1,521 research outputs found
Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NFκB and Interferon signaling; implications for Paget’s disease
No full textPaget’s disease of bone (PDB) is a common disease characterized by osteoclast activation that leads to various skeletal complications. Susceptibility to PDB is mediated by a common variant at the optineurin (OPTN) locus, which is associated with reduced levels of mRNA. However, it is unclear how this leads to the development of PDB. Here, we show that OPTN acts as a negative regulator of osteoclast differentiation in vitro and that mice with a loss-of-function mutation in Optn have increased osteoclast activity and bone turnover. Osteoclasts derived from Optn mutant mice have an increase in NF-κB activation and a reduction in interferon beta expression in response to RANKL when compared to wild-type mice. These studies identify OPTN as a regulator of bone resorption and are consistent with a model whereby genetically determined reductions in OPTN expression predispose to PDB by enhancing osteoclast differentiation
Characterisation of osteoprotegerin autoantibodies in coeliac disease
No full textObjectives: Autoantibodies neutralising the effect of the bone regulatory cytokine osteoprotegerin (OPG) have been described in a patient with severe osteoporosis and coeliac disease. This study aimed to determine the prevalence and epitope specificity of autoantibodies to OPG in patients with coeliac disease, and correlate their presence with bone mineral density. Methods: A direct enzyme linked immunosorbent assay was developed and used to screen patients with coeliac disease for autoantibodies to OPG. Recombinant fragments of OPG were made to evaluate the epitope specificity and affinity of these antibodies. Phenotype information of the patients was obtained by case note review. Results: Raised titres of antibodies to OPG were found in 7/71 (9.8%) patients with coeliac disease, compared with 1/72 (1.4%) non-coeliac osteoporosis clinic control patients (p<0.05). Our results suggest a polyclonal antibody response to OPG is raised in these patients capable of recognising different epitopes of OPG with varying affinity. The titre of OPG antibodies was associated with lower bone mineral density Z score of the hip in coeliac patients on univariate (p<0.05) and multivariate analysis including age, sex height and weight as covariates (p<0.01). Conclusion: Polyclonal antibodies to OPG are more common in patients with coeliac disease and are independently associated with lower bone mineral density Z scores of the hip. Further work is required to establish the clinical utility of testing for OPG antibodies
Redemption in the work of Francis Stuart
No full textThe idea of redemption is central to an understanding of the work
of Francis Stuart. Through an examination of its development and
expression, it is possible to demonstrate the integrity of his work and
its distinctive qualities. Such a demonstration is necessary because
Stuart's writing has been subjected to comparatively little scholarly
inquiry, although reviews of his work, especially that produced since
1949, suggest that it is impressive and important.
First, a general background to Stuart's work, a discussion of the
special problems associated with reading it, and a summary of his corpus
is provided. This indicates that the idea of redemption is important to
his earliest writing. The state of redemption is shown to be a
necessary apotheosis for Stuart's outcast heroes; it involves spiritual
suffering through which may be found a sense of reintegration and a
higher reality. This is expressed through interrelated themes such as
those of gambler, artist and ordinary man; mystic and criminal; sacred
and profane love; and spirituality and the mundane. The nature of the
redemptive experience is further elaborated by distinctive, complex
motifs, especially the hare, the ark and the woman-Christ. Their
recurrence provides an important element in the unity of Stuart's work.
Because Stuart's idea of the outcast raises important biographical
questions, an examination of the relationship between Stuart's life and
his work is made. Finally, the way in which the idea of redemption
exists in the language structures of Stuart's novels is examined, with
especial reference to his most recent work, The High Consistory. The
thesis shows that the development of the these of redemption
demonstrates the integrity of Stuart's work
Addison A. Stuart
No full textAn obituary for Addison A. Stuart, U.S. Civil War veteran and author of the book Iowa Colonels and Regiments
John Stuart Mill’s projected science of society: 1827-1848
No full textThe purpose of the thesis is to examine John Stuart Mill’s political thought from
about 1827 to 1848 as an exercise in intellectual history. It focuses, first, on Mill’s view,
formulated by the late 1830s, that contemporary society was ‘civilized’, and second, on
his project of a science of society, which he aspired to develop in the late 1830s and
early 1840s.
By the late 1830s, Mill came to the view that his contemporary society was a
‘commercial society or civilization’, dominated by the middle, commercial class. The
first part of my thesis, constituted by Chapters 2-4, discusses the way in which Mill
formed his notion of civilization, and what he meant by the term ‘civilization’. Mill paid
attention to the implications of the rise of the middle class, and regarded such
phenomena of contemporary society as the corruption of the commercial spirit and
excessive social conformity as an inevitable consequence of the rise of the middle class.
The second part of the thesis, constituted by Chapters 5-9, examines Mill’s
projected science of society. In the late 1830s and early 1840s, Mill attempted to
develop a new science of society whose subject-matter was the nature and prospects of
commercial, civilized society. This aspiration culminated in A System of Logic,
published in 1843. In examining Mill’s projected science, I pay particular attention to
the fact that he conceived new sciences of history and of the formation of character,
both of which were indispensable in his project, although he failed to give a complete
account of these sciences. My thesis shows that the implications of his interest both in
history and in the formation of character are more significant than Mill scholars have
assumed
Stuart, Jesse Hilton, 1906-1984 (SC 3681)
No full textFinding aid for Manuscripts Small Collection 3681. Various items relating to the work of author Jesse Stuart: inscribed poems and articles; a 1975 commencement speech delivered at Ball State University; highlights of the first year of the Jesse Stuart Foundation; and the Jesse Stuart Land Management and Promotion Plan. Also includes (digital format only - click on Additional Files below for scans) a card index of magazine and newspaper articles by and concerning Stuart located by scholar John H. Spurlock in repositories at Murray State University, Morehead State University, and Marshall University
Bone fractures after menopause
No full textEvery year 30% of individuals above age 65 fall, and falls are the principal cause of bone fractures. To reduce fracture incidence requires both prevention of falls and maintenance of bone strength.PubMed searches were performed, for studies of the epidemiology of fractures, bone physiology, endocrine effects, osteoporosis measurement, genetics, prevention and effectiveness. Topic summaries were presented to the Workshop Group and omissions or disagreements were resolved by discussion.Ageing reduces bone strength in post-menopausal women because estrogen deficiency causes accelerated bone resorption. Bone mineral density (BMD) decreased more than 2.5 standard deviation below the mean of healthy young adults defines osteoporosis, a condition associated with an increased risk of fractures. Risk factors such as age and previous fracture are combined with BMD for a more accurate prediction of fracture risk. The most widely used assessment tool is FRAX (TM) which combines clinical risk factors and femoral neck BMD. General preventive measures include physical exercise to reduce the risk of falling and vitamin D to facilitate calcium absorption. Pharmacological interventions consist mainly in the administration of inhibitors of bone resorption. Randomized controlled trials show treatment improves BMD, and may reduce the relative fracture risk by about 50% for vertebral, 20-25% for non-vertebral and up to 40% for hip fractures although the absolute risk reductions are much lower.Although diagnosis of osteoporosis is an important step, the threshold for treatment to prevent fractures depends on additional clinical risk factors. None of the presently available treatment options provide complete fracture prevention.</p
Mechanism of bone loss in rheumatic diseases
No full textOsteoporosis and fragility fractures are recognized complications of
inflammatory rheumatic diseases. This is thought to result from the effects of
chronic inflammation, relative immobility and corticosteroid use. A rare
syndrome of osteoporosis in a patient with coeliac disease has been
described which results from production of neutralizing antibodies to the bone
protective protein osteoprotegerin (OPG). The aim of my thesis is to evaluate
prevalence and clinical predictors of osteoporosis in a contemporary cohort
of patients with rheumatoid arthritis (RA) and to investigate the role of OPG
autoantibodies in the pathogenesis of osteoporosis in rheumatic diseases.
In a retrospective cohort study, I found that the overall prevalence of
osteoporosis in patients with RA was 29.9% which is in keeping with older
reports that recorded a prevalence rate between 17% and 36%. In our
contemporary cohort osteoporosis was significantly more common than in a
gender and age matched control cohort (17.4%). Further analysis showed
that only age and BMI were independent predictors of osteoporosis in RA. A
predictive tool based on age and BMI was developed which had 91.4%
sensitivity for the detection of osteoporosis in an independent RA population.
I went on to screen for the presence of autoantibodies to OPG in patients
with various rheumatic diseases. In a study of 75 patients with rheumatoid
arthritis and 199 healthy controls OPG autoantibodies were detected in two
controls (1%) compared with seven patients with RA (9.3%). The RA patients
with detectable OPG antibodies had a longer disease duration, higher DAS28
scores and higher levels of the bone resorption marker CTX than RA patients
who did not have autoantibodies. Purified IgG from patients with high levels
of OPG antibodies blocked the ability of recombinant OPG to inhibit RANKL
induced NFκB activation in a HEK293 cell based assay indicating that they
were functional.
In a further study of 134 patients with ankylosing spondylitis (AS), 16
patients (11.9%) had detectable OPG antibodies. The presence of OPG-Ab
was independently associated with reduced hip bone mineral density and an
increased risk of fractures in this population. In patients with a longer
disease duration we have also observed that there was a higher discrepancy
between spinal and hip BMD in OPG-Ab positive patients compared with
OPG ab negative patients (p=0.003).
In order to investigate if OPG antibodies affected measurement of serum
RANKL concentrations as detected by ELISA using OPG as the capture
reagent, I measured OPG ab and free RANKL concentrations in 55
rheumatic disease patients. Surprisingly there was a significant positive
correlation between free RANKL and OPG Ab concentrations (r=0.430,
p=0.001) which was the opposite to what I had expected. These findings
reject the hypothesis that OPG ab block binding of synthetic OPG to RANKL
in the ELISA.
In conclusion, I have shown that osteoporosis is a common complication in
RA and I have developed a new risk prediction tool for the use in clinical
practice. I have also found that OPG antibodies are produced more
commonly in patients with RA and AS than in healthy controls and that
antibody levels correlate with bone resorption markers in RA and bone
mineral density in AS patients. In vitro studies have shown that some OPG
antibodies have functional effects on RANKL signalling. These findings raise
the possibility that OPG antibodies may contribute to the pathogenesis of
local and systemic bone loss in rheumatic diseases and signal the need to
study the relationship between these antibodies and bone disease in large-scale
longitudinal studies
Role of type 2 cannabinoid receptor in bone metabolism
No full textCannabinoid receptors play an important role in regulating bone mass and bone
turnover. Studies in our laboratories have shown that young mice lacking type 1
cannabinoid receptor (CNR1-/-) had increased bone mass and were resistant to
ovariectomy-induced bone loss. Other workers have reported that type 2 cannabinoid
receptor knockout mice (CNR2-/-) develop age-related osteoporosis. The aim of this PhD
thesis was to further investigate the role of CNR2 in bone metabolism in vitro and in
vivo, using genetic and pharmacological approaches.
This study showed that CNR2-/- mice had normal bone mass and bone turnover at 3
months of age, but following ovariectomy, CNR2-/- mice were partially protected from
bone loss, because of a mild defect in osteoclast formation and bone resorption. In
keeping with this, studies in vitro showed that RANKL-stimulated bone marrow cultures
from CNR2-/- mice had fewer osteoclasts than cultures from wild type littermates. The
CNR2-selective antagonist/inverse agonist AM630, inhibited osteoclast formation in
wild type bone marrow cultures in vitro and prevented ovariectomy-induced bone loss in
wild type mice in vivo. In contrast, osteoclast cultures from CNR2-/- mice were resistant
to the inhibitory effects of AM630 at low concentrations and CNR2-/- ovariectomised
mice did not respond to its protective effects at low doses, consistent with a CNR2-
mediated effect. These results indicate that CNR2 regulates bone loss under conditions
of increased bone turnover, such as ovariectomy, by affecting osteoclast differentiation
and function.
CNR2-deficient mice developed accelerated age-related osteoporosis and by 12 months
of age they had a significant reduction in osteoblast numbers and bone formation, whereas osteoclast numbers remained comparable to wild type littermates. In agreement
with this, osteoblasts derived from bone marrow of CNR2-/- mice had reduced PTHstimulated
alkaline phosphatase activity and ability to form bone nodules, when
compared with wild type cultures. The CNR2-selective agonist, HU308, stimulated bone
nodule formation in wild type calvarial osteoblast cultures in vitro and reversed
ovariectomy-induced bone loss in wild type mice in vivo. HU308 had blunted effects on
bone nodule formation in cultures from CNR2-/- mice and no significant effects on
ovariectomy-induced bone loss in CNR2-/- mice, indicating a CNR2-mediated effect.
These studies demonstrate that CNR2 protects against age-related bone loss by mainly
enhancing osteoblast differentiation and bone formation.
In conclusion, type 2 cannabinoid receptors protect from bone loss by maintaining bone
remodelling at balance. In addition, type 2 cannabinoid receptor agonists show evidence
of anabolic activity, whereas antagonists/inverse agonists show evidence of antiosteoclastic
activity in vitro and in vivo
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