内质网应激和胰岛素抵抗

2型糖尿病的发病机制主要涉及胰岛素抵抗,近年来研究表明内质网应激可诱导胰岛素抵抗的形成,并使与改善胰岛素受体敏感性相关的内质网应激标志物分子氧调节蛋白150和转录因子X盒结合蛋白-1表达增强,表明内质网应激对细胞具有双重作用,一方面可诱导胰岛素抵抗,另一方面激发对应激的适应反应。     

Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Structural equation modeling (SEM) was used to examine the development of intellectual functioning in 145 school-age pairs of siblings. Each pair included one child with Fragile X syndrome (FXS) and one unaffected sibling. All pairs of children were evaluated on the Wechsler Intelligence Scale for Children-Third Edition (WISC-III) at time 1 and 80 pairs of children received a second evaluation at time 2 approximately 4 years later. Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points (r=0.55 and 0.64 respectively). However, when gender, age, and the time between assessments were included as covariates in the structural equation model, FMRP accounted for only 5% of the variance in intellectual ability scores at time 1 and 13% of the variance at time 2. The results of this study suggest that slower learning contributes to the low and declining standardized IQ scores observed in children with FXS.     

Emotional Reaction to Fragile X Premutation Carrier Tests Among Infertile Women

Female fragile X premutation carriers are at ∼10-fold increased risk of premature ovarian failure (follicle stimulating hormone >40 mIU/mL, amenorrhea, age <40). A milder degree of premature ovarian aging (diminished ovarian reserve, where follicle stimulating hormone levels are typically 10–20 mIU/mL) results in infertility. Approximately 10% of fertility clinic patients have this diagnosis. A cohort of 20 women diagnosed with diminished ovarian reserve provided a blood specimen (confidential results), and completed structured questionnaires that assessed emotional reactions to potentially being a premutation carrier (pretest questionnaire, n = 20) and the posttest known carrier status (3 month follow-up questionnaire, n = 18 non-carriers). Responses were measured using 9-point scales, and analyzed with Fisher exact and Wilcoxon exact tests. While most participants did not view fragile X premutations as a serious medical condition, perceptions of seriousness were positively correlated with anger and regret about not knowing sooner of the potential association of these premutations with infertility. Overall, when women (pretest) imagined themselves as carriers, their self-esteem and Health Orientation Scale responses were unchanged with the exception of feeling more afraid (p = 0.004). Despite strongly wishing for negative test results, they were glad to know there might be a medical explanation for their infertility. Financial Support: This work was financially supported by a University of Virginia School of Medicine Research & Development Award.     

Working Memory In Individuals With Fragile X Syndrome

The present research tests the hypothesis that fragile X syndrome (FXS) is associated with a deficit in working memory (WM) and the deficit is more pronounced the higher the control requirements of the task. To this purpose, 15 boys with FXS and 15 typically developing children, matched for mental age, assessed with Logical Operation Test, were tested with batteries of 4 verbal and 4 visuospatial WM tasks requiring different levels of control. Children with FXS showed a performance equal to controls, in WM tasks requiring low and medium-low control but significant impairment in correspondence with greater control requirements. Results show that boys with FXS present a WM deficit only when high control is required by the task, supporting the hypothesis that control can be a critical variable distinguishing WM functions and explaining intellectual differences. On the contrary the hypothesis that the FXS is associated with a visuospatial deficit was not supported.     

Selective spatial processing deficits in an at-risk subgroup of the fragile X premutation

Until a decade ago, it was assumed that males with the fragile X premutation were unaffected by any cognitive phenotype. Here we examined the extent to which CGG repeat toxicity extends to visuospatial functioning in male fragile X premutation carriers who are asymptomatic for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Thirty-three premutation males aged 20-68 years [divided into two groups: 16 low-repeat carriers (CGG ≥ 55 ≤ 100) and 17 high-repeat carriers (CGG>100)] with a family history of fragile X syndrome and 62 non-affected adult males with normal FMR1 alleles were recruited. Subjects underwent neuropsychological tests of visuospatial and visual working memory functioning and visuoperceptual processing. On measures of visuospatial processing, the high-repeat carriers performed significantly worse than the normal allele group when age and IQ were covaried out. With increasing age and only in carriers of a larger (>100 repeats) premutation allele was there a greater decrement in visuospatial working memory functioning. Performance on spatial and perceptual judgement tasks failed to show similar specificity in males within the upper premutation range. We conclude that identification of selective visuospatial impairments in carriers of a larger premutation allele indicates greater CGG repeat toxicity in specific neural regions. Longitudinal follow-up studies will be needed to determine whether subtle decline in visuospatial functioning is associated with the later onset of motor symptoms of FXTAS.     

Cognition and lobar morphology in full mutation boys with fragile X syndrome

The aims of the present study are twofold: (1) to examine cortical morphology (CM) associated with alterations in cognition in fragile X syndrome (FXS); (2) to characterize the CM profile of FXS versus FXS with an autism diagnosis (FXS + Aut) as a preliminary attempt to further elucidate the behavioral distinctions between the two sub-groups. We used anatomical magnetic resonance imaging surface-based morphometry in 21 male children (FXS N = 11 and age [2.27-13.3] matched controls [C] N = 10). We found (1) increased whole hemispheric and lobar cortical volume, cortical thickness and cortical complexity bilaterally, yet insignificant changes in hemispheric surface area and gyrification index in FXS compared to C; (2) linear regression analyses revealed significant negative correlations between CM and cognition; (3) significant CM differences between FXS and FXS + Aut associated with their distinctive behavioral phenotypes. These findings are critical in understanding the neuropathophysiology of one of the most common intellectual deficiency syndromes associated with altered cognition as they provide human in vivo information about genetic control of CM and cognition.     

Exploring inhibitory deficits in female premutation carriers of fragile X syndrome: Through eye movements

There is evidence which demonstrates that a subset of males with a premutation CGG repeat expansion (between 55 and 200 repeats) of the fragile X mental retardation 1 gene exhibit subtle deficits of executive function that progressively deteriorate with increasing age and CGG repeat length. However, it remains unclear whether similar deficits, which may indicate the onset of more severe degeneration, are evident in female PM-carriers. In the present study we explore whether female PM-carriers exhibit deficits of executive function which parallel those of male PM-carriers. Fourteen female fragile X premutation carriers without fragile X-associated tremor/ataxia syndrome and fourteen age, sex, and IQ matched controls underwent ocular motor and neuropsychological tests of select executive processes, specifically of response inhibition and working memory. Group comparisons revealed poorer inhibitory control for female premutation carriers on ocular motor tasks, in addition to demonstrating some difficulties in behaviour self-regulation, when compared to controls. A negative correlation between CGG repeat length and antisaccade error rates for premutation carriers was also found. Our preliminary findings indicate that impaired inhibitory control may represent a phenotype characteristic which may be a sensitive risk biomarker within this female fragile X premutation population.