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Biomedical subjects

L Knott

Publications and source records attributed to L Knott.

14 recordsLinked to original sources
PubMed2006

Effects of housing, parturition and diet change on the biochemistry and biomechanics of the support structures of the hoof of dairy heifers.

This study investigated effects of housing, diet and parturition on the biochemistry, biomechanics and pathology of feet of maiden, pregnant and lactating dairy heifers. Strength/laxity, laminar morphology, connective tissue (CT) biochemistry and sole lesions were assessed. Although no animals became clinically lame, severity of sole lesions was significantly greater in heifers housed in cubicles vs. straw yards, and in lactating/pregnant heifers vs. maidens. These effects were additive. Cubicle housing and parturition each increased CT metabolism (and were additive), and altered CT composition. Similarly, both impaired the biomechanical resilience of the hoof. There were no effects for diet. The results indicate that parturition/lactation causes non-inflammatory changes in CT that impair resilience of the feet to external stresses associated with poor housing. This "parturition effect" appears to be unrelated to change in diet and relatively brief, unless exacerbated by additional stresses of housing. Thus heifer lameness may be significantly reduced through short-term, low-cost improvements in husbandry around the time of calving.

Animal Feed↗
PubMed2000

Treating osteoarthritis in practice--the TOP Study.

This study consisted of two nationwide surveys. The first involved 209 general practitioners (GPs) from 22 sampling points in England, Scotland and Wales, and the second involved 510 patients with osteoarthritis (OA) (aged 60 years and above), rheumatoid arthritis (RA) or unspecified arthritis, who had visited their GP for treatment. The results showed that OA has a significant negative impact on patients' quality of life; 79% of patients stated that their condition limited their quality of life. Only 15% of GPs reported prescribing a conventional non-steroidal anti-inflammatory drug (NSAID) as first-line treatment for patients with arthritis. More than half (57%) stated that they would prescribe a simple analgesic or a compound analgesic before trying an NSAID. Forty four per cent of GPs stated that their main therapeutic objective when prescribing an NSAID was to minimise GI side-effects, and therefore start at a low dose. This implies that many patients are likely to be receiving sub-optimal doses. Experiencing breakthrough pain and GI side-effects were common reasons cited for patients re-presenting to GPs. GPs reported their expectation to prescribe GI protectants to a fifth (21%) of their patients on NSAIDs and estimated one in six patients (17%) take OTC products to relieve GI symptoms. This research demonstrates that there is considerable dissatisfaction with currently used treatment regimens for osteoarthritis, from both the GP and patient perspectives.

Aged↗
PubMed1999

Collagen biochemistry of avian bone: comparison of bone type and skeletal site.

1. Skeletal disorders in poultry are of considerable welfare and economic importance. The collagenous matrix in bone is involved in many human skeletal disorders, however little is known about the nature of the collagenous matrix in avian bone. 2. This paper describes an investigation of the collagen and mineral biochemistry together with the biomechanics of bone from different sites (humerus and tibiotarsus) and with differing functions (medullary and cortical bone). In vivo and in vitro studies of immature bone assessed the changes in collagen biochemistry during bone maturation. 3. The material strength of the humerus was greater than the tibiotarsus; this difference in strength was reflected in both the collagen and mineral matrix biochemistry. 4. The bone matrix of the humerus was more mature than that of the tibiotarsus, suggesting a higher level of matrix turnover in the tibiotarsus. The pyrrole collagen cross-link concentrations were positively correlated with breaking stress, in contrast to the pyridinoline cross-link concentrations, neither of which showed any correlation with bone strength. 5. The in vivo and in vitro maturation studies underline the importance of the pyrrole cross-link in avian bone and support the mechanism postulated by Kuypers et al. (1992) for the formation of the pyrrole cross-link from a lysine aldehyde and the immature cross-links HLKNL or LKNL. 6. Medullary bone had no biomechanical influence on the breaking stress of the bone. The biochemistry of the matrix was dramatically different. The high level of collagen lysine hydroxylation affected the cross-link profile and may be responsible for the narrow fibrils and disorganised matrix of this bone. 7. Avian bone matrix varies greatly with skeletal site and reflects the differing functions of bone. Further investigation of the collagenous matrix of both normal and diseased avian bone has the potential to aid our understanding of the aetiology of avian skeletal disease.

Animals↗
PubMed1998

Mechanisms of maturation and ageing of collagen.

The deleterious age-related changes in collagen that manifest in the stiffening of the joints, the vascular system and the renal and retinal capillaries are primarily due to the intermolecular cross-linking of the collagen molecules within the tissues. The formation of cross-links was elegantly demonstrated by Verzar over 40 years ago but the nature and mechanisms are only now being unravelled. Cross-linking involves two different mechanisms, one a precise enzymically controlled cross-linking during development and maturation and the other an adventitious non-enzymic mechanism following maturation of the tissue. It is this additional non-enzymic cross-linking, known as glycation, involving reaction with glucose and subsequent oxidation products of the complex, that is the major cause of dysfunction of collagenous tissues in old age. The process is accelerated in diabetic subjects due to the higher levels of glucose. The effect of glycation on cell-matrix interactions is now being studied and may be shown to be an equally important aspect of ageing of collagen. An understanding of these mechanisms is now leading to the development of inhibitors of glycation and compounds capable of cleaving the cross-links, thus alleviating the devastating effects of ageing.

Aging↗
PubMed1998

Differences between the thermal stabilities of the three triple-helical domains of type IX collagen.

Fibre-forming collagens in dilute solution show highly co-operative helix-coil transitions at temperatures that are remarkably close to the body temperature of the animal from which the collagen was extracted. This close correlation holds across animal Phyla and the transition temperatures, which range from 5 degrees C to 40 degrees C, are adjusted to suit by changing the primary structure, especially the concentration of the water-bridge-enhancing hydroxyproline residue. Fibril-forming collagens are thermally stabilised by fibrillogenesis, which causes a loss of random coil configurational entropy by intermolecular and intramolecular cross-linking and by spacial confinement of the molecule within the lattice of the fibre. But this mechanism cannot apply to the full length of the type IX collagen molecule, since its COL3 arm, according to current models, projects out from the stabilising influence of the type II fibre. In this paper we examine the thermal stability of the type IX collagen molecule and its three triple-helical domains, thereby demonstrating that the COL3 arm is much more stable than the rest of the molecule. At a scanning rate of 60 deg. C/h COL3 exhibited an unfolding endotherm with a tmax at 49.0 degrees C, well above body temperature. Corresponding peak maxima for COL1 and COL2 were seen at 40.6 degrees C and 39.6 degrees C, respectively. The sizes of the thermally labile units of COL1, COL2 and COL3, calculated from the measured activation enthalpies, were 24, 28 and 28 residues, respectively, much smaller than type I (65 residues) because of the relatively short lengths of triple helix to be unfolded. However, unlike type I collagen, no regions of the required size were found completely devoid of hydroxyproline. Consequently, the intrinsic stabilities of these thermally labile units were higher than that of type I with DeltaH updownarrow DeltaS updownarrow for COL1, COL2 and COL3 being, respectively, 385 K, 371 K and 384 K, contrasting with the much lower 349 K of type I collagen. We therefore speculate that the increased thermal stability of the thermally labile units was caused by the presence of the water-bridge-enhancing residue, hydroxyproline. Finally the stabilisation of type IX collagen tissue is considered and an alternative structural organisation of the type IX molecule on the type II fibre is proposed.

Animals↗
PubMed1998

Collagen cross-links in mineralizing tissues: a review of their chemistry, function, and clinical relevance.

Bone collagen cross-links are now widely used to assess bone resorption levels in many metabolic bone diseases. The post-translational modifications of bone and other mineralizing collagens are significantly different from those of other type I collagen matrices, a fact that has been exploited during recent advances in the development of biochemical markers of bone resorption. The enzymatic collagen cross-linking mechanism is based upon aldehyde formation from specific telopeptide lysine or hydroxylysine residues. The immature ketoimine cross-links in bone form via the condensation of a telopeptide aldehyde with a helical lysine or hydroxylysine. Subsequent maturation to the pyridinoline and pyrrole cross-links occur by further reaction of the ketoimines with telopeptide aldehydes. In mineralizing tissues, a relatively low level of lysyl hydroxylation results in low levels of hydroxylysyl pyridinoline, and the occurrence of the largely bone specific lysyl pyridinoline and pyrrolic cross-links. The collagen post-translational modifications appear to play an integral role in matrix mineralization. The matrix of the turkey tendon only mineralizes after a remodeling of the collagen and the subsequent formation of a modified matrix more typical of bone than tendon. Further, disturbances in the post-translational modification of collagen can also affect the mineralization density and crystal structure of the tissue. In addition to their use as a convenient measure of matrix degradation, collagen cross-links are of significant importance for the biomechanical integrity of bone. Recent studies of osteoporotic bone, for example, have demonstrated that subtle perturbations in the pattern of lysine hydroxylation result in changes in the cross-link profile. These alterations, specifically changes in the level of the pyrrolic cross-link, also correlate with the strength of the bone. Further research into the biochemistry of bone collagen cross-links may expand current understanding and their clinical application in metabolic bone disease. This review also demonstrates the potential for further study into this area to provide more subtle information into the mechanisms and etiology of disease and aging of mineralizing tissues.

Aging↗
PubMed1997

Chemistry of collagen cross-linking: biochemical changes in collagen during the partial mineralization of turkey leg tendon.

With age, the proximal sections of turkey leg tendons become calcified, and this phenomenon has led to their use as a model for collagen mineralization. Mineralizing turkey leg tendon was used in this study to characterize further the composition and cross-linking of collagen in calcified tissues. The cross-link profiles of mineralizing collagen are significantly different from those of other collagenous matrices with characteristically low amounts of hydroxylysyl-pyridinoline and the presence of lysyl-pyridinoline and pyrrolic cross-links. However, the presence of the immature cross-link precursors previously reported in calcifying tissues was not supported in the present study, and was found to be due to the decalcification procedure using EDTA. Analysis of tendons from young birds demonstrated differences in the cross-link profile which indicated a higher level of hydroxylation of specific triple-helical lysines involved in cross-linking of the proximal tendon. This may be related to later calcification, suggesting that this part of the tendon is predestined to be calcified. The minimal changes in lysyl hydroxylation in both regions of the tendon with age were in contrast with the large changes in the cross-link profile, indicating differential hydroxylation of the helical and telopeptide lysine residues. Changes with age in the collagen matrix, its turnover and thermal properties in both the proximal and distal sections of the tendon clearly demonstrate that a new and modified matrix is formed throughout the tendon, and that a different type of matrix is formed at each site.

Age Factors↗
PubMed1995

Biochemical changes in the collagenous matrix of osteoporotic avian bone.

No detailed biochemical analysis has been carried out of the compositional changes in the collagen matrix of avian bone in relation to increased bone fragility in osteoporosis. We have shown that osteoporosis in avian bone is certainly not just a simple loss of apatite and collagen, but involves significant changes in the biochemistry of the collagen molecule and consequently in the physical properties of the fibre. The decreased mechanical strength and the change in the thermal stability can be directly related to changes in post-translational modifications, i.e. lysine hydroxylation and the intermolecular cross-link profile. The increased hydroxylation and change in cross-linking are consistent with increased turnover of the collagen, possibly in an attempt to initiate a repair mechanism which, in fact, leads to an acceleration in the increase in fragility of the bone. Clearly there are post-translational modifications of the newly synthesized collagen in avian osteoporosis, and these changes may play a role in the pathogenesis of the disease.

Animals↗
PubMed1990

Expression of the human carbonic anhydrase I gene is activated late in fetal erythroid development and regulated by stage-specific trans-acting factors.

Using flow cytometric analysis of red cells from different stages of ontogeny with anti-CAI antibody, it was shown that the human carbonic anhydrase I (HCAI) gene product appears in a developmental stage-specific manner. Virtually no CAI protein was detectable in fetal red cells prior to birth. However, at about the time of normal delivery (40 weeks gestation) CAI production is switched on. The proportion of cells containing CAI reaches adult levels during the second half of the first year of life. Northern analysis suggests that the appearance of CAI protein results directly from the activation of the gene and the production of new mRNA. A transient heterokaryon system was set up by fusing the erythroleukaemic cell lines MEL C88 (a mouse cell line in which CAI is expressed) and K562 SAI (a human cell line with an embryonic/fetal phenotype, not expressing CAI). SP6 RNAase mapping of RNA from the fused cells showed activation of the human CAI gene. This shows the developmental stage-specific expression of HCAI to be regulated by trans-acting factors.

Adult↗
PubMed1986

Allogeneic bone marrow transplantation for adult leukaemia with soy bean lectin fractionated marrow.

A heterogeneous group of 11 consecutive patients with leukaemia have been transplanted successfully with allogeneic marrow depleted of T lymphocytes by soy bean lectin agglutination and neuraminidase-treated sheep erythrocyte rosetting. Effective depletion was achieved, leaving less than 1% of donor T lymphocytes. Despite the small numbers of nucleated cells infused (mean 0.14 X 10(8)/kg) there was only moderately delayed recovery of peripheral blood counts and no graft failures have occurred. Standard methotrexate prophylaxis against graft-versus-host disease (GVHD) was also employed in the first four transplants. Only one case of mild grade I (skin only) acute GVHD has occurred and there has been no chronic GVHD to date. The group of patients show an actuarial cumulative survival of 55% with two early infective deaths (days 42 and 44 post-transplant) and three late deaths, two with leukaemic relapse and the third with probable viral encephalitis. The longest survivor is now 1109 days post-transplant. This series indicates that lectin fractionation of donor marrow, previously employed mainly in children, can also be effective in minimizing GVHD in adults without endangering successful engraftment.

Adolescent↗