80 research outputs found
Human Trichohyalin Gene Is Clustered with the Genes for Other Epidermal Structural Proteins and Calcium-Binding Proteins at Chromosomal Locus 1q21
Trichohyalin is a major differentiation product of hard keratinizing tissues such as the inner root sheath and medullary cells of the hair follicle and the filiform papillae of the tongue, as well as terminally differentiating epidermal cells. It consists largely of quasi-repeating peptide repeats and functions primarily as an intermediate filament-associated protein in these tissues. By mapping with human-rodent somatic cell hybrids and fluorescent in situ hybridization, we demonstrate that its gene maps to chromosomal region 1q21. Interestingly, genes encoding several other structural proteins expressed during terminal differentiation in the epidermis map to this region, as do also several members of the S-100 class of small calcium-binding proteins
Evolution and Organization of the Fibrinogen Locus on Chromosome 4: Gene Duplication Accompanied by Transposition and Inversion
Human fibrinogen cDNA probes for the alpha-, beta-, and gamma-polypeptide chains have been used to isolate the corresponding genes from human genomic libraries. There is a single copy of each gene. Restriction endonuclease analysis of isolated genomic clones and human genomic DNA indicates that the human alpha-, beta-, and gamma-fibrinogen genes are closely linked in a 50-kilobase region of a single human chromosome: the alpha-gene in the middle flanked by the beta-gene on one side and the gamma-gene on the other. The alpha- and gamma-chain genes are oriented in tandem and transcribed toward the beta-chain gene. The beta-chain gene is transcribed from the opposite DNA strand toward the gamma- and alpha-chain genes. The three genes have been localized to the distal third of the long arm of chromosome 4, bands q23-q32, by in situ hybridization with fibrinogen cDNAs and by examination of DNA from multiple rodent-human somatic cell hybrids. Alternative explanations for the present arrangement of the three fibrinogen genes involve either a three-step mechanism with inversion of the alpha /gamma-region or a two-step mechanism involving remote transposition and inversion. The second more simple mechanism has a precedent in the origin of repeated regions of the fibrinogen and immunoglobulin genes
Assessment of abdominal aortic aneurysm biology using magnetic resonance imaging and positron emission tomography-computed tomography.
Background
Although abdominal aortic aneurysm (AAA) growth is non-linear, serial
measurements of aneurysm diameter are the mainstay of aneurysm surveillance and
contribute to decisions on timing of intervention. Aneurysm biology plays a key part
in disease evolution but is not currently routinely assessed in clinical practice.
Magnetic Resonance Imaging (MRI) and Positron Emission Tomography-Computed
Tomography (PET-CT) provide insight into disease processes on a cellular or
molecular level, and represent exciting new imaging biomarkers of disease activity.
Macrophage-mediated inflammation may be assessed using ultrasmall
superparamagnetic particles of iron oxide (USPIO) MRI and the PET radiotracer 18FSodium
Fluoride (18F-NaF) identifies microcalcification which is a response to
underlying necrotic inflammation. The central aim of this thesis was to investigate
these imaging modalities in patients with AAA.
Methods and Results
USPIO MRI: MULTI-CENTRE STUDY
In a prospective multi-centre observational cohort study, 342 patients (85.4% male,
mean age 73.1±7.2 years, mean AAA diameter 49.6±7.7mm) with asymptomatic
AAA ≥4 cm anteroposterior diameter underwent MRI before and 24-36 hours after
intravenous administration of USPIO. Colour maps (depicting the change in T2*
caused by USPIO) were used to classify aneurysms on the basis of the presence of
USPIO uptake in the aneurysm wall, representing mural inflammation. Intra- and
inter-observer agreement were found to be very good, with proportional agreement
of 0.91 (kappa 0.82) and 0.83 (kappa 0.66), respectively. At 1 year, there was 29.3%
discordant classification of aneurysms on repeated USPIO MRI and at 2 years,
discordance was 65%, suggesting that inflammation evolves over time. In the
observational study, after a mean of 1005±280 days of follow up, there were 126
(36.8%) aneurysm repairs and 17 (5.0%) ruptures. Participants with USPIO
enhancement (42.7%) had increased aneurysm expansion rates (3·1±2·5 versus
2·5±2·4 mm/year; difference 0·6 [95% confidence intervals (CI), 0·02 to 1·2]
mm/year, p=0·0424) and had higher rates of aneurysm rupture or repair
(69/146=47·3% versus 68/191=35·6%; difference 11·7%, 95% CI 1·1 to 22·2%,
p=0·0308). USPIO MRI was therefore shown to predict AAA expansion and the
composite of rupture or repair, however this was not independent of aneurysm
diameter (c-statistic, 0·7924 to 0·7926; unconditional net reclassification -13·5%,
95% confidence intervals -36·4% to 9·3%).
18F-NaF PET-CT: SINGLE-CENTRE STUDY
A sub-group of 76 patients also underwent 18F-NaF PET-CT, which was evaluated
using the maximum tissue-to-background ratio (TBRmax) in the most diseased
segment (MDS), a technique that showed very good intra- (ICC 0.70-0.89) and inter-observer
(ICC 0.637-0.856) agreement. Aneurysm tracer uptake was compared
firstly in a case-control study, with 20 patients matched to 20 control patients for age,
sex and smoking status. 18F-NaF uptake was higher in aneurysm when compared to
control aorta (log2TBRmax 1.712±0.560 vs. 1.314±0.489; difference 0.398 (95% CI
0.057, 0.739), p=0.023), or to non-aneurysmal aorta in patients with AAA
(log2TBRmax 1.647±0.537 vs. 1.332±0.497; difference 0.314 (95% CI 0.0685, 0.560),
p=0.004). An ex vivo study was performed on aneurysm and control tissue, which
demonstrated that 18F-NaF uptake on microPET-CT was higher in the aneurysm
hotspots and higher in aneurysm tissue compared to control tissue. Histological
analysis suggested that 18F-NaF was highest in areas of focal calcification and
necrosis. In an observational cohort study, aneurysms were stratified by tertiles of
TBRmax in the MDS and followed up for 510±196 days, with 6 monthly serial
ultrasound measurements of diameter. Those in the highest tertile of tracer uptake
expanded more than 2.5 times more rapidly than those in the lowest tertile (3.10
[3.58] mm/year vs. 1.24 [2.41] mm/year, p=0.008) and were also more likely to
experience repair or rupture (15.3% vs. 5.6%, log-rank p=0.043). In multivariable
analyses, 18F-NaF uptake on PET-CT emerged as an independent predictor of AAA
expansion (p=0.042) and rupture or repair (HR 2.49, 95% CI1.07, 5.78; p=0.034),
even when adjusted for age, sex, body mass index, systolic blood pressure, current
smoking and, crucially, aneurysm diameter.
Conclusion
These are the largest USPIO MRI and PET-CT studies in AAA disease to date and
the first to investigate 18F-NaF. Both USPIO MRI and 18F-NaF PET-CT are able to
predict AAA expansion and the composite of rupture and repair, with 18F-NaF PETCT
emerging as the first imaging biomarker that independently predicts expansion
and AAA events, even after adjustment for aneurysm diameter. This represents an
exciting new predictor of disease progression that adds incremental value to standard
clinical assessments. Feasibility and randomised clinical trials are now required to
assess the potential of this technique to change the management and outcome of patients with AAA
SEPARATION OF NUCLEI REPRESENTING DIFFERENT PHASES OF THE GROWTH CYCLE FROM UNSYNCHRONIZED MAMMALIAN CELL CULTURES
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