Management of Gustilo-Anderson IIIB open tibial fractures in adults-a systematic review.

INTRODUCTION: Open tibial fractures are the most common open long bone fracture, despite this, the management of these complex injuries still remains a topic of discussion amongst orthopaedic surgeons. SOURCES OF DATA: We searched the EMBASE, MEDLINE and Google Scholar and a systematic review of 7500 articles, leaving 23 after exclusion criteria were applied, in order to analyse the management of open tibial fractures. AREAS OF AGREEMENT AND CONTROVERSY: Infection was noted to be the most significant concern amongst authors, with definitive external fixation having a high rate of superficial pin-site infection and internal fixation having a high deep infection rate. GROWING POINTS: It is essential to have a combined ortho-plastic approach to the management of these fractures as muscle flaps were the most common form of soft tissue coverage. AREAS TIMELY FOR DEVELOPING RESEARCH: A national pragmatic trial into the management of open tibial fractures is required looking at fixation methods and soft tissue coverage, with at least a 2-year follow-up in order to ascertain the most appropriate management of these fractures and patient-related outcomes.

Return to sport following stress fractures of the great toe sesamoids: a systematic review.

Introduction: This review aims to provide information on return rates and times to sport following stress fractures of the great toe sesamoids (SFGTSs). Sources of data: A systematic search of CINAHAL, Cochrane, EMBASE, Google Scholar, Medline, PEDro, Scopus, SPORTDiscus and Web of Science was performed using the keywords 'stress', 'fractures', 'great', 'toe', 'sesamoid', 'athletes', 'sports', 'non-operative', 'conservative', 'operative' and 'return to sport'. Areas of agreement: Fourteen studies were included: three studies reported on the outcome of conservatively-managed SFGTSs; thirteen studies reported on the outcome of surgically-managed SFGTSs. The management principles were to attempt conservative management for 2-6 months using activity modification, analgesia, orthotics and physiotherapy; if symptoms persisted following this, surgical management was to be recommended, either with internal fixation or sesamoidectomy. Areas of controversy: The optimal treatment modalities for SFGTSs remain to be defined. Growing points: Internal fixation shows the best return to full-level sport rates with low rates of complications. Areas timely for developing research: Future prospective studies should aim to establish the optimal treatment modalities for SFGTSs.

Return to sport following clavicle fractures: a systematic review.

INTRODUCTION: This review aims to provide information on the return rates and return times to sport following clavicle fractures. SOURCES OF DATA: A systematic search of Medline, EMBASE, CINAHAL, Cochrane, Web of Science, PEDro, SPORTDiscus, Scopus and Google Scholar was performed using the keywords 'clavicle', 'clavicular', 'fractures', 'athletes', 'sports', 'non-operative', 'conservative', 'operative', 'return to sport'. AREAS OF AGREEMENT: Twenty-three studies were included: 10 reported on mid-shaft fractures, 14 on lateral fractures. The management principles for athletic patients were to attempt non-operative management for undisplaced fractures to undertake operative intervention for displaced lateral fractures and to recommend operative intervention for displaced mid-shaft fractures. AREAS OF CONTROVERSY: The optimal surgical modality for mid-shaft and lateral clavicle fractures. GROWING POINTS: Operative management of displaced mid-shaft fractures offers improved return rates and times to sport compared to non-operative management. Suture fixation and non-acromio-clavicular joint (ACJ)-spanning plate fixation of displaced lateral fractures show promising results. AREAS TIMELY FOR DEVELOPING RESEARCH: Future prospective studies should aim to establish the optimal treatment modalities for clavicle fractures.

Return to sports after stress fractures of the tibial diaphysis: a systematic review.

INTRODUCTION: This review aims to provide information on the time taken to resume sport following tibial diaphyseal stress fractures (TDSFs). SOURCES OF DATA: A systematic search of Medline, EMBASE, CINHAL, Cochrane, Web of Science, PEDro, Sports Discus, Scopus and Google Scholar was performed using the keywords 'tibial', 'tibia', 'stress', 'fractures', 'athletes', 'sports', 'non-operative', 'conservative', 'operative' and 'return to sport'. AREAS OF AGREEMENT: Twenty-seven studies were included: 16 reported specifically on anterior TDSFs and 5 on posterior TDSFs. The general principles were to primarily attempt non-operative management for all TDSFs and to consider operative intervention for anterior TDSFs that remained symptomatic after 3-6 months. Anterior TDSFs showed a prolonged return to sport. AREAS OF CONTROVERSY: The best time to return to sport and the optimal management modalities for TDSFs remain undefined. GROWING POINTS: Management of TDSFs should include a full assessment of training methods, equipment and diet to modify pre-disposing factors. AREAS TIMELY FOR DEVELOPING RESEARCH: Future prospective studies should aim to establish the optimal treatment modalities for TDSFs.

Pleomorphic adenomas: post-operative radiotherapy is unnecessary following primary incomplete excision: a retrospective review.

BACKGROUND: Current standard treatment of Pleomorphic Salivary Adenoma (PSA) of the Parotid Gland is by surgical excision. The management of incomplete excision remains undecided with post-operative radiotherapy advocated by some and observation by others. METHODS: 190 patients who underwent resection of PSA of the parotid gland within the West of Scotland region from 1981 to 2008 were identified and data collected. RESULTS: 78/190 patients had a primary incomplete excision. 25/78 received post-operative radiotherapy and 53 were observed. Recurrences occurred in 11/53 in those observed and in 1/25 of those who received radiotherapy. 21/25 complained of significant side effects from the radiotherapy. 38 surgeons performed 190 procedures, with a range of experience from 1 to28 procedures. CONCLUSIONS: Radiotherapy does appear to reduce recurrence with incomplete excision, however it is associated with significant side effects. We therefore feel radiotherapy should not be routinely recommended. Subspecialisation should be adopted to increase the operating surgeon's experience.

Brachiobasilic fistula formation - single versus two stage procedure.

BACKGROUND: Brachial basilic (BB) fistulae are a form of vascular access for patients requiring dialysis. They are indicated when the cephalic vein is unsuitable for use. This fistula can be created with either a single stage or a two stage procedure. We aimed to compare the two techniques. METHODS: 73 BB fistulae (29 single and 44 two-stage) were created over a 5-year period (2003-2008). Data including sex, age, dialysis and diabetic status was collected from the case notes. Patency and time to maturity data was collected prospectively on an electronic database within the dialysis unit. RESULTS: There was no significant difference in functional patency rates between the two methods. A significant difference was identified between patients who had their fistula created prior to starting dialysis compared to those who had their fistula created after starting dialysis, in both initial patency rate (p = 0.017) and long term survival of the fistulae (p = 0.002). CONCLUSION: We identified no significant difference of patency between the two methods. This implies that a single stage procedure has benefits, by offering a quicker form of vascular access. Patients who had their fistulae created prior to dialysis had improved patency rates.

The surgical treatment of knee stiffness following anterior cruciate ligament reconstruction.

Knee stiffness following anterior cruciate ligament (ACL) reconstruction remains a common complication, which can substantially impair knee function. The aim of this study was to assess the effectiveness of arthroscopic arthrolysis, in conjunction with manipulation under anaesthetic (MUA), in treating stiffness post-ACL reconstruction. We reviewed the records of 18 patients who underwent arthroscopic arthrolysis to treat established stiffness following primary isolated ACL reconstruction. Eight of these patients underwent concomitant MUA at time of arthrolysis. The median time between reconstruction and arthrolysis was nine months. Seven patients had arthrolysis performed within eight months of reconstruction, while 11 patients underwent arthrolysis greater than eight months postreconstruction. Following arthrolysis, the mean extension loss improved from 7° to 1°. In patients with mild extension stiffness (prearthrolysis extension deficits <10°), the mean improvement to extension was 3°. In patients with severe extension stiffness (prearthrolysis extension deficit ≥10°), the mean improvement to extension was 10°. Arthroscopic arthrolysis was significantly more effective in restoring extension loss if carried out within eight months of the primary reconstruction (P < 0.03). In the patients who underwent MUA at time of arthrolysis, the mean flexion loss improved from 16° to 4°. In conclusion, arthroscopic arthrolysis, in conjunction with MUA, is an effective treatment for knee stiffness post-ACL reconstruction but ideally should be carried out within eight months.

hERG subunit composition determines differential drug sensitivity.

BACKGROUND AND PURPOSE: The majority of human ether-a-go-go-related gene (hERG) screens aiming to minimize the risk of drug-induced long QT syndrome have been conducted using heterologous systems expressing the hERG 1a subunit, although both hERG 1a and 1b subunits contribute to the K+ channels producing the repolarizing current I(Kr) . We tested a range of compounds selected for their diversity to determine whether hERG 1a and 1a/1b channels exhibit different sensitivities that may influence safety margins or contribute to a stratified risk analysis. EXPERIMENTAL APPROACH: We used the IonWorks™ plate-based electrophysiology device to compare sensitivity of hERG 1a and 1a/1b channels stably expressed in HEK293 cells to 50 compounds previously shown to target hERG channels. Potency was determined as IC50 values (µM) obtained from non-cumulative, eight-point concentration-effect curves of normalized data, fitted to the Hill equation. To minimize possible sources of variability, compound potency was assessed using test plates arranged in alternating columns of cells expressing hERG 1a and 1a/1b. KEY RESULTS: Although the potency of most compounds was similar for the two targets, some surprising differences were observed. Fluoxetine (Prozac) was more potent at blocking hERG 1a/1b than 1a channels, yielding a corresponding reduction in the safety margin. In contrast, E-4031 was a more potent blocker of hERG 1a compared with 1a/1b channels, as previously reported, as was dofetilide, another high-affinity blocker. CONCLUSIONS AND IMPLICATIONS: The current assays may underestimate the risk of some drugs to cause torsades de pointes arrhythmia, and overestimate the risk of others.

Oral and oropharyngeal cancer in the West of Scotland-long-term outcome data of a prospective audit 1999-2001.

We prospectively studied patients from the west of Scotland who presented with a primary cancer of the oral cavity or oropharynx over a period of 24 months from November 1999, and report long-term outcomes and prognostic factors. A total of 481 patients had squamous cell carcinoma (SCC), 5-year disease-specific survival (DSS) was 50%, and overall survival (OS) was 35%. One hundred were not suitable for treatment with curative intent, and factors other than stage were important in this decision. Of those treated with curative intent, 249 had SCC of the oral cavity (5-year DSS 67%; OS 42%), and 132 had SCC of the oropharynx (5-year DSS 62%; OS 42%). Multivariate analysis showed that pathological nodal stage (p=0.051, 95% CI 0.998-1.955), and perineural invasion (p=0.001, 95% CI 0.186-0.666) were prognostic indicators. Improved results using intensive treatment protocols that have been seen in trials are not likely to translate directly into a general population of patients with head and neck cancer. Algorithms that allow several pathological prognostic indicators to be incorporated into decisions about adjuvant treatment should be used.

Assessing angulation on digital images of radiographs of fractures of the distal radius: visual estimation versus computer software measurement.

We assessed the reliability of visual estimation of angles on computer images of radiographs, and compared their accuracy with the measurement of angles using computer software for ten distal radius fractures. We asked 73 clinicians to visually estimate the dorsal angulation on ten computerized radiographs of fractures of the distal radius. The reliability of these estimations was calculated. Their accuracy was compared to a 'gold standard' obtained by consensus agreement between three consultants measuring these angles using the software. Inter-observer reliability was calculated as ICC = 0.51 and intra-observer reliability as r = 0.76. The visual estimations were less accurate with a mean percentage error of 31% (range, 7-83%). As angulation increased the estimation accuracy improved. Although reliability and accuracy of such estimation was better for clinicians with greater experience, actual measurement was more reliable and accurate.

Knee stiffness following anterior cruciate ligament reconstruction: the incidence and associated factors of knee stiffness following anterior cruciate ligament reconstruction.

We reviewed 100 patients retrospectively following primary ACL reconstruction with quadruple hamstring autografts to evaluate the incidence and factors associated with postoperative stiffness. Stiffness was defined as any loss of motion using the contra-lateral leg as a control. The median delay between injury and operation was 15 months. The incidence of stiffness was 12% at 6 months post-reconstruction. Both incomplete attendance at physiotherapy (p<0.005) and previous knee surgery (p<0.005) were the strongest predictors of the stiffness. Anterior knee pain was also associated with the stiffness (p<0.029). Factors that failed to show a significant association with the stiffness included associated MCL sprain at injury (p=0.32), post-injury stiffness (p=1.00) and concomitant menisectomy at reconstruction (p=0.54). Timing of surgery also did not appear to influence the onset of stiffness (median delays: 29 months for stiff patients; 14 months for non-stiff patients). The rate of stiffness fell to 5% at 12 months postreconstruction, without operative intervention.

HERG trafficking and pharmacological rescue of LQTS-2 mutant channels.

The human ether-a-go-go-related gene (hERG) encodes an ion channel subunit underlying IKr, a potassium current required for the normal repolarization of ventricular cells in the human heart. Mutations in hERG cause long QT syndrome (LQTS) by disrupting IKr, increasing cardiac excitability and, in some cases, triggering catastrophic torsades de pointes arrhythmias and sudden death. More than 200 putative disease-causing mutations in hERG have been identified in affected families to date, but the mechanisms by which these mutations cause disease are not well understood. Of the mutations studied, most disrupt protein maturation and reduce the numbers of hERG channels at the membrane. Some trafficking-defective mutants can be rescued by pharmacological agents or temperature. Here we review evidence for rescue of mutant hERG subunits expressed in heterologous systems and discuss the potential for therapeutic approaches to correcting IKr defects associated with LQTS.

Dynamic control of deactivation gating by a soluble amino-terminal domain in HERG K(+) channels.

K(+) channels encoded by the human ether-à-go-go-related gene (HERG) are distinguished from most other voltage-gated K(+) channels by an unusually slow deactivation process that enables cardiac I(Kr), the corresponding current in ventricular cells, to contribute to the repolarization of the action potential. When the first 16 amino acids are deleted from the amino terminus of HERG, the deactivation rate is much faster (Wang, J., M.C. Trudeau, A.M. Zappia, and G.A. Robertson. 1998. J. Gen. Physiol. 112:637-647). In this study, we determined whether the first 16 amino acids comprise a functional domain capable of slowing deactivation. We also tested whether this "deactivation subdomain" slows deactivation directly by affecting channel open times or indirectly by a blocking mechanism. Using inside-out macropatches excised from Xenopus oocytes, we found that a peptide corresponding to the first 16 amino acids of HERG is sufficient to reconstitute slow deactivation to channels lacking the amino terminus. The peptide acts as a soluble domain in a rapid and readily reversible manner, reflecting a more dynamic regulation of deactivation than the slow modification observed in a previous study with a larger amino-terminal peptide fragment (Morais Cabral, J.H., A. Lee, S.L. Cohen, B.T. Chait, M. Li, and R. Mackinnon. 1998. Cell. 95:649-655). The slowing of deactivation by the peptide occurs in a dose-dependent manner, with a Hill coefficient that implies the cooperative action of at least three peptides per channel. Unlike internal TEA, which slows deactivation indirectly by blocking the channels, the peptide does not reduce current amplitude. Nor does the amino terminus interfere with the blocking effect of TEA, indicating that the amino terminus binding site is spatially distinct from the TEA binding site. Analysis of the single channel activity in cell-attached patches shows that the amino terminus significantly increases channel mean open time with no alteration of the mean closed time or the addition of nonconducting states expected from a pore block mechanism. We propose that the four amino-terminal deactivation subdomains of the tetrameric channel interact with binding sites uncovered by channel opening to specifically stabilize the open state and thus slow channel closing.

Do glia have heart? Expression and functional role for ether-a-go-go currents in hippocampal astrocytes.

Potassium homeostasis plays an important role in the control of neuronal excitability, and diminished buffering of extracellular K results in neuronal Hyperexcitability and abnormal synchronization. Astrocytes are the cellular elements primarily involved in this process. Potassium uptake into astrocytes occurs, at least in part, through voltage-dependent channels, but the exact mechanisms involved are not fully understood. Although most glial recordings reveal expression of inward rectifier currents (K(IR)), it is not clear how spatial buffering consisting of accumulation and release of potassium may be mediated by exclusively inward potassium fluxes. We hypothesized that a combination of inward and outward rectifiers cooperate in the process of spatial buffering. Given the pharmacological properties of potassium homeostasis (sensitivity to Cs(+)), members of the ether-a-go-go (ERG) channel family widely expressed in the nervous system could underlie part of the process. We used electrophysiological recordings and pharmacological manipulations to demonstrate the expression of ERG-type currents in cultured and in situ hippocampal astrocytes. Specific ERG blockers (dofetilide and E 4031) inhibited hyperpolarization- and depolarization-activated glial currents, and ERG blockade impaired clearance of extracellular potassium with little direct effect on hippocampal neuron excitability. Immunocytochemical analysis revealed ERG protein mostly confined to astrocytes; ERG immunoreactivity was absent in presynaptic and postsynaptic elements, but pronounced in glia surrounding the synaptic cleft. Oligodendroglia did not reveal ERG immunoreactivity. Intense immunoreactivity was also found in perivascular astrocytic end feet at the blood-brain barrier. cDNA amplification showed that cortical astrocytes selectively express HERG1, but not HERG2-3 genes. This study provides insight into a possible physiological role of hippocampal ERG channels and links activation of ERG to control of potassium homeostasis.

The eag family of K+ channels in Drosophila and mammals.

Mutations of eag, first identified in Drosophila on the basis of their leg-shaking phenotype, cause repetitive firing and enhanced transmitter release in motor neurons. The encoded EAG polypeptide is related both to voltage-gated K+ channels and to cyclic nucleotide-gated cation channels. Homology screens identified a family of eag-related channel polypeptides, highly conserved from nematodes to humans, comprising three subfamilies: EAG, ELK, and ERG. When expressed in frog oocytes, EAG channels behave as voltage-dependent, outwardly rectifying K(+)-selective channels. Mutations of the human eag-related gene (HERG) result in a form of cardiac arrhythmia that can lead to ventricular fibrillation and sudden death. Electrophysiological and pharmacological studies have provided evidence that HERG channels specify one component of the delayed rectifier, IKr, that contributes to the repolarization phase of cardiac action potentials. An important role for HERG channels in neuronal excitability is also suggested by the expression of these channels in brain tissue. Moreover, mutations of ERG-type channels in the Drosophila sei mutant cause temperature-induced convulsive seizures associated with aberrant bursting activity in the flight motor pathway. The in vivo function of ELK channels has not yet been established, but when these channels are expressed in frog oocytes, they display properties intermediate between those of EAG- and ERG-type channels. Coexpression of the K(+)-channel beta subunit encoded by Hk with EAG in oocytes dramatically increases current amplitude and also affects the gating and modulation of these currents. Biochemical evidence indicates a direct physical interaction between EAG and HK proteins. Overall, these studies highlight the diverse properties of the eag family of K+ channels, which are likely to subserve diverse functions in vivo.

Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel.

BACKGROUND: The congenital long-QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential and a QT interval that leads to arrhythmia. Mutations in the human ether-a-go-go-related gene (HERG), which encodes the rapidly activating component of the delayed rectifier current (IKr), cause chromosome 7-linked LQTS (LQT2). Studies of mutant HERG channels in heterologous systems indicate that the mechanisms mediating LQT2 are varied and include mutant subunits that form channels with altered kinetic properties or nonfunctional mutant subunits. We recently reported a novel missense mutation of HERG (G601S) in an LQTS family that we have characterized in the present work. METHODS AND RESULTS: To elucidate the electrophysiological properties of the G601S mutant channels, we expressed these channels in mammalian cells and Xenopus oocytes. The G601S mutant produced less current than wild-type channels but exhibited no change in kinetic properties or dominant-negative suppression when coexpressed with wild-type subunits. To examine the cellular trafficking of mutant HERG channel subunits, enhanced green fluorescent protein tagging and Western blot analyses were performed. These showed deficient protein trafficking of the G601S mutant to the plasma membrane. CONCLUSIONS: Our results from both the Xenopus oocyte and HEK293 cell expression systems and green fluorescent protein tagging and Western blot analyses support the conclusion that the G601S mutant is a hypomorphic mutation, resulting in a reduced current amplitude. Thus, it represents a novel mechanism underlying LQT2.

Functional analysis of a mouse brain Elk-type K+ channel.

Members of the Ether à go-go (Eag) K+ channel subfamilies Eag, Erg, and Elk are widely expressed in the nervous system, but their neural functions in vivo remain largely unknown. The biophysical properties of channels from the Eag and Erg subfamilies have been described, and based on their characteristic features and expression patterns, Erg channels have been associated with native currents in the heart. Little is known about the properties of channels from the Elk subfamily. We have identified a mouse gene, Melk2, that encodes a predicted polypeptide with 48% amino acid identity to Drosophila Elk but only 40 and 36% identity with mouse Erg (Merg) and Eag (Meag), respectively. Melk2 RNA appears to be expressed at high levels only in brain tissue. Functional expression of Melk2 in Xenopus oocytes reveals large, transient peaks of current at the onset of depolarization. Like Meag currents, Melk2 currents activate relatively quickly, but they lack the nonsuperimposable Cole-Moore shift characteristic of the Eag subfamily. Melk2 currents are insensitive to E-4031, a class III antiarrhythmic compound that blocks the Human Ether-à-go-go-Related Gene (HERG) channel and its counterpart in native tissues, IKr. Melk2 channels exhibit inward rectification because of a fast C-type inactivation mechanism, but the slower rate of inactivation and the faster rate of activation results in less inward rectification than that observed in HERG channels. This characterization of Melk currents should aid in identification of native counterparts to the Elk subfamily of channels in the nervous system.

Regulation of deactivation by an amino terminal domain in human ether-à-go-go-related gene potassium channels.

Abnormalities in repolarization of the cardiac ventricular action potential can lead to life-threatening arrhythmias associated with long QT syndrome. The repolarization process depends upon the gating properties of potassium channels encoded by the human ether-à-go-go-related gene (HERG), especially those governing the rate of recovery from inactivation and the rate of deactivation. Previous studies have demonstrated that deletion of the NH2 terminus increases the deactivation rate, but the mechanism by which the NH2 terminus regulates deactivation in wild-type channels has not been elucidated. We tested the hypothesis that the HERG NH2 terminus slows deactivation by a mechanism similar to N-type inactivation in Shaker channels, where it binds to the internal mouth of the pore and prevents channel closure. We found that the regulation of deactivation by the HERG NH2 terminus bears similarity to Shaker N-type inactivation in three respects: (a) deletion of the NH2 terminus slows C-type inactivation; (b) the action of the NH2 terminus is sensitive to elevated concentrations of external K+, as if its binding along the permeation pathway is disrupted by K+ influx; and (c) N-ethylmaleimide, covalently linked to an aphenotypic cysteine introduced within the S4-S5 linker, mimics the N deletion phenotype, as if the binding of the NH2 terminus to its receptor site were hindered. In contrast to N-type inactivation in Shaker, however, there was no indication that the NH2 terminus blocks the HERG pore. In addition, we discovered that separate domains within the NH2 terminus mediate the slowing of deactivation and the promotion of C-type inactivation. These results suggest that the NH2 terminus stabilizes the open state and, by a separate mechanism, promotes C-type inactivation.

Therapeutic fasciectomy for eosinophilic fasciitis.

Eosinophilic fasciitis is an uncommon and potentially debilitating sclerodermalike connective tissue disorder. A patient is presented for whom medical and pharmacological management had failed to prevent the progression of forearm pain, fibrosis, and flexor contractures. Definitive management with forearm fasciectomy resolved the pain and contractures of the hand. Therapeutic fasciectomy may be a consideration earlier in the course of this disease to ameliorate its debilitating factors. The literature is reviewed.