Experiences with the Streptococcus mutans in Lakota Sioux (SMILeS) Study: Risk Factors for Caries in American Indian Children 0-3 Years

Severe Early Childhood Caries (S-ECC) is a terribly aggressive and devastating disease that is all too common in lower socio-economic children, but none more so that what is encountered in American Indian Tribes. Nationwide, approximately 27% of 2-5 year olds have decay while 62% percent of American Indian/Alaska Native children in the same age group have a history of decay (IHS 2010, NHANES 1999-2002). We have conducted a study of children from birth to 36 months of age on Pine Reservation to gain a better understanding of the variables that come into play in the development of this disease, from transmission and acquisition of Streptococcus mutans genotypes from mother to child to multiple dietary and behavioral components. This article describes how we established a direct partnership with the Tribe and the many opportunities and challenges we faced in performing this 5-year field study

Relationship between inflammatory cytokines and self-report measures of training overload

It has been purported that inflammatory cytokines may be responsible for the aetiology of overtraining. The aim of the present study was to investigate the relationship between self-reported measures of overtraining and inflammatory cytokines. Eight elite male rowers were monitored in their natural training environment for 8 weeks prior to the 2007 Rowing World Championships. During this period of intense endurance training, self-report measures of overtraining and inflammatory cytokines (Interleukin (IL)-1&beta;, IL-6, IL-8, IL-10, IL-12p70, and Tumor Necrosis Factor (TNF)-) were assessed fortnightly. Consistent with previous findings, proinflammatory cytokines IL-1&beta; and TNF- were significantly associated (p &le; 0.05) with measures of depressed mood, sleep disturbances, and stress. Similarly, IL-6 was significantly associated (p &le; 0.01) with measures of depressed mood, sleep disturbances, and fatigue. These results are consistent with previous hypotheses describing how overtraining may be caused by excessive cytokine release, and lend further support for a cytokine hypothesis of overtraining. <br /

The XMM Cluster Survey: The Dynamical State of XMMXCS J2215.9-1738 at z=1.457

We present new spectroscopic observations of the most distant X-ray selected galaxy cluster currently known, XMMXCS J2215.9-1738 at z=1.457, obtained with the DEIMOS instrument at the W. M. Keck Observatory, and the FORS2 instrument on the ESO Very Large Telescope. Within the cluster virial radius, as estimated from the cluster X-ray properties, we increase the number of known spectroscopic cluster members to 17 objects, and calculate the line of sight velocity dispersion of the cluster to be 580+/-140 km/s. We find mild evidence that the velocity distribution of galaxies within the virial radius deviates from a single Gaussian. We show that the properties of J2215.9-1738 are inconsistent with self-similar evolution of local X-ray scaling relations, finding that the cluster is underluminous given its X-ray temperature, and that the intracluster medium contains ~2-3 times the kinetic energy per unit mass of the cluster galaxies. These results can perhaps be explained if the cluster is observed in the aftermath of an off-axis merger. Alternatively, heating of the intracluster medium through supernovae and/or Active Galactic Nuclei activity, as is required to explain the observed slope of the local X-ray luminosity-temperature relation, may be responsible.Comment: 13 pages, 6 figures, accepted for publication in Ap

Timing of primary tooth emergence among U.S. racial and ethnic groups

ObjectivesTo compare timing of tooth emergence among groups of American Indian (AI), Black and White children in the United States at 12 months of age.MethodsData were from two sources – a longitudinal study of a Northern Plains tribal community and a study with sites in Indiana, Iowa and North Carolina. For the Northern Plains study, all children (n = 223) were American Indian, while for the multisite study, children (n = 320) were from diverse racial groups. Analyses were limited to data from examinations conducted within 30 days of the child’s first birthday.ResultsAI children had significantly more teeth present (Mean: 7.8, Median: 8.0) than did Whites (4.4, 4.0, P < 0.001) or Blacks (4.5, 4.0, P < 0.001). No significant differences were detected between Black and White children (P = 0.58). There was no significant sex difference overall or within any of the racial groups.ConclusionsTooth emergence occurs at a younger age for AI children than it does for contemporary White or Black children in the United States.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135387/1/jphd12154.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135387/2/jphd12154_am.pd

Aquilegia, Vol. 13 No. 1, January-February 1989: Newsletter of the Colorado Native Plant Society

https://epublications.regis.edu/aquilegia/1044/thumbnail.jp

The XMM Cluster Survey: Active Galactic Nuclei and Starburst Galaxies in XMMXCS J2215.9-1738 at z=1.46

We use Chandra X-ray and Spitzer infrared observations to explore the AGN and starburst populations of XMMXCS J2215.9-1738 at z=1.46, one of the most distant spectroscopically confirmed galaxy clusters known. The high resolution X-ray imaging reveals that the cluster emission is contaminated by point sources that were not resolved in XMM observations of the system, and have the effect of hardening the spectrum, leading to the previously reported temperature for this system being overestimated. From a joint spectroscopic analysis of the Chandra and XMM data, the cluster is found to have temperature T=4.1_-0.9^+0.6 keV and luminosity L_X=(2.92_-0.35^+0.24)x10^44 erg/s extrapolated to a radius of 2 Mpc. As a result of this revised analysis, the cluster is found to lie on the sigma_v-T relation, but the cluster remains less luminous than would be expected from self-similar evolution of the local L_X-T relation. Two of the newly discovered X-ray AGN are cluster members, while a third object, which is also a prominent 24 micron source, is found to have properties consistent with it being a high redshift, highly obscured object in the background. We find a total of eight >5 sigma 24 micron sources associated with cluster members (four spectroscopically confirmed, and four selected using photometric redshifts), and one additional 24 micron source with two possible optical/near-IR counterparts that may be associated with the cluster. Examining the IRAC colors of these sources, we find one object is likely to be an AGN. Assuming that the other 24 micron sources are powered by star formation, their infrared luminosities imply star formation rates ~100 M_sun/yr. We find that three of these sources are located at projected distances of <250 kpc from the cluster center, suggesting that a large amount of star formation may be taking place in the cluster core, in contrast to clusters at low redshift.Comment: Accepted for publication in ApJ, 16 pages, 10 figure

HBO1 is required for the maintenance of leukaemia stem cells.

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)1. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings

Guidance to inform research recruitment processes for studies involving critically ill patients

Clinical research in intensive care units (ICUs) is essential for improving treatments for critically ill patients. However, invitations to participate in clinical research in this situation pose numerous challenges. Studies are frequently initiated within a narrow time window when patients are often unconscious and unable to consent. Consultations or consent discussions must therefore be held with consultees or representatives, usually the patient’s relatives. Conversations about research participation in this setting may be difficult, as relatives are often overwhelmed and may feel uneasy about making decisions on behalf of their relatives. In some circumstances, legislation allows doctors to act as consultees or representatives to enrol patients in research. However, there is little good quality evidence on UK stakeholders’ perspectives to inform how recruitment is carried out in ICU studies. The Perspectives Study collected evidence on the views of over 1400 stakeholders, including patients, relatives and healthcare practitioners, many of whom had first-hand experience of ICU treatment and research. This evidence was used to inform good practice guidance on recruitment of critically ill patients to research. Established social science methods and empirical ethics were employed to reflect the interests of stakeholders and justify recommendations. This guidance aims to bridge the gap between the legal frameworks and the realities of ICU studies and to ensure that research recruitment processes reflect the views of patients and families. Researchers and an expert Advisory Group brought different perspectives to interpreting the evidence to develop the guidance. In this article we present guidance for future ICU studies

Homologous recombination DNA repair defects in PALB2- associated breast cancers

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD