Type I interferons are important co-stimulatory signals during T cell receptor mediated human MAIT cell activation

Mucosal associated invariant T (MAIT) cells are abundant unconventional T cells that can be stimulated either via their TCR or by innate cytokines. The MAIT cell TCR recognises a pyrimidine ligand, derived from riboflavin synthesising bacteria, bound to MR1. In infection, bacteria not only provide the pyrimidine ligand but also co-stimulatory signals, such as TLR agonists, that can modulate TCR-mediated activation. Recently, type I interferons (T1-IFNs) have been identified as contributing to cytokine-mediated MAIT cell activation. However, it is unknown whether T1-IFNs also have a role during TCR-mediated MAIT cell activation. In this study, we investigated the co-stimulatory role of T1-IFNs during TCR-mediated activation of MAIT cells by the MR1 ligand 5-amino-6-d -ribitylaminouracil/methylglyoxal. We found that T1-IFNs were able to boost interferon-γ and granzyme B production in 5-amino-6-d -ribitylaminouracil/methylglyoxal-stimulated MAIT cells. Similarly, influenza virus-induced T1-IFNs enhanced TCR-mediated MAIT cell activation. An essential role of T1-IFNs in regulating MAIT cell activation by riboflavin synthesising bacteria was also demonstrated. The co-stimulatory role of T1-IFNs was also evident in liver-derived MAIT cells. T1-IFNs acted directly on MAIT cells to enhance their response to TCR stimulation. Overall, our findings establish an important immunomodulatory role of T1-IFNs during TCR-mediated MAIT cell activation.     

A study of idiopathic generalised epilepsy in an Irish population.

Idiopathic generalised epilepsy (IGE) is subdivided into syndromes based on clinical and EEG features. PURPOSE: The aim of this study was to characterise all cases of IGE with supportive EEG abnormalities in terms of gender differences, seizure types reported, IGE syndromes, family history of epilepsy and EEG findings. We also calculated the limited duration prevalence of IGE in our cohort. METHODS: Data on abnormal EEGs were collected retrospectively from two EEG databases at two tertiary referral centres for neurology. Clinical information was obtained from EEG request forms, standardised EEG questionnaires and medical notes of patients. RESULTS: two hundred twenty-three patients met our inclusion criteria, 89 (39.9%) male and 134 (60.1%) females. Tonic clonic seizures were the most common seizure type reported, 162 (72.65%) having a generalised tonic clonic seizure (GTCS) at some time. IGE with GTCS only (EGTCSA) was the most common syndrome in our cohort being present in 94 patients (34 male, 60 female), with 42 (15 male, 27 female) patients diagnosed with Juvenile myoclonic epilepsy (JME), 23 (9 male, 14 female) with Juvenile absence epilepsy (JAE) and 20 (9 male, 11 female) with childhood absence epilepsy (CAE). EEG studies in all patients showed generalised epileptiform activity. CONCLUSIONS: More women than men were diagnosed with generalised epilepsy. Tonic clonic seizures were the most common seizure type reported. EGTCSA was the most frequent syndrome seen. Gender differences were evident for JAE and JME as previously reported and for EGTCSA, which was not reported to date, and reached statistical significance for EGTCA and JME.     

DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers

For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.     

Synucleinopathies: clinical and pathological implications

The synucleinopathies are a diverse group of neurodegenerative disorders that share a common pathologic lesion composed of aggregates of insoluble alpha-synuclein protein in selectively vulnerable populations of neurons and glia. Growing evidence links the formation of abnormal filamentous aggregates to the onset and progression of clinical symptoms and the degeneration of affected brain regions in neurodegenerative disorders. These disorders may share an enigmatic symmetry, i.e., missense mutations in the gene encoding for the disease protein (alpha-synuclein) cause familial variants of Parkinson disease as well as its hallmark brain lesions, but the same brain lesions also form from the corresponding wild-type brain protein in the more common sporadic varieties of Parkinson disease. It is likely that clarification of this enigmatic symmetry in 1 form of synucleinopathy will have a profound impact on understanding the mechanisms underlying all these disorders. Furthermore, these efforts will likely lead to novel diagnostic and therapeutic strategies in regard to the synucleinopathies.     

No aliasing at edges in normal viewing

Although spatial aliasing by the extrafoveal retina can occur under natural viewing conditions, it does not commonly disturb our vision. One possible explanation for this is that real scenes do not have sufficient power in the high frequencies to produce aliasing. We examined whether aliasing distorted the appearance of a high contrast edge, which is a common stimulus in the environment. Observers made a two-interval forced-choice discrimination between low-pass filtered and unfiltered edges at 0, 10, 20, and 40 deg eccentricity. This discrimination could be made only when frequency components were removed below both the cone and ganglion cell Nyquist frequencies at each eccentricity. Since supra-Nyquist frequency components could not be detected in edges, they are incapable of producing aliasing.