Major joint replacement. A model for antithrombotic drug development: from proof-of-concept to clinical use.

AIM: Development of antithrombotic compounds has traditionally been performed in patients undergoing total hip and knee replacement surgery. A high number of asymptomatic deep-vein thromboses are radiologically detectable, and bleeding and other adverse events (AE) are easy to observe. However, standardization of study procedures and endpoints in early proof-of-concept studies and late pure clinical endpoint studies has been lacking. This has made comparison between studies difficult, economic analyses speculative and potential benefits of applying the drug regimen in non-selected patients uncertain. In this paper, the International Surgical Thrombosis Forum proposes a strategy for the clinical investigation of new pharmacological agents for the prophylaxis of postoperative thrombotic events. METHODS: First, dose titration safety studies of short duration, in highly selected patients using objective venographic endpoints are recommended. Bleeding should be divided into the quantified volume of surgical bleeding and other adjudicated clinical bleeding events. The number of AE should be described for each dose step and classified according to International Coding of Diagnoses (ICD). Second, a dose confirmatory study of moderate exposure period and sufficient follow-up time is recommended. The exclusion criteria should be restricted to contraindications of the compared drugs and technical procedure. RESULTS: The efficacy, bleeding and AE should be similar to those used in dose-titration studies. In addition, the failure rate of the drug to exert its effect and the net clinical benefit should be calculated. CONCLUSION: Finally, trials with simple clinical endpoints and long follow-up should be conducted to evaluate the potential benefits of the drug-regimen in non-selected populations.

Unlinked elbow arthroplasty as primary treatment for fractures of the distal humerus.

This study reviews our experience with primary total elbow arthroplasty in the management of acute distal humeral fractures by use of the iBP unlinked elbow prosthesis. We followed up 9 elbows in 9 patients (including 2 with rheumatoid arthritis), with a mean age of 73 years, for a mean of 3.5 years. Functional outcome was assessed with the Mayo Elbow Performance Score and the recently developed Liverpool Elbow Score. Clinical examination and radiologic assessment were performed by an independent surgeon. All elbows were stable at the latest follow-up examination, all patients were able to perform daily activities, and pain relief was satisfactory. The median value for the Mayo Elbow Performance Score was 95 (range, 65-100). This is the first report of the use of an unlinked prosthesis for the treatment of distal humeral fractures. Our results show that this method of treatment provides a reliable and effective way of dealing with these very difficult fractures when internal fixation is not a viable option.

Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial.

BACKGROUND: Oral anticoagulants, such as dabigatran etexilate, an oral, direct thrombin inhibitor, that do not require monitoring or dose adjustment offer potential for prophylaxis against venous thromboembolism (VTE) after total knee replacement surgery. METHODS: In this randomized, double-blind study, 2076 patients undergoing total knee replacement received dabigatran etexilate, 150 mg or 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery, for 6-10 days. Patients were followed-up for 3 months. The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events. RESULTS: The primary efficacy outcome occurred in 37.7% (193 of 512) of the enoxaparin group versus 36.4% (183 of 503) of the dabigatran etexilate 220 mg group (absolute difference, -1.3%; 95% CI, -7.3 to 4.6) and 40.5% (213 of 526) of the 150 mg group (2.8%; 95% CI, -3.1 to 8.7). Both doses were noninferior to enoxaparin based on the pre-specified noninferiority criterion. The incidence of major bleeding did not differ significantly between the three groups (1.3% versus 1.5% and 1.3% respectively). No significant differences in the incidences of liver enzyme elevation and acute coronary events were observed during treatment or follow-up. CONCLUSIONS: Dabigatran etexilate (220 mg or 150 mg) was at least as effective and with a similar safety profile as enoxaparin for prevention of VTE after total knee-replacement surgery.

Strength and fatigability of selected muscles in upper limb: assessing muscle imbalance relevant to tennis elbow.

PURPOSE: The aetiology of tennis elbow has remained uncertain for more than a century. To examine muscle imbalance as a possible pathophysiological factor requires a reliable method of assessment. This paper describes the development of such a method and its performance in healthy subjects. We propose a combination of surface and fine-wire EMG of shoulder and forearm muscles and wrist strength measurements as a reliable tool for assessing muscle imbalance relevant to the pathophysiology of tennis elbow. METHODS: Six healthy volunteers participated. EMG data were acquired at 50% maximal voluntary isometric contraction from five forearm muscles during grip and three shoulder muscles during external rotation and abduction, and analysed using normalized median frequency slope as a fatigue index. Wrist extension/flexion strength was measured using a purpose-built dynamometer. RESULTS: Significant negative slope of median frequency was found for all muscles, with good reproducibility, and no significant difference in slope between the different muscles of the shoulder and the wrist. (Amplitude slope showed high variability and was therefore unsuitable for this purpose.) Wrist flexion was 27+/-8% stronger than extension (mean+/-SEM, p=0.006). CONCLUSION: This is a reliable method for measuring muscle fatigue in forearm and shoulder. EMG and wrist strength studies together can be used for assessing and identifying the muscle balance in the wrist-forearm-shoulder chain.

Botulinum toxin injection in the treatment of tennis elbow. A double-blind, randomized, controlled, pilot study.

BACKGROUND: A recent report has suggested that local injection of botulinum toxin type A is an effective method of treatment for chronic tennis elbow. The toxin is thought to provide temporary paralysis of the painful common extensor origin, thereby allowing a healing response to occur. To test this theory, we performed a double-blind, randomized, controlled, pilot trial comparing injections of botulinum toxin type A with those of a placebo (normal saline solution) in the treatment of chronic tennis elbow. METHODS: Forty patients with a history of chronic tennis elbow for which all conservative treatment measures, including steroid injection, had failed were randomized into two groups. Half the patients received 50 units of botulinum toxin type A, and the remainder received normal saline solution. The intramuscular injections were performed 5 cm distal to the maximum point of tenderness at the lateral epicondyle, in line with the middle of the wrist. The two solutions used for the injections were identical in appearance and temperature. The results of a quality-of-life assessment with the Short Form-12 (SF-12), the pain score on a visual analogue scale, and the grip strength measured with a validated Jamar dynamometer were recorded before and three months after the injection. RESULTS: Three months following the injections, there was no significant difference between the two groups with regard to grip strength, pain, or quality of life. CONCLUSIONS: With the numbers studied, we failed to find a significant difference between the two groups; thus, we have no evidence of a benefit from botulinum toxin injection in the treatment of chronic tennis elbow.

Sliding external fixator "a product design and cadaveric experiment".

BACKGROUND: External fixation spanning a joint like the elbow, while maintaining joint mobility, is a well-established practice, and it could be done with a variety of external fixation systems. In current systems, correct identification of the elbow center of rotation under X-ray guidance with lateral views is mandatory. If the center of rotation of the fixator is not aligned with that of the elbow joint, the assembly will not work. This new design idea aims to propagate the principle of sliding external fixation applied on the extensor side of a joint, with the limbs of the fixator being able to slide in and out during joint extension and flexion, respectively, without hindering the joint movement, without the need to use X-ray guidance to identify the center of rotation. MATERIALS AND METHODS: A cadaveric experiment was carried on using a sliding fixator prototype applies on two cadaveric elbow specimens, which were tested though the arc of movement. RESULTS: Assembling the fixator over the intact elbows without identifying the center of rotation did not impede the joint movement. Furthermore, after surgical dislocation of the elbow, the external fixator was able to keep the joint congruent, throughout the movement arc. CONCLUSION: It was possible to apply a sliding external fixator on the extensor surface of a joint without identifying the center of rotation, and that does not seem to impede the joint movement, while can still keep the dislocated joint congruent despite attempted distraction.

Electromyographic assessment of muscle fatigue in massive rotator cuff tear.

Shoulder muscle fatigue has not been assessed in massive rotator cuff tear (MRCT). This study used EMG to measure fatigability of 13 shoulder muscles in 14 healthy controls and 11 patients with MRCT. A hand grip protocol was applied to minimise artifacts due to pain experience during measurement. The fatigue index (median frequency slope) was significantly non-zero (negative) for anterior, middle, and posterior parts of deltoid, supraspinatus and subscapularis muscles in the controls, and for anterior, middle, and posterior parts of deltoid, and pectoralis major in patients (p ≤ 0.001). Fatigue was significantly greater in patients compared to the controls for anterior and middle parts of deltoid and pectoralis major (p ≤ 0.001). A submaximal grip task provided a feasible way to assess shoulder muscle fatigue in MRCT patients, however with some limitations. The results suggest increased activation of deltoid is required to compensate for lost supraspinatus abduction torque. Increased pectoralis major fatigue in patients (adduction torque) likely reflected strategy to stabilise the humeral head against superior subluxing force of the deltoid. Considering physiotherapy as a primary or adjunct intervention for the management of MRCT, the findings of this study generate a base for future clinical studies aiming at the development of evidence-based protocols.

Expression of Schwann cell-specific proteins and low-molecular-weight neurofilament protein during regeneration of sciatic nerve treated with neurotrophin-4.

Neurotrophin-4 acts as a potent survival factor for subpopulations of motoneurons. To investigate its effect on Schwann cell sheath and axonal proteins during peripheral nerve regeneration, sciatic nerves in adult rats were transected and repaired, and fibrin glue containing neurotrophin-4 injected around the repair site. At 5, 15, 30 and 60 days after repair, 5-mm nerve segments distal to the repair were collected, and western blotting was used to measure myelin-associated glycoprotein, myelin basic protein and low-molecular-weight neurofilament protein. In control groups these dramatically declined at 5 and 15 days then increased from 30 and 60 days. However, in the neurotrophin-4 group there was a significant increase (to several times basal values) in myelin-associated glycoprotein and myelin basic protein at 5-15 days. The relatively small increases (<7%) in Schwann cell numbers suggest that this is mainly due to increased synthesis per cell. The neurotrophin-4 group also showed a small but significant increase at 15 days in low-molecular-weight neurofilament protein, which however remained much lower than basal. We conclude that neurotrophin-4 regulates the expression of myelin-associated glycoprotein, myelin basic protein, and to a lesser extent low-molecular-weight neurofilament protein, during peripheral nerve regeneration.

The rising number of underfoot accidents after the menopause causes both fractures and non-fracture injuries.

To test our hypothesis that the onset of the menopause would be associated with an increased number of underfoot accidents in the female population for both fracture and non-fracture injuries, we analysed 90061 accidents recorded by the Home Accident Surveillance System and classified them as to (a) whether a fracture resulted, and (b) whether they were 'underfoot'. We defined 'underfoot' accidents to have an event such as a trip, slip, missed footing, twisted or turned ankle, on the level or on stairs. All other accidents, including falls from or off structures, or falls caused by medical conditions were classified as 'not underfoot'. Overall, 51.3% of women and 32% of men were injured in underfoot accidents. There was an increase with age in the percentage of fractures in both men and women, mainly due to an increased risk of fracture in underfoot accidents: underfoot accidents caused 75.9% of all fractures in women and 55.4% in men. The number of women who had fractures following underfoot accidents increased sharply after the age of 50 years, and the number continued to rise up to 80 years. The number of non-fracture injuries in elderly women from underfoot accidents also increased with age. Osteoporosis on its own does not explain our result, and changes in muscle strength and reaction time, with age in both men and women, and at a greater rate in postmenopausal women, may be an important factor in underfoot accidents.

Cellular energetics of dystrophic muscle.

Cytosolic pH and phosphorus metabolite ratios in skeletal muscle were measured by 31P magnetic resonance spectroscopy in patients with Duchenne muscular dystrophy (DMD) and Becker's muscular dystrophy (BMD) and in Duchenne/Becker carriers. In resting dystrophin-deficient muscle, there was a decrease in phosphocreatine (PCr) and increase in orthophosphate (Pi) relative to ATP, and an increase in calculated free [ADP]. Phosphomonester and phosphodiester were also increased relative to ATP. These changes were largest in DMD, smaller in BMD and small or absent in carriers. Cytosolic pH was increased substantially in DMD, moderately in BMD and slightly but significantly in gastrocnemius of carriers. Raised intracellular pH thus appears to be the most characteristic abnormality in dystrophin-deficient muscle. Responses to erobic exercise were studied in the forearm muscle flexor digitorum superficialis of carriers. PCr depletion during exercise was greater than normal but the fall in pH was disproportionately small, resulting in increased [ADP]. This is likely to result either from reduced anaerobic glycogenolysis to lactic acid or from increased proton efflux (as is seen in mitochondrial myopathy). Detailed analysis suggests: (1) at the start of exercise, calculated lactic acid production was increased, as was the rate of PCr depletion, suggesting that there was no absolute defect of glycogenolysis. (2) At the start of recovery, calculated proton efflux was not increased, although as the pH at the end of exercise was higher than in controls and proton efflux is normally pH-dependent, an up-regulation of proton efflux cannot be excluded. (3) Recovery of PCr, Pi and ADP after exercise were not impaired, suggesting that mitochondrial function is normal.

The kinematics and kinetics of slipknots for arthroscopic Bankart repair.

An apparatus has been developed to enable the in vitro measurement of the kinematics and kinetics of a slipknot, both while the knot is being tightened and with the knot in place and the tension removed. During tightening, the apparatus provides a linearly increasing resistance, which may be considered analogous to the resistance experienced when the labrum is drawn toward and apposed to the edge of the glenoid cavity during a Bankart repair. The tension to close the knot is measured with a tensiometer, in tandem with the closure of the capsule model onto the bone anchor, which is measured with a datalogger. The tightening tension was limited to 25 N and intraoperator and interoperator comparisons were made for four knots tied by six participants. Failure of a knot was taken to be reverse slippage of 2 mm. A second criterion of ease of slide was used to assess each knot. We found wide interoperator variability with regard to slipknot tying. A methodology for quality control of slipknot tying is presented.

A study of the reproducibility of three different normalisation methods in intramuscular dual fine wire electromyography of the shoulder.

The purpose of this study was to determine the most appropriate method of normalisation for dual fine wire electromyography of shoulder muscles. Five healthy subjects were studied, with one muscle investigated in each subject (2 supraspinatus, 2 infraspinatus, 1 subscapularis). Three dual fine wire electrodes were inserted 1 cm apart around the recognised insertion points. Each subject performed five types of cyclic exercise on an isokinetic muscle dynamometer with an isometric maximal voluntary contraction (MVC) being performed before and after the exercise protocol. The EMG signal was normalised using each of the MVC voltage, the peak voltage and the whole-cycle mean voltage. There was a considerable difference (5-143%) between the MVC signals pre- and post-protocol, although no systematic trend was demonstrable. The overall mean between electrode variation in the normalised signal measured at the peak of the cycle ranged from 48-71% when normalised to pre-protocol MVC, but only 4-13% when normalised to the peak voltage and 9-17% using the whole-cycle mean voltage. However the pattern of activation within the movement cycle, which was preserved by normalisation using the peak or mean signal, was consistent between different electrode positions. It was concluded that the EMG signal depended on electrode position even when near the recognised insertion point, and that the MVC signal is highly variable in magnitude between electrodes and between pre- and post-protocol measurements.

The management of facial injuries in rugby union.

BACKGROUND: There are as yet no guidelines in rugby union for the management of facial lacerations which account for one-third of total injuries sustained by players. METHOD: We devised a questionnaire to establish the current standards in rugby union clubs in England. The questionnaire covered such issues as inadequate wound cleansing, inappropriate suture material, the use of sterile suture equipment, and advice required for suture removal. RESULTS: We recommend that a dedicated medical room should be available in all clubs, the doctor should always wear gloves, and local anaesthetic and sterile suture packs and instruments should be provided.

The physiological and metabolic consequences of muscle denervation.

Fundamental metabolic changes occur in muscle following damage of the nerve supply. These changes include alterations in the enzyme activities associated with oxidative phosphorylation and glycolysis, and alteration in the metabolism of cAMP, changes in the sensitivity to insulin and other alterations of the handling of glucose and probably also an alteration in the metabolism of Ca2+ possibly resulting in a metabolic myopathy. There are also changes in the turnover of acetylcholine receptors and possibly cytoskeletal proteins such as dystrophin-related protein. The biochemical changes are paralleled by similar alterations in physiological parameters such as electromyographic measurements and structural changes such as those that occur at the endplate. Similar genes to those which are active during muscle cell development may be "switched-on" following a nerve injury. The return of these parameters to normal after reinnervation is variable and may be incomplete.

Pisotriquetral loose body. An unusual cause of wrist pain.

A loose body flicking in and out of the pisotriquetral joint was found to be the cause of intermittent wrist pain and locking in two patients. Appropriate X-rays gave the diagnosis and surgical removal provided a satisfactory cure.

Neurotrophins, neurones and peripheral nerve regeneration.

Successful peripheral nerve regeneration requires optimal conditions both in the macro-environment and micro-environment. Many methods have been used to improve the macro-environment for the regenerating nerve. However, much less is known about the micro-environment, and in particular the complex neurochemical interactions involved. Several neurotrophic factors have been shown to play an essential trophic role in the development, maintenance and regulation of neuronal function. These include nerve growth factor (NGF) and several recently identified members of the NGF family, namely brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5) and neurotrophin-6 (NT-6). In this review we summarize recent studies of the effects of these neurotrophins on neurones, especially their effects on motor neurones and their axonal outgrowth. We discuss prospects for the future and point out what remains to be understood about the role of neurotrophins to enhance peripheral nerve regeneration.

Denervation of the rabbit hind limb studied by 31-phosphorus magnetic resonance spectroscopy.

An animal model of muscle denervation was examined by 31P. magnetic resonance spectroscopy. The experiments demonstrated that there is a significant alteration in high and low energy phosphate metabolites in rabbit muscle after nerve section. The data show that there is an early change in the metabolites which appears to plateau at about six weeks. High resolution spectra of muscle cell extracts demonstrate qualitative alterations in the phosphate resonances found in the phosphodiester and phosphomonoester regions of the spectra. There would seem to be a time-related alteration in these components.

Human muscle cell denervation: the results of a 31-phosphorus magnetic resonance spectroscopy study.

The results presented here demonstrate that there is a major abnormality of high and low energy phosphate metabolism in muscle following peripheral nerve damage. Using 31-phosphorus magnetic resonance spectroscopy the changes in phosphocreatine, adenosine triphosphate, inorganic phosphate and metabolites of membrane metabolism could be observed in vivo in human subjects. The data indicate that there may be a metabolic myopathy in the muscle cells after nerve injury. Further, the metabolic changes did not always return to the control level, indicating a persistence of the abnormality. This failure of the metabolic function of the cells may be important in determining the ultimate outcome of peripheral nerve surgery.

Heparin induced thrombosis: an important complication of heparin prophylaxis for thromboembolic disease in surgery.

Heparin induced thrombocytopenia with thrombosis, or the "white clot syndrome," is a rare but recognised complication of heparin therapy. The syndrome is idiosyncratic, immune mediated, and not dose dependent and therefore is equally likely to occur with prophylactic and therapeutic heparin dosage regimens. Despite published reports on the subject we were alarmed that many surgeons who regularly use heparin to prevent or treat thrombosis were unaware that heparin can induce thrombotic complications in susceptible patients. We present three typical case histories, a brief discussion of the condition, and some guidelines on its prevention and treatment.

Shoulder muscle activation and fatigue during a controlled forceful hand grip task.

PURPOSE: Reliable electromyographic evaluation of the shoulder in common painful conditions is a major challenge due to a reduced range of movement and pain-related muscle inhibition. This study investigates the use of a hand grip task for the assessment of shoulder muscle activation. METHODS: Muscle activity and fatigue for supraspinatus and infraspinatus muscles were measured in 16 healthy controls using fine-wire electrodes during a controlled gripping task at 50% of maximum voluntary contraction, in a standardized sitting and arm position. Changes in muscle activity and fatigue were measured by the time-slope of root mean square amplitude and median frequency, respectively. RESULTS: A significant positive amplitude slope (p<0.01) was found for both supraspinatus and infraspinatus, indicating that the task resulted in increasing muscle activity. Judging by the median frequency slope, there was no sign of fatigue progression. CONCLUSION: A standardized hand grip task in a neutral position activates key rotator cuff muscles. This might provide a method for electromyographic assessment of shoulder girdle muscles which avoids problems due to pain-related limitation of movement, and might be useful in the development and monitoring of shoulder rehabilitation strategies.