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Tim Cundy

Publications and source records attributed to Tim Cundy.

30 records · Page 2Linked to original sources
PubMed2004

Comparative responses of bone turnover markers to bisphosphonate therapy in Paget's disease of bone.

The measurement of biochemical markers of bone turnover is integral to the diagnosis and management of Paget's disease. Recently, there has been a proliferation of new markers and a move to carry out existing assays on automated platforms. We have assessed the performance of seven currently available markers in 20 patients with Paget's disease undergoing ibandronate therapy (6 or 12 mg) and in nine placebo-treated controls. Samples were collected at baseline and 6 months following intervention. The mean reductions in serum markers following treatment with either dose of ibandronate were: total alkaline phosphatase (AP; Roche Modular) 70%, bone AP (Beckman Access, Ostase) 80%, osteocalcin (Roche Elecsys 2010) 33%, beta-C-terminal telopeptide of type I collagen (betaCTX; Roche Elecsys 2010) 50%, and procollagen-N-terminal peptide (P1NP; Roche Elecsys 2010) 80%. For urine markers the reductions were: free deoxypyridinoline/creatinine (fDPD/creat) (DPC Immulite 2000) 36%, and N-telopeptide/creatinine (NTX/creat) (Osteomark) 81%. Total AP, bone AP, P1NP, and NTX all showed >95% of subjects to have abnormal values at baseline, reducing to 15-30% following treatment, and these treatment effects were highly significant (P < or = 0.0005), except for NTX (P = 0.02). The poorer precision of NTX reduced its utility. Baseline sensitivity was lower for the other markers (osteocalcin 68% of subjects abnormal, fDPD 22%, betaCTX 50%). Total AP, bone AP, and P1NP are suitable osteoblast markers for monitoring bisphosphonate therapy in Paget's disease, with performance approaching that of bone scintigraphy. NTX is less sensitive in detecting the effects of therapy, but is the best performing bone resorption marker. There is no clear evidence from this study that any of these newer markers are superior to total AP in assessing patients with this severity of Paget's disease.

Aged↗
PubMed2004

Vitamin D antagonist, TEI-9647, inhibits osteoclast formation induced by 1alpha,25-dihydroxyvitamin D3 from pagetic bone marrow cells.

(23S)-25-Dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647) functions an antagonist of the 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) nuclear receptor (VDR)-mediated differentiation of human leukemia (HL-60) cells [J. Biol. Chem. 274 (1999) 16392]. We examined the effect of vitamin D antagonist, TEI-9647, on osteoclast formation induced by 1alpha,25-(OH)(2)D(3) from bone marrow cells of patients with Paget's disease. TEI-9647 itself never induced osteoclast formation even at 10(-6)M, but dose-dependently (10(-10) to 10(-6)M) inhibited osteoclast formation induced by physiologic concentrations of 1alpha,25-(OH)(2)D(3) (41 pg/ml, 10(-10)M) from bone marrow cells of patients with Paget's disease. At the same time, 10(-8)M of TEI-9647 alone did not cause 1alpha,25-(OH)(2)D(3) dependent gene expression, but almost completely suppressed TAF(II)-17, a potential coactivator of VDR and 25-hydroxyvitamin D(3)-24-hydroxylase (25-OH-D(3)-24-hydroxylase) gene expression induced by 10(-10)M 1alpha,25-(OH)(2)D(3) in bone marrow cells of patients with Paget's disease. Moreover, TEI-9647 dose-dependently inhibited bone resorption induced by 10(-9)M 1alpha,25-(OH)(2)D(3) by osteoclasts produced by RANKL and M-CSF treatment of measles virus nucleocapsid gene transduced bone marrow cells. These results suggest that TEI-9647 acts directly on osteoclast precursors and osteoclasts, and that TEI-9647 may be a novel agent to suppress the excessive bone resorption and osteoclast formation in patients with Paget's disease.

Base Sequence↗
PubMed2004

Insulin sensitivity in the offspring of women with type 1 and type 2 diabetes.

OBJECTIVE: To determine if insulin sensitivity is altered in prepubertal offspring exposed to a diabetic intrauterine environment. RESEARCH DESIGN AND METHODS: Fifteen control children, 17 offspring of type 1 diabetic women, and 10 offspring of type 2 diabetic women, aged between 5 and 10 years, underwent a frequently sampled intravenous glucose tolerance test (FSIGTT). Weight and height were measured, and body composition was calculated using bioelectrical impedance. Bergman's minimal model was applied to the glucose and insulin measurements to obtain values for insulin sensitivity (Si), acute insulin response (AIR), and glucose effectiveness (Sg). RESULTS: Si was lowest in the offspring of type 2 diabetic mothers, and AIR was highest in this group, although neither of these changes reached significance (Si, P = 0.2, and AIR, P = 0.3). Offspring of type 2 diabetic mothers had higher BMI SD scores (P = 0.004) and percentage fat mass (P = 0.002) than the children in the other two groups. The BMI SD score and percentage fat mass in the subjects, as well as maternal insulin dose, were negatively correlated with offspring insulin sensitivity. CONCLUSIONS: Intrauterine exposure to hyperglycemia by itself was not associated with alterations in glucose regulation in prepubertal offspring. Children of mothers with type 2 diabetes, however, were overweight, and they had a tendency for a reduced Si. The combined effect of genetic and postnatal environmental factors, rather than prenatal exposure to hyperglycemia, may place this group at risk for developing impaired glucose tolerance in later life.

Adipose Tissue↗
PubMed2003

The deleted in colorectal carcinoma (DCC) gene 201 R --> G polymorphism: no evidence for genetic association with autoimmune disease.

The product of the deleted in colorectal carcinoma (DCC) gene has a role in apoptosis and is a positional candidate for IDDM6, the putative chromosome 18q12-q23 autoimmune disease locus. We hypothesised that a nonconservative substitution (DCC 201 R --> G; nucleotide (nt) 601 C --> G), located in an extracellular immunoglobulin-like domain of DCC, is an aetiological determinant of autoimmunity. We tested this hypothesis by genetically testing the nt 601 C --> G polymorphism for association with three autoimmune phenotypes in a large population-based case-control study. There was no evidence for association of DCC nt 601 C --> G with autoimmune disease in cohorts comprising 2253 subjects with rheumatoid arthritis, type I diabetes and Graves' disease, and 2225 control subjects, from New Zealand and the United Kingdom. Furthermore, using the transmission disequilibrium test, there was no significant evidence for biased transmission of the nt 601 C --> G polymorphism to probands within a 382 family type I diabetes affected sibpair cohort from the United Kingdom. Thus, the DCC 201 R --> G polymorphism does not appreciably influence risk of developing the autoimmune diseases tested.

Adult↗
PubMed2003

A randomized controlled trial of estrogen replacement therapy in long-term users of depot medroxyprogesterone acetate.

Long-term use of the injectable contraceptive depot medroxyprogesterone acetate (DMPA, Depo-Provera) is associated with a reduction in bone mineral density (BMD), particularly in the lumbar spine. The cause of DMPA-associated bone loss is not known, but the relative estrogen deficiency induced by DMPA use could be responsible. We have undertaken a randomized, double-blind controlled trial of oral estrogen replacement therapy in 38 premenopausal women (mean age 37) with a minimum 2 yr DMPA use who had a below average baseline lumbar spine BMD (T score < or = 0). Nineteen women were allocated to receive conjugated estrogens (0.625 mg/d orally) and 19 to receive a matching placebo. All continued with regular DMPA injections throughout the study. Areal bone density was measured by dual energy x-ray absorptiometry at the lumbar spine, femoral neck, and total body sites every 6 months for 2 yr; the main outcome measure being the change in areal BMD at the lumbar spine. At baseline, the two groups were well matched for demographic, anthropometric, and biochemical variables, and for BMD. Twenty-seven subjects completed at least 18 months in the study, and 26 the full 2 yr, with similar numbers dropping out from each group (mainly for personal reasons). In the estrogen-treated group, mean lumbar spine BMD increased 1%, whereas in the placebo group it fell 2.6%, over 2 yr. The between group differences were 2.0% at 12 months (P = 0.058), 3.2% at 18 months (P < 0.01), and 3.5% at 24 months (P < 0.002). Differences of lesser statistical magnitude were seen at the femoral neck (between group differences at 2 yr: 2.7%, P = 0.24), Ward's triangle (5.0%, P = 0.055), greater trochanter (3.6%, P = 0.056), total body (1.3%, P = 0.046), legs (1.3%, P = 0.065), and trunk (2.0%, P = 0.029). There were no major adverse events. These data support the view that the likely cause of DMPA-associated bone loss is estrogen deficiency and demonstrate that it can be arrested by estrogen replacement therapy.

Absorptiometry, Photon↗
PubMed2002

Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease.

Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of increased and disorganized bone turnover. Genetic factors are important in the pathogenesis of PDB, and in previous studies, we and others identified a locus for familial PDB by genome-wide search on 5q35-qter (PDB3). The gene encoding sequestosome 1 (SQSTM1/p62) maps to within the PDB3 critical region, and recent studies have identified a proline-leucine amino acid change at codon 392 of SQSTM1 (P392L) in French-Canadian patients with PDB. We conducted mutation screening of positional candidate genes in the PDB3 locus in patients with PDB, and also identified mutations in the gene encoding SQSTM1 as a common cause of familial and sporadic PDB. Three different mutations were found, all affecting the highly conserved ubiquitin-binding domain. The most common mutation was the P392L change in exon 8, which was found in 13 of 68 families (19.1%). Another mutation-a T insertion that introduces a stop codon at position 396 in exon 8-was found in four (5.8%) families. A third mutation affecting the splice donor site in intron 7 was found in one (1.5%) family. The P392L mutation was also found in 15 of 168 (8.9%) of patients with sporadic PDB and 0 of 160 of age- and sex-matched controls (P<0.0001). These studies confirm that mutations affecting the ubiquitin-binding domain of SQSTM1 are a common cause of familial and sporadic Paget's disease of bone.

Adaptor Proteins, Signal Transducing↗
PubMed2002

A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype.

Idiopathic hyperphosphatasia is an autosomal recessive bone disease characterized by deformities of long bones, kyphosis and acetabular protrusion, increasing in severity as affected children pass through adolescence. Biochemical and histological evidence indicate that there is extremely rapid bone turnover, with indices of both bone resorption and formation greatly increased. A genome-wide search, in a family with three children affected by idiopathic hyperphosphatasia, suggested linkage to a locus on the long arm of chromosome 8 (8q24). The gene TNFRSF11B encoding osteoprotegerin (OPG), which lies within this locus, was an obvious candidate, given the critical role of OPG in regulating osteoclast development. All three affected siblings were homozygous for a 3 bp inframe deletion in exon 3 of the TNFRSF11B gene, resulting in the loss of an aspartate residue. Their parents (who were first cousins) were heterozygous for the mutation. Recombinant wild-type and mutant OPG cDNAs were expressed in human epithelial kidney cells, and secreted OPG was collected from the conditioned medium. In vitro measurements of bone resorption showed that wild-type OPG suppressed bone resorption, whereas the mutant form did not, confirming this to be an inactivating mutation. This description of abnormal OPG function in humans expands the spectrum of genetic bone diseases arising from perturbations of the OPG/RANK-L/RANK system that regulates osteoclastogenesis.

Adolescent↗
PubMed2002

Idiopathic hyperphosphatasia.

Idiopathic hyperphosphatasia is a rare autosomal recessive bone disorder, characterized by excessive bone resorption and bone formation. The radiographic appearances include widening of the diaphyses, vertebral osteoporosis, acetabular protrusion, and thickening of the skull vault. There is considerable variability in phenotype, with some cases diagnosed in infancy and others in later childhood. Most cases appear to arise from inactivating mutations in the gene encoding osteoprotegerin, a product of osteoblasts that is critically involved in osteoclastogenesis. Treatment with inhibitors of bone resorption (calcitonin or bisphosphonates) is successful in ameliorating some aspects of the disorder.

Calcitonin↗
PubMed2002

Menopausal bone loss in long-term users of depot medroxyprogesterone acetate contraception.

OBJECTIVE: The purpose of this study was to determine the rate of early postmenopausal bone loss in women who had used depot medroxyprogesterone acetate contraception through to menopause. STUDY DESIGN: Bone mineral density at the lumbar spine and femoral neck was assessed prospectively over 3 years in 15 women who reached a natural menopause and who did not undergo hormone replacement therapy and in 16 long-term users of depot medroxyprogesterone acetate who discontinued depot medroxyprogesterone acetate only on reaching menopause. Of the latter, 5 women subsequently underwent hormone replacement therapy. RESULTS: Early menopausal bone loss was rapid in the control group (6% from both sites over 3 years), but the users of depot medroxyprogesterone acetate (who did not take hormone replacement therapy) showed little change in bone mineral density. Between-group differences were statistically significant at years 2 and 3 at both sites (P <.03-<.002). In the users of depot medroxyprogesterone acetate who underwent hormone replacement therapy, bone mineral density increased significantly (P <.03) at the lumbar spine and was stable at the femoral neck. CONCLUSION: Women who use depot medroxyprogesterone acetate through to menopause have attenuated rates of bone loss from the lumbar spine and femoral neck, presumably because they have already lost the estrogen-sensitive component of bone.

Bone Density↗
PubMed2002

Sequence analysis of measles virus nucleocapsid transcripts in patients with Paget's disease.

It has been debated for almost 30 years whether Paget's disease of bone results from paramyxoviral infection of osteoclasts (OCs). Paramyxoviral-like nuclear inclusions are found in OCs from patients with Paget's disease, and measles virus (MV) or canine distemper virus (CDV) messenger RNA (mRNA) transcripts have been detected by in situ hybridization in bone cells from pagetic lesions. Furthermore, immunocytochemical studies have shown the presence of several paramyxoviral species in OCs from patients with Paget's disease. However, others have been unable to detect paramyxoviral transcripts in bone samples from patients with Paget's disease or marrow cultures from involved sites of patients with Paget's disease. Furthermore, no one has been able to isolate an infectious virus from pagetic bone samples or marrow cells from patients with Paget's disease, and a full-length viral gene has not been sequenced from pagetic samples. In this study, we have obtained the full-length sequence for the MV nucleocapsid (MVNP) gene in bone marrow from an involved site from a patient with Paget's disease and more than 700 base pairs (bps) of MVNP sequence in 3 other patients with Paget's disease. These sequences were undetectable in four normal marrow samples studied simultaneously. The sequences from the patients contained multiple mutations that differed from the Edmonston strain MVNP gene. These findings are consistent with the presence of a chronic MV infection in affected sites from these patients with Paget's disease.

Aged↗