Ceramic-on-ceramic bearing fractures in total hip arthroplasty: an analysis of data from the National Joint Registry.

AIMS: Ceramic-on-ceramic (CoC) bearings in total hip arthroplasty (THA) are commonly used, but concerns exist regarding ceramic fracture. This study aims to report the risk of revision for fracture of modern CoC bearings and identify factors that might influence this risk, using data from the National Joint Registry (NJR) for England, Wales, Northern Ireland and the Isle of Man. PATIENTS AND METHODS: We analysed data on 223 362 bearings from 111 681 primary CoC THAs and 182 linked revisions for bearing fracture recorded in the NJR. We used implant codes to identify ceramic bearing composition and generated Kaplan-Meier estimates for implant survivorship. Logistic regression analyses were performed for implant size and patient specific variables to determine any associated risks for revision. RESULTS: A total of 222 852 bearings (99.8%) were CeramTec Biolox products. Revisions for fracture were linked to seven of 79 442 (0.009%) Biolox Delta heads, 38 of 31 982 (0.119%) Biolox Forte heads, 101 of 80 170 (0.126%) Biolox Delta liners and 35 of 31 258 (0.112%) Biolox Forte liners. Regression analysis of implant size revealed smaller heads had significantly higher odds of fracture (chi-squared 68.0, p < 0.001). The highest fracture risk was observed in the 28 mm Biolox Forte subgroup (0.382%). There were no fractures in the 40 mm head group for either ceramic type. Liner thickness was not predictive of fracture (p = 0.67). Body mass index (BMI) was independently associated with revision for both head fractures (odds ratio (OR) 1.09 per unit increase, p = 0.031) and liner fractures (OR 1.06 per unit increase, p = 0.006). CONCLUSIONS: We report the largest independent study of CoC bearing fractures to date. The risk of revision for CoC bearing fracture is very low but previous studies have underestimated this risk. There is good evidence that the latest generation of ceramic has greatly reduced the odds of head fracture but not of liner fracture. Small head size and high patient BMI are associated with an increased risk of ceramic bearing fracture. Cite this article: Bone Joint J 2017;99-B:1012-19.

Fatal pulmonary embolism following elective total hip arthroplasty: a 12-year study.

AIMS: The place of thromboprophylaxis in arthroplasty surgery remains controversial, with a challenging requirement to balance prevention of potentially fatal venous thrombo-embolism with minimising wound-related complications leading to deep infection. We compared the incidence of fatal pulmonary embolism in patients undergoing elective primary total hip arthroplasty (THA) between those receiving aspirin, warfarin and low molecular weight heparin (LMWH) for the chemical component of a multi-modal thromboprophylaxis regime. PATIENTS AND METHODS: A prospective audit database was used to identify patients who had died within 42 and 90 days of surgery respectively between April 2000 and December 2012. A case note review was performed to ascertain the causes of death. RESULTS: During this period 7983 THAs were performed. The rate of mortality was 0.43% and 0.58% at 42 and 90 days respectively. The groups comprised 1571 patients (19.7%) on warfarin, 1838 (23.0%) on LMWH and 4574 (57.3%) on aspirin. The 90-day mortality for these three groups was 0.38%, 1.09% and 0.43% respectively. The higher mortality rate for LMWH was significant (p < 0.05). There were six fatal pulmonary emboli (PEs) (0.08%). A total of three occurred within 42 days, all in the LMWH group. A total of three occurred between 42 and 90 days; one on warfarin, two on LMWH. The leading causes of death in all three groups were lower respiratory tract infections and myocardial infarction. CONCLUSION: We confirmed that fatal PE following elective THA with a multi-modal prophylaxis regime is rare. We further found that LMWH conferred no benefit over aspirin in this context, and is associated with a higher all-cause rate of mortality. TAKE HOME MESSAGE: This study proposes that aspirin may be an appropriate thromboprophylaxis agent when used as part of a multi-modal regimen, suggesting current guidelines should be reviewed. Cite this article: Bone Joint J 2016;98-B:585-8.

Femoral impaction bone allografting with an Exeter cemented collarless, polished, tapered stem in revision hip replacement: a mean follow-up of 10.5 years.

Femoral impaction bone allografting has been developed as a means of restoring bone stock in revision total hip replacement. We report the results of 75 consecutive patients (75 hips) with a mean age of 68 years (35 to 87) who underwent impaction grafting using the Exeter collarless, polished, tapered femoral stem between 1992 and 1998. The mean follow-up period was 10.5 years (6.3 to 14.1). The median pre-operative bone defect score was 3 (interquartile range (IQR) 2 to 3) using the Endo-Klinik classification. The median subsidence at one year post-operatively was 2 mm (IQR 1 to 3). At the final review the median Harris hip score was 80.6 (IQR 67.6 to 88.9) and the median subsidence 2 mm (IQR 1 to 4). Incorporation of the allograft into trabecular bone and secondary remodelling were noted radiologically at the final follow-up in 87% (393 of 452 zones) and 40% (181 of 452 zones), respectively. Subsidence of the Exeter stem correlated with the pre-operative Endo-Klinik bone loss score (p = 0.037). The degree of subsidence at one year had a strong association with long-term subsidence (p < 0.001). There was a significant correlation between previous revision surgery and a poor Harris Hip score (p = 0.028), and those who had undergone previous revision surgery for infection had a higher risk of complications (p = 0.048). Survivorship at 10.5 years with any further femoral operation as the end-point was 92% (95% confidence interval 82 to 97).

A stemmed acetabular component in the management of severe acetabular deficiency.

We evaluated the use of a stemmed acetabular component in the treatment of severe acetabular deficiency during revision and complex primary total hip arthroplasty. There were 31 hips of which 24 were revisions (20 for aseptic loosening, four for infection) and the remainder were complex primary arthroplasties. At a mean follow-up of 10.7 years (6 to 12.8), no component had been revised for aseptic loosening; one patient had undergone a revision of the polyethylene liner for wear. There was one failure because of infection. At the latest follow-up, the cumulative survival rate for aseptic loosening, with revision being the end-point, was 100%; for radiographic loosening it was 92% and for infection and radiographic loosening it was 88%. These results justify the continued use of this stemmed component for the reconstruction of severe acetabular deficiency.

The uncemented Bicontact total hip arthroplasty in octogenarians. Medium-term results.

Uncemented total hip arthroplasty was developed on the principle of biological fixation to enhance longevity of the prosthesis. Though the role of uncemented total hip replacement as an alternative is well accepted in young patients, its role in elderly remains controversial. We reviewed a consecutive series of 60 uncemented Bicontact total hip arthroplasties in 51 octogenarian patients with a mean follow-up of 7 (range 5-9) years. Mean patient age was 87.8 (range 80-97) years. Mean preoperative Harris hip score of 48 (range 32-65) improved postoperatively to a mean of 88 (range 58-94). There were 26 hydroxyapatite (HA) and 34 non-HA plasma pore-coated acetabular cups; one cup was revised for recurrent dislocation. Radiological evaluation revealed no unstable cups; however, two were "probably unstable" (one non-HA and one infection in an HA-coated cup) and two "possibly unstable" (one HA and one non-HA cup) ( P <0.05). None of these cups were clinically symptomatic. Two femoral stems were considered "possibly unstable" and one stem "fibrous stable", while the remaining stems were "osseo-integrated". There were no revisions of either femoral stem or cup for aseptic loosening. Using the recommendation of revision as the end point, cumulative prosthesis survival rate was 98.4% at a mean follow-up of 7 years (95%CI: 95.9-99.4%). However, cumulative survival with revision being the end point for aseptic loosening was 100% for the Bicontact prosthesis. Results of our series are encouraging and justify the continued use of this prosthesis in the elderly.

Synthesis of the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine dimer.

We report the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer 16 synthesised through a new and efficient route, thus establishing that C2-C3-endo unsaturation enhances both cytotoxicity and DNA-binding affinity in A-Ring-linked PBD dimers but to a lesser extent than C2/C2'-exo-unsaturation. This new route has allowed the preparation of multi-gram quantities of the related clinical candidate 1 and should lead to more structurally diverse PBD dimer analogues.

Hip abductor strength following total hip arthroplasty: a prospective comparison of the posterior and lateral approach in 100 patients.

We studied the hip abductor strength and Trendelenburg test prospectively in 100 patients undergoing total hip replacement via a lateral or posterior approach. In 49 patients, we used the lateral approach to implant the Charnley total hip replacement, and in 51 patients, the posterior approach to implant the Exeter total hip. Isometric abductor strength was measured with the kinetic communicator device and the Trendelenburg test was recorded preoperatively and at 3 and 12 months postoperatively. Of the original 100 patients, 83 were available for study at 3 months and 73 at 12 months. Hip abductor strength and the Trendelenburg test improved postoperatively in both groups, but we found no difference in hip abductor strength recovery at 3 and 12 months between the lateral approach and the posterior approach. Similarly there was no difference in the Trendelenburg test between the two groups 3 and 12 months following hip replacement.

A point mutation in the LIM domain of Lhx3 reduces activation of the glycoprotein hormone alpha-subunit promoter.

Lhx3, a member of the LIM homeodomain family of transcription factors, is required for development of the pituitary in mice. A recent report has described a point mutation in the human LHX3 gene that is associated with a combined pituitary hormone disorder. The mutation is predicted to lead to the replacement of a tyrosine residue with a cysteine in the second LIM domain of LHX3. We have characterized the effects of this point mutation (Y114C) when analyzed in the context of the mouse Lhx3 coding sequence. Mobility shift assays demonstrated that the Lhx3 Y114C mutant is capable of binding DNA, although a decrease in the formation of a specific complex was observed. Transfection assays using an expression vector for either full-length Lhx3 or a GAL4-Lhx3 LIM domain fusion provided evidence that the Lhx3 Y114C mutant has a decreased ability to stimulate transcription. In particular, a GAL4-Lhx3 Y114C LIM mutant was unable to support Ras responsiveness of a modified glycoprotein hormone alpha-subunit reporter gene. Protein interaction studies suggest that the Y114C mutation may modestly reduce binding to the POU transcription factor, Pit-1. Interestingly, the Y114C mutation essentially abrogated binding to the putative co-activator/adapter, selective LIM-binding protein. The findings provide insights into the mechanisms mediating transcriptional activation by Lhx3 and suggest that the observed phenotype of the human mutation probably involves reduced transcriptional activity of the mutant LHX3.

Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity.

A novel sequence-selective pyrrolobenzodiazepine (PBD) dimer 5 (SJG-136) has been developed that comprises two C2-exo-methylene-substituted DC-81 (3) subunits tethered through their C8 positions via an inert propanedioxy linker. This symmetric molecule is a highly efficient minor groove interstrand DNA cross-linking agent (XL(50) = 0.045 microM) that is 440-fold more potent than melphalan. Thermal denaturation studies show that, after 18 h incubation with calf thymus DNA at a 5:1 DNA/ligand ratio, it increases the T(m) value by 33.6 degrees C, the highest value so far recorded in this assay. The analogous dimer 4 (DSB-120) that lacks substitution/unsaturation at the C2 position elevates melting by only 15.1 degrees C under the same conditions, illustrating the effect of introducing C2-exo-unsaturation which serves to flatten the C-rings and achieve a superior isohelical fit within the DNA minor groove. This behavior is supported by molecular modeling studies which indicate that (i) the PBD units are covalently bonded to guanines on opposite strands to form a cross-link, (ii) 5 has a greater binding energy compared to 4, and (iii) 4 and 5 have equivalent binding sites that span six base pairs. Dimer 5 is significantly more cytotoxic than 4 in a number of human ovarian cancer cell lines (e.g., IC(50) values of 0.0225 nM vs 7.2 nM, respectively, in A2780 cells). Furthermore, it retains full potency in the cisplatin-resistant cell line A2780cisR (0.024 nM), whereas 4 loses activity (0.21 microM) with a resistance factor of 29.2. This may be due to a lower level of inactivation of 5 by intracellular thiol-containing molecules. A dilactam analogue (21) of 5 that lacks the electrophilic N10-C11/N10'-C11' imine moieties has also been synthesized and evaluated. Although unable to interact covalently with DNA, 21 still stabilizes the helix (Delta T(m) = 0.78 degrees C) and has significant cytotoxicity in some cell lines (i.e., IC(50) = 0.57 microM in CH1 cells), presumably exerting its effect through noncovalent interaction with DNA.

Design and synthesis of novel pyrrolobenzodiazepine (PBD) prodrugs for ADEPT and GDEPT.

Three N10-(4-nitrobenzyl)carbamate-protected PBD prodrugs (9a, 9b and 15) have been synthesized and evaluated for potential use in nitroreductase-based ADEPT and GDEPT therapies. An approximately 100-fold activation was observed for the DC-81 prodrug 9a.

Effect of C2-exo unsaturation on the cytotoxicity and DNA-binding reactivity of pyrrolo[2,1-c][1,4]benzodiazepines.

A series of novel C2-exo unsaturated pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) has been synthesised via a versatile pro-C2 ketone precursor. C2-exo-unsaturation enhances both DNA-binding reactivity and in vitro cytotoxic potency.

Effect of C2/C3-endo unsaturation on the cytotoxicity and DNA-binding reactivity of pyrrolo[2,1-c][1,4]benzodiazepines.

A series of novel C2,C3-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) has been synthesised via cleavage of the N10-Alloc protecting group from appropriate precursors. Biophysical and biological evaluations show that the presence of C2/C3-endo unsaturation in the PBD C-ring enhances both DNA-binding reactivity and in vitro cytotoxic potency.

Identification of a conserved protein that interacts with specific LIM homeodomain transcription factors.

Lhx3, a member of the LIM homeodomain family of transcription factors, is required for development of the pituitary and is implicated in the transcription of pituitary-specific hormone genes. In this report we describe a novel gene product, SLB, that selectively interacts with Lhx3 and the closely related LIM factor, Lhx4. The SLB cDNA encodes a 1749-residue protein that contains seven WD40 repeats near the amino terminus and a putative nuclear localization signal and does not contain other recognizable motifs. SLB is expressed in a tissue-specific manner with the highest concentrations of SLB mRNA in the testis and pituitary cells. We demonstrate that SLB specifically binds to Lhx3 and Lhx4 with high affinity both in vitro and in vivo. SLB has much lower affinity or no detectable affinity for other LIM domains. An expression vector for a fragment of SLB containing the LIM-interaction domain was shown to reduce expression of Lhx3-responsive reporter genes. The ability of the LIM-interacting domain of SLB to alter reporter gene activity as well as the tissue-specific expression and the specificity of SLB binding to LIM factors suggest a possible role in modulating the transcriptional activity of specific LIM factors.

Partially hydroxyapatite-coated stemmed acetabular cup and nonstructural bone-graft in the management of severe acetabular deficiency.

We evaluated the use of a stemmed acetabular cup with morcellized allograft in the treatment of severe acetabular deficiency requiring reconstruction at arthroplasty. There were 29 hips, of which 22 were revision operations (18 aseptic, 4 postinfective) and 7 were complex primary hip replacements. All patients had severe acetabular deficiency as classified by the American Academy of Orthopaedic Surgeons: type IIB, 3; type IIIa, 18; type IIIB, 8. The patients had a mean follow-up of 46 months (range, 14-74 months). The hip center of rotation improved from a mean preoperative, side-to-side difference of 11.5 mm to 2.5 mm postoperatively (P < .001 ). The medial bone stock improved from a mean preoperative value of 1.5 mm to 11 mm postoperatively (P < .001). The Harris Hip Score improved from a mean preoperative score of 42 points to a postoperative score of 84 points (P < .001 ). There was 1 case of failure resulting from sepsis. The early results with this method of reconstruction of severe acetabular deficiency show encouraging restoration of bone stock, with no cases of aseptic loosening until the last follow-up.

Synthesis, in vitro antiproliferative activity, and DNA-binding properties of hybrid molecules containing pyrrolo[2,1-c][1, 4]benzodiazepine and minor-groove-binding oligopyrrole carriers.

The synthesis, biological activity, and DNA-binding properties of a series of four hybrids prepared by combining polypyrrole minor groove binders and pyrrolo[2,1-c][1,4]benzodiazepine (PBD) 13, related to the naturally occurring anthramycin (3) and DC-81 (4), have been described, and structure-activity relationships have been discussed. These hybrids 22-25 contain from one to four pyrrole units, respectively. To investigate sequence selectivity and stability of drug/DNA complexes, DNase I footprinting and arrested polymerase chain reaction (PCR) were performed on human c-myc oncogene, estrogen receptor gene, and human immunodeficiency virus type 1 long terminal repeat (HIV-1 LTR) gene sequences. The antiproliferative activity of the hybrids has been tested in vitro on human myeloid leukemia K562 and T-lymphoid Jurkat cell lines and compared to antiproliferative effects of the natural product distamycin A 1, its tetrapyrrole homologue 17, DC 81 (4), and the PBD methyl ester 12. The results obtained demonstrate that the hybrids 22-25 exhibit different DNA-binding activity with respect to both distamycin A 1 and PBD 12. In addition, a direct relationship was found between number of pyrrole rings present in the hybrids 22-25 and stability of drug/DNA complexes. With respect to antiproliferative effects, it was found that the increase in the length of the polypyrrole backbone leads to an increase of in vitro antiproliferative effects, i.e., the hybrid 25 containing the four pyrroles is more active than 22, 23, and 24 both against K562 and Jurkat cell lines.

Design, synthesis, and evaluation of a novel sequence-selective epoxide-containing DNA cross-linking agent based on the pyrrolo[2, 1-c][1,4]benzodiazepine system.

Synthetic routes have been investigated to prepare a novel C8-epoxide-functionalized pyrrolo[2,1-c][1,4]benzodiazepine 6 as a potential sequence-selective DNA cross-linking agent (Wilson et al. Tetrahedron Lett. 1995, 36, 6333-6336). A successful synthesis was accomplished via a 10-step route involving a pro-N10-Fmoc cleavage method that should have general applicability to other pyrrolobenzodiazepine (PBD) molecules containing acid- or nucleophile-sensitive groups. During the course of this work, a one-pot reductive cyclization procedure for the synthesis of PBD N10-C11 imines from nitro dimethyl acetals was also discovered, although this method results in C11a racemization which can reduce DNA binding affinity and cytotoxicity. The target epoxide 6 was shown by thermal denaturation studies to have a significantly higher DNA-binding affinity than the parent DC-81 (3) or the C8-propenoxy-PBD (15), which is structurally similar but lacks the epoxide moiety. The time course of effects upon thermal denaturation indicated a rapid initial binding phase followed by a slower phase consistent with the stepwise cross-linking of DNA observed for a difunctional agent. This was confirmed by an electrophoretic assay which demonstrated efficient induction of interstrand cross-links in plasmid DNA at concentrations >1 microM. Higher levels of interstrand cross-linking were observed at 24 h compared to 6 h incubation. A Taq polymerase stop assay indicated a preference for binding to guanine-rich sequences as predicted for bis-alkylation in the minor groove of DNA by epoxide and imine moieties. The pattern of stop sites could be partly rationalized by molecular modeling studies which suggested low-energy models to account for the observed binding behavior. The epoxide PBD 6 was shown to have significant cytotoxicity (45-60 nM) in the A2780, CH1, and CH1cis(R) human ovarian carcinoma cell lines and an IC(50) of 0.2 microM in A2780cis(R). The significant activity of 6 in the cisplatin-resistant CH1cis(R) cell line (IC(50) = 47 nM) gave a resistance factor of 0.8 compared to the parent cell line, demonstrating no cross-resistance with the major groove cross-linking agent cisplatin.

Effect of A-ring modifications on the DNA-binding behavior and cytotoxicity of pyrrolo[2,1-c][1,4]benzodiazepines.

Several A-ring-modified analogues of the DNA-binding antitumor agent DC-81 (5) have been synthesized in order to study structure-reactivity/cytotoxicity relationships. For two molecules (23 and 30) the modifications required the addition of a fourth ring to give the novel dioxolo[4,5-h]- and dioxano[5,6-h]pyrrolo[2,1-c][1, 4]benzodiazepin-11-one (PBD) ring systems, respectively. Another three analogues (34, 38, and 48) have the native benzenoid A-ring replaced with pyridine, diazine, or pyrimidine rings to give the novel pyrrolo[2,1-c][1,4]pyridodiazepine, pyrrolo[2,1-c][1, 4]diazinodiazepine, and pyrrolo[2,1-c][1,4]pyrimidinodiazepine systems, respectively. The other new analogues (16a,b) have extended chains at the C8-position of the DC-81 structure. During the synthesis of these compounds, a novel tin-mediated regiospecific cleavage reaction of the dioxole intermediate 18 was discovered, leading to the previously unknown iso-DC-81 (20). In addition, an unusual simultaneous nitration-oxidation reaction of 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (8) was found to produce 3-(4-carboxy-2-methoxy-5-nitrophenoxy)propanoic acid (9), a key intermediate, in high yield. In general, the results of cytotoxicity and DNA-binding studies indicated that none of the changes made to the A-ring of the PBD system significantly improved either binding affinity or cytotoxicity in comparison to DC-81. This result suggests that the superior potency of natural products such as anthramycin (1), tomaymycin (2), and sibiromycin (3) is due entirely to differences in C-ring structure, and in particular exo or endo unsaturation at the C2-position and C2-substituents containing unsaturation. This study also provided information regarding the influence of A-ring substitution pattern on the relative stability of the interconvertible N10-C11 carbinolamine, carbinolamine methyl ether, and imine forms of PBDs.

The treatment of difficult proximal femoral fractures with the Russell-Taylor reconstruction nail.

The outcome of 30 proximal femoral fractures and pathological lesions in 29 patients treated with the Russell-Taylor reconstruction nail are reported. Four patients had fractures involving both the femoral neck and shaft (segmental). Fifteen patients had extensive comminuted fractures of the proximal femur and ten patients underwent nailing because of pathological fractures (one bilateral). In nineteen operations there were technical difficulties, nail insertion and proximal interlocking being the commonest. In the elderly there was a high post-operative complication rate. Three nails needed to be revised for failure of fixation. On review, all patients under sixty years of age regained full mobility and returned to their pre-fracture level of activities. Patients with per-trochanteric fractures over the age of sixty had less favourable results. No cancer patient returned to their prefracture mobility level. The Russell-Taylor reconstruction nail proved to be useful in the treatment of segmented and, in a lesser degree, pathological fractures. However, the surgical technique is demanding and there is a high incidence of post-operative complications in the patients over the age of sixty.

Olecranon screw traction for displaced supracondylar fractures of the humerus in children.

Twenty six children with severely displaced supracondylar fractures were treated with closed reduction and vertical osseous traction with an olecranon screw. Four children required a second operation in the form of open reduction and K-wire fixation for failure to achieve a satisfactory reduction. After a mean follow up of 48 weeks, 20 children (91 per cent) had an excellent result with no significant loss of movement. Two children (9 per cent) had minimal cubitus varus (av. 8 degrees) which did not require a corrective osteotomy. All four children who had a second operation had an excellent result. The average hospitalisation time was 19 days. The method of olecranon screw traction is technically easy to perform and carries few risks of complications.

Migration and failure of the Mecron screw-in acetabular prosthesis.

Early results with the Mecron prosthesis have been variable. We report our experience with this prosthesis at medium- to long-term follow-up. At 5 to 9 years after surgery, 43 patients (49 implants) were reviewed. Radiographic measurements of superior migration, alteration in the opening angle, and thread engagement were made. The failure rate was very high, 33% having been revised or awaiting revision. Of the remainder, 80% had migrated, 86% had changes in the opening angle, and 65% had fewer threads engaged. Many have low-grade symptoms insufficient to merit revision, but the extent of loosening makes eventual revision likely. We feel this represents an example of a new design gaining widespread usage before adequate follow-up studies.