心血管领域-心律失常方向

METHODS::The protein myelin oligodendrocyte glycoprotein (MOG) is a key component of myelin and an autoantigen in the disease multiple sclerosis (MS). Post-translational N-glycosylation of Asn31 of MOG seems to play a key role in modulating the immune response towards myelin. This is mediated by the interaction of Lewis-type glycan structures in the N-glycan of MOG with the DC-SIGN receptor on dendritic cells (DCs). Here, we report the synthesis of an unnatural Lewis X (LeX )-containing Fmoc-SPPS-compatible asparagine building block (SPPS=solid-phase peptide synthesis), as well as asparagine building blocks containing two LeX -derived oligosaccharides: LacNAc and Fucα1-3GlcNAc. These building blocks were used for the glycosylation of the immunodominant portion of MOG (MOG31-55 ) and analyzed with respect to their ability to bind to DC-SIGN in different biological setups, as well as their ability to inhibit the citrullination-induced aggregation of MOG31-55 . Finally, a cytokine secretion assay was carried out on human monocyte-derived DCs, which showed the ability of the neoglycopeptide decorated with a single LeX to alter the balance of pro- and anti-inflammatory cytokines, inducing a tolerogenic response.

METHODS::Acute cerebellar ataxia is a rare primary manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE). We report a case of a 22-year-old woman who presented with gait instability, behavioural changes and new-onset seizures. The tempo of disease progression was explained by an autoimmune cause, eventually fulfilling the criteria for systemic lupus erythematosus. The patient's neurological symptoms improved markedly following administration of steroids and immunomodulators. A review of literature on cerebellar ataxia in NPSLE and a summary of all reported cases to date are also presented.

METHODS::Henry R. Viets (1890-1969) was both a noted neurologist and medical historian. While at Harvard Medical School, from which he graduated in 1916, he attracted the attention of Harvey Cushing who directed Viets into these disciplines. Cushing arranged for Viets to take a fellowship in Oxford in the year after his graduation. With Cushing's recommendation, he lived with Sir William and Lady Osler and did research with the famous neurologist Sir Charles Sherrington. Viets was in London in 1935 when he heard about the remarkable success of Mary Walker in treating myasthenia gravis, first with physostigmine and then with neostigmine (Prostigmin). Securing an ampoule of this drug, he took it to the Massachusetts General Hospital where he was an attending neurologist and in March 1935 injected it into a myasthenic patient with great success. He established the first Myasthenia Gravis clinic in the world and was a pioneer in the treatment of this once obscure disease; he evaluated hundreds of patients and published many articles on myasthenia. He continued this association for more than 30 years. Under the tutelage of Cushing and Osler, Viets became a medical historian and bibliophile, publishing hundreds of articles and several books on many different subjects in the history of medicine. He was a president of the American Association for the History of Medicine and curator of the Boston Medical Library that eventually joined with the Harvard Medical School Library. Viets served on the Editorial Board of the New England Journal of Medicine for 40 years.

METHODS::Cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA is critical for the immune response to cancer and pathogen infection. Here, we discover that cGAS-DNA phase separation is required to resist negative regulation and allow efficient sensing of immunostimulatory DNA. We map the molecular determinants of cGAS condensate formation and demonstrate that phase separation functions to limit activity of the cytosolic exonuclease TREX1. Mechanistically, phase separation forms a selective environment that suppresses TREX1 catalytic function and restricts DNA degradation to an outer shell at the droplet periphery. We identify a TREX1 mutation associated with the severe autoimmune disease Aicardi-Goutières syndrome that increases penetration of TREX1 into the repressive droplet interior and specifically impairs degradation of phase-separated DNA. Our results define a critical function of cGAS-DNA phase separation and reveal a molecular mechanism that balances cytosolic DNA degradation and innate immune activation.

METHODS:Importance:Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease of the central nervous system characterized by inflammatory demyelination with axonal transection. MS affects an estimated 900 000 people in the US. MS typically presents in young adults (mean age of onset, 20-30 years) and can lead to physical disability, cognitive impairment, and decreased quality of life. This review summarizes current evidence regarding diagnosis and treatment of MS. Observations:MS typically presents in young adults aged 20 to 30 years with unilateral optic neuritis, partial myelitis, sensory disturbances, or brainstem syndromes such as internuclear ophthalmoplegia developing over several days. The prevalence of MS worldwide ranges from 5 to 300 per 100 000 people and increases at higher latitudes. Overall life expectancy is less than in the general population (75.9 vs 83.4 years), and MS more commonly affects women (female to male sex distribution of nearly 3:1). Diagnosis is made based on a combination of signs and symptoms, radiographic findings (eg, magnetic resonance imaging [MRI] T2 lesions), and laboratory findings (eg, cerebrospinal fluid-specific oligoclonal bands), which are components of the 2017 McDonald Criteria. Nine classes of disease-modifying therapies (DMTs), with varying mechanisms of action and routes of administration, are available for relapsing-remitting MS, defined as relapses at onset with stable neurologic disability between episodes, and secondary progressive MS with activity, defined as steadily increasing neurologic disability following a relapsing course with evidence of ongoing inflammatory activity. These drugs include interferons, glatiramer acetate, teriflunomide, sphingosine 1-phosphate receptor modulators, fumarates, cladribine, and 3 types of monoclonal antibodies. One additional DMT, ocrelizumab, is approved for primary progressive MS. These DMTs reduce clinical relapses and MRI lesions (new T2 lesions, gadolinium-enhancing lesions). Efficacy rates of current DMTs, defined by reduction in annualized relapse rates compared with placebo or active comparators, range from 29%-68%. Adverse effects include infections, bradycardia, heart blocks, macular edema, infusion reactions, injection-site reactions, and secondary autoimmune adverse effects, such as autoimmune thyroid disease. Conclusions and Relevance:MS is characterized by physical disability, cognitive impairment, and other symptoms that affect quality of life. Treatment with DMT can reduce the annual relapse rate by 29% to 68% compared with placebo or active comparator.

METHODS::Anti-IgLON5 disease is a newly discovered novel sleep disorder at the crossroads of neurology and immunology. In addition to the underlying sleep disorder, anti-IgLON5 manifests with progressive aerodigestive symptoms such as dysphagia, stridor, and vocal cord paresis in 90% cases and may present to the otolaryngologist. Herein we present a case of a patient with anti-IgLON5 disease who presented to the hospital with an acute airway including marked stridor and respiratory failure requiring intubation and subsequently a tracheostomy. Laryngoscope, 131:E724-E726, 2021.

METHODS::Presentation of severe pain syndromes prior to onset of motor weakness is an uncommon but documented finding in patients with Guillain-Barré syndrome (GBS). Sciatica in GBS is a difficult diagnosis when patients present with acute radiculopathy caused by herniated disc or spondylolysis. A middle-aged woman was admitted for severe low back pain, symptomatic hyponatraemia, vomiting and constipation. On further investigation, she was diagnosed with radiculopathy, and appropriate treatment was initiated. Brief symptomatic improvement was followed by new-onset weakness in lower limbs, which progressed to involve upper limbs and right extraocular muscles. With progressive, ascending, new-onset motor and sensory deficits and laboratory evidence of demyelination by Nerve Conduction Study, a diagnosis of variant GBS was made. She was treated with intravenous immunoglobulin 2 g/kg over 5 days. The presentation of severe low back pain that was masking an existing aetiology and possible dysautonomia and the unilateral right extraocular muscles instead of bilateral make our case unique and rare.

METHODS:BACKGROUND:Inflammatory spinal cord diseases are difficult to differentiate based on magnetic resonance (MR) morphological properties. However, correct diagnosis is crucial for treatment and outcome. OBJECTIVES:What MR characteristics allow correct classification? MATERIALS AND METHODS:A literature search for articles published in PubMed about various forms of transverse myelitis was performed. RESULTS:The length of the lesions, the level and location in the cross-section, and the enhancement pattern gives good clues for the correct diagnosis. The most important characteristics have been summarized in a table. CONCLUSIONS:In most cases, it is not possible to make a conclusive diagnosis, because many diseases overlap. ZUSAMMENFASSUNG:HINTERGRUND: Entzündliche Rückenmarkerkrankungen zeigen MR-morphologisch recht einheitliche Bilder, dennoch sind deren richtige Zuordnung zu einer Krankheit für die Therapie und weiteren Verlauf entscheidend. FRAGESTELLUNG:Welche Merkmale der Läsionen erlauben eine richtige Einordnung? MATERIAL UND METHODE:Recherche von Artikeln in pubmed.gov, die Myelitiden verschiedener Ätiologie beschreiben. ERGEBNISSE:Die Länge der Läsionen, deren Lokalisation im Rückenmark sowohl bezüglich Höhe als auch im Myelonquerschnitt, und das Kontrastmittelverhalten erlauben in vielen Fällen zumindest eine Eingrenzung der Differenzialdiagnosen. Zum Überblick werden die wichtigsten Charakteristika in einer Tabelle zusammengefasst. SCHLUSSFOLGERUNG:Eine sichere Zuordnung ist nur in Ausnahmefällen möglich, da sich viele Entitäten überlappen. Besonders schwierig ist dies bei Erkrankungen, die seltener vorkommen, und deswegen diesbezüglich wenig Erfahrung vorhanden ist.

METHODS:RATIONALE:The Miller Fisher syndrome (MFS) is an acute polyradiculoneuritis regarded as an uncommon clinical variant of the Guillain-Barre syndrome (GBS). It is characterized by the clinical triad of ophthalmoplegia, ataxia, and areflexia. The diagnosis of MFS is based on clinical presentation, presence of albuminocytologic dissociation in the cerebrospinal fluid (CSF), and normal brain imaging results. The presence of anti-ganglioside antibodies (GQlb) in the serum is helpful for the diagnosis. A history of upper respiratory tract infection or diarrhea 3 days to 6 weeks before the onset of MFS is common. However, there are some patients with atypical manifestations who are difficult to diagnose. Here, we present an incomplete form of MFS where antibodies against GQ1b were detected in the serum following an Epstein Barr virus (EBV) infection. PATIENT CONCERNS:A 77-year-old Chinese woman was admitted to the hospital with acute diplopia and right blepharoptosis. She had a history of mild upper respiratory tract infection 2 weeks ago. In 1 week, the symptoms rapidly progressed into bilateral ophthalmoplegia and hyporeflexia of the limbs without ataxia. CSF analysis on the third day after onset was normal, without albuminocytologic dissociation. EBV immunoglobulin G (IgG) antibodies were detected in the CSF. GQ1b and GD1b IgG antibodies were positive in the serum and negative in the CSF. No responsible lesion was found on brain imaging examination. DIAGNOSES:In accordance with the progressive bilateral ophthalmoplegia and hyporeflexia, the history of upper respiratory tract infection, the detection of EBV and GQ1b antibodies, and the negative brain imaging examination, the diagnosis of MFS was confirmed. INTERVENTIONS:The patient was administered intravenous immunoglobulin for 5 days. OUTCOMES:She had a favorable outcome after treatment. At the 6-week follow-up, bilateral ocular movement limitation and tendon reflexes had recovered. LESSONS:The diagnosis of MFS can be challenging, especially when encountered with incomplete symptoms and normal CSF results. Attention should be paid to the presence of anti-GQ1b IgG antibodies when the clinical manifestations are incomplete. Furthermore, EBV primary infection could be associated with MFS and considered a potential causative agent.

METHODS:BACKGROUND:Anxiety, depression and reduction of quality of life (QoL) are common in people with multiple sclerosis (pwMS). Fear of getting sick from COVID-19, government's lockdown and the imposed social distancing might have had an impact on psychological distress and QoL. OBJECTIVES:The aim of our study was to investigate anxiety, depression and QoL changes in pwMS during SARS-CoV-2 outbreak and lockdown in Italy. METHODS:67 pwMS with a previous (less than 6 months) neuropsychological evaluation before SARS-CoV-2 outbreak (T0) were re-evaluated at the time of the outbreak and lockdown in Italy (T1). They underwent a clinical and neurological evaluation and completed the State-Trait Anxiety Inventory (STAI-Y1), the Beck Depression Inventory second edition (BDI-II), and Multiple Sclerosis Quality of Life-54 (MsQoL-54) at T0 and T1. Benjamini-Hochberg procedure was applied to control the false discovery rate. RESULTS:BDI-II and STAI-Y1 scores did not change between T0 and T1. At T1, MsQoL-54 scores were higher on the satisfaction with sexual life and the social function subscales, and lower on the limitation due to emotional problems subscale. CONCLUSIONS:This is the first study that evaluated mood and QoL levels before and during the lockdown due to COVID-19 pandemic in pwMS. No worsening of anxiety and depression levels was found. Contrariwise some improvements were noted on QoL, the most reliable regarding the sexual satisfaction and the social function.