2,039 research outputs found
âYOU HAVE MADE NO MISTAKE IN SEEKING TO SAVE SOULS AMONG USâ: CATHOLIC EVANGELIZATION AMONG BLACK NASHVILLIANS, 1898-1908
In 1905, Catholic Bishop Thomas Sebastian Byrne of Nashville, Tennessee announced that the Sisters of the Blessed Sacrament would open an academy and industrial school for black girls in a recently purchased mansion formerly inhabited by wealthy white Nashville banker Samuel J. Keith. Keith and hundreds of white Nashvillians protested the move, but Bishop Byrne and his collaborators refused to give up their plan and established Immaculate Mother Academy. Many black Nashvillians supported the new school, seeing Byrneâs efforts as a challenge to racial prejudice. This study tells the story of the establishment of the first stable black Catholic institutions in Nashville and their reception by white and black Nashvillians. The history of Immaculate Mother Academy shows the complex interconnection of race, religion, segregation, education, and urbanization in Nashville in the late nineteenth and early twentieth centuries. The schoolâs establishment was one step towards remedying the double bind in which black Catholics found themselvesârequired as Catholics by the Catholic bishops to educate their children in Catholic schools, they found the doors of most Catholic schools closed to black students. The schoolâs founding took place at a time of serious discussion in Nashville and throughout the U.S. of models of black education and dispute as to whether black students should be denied avenues to higher education. It likewise took place at a time of rapid demographic change in the city of Nashville, as the city center was changed by the expansion of railroads, industry, and the advent of electric streetcars while segregation became more pronounced. This study demonstrates that while anti-black prejudice trumped anti-Catholicism as a motivating factor for white Nashvillians such as Keith, Catholic efforts in the face of such prejudice served as an invitation to black leaders to consider the merits of the Catholic position, and to see Catholics as allies in challenging racial prejudice. The school once successfully established was painted by some white Nashvillians as doing good service in the training of future servants, but by many black Nashvillians as offering black students an opportunity for academic learning and musical education as well as industrial training
Topical Application of a Mucoadhesive Freeze-Dried Black Raspberry Gel Induces Clinical and Histologic Regression and Reduces Loss of Heterozygosity Events in Premalignant Oral Intraepithelial Lesions: Results from a Multicentered, Placebo-Controlled Clinical Trial
Approximately 30%higher-grade premalignant oral intraepithelial neoplasia (OIN) lesions will progress to oral cancer. While surgery is the OIN treatment mainstay, many OIN lesions recur which is highly problematic for both surgeons and patients. This clinical trial assessed the chemopreventive efficacy of a natural-product based bioadhesive gel on OIN lesions
Sexual and reproductive health and human rights of women living with HIV
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138378/1/jia20834-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138378/2/jia20834.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138378/3/jia20834-sup-0002.pd
Auditory Function in the Tc1 Mouse Model of Down Syndrome Suggests a Limited Region of Human Chromosome 21 Involved in Otitis Media
Down syndrome is one of the most common congenital disorders leading to a wide range of health problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed in humans affected by Down syndrome with trisomy of chromosome 21. However, it is unknown whether Tc1 mice exhibit a hearing phenotype and might thus represent a good model for understanding the hearing loss that is common in Down syndrome. In this study we carried out a structural and functional assessment of hearing in Tc1 mice. Auditory brainstem response (ABR) measurements in Tc1 mice showed normal thresholds compared to littermate controls and ABR waveform latencies and amplitudes were equivalent to controls. The gross anatomy of the middle and inner ears was also similar between Tc1 and control mice. The physiological properties of cochlear sensory receptors (inner and outer hair cells: IHCs and OHCs) were investigated using single-cell patch clamp recordings from the acutely dissected cochleae. Adult Tc1 IHCs exhibited normal resting membrane potentials and expressed all K+ currents characteristic of control hair cells. However, the size of the large conductance (BK) Ca2+ activated K+ current (IK,f), which enables rapid voltage responses essential for accurate sound encoding, was increased in Tc1 IHCs. All physiological properties investigated in OHCs were indistinguishable between the two genotypes. The normal functional hearing and the gross structural anatomy of the middle and inner ears in the Tc1 mouse contrast to that observed in the Ts65Dn model of Down syndrome which shows otitis media. Genes that are trisomic in Ts65Dn but disomic in Tc1 may predispose to otitis media when an additional copy is active
p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study
Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC
Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10â000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 Ă 10-20), ER-negative BC (P=1.1 Ă 10-13), BRCA1-associated BC (P=7.7 Ă 10-16) and triple negative BC (P-diff=2 Ă 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 Ă 10-3) and ABHD8 (P<2 Ă 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3âČ-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk
Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.
To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease
Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource â Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre
Recommended from our members
Phenotypic Characterization of <i>EIF2AK4</i> Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension
Background:
Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (
BMPR2
) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (
EIF2AK4
) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH.
Methods:
Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResourceâRare Diseases study. Heterozygous variants in
BMPR2
and biallelic
EIF2AK4
variants with a minor allele frequency of <1:10â000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and
sorting intolerant from tolerant
predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured.
Results:
Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in
BMPR2
were identified in 130 patients (14.8%). Biallelic mutations in
EIF2AK4
were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic
EIF2AK4
mutations. These patients had a reduced transfer coefficient for carbon monoxide (K
co
; 33% [interquartile range, 30%â35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23â38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without
EIF2AK4
mutations. However, radiological assessment alone could not accurately identify biallelic
EIF2AK4
mutation carriers. Patients with PAH with biallelic
EIF2AK4
mutations had a shorter survival.
Conclusions:
Biallelic
EIF2AK4
mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K
co
and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.
</jats:sec
- âŠ