CADASIL or MS? Consider “Red Flags” but Avoid a Misdiagnosis: Case Series of a Concomitant Diagnosis

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic autosome-dominant disease with chronic clinical course. Rarely, CADASIL may present with atypical relapsing-remitting manifestations, cerebral and spinal white matter lesions, mimicking inflammatory CNS disease as multiple sclerosis (MS). The rarely co-occurrence of MS and CADASIL may represent a hard challenging diagnosis even for an expert neurologist. Here, we present a case series of two patients with CADASIL showing MRI pattern overlapping MS. They were the only case of co-occurrence of CADASIL and MS in their own family. Both patients were treated with anti-inflammatory and anti-platelet drugs, mostly with good response. Pathogenic hypothesis highlights that genetic events, related to monogenic disease, may expose CNS antigens with a consequent self-immune attack. In CADASIL, the function of Notch3 receptor showed a consistent interplay with immune system activity. Indeed, certain mutations of Notch3 receptor show abnormal upregulation of specific pro-inflammatory patterns. However, even if it is not possible to determinate if the proinflammatory activity may be promoted by pathogenic mutations in Notch3, the "apparent" difference between MS and “inflammatory CADASIL” could be considered more semantic than etiologic

The ER-Bound RING Finger Protein 5 (RNF5/RMA1) Causes Degenerative Myopathy in Transgenic Mice and Is Deregulated in Inclusion Body Myositis

Growing evidence supports the importance of ubiquitin ligases in the pathogenesis of muscular disorders, although underlying mechanisms remain largely elusive. Here we show that the expression of RNF5 (aka RMA1), an ER-anchored RING finger E3 ligase implicated in muscle organization and in recognition and processing of malfolded proteins, is elevated and mislocalized to cytoplasmic aggregates in biopsies from patients suffering from sporadic-Inclusion Body Myositis (sIBM). Consistent with these findings, an animal model for hereditary IBM (hIBM), but not their control littermates, revealed deregulated expression of RNF5. Further studies for the role of RNF5 in the pathogenesis of s-IBM and more generally in muscle physiology were performed using RNF5 transgenic and KO animals. Transgenic mice carrying inducible expression of RNF5, under control of β-actin or muscle specific promoter, exhibit an early onset of muscle wasting, muscle degeneration and extensive fiber regeneration. Prolonged expression of RNF5 in the muscle also results in the formation of fibers containing congophilic material, blue-rimmed vacuoles and inclusion bodies. These phenotypes were associated with altered expression and activity of ER chaperones, characteristic of myodegenerative diseases such as s-IBM. Conversely, muscle regeneration and induction of ER stress markers were delayed in RNF5 KO mice subjected to cardiotoxin treatment. While supporting a role for RNF5 Tg mice as model for s-IBM, our study also establishes the importance of RNF5 in muscle physiology and its deregulation in ER stress associated muscular disorders

Vessel-associated stem cells from skeletal muscle: From biology to future uses in cell therapy

Over the last years, the existence of different stem cells with myogenic potential has been widely investigated. Besides the classical skeletal muscle progenitors represented by satellite cells, numerous multipotent and embryologically unrelated progenitors with a potential role in muscle differentiation and repair have been identified. In order to conceive a therapeutic approach for degenerative muscle disorders, it is of primary importance to identify an ideal stem cell endowed with all the features for a possible use in vivo. Among all emerging populations, vessel-associated stem cells are a novel and promising class of multipotent progenitors of mesodermal origin and with high myogenic potential which seem to best fit all the requirements for a possible cell therapy. In vitro and in viv

Oxidized buckypaper for stir-disc solid phase extraction: evaluation for several classes of environmental pollutants recovered from surface water samples

This paper describes, for the first time, the use of oxidized buckypaper (BP) as a sorbent membrane of a stir-disc solid phase extraction module. The original device, consisting of a BP disc (d = 34 mm) enveloped in a polypropylene mesh pouch, was designed to extract organic micropollutants (OMPs) from environmental water samples in dynamic mode. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to analyze the extracts. Several classes of pesticides and pharmaceuticals were chosen as model compounds to evaluate key parameters affecting the recovery rates. To this end, the effects of adsorption time, desorption time, stirring speed, type and volume of solvent, and sample volume were thoroughly examined. After optimization, a novel and in-depth study was conducted to find a correlation between physicochemical properties of the analytes and extraction yields. Recoveries were mainly governed by a combination of logP and pK a values. As indicated, hydrophilic compounds with logP 1 exhibited recoveries ranging between 50% and 100% depending on their pK a , while compounds with pK a between 6 and 7.5 gave low yields irrespective of their logP. The analytical method was also validated and tested as large scale screening method of OMPs in surface waters. The analysis of real samples revealed the presence of some nonsteroidal anti-inflammatory drugs, sulfonamides, and pesticides at low ng L -1 concentration levels with relative standard deviations lower than 8%. Copyright © 2018 American Chemical Society

Hereditary inclusion-body myopathy: clues on pathogenesis and possible therapy

Hereditary inclusion-body myopathy (h-IBM), or distal myopathy with rimmed vacuoles (DMRV), is an autosomal recessive disorder with onset in early adult life and a progressive course leading to severe disability. h-IBM/DMRV is due to mutations of a gene (GNE) that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. Despite the identification of the causative gene defect, it has not been unambiguously clarified how GNE gene mutations impair muscle metabolism. Although numerous studies have indicated a key role of hyposialylation of glycoproteins in h-IBM/DMRV pathogenesis, others have demonstrated new and unpredicted functions of the GNE gene, outside the sialic acid biosynthetic pathway, that may also be relevant. This review illustrates the clinical and pathologic characteristics of h-IBM/DMRV and the main clues available to date concerning the possible pathogenic mechanisms and therapeutic perspectives of this disorde

Oxidized Buckypaper for Stir-Disc Solid Phase Extraction: Evaluation of Several Classes of Environmental Pollutants Recovered from Surface Water Samples

This paper describes, for the first time, the use of oxidized buckypaper (BP) as a sorbent membrane of a stir-disc solid phase extraction module. The original device, consisting of a BP disc (<i>d</i> = 34 mm) enveloped in a polypropylene mesh pouch, was designed to extract organic micropollutants (OMPs) from environmental water samples in dynamic mode. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to analyze the extracts. Several classes of pesticides and pharmaceuticals were chosen as model compounds to evaluate key parameters affecting the recovery rates. To this end, the effects of adsorption time, desorption time, stirring speed, type and volume of solvent, and sample volume were thoroughly examined. After optimization, a novel and in-depth study was conducted to find a correlation between physicochemical properties of the analytes and extraction yields. Recoveries were mainly governed by a combination of log<i>P</i> and p<i>K</i>_a values. As indicated, hydrophilic compounds with log<i>P</i> < 1 showed poor affinity for the oxidized BP, compounds having log<i>P</i> > 1 exhibited recoveries ranging between 50% and 100% depending on their p<i>K</i>_a, while compounds with p<i>K</i>_a between 6 and 7.5 gave low yields irrespective of their log<i>P</i>. The analytical method was also validated and tested as large scale screening method of OMPs in surface waters. The analysis of real samples revealed the presence of some nonsteroidal anti-inflammatory drugs, sulfonamides, and pesticides at low ng L^–1 concentration levels with relative standard deviations lower than 8%

TWEAK in inclusion-body myositis muscle: possible pathogenic role of a cytokine inhibiting myogenesis

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 exert pleiotropic effects, including regulation of myogenesis. Sporadic inclusion-body myositis (IBM) is the most common muscle disease of the elderly population and leads to severe disability. IBM mesoangioblasts, different from mesoangioblasts in other inflammatory myopathies, display a myogenic differentiation defect. The objective of the present study was to investigate TWEAK-Fn14 expression in IBM and other inflammatory myopathies and explore whether TWEAK modulation affects myogenesis in IBM mesoangioblasts. TWEAK, Fn14, and NF-\u3baB expression was assessed by immunohistochemistry and Western blot in cell samples from both muscle biopsies and primary cultures. Mesoangioblasts isolated from samples of IBM, dermatomyositis, polymyositis, and control muscles were treated with recombinant human TWEAK, Fn14-Fc chimera, and anti-TWEAK antibody. TWEAK-RNA interference was performed in IBM and dermatomyositis mesoangioblasts. TWEAK levels in culture media were determined by enzyme-linked immunosorbent assay. In IBM muscle, we found increased TWEAK-Fn14 expression. Increased levels of TWEAK were found in differentiation medium from IBM mesoangioblasts. Moreover, TWEAK inhibited myogenic differentiation of mesoangioblasts. Consistent with this evidence, TWEAK inhibition by Fn14-Fc chimera or short interfering RNA induced myogenic differentiation of IBM mesoangioblasts. We provide evidence that TWEAK is a negative regulator of human mesoangioblast differentiation. Dysregulation of the TWEAK-Fn14 axis in IBM muscle may induce progressive muscle atrophy and reduce activation and differentiation of muscle precursor cells

Prolonged Secondary Stroke Prevention with Edoxaban: A Long-Term Follow-Up of the SATES Study

Background: Little evidence is available on the long-term efficacy and safety of edoxaban, mainly due to the recent release date. The primary objective of the study was to evaluate the safety of edoxaban, defined by the incidence of major bleedings. We then aimed to evaluate the incidence of thromboembolic events and the persistence of edoxaban therapy in the long-term. Methods: In this observational cohort study, we included ischemic stroke patients enrolled in a previous study to evaluate the safety and efficacy of long-term edoxaban treatment. Data were collected by a trained investigator through a structured telephone interview. Results: Sixty-three subjects (median age 81.0 (73.5–88.0) years, 38.1% male) were included in the study, with a mean follow-up of 4.4 ± 0.7 years (range: 3.2–5.5 years). Only one patient (1.6%, 0.4%/year) presented a major extracranial bleeding, and none had cerebral hemorrhage. Six thromboembolic events occurred in five patients (7.9%): three recurrent strokes, two transient ischemic attacks, and one myocardial infarction (2.2%/year). Over a follow-up period of more than three years, 13 patients discontinued edoxaban (20.6%). Conclusions: Edoxaban seems to be effective and safe in the long-term. The persistence rate of edoxaban therapy is optimal after more than three years of treatment

Prospective Observational Study of Safety of Early Treatment with Edoxaban in Patients with Ischemic Stroke and Atrial Fibrillation (SATES Study)

New direct oral anticoagulants are recommended for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). However, no data are available regarding the optimal time to start oral anticoagulation after acute stroke. The aim of our study was to evaluate the occurrence of symptomatic bleedings within 90 days from acute cardioembolic stroke in patients who received early treatment with Edoxaban. The study was conducted according to an observational prospective uncontrolled design. Secondary endpoints were the incidence of major bleeding (MB), hemorrhagic transformation within the first week of Edoxaban treatment, minor bleeding, and recurrent stroke. We included patients with Alberta Stroke Program Early Computed Tomography Score (ASPECTS) &ge; 6, NVAF, no previous treatment with any other anticoagulant, preserved swallowing function. Patients with estimated Glomerular Filtration Rate &lt; 50 mL/min, body weight &lt; 60 kg, receiving cyclosporine, dronedarone, erythromycin, ketoconazole, or previous treatment with any other anticoagulant were excluded. We enrolled 75 elderly patients with moderate disability. We did not observe any symptomatic intracranial bleeding or recurrent stroke after 3 months of treatment with early administration of Edoxaban, while two gastrointestinal MB, and 11 minor bleedings were reported. Asymptomatic bleeding was evaluated with a brain Magnetic Resonance Imaging performed 5 days after starting anticoagulant treatment with Edoxaban. Specifically, we observed small petechiae in 12% of the patients, confluent petechiae in 6.6% of the patients, and small hematoma of the infarcted area in 2.7% of the patients. No intralesional hematoma or hemorrhagic lesion outside the infarcted area were observed. According to our data, the early use of Edoxaban seems to be safe in patients after cardioembolic stroke. However, due to the small size of the study sample, and the short follow-up period, further studies are needed