Sabrina Esposito

Genetic and epigenetic mutations affect the DNA binding capability of human ZFP57 in transient neonatal diabetes type 1

In the mouse, ZFP57 contains three classical Cys2His2 zinc finger domains (ZF) and recognizes the methylated TGCmetCGC target sequence using the first and the second ZFs. In this study, we demonstrate that the human ZFP57 (hZFP57) containing six Cys2His2 ZFs, binds the same methylated sequence through the third and the fourth ZFs, and identify the aminoacids critical for DNA interaction. In addition, we present evidences indicating that hZFP57 mutations and hypomethylation of the TNDM1 ICR both associated with Transient Neonatal Diabetes Mellitus type 1 result in loss of hZFP57 binding to the TNDM1 locus, likely causing PLAGL1 activation.

NMR assignments of the DNA binding domain of Ml4 protein from Mesorhizobium loti

Ml4 protein from Mesorhizobium loti has a 58% sequence identity with the Ros protein from Agrobacterium tumefaciens that contains a prokaryotic Cys2His2 zinc finger domain. Interestingly, Ml4 is a zinc-lacking protein that does not contain the Cys2His2 motif and is able to bind the Ros DNA target sequence with high affinity. Here we report the 1H, 15N and 13C NMR assignments of the Ml4 protein DNA binding domain (residue 52–151), as an important step toward elucidating at a molecular level how this prokaryotic domain can overcome the metal requirement for proper folding and DNA-binding activity.

Health-Related Coping and Social Interaction in People with Multiple Sclerosis Supported by a Social Network: Pilot Study With a New Methodological Approach

Background Social media are a vital link for people with health concerns who find in Web communities a valid and comforting source for information exchange, debate, and knowledge enrichment. This aspect is important for people affected by chronic diseases like multiple sclerosis (MS), who are very well informed about the disease but are vulnerable to hopes of being cured or saved by therapies whose efficacy is not always scientifically proven. To improve health-related coping and social interaction for people with MS, we created an MS social network (SMsocialnetwork.com) with a medical team constantly online to intervene promptly when false or inappropriate medical information are shared. Objective The goal of this study was to assess the impact of SMsocialnetwork.com on the health-related coping and social interaction of people with MS by analyzing areas of interest through a Web-based survey. Methods Referring to previous marketing studies analyzing the online platform’s role in targeted health care, we conducted a 39-item Web-based survey. We then performed a construct validation procedure using a factorial analysis, gathering together like items of the survey related to different areas of interest such as utility, proximity, sharing, interaction, solving uncertainty, suggestion attitude, and exploration. Results We collected 130 Web-based surveys. The areas of interest analysis demonstrated that the users positively evaluated SMsocialnetwork.com to obtain information, approach and solve problems, and to make decisions (utility: median 4.2); improve feeling of closeness (proximity: median 5); catalyze relationships and text general personal opinions (sharing: median 5.6); get in touch with other users to receive innovative, effective, and practical solutions (interaction, solving uncertainty, and suggestion attitude medians were respectively: 4.1, 3, and 3); and share information about innovative therapeutic approaches and treatment options (suggestion attitude: median: 3.3). Conclusions SMsocialnetwork.com was perceived by users to be a useful tool to support health-related coping and social interaction, and may suggest a new kind of therapeutic alliance between physicians and people with MS.

Assessing association of comorbidities with treatment choice and persistence in MS: A real-life multicenter study

Objective: To assess whether the presence of concomitant diseases at multiple sclerosis (MS) diagnosis is associated with the choice and the treatment persistence in an Italian MS cohort. Methods: We included newly diagnosed patients (2010–2016) followed in 20 MS centers and collected demographic and clinical data. We evaluated baseline factors related to the presence of comorbidities and the association between comorbidities and the clinical course of MS and the time to the first treatment switch. Results: The study cohort included 2,076 patients. Data on comorbidities were available for 1,877/2,076 patients (90.4%). A total of 449/1,877 (23.9%) patients had at least 1 comorbidity at MS diagnosis. Age at diagnosis (odds ratio 1.05, 95% confidence interval [CI] 1.04–1.06; p < 0.001) was the only baseline factor independently related to the presence of comorbidities. Comorbidities were not significantly associated with the choice of the first disease-modifying treatment, but were significantly associated with higher risk to switch from the first treatment due to intolerance (hazard ratio 1.42, CI 1.07–1.87; p = 0.014). Association of comorbidities with risk of switching for intolerance was significantly heterogeneous among treatments (interferon β, glatiramer acetate, natalizumab, or fingolimod; interaction test, p = 0.04). Conclusions: Comorbidities at diagnosis should be taken into account at the first treatment choice because they are associated with lower persistence on treatment.

Default mode network changes in multiple sclerosis: a link between depression and cognitive impairment?

In multiple sclerosis (MS), depression is a common disorder whose pathophysiology is still debated. To gain insights into the pathophysiology of depression in MS, resting‐state (RS) functional connectivity (FC) changes of the default mode network (DMN), salience network (SN) and executive control network (ECN) were assessed in a group of depressed MS (D‐MS) patients and in appropriately matched control groups.

Livedo and ischemic strokes: diagnostic hints of a rare condition

Sneddon’s syndrome (SS) is a rare condition characterized by the combination of ischemic strokes and cutaneous livedo [1, 2], defined as the ‘‘persistent, not reversible with rewarming, violaceous, reticular or mottled pattern of the skin of trunk, arms or legs, consisting of regular unbroken circles (livedo reticularis) or irregular-broken circles (livedo racemosa)’’. Other well-defined neurological manifestations of SS include headache, seizures, and vascular dementia. Here, we report two cases with clinical and imaging features suggestive of SS. In both patients skin biopsy was performed and sections were stained with hematoxylin and eosin (HE general examination revealed diffused livedo racemosa (Fig. 1a). An extensive cardiological evaluation including an electrocardiogram, an echocardiogram and carotid ultrasound evaluation ruled out cardiovascular causes of stroke. Coagulation parameters (including fibrinogen and D-dimer), inflammatory indexes, syphilis serology, and autoimmune antibody panels including, ANA, ENA, ANCA, lupus anti-coagulants (LAC) and antiphospholipid antibodies (IgM and IgG anti-cardiolipin and anti-b2-microglobulin) were negative. A heterozygous mutation of factor V Leiden was detected. Brain MRI showed cortical atrophy and multiple ischemic lesions involving both the superficial and deep territories of posterior and middle cerebral artery (Fig. 1b). Skin biopsy showed intra-capillary and parietal widespread thrombosis (Fig. 1c). Oral anticoagulants and antipsychotic were added to therapy. A 65-year-old man (Case 2) presented with a 3-year history of progressive lower limbs weakness and mixed dysphagia. He had been having recurrent ischemic strokes since he was 55. He had history of myocardial infarcts, hypertension, and smoking. His neurological examination revealed dysphagia, ataxic and spastic gait, limbs hyperreflexia, right extensor plantar response. General examination revealed diffused livedo racemosa at the trunk and lower limbs (Fig. 1a). A cardiological evaluation and electrocardiogram ruled out the presence of heart arrhythmia; echocardiography demonstrated mild hypokinesia of apical and distal septum of lateral ventricle, as consequence of previous myocardial infarcts. Coagulation parameters and thrombophilic screening were normal. Brain MRI showed diffused cortical atrophy and multiple ischemic lesions (Fig. 1b) in both medium-sized superficial and deep, posterior and middle cerebral artery territories. Skin biopsy revealed intra-capillary and parietal widespread thrombosis (Fig. 1c). As for the first patient, oral anticoagulants were added to therapy. G. Cirillo A. Tessitore (&) F. Salemi S. Liguori S. Esposito G. Tedeschi Department of Neurology, Second University of Naples, 80138 Naples, Italy e-mail: alessandro.tessitore@unina2.it

Determinants of therapy switch in multiple sclerosis treatment-naïve patients: A real-life study:

Background: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences. Objectives: To identify prognostic factors for early switch after first therapy choice. Methods: Newly diagnosed relapsing–remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models. Results: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p = 0.009), natalizumab (HR = 0.13; p < 0.001), dimethyl-fumarate (HR = 0.60; p = 0.037), teriflunomide (HR = 0.21; p = 0.031) as compared to interferons. Younger age (HR = 0.96; p < 0.001), diagnosis delay (HR = 1.23; p = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17; p = 0.001), and spinal cord lesions (HR = 1.46; p = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61; p = 0.001), fingolimod (HR = 0.35; p = 0.002), and dimethyl-fumarate (HR = 0.57; p = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43; p = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28; p = 0.047). Conclusion: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.