Centrilobular emphysema and coronary artery calcification: mediation analysis in the SPIROMICS cohort

Background

Chronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease independent of shared risk factors. This association is hypothesized to be mediated by systemic inflammation but this link has not been established.

Methods

We included 300 participants enrolled in the SPIROMICS cohort, 75 each of lifetime non-smokers, smokers without airflow obstruction, mild-moderate COPD, and severe-very severe COPD. We quantified emphysema and airway disease on computed tomography, characterized visual emphysema subtypes (centrilobular and paraseptal) and airway disease, and used the Weston visual score to quantify coronary artery calcification (CAC). We used the Sobel test to determine whether markers of systemic inflammation mediated a link between spirometric and radiographic features of COPD and CAC.

Results

FEV₁/FVC but not quantitative emphysema or airway wall thickening was associated with CAC (p?=?0.036), after adjustment for demographics, diabetes mellitus, hypertension, statin use, and CT scanner type. To explain this discordance, we examined visual subtypes of emphysema and airway disease, and found that centrilobular emphysema but not paraseptal emphysema or bronchial thickening was independently associated with CAC (p?=?0.019). MMP3, VCAM1, CXCL5 and CXCL9 mediated 8, 8, 7 and 16% of the association between FEV₁/FVC and CAC, respectively. Similar biomarkers partially mediated the association between centrilobular emphysema and CAC.

Conclusions

The association between airflow obstruction and coronary calcification is driven primarily by the centrilobular subtype of emphysema, and is linked through bioactive molecules implicated in the pathogenesis of atherosclerosis.

Trial Registration

ClinicalTrials.gov: Identifier: NCT01969344.

     

Macronuclear gene-sized molecules of hypotrichs.

The macronuclear genome of hypotrichous ciliates consists of DNA molecules of gene-sized length. A macronuclear DNA molecule contains a single coding region. We have analyzed the many hypotrich macronuclear DNA sequences sequenced by us and others. No highly conserved promoter sequences nor replication initiation sequences have been identified in the 5' nor in the 3' non-translated regions, suggesting that promoter function in hypotrichs may differ from other eukaryotes. The macronuclear genes are intron-poor; approximately 19% of the genes sequenced to date have one to three introns. Not all macronuclear DNA molecules may be transcribed; some macronuclear molecules may not have any coding function. Codon bias in hypotrichs is different in many respects from other ciliates and from other eukaryotes.     

Response

Summary  The posited universal cause of codon disappearance, extreme genomic % GC, is apparently not required for codon reassignment. Rigorously interpreted, this does not eliminate codon disappearance as a contributor to reassignment, but it implies that all reassignments are unlikely to be so caused. Even more significantly, the rationale for the axiom that reassigned codons must first disappear has been eliminated. That is, it has been asserted that a codon with two meanings would be lethal (Osawa and Jukes 1989). A complete inability to distinguish serine and leucine is of course lethal. However, a state of reduced ambiguity in which CUG means both serine and leucine not only stably exists in wild-type organisms in which leucine-to-serine reassignment has occurred, but such ambiguity may even have a favorable, rather than a lethal, phenotype. The potential list of possible ambiguous intermediates has been expanded by the discovery of the multiple amino acid specificity of Candida Ser- and Leu-tRNA^Ser (Suzuki et al. 1997). Other means of making codons ambiguous, such as ribosomal ambiguity or unusual concentrations or sequences of particular tRNAs, are easily envisioned. We look forward to further fossil ambiguous states and further elucidation of their phenotypes. From such data we may ultimately be able to deduce the forces that occasionally drive modern codons from one meaning to another.     

The beaded filament of the eye lens: an unexpected key to intermediate filament structure and function

In 1959, an unusual filamentous polymer, now called the beaded filament, was described in the lens of the eye. The constituent proteins, assembly properties and functions of the beaded filament have been elusive. The recent publication of the sequences for two major lens filament proteins (CP49 and filensin) and the reconstitution in vitro of structures closely resembling beaded filaments, suggests that the beaded filament is related structurally to intermediate filaments (IFs). The association of the lenticular chaperones, the alpha-crystallins, with the filament contributes to the characteristic beaded morphology, as well as giving important clues to the function of this unusual filament in the lens. These recent results have several implications for IF function and assembly.     

Chorion type as a possible influence on the results and interpretation of twin study data.

The estimation of genetic effects from twin studies usually relies upon the equal environment assumption--that monozygous (MZ) and dizygous (DZ) twin pairs experience equal similarity of their environments from prenatal experiences through adulthood. However, the sharing of a chorion may make a subset of identical twins more similar, or in some cases, more different, than twins that do not share a chorion. Recent studies suggest monochorionic MZ twins resemble one another more than dichorionic MZ twins in cognitive abilities, personality, and risk for psychiatric disorder. To the extent that prenatal environment affects these characteristics, the traditional twin method will yield biased estimates of genetic and environmental influences. We develop models for quantifying this bias and estimating the influence of chorion type on estimates of heritability.     

Isolation and some characteristics of glutathione reductase from rabbit erythrocytes (38548).

Glutathione reductase from rabbit erythrocytes was pruified to homogeneity and found to be a monomer with a mol wt of 60,000. Both NADPH and HADH were capable of acting as cofactors for the reduction of GSSG and the following kinetic values were obtained: Km, GSSG = 120 muM; Km, NADPH = 37 muM; Vmax = 23 mumoles NADPH/min/mg protein, Km, NADH = 420 muM; Vmax = 3 mumoles NADH/min/mg protein. Rabbit erythrocyte GR exhibited substrate inhibition, and was susceptible to inhibition by p-hydroxymercuribenzoate under certain conditions.     

REFORMATION OF NUCLEOLUS-LIKE BODIES IN THE ABSENCE OF POSTMITOTIC RNA SYNTHESIS

The dependence of nucleolar reformation on RNA synthesis that resumes in late anaphase or early telophase has been investigated in synchronously dividing Amoeba proteus. RNA synthesis was completely inhibited throughout all stages of mitosis and the early hours of interphase with high concentrations of actinomycin D. In such cells, nucleolus-like bodies that bind azure B and pyronin were apparent in the reformed nuclei. The bodies appear as dense, fibrous masses with loosely associated, finely fibrillar material. There are no characteristic granular regions in the reformed structures. It is suggested that the bodies probably represent mainly nucleolar protein and residual RNA which can bring about the reorganization of nucleoli in the absence of postmitotic RNA synthesis.