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Abstract: The genomics era has facilitated the discovery of new genes that predispose individuals to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ETS-related gene (ERG), a novel, autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor that is critical for definitive hematopoiesis, stem cell function, and platelet maintenance. ERG colocalizes with other transcription factors, including RUNX family transcription factor 1 (RUNX1) and GATA binding protein 2 (GATA2), on promoters or enhancers of genes that orchestrate hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 individuals with thrombocytopenia from 1 family and 14 additional ERG variants in unrelated individuals with BMF/HM, including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germ line ERG variants included cytopenias (thrombocytopenia, neutropenia, and pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, and acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense and 1 truncating), including 3 missense population variants, were functionally characterized. Thirteen potentially pathogenic erythroblast transformation specific (ETS) domain missense variants displayed loss-of-function (LOF) characteristics, thereby disrupting transcriptional transactivation, DNA binding, and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture and to promote acute erythroleukemia when transplanted into mice, concordant with these being LOF variants. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germ line ERG variants has clinical implications for patient and family diagnoses, counseling, surveillance, and treatment strategies, including selection of bone marrow donors and cell or gene therapy., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Patient-derived xenograft (PDX) modeling is a valuable tool for the study of leukemia pathogenesis, progression, and therapy response. Engraftment of human leukemia cells occurs following injection into the tail vein (or retro-orbital vein) of preconditioned immunocompromised mice. Injected mice are maintained in a sterile and supportive housing environment until leukemia engraftment is observed, at which time studies such as drug treatments or leukemia sampling can occur. Here, we outline a method for generating PDXs from Acute Myeloid Leukemia (AML) patient samples using tail vein injection; however it can also be readily applied to T- and B- Acute Lymphoblastic Leukemia (ALL) samples., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Individual differences in attachment insecurity can have important implications for experiences of positive emotions. However, existing research on the link between attachment insecurity and positive emotional experiences has typically used a composite measure of positive emotions, overlooking the potential importance of differentiating discrete emotions., Method: We conducted a meta-analysis of 10 cross-sectional samples (N = 3215), examining how attachment insecurity is associated with self-reported frequency of experiencing positive emotions, with a distinction made between more social (i.e., love and gratitude) and less social (i.e., peace and awe or curiosity) positive emotions., Results: High (vs. low) levels of both attachment anxiety and avoidance were associated with less frequent experience of positive emotions regardless of their social relevance. When analyzing each emotion separately, we found that attachment anxiety showed negative relations to all emotions except gratitude. Attachment avoidance was negatively associated with all emotions, and the link was even stronger with love (vs. peace, awe, or curiosity). Additional analyses of daily diary data revealed that attachment anxiety and avoidance were also negatively associated with daily experiences of positive emotions, regardless of social relevance., Conclusion: Our results underscore the need to further investigate the mechanisms underlying insecure individuals' blunted positive emotional experiences., (© 2022 Wiley Periodicals LLC.)

Nonverbal cues powerfully shape interpersonal experiences with close others; yet, there has been minimal cross-fertilization between the nonverbal behavior and close relationships literatures. Using examples of responsive nonverbal behavior conveyed across vocal, tactile, facial, and bodily channels of communication, we illustrate the utility of assessing and isolating their effects to differentiate the contributions of verbal and nonverbal displays of listening and responsiveness to relationship outcomes. We offer suggestions for methodological approaches to better capture responsive behavior across verbal and nonverbal channels, and discuss theoretical and practical implications of carrying out this work to better clarify what makes people feel understood, validated, listened to, and cared for., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The epithelial to mesenchymal transition (EMT) is a fundamental developmental process essential for normal embryonic development. It is also important during various pathogenic processes including fibrosis, wound healing and epithelial cancer cell metastasis and invasion. EMT is regulated by a variety of cell signalling pathways, cell-cell interactions and microenvironmental cues, however the key drivers of EMT are transcription factors of the ZEB, TWIST and SNAIL families. Recently, novel and unexpected roles for these EMT transcription factors (EMT-TFs) during normal blood cell development have emerged, which appear to be largely independent of classical EMT processes. Furthermore, EMT-TFs have also begun to be implicated in the development and pathogenesis of malignant hematological diseases such as leukemia and lymphoma, and now present themselves or the pathways they regulate as possible new therapeutic targets within these malignancies. In this review, we discuss the ZEB, TWIST and SNAIL families of EMT-TFs, focusing on what is known about their normal roles during hematopoiesis as well as the emerging and "unexpected" contribution they play during development and progression of blood cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Radhakrishnan, Truong and Carmichael.)

How are different social relationships jointly and uniquely associated with older women's health and well-being, and what is the directionality of these associations? We address these questions using longitudinal data from the Midlife in the United States study. We find that relationship quality with romantic partners, family, and friends is positively linked with better health and well-being concurrently and longitudinally. Cross-lagged analyses indicate that romantic relationships are more predictive of than predicted by health and well-being, family relationships are more predicted by than predictive of health and well-being, and friendships are both predicted by and predictive of health and well-being.

Modulators of epithelial-to-mesenchymal transition (EMT) have recently emerged as novel players in the field of leukemia biology. The mechanisms by which EMT modulators contribute to leukemia pathogenesis, however, remain to be elucidated. Here we show that overexpression of SNAI1, a key modulator of EMT, is a pathologically relevant event in human acute myeloid leukemia (AML) that contributes to impaired differentiation, enhanced self-renewal, and proliferation of immature myeloid cells. We demonstrate that ectopic expression of Snai1 in hematopoietic cells predisposes mice to AML development. This effect is mediated by interaction with the histone demethylase KDM1A/LSD1. Our data shed new light on the role of SNAI1 in leukemia development and identify a novel mechanism of LSD1 corruption in cancer. This is particularly pertinent given the current interest surrounding the use of LSD1 inhibitors in the treatment of multiple different malignancies, including AML., (© 2020 by The American Society of Hematology.)

Given the powerful implications of relationship quality for health and well-being, a central mission of relationship science is explaining why some romantic relationships thrive more than others. This large-scale project used machine learning (i.e., Random Forests) to 1) quantify the extent to which relationship quality is predictable and 2) identify which constructs reliably predict relationship quality. Across 43 dyadic longitudinal datasets from 29 laboratories, the top relationship-specific predictors of relationship quality were perceived-partner commitment, appreciation, sexual satisfaction, perceived-partner satisfaction, and conflict. The top individual-difference predictors were life satisfaction, negative affect, depression, attachment avoidance, and attachment anxiety. Overall, relationship-specific variables predicted up to 45% of variance at baseline, and up to 18% of variance at the end of each study. Individual differences also performed well (21% and 12%, respectively). Actor-reported variables (i.e., own relationship-specific and individual-difference variables) predicted two to four times more variance than partner-reported variables (i.e., the partner's ratings on those variables). Importantly, individual differences and partner reports had no predictive effects beyond actor-reported relationship-specific variables alone. These findings imply that the sum of all individual differences and partner experiences exert their influence on relationship quality via a person's own relationship-specific experiences, and effects due to moderation by individual differences and moderation by partner-reports may be quite small. Finally, relationship-quality change (i.e., increases or decreases in relationship quality over the course of a study) was largely unpredictable from any combination of self-report variables. This collective effort should guide future models of relationships., Competing Interests: The authors declare no competing interest.

Acute erythroleukemia (AEL or acute myeloid leukemia [AML]-M6) is a rare but aggressive hematologic malignancy. Previous studies showed that AEL leukemic cells often carry complex karyotypes and mutations in known AML-associated oncogenes. To better define the underlying molecular mechanisms driving the erythroid phenotype, we studied a series of 33 AEL samples representing 3 genetic AEL subgroups including TP53-mutated, epigenetic regulator-mutated (eg, DNMT3A, TET2, or IDH2), and undefined cases with low mutational burden. We established an erythroid vs myeloid transcriptome-based space in which, independently of the molecular subgroup, the majority of the AEL samples exhibited a unique mapping different from both non-M6 AML and myelodysplastic syndrome samples. Notably, >25% of AEL patients, including in the genetically undefined subgroup, showed aberrant expression of key transcriptional regulators, including SKI, ERG, and ETO2. Ectopic expression of these factors in murine erythroid progenitors blocked in vitro erythroid differentiation and led to immortalization associated with decreased chromatin accessibility at GATA1-binding sites and functional interference with GATA1 activity. In vivo models showed development of lethal erythroid, mixed erythroid/myeloid, or other malignancies depending on the cell population in which AEL-associated alterations were expressed. Collectively, our data indicate that AEL is a molecularly heterogeneous disease with an erythroid identity that results in part from the aberrant activity of key erythroid transcription factors in hematopoietic stem or progenitor cells., (© 2020 by The American Society of Hematology.)

Introduction: Anxiety is prevalent, costly, and associated with significant adverse outcomes. The importance of nutrition is underestimated in the management of mental health disorders. In particular, omega-3 fatty acids (ω-3 FAs) are a critical component for healthy development and have been shown to reduce anxiety symptoms. Objective: This paper reviews the current state of the research to identify potential mechanisms underlying the relationship between ω-3 FAs and anxiety reduction. Method: Studies were identified using PubMed, PsycINFO, and CINAHL databases. Results: Of the 197 full-text studies screened, six met criteria for inclusion. Four mechanisms were identified based on primary outcomes reported by each study, Inflammatory Response, Brain-Derived Neurotrophic Factor (BDNF), Cortisol, and Cardiovascular Activity. Conclusion: Five key recommendations are provided to guide future research examining ω-3 FAs and anxiety. They include: (1) standardization of dosage and duration of ω-3 supplementation, (2) more rigorous measurement of variables, (3) effective blinding of participants, (4) designing experiments that test mediation, and (5) increasing sample diversity.

First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM., (© 2020 by The American Society of Hematology.)

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.

Direct and overt visible support promotes recipients' relationship satisfaction but can also exacerbate negative mood. In contrast, subtle and indirect invisible support can bypass costs to mood, but it is unclear whether it undermines or boosts relationship satisfaction. Because invisible support is not perceived by recipients, its relational impact may be delayed across time. Thus, the current research used three dyadic daily diary studies (total N = 322 married couples) to explore, for the first time, both the immediate (same day) and lagged (next day) effects of visible and invisible support on recipients' mood and relationship satisfaction. Consistent with prior research, visible support was associated with recipients reporting greater relationship satisfaction and greater anxiety the same day. In contrast, but also consistent with prior research, invisible support had no significant same-day effects, and thus avoided mood costs. Nevertheless, invisible support was associated with recipients reporting greater relationship satisfaction the next day. Study 3 provided evidence that such effects emerged because invisible support was also associated with greater satisfaction with partners' helpful behaviors (e.g., household chores) and relationship interactions (e.g., time spent together) on the next day. These studies demonstrate the importance of assessing different temporal effects associated with support acts (which may otherwise go undetected) and provide the first evidence that invisible support enhances relationship satisfaction but does so across days. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Snail family proteins are key inducers of the epithelial-mesenchymal transition (EMT), a critical process required for normal embryonic development. They have also been strongly implicated in regulating the EMT-like processes required for tumour cell invasion, migration, and metastasis. Whether these proteins also contribute to normal blood cell development, however, remains to be clearly defined. Increasing evidence supports a role for the Snail family in regulating cell survival, migration, and differentiation within the haematopoietic system, as well as potentially an oncogenic role in the malignant transformation of haematopoietic stem cells. This review will provide a broad overview of the Snail family, including key aspects of their involvement in the regulation and development of solid organ cancer, as well as a discussion on our current understanding of Snail family function during normal and malignant haematopoiesis., (© 2017 S. Karger AG, Basel.)

Social connection, a leading factor in the promotion of health, well-being, and longevity, requires social knowledge and the capacity to cultivate intimacy. Life span development theorists have speculated that social information-seeking goals, emphasized at the beginning of early adulthood, give way to emotional closeness goals in later stages of early adulthood. Drawing on developmental theory (Baltes & Carstensen, 2003; Baltes, 1997), this 30-year prospective study assessed social activity at age 20 and age 30 with experience sampling methods, and psychosocial outcomes (social integration, friendship quality, loneliness, depression, and psychological well-being) at age 50. Results supported the hypothesis that the quantity (but not the quality) of social interactions at age 20, and the quality (but not the quantity) of social interactions at age 30 predict midlife psychosocial outcomes. Longitudinal structural models revealed that age-20 interaction quantity had a direct, unmediated effect on age-50 social and psychological outcomes. The effects of age-20 interaction quality on midlife outcomes, on the other hand, were mediated by age-30 interaction quality. Our findings are consistent with the idea that selection and optimization serve important functions in early adulthood, and that engaging in developmentally appropriate social activity contributes to psychosocial adjustment in the decades that follow., ((c) 2015 APA, all rights reserved).)

To define genetic lesions driving leukemia, we targeted cre-dependent Sleeping Beauty (SB) transposon mutagenesis to the blood-forming system using a hematopoietic-selective vav 1 oncogene (vav1) promoter. Leukemias of diverse lineages ensued, most commonly lymphoid leukemia and erythroleukemia. The inclusion of a transgenic allele of Janus kinase 2 (JAK2)V617F resulted in acceleration of transposon-driven disease and strong selection for erythroleukemic pathology with transformation of bipotential erythro-megakaryocytic cells. The genes encoding the E-twenty-six (ETS) transcription factors Ets related gene (Erg) and Ets1 were the most common sites for transposon insertion in SB-induced JAK2V617F-positive erythroleukemias, present in 87.5% and 65%, respectively, of independent leukemias examined. The role of activated Erg was validated by reproducing erythroleukemic pathology in mice transplanted with fetal liver cells expressing translocated in liposarcoma (TLS)-ERG, an activated form of ERG found in human leukemia. Via application of SB mutagenesis to TLS-ERG-induced erythroid transformation, we identified multiple loci as likely collaborators with activation of Erg. Jak2 was identified as a common transposon insertion site in TLS-ERG-induced disease, strongly validating the cooperation between JAK2V617F and transposon insertion at the Erg locus in the JAK2V617F-positive leukemias. Moreover, loci expressing other regulators of signal transduction pathways were conspicuous among the common transposon insertion sites in TLS-ERG-driven leukemia, suggesting that a key mechanism in erythroleukemia may be the collaboration of lesions disturbing erythroid maturation, most notably in genes of the ETS family, with mutations that reduce dependence on exogenous signals.

The tetracycline (tet)-regulated expression system allows for the inducible overexpression of protein-coding genes, or inducible gene knockdown based on expression of short hairpin RNAs (shRNAs). The system is widely used in mice, however it requires robust expression of a tet transactivator protein (tTA or rtTA) in the cell type of interest. Here we used an in vivo tet-regulated fluorescent reporter approach to characterise inducible gene/shRNA expression across a range of hematopoietic cell types of several commonly used transgenic tet transactivator mouse strains. We find that even in strains where the tet transactivator is expressed from a nominally ubiquitous promoter, the efficiency of tet-regulated expression can be highly variable between hematopoietic lineages and between differentiation stages within a lineage. In some cases tet-regulated reporter expression differs markedly between cells within a discrete, immunophenotypically defined population, suggesting mosaic transactivator expression. A recently developed CAG-rtTA3 transgenic mouse displays intense and efficient reporter expression in most blood cell types, establishing this strain as a highly effective tool for probing hematopoietic development and disease. These findings have important implications for interpreting tet-regulated hematopoietic phenotypes in mice, and identify mouse strains that provide optimal tet-regulated expression in particular hematopoietic progenitor cell types and mature blood lineages.

The transcription factor encoded by the E-twenty-six (ETS)-related gene, ERG, is an essential regulator of hematopoietic stem cell function and a potent human oncoprotein. Enforced expression of ERG in murine hematopoietic cells leads to the development of a well-characterized lymphoid leukemia and a less well-defined non lymphoid disease. To clarify the latter, we generated murine bone marrow chimeras with enforced Erg expression in engrafted hematopoietic progenitor cells. As expected, these mice developed lymphoid leukemia. However, the previously reported non lymphoid disease that developed was shown to be a uniform, transplantable leukemia with both erythroid and megakaryocytic characteristics. In vivo, this disease had the overall appearance of an erythroleukemia, with an accumulation of immature erythroblasts that infiltrated the bone marrow, spleen, liver, and lung. However, when stimulated in vitro, leukemic cell clones exhibited both erythroid and megakaryocytic differentiation, suggesting that transformation occurred in a bipotential progenitor. Thus, in mice, Erg overexpression induces the development of not only lymphoid leukemia but also erythro-megakaryocytic leukemia.

We report the discovery of GATA2 as a new myelodysplastic syndrome (MDS)-acute myeloid leukemia (AML) predisposition gene. We found the same, previously unidentified heterozygous c.1061C>T (p.Thr354Met) missense mutation in the GATA2 transcription factor gene segregating with the multigenerational transmission of MDS-AML in three families and a GATA2 c.1063_1065delACA (p.Thr355del) mutation at an adjacent codon in a fourth MDS family. The resulting alterations reside within the second zinc finger of GATA2, which mediates DNA-binding and protein-protein interactions. We show differential effects of the mutations on the transactivation of target genes, cellular differentiation, apoptosis and global gene expression. Identification of such predisposing genes to familial forms of MDS and AML is critical for more effective diagnosis and prognosis, counseling, selection of related bone marrow transplant donors and development of therapies.

Platelets are the small anuclear blood cells that are the product of megakaryocytopoiesis, the process of hematopoietic stem cell commitment to megakaryocyte production and the differentiation and maturation of these cells for platelet release. Deregulation or disruption of megakaryocytopoiesis can result in platelet deficiencies, the thrombocytopenias, with attendant risk of hemorrhage or thrombocytosis, a pathological excess of platelet numbers. Mouse models, particularly those engineered to carry genetic alterations modeling mutations associated with human disease, have provided important insights into megakaryocytopoiesis and deregulation of this process in disease. This review focuses on mouse models of diseases of altered megakaryocyte and platelet number, illustrating the profound contribution of these models in validating suspected roles of disease-associated genetic alterations, promoting discovery of new links between genetic mutations and specific diseases, and providing unique tools for better understanding of disease pathophysiology and progression, as well as resources to define drug action or develop new therapeutic strategies.

Background: RNA interference (RNAi) is a powerful tool for suppressing gene function. The tetracycline (tet)-regulated expression system has recently been adapted to allow inducible RNAi in mice, however its efficiency in a particular cell type in vivo depends on a transgenic tet transactivator expression pattern and is often highly variable., Objective: We aimed to establish a transgenic strategy that allows efficient and inducible gene knockdown in particular hematopoietic lineages in mice., Methods and Results: Using a tet-regulated reporter gene strategy, we found that transgenic mice expressing the rtTA (tet-on) transactivator under control of the cytomegalovirus (CMV) promoter (CMV-rtTA mice) display inducible reporter gene expression with unusual and near-complete efficiency in megakaryocytes and platelets. To test whether the CMV-rtTA transgene can drive inducible and efficient gene knockdown within this lineage, we generated a novel mouse strain harboring a tet-regulated short hairpin RNA (shRNA) targeting Bcl-x(L) , a pro-survival Bcl-2 family member known to be essential for maintaining platelet survival. Doxycycline treatment of adult mice carrying both transgenes induces shRNA expression, depletes Bcl-x(L) in megakaryocytes and triggers severe thrombocytopenia, whereas doxycycline withdrawal shuts off shRNA expression, normalizes Bcl-x(L) levels and restores platelet numbers. These effects are akin to those observed with drugs that target Bcl-x(L) , clearly demonstrating that this transgenic system allows efficient and inducible inhibition of genes in megakaryocytes and platelets., Conclusions: We have established a novel transgenic strategy for inducible gene knockdown in megakaryocytes and platelets that will be useful for characterizing genes involved in platelet production and function in adult mice., (© 2010 International Society on Thrombosis and Haemostasis.)

Sharing good news with others is one way that people can savor those experiences while building personal and interpersonal resources. Although prior research has established the benefits of this process, called capitalization, there has been little research and no experiments to examine the underlying mechanisms. In this article, we report results from 4 experiments and 1 daily diary study conducted to examine 2 mechanisms relevant to capitalization: that sharing good news with others increases the perceived value of those events, especially when others respond enthusiastically, and that enthusiastic responses to shared good news promote the development of trust and a prosocial orientation toward the other. These studies found consistent support for these effects across both interactions with strangers and in everyday close relationships.

We examined whether accuracy of affective forecasting for significant life events was moderated by a theoretically relevant individual difference (anxious attachment), with different expected relations to predicted and actual happiness. In 3 studies (2 cross-sectional, 1 longitudinal), participants predicted what their happiness would be after entering or ending a romantic relationship. Consistent with previous research, people were generally inaccurate forecasters. However, inaccuracy for entering a relationship was significantly moderated by anxious attachment. Predictions were largely unrelated to anxious attachment, but actual happiness was negatively related to attachment anxiety. Moderation for breaking up showed a similar but less consistent pattern. These results suggest a failure to account for one's degree of anxious attachment when making affective forecasts and show how affective forecasting accuracy in important life domains may be moderated by a focally relevant individual difference, with systematically different associations between predicted and actual happiness.

Down syndrome is characterized by multiple phenotypic manifestations associated with trisomy of chromosome 21. The transient myeloproliferative disorder and acute megakaryocytic leukemia associated with Down syndrome are uniquely associated with mutations in the transcription factor GATA1; however, the identity of trisomic genes on chromosome 21 that predispose to these hematologic disorders remains unknown. Using a loss-of-function allele, we show that specific reduction to functional disomy of the Erg gene corrects the pathologic and hematologic features of myeloproliferation in the Ts(17(16))65Dn mouse model of Down syndrome, including megakaryocytosis and progenitor cell expansion. Our data provide genetic evidence establishing the need for Erg trisomy for myeloproliferation in Ts(17(16))65Dn mice and imply that increased ERG gene dosage may be a key consequence of trisomy 21 that can predispose to malignant hematologic disorders in Down syndrome.

Down syndrome (DS) persons are born with various hematopoietic abnormalities, ranging from relatively benign, such as neutrophilia and macrocytosis, to a more severe transient myeloproliferative disorder (TMD). In most cases, these abnormalities resolve in the first few months to years of life. However, sometimes the TMD represents a premalignant disease that develops into acute megakaryocytic leukemia (AMKL), usually in association with acquired GATA1 mutations. To gain insight into the mechanisms responsible for these abnormalities, we analyzed the hematopoietic development of the Ts1Cje mouse model of DS. Our analyses identified defects in mature blood cells, including macrocytosis and anemia, as well as abnormalities in fetal liver and bone marrow stem and progenitor cell function. Despite these defects, the Ts1Cje mice do not develop disease resembling either TMD or AMKL, and this was not altered by a loss of function allele of Gata1. Thus, loss of Gata1 and partial trisomy of chromosome 21 orthologs, when combined, do not appear to be sufficient to induce TMD or AMKL-like phenotypes in mice.

The Ts65Dn mouse is the most widely investigated segmentally trisomic mouse model of Down syndrome. Quantitative PCR based methods are the preferred way of detecting the trisomic segment for genotyping purposes. However, identification of a 1.5 fold difference in target DNA is at the limit of detection of most quantitative PCR based methods, and in practice this can lead to difficulties in assigning genotypes. We report a 100% accurate multiplex ligation-dependent probe amplification (MLPA) assay for genotyping the Ts65Dn mouse that is also applicable to all other segmentally trisomic mouse models of Down syndrome.

This study examined the role of attachment insecurity in sleep problems among married adults (N=78 couples). Using the Pittsburgh Sleep Quality Index and structural equation modeling, attachment anxiety was associated with higher levels of self-reported sleep difficulties for men and women, whereas attachment avoidance was not. Depressed affect was included as a control variable, and the effect of attachment anxiety remained significant. Men and women did not differ significantly in the magnitude of the effect of attachment anxiety on sleep quality. In addition, there were no cross-partner effects of attachment insecurity on sleep quality or depressed affect. Implications and future directions are discussed., ((c) 2005 APA, all rights reserved)

An investigation to assess the impact of fluoridation on the caries experience of young children at high and low levels of material deprivation measured by the Townsend Index was undertaken in County Durham. Electoral wards were ranked for deprivation from 1991 Census data. Dental caries data for 2,751 five-year-old children resident in electoral wards in the upper and lower quartiles of material deprivation in the County were obtained from a dental survey conducted in 1991-92. Wards were stratified for fluoridated and non-fluoridated water supply and the dental data for the resultant four populations, defined by high and low material deprivation and the presence or absence of fluoridation, were analysed. The mean dmft values in the four groups were 0.8 in the fluoridated low deprivation group, 1.2 in the non-fluoridated low deprivation group, 1.2 in the fluoridated high deprivation wards and 2.1 in the non-fluoridated high deprivation wards. Thus, with fluoridation the variation in caries between high and low deprivation groups was significantly reduced but not eliminated, leaving the level significantly lower in the least deprived group, to the continuing disadvantage of that deprived group.

An investigation of the potential for an index of material deprivation to indicate groups of young children at risk to dental caries and to assess caries experience in their age group at three levels of deprivation, measured by the Townsend Index, was undertaken in County Durham. Electoral wards were ranked on an index of material deprivation derived from 1991 Census data. Dental caries data for the upper quartile, inter-quartile range and lower quartile of material deprivation in the County were obtained from a dental survey of 6052 five-year-old children in 1991-92. The number of children in each group ranged from 1145 to 3058. Significant differences in dental caries experience between high, middle and low ranges of material deprivation existed. The index of material deprivation can indicate groups of children in the community at high and low risk of dental caries.

One hundred and twenty-nine physically handicapped children (89 males, 40 females) were dentally examined in a local authority residential special school taking pupils from a wide geographical area in the Northern Region, for caries, periodontal disease, malocclusions and treatment need using World Health Organization criteria. The children were aged between 3 and 17 years with a mean age of 10.7 years. Mean deciduous caries experience (dft) was 0.9 and the mean permanent caries experience (DMFT) was 2.0. The mean dfs/DMFS values were 2.5 and 3.4 respectively. A higher experience of deciduous caries was found in girls, dft = 1.3, than in boys who had a mean dft value of 0.8 and in the permanent dentition girls had a mean DMFT value of 2.8 compared with 1.6 for boys. Each component of the index was also higher for girls in both dentitions. The gender difference identified in caries experience extended to treatment need for the permanent dentition, where more girls were recorded as requiring treatment than boys. Of the 129 children, 126 were assessed for treatment co-operation. Only 18 (14.3 per cent) were assessed as being amenable to routine dental care, 66 (52.4 per cent) were thought likely to present some management problems and the remaining 42 (33.3 per cent) were thought to require all their treatment under a general anaesthetic.

The 1979/1989 patterns of General Dental Service provision in the Northern Region and its nine FPC/FHSA areas have been examined in relation to intraregional variations and assessed against the national average and other regions. Attention is drawn to the Northern Region's failure to reach national averages in a number of key measures of dental care, owing to the low numbers of practitioners working within the Region. It is clear that redistribution of dental manpower will not be generated under the present system. Alternatives are required if dentistry is to continue to be an essential part of a comprehensive health service for all.

The dental health of 457 5-year-old children who have lived continuously in fluoridated (at 1.0 mg F/litre) Newcastle and 370 children of the same age in non-fluoridated (less than 0.1 mg F/litre) South Northumberland has been reported. This paper examines in detail the caries prevalence in social class groups I + II, III, IV + V, and the social class/fluoridation relationship in 1987. The prevalence of dental caries in the three social class groupings I + II, III, and IV + V (and the mean dmft), respectively, was 35% (1.1), 46% (1.7) and 67% (2.4) in the fluoridated area, and 59% (2.2), 67% (3.7) and 77% (5.0) in the non-fluoridated area. Fluoridation was effective in all social class groupings and, because caries levels were higher in social classes IV + V, fluoridation brought about greater savings for these children than for those in social classes I + II. Fluoridation reduces but does not eliminate social inequalities, leaving social disadvantage/social background/social class as the major factors in caries prevalence for this age group. Further research into the fluoridation/social class relationship is required, particularly since the understanding of occupational class, now considered an imperfect representation of social class, is being superseded by other criteria which have stronger associations with measures of poor health.

Reorganisation of dental services in Britain gives new opportunities for planning. Geographical methodology provides new techniques. An elementary spatial analysis of variations in dental health in Newcastle Area Health Authority (Teaching) shows that dental health varies with availability and access to treatment facilities. Opposite types of geographical distribution of community (School) and general dental services are illustrated showing location biases for each type of service. The evaluation of the spatial distribution of dental services is shown to be basic to planning and a key to improved dental health.