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    • A new study by Zimerman and colleagues in

    2018-10-23

    A new study by Zimerman and colleagues in this issue of is one of the first to attempt to confirm animal-generated hypotheses in human patients and is of significant interest to NF1 cognitive research (). The authors examined the relationship between inhibitory GABAergic neurotransmission and motor skill learning in a highly selected sample of NF1 adults with normal cognitive and functional abilities. Compared to matched controls, the NF1 group demonstrated deficient learning of a fine motor task over a five day period, with impairments driven by poorer initial learning (fast online) and reduced offline consolidation of learned skills between training sessions. This was accompanied by a double-pulse transcranial magnetic stimulation (TMS) experiment assessing short intracortical inhibition (SICI) during performance of a reaction time task as used previously (). In control participants, reduced inhibition was reported at the end of the reaction time proteases (i.e. just before movement onset) compared to levels measured at the beginning of the reaction time period (i.e. beginning of movement preparation). In contrast, this task-related modulation of SICI was not observed in patients with NF1, with trends towards increased inhibitory processes. Interestingly, the authors report significant correlations between behavioral improvements and the degree of SICI modulation, with a relative increase in intracortical inhibition associated with reduced levels of skill acquisition for NF1 patients. Interpreted within the context of the animal literature, these findings provide an important step in bridging the gap between animal models and the human condition, suggesting dysfunctional GABAergic neurotransmission contributes to procedural learning in patients with NF1. Results from a recent magnetic resonance spectroscopy study, however, suggests the relationship between GABA levels and the human phenotype is more complex (). Lower levels of prefrontal GABA were identified in children with NF1, which was significantly associated with poorer IQ, but also with better inhibitory control. These data support the notion that abnormal inhibitory neurotransmission contributes to the cognitive phenotype in NF1, however together with the present data by Zimerman et al., they also indicate a more complex relationship between abnormal GABA-ergic neurotransmission and cognitive functions. There might not be a unitary influence of GABA-ergic dysfunction on all cognitive domains with the same impact, but with differing relevance depending on factors, such as age, cognitive function or cortical area. Limitations of the Zimerman et al. study include small sample sizes and a highly selected NF1 group controlled for confounding factors that does not represent the broader NF1 population, limiting conclusions that can be drawn.
    (MERS-CoV), a novel human virus that emerged in 2012, has caused significant respiratory disease and kindled fears of a SARS-like epidemic traversing the world (). While lacking the rapid human-to-human spread seen with its SARS-CoV cousin, the outbreak of MERS-CoV has continued in the Middle East over the past three years and has lead to infection in 26 countries, >1500 cases, and >550 deaths (). With periodic reintroduction from zoonotic sources and the possibility for further human adaptation, MERS-CoV remains a significant global public health threat and highlights the need for therapeutic countermeasures to limit infection and spread. Despite several years of study, understanding of MERS-CoV infection has been limited by a variety of factors including difficulty accessing samples, limited autopsy data, and the lack of robust animal models of disease (). However, a number of reports have provided both insights and tools for further study including extensive sequencing data, reverse genetic resources, and monoclonal antibodies for treatment of infection (). In contrast, vaccine strategies have been limited due to the absence of robust animal models. Typically examined in mice, the presence of specific charge and glycosylation difference between human and rodent DPP4, the receptor for MERS-CoV, prevent infection (). Therefore, the traditional approaches to study pathogenesis and vaccine efficacy have been stunted. The lack of a small animal model has shifted MERS-CoV research into larger models including non-human primates and ungulates (). Koch\'s postulates were first achieved for MERS-CoV in rhesus macaques (). Subsequently, other large animal models have been reported including marmosets, camels, rabbits, and alpacas and vary in their levels of MERS-CoV pathogenesis (). While new small animal models have been described and continue to be developed, in the short term, non-human primates provide the best model for testing vaccines and therapeutics.