Optimal posterior screw placement configuration in Sanders 2B calcaneal fractures: A biomechanical study. / [Artículo traducido] Configuración y localización óptima de los tornillos posteriores en las fracturas de calcáneo Sanders 2B: estudio biomecánico.

BACKGROUND: Calcaneal fractures can be high energy intra-articular injuries associated with joint depression. Challenges to fracture reduction include lateral wall blow out, medial wall overlap, comminution and central bone loss. Secondary deformity such as hindfoot varus alters foot biomechanics. Minimally invasive approaches with indirect reduction of the calcaneal tuberosity to maintain the reduction using posterior screws is routinely being used in the treatment of joint depression fractures. Biomechanically, optimum screw numbers and configuration is not known. Biomechanical studies have evaluated and proposed different screw configurations, however, it is not clear which configuration best controls varus deformity. This study aims to determine the optimum screw configuration to control varus deformity in Sanders 2B calcaneal fractures. METHODS: Sawbone models were prepared to replicate Sanders type 2-B fracture, with central bone loss and comminution. 0.5 cm medial wedge of the calcaneal tuberosity was removed to create varus instability. After stabilising posterior facet with a single 4 mm partial threaded screw, and applied an 8 hole contoured plate to stabilise the angle of Gissane, inserted one or two 7 mm cannulated partially threaded CharlotteTM (Wright Medical Technology, Memphis, USA) Headless Multi-use Compression (under image guidance) extra screws to control varus and subsidence deformity of the fracture. Coronal plane displacement of the dissociated calcaneal tuberosity fragment relative to the body when applying 5 N, 10 N and 20 N force was measured in millimetres (mm). RESULTS: 2 screws inserted (one medial screw into the sustentaculum talus from inferior to superior and, one lateral screw into the long axis anterior process) provides the least displacement (0.88 ± 0.390 at 5 N and 1.7 ± 1.251 at 20 N) and the most stable construct (p < 0.05) when compared to other configurations. A single medial screw into the sustentaculum tali (conf. 3) resulted in the least stable construct and most displacement (4.04 ± 0.971 at 5 N and 11.24 ± 7.590 at 20 N) (p < 0.05). CONCLUSION: This study demonstrates the optimal screw configuration to resist varus in calcaneal fractures using minimally invasive techniques. Optimal stability is achieved using 2 screws; one located along the long axis of the calcaneus (varus control) and the other placed in the short axis directed towards the posterior facet of the calcaneus (control varus and subsidence). Further cadaver research would help evaluate optimal screw placement in simulated fractures to further assess reproducibility.

Optimal posterior screw placement configuration in Sanders 2B calcaneal fractures: A biomechanical study.

BACKGROUND: Calcaneal fractures can be high energy intra-articular injuries associated with joint depression. Challenges to fracture reduction include lateral wall blow out, medial wall overlap, comminution and central bone loss. Secondary deformity such as hindfoot varus alters foot biomechanics. Minimally invasive approaches with indirect reduction of the calcaneal tuberosity to maintain the reduction using posterior screws is routinely being used in the treatment of joint depression fractures. Biomechanically, optimum screw numbers and configuration is not known. Biomechanical studies have evaluated and proposed different screw configurations, however, it is not clear which configuration best controls varus deformity. This study aims to determine the optimum screw configuration to control varus deformity in Sanders 2B calcaneal fractures. METHODS: Sawbone models were prepared to replicate Sanders type 2-B fracture, with central bone loss and comminution. 0.5cm medial wedge of the calcaneal tuberosity was removed to create varus instability. After stabilising posterior facet with a single 4mm partial threaded screw, and applied an 8 hole contoured plate to stabilise the angle of Gissane, inserted one or two 7mm cannulated partially threaded Charlotte™ (Wright Medical Technology, Inc. 5677 Airline Road Arlington, TN) Headless Multi-use Compression (under image guidance) extra screws to control varus and subsidence deformity of the fracture. Coronal plane displacement of the dissociated calcaneal tuberosity fragment relative to the body when applying 5N, 10N and 20N force was measured in millimetres (mm). RESULTS: 2 screws inserted (one medial screw into the sustentaculum talus from inferior to superior and, one lateral screw into the long axis anterior process) provides the least displacement (0.88±0.390 at 5N and 1.7±1.251 at 20N) and the most stable construct (p<0.05) when compared to other configurations. A single medial screw into the sustentaculum tali (conf. 3) resulted in the least stable construct and most displacement (4.04±0.971 at 5N and 11.24±7.590 at 20N) (p<0.05). CONCLUSION: This study demonstrates the optimal screw configuration to resist varus in calcaneal fractures using minimally invasive techniques. Optimal stability is achieved using 2 screws; one located along the long axis of the calcaneus (varus control) and the other placed in the short axis directed towards the posterior facet of the calcaneus (control varus and subsidence). Further cadaver research would help evaluate optimal screw placement in simulated fractures to further assess reproducibility.

Tennis elbow: A clinical review article.

Lateral epicondylitis, or tennis elbow is a common condition that presents with pain and tenderness around the common extensor origin of the elbow. Tennis elbow is estimated to affect 1-3% of the adult population each year and is more common in the dominant arm. It is generally regarded as an overuse injury involving repeated wrist extension against resistance, although it can occur as an acute injury (trauma to the lateral elbow). Up to 50% of all tennis players develop symptoms due to various factors including poor swing technique the use of heavy racquet. It's also seen in labourers who utilise heavy tools or engage in repetitive gripping or lifting task. In this article, we discuss the existing literature in the field and the current thinking on optimum treatment modalities. We have reviewed the literature available on med line and have discussed the condition with our specialist colleagues in the field.

Centromere protein B null mice are mitotically and meiotically normal but have lower body and testis weights.

CENP-B is a constitutive centromere DNA-binding protein that is conserved in a number of mammalian species and in yeast. Despite this conservation, earlier cytological and indirect experimental studies have provided conflicting evidence concerning the role of this protein in mitosis. The requirement of this protein in meiosis has also not previously been described. To resolve these uncertainties, we used targeted disruption of the Cenpb gene in mouse to study the functional significance of this protein in mitosis and meiosis. Male and female Cenpb null mice have normal body weights at birth and at weaning, but these subsequently lag behind those of the heterozygous and wild-type animals. The weight and sperm content of the testes of Cenpb null mice are also significantly decreased. Otherwise, the animals appear developmentally and reproductively normal. Cytogenetic fluorescence-activated cell sorting and histological analyses of somatic and germline tissues revealed no abnormality. These results indicate that Cenpb is not essential for mitosis or meiosis, although the observed weight reduction raises the possibility that Cenpb deficiency may subtly affect some aspects of centromere assembly and function, and result in reduced rate of cell cycle progression, efficiency of microtubule capture, and/or chromosome movement. A model for a functional redundancy of this protein is presented.

Adult respiratory distress syndrome.

Adult respiratory distress syndrome (ARDS) has now been described as a sequela to such diverse conditions as burns, amniotic fluid embolism, acute pancreatitis, trauma, sepsis and damage as a result of elective surgery in general. Patients with ARDS require immediate intubation, with the average patient now being ventilated for between 8 and 11 days. While the acute management of ARDS is conducted by the critical care team, almost any surgical patient can be affected by the condition and we believe that it is important that a broader spectrum of hospital doctors gain an understanding of the nature of the pathology and its current treatment.

Formaldehyde activation of mitoxantrone yields CpG and CpA specific DNA adducts.

Recently we have found that mitoxantrone, like Adria-mycin, can be activated by formaldehyde and subsequently form adducts which stabilise double-stranded DNA in vitro. This activation by formaldehyde may be biologically relevant since formaldehyde levels are elevated in those tumours in which mitoxan-trone is most cytotoxic. In vitro transcription analysis revealed that these adducts block the progression of RNA polymerase during transcription and cause truncated RNA transcripts. There was an absolute requirement for both mitoxantrone and formaldehyde in transcriptional blockage formation and the activated complex was found to exhibit site specificity, with blockage occurring prior to CpG and CpA sites in the DNA (non-template strand). The stability of the adduct at 37 degrees C was site dependent. The half-lives ranged from 45 min to approximately 5 h and this was dependent on both the central 2 bp blockage site as well as flanking sequences. The CpG specificity of mitoxantrone adduct sites was also confirmed independently by a lambda exonuclease digestion assay.

Interstrand cross-linking by adriamycin in nuclear and mitochondrial DNA of MCF-7 cells.

Activation of Adriamycin by formaldehyde leads to the formation of drug-DNA adducts in vitro and these adducts stabilise the DNA to such a degree that they function as virtual interstrand cross-links. The formation of these virtual interstrand cross-links by Adriamycin was investigated in MCF-7 cells using a gene-specific interstrand cross-linking assay. Cross-linking was measured in both the nuclear-encoded DHFR gene and in mitochondrial DNA (mtDNA). Cross-link formation increased linearly with Adriamycin concentration following a 4 h exposure to the drug. The rate of formation of Adriamycin cross-links in each of the genomes was similar, reaching maximal levels of 0.55 and 0.4 cross-links/10 kb in the DHFR gene and mtDNA respectively, following exposure to 20 micro M Adriamycin for 8 h. The interstrand cross-link was short lived in both DNA compartments, with a half-life of 4.5 and 3.3 h in the DHFR gene and mtDNA respectively. The kinetics of total Adriamycin adduct formation, detected using [(14)C]Adriamycin, was similar to that of cross-link formation. Maximal adduct levels (30 lesions/10 kb) were observed following incubation at 20 micro M drug for 8 h. The formation of such high levels of adducts and cross-links could therefore be expected to contribute to the mechanism of action of Adriamycin.

Molecular basis for the synergistic interaction of adriamycin with the formaldehyde-releasing prodrug pivaloyloxymethyl butyrate (AN-9).

The interaction of Adriamycin and pivaloyloxymethyl butyrate (AN-9) was investigated in IMR-32 neuroblastoma and MCF-7 breast adenocarcinoma cells. Adriamycin is a widely used anticancer drug, whereas AN-9 is an anticancer agent presently undergoing Phase II clinical trials. The anticancer activity of AN-9 has been attributed to its ability to act as a butyric acid prodrug, although it also releases formaldehyde and pivalic acid. Adriamycin and AN-9 in combination display synergy when exposed simultaneously to cells or when AN-9 treatment is up to 18 h after Adriamycin administration. However, the reverse order of addition results in antagonism. These interactions have been established using cell viability assays and classical isobologram analysis. To understand the molecular basis of this synergy, the relative levels of Adriamycin-DNA adducts were determined using various treatment combinations. Levels of Adriamycin-DNA adducts were enhanced when treatment combinations known to be synergistic were used and were diminished using those treatments known to be antagonistic. The relative timing of the addition of Adriamycin and AN-9 was critical, with a 20-fold enhancement of Adriamycin-DNA adducts occurring when AN-9 was administered 2 h after the exposure of cells to Adriamycin. The enhanced levels of these adducts and the accompanying decreased cell viability were directly related to the esterase-dependent release of formaldehyde from AN-9, providing evidence for the formaldehyde-mediated activation of Adriamycin.

Recent advances in understanding and exploiting the activation of anthracyclines by formaldehyde.

The anthracycline group of compounds are amongst the most effective chemotherapy agents currently in use for cancer treatment. They are generally classified as topoisomerase II inhibitors but also have a variety of other targets in cells. It has been known for some years that the anthracyclines are capable of forming DNA adducts, but the relevance and extent of these DNA adducts in cells and their role in causing cell death has remained obscure. When the adduct structure was solved, it became clear that formaldehyde was an absolute requirement for adduct formation. This led to a renewed interest in the capacity of anthracyclines to form DNA adducts, and there are now several ways in which adduct formation can be facilitated in cells. These involve strategies to provide the requisite formaldehyde in the form of anthracycline-formaldehyde conjugates, and the use of formaldehyde-releasing drugs in combination with anthracyclines. Of particular interest is the new therapeutic compound AN-9 that releases both butyric acid and formaldehyde, leading to efficient anthracycline-DNA adduct formation, and synergy between the two compounds. Targeted formation of adducts using anthracycline-formaldehyde conjugates tethered to cell surface targeted molecules is now also possible. Some of the cellular consequences of these adducts have now been studied, and it appears that their formation can overcome anthracycline-resistance mechanisms, and that they are more efficient at inducing apoptosis than when functioning primarily through impairment of topoisomerase II. The clinical application of the use of anthracyclines as DNA adduct forming agents is now being explored.

Expression of the 17-1A antigen in gastric and gastro-oesophageal junction adenocarcinomas: a potential immunotherapeutic target?

BACKGROUND: A murine monoclonal antibody against the 17-1A epithelial antigen has been shown to be a useful adjuvant therapy in colorectal cancer. Its clinical use could be extended to patients with upper gastrointestinal adenocarcinoma. AIM: To determine the distribution of the antigen in gastric and oesophageal adenocarcinoma. METHODS: The activity of two monoclonal antibodies active against 17-1A epithelial antigen was studied in gastric and gastro-oesophageal junction adenocarcinomas: fresh frozen tissue from both the carcinoma and adjacent mucosa was stained using immunocytochemistry with a murine monoclonal antibody (17-1A edrecolomab, Glaxo Wellcome); paraffin embedded tissue was stained using the humanised monoclonal antibody 3622W94 (Glaxo Wellcome). RESULTS: 29 of 33 cancers (88%) stained with the murine antibody and 39 of 40 (98%) with the humanised antibody. The degree of staining was greater in well differentiated and moderately differentiated tumours. There was no staining of the normal background gastric or oesophageal mucosa, but areas of intestinal metaplasia stained intensely. The humanised monoclonal 3622W94 antibody produced more intense staining than the murine antibody. CONCLUSIONS: The high incidence of expression of the 17-1A antigen in patients with gastric and gastro-oesophageal junction adenocarcinomas suggests a potential role for these antibodies as an adjuvant treatment for these common cancers.

The binding of [(en)Pt(mu-dpzm)2Pt(en)]4+ to G/C-rich regions of DNA.

The non-covalent binding of [(en)Pt(mu-dpzm)2Pt(en)]4+ to segments of DNA containing only G and C bases has been studied to gain an understanding of the pre-covalent binding association of cationic polynuclear platinum(II) anti-cancer drugs at G/C sites. 1H-NMR and CD spectroscopy were used to study the binding of the metal complex to the oligonucleotide d(GC)5 and the polynucleotide poly(dG-dC).poly(dG-dC), respectively. NOE contacts between the metal complex protons and the oligonucleotide sugar H1' protons observed in NOESY spectra indicated that the metal complex bound in the minor groove at the central C4 to G7 region of the oligonucleotide. This result indicates that even though cationic polynuclear platinum(II) complexes bind covalently in the major groove at G/C sites, the pre-covalent binding association is favoured in the minor groove. CD spectra indicated that the addition of the metal complex to poly(dG-dC)-poly(dG-dC) induced some conformational changes, but it was not possible to conclude that [(en)Pt(mu-dpzm)2Pt(en)]4+ induced a B- to Z-type DNA transition. In addition, in vitro transcription assays using the lac UV5 promoter showed that the non-covalent binding of [(en)Pt(mu-dpzm)2Pt(en)]4+ was sufficiently stable to inhibit transcription, and at particular sites.

Barminomycin functions as a potent pre-activated analogue of Adriamycin.

The anthracycline Adriamycin is known to form adducts with DNA, but requires prior activation by formaldehyde. In contrast, the anthracycline barminomycin is also able to form adducts with DNA, but does not require activation by formaldehyde. Barminomycin, therefore, appears to function as a pre-activated form of Adriamycin. The DNA adducts formed by both anthracyclines are bound covalently to only one strand of DNA, but both also stabilise duplex DNA sufficiently that they can be detected as virtual interstrand crosslinks in heat denaturation electrophoretic crosslinking assays. The barminomycin-DNA adducts form extremely rapidly with DNA, and at exceedingly low concentrations (approximately 50-fold lower than with Adriamycin in the presence of excess formaldehyde), both characteristics consistent with barminomycin being in a pre-activated state, hence, undergoing a bimolecular reaction with DNA compared with the trimolecular reaction (drug, formaldehyde and DNA) required with Adriamycin. Surprisingly, barminomycin-DNA adducts are substantially more stable (essentially irreversible) than Adriamycin-DNA adducts (half life of approximately 25 h at 37 degrees C). Due to this understanding of the reactivity of barminomycin and its exceptional cytotoxicity (1000-fold more cytotoxic than Adriamycin), detailed structural studies of barminomycin-DNA adducts are now warranted, both in vitro and in tumour cells.

Plantar fasciitis.

INTRODUCTION: In this article we look at the aetiology of plantar fasciitis, the other common differentials for heel pain and the evidence available to support each of the major management options. We also review the literature and discuss the condition. METHODS: A literature search was performed using PubMed and MEDLINE(®). The following keywords were used, singly or in combination: 'plantar fasciitis', 'plantar heel pain', 'heel spur'. To maximise the search, backward chaining of reference lists from retrieved papers was also undertaken. FINDINGS: Plantar fasciitis is a common and often disabling condition. Because the natural history of plantar fasciitis is not understood, it is difficult to distinguish between those patients who recover spontaneously and those who respond to formal treatment. Surgical release of the plantar fascia is effective in the small proportion of patients who do not respond to conservative measures. New techniques such as endoscopic plantar release and extracorporeal shockwave therapy may have a role but the limited availability of equipment and skills means that most patients will continue to be treated by more traditional techniques.

Processing of anthracycline-DNA adducts via DNA replication and interstrand crosslink repair pathways.

Anthracycline chemotherapeutics are well characterised as poisons of topoisomerase II, however many anthracyclines, including doxorubicin, are also capable of forming drug-DNA adducts. Anthracycline-DNA adducts present an unusual obstacle for cells as they are covalently attached to one DNA strand and stabilised by hydrogen bonding to the other strand. We now show that in cycling cells processing of anthracycline adducts through DNA replication appears dominant compared to processing via transcription-coupled pathways, and that the processing of these adducts into DNA breaks is independent of topoisomerase II. It has previously been shown that cells deficient in homologous recombination (HR) are hypersensitive to adduct forming treatments. Given that anthracycline-DNA adducts, whilst not true crosslinks, are associated with both DNA strands, the role of ICL repair pathways was investigated. Mus81 is a structure specific nuclease implicated in Holliday junction resolution and the resolution of branched DNA formed by stalled replication forks. We now show that ICL repair deficient cells (Mus81(-/-)) are hypersensitive to anthracycline-DNA adducts and ET-743, a compound which causes a chemically similar type of DNA damage. Further analysis of this mechanism showed that Mus81 does not appear to cause DNA breaks resulting from either anthracycline- or ET743-DNA adducts. This suggests Mus81 processes these novel forms of DNA damage in a fundamentally different way compared to the processing of classical covalent crosslinks. Improved understanding of the role of DNA repair in response to such adducts may lead to more effective chemotherapy for patients with BRCA1/2 mutations and other HR deficiencies.

Fascia iliaca compartment block reduces morphine requirement pre-operatively for patients with fractured neck of femur.

INTRODUCTION: Fascia iliaca compartment block, performed in the emergency department (A&E) in patients presenting with femoral neck fracture, has gained increasing recognition as an adjunctive analgesic. The purpose of this study was to investigate whether fascia iliaca block (FIB) significantly reduced the requirement for systemic opiates in the pre-operative setting. MATERIALS AND METHODS: Analgesia requirements for all patients admitted with fractured neck of femur to one unit over a 9-month period were gathered prospectively. Fifty percent of patients had received FIB at diagnosis in the A&E, dependant on the expertise of the attending physician. Morphine administration between groups was analysed. RESULTS: Over a 9-month period, 286 patients with complete documentation were admitted with fractured neck of femur. At the start of the study, an informal education programme in A&E was introduced, increasing the incidence of FIB provision at diagnosis (p = <0.0001, Fisher's exact test) and reducing the average amount of morphine administered (p = 0.027, linear regression analysis). The administration of FIB reduced the average morphine requirement for a patient in A&E by 41 % when compared with those who received systemic analgesia alone (p = 0.018, Mann-Whitney test). No adverse effects were reported with FIB. CONCLUSION: Fascia iliaca compartment block is a safe and effective method of providing analgesia to patients with fractured neck of femur and reduces morphine requirement.

The use of cerclage wires as a suture passer in the repair of quadriceps tendon ruptures.

We describe a novel, simple and cost-effective method of passing sutures through the patella, without the need for expensive or specialised equipment.

Barminomycin, a model for the development of new anthracyclines.

Barminomycin is a member of the anthracycline class of anticancer agents and was originally discovered as a pink/red complex with DNA and RNA and named SN-07. The chromophore was subsequently separated from the nucleic acids by nuclease digestion and contained the four-membered anthraquinone ring system characteristic of anthracyclines, but with an unusual eight membered ring that contained a carbinolamine which readily interconverted to an imine. The imine form is analogous to the formaldehyde-activated form of other anthracyclines such as doxorubicin. The imine form confers exceptional activity to barminomycin which is 1,000-fold more cytotoxic than doxorubicin. Barminomycin rapidly forms adducts with DNA, reacting with the exocyclic amino group of guanine residues and with high selectivity for 5'-GC-3' sequences. The coupling to DNA appears to be identical to the N-C-N aminal linkage formed between doxorubicin and DNA where the carbon derives from formaldehyde for doxorubicin-DNA adducts, whereas this "activated carbon" is an inherent component of the imine group in the eight membered ring of barminomycin. Although the linkage of both drugs to DNA appears to be identical, barminomycin-DNA complexes are essentially irreversible compared to the labile doxorubicin-DNA adducts which have an in vitro (purified DNA) half-life of 25 h at 37 degrees C. A 3D model of the barminomycin-DNA complex has been defined from 307 NOE distance constraints. The enhanced stability of barminomycin-DNA adducts appears to be due primarily to protection of the aminal linkage from hydrolysis and this has provided insight into the design of new anthracycline derivatives with enhanced stability and activity. Strategies for harnessing the extreme reactivity and activity of barminomycin are also presented.