Long-term management of natalizumab discontinuation in a large monocentric cohort of multiple sclerosis patients

Background Pivotal and post-marketing studies demonstrated the impressive efficacy and the good tolerability profile of natalizumab in Multiple Sclerosis patients. On the other hand long-term safety of natalizumab therapy is burdened by the risk of progressive multifocal leukoencephalopathy, especially in anti-JCV seropositive patients treated for more than two years. Some of these patients must stop the drug at the risk of disease reactivation. Objectives To evaluate the effects of natalizumab discontinuation in a monocentric cohort of multiple sclerosis patients followed for a mean time of 22.4 months. Methods One hundred and ten patients, who stopped therapy after at least 12 infusions, were followed with periodic clinical and magnetic resonance imaging evaluations. One hundred patients started either immunomodulant therapy (n=90) or fingolimod (n=10) while 10 remained without any drug. Results "Disease-activity free" patients were 25% at one year after discontinuation and annualized relapse rate significantly increased from 0.06 to 0.84 (p<0.0001). We found that the risk of reactivation peaked despite alternative treatments between the second and the eighth month after suspension, a so-called "high risk period". During this period the majority of patients showed a return to pre-natalizumab disease activity while 10% of patients presented a "rebound activity". A higher pre-natalizumab disease activity was correlated with an increased risk of reactivation (p=0.004). Conclusions Our data suggest that disease reactivation peaked during a "high risk period" between the second and the eighth month since stopping the drug. During this period no alternative treatments seemed to provide an adequate protection from disease reactivation. Though transient, this phase could be potentially dangerous, therefore we need to develop more effective strategies to deal with this challenge

Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism

Cystic fibrosis (CF) is a hereditary disease, with 70% of patients developing a proteinopathy related to the deletion of phenylalanine 508. CF is associated with multiple organ dysfunction, chronic inflammation, and recurrent lung infections. CF is characterized by defective autophagy, lipid metabolism, and immune response. Intracellular lipid accumulation favors microbial infection, and autophagy deficiency impairs internalized pathogen clearance. Myriocin, an inhibitor of sphingolipid synthesis, significantly reduces inflammation, promotes microbial clearance in the lungs, and induces autophagy and lipid oxidation. RNA-seq was performed in Aspergillusfumigatus-infected and myriocin-treated CF patients' derived monocytes and in a CF bronchial epithelial cell line. Fungal clearance was also evaluated in CF monocytes. Myriocin enhanced CF patients' monocytes killing of A. fumigatus. CF patients' monocytes and cell line responded to infection with a profound transcriptional change; myriocin regulates genes that are involved in inflammation, autophagy, lipid storage, and metabolism, including histones and heat shock proteins whose activity is related to the response to infection. We conclude that the regulation of sphingolipid synthesis induces a metabolism drift by promoting autophagy and lipid consumption. This process is driven by a transcriptional program that corrects part of the differences between CF and control samples, therefore ameliorating the infection response and pathogen clearance in the CF cell line and in CF peripheral blood monocytes

Habitats Directive in northern Italy: a series of proposals for habitat definition improvement

Habitats Directive (92/43/EEC) is the cornerstone of nature conservation in Europe and is at the core of the EU Biodiversity Strategy for 2030. There is room, however, for its improvement, at least for northern Italy, where ambiguities in the definition of habitat types of Annex I of the Habitats Directive are not novel and interpretation difficulties have been highlighted. Sharpening the characterization of habitat types represents an opportunity for lowering classification uncertainties and improving conservation success. With the aim to refine the definitions of habitat types and associated typical species of the Habitats Directive, a group of vegetation scientists of the Italian Society of Vegetation Science based in northern Italy made the exercise of finding viable proposals for those habitat types having a problematic interpretation in the Alpine biogeographical region of Italy. Such proposals arise from group discussions among scientists, and professionals, thus offering a shared view. We prepared 9 habitat proposals important for this geographic area. They include new habitat types at the European level, new subtypes within pre-existing habitat types, including some adjustments of the recently proposed subtypes with respect to northern Italy, and recognition of priority criteria for a pre-existing habitat type. With a vision of tailored conservation, our proposals represent a starting point in view of a future update of Annex I. Furthermore, the list of typical species could be useful for preparing expert systems for automatic classification. Irrespective of legally binding solutions in place, we caution these proposals represent relevant baseline conservation indications that local and regional administrations of the Alpine Arch should consider

Opioid use is associated with increased out-of-hospital cardiac arrest risk among 40,000-cases across two countries

AIMS: Opioid use has substantially increased in the last decade and is associated with overdose mortality, but also with increased mortality from cardiovascular causes. This finding may partly reflect an association between opioids and out‐of‐hospital cardiac arrest (OHCA). Therefore, we aimed to investigate OHCA‐risk of opioids in the community. METHODS: We conducted 2 population‐based case–control studies separately in the Netherlands (2009–2018) and Denmark (2001–2015). Cases were individuals who experienced OHCA of presumed cardiac cause. Each case was matched with up to 5 non‐OHCA‐controls according to age, sex and OHCA‐date. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We included 5473 OHCA‐cases matched with 21 866 non‐OHCA‐controls in the Netherlands, and 35 017 OHCA‐cases matched with 175 085 non‐OHCA‐controls in Denmark. We found that use of opioids (the Netherlands: cases: 5.4%, controls: 1.8%; Denmark: cases: 11.9%, controls: 4.4%) was associated with increased OHCA‐risk in both regions (the Netherlands: OR 2.1 [95% CI 1.8–2.5]; Denmark: OR 1.8 [95% CI 1.5–2.1]). The association was observed in both sexes, and in individuals with cardiovascular disease (the Netherlands: OR 1.8 [95% CI 1.5–2.1]; Denmark: OR 1.6 [95% CI 1.5–1.7]) or without (the Netherlands: OR 3.4 [95% CI: 2.4–4.8], P (interaction) < .0001; Denmark: OR 2.3 [95% CI: 2.0–2.5], P (interaction) < .0001). CONCLUSION: Use of opioids is associated with increased OHCA‐risk in both sexes, independently of concomitant cardiovascular disease. These findings should be considered when evaluating the harms and benefits of treatment with opioids

Pentoxifylline prevents spontaneous brain ischemia in stroke-prone rats

Anti-inflammatory properties of pentoxifylline (PTX) have recently been described. Spontaneously hypertensive stroke-prone rats (SHRSP) constitute an animal model that develops an inflammatory condition that precedes the appearance of brain abnormalities. The aim of the present investigation was to assess: 1) the efficacy of PTX treatment in protecting the neural system in SHRSP, and 2) how its anti-inflammatory properties might be involved in this effect. Male SHRSP fed with a permissive diet received no drug or PTX (100 or 200 mg/kg/day). Brain abnormalities detected by magnetic resonance imaging developed spontaneously in control rats after 42 +/- 3 days, whereas in rats treated with 100 mg/kg/day PTX, abnormalities developed in only 80% of the animals and only after 70 to 80 days. Treatment with a higher dose of PTX (200 mg/kg/day) completely protected the brain from abnormal development. The drug treatment prevented the accumulation of macrophages or CD4+ positive cells, the activation of glia in brain tissues, and the appearance of inflammatory proteins and thiobarbituric acid-reactive substances in body fluids. PTX treatment did induce a greater increase of serum tumor necrosis factor-alpha (TNF-alpha), but not of interleukin (IL)-1beta and IL-6 induced by in vivo administration of lipopolysaccharide (LPS), which suggests a protective role for TNF-alpha. PTX also exerted protective effects when it was administered after the first occurrence of proteinuria (>40 mg/day). These data indicate that PTX treatment dose-dependently prevents the occurrence of spontaneous brain damage by reducing inflammatory events. We also hypothesize that the increase of TNF-alpha by PTX treatment represents a protective mechanism in SHRSP

Risk of out-of-hospital cardiac arrest in antidepressant drug users

Conflicting results have been reported regarding the association between antidepressant use and out‐of‐hospital cardiac arrest (OHCA) risk. We investigated whether the use of antidepressants is associated with OHCA. METHODS: We conducted a nationwide nested case–control study to assess the association of individual antidepressant drugs within drug classes with the hazard of OHCA. Cases were defined as OHCA from presumed cardiac causes. Cox regression with time‐dependent exposure and time‐dependent covariates was conducted to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) overall and in subgroups defined by established cardiac disease and cardiovascular risk factors. Also, we studied antidepressants with and without sodium channel blocking or potassium channel blocking properties separately. RESULTS: During the study period from 2001 to 2015 we observed 10 987 OHCA cases, and found increased OHCA rate for high‐dose citalopram (>20 mg) and high‐dose escitalopram (>10 mg; HR:1.46 [95% CI:1.27–1.69], HR:1.43 [95% CI:1.16–1.75], respectively) among selective serotonin reuptake inhibitors (reference drug sertraline), and for high‐dose mirtazapine (>30; HR:1.59 [95% CI:1.18–2.14]) among the serotonin–norepinephrine reuptake inhibitors or noradrenergic and specific serotonergic antidepressants (reference drug duloxetine). Among tricyclic antidepressants (reference drug amitriptyline), no drug was associated with significantly increased OHCA rate. Increased OHCA rate was found for antidepressants with known potassium channel blocking properties (HR:1.14 [95% CI:1.05–1.23]), but for not those with sodium channel blocking properties. Citalopram, although not statistically significant, and mirtazapine were associated with increased OHCA rate in patients without cardiac disease and cardiovascular risk factors. CONCLUSION: Our findings indicate that careful titration of citalopram, escitalopram and mirtazapine dose may have to be considered due to drug safety issues

Notulae to the Italian flora of algae, bryophytes, fungi and lichens: 3

In this contribution, new data concerning bryophytes, fungi and lichens and of the Italian flora are presented. It includes new records and confirmations for the bryophyte genera Dicranodontium, Fontinalis, Lophocolea and Riccia, the fungal genus Diplolaeviopsis, the lichen genera Agonimia, Cladonia, Protoparmelia, Rhizocarpon, and Scytinium

Contacts With the Health Care System Before Out-of-Hospital Cardiac Arrest

BACKGROUND: It remains challenging to identify patients at risk of out‐of‐hospital cardiac arrest (OHCA). We aimed to examine health care contacts in patients before OHCA compared with the general population that did not experience an OHCA. METHODS AND RESULTS: Patients with OHCA with a presumed cardiac cause were identified from the Danish Cardiac Arrest Registry (2001–2014) and their health care contacts (general practitioner [GP]/hospital) were examined up to 1 year before OHCA. In a case‐control study (1:9), OHCA contacts were compared with an age‐ and sex‐matched background population. Separately, patients with OHCA were examined by the contact type (GP/hospital/both/no contact) within 2 weeks before OHCA. We included 28 955 patients with OHCA. The weekly percentages of patient contacts with GP the year before OHCA were constant (25%) until 1 week before OHCA when they markedly increased (42%). Weekly percentages of patient contacts with hospitals the year before OHCA gradually increased during the last 6 months (3.5%–6.6%), peaking at the second week (6.8%) before OHCA; mostly attributable to cardiovascular diseases (21%). In comparison, there were fewer weekly contacts among controls with 13% for GP and 2% for hospital contacts (P<0.001). Within 2 weeks before OHCA, 57.8% of patients with OHCA had a health care contact, and these patients had more contacts with GP (odds ratio [OR], 3.17; 95% CI, 3.09–3.26) and hospital (OR, 2.32; 95% CI, 2.21–2.43) compared with controls. CONCLUSIONS: The health care contacts of patients with OHCA nearly doubled leading up to the OHCA event, with more than half of patients having health care contacts within 2 weeks before arrest. This could have implications for future preventive strategies

The still under-investigated role of cognitive deficits in PML diagnosis.

Background Despite cognitive deficits frequently represent the first clinical manifestations of Progressive Multifocal Leukoencephalopathy (PML) in Natalizumab-treated MS patients, the importance of cognitive deficits in PML diagnosis is still under-investigated. The aim of the current study is to investigate the cognitive deficits at PML diagnosis in a group of Italian patients with PML. Methods Thirty-four PML patients were included in the study. The demographic and clinical data, the lesion load and localization, and the longitudinal clinical course was compared between patients with (n = 13) and without (n = 15) cognitive deficit upon PML suspicion (the remaining six patients were asymptomatic). Clinical presentation of cognitive symptoms was described in detail. Result After symptoms detection, the time to diagnosis resulted to be shorter for patients presenting with cognitive than for patients with non cognitive onset (p = 0.03). Within patients with cognitive onset, six patients were presenting with language and/or reading difficulties (46.15%); five patients with memory difficulties (38.4%); three patients with apraxia (23.1%); two patients with disorientation (15.3%); two patients with neglect (15.3%); one patients with object agnosia (7.7%), one patient with perseveration (7.7%) and one patient with dementia (7.7%). Frontal lesions were less frequent (p = 0.03), whereas temporal lesions were slightly more frequent (p = 0.06) in patients with cognitive deficits. The longitudinal PML course seemed to be more severe in cognitive than in non cognitive patients (F = 2.73, p = 0.03), but differences disappeared (F = 1.24, p = 0.29) when balancing for the incidence of immune reconstitution syndrome and for other treatments for PML (steroids, plasma exchange (PLEX) and other therapies (Mefloquine, Mirtazapine, Maraviroc). Conclusion Cognitive deficits at PML onset manifest with symptoms which are absolutely rare in MS. Their appearance in MS patients should strongly suggest PML. Clinicians should be sensitive to the importance of formal neuropsychological evaluation, with particular focus on executive function, which are not easily detected without a formal assessment