PubMed Health⌕ Search

Biomedical subjects

David Miller

Publications and source records attributed to David Miller.

At least 19 recordsLinked to original sources
PubMed2025

Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes.

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.

Humans↗
PubMed2006

Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA.

Viral infection induces the production of interleukin (IL)-1beta and IL-18 in macrophages through the activation of caspase-1, but the mechanism by which host cells sense viruses to induce caspase-1 activation is unknown. In this report, we have identified a signaling pathway leading to caspase-1 activation that is induced by double-stranded RNA (dsRNA) and viral infection that is mediated by Cryopyrin/Nalp3. Stimulation of macrophages with dsRNA, viral RNA, or its analog poly(I:C) induced the secretion of IL-1beta and IL-18 in a cryopyrin-dependent manner. Consistently, caspase-1 activation triggered by poly(I:C), dsRNA, and viral RNA was abrogated in macrophages lacking cryopyrin or the adaptor ASC (apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain) but proceeded normally in macrophages deficient in Toll-like receptor 3 or 7. We have also shown that infection with Sendai and influenza viruses activates the cryopyrin inflammasome. Finally, cryopyrin was required for IL-1beta production in response to poly(I:C) in vivo. These results identify a mechanism mediated by cryopyrin and ASC that links dsRNA and viral infection to caspase-1 activation resulting in IL-1beta and IL-18 production.

Animals↗
PubMed2006

Bilateral spatial filtering: refining methods for localizing brain activation in the presence of parenchymal abnormalities.

Functional MRI (fMRI) is an important tool for pre-surgical localization of eloquent cortex prior to resection of brain lesions. To increase the inherently low activation signal to noise ratio, fMRI pre-processing steps often include spatial smoothing. However, the effects of smoothing in the presence of brain lesions have not been studied. We have adapted the widely used method of Gaussian spatial filtering to include an "edge stopping" function. This method, termed bilateral filtering, minimizes blurring of apparent brain activity across anatomic boundaries and into regions of non-activation. fMRI data were acquired in a patient with a known low grade glioma during a blocked finger-tapping paradigm. Simulated activity was superimposed on baseline images of non-activated brain using the same paradigm, with additive signal equal to 1, 3, and 5% of the mean physiologic background. Comparison of Gaussian and bilateral filtering suggests that the modified technique more accurately locates brain activation and increases the significance of activation bordering sharp transitions. Thus, spatial pre-processing with a bilateral filter may be particularly useful in the pre-operative assessment of brain lesions.

Brain↗
PubMed2006

Towards a better understanding of RNA carriage by ejaculate spermatozoa.

Research on spermatozoal RNA has made considerable progress since the original reports on its presence appeared in the late 1950s and early 1960s. Through the use of stringent procedures aimed at eliminating contamination artefacts, we now appreciate that a complex cohort of mRNAs persists in the ejaculate cell but that 80S (cytoplasmic) ribosomal complexes are not present in sufficient quantities to support cytoplasmic mRNA translation. Despite this, under certain conditions, at least some cytoplasmic mRNAs can apparently be translated de novo, possibly on mitochondrial polysomes. The detection of mRNA translation by mature spermatozoa essentially supports the earliest research reports on spermatozoal gene expression although the suggested relationship with protein turnover and capacitation is wholly unexpected. We also examine some alternative explanations and roles for RNA carriage, including the RNAs passive retention as a consequence of nuclear shutdown and a more active role in chromatin repackaging, genomic imprinting, gene silencing and post-fertilization requirements of essential paternal RNAs. The recent report of an RNA-mediated epigenetic alteration to phenotype that is likely to be sperm derived is of particular interest in this regard. We finally show that regardless of the biological role(s) of spermatozoal RNA, its utility in infertility studies, particularly when coupled with modern techniques in gene-expression analysis (e.g. microarrays), is obvious. As a wholly non-invasive proxy for the testis, this RNA offers considerable potential as a marker for fertility status and the genetic and environmental influences that could make all the difference between a fertile and an infertile phenotype.

Animals↗
PubMed2006

centrosomin's beautiful sister (cbs) encodes a GRIP-domain protein that marks Golgi inheritance and functions in the centrosome cycle in Drosophila.

The mechanism of inheritance of the Golgi complex is an important problem in cell biology. In this study, we examine the localization and function of a Golgi protein encoded by centrosomin's beautiful sister (cbs) during cleavage in Drosophila melanogaster. Cbs contains a GRIP domain that is 57% identical to vertebrate Golgin-97. Cbs undergoes a dramatic relocalization during mitosis from the cytoplasm to an association with chromosomes from late prometaphase to early telophase, by a transport mechanism that requires the GRIP domain and Arl1, the product of the Arf72A locus. Additionally, Cbs remains independent of the endoplasmic reticulum throughout cleavage. The use of RNAi, Arf72A mutant analysis and ectopic expression of the GRIP domain, shows that cycling of Cbs during mitosis is required for the centrosome cycle. The effects on the centrosome cycle depend on Cbs concentration and Cbs transport from the cytoplasm to DNA. When Cbs levels are reduced centrosomes fail to mature, and when Cbs transport is impeded by ectopic expression of the GRIP domain, centrosomes undergo hypertrophy. We propose that, Cbs is a trans-Golgi protein that links Golgi inheritance to the cell cycle and the Drosophila Golgi is more vertebrate-like than previously recognized.

ADP-Ribosylation Factors↗
PubMed2006

The cyclin-like uracil DNA glycosylase (UDG) of murine oocytes and its relationship to human and chimpanzee homologues.

Examination of electrophoretically resolved randomly generated PCR amplicons from mature murine oocytes revealed the presence of a short sequence with partial homology to a cyclin-like human uracil DNA glycosylase (UDG2), a member of an important group of base-excision enzymes that remove misincorporated or cytosine-derived uracil from nascent DNA. A combination of 3' R.A.C.E. and in silico 'cloning' of the 5' region of the original EST uncovered a predicted murine mRNA sequence with limited homology to human UDG2 at both nucleotide and amino acid levels. An alternative contig for human UDG2 showed stronger similarity with the homologous murine and chimp genomic and protein sequences and contained both N and C terminal cyclin box elements. This contig is also an Ensembl annotated alternative splice-site variant of the UDG2 gene (Udg2v2). We suggest that uracil-excision repair in oocytes is likely to be mediated by Udg2v2, or alternatively that Udg2v2 is involved in a process related to oocyte-specific maturation by virtue of its cyclin-like domains.

Amino Acid Sequence↗
PubMed2006

A divergent external loop confers antagonistic activity on floral regulators FT and TFL1.

The Arabidopsis genes FT and TERMINAL FLOWER1 (TFL1) encode related proteins with similarity to human Raf kinase inhibitor protein. FT, and likely also TFL1, is recruited to the promoters of floral genes through interaction with FD, a bZIP transcription factor. FT, however, induces flowering, while TFL1 represses flowering. Residues responsible for the opposite activities of FT and TFL1 were mapped by examining plants that overexpress chimeric proteins. A region important in vivo localizes to a 14-amino-acid segment that evolves very rapidly in TFL1 orthologs, but is almost invariant in FT orthologs. Crystal structures show that this segment forms an external loop of variable conformation. The only residue unambiguously distinguishing the FT and TFL1 loops makes a hydrogen bond with a residue near the entrance of a potential ligand-binding pocket in TFL1, but not in FT. This pocket is contacted by a C-terminal peptide, which also contributes to the opposite FT and TFL1 activities. In combination, these results identify a molecular surface likely to be recognized by FT- and/or TFL1-specific interactors.

Amino Acid Sequence↗
PubMed2006

Measurement of xenon diffusing capacity in the rat lung by hyperpolarized 129Xe MRI and dynamic spectroscopy in a single breath-hold.

We used the dual capability of hyperpolarized 129Xe for spectroscopy and imaging to develop new measures of xenon diffusing capacity in the rat lung that (analogously to the diffusing capacity of carbon monoxide or DLCO) are calculated as a product of total lung volume and gas transfer rate constants divided by the pressure gradient. Under conditions of known constant pressure breath-hold, the volume is measured by hyperpolarized 129Xe MRI, and the transfer rate is measured by dynamic spectroscopy. The new quantities (xenon diffusing capacity in lung parenchyma (DLXeLP)), xenon diffusing capacity in RBCs (DLXeRBC), and total lung xenon diffusing capacity (DLXe)) were measured in six normal rats and six rats with lung inflammation induced by instillation of fungal spores of Stachybotrys chartarum. DLXeLP, DLXeRBC, and DLXe were 56 +/- 10 ml/min/mmHg, 64 +/- 35 ml/min/mmHg, and 29 +/- 9 ml/min/mmHg, respectively, for normal rats, and 27 +/- 9 ml/min/mmHg, 42 +/- 27 ml/min/mmHg, and 16 +/- 7 ml/min/mmHg, respectively, for diseased rats. Lung volumes and gas transfer times for LP (TtrLP) were 16 +/- 2 ml and 22 +/- 3 ms, respectively, for normal rats and 12 +/- 2 ml and 35 +/- 8 ms, respectively, for diseased rats. Xenon diffusing capacities may be useful for measuring changes in gas exchange associated with inflammation and other lung diseases.

Animals↗
PubMed2006

Algorithms to identify colonic ischemia, complications of constipation and irritable bowel syndrome in medical claims data: development and validation.

PURPOSE: A challenge in the use of insurance claims databases for epidemiologic research is accurate identification and verification of medical conditions. This report describes the development and validation of claims-based algorithms to identify colonic ischemia, hospitalized complications of constipation, and irritable bowel syndrome (IBS). METHODS: From the research claims databases of a large healthcare company, we selected at random 120 potential cases of IBS and 59 potential cases each of colonic ischemia and hospitalized complications of constipation. We sought the written medical records and were able to abstract 107, 57, and 51 records, respectively. We established a 'true' case status for each subject by applying standard clinical criteria to the available chart data. Comparing the insurance claims histories to the assigned case status, we iteratively developed, tested, and refined claims-based algorithms that would capture the diagnoses obtained from the medical records. We set goals of high specificity for colonic ischemia and hospitalized complications of constipation, and high sensitivity for IBS. RESULTS: The resulting algorithms substantially improved on the accuracy achievable from a naïve acceptance of the diagnostic codes attached to insurance claims. The specificities for colonic ischemia and serious complications of constipation were 87.2 and 92.7%, respectively, and the sensitivity for IBS was 98.9%. CONCLUSIONS: U.S. commercial insurance claims data appear to be usable for the study of colonic ischemia, IBS, and serious complications of constipation.

Algorithms↗
PubMed2006

MRI criteria for dissemination in space in patients with clinically isolated syndromes: a multicentre follow-up study.

BACKGROUND: The McDonald International Panel accepted the Barkhof/Tintoré criteria for providing MRI evidence of dissemination in space to allow a diagnosis of multiple sclerosis in patients with clinically isolated syndromes (CIS). We applied these criteria in a large cohort of patients with CIS, representative of those seen in a general diagnostic setting, to assess their accuracy in predicting conversion to definite multiple sclerosis and to identify factors that affect this risk. METHODS: In a collaborative study of seven centres, baseline MRI and clinical follow-up data for 532 patients with CIS were studied, with the development of a second clinical event used as the main outcome. All scans were scored for lesion counts and spatial lesion distribution to assess the fulfilment--ie, at least three out of four--of the Barkhof/Tintoré criteria. We used survival analysis and 2x2 tables to assess the test characteristics of the criteria at baseline. FINDINGS: Overall conversion rate was 32.5% with a median survival time of 85.3 months. Fulfilment of the criteria at baseline showed, after a survival time of 2 years, a conversion rate of about 45% (95% CI 37-53) versus about 10% (6-16) in those with no asymptomatic lesions at baseline (p<0.0001). For patients with a follow-up of at least 2 years, the fulfilment of the MRI criteria showed an accuracy of 68% (sensitivity 49%, specificity 79%) for predicting conversion and an increase in risk of nearly four times for conversion compared with those not fulfilling the criteria (odds ratio 3.7, 95% CI 2.3-5.9; p<0.0001). Cox proportional hazards regression analysis accorded with this increased risk. No effects were recorded on the performance of the criteria by sex, presenting symptoms, or centre. Age at baseline did have a small but significant effect as predictor (hazard ratio 0.97, 0.95-0.99; p=0.002), but did not affect the prognostic value of the MRI criteria. INTERPRETATION: MRI abnormalities have important prognostic value. The cut-off, based on the Barkhof/Tintoré criteria, as incorporated in the McDonald diagnostic scheme yields acceptable specificity, but could have lower sensitivity than previously reported.

Adolescent↗
PubMed2006

Airborne endotoxin is associated with respiratory illness in the first 2 years of life.

To determine the influence of endotoxin on the incidence of acute respiratory illness during the first 2 years of life, we carried out a longitudinal follow-up study, beginning at birth, of 332 children born in Prince Edward Island, Canada. We measured 5-day averaged air endotoxin in the homes of children, whose parents provided information by daily symptom diaries and twice-monthly telephone contact for up to 2 years. Endotoxin concentration was 0.49 +/- 3.49 EU/m3 (geometric mean +/- geometric SD), and number of annualized illness episodes was 6.83 +/- 2.80 (mean +/- SD). A doubling of the air endotoxin concentration was associated with an increase of 0.32 illness episodes per year (p = 0.0003), adjusted for age, year of study, breast-feeding, environmental tobacco smoke, child care attendance, indoor temperature, and income. Indoor mold surface area and fungal ergosterol were not significantly associated with endotoxin. Airborne endotoxin appears to be a risk factor for clinically symptomatic respiratory illnesses during the first 2 years of life independent of indoor fungus.

Air Pollutants↗
PubMed2006

A surgical tip for shoulder hemiarthroplasty in a patient with a deficient rotator cuff.

The deltopectoral approach has long been the workhorse for exposure of the shoulder. However, this exposure involves dividing the subscapularis tendon. Despite meticulous repair, suboptimal return of subscapularis may further reduce a patient's functional capacity with an already deficient rotator cuff. This report describes an alternative approach for shoulder hemiarthroplasty, preserving subscapularis, in a patient with a deficient rotator cuff.

Arthritis↗
PubMed2006

Multifocal osteonecrosis predominantly affecting the knees secondary to chronic alcohol ingestion: A case report and review.

We present a case of multifocal osteonecrosis secondary to alcohol ingestion in a middle aged lady, after the exclusion of other causal factors. It presented initially with knee pain and subsequently necessitated arthroplasty; other areas became more problematic. This condition is rare and we present a literature review that reveals that after steroids the suspected link to alcohol is not so obvious. A high index of suspicion is required and treatment remains expectant and symptomatic. The role of screening is also discussed.

Alcoholism↗
PubMed2005

Smallpox vaccine does not protect macaques with AIDS from a lethal monkeypox virus challenge.

It is unknown whether smallpox vaccination would protect human immunodeficiency virus type 1 (HIV-1)-infected individuals, because helper CD4(+) cells, the targets of HIV-1 infection, are necessary for the induction of both adaptive CD8(+) cell and B cell responses. We have addressed this question in macaques and have demonstrated that, although smallpox vaccination is safe in immunodeficient macaques when it is preceded by immunization with highly attenuated vaccinia strains, the macaques were not protected against lethal monkeypox virus challenge if their CD4(+) cell count was <300 cells/mm(3). The lack of protection appeared to be associated with a defect in vaccinia-specific immunoglobulin (Ig) switching from IgM to IgG. Thus, vaccination strategies that bypass CD4(+) cell help are needed to elicit IgG antibodies with high affinity and adequate tissue distribution and to restore protection against smallpox in severely immunocompromised individuals.

Animals↗