Atypical femoral fractures and bisphosphonate treatment: experience in two large United Kingdom teaching hospitals.

We performed a retrospective review of all patients admitted to two large University Hospitals in the United Kingdom over a 24-month period from January 2008 to January 2010 to identify the incidence of atypical subtrochanteric and femoral shaft fractures and their relationship to bisphosphonate treatment. Of the 3515 patients with a fracture of the proximal femur, 156 fractures were in the subtrochanteric region. There were 251 femoral shaft fractures. The atypical fracture pattern was seen in 27 patients (7%) with 29 femoral shaft or subtrochanteric fractures. A total of 22 patients with 24 atypical fractures were receiving bisphosphonate treatment at the time of fracture. Prodromal pain was present in nine patients (11 fractures); 11 (50%) of the patients on bisphosphonates suffered 12 spontaneous fractures, and healing of these fractures was delayed in a number of patients. This large dual-centre review has established the incidence of atypical femoral fractures at 7% of the study population, 81% of whom had been on bisphosphonate treatment for a mean of 4.6 years (0.04 to 12.1). This study does not advocate any change in the use of bisphosphonates to prevent fragility fractures but attempts to raise awareness of this possible problem so symptomatic patients will be appropriately investigated. However, more work is required to identify the true extent of this new and possibly increasing problem.

Pedestrian head translation, rotation and impact velocity: the influence of vehicle speed, pedestrian speed and pedestrian gait.

In road traffic collisions, pedestrian injuries and fatalities account for approximately 11% and 20% of casualties in the USA and the EU, respectively. In many less motorised countries, the majority of victims are pedestrians. The significant influences of vehicle speed, pedestrian speed and pedestrian gait on pedestrian post-impact kinematics have been qualitatively noted in the literature, but there has been no quantitative approach to this problem. In this paper, the MADYMO MultiBody (MB) pedestrian model is used to analyse the influences of vehicle speed, pedestrian speed and pedestrian gait on the transverse translation of the pedestrian's head, head rotation about the vertical head axis and head impact velocity. Transverse translation has implications for injury severity because of variations in local vehicle stiffness. Head rotation is related to pedestrian stance at impact, which is known to affect the kinematics of a collision. Increased head impact velocity results in greater head injury severity. The results show that transverse translation of the head relative to the primary contact location of the pedestrian on the vehicle decreases with increasing vehicle speed and increases linearly with increasing pedestrian speed. Head rotation decreases with increasing vehicle speed and increases linearly with increasing pedestrian speed, but these variations are small. The range of head rotation values decreases with increasing vehicle speed. Head impact velocity increases linearly with vehicle speed and is largely independent of pedestrian speed. Transverse translation, head rotation and head impact velocity all vary cyclically with gait in clearly definable patterns.

Previously undiagnosed aortic stenosis revealed by auscultation in the hip fracture population--echocardiographic findings, management and outcome.

The 2001 Report of the National Confidential Enquiry into Perioperative Deaths recommended that an echocardiogram should be performed on patients with aortic stenosis prior to anaesthesia. In this study we present the patient details, management and outcome of the 272 hip fracture patients with a previously undiagnosed murmur and echocardiographically proven aortic stenosis admitted from 2001-2005 in our hospital. The patients with aortic stenosis were significantly older, and had significantly lower Abbreviated Mental Test Scores, than the control group of 3698 hip fracture patients without aortic stenosis. There were significant trends toward general anaesthesia over spinal anaesthesia, and use of invasive monitoring of blood pressure, as the severity of the aortic stenosis increased. There were no significant trends towards higher 30-day or 1-year mortality rates as the severity of the aortic stenosis increased. Resources for rapid pre-operative echocardiograms should be made available for hip fracture patients as the results have significant implications for their subsequent anaesthetic management.

Outcome following proximal femoral fracture in Northern Ireland.

OBJECTIVE: To study the outcome following treatment for proximal femoral fracture in elderly people. METHODS: All consecutive males and females admitted to the acute fracture service at the Royal Victoria Hospital and the Belfast City Hospital for the 3 years from 1999 to 2001 were studied. The data was collected by trained research nurses. Variables gathered included age, sex, marital status, mental state, pre-injury Barthel score and the American Society of Anaesthesiology (ASA) physical status grading. The information was gathered on admission to hospital and at four, six and 12 months after the injury. RESULTS: The total number of patients studied between January 1999 to December 2001 was 2834 of whom 77% were female and 23% were male. The mean (median) length of stay in the acute fracture service was 10.7 (9 days). The mean (median) length of stay in the rehabilitation ward was 35.3 (24 days). The 30-day mortality was 6.9%, the four-month mortality 15.6 % and one year mortality 22.3 %. Of those subjects living at home at the time of fracture 68% remained at home at one year. Factors predicting successful return home were higher mental test score, younger age, female sex, higher Barthel score, better pre-injury mobility and better ASA score. Of those able to walk independently outdoors before injury 40% regained this ability by 12 months. Factors predicting return of pre-injury mobility were poorer pre-injury mobility, younger age, higher mental test score, better ASA category, higher Barthel score, and previous residence at home. The proportion admitted from their own home and discharged by 56 days was 56%. CONCLUSION: The standardised measurement of outcome in hip fracture subjects enables comparison between units and facilitates improvement in standards of care available to the increasing number of elderly patients presenting with proximal femoral fracture.

Electrophysiological properties of sodium current subtypes in small cells from adult rat dorsal root ganglia.

1. Whole-cell and single-channel Na+ currents were recorded from small (ca. 20 micron diameter) cells isolated from adult rat dorsal root ganglia (DRG). Currents were classified by their sensitivity to 0.3 microM tetrodotoxin (TTX), electrophysiological properties and single-channel amplitude. Cells were classified according to the types of current recorded from them. 2. Type A cells expressed essentially pure TTX-sensitive (TTX-S) currents. Availability experiments with prepulse durations between 50 ms and 1 s gave a half-available voltage (Vh) of around -65 mV but the availability curves often had a complex shape, consistent with multiple inactivation processes. Measured inactivation time constants ranged from less than 1 ms to over 100 s, depending on the protocol used. 3. Cell types B and C each had, in addition to TTX-S currents, substantial and different TTX-resistant (TTX-R) currents that we have designated TTX-R1 and TTX-R2, respectively. TTX-R1 currents had a 1 s Vh of -29 mV, showed little 1 Hz use dependence at -67 mV and recovered from the inactivation induced by a 60 ms depolarizing pulse with time constants of 1.6 ms (91 %) and 908 ms. They also exhibited slow inactivation processes with component time constants around 10 and 100 s. TTX-R2 currents activated and inactivated at more negative potentials (1 s Vh = -46 mV), showed substantial 1 Hz use dependence and had inactivation (60 ms pulse) recovery time constants at -67 mV of 3.3 ms (58 %) and 902 ms. 4. Type D cells had little or no current in 0.3 microM TTX at a holding potential of -67 mV. Current amplitude increased on changing the holding potential to -107 mV. Type D cell currents had more hyperpolarized availability and I-V curves than even TTX-R2 currents and suggest the existence of TTX-R3 channels. 5. In outside-out patches with 250 mM external NaCl, the single-channel conductance (gamma) of TTX-S channels was 19.5 pS and the potential for half-maximal activation (Va) was -45 mV. One population of TTX-R channels had a gamma of 9.2 pS and a Va of -27 mV. A second population had a gamma of 16.5 pS and a more negative Va of -42 mV. The latter population may underlie the type D cell current. 6. Small DRG cells express multiple Na+ currents with varied time constants and voltage dependences of activation and inactivation. Nociceptive cells still fire when chronically depolarized by an increased external K+ concentration. TTX-R1 and TTX-R2 Na+ channels may support that firing, while the range of inactivation time constants described here would increase the repertoire of DRG cell burst firing behaviour generally.

Influence of outer pore residue K533 on the inhibition of Kv1.4 potassium channels by n-alkyl sulphate anions.

We have previously shown that although n-octyl sulphate (OS-) and n-dodecyl sulphate (DDS-) anions had similar effects on the kinetics and activation voltage dependence of RCK1 (Kv1.1), RCK4 (Kv1.4) and Shaker B channels expressed in Xenopus oocytes, both compounds produced a large decrease in the maximum conductance of RCK4 channels while significantly increasing the conductance of RCK1 and Shaker B. We suggested that this channel-specific inhibition might depend on the nature of the amino-acid residue corresponding to position 533 in RCK4. We now present data on the effects of n-alkyl sulphates on an RCK4 mutant in which the wild-type lysine at position 533 was changed to the corresponding tyrosine residue in RCK1. At a concentration of 15 microM, DDS- caused a 48% reduction in the wild-type current at 50 mV but a 32% increase in the mutant current. n-Hexyl sulphate and OS- had similar differential effects. The activation and inactivation kinetics of the mutant current were still accelerated by n-alkyl sulphates and 15 microM DDS- moved the conductance/voltage curves of both wild-type and mutant channels some 24 mV in the hyperpolarizing direction. The K533Y mutation thus had a selective effect on current inhibition by n-alkyl sulphates.

Local anaesthetic effects on tetrodotoxin-resistant Na+ currents in rat dorsal root ganglion neurones.

Besides the fast tetrodotoxin-sensitive Na+ current, small dorsal root ganglion neurones of rats also possess a slower tetrodotoxin-resistant Na+ current. The blocking effect of commonly used local anaesthetics upon the tetrodotoxin-resistant Na+ current was investigated in the present paper. Dorsal root ganglia were dissected from adult rats and cells were enzymatically isolated. The whole-cell patch clamp technique was then used to measure inward Na+ currents of small dorsal root ganglion neurones. Externally applied local anaesthetics reversibly blocked the tetrodotoxin-resistant Na+ current in a dose-dependent manner. Half-maximal blocking concentrations for tonic block were: lignocaine, 326 microM; prilocaine, 253 microM; mepivacaine, 166 microM; etidocaine, 196 microM bupivacaine, 57 microM procaine, 518 microM benzocaine, 489 microM; tetracaine, 21 microM; and dibucaine, 23 microM. Blocking of the current by lignocaine was independent of temperature. The quaternary lignocaine derivative OX-314 did not have any effect upon the tetrodotoxin-resistant Na+ current when applied externally. High concentrations of tetrodotoxin also blocked the tetrodotoxin-resistant Na+ current with a half-maximal blocking concentration of 115 microM. The block by high tetrodotoxin concentrations did not compete with the lignocaine block, suggesting that there were two independent blocking mechanisms for the two substances. The tetrodotoxin-resistant Na+ currents also showed a marked sensitivity to phasic (use-dependent) block by local anaesthetics.

Open channel block and open channel destabilization: contrasting effects of phenol, TEA+ and local anaesthetics on Kv1.1 K+ channels.

(1) Voltage-gated K+ channels are inhibited by a variety of clinical and experimental drugs. (2) Complex changes in channel gating suggest mechanisms in which drug affinity depends on channel state. (3) Here, we use the effects of external TEA+, two local anaesthetics (lidocaine and bupivacaine), and phenol on rat brain Kv1.1 K+ channels expressed in Xenopus oocytes to illustrate three mechanisms. (4) The open state has the highest affinity in the local anaesthetic model but the lowest in the phenol model, and while local anaesthetics simply block the open channel, phenol can produce a conducting but destabilized open state. (5) All states have equal affinity for external TEA+.

A beginner's guide to computer simulation of voltage-gated ion conductances.

This article provides a simple introduction to the simulation of voltage-dependent ion conductances in both macroscopic and single-channel modes. Only Markovian (time-independent) systems are considered. The programmes listed are written in Microsoft QBasic or QuickBASIC but versions in other languages are available. The Hodgkin-Huxley Na+ current is used as a starting system for which an explicit macroscopic solution may be obtained and compared with the results of numerical simulations employing 4th order Runge-Kutta integration. Non-Hodgkin-Huxley behaviour such as voltage-independent inactivation and double exponential current decay are discussed and simulated. A stochastic programme is used to simulate single channel behaviour. The problems and methodologies involved in fitting experimental data using complex kinetic schemes are briefly discussed, as are alternative sources of simulation software.

Channel-specific effects of n-alkyl sulphate anions on three shaker-related potassium channels expressed in Xenopus oocytes.

n-Alkyl sulphate anions have been shown to reversibly affect the functioning of voltage-gated ion channels in a variety of preparations. They are suggested to exert their effects by increasing the magnitude of the negative surface potential at the external face of the membrane. Here we report the effects of n-octyl sulphate (OS-) and n-dodecyl sulphate (DDS-) on RCK1 (Kv1.1), RCK4 (Kv1.4) and Shaker B potassium channels exogenously expressed in Xenopus oocytes. Both OS- and DDS- produced a hyperpolarising shift in the activation voltage dependence of all three channels, consistent with an increased negative external surface potential. Similar kinetic changes were also observed, the kinetics of both activation and inactivation being accelerated in the presence of OS- and DDS-. However, we also found that while 10 mM OS- and 50 microM DDS- significantly increased the maximum conductance of RCK1 and Shaker B channels, 5 mM OS- and 15 microM DDS- produced a large decrease in RCK4 conductance; the possible involvement of RCK4 residue K533 in this effect is discussed. Our data indicate that n-alkyl sulphate anions can perturb ion channel function in a variety of ways and that their effects are complex and channel specific.

Slow Na+ channel inactivation and bursting discharge in a simple model axon: implications for neuropathic pain.

Neuropathic pain may result from sustained firing of sensory neurones. The questions are what initiates and what stops that firing? Spontaneous firing of a modified Hodgkin-Huxley model axon is induced here by: (1) a depolarizing shift in the K+ channel activation parameter; and (2) a positive change in the K+ equilibrium potential. The duration and pattern of spontaneous discharge is seen to be critically dependent on the level and kinetics of Na+ channel slow inactivation. Slow inactivation of voltage-gated ion channels could be major factors in the induction and treatment of neuropathic pain.

Phenytoin and carbamazepine: differential inhibition of sodium currents in small cells from adult rat dorsal root ganglia.

We determined the effects of carbamazepine and phenytoin, anticonvulsant drugs used to treat neuropathic pain, on the heterogeneous population of Na+ channels in patch-clamped small cells from adult rat dorsal root ganglia. Both fast tetrodotoxin-sensitive (TTX-S) and slow TTX-resistant (TTX-R) currents were inhibited by 10-100 microM drug. TTX-R currents were divided into two classes. Control type I currents had a very depolarized voltage for 50% availability (Vh) of ca. -29 mV and 17% reduction in current by the 20th pulse at 1 Hz. Control type II currents had a Vh closer to -46 mV and 49% reduction in current at 1 Hz. At 0.1 Hz, which gave relatively little loss of control current, 100 microM drug caused 53 +/- 4% (n = 5) block of type I current and 88 +/- 2% inhibition of type II current (n = 4). Strong 1 s hyperpolarizing prepulses relieved most of the fast channel block but had much less effect on blocked TTX-R channels.

Voltage-dependent inhibition of RCK1 K+ channels by phenol, p-cresol, and benzyl alcohol.

Phenol has various medical applications but can cause convulsions and cardiac arrhythmia suggestive of K+ channel block. We examined phenol inhibition of the delayed-rectifier RCK1 (Kv1.1) K+ channel cloned from rat brain and expressed in Xenopus laevis oocytes. Phenol (2.5 mM) caused a 43 +/- 5 mV depolarizing shift in the RCK1 half-activation voltage (Vg) but only a 10 +/- 3% decrease in the peak conductance at 80 mV. The 10-90% rise time was slightly increased, but this was not simply the result of the activation shift. By contrast, deactivation kinetics at -40 mV were greatly accelerated. The importance of the phenolic hydroxyl group was assessed by comparing the effects of p-cresol (a phenol) and its structural isomer benzyl alcohol (an aryl alcohol). p-Cresol (1.5 mM) produced a 53 +/- 2 mV depolarizing shift in Vg, but benzyl alcohol was much less effective--20 mM caused a depolarizing shift of only 23 +/- 1 mV. Both isomers also accelerated channel deactivation. Phenol and p-cresol are better hydrogen bond donors than acceptors, whereas benzyl alcohol is a better acceptor than donor. A hydrogen bond between the phenolic hydroxyl and a presently unknown acceptor group may therefore underlie some aspects of K+ channel inhibition. Depolarizing shifts in Vg and accelerated tail kinetics are consistent with 1) preferential phenol binding to resting channels, causing the shift in Vg, and 2) a conducting phenol-bound open state with faster deactivation kinetics than the unbound open state.

Differential effects of tetrodotoxin (TTX) and high external K+ on A and C fibre compound action potential peaks in frog sciatic nerve.

Monophasic compound action potentials were recorded from Rana sciatic nerves. Three distinct peaks were observed and designated A alpha, A delta and C. All peaks were abolished by replacement of the external medium with Na(+)-free solution. However, the C peak alone was unaffected by external application of 1 microM tetrodotoxin (TTX), both A peaks were completely suppressed. The C peak was also the most resistant to chronic depolarization caused by increased external K+. K+ (17.6 mM) solution reduced peak areas to 5 +/- 4, 27 +/- 11 and 63 +/- 14% of control for A alpha, A delta and C components. The C peak was therefore Na(+)-dependent, TTX-resistant and K(+)-depolarization resistant. These attributes are similar to those described for somatal TTX-resistant Na+ channels in other species. But, application of 1 microM TTX to a K(+)-depolarized nerve caused a further reduction in C peak area, suggestive of a voltage-dependent block by TTX similar to that reported for cardiac muscle Na+ channels.

A study of the role of parvovirus B19 in rheumatoid arthritis.

Serum and synovial tissue from 26 patients with rheumatoid arthritis (RA) (according to the diagnostic criteria of the American Rheumatism Association) and 26 patients with osteoarthritis (OA) were examined. Among the RA group, the female to male ratio was 4.2:1, and the age range was 44-82 yr with a mean of 64.0 yr; joints from which synovium was sampled were hip (n = 12), knee (n = 9), ankle (n = 3) and shoulder (n = 2). The duration of rheumatoid disease ranged from 6 to 24 yr with a mean of 13.9 yr. Among the OA group, the female to male ratio was 2.25:1, and the age range was 51-88 yr with a mean of 68.2 yr; joints from which synovium was sampled were hip (n = 18) and knee (n = 8). Twenty-one patients from the RA group and 20 patients from the OA group had evidence of previous parvovirus B19 infection (serum anti-B19 IgG), and all patients from both groups were serum anti-B19 IgM negative. Synovial sections from all 52 patients were stained with mouse monoclonal antibodies, 3H8 (to B19 capsid proteins) and alpha-P (to blood group P antigen). All tissue sections examined were found to be negative for both B19 capsid proteins and blood group P antigen. Using a nested polymerase chain reaction (PCR) assay, all patients were negative for serum B19 DNA. However, B19 DNA was demonstrated in the synovium of 10 of 26 RA patients and 9 of 26 OA patients; uncorrected chi 2 value = 0.08; degrees of freedom = 1; P = 0.77. All 19 patients testing positive for synovial B19 DNA had evidence of prior exposure to B19 infection (serum anti-B19 IgG). In conclusion, although there is published evidence of chronic rheumatoid-like arthropathy following acute parvovirus B19 infection, our findings do not support the involvement of B19 in the aetiopathogenesis of RA.

Integrative effects of general anaesthetics: why nerve axons should not be ignored.

The effects of low and clinically relevant concentrations of inhalation anaesthetics and related compounds on the firing behaviour of nerve axons from a number of species are described. The observation of substantial, if sometimes transient, changes in excitability is contrasted with the view that axonal ion channels are insensitive to many general anaesthetics. Taking the squid giant axon as a well-studied example, we show that a full understanding of these effects can only be achieved through a detailed investigation of the actions of a range of compounds on a number of ion channels. Small alterations in the properties of individual channel types can in combination result in major changes in the behaviour of a multi-channel system such as an axon. Finally, as an example of the spectrum of activity of structurally related compounds, we compare the effects of inhalation anaesthetics with those of volatile convulsants.

Tibial compartment syndrome complicating closed femoral nailing: diagnosis delayed by an epidural analgesic technique--case report.

A case is described of compartment syndrome of the lower leg after closed intramedullary nailing of the tibia in which the diagnosis was delayed because an epidural analgesia technique masked the pain. The syndrome was treated by open four-compartment fasciotomy.