Transcription factor 7 like 2 (TCF7L2, also termed TCF4), is a Wnt effector induced transiently in the oligodendroglial lineage. The current well accepted hypothesis is that TCF7L2 inhibits oligodendrocyte differentiation and remyelination through canonical Wnt/β-catenin signaling. However, recent studies indicated that TCF7L2 activity is required during oligodendrocyte differentiation and remyelination. In order to clarify this, in situ hybridization, immunofluorescence and western blot analysis using in vivo TCF7L2 conditional knockout mice, were performed and it was found that TCF7L2 promotes oligodendrocyte differentiation during myelin formation and remyelination. Furthermore, it was established that TCF7L2 does not affect oligodendrocyte precursor cells during remyelination. These data are of important clinical significance to develop novel therapeutic targets to overcome multiple sclerosis and other demyelinating diseases.
The nature and magnitude of nocebo responses in primary headache disorders are still unknown. To assess the distribution and possible predictors of nocebo responses in primary headache treatments, databases, including PubMed, EMBASE, and Cochrane Library were searched from 1988 to December 31, 2020, for parallel‐group, double‐blind, randomized placebo‐controlled trials of pharmacologic treatments of primary headaches. The nocebo responses were calculated using a random effects meta‐analysis model. Subgroup and metaregression analyses were performed to determine the associations of study design and demographic characteristics with nocebo responses. A total of 178 randomized controlled trials that satisfied the inclusion criteria were included. Prophylactic treatments elicited stronger nocebo responses than acute treatments. The majority of nocebo adverse events were mild to moderate in severity, with the nervous and digestive systems being the most commonly affected. There was a strong correlation between the active medication and control groups in terms of adverse events, both quantitatively and qualitatively. Long treatment duration, a high proportion of subjects receiving active medications, multicenter design, North America, high body mass index, women, previous treatment experiences, and a high proportion of patients with migraine headache with aura were all found to be significant positive predictors of nocebo responses, whereas the year of publication was found to be inversely related to them. Nocebo effects should be noticed for their contribution to discontinuation of or lack of adherence to active treatments. Clarifying these nocebo‐related risk factors can aid in their clinical prevention and management.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset
neurodegenerative disorder. In 2007, a novel locus, SAX2, which is located on
chromosome 17p13 and contains 3 genes, ankyrin repeat and FYVE domain-containing 1
(ANKFY1), β-arrestin 2 (ARRB2) and
kinesin family member 1C (KIF1C), was linked to ARSACS. We generated
Ankfy1 heterozygous (Ankfy1/+) mice to establish an animal model and examine the
pathophysiological basis of ARSACS. The transgenic mice displayed an abnormal gait
with progressive motor and cerebellar nerve dysfunction that was highly reminiscent
of ARSACS. These clinical features were accompanied by an early-onset and progressive
loss of Purkinje cells, followed by gliosis. Additionally, the loss of Ankfy1
function resulted in an abnormal expression of neurotrophic factors (NTFs) in the
Ankfy1/+ mouse cerebellum. Moreover, Purkinje cells cultured from neonatal Ankfy1/+
mice exhibited a shorter dendritic length and decreased numbers of dendritic spines.
Importantly, cerebellar Purkinje cells from Ankfy1/+ mice and cells transfected with
a lentiviral Ankfy1 shRNA underwent apoptosis. We propose that transgenic Ankfy1/+
mice are a useful model for studying the pathogenesis of ARSACS and for exploring the
molecular mechanisms involved in this neurodegenerative disease.
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