The effect of the diameter of metal-on-metal bearings on systemic exposure to cobalt and chromium.
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Arthroplasty, Replacement, Hip↗
Biomedical subjects
M Lavigne
Publications and source records attributed to M Lavigne.
Resurfacing arthroplasty of the hip in osteopetrosis.
A 34-year-old woman with a benign form of osteopetrosis developed osteoarthritis of the hip. In order to avoid the difficulties associated with inserting the femoral component of a conventional total hip arthroplasty, a hybrid metal-on-metal resurfacing was performed. There were several technical challenges associated with the procedure, including the sizing of the component, press-fit fixation of the acetabular component and femoral head preparation, as well as trying to avoid a fracture. No surgical complication occurred. After more than a year following surgery, the patient showed excellent clinical function and remained satisfied with the outcome. We conclude that the hybrid metal-on-metal resurfacing arthroplasty represents a valuable option for the treatment of patients with osteopetrosis and secondary hip osteoarthritis.
Acetabulum↗
Biomechanical reconstruction of the hip: a randomised study comparing total hip resurfacing and total hip arthroplasty.
We have compared the biomechanical nature of the reconstruction of the hip in conventional total hip arthroplasty (THA) and surface replacement arthroplasty (SRA) in a randomised study involving 120 patients undergoing unilateral primary hip replacement. The contralateral hip was used as a control. Post-operatively, the femoral offset was significantly increased with THA (mean 5.1 mm; -2.8 to 11.6) and decreased with SRA (mean -3.3 mm; -8.9 to 8.2). Femoral offset was restored within sd 4 mm in 14 (25%) of those with THA and in 28 (57%) of the patients receiving SRA (p < 0.001). In the THA group, the leg was lengthened by a mean of 2.6 mm (-6.04 to +12.9), whereas it was shortened by a mean of 1.9 mm (-7.1 to +2.05) in the SRA group, compared with the contralateral side. Leg-length inequality was restored within sd 4 mm in 42 (86%) of the SRA and 33 (60%) of the THA patients. The radiological parameters of acetabular reconstruction were similar in both groups. Restoration of the normal proximal femoral anatomy was more precise with SRA. The enhanced stability afforded by the use of a large-diameter femoral head avoided over-lengthening of the limb or increased offset to improve soft-tissue tension as occurs sometimes in THA. In a subgroup of patients with significant pre-operative deformity, restoration of the normal hip anatomy with lower pre-operative femoral offset or significant shortening of the leg was still possible with SRA.
Acetabulum↗
Removal of acetabular bone in resurfacing arthroplasty of the hip.
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Acetabulum↗
A randomised study comparing resection of acetabular bone at resurfacing and total hip replacement.
We have undertaken a prospective, randomised study to compare conservation of acetabular bone after total hip replacement and resurfacing arthroplasty of the hip. We randomly assigned 210 hips to one of the two treatment groups. Uncemented, press-fit acetabular components were used for both. No significant difference was found in the mean diameter of acetabular implant inserted in the groups (54.74 mm for total hip replacement and 54.90 mm for resurfacing arthroplasty). In seven resurfacing procedures (6.8%), the surgeon used a larger size of component in order to match the corresponding diameter of the femoral component. With resurfacing arthroplasty, conservation of bone is clearly advantageous on the femoral side. Our study has shown that, with a specific design of acetabular implant and by following a careful surgical technique, removal of bone on the acetabular side is comparable with that of total hip replacement.
Acetabulum↗
The regulation of human MMP-13 by licofelone, an inhibitor of cyclo-oxygenases and 5-lipoxygenase, in human osteoarthritic chondrocytes is mediated by the inhibition of the p38 MAP kinase signalling pathway.
BACKGROUND: MMP-13 is one of the most important metalloproteases (MMP) involved in osteoarthritis. Licofelone, a novel dual inhibitor of cyclo-oxygenases (COX) and 5-lipoxygenase (5-LOX), can modulate MMP-13 production in human osteoarthritis chondrocytes. OBJECTIVE: To evaluate the impact of licofelone on MMP-13 expression/production, promoter, and major MAP kinase signalling pathways and transcription factors. METHODS: Human osteoarthritis chondrocytes were stimulated by interleukin 1beta (IL1beta) and treated with or without: licofelone (0.3, 1, or 3 mug/ml); NS-398 (10 muM; a specific COX-2 inhibitor); or BayX-1005 (10 muM; a specific 5-LOX inhibitor). MMP-13 synthesis was determined by specific enzyme linked immunosorbent assay, and expression by real time polymerase chain reaction. The effect of licofelone on the MMP-13 promoter was studied through transient transfection; dexamethasone (10(-7) M) was used as comparison. The effect on IL1beta induced MMP-13 signalling pathways was determined using specific ELISA for phosphorylated MAP kinases and transcription factors. RESULTS: Licofelone dose dependently inhibited the IL1beta stimulated production and expression of MMP-13. NS-398 and BayX-1005 had very little effect. Licofelone also inhibited MMP-13 transcription on each of the promoter constructs used. The licofelone inhibition was comparable to that obtained with dexamethasone. Licofelone had no effect on phosphorylated p44/42 or JNK1/2; however, it decreased phosphorylated c-jun and inhibited phosphorylated p38, CREB, and AP-1 activity. CONCLUSIONS: Licofelone inhibited MMP-13 production under proinflammatory conditions on human osteoarthritis chondrocytes, through inhibition of the p38/AP-1 pathway and the transcription factor CREB. This may explain some of the mechanisms whereby licofelone exerts its positive effect on osteoarthritic changes.
Acetates↗
[Prevention of hypoglycemia in patients with type 1 diabetes].
Hypoglycaemia is the most common metabolic disorder in type 1 diabetic patients. It is rarely dangerous, but significantly alters the quality of life and hinders the achievement of "normoglycaemia". Even if hypoglycaemia is impossible to be avoided, both its frequency and severity may be reduced if patients follow several practical recommendations. After having defined hypoglycaemia, we shall briefly describe its pathophysiology and its main causes in type 1 diabetic patients. Afterwards, the different approaches of prevention of hypoglycaemia will be discussed. We will particularly stress the need to revise the glycaemic target in high-risk patients, the role of optimising insulin therapy, the valuable help of blood glucose monitoring, the critical support of diet adjustments, and the appropriate management in case of physical activity. There is no doubt that patient's education plays a crucial role in such a strategy that aims at preventing severe hypoglycaemia in type 1 diabetic individuals.
Diabetes Mellitus, Type 1↗
The endogenous opioid spinorphin blocks fMet-Leu-Phe-induced neutrophil chemotaxis by acting as a specific antagonist at the N-formylpeptide receptor subtype FPR.
Spinorphin is an endogenous heptapeptide (leucylvalylvalyltyrosylprolyltryptophylthreonine), first isolated from bovine spinal cord, whose sequence matches a conserved region of beta-hemoglobin. Also referred to as LVV-hemorphin-4 and a member of the nonclassical opioid hemorphin family, spinorphin inhibits enkephalin-degrading enzymes and is analgesic. Recently, spinorphin was reported to block neutrophil activation induced by the chemotactic N-formylpeptide N-formylmethionylleucylphenylalanine (fMLF), suggesting a potential role as an endogenous negative regulator of inflammation. Here we use both gain- and loss-of-function genetic tests to identify the specific mechanism of spinorphin action on neutrophils. Spinorphin induced calcium flux in normal mouse neutrophils, but was inactive in neutrophils from mice genetically deficient in the fMLF receptor subtype FPR (N-formylpeptide receptor). Consistent with this, spinorphin induced calcium flux in human embryonic kidney 293 cells transfected with mouse FPR, but had no effect on cells expressing the closely related fMLF receptor subtype FPR2. Despite acting as a calcium-mobilizing agonist at FPR, spinorphin was a weak chemotactic agonist and effectively blocked neutrophil chemotaxis induced by fMLF at concentrations selective for FPR. Spinorphin did not affect mouse neutrophil chemotaxis induced by concentrations of fMLF that selectively activate FPR2. Thus, spinorphin blocks fMLF-induced neutrophil chemotaxis by acting as a specific antagonist at the fMLF receptor subtype FPR.
Animals↗
DNA synthesis by HIV-1 reverse transcriptase at the central termination site: a kinetic study.
Human immunodeficiency virus, type 1 (HIV-1) reverse transcriptase (RT) terminates plus-strand DNA synthesis at the center of the HIV-1 genome, a process important for HIV-1 infectivity. The central termination sequence contains two termination sites (Ter1 and Ter2) located at the 3'-end of A(n)T(m) motifs, and the narrowing of the DNA minor groove generated by these motifs is responsible for termination. Kinetic data associated with the binding of RT and its ability to elongate in vitro various DNA duplexes and triplexes surrounding the Ter2 terminator were analyzed using a simple kinetic scheme. At Ter2, RT still displays a reasonable affinity for the corresponding DNA, but the binding of the next nucleotide and above all its incorporation rate are markedly hampered. Features affecting the width of the minor groove act directly at this last step. The constraint exerted against elongation by the A(n)T(m) tract persists at two positions downstream of the terminator.
Base Sequence↗
Structures of complexes formed by HIV-1 reverse transcriptase at a termination site of DNA synthesis.
This study presents structural parameters associated with termination of human immunodeficiency virus, type 1 (HIV-1) reverse transcriptase (RT) at Ter2, the major termination site located in the center of the HIV-1 genome. DNA footprinting studies of various elongation complexes formed by RT around wild type and mutant Ter2 sites have revealed two major structural transformations of these complexes when the enzyme gets closer to Ter2. First, the interactions between RT and the DNA duplex are less extended, although the global affinity of the enzyme for this duplex is only decreased by 2-fold. Second, there is an atypical positioning of the RT RNase H domain on the DNA duplex. We interpret our data as indicating that the A(n)T(m) motif located upstream of Ter2 prevents a classical positioning of the enzyme on the double-stranded part of the DNA duplex at some precise positions of elongation downstream of this motif. Instead, novel species of binary and/or ternary complexes, characterized by atypical footprints, are formed. The new rate-limiting step of the reaction, characterized in the preceding paper (Lavigne, M., Polomack, L., and Buc, H. (2001) J. Biol. Chem. 276, 31429-31438), would be a transition leading from these new species to a catalytically competent ternary complex.
Base Sequence↗
Compression of the DNA minor groove is responsible for termination of DNA synthesis by HIV-1 reverse transcriptase.
HIV-1 reverse transcriptase (RT) generally terminates plus strand DNA synthesis at the centre of the viral genome. The central termination sequence (CTS) contains two termination sites which are located at the 3' end of AnTm motifs. These motifs generate a global curvature of the DNA helix which correlates with termination of DNA synthesis. Here, we have characterized HIV-1 RT termination sites on different DNA sequences. Again, they are located at the 3' end of A-tracts. Using hydroxyl radicals as a probe of the width of the DNA helix, we have shown that RT termination sites are always located a few base-pairs downstream of a compressed minor groove. Mutations which relieve these compressions also abolish the termination events. The replacement of the adenine tracts by 2,6-diaminopurine tracts has a similar effect. Moreover, no termination site is observed on DNA sequences containing phased GC-tracts which curve the DNA helix but compress the major groove. The compression of the DNA minor groove and not necessarily the curved trajectory of the DNA is, therefore, responsible for termination of DNA synthesis at the CTS by HIV-1 RT. This conclusion is consistent with interpretation of other biochemical data on the processivity of HIV-1 RT, based on the structure of a DNA-enzyme complex.
2-Aminopurine↗
LCC15-MB: a vimentin-positive human breast cancer cell line from a femoral bone metastasis.
The LCC15-MB cell line was established from a femoral bone metastasis that arose in a 29-year-old woman initially diagnosed with an infiltrating ductal mammary adenocarcinoma. The tumor had a relatively high (8%) S-phase fraction and 1/23 positive lymph nodes (LN). Both the primary tumor and LN metastasis were positive for estrogen receptor (ER) and progesterone receptor (PgR), but lacked erbB2 expression. Approximately one year later, the patient presented with a 0.8 cm comedo-type intraductal mammary adenocarcinoma in the left breast that was negative for ER and PgR, but positive for erbB2. Thirty-five months after the initial diagnosis she was treated for acute skeletal metastasis, and stabilized with a hip replacement. At this time, tumor cells were removed from surplus involved bone, inoculated into cell culture, and developed into the LCC 15-MB cell line. The bone metastasis was a poorly differentiated adenocarcinoma lacking ER, PgR, and erbB2, characteristics shared by the LCC15-MB cells, although ER can be re-expressed by treatment of the LCC15-MB cells for 5 days with 75 microM 5-aza-2'-deoxycytidine. The LCC15-MB cell line is tumorigenic when implanted subcutaneously in NCr nu/nu mice and produces long-bone metastases after intracardiac injection. Although the bone metastasis from which the LCC15-MB cell line was derived lacked vimentin (VIM) expression, the original primary tumor and lymph node metastasis were strongly VIM positive, as are LCC15-MB cells in vitro and in nude mice. The karyotype and isozyme profiles of LCC15-MB cells are consistent with its origin from a human female, with most chromosome counts in the hypertriploid range. Thirty-two marker chromosomes are present. These cells provide an in vitro/in vivo model in which to study the inter-relationships between ER, VIM, and bone metastasis in human breast cancer.
Adult↗
DNA curvature controls termination of plus strand DNA synthesis at the centre of HIV-1 genome.
In vivo and in vitro, reverse transcriptase (RT) from human immunodeficiency virus type 1 (HIV-1) terminates plus strand synthesis at the centre of the viral genome. The central termination sequence (CTS) contains curved DNA fragments located upstream of each terminator site. Two different models, relying either on the A-tract or general sequence roll assumptions, were used to predict the extent and the direction of this curvature as well as to design mutants, which abolished it. Straightening of each curved element abolished termination at the site located immediately downstream from the curvature. When synthesis was performed on the other strand and in the opposite direction, the two curved elements C1 and C2 associated with the two termination sites Ter1 and Ter2, led again to termination of DNA synthesis. Therefore, termination occurred as a nascent bent duplex was synthesized within the template primer binding cleft of RT, even when putative strand-specific motifs have been removed by the inversion. Computation of DNA paths upstream of other known arrest sites suggested that this feature was of general relevance for termination. At the CTS, termination occurred more precisely at the 3' end of an AnTm motif (n + m = 7). The possible structures, adopted by this motif, are discussed and confronted with the present crystallographic and biochemical data obtained on HIV-1 RT-DNA interactions and on HIV-1 RT processivity.
Base Sequence↗
CRP fixes the rotational orientation of covalently closed DNA molecules.
Five minicircles of 284 bp were constructed with a reporter sequence located approximately opposite a CRP binding site. The spacing between the center of the CRP site and this sequence is varied within 1.2 helical turns. The reactivity of the reference sequence to DNAse I was determined on the minicircles and on the corresponding fragments, in both the absence and presence of CRP. A rigorous mathematical analysis of the data shows that in the absence of CRP no preferred rotational orientation of the DNA is observed. In contrast, binding of CRP fixes, in a phase-dependent manner, the rotational orientation of the reporter sequence in the minicircles. This result illustrates the transmission at a distance along the DNA molecule of a structural modification. Such effects modulate the extent of synergy between activators and polymerases during the initiation of transcription.
Binding Sites↗
Does wild-type p53 play a role in normal cell differentiation?
Inactivation of the p53 tumor suppressor gene plays a major role in malignant transformation. The central question in this issue is concerned with the understanding of the function of p53 in normal cells and its deregulation in cancer cells. Several in vitro and in vivo experimental models have indicated that induction of cells to undergo differentiation involve up-regulation in the expression of the p53. In the case of B cell differentiation, p53 was found to be involved in several steps of the differentiation pathway. The conclusion that p53 plays a role in normal development and differentiation in vivo is substantiated by the observation that p53 is expressed during embryonic development and is detected at low levels in a number of organs of adult mice. Accentuated levels of p53 in testes of adult mice, suggests that p53 plays a role in the meiotic process of spermatogenesis. B cell differentiation and spermatogenesis are biological pathways which normally involve DNA reshuffling and rearrangements. In accordance with the notion that p53 is associated with DNA repair it is tempting to speculate that at least in these physiological pathways p53 functions as a master gene that controls genome integrity.
Animals↗
E. coli RNA polymerase, deleted in the C-terminal part of its alpha-subunit, interacts differently with the cAMP-CRP complex at the lacP1 and at the galP1 promoter.
A deletion of the C-terminal part of the alpha-subunit of RNA polymerase is known to affect differently promoters activated by CRP depending on the location of the CRP binding site at the promoter. When the CRP binding site is located at -61.5, as at lacP1 (a type I promoter), activation is strongly impaired while it is not significantly affected at galP1 where CRP binds 41.5 bp upstream of the start of the message (type II promoter). We have investigated the differences in the architecture of the corresponding open complexes by comparing the positioning of holoenzymes reconstituted respectively with native or with truncated alpha-subunits (containing the first 235 or 256 residues of a) at two 'up' promoter mutants of the lacP1 and galP1 promoters (respectively lacUV5 and gal9A16C). First, the affinity of wild-type RNA polymerase for both promoters is increased by the presence of CRP and cAMP. By contrast, holoenzymes reconstituted with truncated alpha-subunits, show cooperative binding at the galP1 promoter only. Second, footprinting data confirm these observations and indicate that the truncated holoenzymes are unable to recognize regions of the promoter upstream from position -40. The absence of contacts between the truncated enzymes and CRP at the lacP1 promoter can explain the deficiency in activation. At the galP1 promoter, where the CRP site is closer to the initiation site, protein-protein contacts can still occur with the truncated polymerases, showing that the C-terminal part of the alpha-subunit is not involved in activation.
Carrier Proteins↗
Transcription activation by cAMP receptor protein (CRP) at the Escherichia coli gal P1 promoter. Crucial role for the spacing between the CRP binding site and the -10 region.
The cAMP-CRP complex activates the initiation of transcription at the Escherichia coli gal P1 promoter, and the activation efficiency is highly sensitive to the location of the complex on this promoter region. Moving the CRP binding site by one base pair toward the start of transcription significantly decreases the extent of activation in vivo and actually turns the cAMP-CRP complex into an inhibitor in in vitro experiments. A structural analysis of open complexes formed on the two promoter fragments at 37 degrees C has revealed three elements crucial for an optimal activation process: a strong upstream anchorage of RNA polymerase, a cooperative binding of CRP and RNA polymerase, and an accurate orientation of the two promoter regions located upstream and downstream of the CRP binding site. Furthermore, structural analysis of polymerase promoter complexes at lower temperatures suggests that RNA polymerase initially recognizes the upstream region of the gal P1 promoter and subsequently interacts with sequences from the -10 to +20 region to yield the final open complex structure. The involvement of CRP in these sequential events has been examined.
Base Sequence↗
Upstream curved sequences influence the initiation of transcription at the Escherichia coli galactose operon.
The two overlapping promoters that control mRNA synthesis at the galactose operon contain three phased stretches of adenine residues, located around positions -84.5, -74 and -63, with respect ot the start of the P1 promoter. As a result, the corresponding DNA sequence is bent, an anomaly that is relieved by the addition of small concentrations of drugs like distamycin A or netropsin. By abortive initiation assays performed on several DNA fragments derived from the wild-type promoter or from various mutants we show that the curved sequence increases the strength of the P1 promoter. In the absence of cyclic AMP (cAMP) and of the corresponding receptor protein (CRP), the upstream curved sequences enhance the rate of isomerization from the closed to the open complex at P1. This effect is abolished when distamycin A is bound in the bent region. In the presence of cAMP-CRP, a more drastic change is observed: activation of the gal P1 promoter takes place at a different formal step, depending whether the upstream curved sequence is present or not (enhancement of the rate of conversion from a closed to an open complex instead of an increase in the affinity of the enzyme during closed complex formation). These data, together with previous results obtained with other mutants of the gal control region, suggest that several closed complexes corresponding to different nucleoprotein arrangements are formed during open complex formation at gal P1, in the presence of CRP.
Base Sequence↗