR-MS. Signaling through glutamate NMDARs enhances both compensatory synaptic plasticity and excitotoxic neurodegeneration, impacting in opposite ways on RR-MS and PP-MS pathophysiological mechanisms.

Proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1β (IL1β) regulate both excitatory and inhibitory synaptic transmission in the central nervous system. The interaction between IL1β and endocannabinoid system (ECS) is also emerging, based on the evidence that IL1β effects on striatal spontaneous excitatory and inhibitory postsynaptic currents are regulated by transient receptor potential vanilloid 1 (TRPV1) channels, members of the ECS. Furthermore, IL1β has also been shown to control the sensitivity of cannabinoid CB1 receptors controlling GABA transmission (CB1Rs(GABA)) in the striatum. To better detail the synaptic action of IL1β, and to clarify its complex interaction with the ECS, here we investigated the possible interplay between IL1β and CB1Rs controlling glutamate transmission (CB1Rs(glu)), other critical elements of the ECS. Our results show that the sensitivity of CB1Rs(glu) is fully blocked in the presence of IL1β in corticostriatal brain slices, and that the protein kinase C/TRPV1 pathway is involved in this effect. IL1β failed to modulate the sensitivity of glutamate synapses to the stimulation of GABAB receptors. We also provided evidence that IL1β-CB1Rs(GABA) but not IL1β-CB1Rs(glu) interaction is under the control of the brain-derived neurotrophic factor (BDNF)/trkB signaling and of lipid raft composition, because BDNF gene partial deletion, pharmacological blockade of trkB and membrane cholesterol removal with methyl-β-cyclodextrin all blocked IL1β-mediated inhibition of CB1Rs(GABA) but left unaltered the sensitivity of CB1Rs(glu) to this cytokine. Our results provide further evidence that synaptic transmission and the ECS are regulated by IL1β in the striatum.

Figure 2. Coronal enhanced computed tomography image showing small bowel loops located to the left of the Treitz ligament. Mesenteric vessels are displaced in the left quadrant. A 15-year-old boy presented with a 3-week history of postprandial self-limiting episodes of colicky abdominal pain with abdominal distension and sometimes vomiting. The physical examination was normal, but after a meal the patient experienced intense abdominal pain and sweating. A tender mass was palpated in the left upper quadrant. Abdominal radiograph and computed tomography scan revealed a cluster of dilated small bowel loops to the left of the Treitz ligament (Figures 1 and 2). A left paraduodenal hernia was suspected, and this was confirmed on laparoscopy. The patient was discharged 3 days after undergoing laparoscopic hernia repair. Left paraduodenal hernia occurs when small bowel loops prolapse into Landzert fossa through a congenital defect; this occurs in approximately 2% of the population. This may cause acute intestinal infarction owing to stretching of blood vessels. Classically, patients experience marked abdominal asymmetry, sweating, and tachycardia during the episodes of abdominal pain, but are usually asymptomatic between crises. Pediatricians should take care to not erroneously misdiagnose these cases as functional recurrent abdominal pain. n

How sensory stimuli are encoded in neuronal activity is a major challenge for understanding perception. A prominent effect of sensory stimulation is to elicit oscillations in EEG and Local Field Potential (LFP) recordings over a broad range of frequencies. Belitski et al. [1] recorded LFPs and spiking activity in the primary visual cortex of anaesthetized macaques presented with naturalistic movies and found that the power of the gamma and low-frequency bands of LFP carried largely independent information about visual stimuli, while the information carried by the spiking activity was largely redundant with that carried by the gamma-band LFPs. To understand better how different frequency bands of the LFP are controlled by sensory input, we computed analytically the power spectrum of the LFP of a theoretical model of V1 (a network composed of two populations of neurons - excitatory and inhibitory), subjected to time-dependent external inputs modelling inputs from the LGN, as a function of the parameters characterizing single neurons, synaptic connectivity, as well as parameters characterizing the statistics of external inputs. Our model consists in a two populations network of excitatory and inhibitory leaky integrate-and-fire neurons. Standard analytical methods using the Fokker-Planck formalism can be used to compute average firing rates of both populations in the asynchronous state of the network, as well as the region of parameters for which this state is stable ([2,3]). The power spectrum of the global activity and the LFP (sum of average excitatory and inhibitory currents onto pyramidal cells of the network) can also be computed in a network of finite size ([2]). Using linear response theory we then calculated the response of the network to a dynamic input ([4]). The final result was an equation giving the LFP power spectrum as a function of the intrinsic parameters of the network and of the parameters characterizing the dynamic input. We then used the analytical expression of the LFP power to fit the experimental data of [1]. The data consists in LFP recordings from primary visual cortex of monkeys, during the presentation of a movie that last several minutes. In order to capture the LFP power changes during the movie presentation, the LFP traces were divided into 2 seconds non-overlapping scenes. We then fitted the LFP power of all the scenes with the same network parameters, but with input parameters free to vary scene-by-scene. We used a simplex method repeatedly applied for different initial conditions. The parameter set that was selected was the one that minimized the reduced chisquare, among sets for which the asynchronous state was stable. The model provided excellent fits of the data. The fitting procedure permitted to extract the values of the firing rates of the excitatory and inhibitory populations and the parameters characterizing the external input for most of the scenes of the movie. These outcomes could be then correlated with experimental firing rates and the features of the movie itself, such as temporal and spatial contrast as well as orientation. We found a significant correlation both between firing rates extracted from fit and the multi-unit activity recorded during the movie and between the parameters characterizing the external input and the features of the movie. These results show how an analytical approach can be used to estimate the key parameters underlying changes in the LFP spectral dynamics.

Background and purpose Multiple sclerosis (MS) patients discontinuing natalizumab are at risk of rebound of disease activity. Methods In the present multi-center, open-label, non-randomized, prospective, pilot study, we tested whether treatment with glatiramer acetate (GA) is safe and effective after natalizumab in MS patients. The study was performed at academic tertiary medical centers. Forty active relapsing–remitting MS patients who never failed GA therapy and who discontinued natalizumab after 12–18 months of therapy were enrolled. GA was initiated 4 weeks after the last dose of natalizumab. Results 62.5% of patients were relapse-free 12 months after GA initiation. Annualized relapse rate and time to relapse were significantly lower than before natalizumab. Notably, the frequency of relapses was significantly lower amongst those patients who had experienced ≤2 relapses the year before initiation of natalizumab therapy, compared with patients who had had three or more relapses. No evidence of rebound was observed in magnetic resonance imaging scans. Furthermore, Expanded Disability Status Scale and Multiple Sclerosis Functional Composite were stable in our patients, again suggesting that 12 months of post-natalizumab–GA therapy is not associated with clinical deterioration. Conclusions Following discontinuation of natalizumab, 12 months of therapy with GA is safe and well tolerated in MS patients. GA can reduce the risk of early reactivation/rebound of disease activity in this setting.