PIGH deficiency can be associated with severe neurodevelopmental and skeletal manifestations

Phosphatidylinositol Glycan Anchor Biosynthesis class H (PIGH) is an essential player in the glycosylphosphatidylinositol (GPI) synthesis, an anchor for numerous cell membrane‐bound proteins. PIGH deficiency is a newly described and rare disorder associated with developmental delay, seizures and behavioral difficulties. Herein, we report three new unrelated families with two different bi‐allelic PIGH variants, including one new variant p.(Arg163Trp) which seems associated with a more severe phenotype. The common clinical features in all affected individuals are developmental delay/intellectual disability and hypotonia. Variable clinical features include seizures, autism spectrum disorder, apraxia, severe language delay, dysarthria, feeding difficulties, facial dysmorphisms, microcephaly, strabismus, and musculoskeletal anomalies. The two siblings homozygous for the p.(Arg163Trp) variant have severe symptoms including profound psychomotor retardation, intractable seizures, multiple bone fractures, scoliosis, loss of independent ambulation, and delayed myelination on brain MRI. Serum iron levels were significantly elevated in one individual. All tested individuals with PIGH deficiency had normal alkaline phosphatase and CD16, a GPI‐anchored protein (GPI‐AP), was found to be decreased by 60% on granulocytes from one individual. This study expands the PIGH deficiency phenotype range toward the severe end of the spectrum with the identification of a novel pathogenic variant

Patterns of Hybrid Loss of Imprinting Reveal Tissue- and Cluster-Specific Regulation

Background: Crosses between natural populations of two species of deer mice, Peromyscus maniculatus (BW), and P. polionotus (PO), produce parent-of-origin effects on growth and development. BW females mated to PO males (bw6po) produce growth-retarded but otherwise healthy offspring. In contrast, PO females mated to BW males (PO6BW) produce overgrown and severely defective offspring. The hybrid phenotypes are pronounced in the placenta and include PO6BW conceptuses which lack embryonic structures. Evidence to date links variation in control of genomic imprinting with the hybrid defects, particularly in the PO6BW offspring. Establishment of genomic imprinting is typically mediated by gametic DNA methylation at sites known as gDMRs. However, imprinted gene clusters vary in their regulation by gDMR sequences. Methodology/Principal Findings: Here we further assess imprinted gene expression and DNA methylation at different cluster types in order to discern patterns. These data reveal PO6BW misexpression at the Kcnq1ot1 and Peg3 clusters, both of which lose ICR methylation in placental tissues. In contrast, some embryonic transcripts (Peg10, Kcnq1ot1) reactivated the silenced allele with little or no loss of DNA methylation. Hybrid brains also display different patterns of imprinting perturbations. Several cluster pairs thought to use analogous regulatory mechanisms are differentially affected in the hybrids. Conclusions/Significance: These data reinforce the hypothesis that placental and somatic gene regulation differs significantly, as does that between imprinted gene clusters and between species. That such epigenetic regulatory variatio

Estrogen receptor transcription and transactivation: Estrogen receptor alpha and estrogen receptor beta - regulation by selective estrogen receptor modulators and importance in breast cancer

Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the estrogen receptor (ER), now referred to as selective estrogen receptor modulators (SERMs), can demonstrate remarkable differences in activity in the various estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for understanding these tissue-selective actions. As discussed in this thematic review, the development of optimal SERMs should now be viewed in the context of two estrogen receptor subtypes, ERα and ERβ, that have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites. Cellular, biochemical, and structural approaches have also shown that the nature of the ligand affects the conformation assumed by the ER-ligand complex, thereby regulating its state of phosphorylation and the recruitment of different coregulator proteins. Growth factors and protein kinases that control the phosphorylation state of the complex also regulate the bioactivity of the ER. These interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as medical therapeutic agents

Clinical characteristics and outcomes of patients with acute myelogenous leukemia admitted to intensive care: a case-control study

<p>Abstract</p> <p>Background</p> <p>There is limited epidemiologic data on patients with acute myelogenous (myeloid) leukemia (AML) requiring life-sustaining therapies in the intensive care unit (ICU). Our objectives were to describe the clinical characteristics and outcomes in critically ill AML patients.</p> <p>Methods</p> <p>This was a retrospective case-control study. Cases were defined as adult patients with a primary diagnosis of AML admitted to ICU at the University of Alberta Hospital between January 1^st2002 and June 30^th2008. Each case was matched by age, sex, and illness severity (ICU only) to two control groups: hospitalized AML controls, and non-AML ICU controls. Data were extracted on demographics, course of hospitalization, and clinical outcomes.</p> <p>Results</p> <p>In total, 45 AML patients with available data were admitted to ICU. Mean (SD) age was 54.8 (13.1) years and 28.9% were female. Primary diagnoses were sepsis (32.6%) and respiratory failure (37.3%). Mean (SD) APACHE II score was 30.3 (10.3), SOFA score 12.6 (4.0) with 62.2% receiving mechanical ventilation, 55.6% vasoactive therapy, and 26.7% renal replacement therapy. Crude in-hospital, 90-day and 1-year mortality was 44.4%, 51.1% and 71.1%, respectively. AML cases had significantly higher adjusted-hazards of death (HR 2.23; 95% CI, 1.38-3.60, p = 0.001) compared to both non-AML ICU controls (HR 1.69; 95% CI, 1.11-2.58, p = 0.02) and hospitalized AML controls (OR 1.0, reference variable). Factors associated with ICU mortality by univariate analysis included older age, AML subtype, higher baseline SOFA score, no change or an increase in early SOFA score, shock, vasoactive therapy and mechanical ventilation. Active chemotherapy in ICU was associated with lower mortality.</p> <p>Conclusions</p> <p>AML patients may represent a minority of all critically ill admissions; however, are not uncommonly supported in ICU. These AML patients are characterized by high illness severity, multi-organ dysfunction, and high treatment intensity and have a higher risk of death when compared with matched hospitalized AML or non-AML ICU controls. The absence of early improvement in organ failure may be a useful predictor for mortality for AML patients admitted to ICU.</p

Asteroseismology and Interferometry

Asteroseismology provides us with a unique opportunity to improve our understanding of stellar structure and evolution. Recent developments, including the first systematic studies of solar-like pulsators, have boosted the impact of this field of research within Astrophysics and have led to a significant increase in the size of the research community. In the present paper we start by reviewing the basic observational and theoretical properties of classical and solar-like pulsators and present results from some of the most recent and outstanding studies of these stars. We centre our review on those classes of pulsators for which interferometric studies are expected to provide a significant input. We discuss current limitations to asteroseismic studies, including difficulties in mode identification and in the accurate determination of global parameters of pulsating stars, and, after a brief review of those aspects of interferometry that are most relevant in this context, anticipate how interferometric observations may contribute to overcome these limitations. Moreover, we present results of recent pilot studies of pulsating stars involving both asteroseismic and interferometric constraints and look into the future, summarizing ongoing efforts concerning the development of future instruments and satellite missions which are expected to have an impact in this field of research.Comment: Version as published in The Astronomy and Astrophysics Review, Volume 14, Issue 3-4, pp. 217-36

Gender differences in the associations between age trends of social media interaction and well-being among 10-15 year olds in the UK

Background Adolescents are among the highest consumers of social media while research has shown that their well-being decreases with age. The temporal relationship between social media interaction and well-being is not well established. The aim of this study was to examine whether the changes in social media interaction and two well-being measures are related across ages using parallel growth models. Methods Data come from five waves of the youth questionnaire, 10-15 years, of the Understanding Society, the UK Household Longitudinal Study (pooled n =9859). Social media interaction was assessed through daily frequency of chatting on social websites. Well-being was measured by happiness with six domains of life and the Strengths and Difficulties Questionnaire. Results Findings suggest gender differences in the relationship between interacting on social media and well-being. There were significant correlations between interacting on social media and well-being intercepts and between social media interaction and well-being slopes among females. Additionally higher social media interaction at age 10 was associated with declines in well-being thereafter for females, but not for males. Results were similar for both measures of well-being. Conclusions High levels of social media interaction in early adolescence have implications for well-being in later adolescence, particularly for females. The lack of an association among males suggests other factors might be associated with their reduction in well-being with age. These findings contribute to the debate on causality and may inform future policy and interventions

Anti-emetic drugs in oncology: pharmacology and individualization by pharmacogenetics

Objective Nausea and vomiting are the most distressful side effects of cytotoxic drugs in cancer patients. Antiemetics are commonly used to reduce these side effects. However, the current antiemetic efficacy is about 70–80% in patients treated with highly-emetogenic cytotoxic drugs. One of the potential factors explaining this suboptimal response is variability in genes encoding enzymes and proteins which play a role in metabolism, transport and receptors related to antiemetic drugs. Aim of this review was to describe the pharmacology and pharmacogenetic concepts of of antiemetics in oncology. Method Pharmacogenetic and pharmacology studies of antiemetics in oncology published between January 1997 and February 2010 were searched in PubMed. Furthermore, related textbooks were also used for exploring the pharmacology of antiemetic drugs. The antiemetic drugs which were searched were the 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs), dopamine antagonists, corticosteroids, benzodiazepines, cannabinoids, antihistamines and neurokinin-1 antagonists. Result The 5-HT3RAs are widely used in highly emetogenic chemotherapy in combination with dexamethasone and a neurokinin-1 antagonist, especially in acute phase. However, the dopamine antagonists and benzodiazepines were found more appropriate for use in breakthrough and anticipatory symptoms or in preventing the delayed phase of chemotherapy induced nausea and vomiting. The use of cannabinoids and antihistamines need further investigation. Only six articles on pharmacogenetics of the 5-HT3RAs in highly emetogenic chemotherapy are published. Specifically, these studies investigated the association of the efficacy of 5-HT3RAs and variants in the multi drug resistance 1 (MDR1) gene, 5-HT3A,B and C receptor genes and CYP2D6 gene. The pharmacogenetic studies of the other antiemetics were not found in this review. Conclusion It is concluded that pharmacogenetic studies with antiemetics are sparse. It is too early to implement results of pharmacogenetic association studies of antiemetic drugs in clinical practice: confirmation of early findings is required

Cognitive and Tactile Factors Affecting Human Haptic Performance in Later Life

Background: Vision and haptics are the key modalities by which humans perceive objects and interact with their environment in a target-oriented manner. Both modalities share higher-order neural resources and the mechanisms required for object exploration. Compared to vision, the understanding of haptic information processing is still rudimentary. Although it is known that haptic performance, similar to many other skills, decreases in old age, the underlying mechanisms are not clear. It is yet to be determined to what extent this decrease is related to the age-related loss of tactile acuity or cognitive capacity. Methodology/Principal Findings: We investigated the haptic performance of 81 older adults by means of a cross-modal object recognition test. Additionally, we assessed the subjects ’ tactile acuity with an apparatus-based two-point discrimination paradigm, and their cognitive performance by means of the non-verbal Raven-Standard-Progressive matrices test. As expected, there was a significant age-related decline in performance on all 3 tests. With the exception of tactile acuity, this decline was found to be more distinct in female subjects. Correlation analyses revealed a strong relationship between haptic and cognitive performance for all subjects. Tactile performance, on the contrary, was only significantly correlated with male subjects ’ haptic performance. Conclusions: Haptic object recognition is a demanding task in old age, especially when it comes to the exploration o

Association of objective sedentary behaviour and self-rated health in English older adults

Abstract Objective Reducing sedentary behaviour (SB) might improve the health of older adults. However, we know little about how objectively measured SB impacts on self-rated health in older adults. We aimed to explore the associations between objectively measured SB and self-rated health in English older adults. Results A random sub-sample of older adults (≥ 65 years old) from the 2008 Health Survey for England wore an ActiGraph GT1M accelerometer for 7 days. Self-rated health was measured using an item from the General Health Questionnaire. Linear regression and analysis of covariance were used to test the associations between percentage time spent in SB and mean daily minutes in SB and self-rated health (very good/good; fair; bad/very bad), adjusting for covariates. Valid accelerometry datasets were returned by 578 individuals. Significant negative associations between percentage time and mean daily minutes in SB and self-rated health were found. In particular, individuals spending reduced percentages of time being sedentary had higher self-rated health. In conclusion, SB appears to be associated with self-rated health in older people independently from MVPA. If longitudinal research could determine how changes in SB influence self-rated health as individuals’ age, this might be an important lifestyle variable to target for health improvement