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Biomedical subjects

C Webber

Publications and source records attributed to C Webber.

At least 19 recordsLinked to original sources
PubMed2005

Alendronate for steroid-induced osteopenia in children with acute lymphoblastic leukaemia or non-Hodgkin's lymphoma: results of a pilot study.

BACKGROUND/OBJECTIVES: Osteopenia is a significant morbidity in children undergoing therapy for acute lymphoblastic leukaemia (ALL) or non-Hodgkin's lymphoma (NHL). We conducted a pilot study to assess the impact of alendronate on whole body bone mineral content (WB-BMC), lumbar spine bone mineral density (LS-BMD), biochemical measures of bone mineral metabolism, as well as gross motor function and health-related quality of life (HRQL) in children undergoing therapy for ALL or NHL. METHODS: Ten children (nine boys) between the ages of 3.6 and 14.6 years, on identical maintenance chemotherapy for ALL or NHL were treated with oral alendronate once weekly, and daily calcium supplementation, for a period of six months. Outcome measures were WB-BMC and LS-BMD; biochemical measures of bone mineral metabolism including plasma osteocalcin, C-terminal telopeptide of type I collagen (CTx), serum calcium, 25-hydroxy-vitamin D (25-OHD), and parathyroid hormone (PTH); as well as assessments of motor function and HRQL. RESULTS: A gain in Z score was observed in 7/9 evaluable patients for WB-BMC (mean increase of 0.49) and LS-BMD (0.51). Plasma osteocalcin and CTx showed a change in bone turnover favouring formation over resorption. Serum calcium and 25-OHD remained normal throughout treatment. After an initial spike, serum PTH returned to baseline values at week 4. Measures of motor function showed some improvement and there were modest gains in HRQL. CONCLUSIONS: Alendronate therapy was tolerated well. Further study in a larger sample of children with ALL or NHL is warranted, in the context of a randomized clinical trial.

Absorptiometry, Photon↗
PubMed2003

Efficacy of home-based exercise for improving quality of life among elderly women with symptomatic osteoporosis-related vertebral fractures.

This randomized controlled trial was designed to investigate the effect of a 6-month home-based exercise program versus control (usual activities) on quality of life for postmenopausal women with osteoporosis who had at least one vertebral fracture. Twelve-month assessments of outcomes were completed to determine if women would continue exercising with minimal supervision and if benefit could be sustained. The home exercise program followed a "lifestyle exercise" approach where participants completed exercises 60 min per day, 3 days a week and could complete exercises in small periods of time throughout the day. Exercise activities included stretching, strength training and aerobics (i.e. walking). Participants were assessed at baseline, 6 months, and 12 months using the Osteoporosis Quality of Life Questionnaire (OQLQ), the Sickness Impact Profile (SIP), a balance test, and the Timed Up And Go test. Bone mineral density was assessed at baseline and 12 months for both the lumbar spine and femoral neck. Quality of life (OQLQ) improved over 6 months in the exercise group compared to the control group in the domains of symptoms (P=0.003), emotion (P=0.01) and leisure (P=0.03). Results from the balance test indicated a greater effect in the exercise group over 12 months (P<0.05). There were no significant differences between groups in measures of Timed Up and Go, SIP at 6 and 12 months, and femoral neck and lumbar spine bone mineral density at 12 months. Home-based exercise with minimal supervision improves quality of life in elderly women with vertebral fractures. Future research is needed to determine if home exercise programs reduce falls and fall-related injuries in the elderly.

Aged↗
PubMed2003

Pharmacokinetics and metabolism of the cholecystokinin antagonist dexloxiglumide in male human subjects.

1. Mean concentrations of total (14)C and of dexloxiglumide at the end of single 20-min infusion doses of (14)C-dexloxiglumide (200 mg) to four healthy male subjects were 18.5 microg eq x ml(-1) and 19.5 microg ml(-1) respectively. The mean plasma clearance (0.22 l h(-1) x kg(-1)) and mean volume of distribution (V(ss) = 0.18 l kg(-1)) were low. 2. Single oral doses of a solid formulation of (14)C-dexloxiglumide (200 mg) to the same subjects appeared to be rapidly and well absorbed. Mean peak plasma concentrations (C(max)) of total (14)C (2.8 microg eq x ml(-1)) and of dexloxiglumide (2.2 microg x ml(-1)) occurred at about 1.5 h. Systemic availabilities of the oral dose based on total (14)C and dexloxiglumide were 70 and 48%, respectively. Thus, a proportion of an oral dose was subjected to presystemic elimination and the absorbed dose mainly eliminated by metabolism. Binding of dexloxiglumide to plasma proteins was extensive (96.6-99.2%). 3. Total (14)C was excreted mainly in the faeces. Mass balance of (14)C excretion was almost complete within 7 days when a mean of > 93% of the dose had been recovered. After the intravenous (i.v.) dose, mean totals of 23.7 and 69.8% of the dose were excreted in urine and faeces, respectively, during 7 days, and 19.5 and 73.7% of the dose, respectively, after the oral dose. The data were consistent with biliary excretion and perhaps some enterohepatic circulation of conjugates of dexloxiglumide and at least one of its metabolites. 4. LC-MS/MS of urine extracts showed that dexloxiglumide was metabolized by oxidation and conjugation. The former included at least two metabolites formed by monohydroxylation in the N-(3-methoxypropyl) pentyl side chain, and O-demethylation of this side chain followed by subsequent oxidation of the resultant alcohol to the dicarboxylic acid. At least one glucuronide was also present in urine. The main components in faeces appeared to be dexloxiglumide and a dicarboxylic metabolite formed by O-demethylation followed by oxidation of the N-(3-methoxypropyl) side chain. Both compounds were identified as their corresponding methyl esters formed because acid and methanol were used in the extraction procedure. Dexloxiglumide and the dicarboxylic acid were presumably excreted in bile as the glucuronic acid conjugates.

Administration, Oral↗
PubMed2002

Excessive degradation of type II collagen in articular cartilage in equine osteochondrosis.

Articular osteochondrosis (OCD) occurs in both man and animals. The etiology remains to be determined. Studies of OCD lesions in animals may provide clues as to its pathogenesis. The aim of our study was to determine whether there was evidence for increased degradation namely proteoglycan (PG) release and type II collagen cleavage in articular cartilage harvested from OCD lesions. We examined ex vivo explants at post-mortem from equine OCD lesions and macroscopically normal site and age matched cartilage. These were cultured over a 10 day period in serum-free medium. Type II collagen cleavage was measured in articular cartilage and media using an Elisa assay to detect the COL2-3/4C(short) epitope, which is generated on cleavage of the triple helix of type II collagen by collagenases. PG release was measured by a dye-binding assay. Cumulative release of PG and COL2-3/4C(short) and their contents in cartilage at the end of the culture period were determined. In OCD lesions there was a significant increase in type II collagen cleavage by collagenase but no evidence for increase of PG degradation. These findings point to a selective increase in type II collagen cleavage by collagenases, in OCD lesions of the kind observed in osteoarthritis. Further work is needed to determine whether changes represent primary or secondary events in the pathogenesis of OCD.

Animals↗
PubMed2001

Gene structure and expression of the mouse adipocyte enhancer-binding protein.

The adipocyte enhancer-binding protein (AEBP1) is a transcriptional repressor with carboxypeptidase activity. AEBP1 expression is down-regulated during adipogenesis. Aortic carboxypeptidase-like protein (ACLP) is a non-nuclear isoform of AEBP1 that has an N-terminal extension of 380 amino acids. ACLP expression is up-regulated during vascular smooth muscle cell differentiation. To gain insight into the regulation of AEBP1 isoform expression, we have determined the structural organization of the mouse AEBP1 gene. This gene extends over 10 kb, has 21 exons, and gives rise to two mRNAs (AEBP1 and ACLP). The 9th intron is retained in the mature AEBP1 transcript. Thus, ACLP encodes an additional 380 amino acids N-terminal to the first ATG codon of AEBP1 which is located in exon 10. RT-PCR experiments showed that both transcripts are expressed ubiquitously in all mouse tissues examined, while Western blot analysis suggested that expression is translationally regulated. Our results provide evidence that two isoforms of AEBP1 with very different functions are produced by an alternative splicing mechanism. This represents a new example of regulation of subcellular localization by protein truncation.

Amino Acid Sequence↗
PubMed2001

Abilities and attainment in Smith-Magenis syndrome.

This study reports on cognitive abilities and attainment in 29 children and 21 adults with Smith-Magenis syndrome. There were 13 boys and 16 girls aged 6 to 16 years, and nine men and 12 women aged 16 to 52 years. All had mild to severe learning disabilities* with no differences overall between verbal and performance skills, but with a particular profile of cognitive strengths and weaknesses. Levels of attainment and of adaptive behaviour were strikingly low, and the group of adults emerged as much more dependent on carers than might have been expected from their general level of intellectual functioning. Reasons for this discrepancy are explored in terms of the severe behavioural difficulties characteristic of the syndrome.

Abnormalities, Multiple↗
PubMed2001

Scooter injuries in children.

OBJECTIVES: To study the causes, patterns of injury and use of safety equipment in children presenting with 'push/kick' scooter-related injuries. To draw comparisons with in-line skate, skateboard and bicycle injuries and to suggest strategies for injury prevention. METHODS: A retrospective review of medical data was undertaken for 12 consecutive months to September 2000. All children aged < 15 years who had attended the Sydney Children's Hospital with scooter, in-line skate (rollerblade), skateboard or bicycle injuries were identified. Children with scooter injuries for the latter 6 month period were contacted by telephone and interviewed, together with their parents, using a structured questionnaire. RESULTS: There was a marked rise in the number of scooter injuries from October 1999 to September 2000. Sixty-one per cent of these injuries occurred during the final 3 months of the study period, making scooters the most common cause of injury in the studied groups for this period. Forty-two per cent of scooter injuries were fractures. Only 3% of children used safety equipment at the time of injury, despite 86% owning some form of safety equipment. Children were less likely to use safety equipment with a scooter than with any other form of activity studied. (Chi-squared P=0.000). CONCLUSIONS: Scooters are a common cause of childhood injury, resulting in injury patterns similar to those caused by in-line skates, skateboards and bicycles. Safety equipment is rarely worn when scooters are ridden. Injury patterns and riding styles suggest that if existing guidelines for in-line skating, skateboarding and bicycling are modified and applied to scooters, a reduction in injury numbers may be achieved.

Accident Prevention↗
PubMed2001

Estimation of P-values for global alignments of protein sequences.

MOTIVATION: The global alignment of protein sequence pairs is often used in the classification and analysis of full-length sequences. The calculation of a Z-score for the comparison gives a length and composition corrected measure of the similarity between the sequences. However, the Z-score alone, does not indicate the likely biological significance of the similarity. In this paper, all pairs of domains from 250 sequences belonging to different SCOP folds were aligned and Z-scores calculated. The distribution of Z-scores was fitted with a peak distribution from which the probability of obtaining a given Z-score from the global alignment of two protein sequences of unrelated fold was calculated. A similar analysis was applied to subsequence pairs found by the Smith-Waterman algorithm. These analyses allow the probability that two protein sequences share the same fold to be estimated by global sequence alignment. RESULTS: The relationship between Z-score and probability varied little over the matrix/gap penalty combinations examined. However, an average shift of +4.7 was observed for Z-scores derived from global alignment of locally-aligned subsequences compared to global alignment of the full-length sequences. This shift was shown to be the result of pre-selection by local alignment, rather than any structural similarity in the subsequences. The search ability of both methods was benchmarked against the SCOP superfamily classification and showed that global alignment Z-scores generated from the entire sequence are as effective as SSEARCH at low error rates and more effective at higher error rates. However, global alignment Z-scores generated from the best locally-aligned subsequence were significantly less effective than SSEARCH. The method of estimating statistical significance described here was shown to give similar values to SSEARCH and BLAST, providing confidence in the significance estimation. AVAILABILITY: Software to apply the statistics to global alignments is available from http://barton.ebi.ac.uk. CONTACT: geoff@ebi.ac.uk

Databases, Protein↗
PubMed2000

Selective assembly and remodelling of collagens II and IX associated with expression of the chondrocyte hypertrophic phenotype.

The assembly and resorption of the extracellular matrix in the physis of the growth plate are poorly understood. By examining isolated fetal growth plate chondrocytes in culture and using immunochemical methods we show that type II collagen, proteoglycan aggrecan, and type IX collagen are assembled into a matrix that is initially enriched in type II collagen over proteoglycan and type IX collagen. When compared to the content of the COL2 domain in the alpha(1)(IX) chain it is evident that the majority ( 90%) of type IX molecules lack the NC4 domain unlike in articular cartilage. During matrix assembly the molar ratio of type II/COL2 of alpha(1)(IX) varied from 25:1 to 2.5:1. Following expression of the hypertrophic phenotype (initiation of type X collagen synthesis) there are parallel changes in both collagen and proteoglycan contents (inversely related to collagenase cleavage of type II collagen). The NC4 domain is then selectively, rapidly and irreversibly removed as mineralization is initiated, leaving the alpha(1)(IX) chain COL2 domain. Subsequently as mineralization progresses type II and type IX collagen (COL2 domain), but not the proteoglycan aggrecan, are resorbed coincident with a markedly increased cleavage of type II collagen by collagenase as mineral is deposited in the matrix. This study, therefore reveals a carefully orchestrated series of events in matrix assembly and resorption that prepares the extracellular matrix for mineralization.

Animals↗
PubMed1999

A radiation hybrid map of the rat genome containing 5,255 markers.

A whole-genome radiation hybrid (RH) panel was used to construct a high-resolution map of the rat genome based on microsatellite and gene markers. These include 3,019 new microsatellite markers described here for the first time and 1,714 microsatellite markers with known genetic locations, allowing comparison and integration of maps from different sources. A robust RH framework map containing 1,030 positions ordered with odds of at least 1,000:1 has been defined as a tool for mapping these markers, and for future RH mapping in the rat. More than 500 genes which have been mapped in mouse and/or human were localized with respect to the rat RH framework, allowing the construction of detailed rat-mouse and rat-human comparative maps and illustrating the power of the RH approach for comparative mapping.

Animals↗
PubMed1998

A physical map of 30,000 human genes.

A map of 30,181 human gene-based markers was assembled and integrated with the current genetic map by radiation hybrid mapping. The new gene map contains nearly twice as many genes as the previous release, includes most genes that encode proteins of known function, and is twofold to threefold more accurate than the previous version. A redesigned, more informative and functional World Wide Web site (www.ncbi.nlm.nih.gov/genemap) provides the mapping information and associated data and annotations. This resource constitutes an important infrastructure and tool for the study of complex genetic traits, the positional cloning of disease genes, the cross-referencing of mammalian genomes, and validated human transcribed sequences for large-scale studies of gene expression.

Animals↗
PubMed1998

Arthritis induced by proteoglycan aggrecan G1 domain in BALB/c mice. Evidence for t cell involvement and the immunosuppressive influence of keratan sulfate on recognition of t and b cell epitopes.

Our previous work showed that the proteoglycan aggrecan can induce erosive polyarthritis and spondylitis in BALB/c mice, and that the G1 domain of the proteoglycan aggrecan (G1) is the arthritogenic region. In this study, two T cell epitopes residing on G1 within residues 70-84 (peptide G5) and 150-169 (peptide G9) were identified using synthetic peptides and aggrecan-specific T cell lines. Two G1-specific T cell hybridomas exclusively responded to peptide G5. When the G5-specific T cell line was injected intraperitoneally into BALB/c mice, it induced acute inflammatory arthritis in joints, but only in those that had been injected with the epitope recognized by these T cells. Furthermore, we also demonstrate that the keratan sulfate chain(s) (KS) on G1 possess immunosuppressive properties with respect to T and B cell epitope recognition. T cell lines that recognize both G1 and peptide G5 show an increased response to G1 after KS is removed. Antibodies in hyperimmune sera of mice immunized with G1 show increased epitope recognition (quantitative and qualitative) after KS removal before immunization. These studies reveal that a T cell line specific to an epitope on the G1 domain of aggrecan, also recognizing a corresponding mouse G1 epitope, can induce arthritis by adoptive transfer and homing to the intraarticular epitope, thereby implicating T cells in arthritis development caused by immunity to the G1 domain of aggrecan. Moreover, the presence of KS on G1 can inhibit arthritis development by suppressing T and B cell epitope recognition.

Aggrecans↗
PubMed1998

Induction of arthritis in BALB/c mice by cartilage link protein: involvement of distinct regions recognized by T and B lymphocytes.

Both type II collagen and the proteoglycan aggrecan are capable of inducing an erosive inflammatory polyarthritis in mice. In this study we provide the first demonstration that link protein (LP), purified from bovine cartilage, can produce a persistent, erosive, inflammatory polyarthritis when injected repeatedly intraperitoneally into BALB/c mice. We discovered a single T-cell epitope, located within residues 266 to 290 of bovine LP (NDGAQIAKVGQIFAAWKLLGYDRCD), which is recognized by bovine LP-specific T lymphocytes. We also identified three immunogenic regions in bovine LP that contain epitopes recognized by antibodies in hyperimmunized sera. One of these B-cell regions is found in the most species-variable domain of LP (residues 1 to 36), whereas the other epitopes are located in the most conserved regions (residues 186 to 230 and 286 to 310). The latter two regions contain an AGWLSDGSVQYP motif shared by the G1 globulin domain of aggrecan core protein, versican, neurocan, glial hyaluronan-binding protein, and the hyaluronan receptor CD44. Our data reveal that the induction of arthritis is associated with antibody reactivities to B-cell epitopes located at residues 1 to 19. Together, these observations show that another cartilage protein, LP, like type II collagen and the proteoglycan aggrecan, is capable of inducing an erosive inflammatory arthritis in mice and that the immunity to LP involves recognition of both T- and B-cell epitopes. This immunity may be of importance in the pathogenesis of inflammatory joint diseases, such as juvenile rheumatoid arthritis, in which cellular immunity to LP has been demonstrated.

Amino Acid Sequence↗
PubMed1998

Heparin improves gas exchange during experimental acute lung injury in newborn piglets.

Although intrapulmonary fibrin deposition is a pathognomonic feature of acute lung injury, it remains uncertain whether thrombin inhibitors affect clinically important outcomes. We hypothesized that both heparin and antithrombin (AT) concentrate improve gas exchange during experimental respiratory distress syndrome. We also tested whether combination therapy is more beneficial than monotherapy. Forty-eight newborn piglets were randomized within 12 litters to one of four groups in a factorial design: (1) AT; (2) heparin; (3) AT plus heparin; (4) untreated control animals. After lung lavage and 4 h of barovolutrauma, mechanical ventilation was continued for 24 h during which ventilator pressures and inspired oxygen were adjusted to maintain normal blood gases. The arterial/ alveolar oxygen tension ratio (a/A ratio) and the ventilator efficiency index (VEI) at 18 and 24 h were compared by repeated measures analysis of variance (ANOVA). In contrast to our hypothesis, only heparin improved gas exchange, and we found little evidence of an interaction with AT. The a/A ratio was 0.48 +/- 0.27 (mean +/- SD) in the presence of heparin versus 0.33 +/- 0.26 in its absence; p = 0.01. Corresponding VEI was 0.30 +/- 0.12 versus 0.25 +/- 0.14; p = 0.04. Hyaline membrane formation was also decreased in heparin-treated animals (p = 0.02).

Analysis of Variance↗
PubMed1998

Homozygous protein C deficiency: description of a new mutation and successful treatment with low molecular weight heparin.

We present a kindred with a new mutation of the protein C gene, in which the proband had an unusual clinical presentation. The relationship between warfarin induced skin necrosis and level of anticoagulation was investigated. The pharmacokinetics of protein C concentrate was assessed to determine frequency of replacement therapy. The clinical and biochemical efficacy of therapy with low molecular weight heparin (LMWH) was assessed. The effect of long-term LMWH on bone density in the growing child was monitored using whole body densitometry. Warfarin therapy required an INR of greater than 3.5 to avoid skin necrosis. If protein C replacement was to be used, doses of 100 U/kg/day would have been required to maintain protein C levels consistently at or above 0.20 U/ml. While receiving prophylactic therapy with LMWH for almost 3 years, there were no episodes of recurrent thrombosis, no skin necrosis and no bleeding. Biochemical markers of in vivo thrombin generation were suppressed and within the normal range. Bone density continued to increase at the normal rate throughout the treatment period. LMWH is an effective form of long-term therapy for homozygous protein C deficient patients with measurable protein C levels.

Adult↗
PubMed1998

Autoimmunity to cartilage link protein in patients with rheumatoid arthritis and ankylosing spondylitis.

OBJECTIVE: To determine whether patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) express cellular immunity to cartilage link protein (LP). METHODS: LP was purified from human fetal epiphyseal and bovine adult nasal cartilage. It was used in proliferation assays with the peripheral blood lymphocytes (PBL) isolated from 83 patients with RA, 21 patients with AS, and 30 healthy controls. RESULTS: Patients with RA (34%) and AS (71%) expressed a significantly higher prevalence of cellular immune responses to human LP compared with the healthy control group (13%). Such significant differences were not observed for bovine LP. Half the patients with RA responding to LP exhibited cellular immunity to both human and bovine protein. In the AS group, PBL from a majority of responders to LP recognized only human LP. CONCLUSION: These data suggest that LP is a potential autoantigen in the development of RA and AS and that cellular immune reactivity to common and distinct LP epitopes in patients with RA and AS may play a role in the pathogenesis of these diseases.

Adult↗