Bicuspid aortic valve and aortic coarctation are linked to deletion of the X chromosome short arm in Turner syndrome.

BACKGROUND: Congenital heart disease (CHD) is a cardinal feature of X chromosome monosomy, or Turner syndrome (TS). Haploinsufficiency for gene(s) located on Xp have been implicated in the short stature characteristic of the syndrome, but the chromosomal region related to the CHD phenotype has not been established. DESIGN: We used cardiac MRI to diagnose cardiovascular abnormalities in four non-mosaic karyotype groups based on 50-metaphase analyses: 45,X (n=152); 46,X,del(Xp) (n=15); 46,X,del(Xq) (n=4); and 46,X,i(Xq) (n=14) from peripheral blood cells. RESULTS: Bicuspid aortic valves (BAV) were found in 52/152 (34%) 45,X study subjects and aortic coarctation (COA) in 19/152 (12.5%). Isolated anomalous pulmonary veins (APV) were detected in 15/152 (10%) for the 45,X study group, and this defect was not correlated with the presence of BAV or COA. BAVs were present in 28.6% of subjects with Xp deletions and COA in 6.7%. APV were not found in subjects with Xp deletions. The most distal break associated with the BAV/COA trait was at cytologic band Xp11.4 and ChrX:41,500 000. One of 14 subjects (7%) with the 46,X,i(Xq) karyotype had a BAV and no cases of COA or APV were found in this group. No cardiovascular defects were found among four patients with Xq deletions. CONCLUSIONS: The high prevalence of BAV and COA in subjects missing only the X chromosome short arm indicates that haploinsufficiency for Xp genes contributes to abnormal aortic valve and aortic arch development in TS.

Transitions in intrinsic capacity among community-dwelling older people and their associated factors: a multistate modelling analysis.

OBJECTIVES: Trajectory of intrinsic capacity (IC) can be non-linear and discontinuous, which traditional linear models may not be able to handle. This study thus aimed to model the trajectory of IC as transitions between different IC states and examine their associated factors. METHODS: Longitudinal data from a sample of community-dwelling older people aged 60 years or above (n = 1,588) was analysed. A set of 14 self-reported items representing different domains of IC were administered annually to measure IC at four time points. Based on the number of impaired IC domains (i.e., cognitive, locomotor, vitality, sensory, and psychological), participants at each time point were classified into one of three IC states, namely state 1 (0 impaired domain), state 2 (1-2 impaired domains), and state 3 (3-5 impaired domains). Multistate modelling was used to identify factors associated with the transitions from one state to another. RESULTS: The mean age of participants was 75.0 years, and 77.4% of them were female. At baseline, 12.4% were in state 1, 51.8% were in state 2, and 35.8% were in state 3. 62.8% of participants experienced at least one transition between states, among which 12% experienced a transition every year. The transitions occurred mostly between adjacent IC states and could take place back and forth. Age, sex, marital status, perceived financial adequacy, number of chronic diseases, and self-rated health were the factors associated with the transitions. CONCLUSION: Findings may serve as a valuable reference for guiding future policies to optimize IC and promote healthy ageing using a person-centred approach.

Translation, Cultural Adaptation, and Validation of the Cantonese Version of SarQoL in Hong Kong's Older Population: An Interviewer-Administered Questionnaire for Assessing Sarcopenia-Specific Quality of Life in Fieldwork Practice.

Objective: This study examined the psychometric properties of the Cantonese version of the SarQoL® questionnaire. Participants: A total of 118 (including 60 non-sarcopenic and 58 sarcopenic) community-dwelling older adults aged 65 years or above with Cantonese as their mother tongue. Methods: Translation and cultural adaptation of the SarQoL were conducted using a standardized protocol. To validate the Cantonese SarQoL, psychometric properties including discriminative power, reliability (including internal consistency and test-retest reliability), and construct validity (including convergent and divergent validity), as well as floor and ceiling effects, were assessed. Results: The translation of the questionnaire was completed without significant difficulties. Results indicated that the Cantonese SarQoL had (1) good discriminative power (sarcopenic participants had lower overall scores, mean = 66.1 vs 75.0, p < 0.001; the overall score was negatively predictive of the presence of sarcopenia, adjusted OR = 0.949, 95% CI = [0.912, 0.983]), (2) good internal consistency (Cronbach's alpha = 0.835; correlations between domain and overall scores ranged from 0.576 to 0.868), (3) excellent test-retest agreement (intraclass correlation coefficient = 0.801), (4) good construct validity (convergent: moderate to strong correlations were found between the overall score and almost all of the SF-36 and EQ-5D domains; divergent: weaker correlations were found between the overall score and SF-36 social functioning, ρ = -0.098, and EQ-5D self-care, ρ = -0.331), and (5) no floor or ceiling effect. Conclusion: The Cantonese SarQoL is valid and reliable, and thus can be used as an interviewer-administered questionnaire for assessing sarcopenia-specific quality of life in fieldwork practice.

Autoimmune disorders in women with turner syndrome and women with karyotypically normal primary ovarian insufficiency.

The higher prevalence of autoimmune diseases in women compared to men could be due to effects of ovarian hormones, pregnancy and/or the presence of a second X chromosome. To elucidate the role of these factors, we investigated the prevalence and spectrum of autoimmune diagnoses in women with primary ovarian insufficiency associated with X chromosome monosomy (Turner syndrome, TS, n = 244) and women with karyotypically normal (46,XX) primary ovarian insufficiency (POI, n = 457) in a prospective study, conducted at the National Institutes of Health. We compared the study group prevalence to normative data for the U.S. population of women. Chronic lymphocytic (Hashimoto's) thyroiditis (HT) occurred in 37% of women with TS vs. 15% with POI (P < 0.0001); HT prevalence in both ovarian insufficiency groups significantly exceeded that in U.S. population of women (5.8%). Inflammatory bowel (IBD, 4%) and celiac disease (CD, 2.7%) were significantly increased in TS, but not in POI. No other autoimmune diagnosis, including Graves' disease or Type 1 diabetes appears to be significantly increased in either group. Women with TS had higher pro-inflammatory IL6 and TGF ß1 levels (p < 0.0001 for both), and lower anti-inflammatory IL10 and TGF ß2 levels (p < 0.005 for both) compared to POI and to normal volunteers. Lifetime estrogen exposure and parity were significantly lower in TS compared to POI, which were in turn lower than the general population of women. The finding that lymphocytic thyroiditis is greatly increased in both women with TS and POI suggests that factors associated with ovarian insufficiency per se promote this form of autoimmunity. The absence of a normal second X-chromosome further contributes to increased autoimmunity in TS.

Genomic imprinting and Turner syndrome.

The term 'genomic imprinting' refers to selective repression of transcription from distinct chromosomal regions determined by their maternal or paternal inheritance. There are two potentially important aspects of imprinting that may manifest in individuals with X monosomy, or Turner syndrome (TS). Given that men are monosomic for Xm while women are mosaic for Xm:Xp, genomic imprinting of important X-linked genes should be associated with sexually dimorphic traits, e.g., social skills, regional fat deposition and adult height. Such X-imprinted traits are predicted to differ in Turner groups monosomic for Xm vs. Xp. We review relevant studies of psychosocial attributes, regional fat distribution and height in TS related to parent of origin for the single normal X chromosome. In addition, we review recent evidence that monosomy for the X chromosome per se, regardless of the parental origin, may disrupt the normal distribution of autosomal imprint patterns. This may contribute to a high rate of fetal loss in human monosomy via impaired placentation in the most severe cases, and to loss of paternal contribution to growth in the mildest manifestation.

Perturbation of the transforming growth factor ß system in Turner syndrome.

OBJECTIVE: To measure components of the circulating transforming growth factor ß (TGFß) system in patients with Turner syndrome (TS) compared to relevant controls and to ascertain correlation with endocrine and cardiovascular parameters. METHODS: TGFß1, TGFß2 and endoglin (a vascular TGF receptor component) were measured using enzyme-linked immunoassays in the sera of 40 subjects with TS and 40 healthy volunteer women. The cardiovascular phenotype in TS subjects was extensively characterized by cardiac magnetic resonance (MR) and echo. RESULTS: TGFß1 levels were about 3-fold higher in TS while TGFß2 levels were about 3.5-fold higher in controls (P<0.000 1 for both). Soluble endoglin levels were 25% higher in TS (P<0.000 1). Variation in TGFß system components was not explained by age, blood pressure, platelet count, thyroid function, body proportions or cardiovascular phenotype. CONCLUSION: There is profound perturbation of the TGFß system evident in the circulation of individuals with TS.

Monosomy for the X chromosome.

Dosage compensation serves to equalize X chromosome gene expression in mammalian males and females and involves extensive silencing of the 2nd X chromosome in females. If dosage compensation mechanisms completely suppressed the 2nd X chromosome, then actual physical loss of this "eXtra" chromosome should have few consequences. However, X monosomy has major effects upon normal development, fertility and longevity in humans and some other species. This article reviews observations and arguments attempting to explain the phenotypic effects of X monosomy in humans and other mammals in terms of X chromosome gene dosage.

Tau is hyperphosphorylated in the insulin-like growth factor-I null brain.

IGF action has been implicated in the promotion of oxidative stress and aging in invertebrate and murine models. However, some in vitro models suggest that IGF-I specifically prevents neuronal oxidative damage. To investigate whether IGF-I promotes or retards brain aging, we evaluated signs of oxidative stress and neuropathological aging in brains from 400-d-old Igf1-/- and wild-type (WT) mice. Lipofuscin pigment accumulation reflects oxidative stress and aging, but we found no difference in lipofuscin deposition in Igf1-/- and WT brains. Likewise, there was no apparent difference in accumulation of nitrotyrosine residues in Igf1-/- and WT brains, except for layer IV/V of the cerebral cortex, where these proteins were about 20% higher in the Igf1-/- brain (P = 0.03). We found no difference in the levels of oxidative stress-related enzymes, neuronal nitric oxide synthase, inducible nitric oxide synthase, and superoxide dismutase in Igf1-/- and WT brains. Tau is a microtubule-associated protein that causes the formation of neurofibrillary tangles and senile plaques as it becomes hyperphosphorylated in the aging brain. Tau phosphorylation was dramatically increased on two specific residues, Ser-396 and Ser-202, both glycogen synthase kinases target sites implicated in neurodegeneration. These observations indicate that IGF-I has a major role in regulating tau phosphorylation in the aging brain, whereas its role in promoting or preventing oxidative stress remains uncertain.

An inkblot for attitudes: affect misattribution as implicit measurement.

Misattributions people make about their own affective reactions can be used to measure attitudes implicitly. Combining the logic of projective tests with advances in priming research, the affect misattribution procedure (AMP) was sensitive to normatively favorable and unfavorable evaluations (Experiments 1-4), and the misattribution effect was strong at both fast and slow presentation rates (Experiments 3 and 4). Providing further evidence of validity, the AMP was strongly related to individual differences in self-reported political attitudes and voting intentions (Experiment 5). In the socially sensitive domain of racial attitudes, the AMP showed in-group bias for Black and White participants. AMP performance correlated with explicit racial attitudes, a relationship that was moderated by motivations to control prejudice (Experiment 6). Across studies, the task was unaffected by direct warnings to avoid bias. Advantages of the AMP include large effect sizes, high reliability, ease of use, and resistance to correction attempts.

A ketogenic diet increases brain insulin-like growth factor receptor and glucose transporter gene expression.

A ketogenic diet suppresses seizure activity in children and in juvenile rats. To investigate whether alteration in brain IGF activity could be involved in the beneficial effects of the ketogenic diet, we examined the effects of this diet on IGF system gene expression in the rat brain. Juvenile rats were fed one of three different diets for 7 d: ad libitum standard rat chow (AL-Std), calorie-restricted standard chow (CR-Std), or a calorie-restricted ketogenic diet (CR-Ket). The calorie-restricted diets contained 90% of the rats' calculated energy requirements. The AL-Std diet group increased in weight, whereas the two CR groups merely maintained their weight during the 7-d diet. Glucose levels were significantly reduced in both CR groups compared with the AL-Std group, but only the CR-Ket group developed ketonemia. IGF1 mRNA levels were reduced by 30-50% in most brain regions in both CR groups. IGF1 receptor (IGF1R) mRNA levels were decreased in the CR-Std group but were increased in the CR-Ket diet group. Brain IGF binding protein (IGFBP)-2 and -5 mRNA levels were not altered by diet, but IGFBP-3 mRNA levels were markedly increased by the ketogenic diet while not altered by calorie restriction alone. Brain glucose transporter expression was also investigated in this study. Glucose transporter (GLUT) 4 mRNA levels were quite low and not appreciably altered by the different diets. Parenchymal GLUT1 mRNA levels were increased by the CR-Ket diet, but endothelial GLUT1 mRNA levels were not affected. Neuronal GLUT3 expression was decreased with the CR-Std diet and increased with the CR-Ket diet, in parallel with the IGF1R pattern. These observations reveal divergent effects of dietary caloric content and macronutrient composition on brain IGF system and GLUT expression. In addition, the data may be consistent with a role for enhanced IGF1R and GLUT expression in ketogenic diet-induced seizure suppression.

A physiologic role for testosterone in limiting estrogenic stimulation of the breast.

OBJECTIVE: The normal ovary produces abundant testosterone in addition to estradiol (E(2)) and progesterone, but usually only the latter two hormones are "replaced" in the treatment of ovarian failure and menopause. Some clinical and genetic evidence suggests, however, that endogenous androgens normally inhibit estrogen-induced mammary epithelial proliferation (MEP) and thereby may protect against breast cancer. DESIGN: To investigate the role of endogenous androgen in regulating mammary epithelial proliferation, normal-cycling rhesus monkeys were treated with flutamide, an androgen receptor antagonist. To evaluate the effect of physiological testosterone (T) supplementation of estrogen replacement therapy, ovariectomized monkeys were treated with E(2), E(2) plus progesterone, E(2) plus T, or vehicle. RESULTS: We show that androgen receptor blockade in normal female monkeys results in a more than twofold increase in MEP, indicating that endogenous androgens normally inhibit MEP. Moreover, we show that addition of a small, physiological dose of T to standard estrogen therapy almost completely attenuates estrogen-induced increases in MEP in the ovariectomized monkey, suggesting that the increased breast cancer risk associated with estrogen treatment could be reduced by T supplementation. Testosterone reduces mammary epithelial estrogen receptor (ER) alpha and increases ERbeta expression, resulting in a marked reversal of the ERalpha/beta ratio found in the estrogen-treated monkey. Moreover, T treatment is associated with a significant reduction in mammary epithelial MYC expression, suggesting that T's antiestrogenic effects at the mammary gland involve alterations in ER signaling to MYC. CONCLUSIONS: These findings suggest that treatment with a balanced formulation including all ovarian hormones may prevent or reduce estrogenic cancer risk in the treatment of girls and women with ovarian failure.

Signaling by insulin-like growth factor 1 in brain.

The homologous insulin and insulin-like growth factor (IGF) receptors are both expressed in the brain, in overlapping but distinct neuroanatomical patterns. In contrast to insulin, IGF1 is also highly expressed within the brain and is essential for normal brain development. IGF1 promotes projection neuron growth, dendritic arborization and synaptogenesis. IGF1 acts in an autocrine and/or paracrine manner to promote glucose utilization, using phosphatidylinositol 3 kinase (PI3K)/Akt, also known as protein kinase B (PKB)/glycogen synthase kinase 3beta (GSK3beta) pathways similar to insulin signaling in peripheral tissues. IGF1 promotes neuronal survival during normal brain development mainly in hippocampal and olfactory systems that depend on postnatal neurogenesis. IGF1's anabolic and neuroprotective roles may be coordinated by inhibition of GSK3beta. The identification of GSK3beta as a major target of brain IGF1 signaling provides a unifying pathway for IGF1's well-established anabolic and anti-apoptotic functions, with IGF1-induced inhibition of GSK3beta triggering multifaceted anabolic and neuroprotective effects.

Self-monitoring without awareness: using mimicry as a nonconscious affiliation strategy.

This research sought to extend the current conceptualization of self-monitoring by examining whether self-monitoring motives and behaviors can operate outside of conscious awareness. Two studies examined nonconscious mimicry among high and low self-monitors in situations varying in affiliative cues. Participants interacted with a confederate who shook her foot (Study 1) or touched her face (Study 2). In both studies, high self-monitors were more likely to mimic the confederate's subtle gestures when they believed the confederate to be a peer (Study 1) or someone superior to them (Study 2). Low self-monitors mimicked to the same degree across conditions. Thus, when the situation contains affiliative cues, high self-monitors use mimicry as a nonconscious strategy to get along with their interaction partner.

X-chromosome gene dosage and the risk of diabetes in Turner syndrome.

BACKGROUND: Turner syndrome (TS) is caused by the absence or fragmentation of the second sex chromosome. An increased risk of diabetes mellitus (DM) has consistently been noted, but the specific phenotype and genetic etiology of this trait are unknown. METHODS: In a prospective study, we examined the prevalence of DM in adult participants in an intramural National Institutes of Health (NIH) TS study. Results were analyzed with respect to karyotype, age, body mass index (BMI), and autoimmune indices. Insulin sensitivity and secretion were compared in age- and BMI-matched euglycemic women with TS and healthy female controls. We compared gene expression profiles in lymphocytes from differentially affected TS groups. RESULTS: Type 2 DM was present in 56 of 224 (25%) of the women with TS; type 1 DM was found in only one woman (<0.5%). DM was more prevalent among women with an isoXq chromosome compared to X monosomy (40.0 vs. 17.3%; P = 0.004). Euglycemic women with TS (n = 72; age, 33 +/- 12 yr; BMI, 23 +/- 3 kg/m(2)) had significantly higher glycemic and lower insulin responses to OGTT, with insulin sensitivity similar to controls. Gene expression profiles comparing 46,X,i(X)q vs. 45,X groups showed a significant increase in Xq transcripts and in potentially diabetogenic autosomal transcripts in the isoXq group. CONCLUSION: Type 2 DM associated with deficient insulin release is significantly increased among women with monosomy for the X-chromosome but is increased even more among women with monosomy for Xp coupled with trisomy for Xq. These data suggest that haploinsufficiency for unknown Xp genes increases risk for DM and that excess dosage of Xq genes compounds the risk.

Identification of genes expressed in primate primordial oocytes.

BACKGROUND: The factors involved in oocyte survival and transition from quiescence to the growing phenotype remain unknown. Herein we report genes that are differentially expressed in the primordial oocyte revealed by DNA arrays. METHODS: Primordial oocytes were captured selectively in rhesus monkey ovary sections using laser capture microdissection. The RNA was extracted and amplified in two rounds by T7-based linear RNA amplification, fluorescence labelled and then hybridized to human cDNA arrays containing 7680 elements. RNA from human placenta served as a reference sample. RESULTS: Ninety-five genes were found to be consistently expressed at a higher level in primordial oocytes. Expression of several of these genes in the oocyte has been reported before, e.g. deleted in azoospermia (DAZ), prohibitin and transglutaminase 2. Oocyte expression of several novel transcripts revealed on array hybridization, such as gene 33, ubiquitin-conjugating enzyme E2A, G1 to S phase transition 1, growth arrest and DNA damage-inducible (GADD), and dendritic cell-derived ubiquitin-like protein (DC-UbP) was confirmed by in situ hybridization. Some array-identified gene products [integrin beta3, alpha-tubulin, regulatory telomere elongation protein (RAP1) and cellular repressor of EIA-stimulated genes (CREG protein)] were detected in human oocytes by immunofluorescence. Bioinformatic analysis of the oocyte-enriched transcripts reveals a functional profile summarized as follows: cell cycle (14%); transporter (13%); signal transduction (10%); cytoskeletal (7%); transcription factor (5%); immune response (5%); apoptosis-related (5%); RNA processing (5%); and the remainder of miscellaneous categories. CONCLUSIONS: These observations may contribute to the elucidation of molecular pathways involved in oocyte survival and maturation.

Caloric restriction augments brain glutamic acid decarboxylase-65 and -67 expression.

The ketogenic diet is a very low-carbohydrate, high-fat diet used to treat refractory epilepsy. We hypothesized that this diet may act by increasing expression of glutamic acid decarboxylase (GAD), the rate-limiting enzyme in gamma-aminobutyric acid (GABA) synthesis. Thus, we evaluated brain GAD levels in a well-established, seizure-suppressing, rodent model of the ketogenic diet. Because the diet is most effective when administered with a modest ( approximately 10%) calorie restriction, we studied three groups of animals: rats fed ad libitum standard rat chow (Ad lib-Std); calorie-restricted standard chow (CR-Std); and an isocaloric, calorie-restricted ketogenic diet (CR-Ket). We found that GAD67 mRNA was significantly increased in the inferior and superior colliculi and cerebellar cortex in both CR diet groups compared with control (e.g., by 45% in the superior colliculus and by 71% in the cerebellar cortex; P <.001). GAD65 mRNA was selectively increased in the superior colliculus and temporal cortex in both CR-Std and CR-Ket diet groups compared with ad lib controls. The only apparent CR-Ket-specific effect was a 30% increase in GAD67 mRNA in the striatum (P =.03). Enhanced GAD immunoreactivity was detected in parallel with the mRNA changes. These data clearly show that calorie restriction increases brain GAD65 and -67 expression in several brain regions, independent of ketogenic effects. These observations may explain why caloric restriction improves the efficacy of the ketogenic diet in treating epilepsy and suggest that diet modification might be useful in treatment of a number of brain disorders characterized by impaired GAD or GABA activity.

Insulin-like growth factor 1 is essential for normal dendritic growth.

This study evaluated somatic and dendritic growth of neurons in the frontoparietal cortex of Igf1-/- brains. Pyramidal neuron density was increased by approximately 25% (P =.005) and soma size reduced by approximately 10% (P <.001). Golgi staining revealed that cortical layer II-III neurons exhibited a significant reduction in dendritic length and complexity in Igf1 null mice. Dendritic spine density and presumably synaptic contacts were reduced by 16% (P =.002). Similar findings were obtained for cortical layer V and piriform cortex pyramids. Supporting a reduction in synapses, synaptotagmin levels were reduced by 30% (P <.02) in the Igf1 null brain. Investigation of factors critically involved in dendritic growth and synaptogenesis showed an approximately 50% reduction in cortical CDC42 protein expression (P <.001) and an approximately 10% reduction in brain cholesterol levels (P <.01) in Igf1 null mice. Evidence is presented that Igf1 deletion causes disruptions in lipid and microtubule metabolism, leading to impaired neuronal somatic and dendritic growth. Published 2003 Wiley-Liss, Inc.