Bereavement is associated with an increased risk of cardiovascular disease; however, no reports exist of interventions to reduce risk. In a randomized, double-blind, placebo-controlled trial of 85 ...recently bereaved participants, we determined whether β-blocker (metoprolol 25 mg) and aspirin (100 mg) reduce cardiovascular risk markers and anxiety, without adversely affecting bereavement intensity.
Participants were spouses (n = 73) or parents (n = 12) of deceased from 5 hospitals in Sydney, Australia, 55 females, 30 males, aged 66.1 ± 9.4 years. After assessment within 2 weeks of bereavement, subjects were randomized to 6 weeks of daily treatment or placebo, and the effect evaluated using ANCOVA, adjusted for baseline values (primary analysis).
Participants on metoprolol and aspirin had lower levels of home systolic pressure (P = .03), 24-hour average heart rate (P < .001) and anxiety (P = .01) platelet response to arachidonic acid (P < .001) and depression symptoms (P = .046) than placebo with no difference in standard deviation of NN intervals index (SDNNi), von Willebrand Factor antigen, platelet-granulocyte aggregates or bereavement intensity. No significant adverse safety impact was observed.
In early bereavement, low dose metoprolol and aspirin for 6 weeks reduces physiological and psychological surrogate measures of cardiovascular risk. Although further research is needed, results suggest a potential preventive benefit of this approach during heightened cardiovascular risk associated with early bereavement.
Complex developmental processes such as hematopoiesis require a series of precise and coordinated changes in cellular identity to ensure blood homeostasis. Epigenetic mechanisms help drive changes in ...gene expression that accompany the transition from hematopoietic stem cells to terminally differentiated blood cells. Genome-wide profiling technologies now provide valuable glimpses of epigenetic changes that occur during normal hematopoiesis, and genetic mouse models developed to investigate the in vivo functions of chromatin-modifying enzymes clearly demonstrate significant roles for these enzymes during embryonic and adult hematopoiesis. Here, we will review the basic science aspects of chromatin modifications and the enzymes that add, remove, and interpret these epigenetic marks. This overview will provide a framework for understanding the roles that these molecules play during normal hematopoiesis. Moreover, many chromatin-modifying enzymes are involved in hematologic malignancies, underscoring the importance of establishing and maintaining appropriate chromatin modification patterns to normal hematology.
Friedreich's ataxia (FRDA) is an autosomal recessive neurological disease caused by expansions of guanine-adenine-adenine (GAA) repeats in intron 1 of the frataxin (FXN) gene. The expansion results ...in significantly decreased frataxin expression. We report that human FRDA cells can be corrected by zinc finger nuclease-mediated excision of the expanded GAA repeats. Editing of a single expanded GAA allele created heterozygous, FRDA carrier-like cells and significantly increased frataxin expression. This correction persisted during reprogramming of zinc finger nuclease-edited fibroblasts to induced pluripotent stem cells and subsequent differentiation into neurons. The expression of FRDA biomarkers was normalized in corrected patient cells and disease-associated phenotypes, such as decreases in aconitase activity and intracellular ATP levels, were reversed in zinc finger nuclease corrected neuronal cells. Genetically and phenotypically corrected patient cells represent not only a preferred disease-relevant model system to study pathogenic mechanisms, but also a critical step towards development of cell replacement therapy.
The home‐care workforce is in high demand globally. Home‐care workers provide care for people at home, including practical and personal care, as well as other tasks such as medication management. We ...conducted a systematic review with the aims of understanding methods of observation that have been employed to study home care and to explore how these methods have enabled researchers to understand the quality of home care. We searched the literature using PubMed and CINAHL databases in May 2018, with no limits applied to date of publication. We searched for MeSH terms of ‘Home Care Services’, ‘Home Health Care’, ‘Home Nursing’ and ‘Observation*’. Across 15 eligible studies, the types of observation methods employed were categorised as structured, guided and unstructured. The characteristics of these methods, such as the level of participation adopted by the observer, varied across the studies. Three themes were developed through a narrative synthesis of the included studies’ findings: ‘The impact of care delivery and organisational factors’, ‘Observing relationships and communications’, and ‘People and places behind closed doors’. We conclude that methods of observation are a fairly novel, yet rich and meaningful way of exploring home‐care practice. Researchers undertaking observations should consider elements such as the number of researchers observing and the potential for variations, how and when to record the observations, possible triangulation of data, the researcher's reflective stance as an observer, as well as ethical considerations.
Precise transcriptional networks drive the orchestration and execution of complex developmental processes. Transcription factors possessing sequence-specific DNA binding properties activate or ...repress target genes in a step-wise manner to control most cell lineage decisions. This regulation often requires the interaction between transcription factors and subunits of massive protein complexes that bear enzymatic activities towards histones. The functional coupling of transcription proteins and histone modifiers underscores the importance of transcriptional regulation through chromatin modification in developmental cell fate decisions and in disease pathogenesis.
A number of events must occur to preserve the integrity of the chromatin template during gene transcription. A study in this issue reveals a novel mechanism whereby chromatin remodelers are recruited ...to histone modifications within gene bodies to prevent aberrant histone exchange during transcriptional elongation.
ASH2L encodes a trithorax group protein that is a core component of all characterized mammalian histone H3K4 methyltransferase complexes, including mixed lineage leukemia (MLL) complexes. ASH2L ...protein levels in primary leukemia patient samples have not yet been defined. We analyzed ASH2L protein expression in 511 primary AML patient samples using reverse phase protein array (RPPA) technology. We discovered that ASH2L expression is significantly increased in a subset of patients carrying fms-related tyrosine kinase 3 (FLT3) mutations. Furthermore, we observed that low levels of ASH2L are associated with increased overall survival. We also compared ASH2L levels to the expression of 230 proteins previously analyzed on this array. ASH2L expression was inversely correlated with 32 proteins, mostly involved in cell adhesion and cell cycle inhibition, while a positive correlation was observed for 50 proteins, many of which promote cell proliferation. Together, these results indicate that a lower level of ASH2L protein is beneficial to AML patients.
Purpose
To build an evidence-informed theoretical model describing how to support people with dementia to live well or for longer at home.
Methods
We searched electronic databases to August 2018 for ...papers meeting predetermined inclusion criteria in two reviews that informed our model. We scoped literature for theoretical models of how to enable people with dementia to live at home independently, with good life quality or for longer. We systematically reviewed Randomised Controlled Trials (RCTs) reporting psychosocial intervention effects on time lived with dementia at home. Two researchers independently rated risk of bias. We developed our theoretical model through discussions with experts by personal, clinical and academic experiences, informed by this evidence base.
Results
Our scoping review included 52 studies. We divided models identified into: values and approaches (relational and recovery models; optimising environment and activities; family carer skills and support); care strategies (family carer-focused; needs and goal-based; self-management); and service models (case management; integrated; consumer-directed). The 11 RCTs included in our systematic review, all judged at low risk of bias, described only two interventions that increased time people with dementia lived in their own homes. These collectively encompassed all these components except for consumer-directed and integrated care. We developed and revised our model, using review evidence and expert consultation to define the final model.
Conclusions
Our theoretical model describes values, care strategies and service models that can be used in the design of interventions to enable people with dementia to live well and for longer at home.
Trial registration
PROSPERO 2018 registration number: CRD42018099693 (scoping review).
PROSPERO 2018 registration number: CRD42018099200 (RCT systematic review).
A balance in the activities of the Ipl1 Aurora kinase and the Glc7 phosphatase is essential for normal chromosome segregation in yeast. We report here that this balance is modulated by the Set1 ...methyltransferase. Deletion of
SET1 suppresses chromosome loss in
ipl1-2 cells. Conversely, combination of
SET1 and
GLC7 mutations is lethal. Strikingly, these effects are independent of previously defined functions for Set1 in transcription initiation and histone H3 methylation. We find that Set1 is required for methylation of conserved lysines in a kinetochore protein, Dam1. Biochemical and genetic experiments indicate that Dam1 methylation inhibits Ipl1-mediated phosphorylation of flanking serines. Our studies demonstrate that Set1 has important, unexpected functions in mitosis. Moreover, our findings suggest that antagonism between lysine methylation and serine phosphorylation is a fundamental mechanism for controlling protein function.
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