Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study

Fanconi anemia (FA) is an autosomal recessive disorder that is defined by cellular hypersensitivity to DNA cross-linking agents, and is characterized clinically by developmental abnormalities, progressive bone-marrow failure, and predisposition to leukemia and solid tumors. There is extensive genetic heterogeneity, with at least 11 different FA complementation groups. FA-A is the most common group, accounting for approximately 65% of all affected individuals. The mutation spectrum of the FANCA gene, located on chromosome 16q24.3, is highly heterogeneous. Here we summarize all sequence variations (mutations and polymorphisms) in FANCA described in the literature and listed in the Fanconi Anemia Mutation Database as of March 2004, and report 61 novel FANCA mutations identified in FA patients registered in the International Fanconi Anemia Registry (IFAR). Thirty-eight novel SNPs, previously unreported in the literature or in dbSNP, were also identified. We studied the segregation of common FANCA SNPs in FA families to generate haplotypes. We found that FANCA SNP data are highly useful for carrier testing, prenatal diagnosis, and preimplantation genetic diagnosis, particularly when the disease-causing mutations are unknown. Twenty-two large genomic deletions were identified by detection of apparent homozygosity for rare SNPs. In addition, a conserved SNP haplotype block spanning at least 60 kb of the FANCA gene was identified in individuals from various ethnic groups.     

Frontal theta and posterior alpha in resting EEG: A critical examination of convergent and discriminant validity

Prior research has identified two resting EEG biomarkers with potential for predicting functional outcomes in depression: theta current density in frontal brain regions (especially rostral anterior cingulate cortex) and alpha power over posterior scalp regions. As little is known about the discriminant and convergent validity of these putative biomarkers, a thorough evaluation of these psychometric properties was conducted toward the goal of improving clinical utility of these markers. Resting 71-channel EEG recorded from 35 healthy adults at two sessions (1-week retest) were used to systematically compare different quantification techniques for theta and alpha sources at scalp (surface Laplacian or current source density [CSD]) and brain (distributed inverse; exact low resolution electromagnetic tomography [eLORETA]) level. Signal quality was evaluated with signal-to-noise ratio, participant-level spectra, and frequency PCA covariance decomposition. Convergent and discriminant validity were assessed within a multitrait-multimethod framework. Posterior alpha was reliably identified as two spectral components, each with unique spatial patterns and condition effects (eyes open/closed), high signal quality, and good convergent and discriminant validity. In contrast, frontal theta was characterized by one low-variance component, low signal quality, lack of a distinct spectral peak, and mixed validity. Correlations between candidate biomarkers suggest that posterior alpha components constitute reliable, convergent, and discriminant biometrics in healthy adults. Component-based identification of spectral activity (CSD/eLORETA-fPCA) was superior to fixed, a priori frequency bands. Improved quantification and conceptualization of frontal theta is necessary to determine clinical utility.     

Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer's disease

The allelic frequency of the gene for the K variant of butyrylcholinesterase (BCHE-K) was 0.17 in 74 subjects with late-onset (age > 65 years) histopathologically diagnosed Alzheimer's disease (AD), which was higher than the frequencies in 104 elderly control subjects (0.09), in 14 early-onset cases of confirmed AD (0.07) and in 29 confirmed cases of other dementia (0.10). The association of BCHE-K with late-onset AD was limited to carriers of the epsilon 4 allele of the apolipoprotein E gene (APOE), among whom the presence of BCHE-K gave an odds ratio of confirmed late-onset AD of 6.9 (95% C.I. 1.65-29) in subjects > 65 years and of 12.8 (1.9-86) in subjects > 75 years. In APOE epsilon 4 carriers over 75 years, only 1/22 controls, compared with 10/24 confirmed late-onset AD cases, had BCHE-K. We suggest that BCHE-K, or a nearby gene on chromosome 3, acts in synergy with APOE epsilon 4 as a susceptibility gene for late-onset AD.      

ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome

It was shown recently that mutations of the ATRX gene give rise to a severe, X-linked form of syndromal mental retardation associated with alpha thalassaemia (ATR-X syndrome). In this study, we have characterised the full-length cDNA and predicted structure of the ATRX protein. Comparative analysis shows that it is an entirely new member of the SNF2 subgroup of a superfamily of proteins with similar ATPase and helicase domains. ATRX probably acts as a regulator of gene expression. Definition of its genomic structure enabled us to identify four novel splicing defects by screening 52 affected individuals. Correlation between these and previously identified mutations with variations in the ATR-X phenotype provides insights into the pathophysiology of this disease and the normal role of the ATRX protein in vivo.      

Identification of non-amplifying CYP21 genes when using PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees

Steroid 21-hydroxylase deficiency is among the most common inborn errors of metabolism in man. Characterization of mutations in the 21- hydroxylase gene (CYP21) has permitted genetic diagnosis, facilitated by the polymerase chain reaction (PCR). The most common mutation is conversion of an A or C at nt656 to a G in the second intron causing aberrant splicing of mRNA. Homozygosity for nt656G is associated with profoundly deficient adrenal cortisol and aldosterone synthesis, secondary hypersecretion of adrenal androgens, and a severe form of congenital adrenal hyperplasia (CAH) characterized by ambiguous genitalia and/or sodium wasting in newborns. During the course of genetic analysis of CYP21 mutations in CAH families, we and others have noticed a number of relatives genotyped as nt656G homozygotes, yet showing no clinical signs of disease. A number of lines of evidence have led us to propose that the putative asymptomatic nt656G/G individuals are incorrectly typed due to dropout of one haplotype during PCR amplification of CYP21. For prenatal diagnosis, we recommend that microsatellite typing be used as a supplement to CYP21 genotyping in order to resolve ambiguities at nt656.      

社交性应激反应问卷中文版在大学生中应用的信效度初步评价

目的：建立社交性应激反应问卷（RSQ-SSV）中文版，并分析其信、效度。方法：按量表翻译程序将RSQ—SSV翻译成中文，整群分层选取409名大学生进行RSQ—SSV中文版的测量。随机抽取90名学生于初评后一个月进行重测，并与美国样本进行比较。结果：RSQ-SSV中文版整个问卷的Cronbach α系数为0．88，各因子仅系数在0．73～0．81之间；重测信度为0．70；全量表的条目间平均相关系数为0．11，5因子的条目间平均相关系数在0．19～0．29之间，因子间相关系数在0．12～0．76之间；条目对因子负荷系数在0．38—0．86之间，复相关系数在0．14—0．74之间；验证性因子分析的指标：IFI为0．93，CFI为0．93，TLI为0．92，RMSEA为0．06。中国大学生样本的不随意的逃避反应因子得分高于美国大学生样本[（0．97±0．41）vs．（0．91±0．48），P=0．002]，而初级亲近控制应对反应、次级亲近控制应对反应、不随意的亲近反应得分均低于美国大学生样本[（1．75±0．49）vs．（2．12±0．50）、（1．51±0．43）vs．（1．80±0．48）、（1．17±0．44）vs．（1．36±0．56），均P〈0．001]。结论：RSQ-SSV中文版具有良好的信、效度，可以试用于我国大学生社交性应激反应的测评。     

Incorporating spiritual beliefs into a cognitive model of worry

Cognitive theory and research have traditionally highlighted the relevance of the core beliefs about oneself, the world, and the future to human emotions. For some individuals, however, core beliefs may also explicitly involve spiritual themes. In this article, we propose a cognitive model of worry, in which positive/negative beliefs about the Divine affect symptoms through the mechanism of intolerance of uncertainty. Using mediation analyses, we found support for our model across two studies, in particular, with regards to negative spiritual beliefs. These findings highlight the importance of assessing for spiritual alongside secular convictions when creating cognitive-behavioral case formulations in the treatment of religious individuals.     

Sleep architecture and sleep-related mentation in securely and insecurely attached people

Based on REM sleep's brain activation patterns and its participation in consolidation of emotional memories, we tested the hypothesis that measures of REM sleep architecture and REM sleep-related mentation would be associated with attachment orientation. After a habituation night in a sleep lab, a convenience sample of 64 healthy volunteers were awakened 10 minutes into a REM sleep episode and 10 minutes into a control NREM sleep episode in counterbalanced order, then asked to report a dream and to rate themselves and a significant other on a list of trait adjectives. Relative to participants classified as having secure attachment orientations, participants classified as anxious took less time to enter REM sleep and had a higher frequency of REM dreams with aggression and self-denigrating themes. There were no significant differences across attachment groups in other measures of sleep architecture or in post REM-sleep awakening ratings on PANAS subscales reflecting mood and alertness. Selected aspects of REM sleep architecture and mentation appeared to be associated with attachment orientation. We suggest that REM sleep plays a role in processing experiences and emotions related to attachment, and that certain features of sleep and dreaming reflect attachment orientations.