Walter Mercer's (1891-1971) contribution to the surgical treatment of low back pain.

In 1936, Walter Mercer described a new method for the operative treatment of patients with spondylolisthesis. Using a transabdominal approach in two patients he inserted iliac crest bone graft into the intervertebral disc. His publication in the Edinburgh Medical Journal caused a furore as the levels operated on did not reflect the description and one of the two patients died post-operatively. However, Mercer continued to promote the operation in his textbooks. The anterior approach to the lumbar spine is now performed routinely. This paper explores Mercer's contribution to anterior spinal surgery.

The pathogenesis of degeneration of the intervertebral disc and emerging therapies in the management of back pain.

This article reviews the current knowledge of the intervertebral disc (IVD) and its association with low back pain (LBP). The normal IVD is a largely avascular and aneural structure with a high water content, its nutrients mainly diffusing through the end plates. IVD degeneration occurs when its cells die or become dysfunctional, notably in an acidic environment. In the process of degeneration, the IVD becomes dehydrated and vascularised, and there is an ingrowth of nerves. Although not universally the case, the altered physiology of the IVD is believed to precede or be associated with many clinical symptoms or conditions including low back and/or lower limb pain, paraesthesia, spinal stenosis and disc herniation. New treatment options have been developed in recent years. These include biological therapies and novel surgical techniques (such as total disc replacement), although many of these are still in their experimental phase. Central to developing further methods of treatment is the need for effective ways in which to assess patients and measure their outcomes. However, significant difficulties remain and it is therefore an appropriate time to be further investigating the scientific basis of and treatment of LBP.

Correlation of nerve root pain with dermatomal sensory threshold and back pain with spinal movement in single level lumbar spondylosis.

We studied 27 patients with low back pain and unilateral L5 or S1 spinal nerve root pain. Significant radiological changes were restricted to the symptomatic root level, when compared with controls. Low back and leg pain were graded on a visual analogue scale. Dermatomal quantitative sensory tests revealed significant elevations of warm, cool and touch perception thresholds in the affected dermatome, compared with controls. These elevations correlated with root pain (warm v L5 root pain; r = 0.88, p < 0.0001), but not with back pain. Low back pain correlated with restriction of anteroposterior spinal flexion (p = 0.02), but not with leg pain. A subset of 16 patients underwent decompressive surgery with improvement of pain scores, sensory thresholds and spinal mobility. A further 14 patients with back pain, multilevel nerve root symptoms and radiological changes were also studied. The only correlation found was of low back pain with spinal movement (p < 0.002). We conclude that, in patients with single level disease, dermatomal sensory threshold elevation and restriction of spinal movement are independent correlates of sciatica and low back pain.

Methicillin-resistant Staphylococcus aureus in orthopaedic surgery.

We prospectively studied the incidence of methicillin-resistant Staphylococcus aureus (MRSA) colonisation and infection, the patterns and types of operation associated with MRSA acquisition in an orthopaedic and trauma unit in London, UK. Over the 12-month study period from January to December 2000, we found that 1.6% of the total admission was diagnosed to be either MRSA infected or colonised, with an average of three new MRSA cases detected per month. A significant proportion of patients (23%) were diagnosed within the first 48h of admission. Both hip joint surgery, especially emergency procedures for femoral neck fractures, and the presence of a wound presented higher risk of infection. The Intensive Care Unit (ICU) did not appear to be a significant source for intra-hospital dissemination among the orthopaedic patients. MRSA infection or colonisation contributed to an increased length of hospital stay; 88 days compared to 11 days on average for non-MRSA patients; 41% of the positive patients still carried MRSA on discharge. Our data show the importance of diagnosing MRSA in orthopaedic surgery and emphasises that understanding its epidemiology will be crucial to secure a decrease in the incidence of MRSA. Hand hygiene, patient screening, careful surveillance of infections and the prompt implementation of isolation policies, are essential components of control.

Antibiotic prophylaxis in surgery of the intervertebral disc. A comparison between gentamicin and cefuroxime.

Antibiotics are often administrated prophylactically in spinal procedures to reduce the risk of infection of the disc space. It is still not known which antibiotics are able to penetrate the intervertebral disc effectively. In a prospective, randomised, double-blind clinical study, we examined the penetration of the intervertebral discs of two commonly used antibiotics, cefuroxime and gentamicin. The patients, randomised into two groups, received either 1.5 g of cefuroxime or 5 mg/kg of gentamicin prophylactically two hours before their intervertebral discs were removed. A specimen of blood, from which serum antibiotic levels were determined, was obtained at the time of discectomy. Therapeutic levels of antibiotic were detectable in the intervertebral discs of the ten patients who received gentamicin. Only two of the ten patients (20%) who received cefuroxime had a quantifiable level of antibiotic in their discs although therapeutic serum levels of cefuroxime were found in all ten patients. Our results show that cefuroxime does not diffuse into human intervertebral discs as readily as gentamicin. It is possible that the charge due to ionisable groups on the antibiotics can influence the penetration of the antibiotics. We therefore recommend the use of gentamicin in a single prophylactic dose for all spinal procedures in order to reduce the risk of discitis.

Geometrical dimensions of the lower lumbar vertebrae--analysis of data from digitised CT images.

The precise dimensions of the lumbar vertebrae and discs are critical for the production of appropriate spinal implants. Unfortunately, existing databases of vertebral and intervertebral dimensions are limited either in accuracy, study population or parameters recorded. The objective of this study is to provide a large and accurate database of lumbar spinal characteristics from 126 digitised computed tomographic (CT) images, reviewed using the Picture Archiving Communication System (PACS) coupled with its internal measuring instrumentation. These CT images were obtained from patients with low back pain attending the spinal clinic at the Hammersmith Hospitals NHS Trust. Measurements of various aspects of vertebral dimensions and geometry were recorded, including vertebral and intervertebral disc height. The results from this study indicated that the depth and width of the vertebral endplate increased from the third to the fifth lumbar vertebra. Anterior vertebral height remained the same from the third to the fifth vertebra, but the posterior vertebral height decreased. Mean disc height in the lower lumbar segments was 11.6 +/- 1.8 mm for the L3/4 disc, 11.3 +/- 2.1 mm for the L4/5, and 10.7 +/- 2.1 mm for the L5/S1 level. The average circumference of the lower endplate of the fourth lumbar vertebra was 141 mm and the average surface area was 1,492 mm2. An increasing pedicle width from a mean of 9.6 +/- 2.2 mm at L3 through to 16.2 +/- 2.8 mm at L5 was noted. A comprehensive database of vertebral and intervertebral dimensions was generated from 378 lumbar vertebrae from 126 patients measured with a precise digital technique. These results are invaluable in establishing an anthropometric model of the human lumbar spine, and provide useful data for anatomical research. In addition this is important information for the scientific planning of spinal surgery and for the design of spinal implants.

Local and systemic concentrations of tumour necrosis factor-alpha, interleukin-6 and interleukin-8 in bacterial osteomyelitis.

Osteomyelitis is a major cause of morbidity worldwide but there are few data investigating pathogenesis of infection and no investigations into local secretion of proinflammatory cytokines in patients. Tumour necrosis factor-alpha (TNF), interleukin (IL)-6 and IL-8 concentrations were measured in pus of infected bone from 30 Zambian patients with chronic osteomyelitis (principally caused by Staphylococcus aureus), in plasma, and after lipopolysaccharide stimulation of whole-blood leucocytes. Patients had reduced body mass index compared to controls (P = 0.025) and an acute-phase response. Elevated concentrations of proinflammatory cytokines were detected in bone compared to plasma (all P < 0.0002). Bone IL-8 concentrations were greater than IL-8 levels after lipopolysaccharide stimulation of whole blood (P < 0.01). In contrast, systemic and ex-vivo-stimulated concentrations of proinflammatory cytokine were similar in patients and controls, despite differences in body mass index and an acute-phase response. In summary, we observed marked local TNF, IL-6 and IL-8 secretion in established bacterial osteomyelitis without systemic cytokine release.

Nitric oxide in fracture repair. Differential localisation, expression and activity of nitric oxide synthases.

Our aim was to investigate whether nitric oxide synthase (NOS) isoforms, responsible for the generation of NO, are expressed during the healing of fractures. To localise the sites of expression compared with those in normal bone we made standardised, stabilised, unilateral tibial fractures in male Wistar rats. Immunostaining was used to determine the precise tissue localisation of the different NOS isoforms. Western blotting was used to assess expression of NOS isoform protein and L-citrulline assays for studies on NOS activity. Control tissue was obtained from both the contralateral uninjured limb and limbs of normal rats. Immunohistochemistry showed increased expression of endothelial NOS (eNOS) to be strongest in the cortical blood vessels and in osteocytes in the early phase of fracture repair. Western blot and image analysis confirmed this initial increase. Significantly elevated calcium-dependent NOS activity was observed at day 1 after fracture. Inducible NOS (iNOS) was localised principally in endosteal osteoblasts and was also seen in chondroblasts especially in the second week of fracture healing. Western blotting showed a reduction in iNOS during the early healing period. Significantly reduced calcium-independent NOS activity was also seen. No neuronal NOS was seen in either fracture or normal tissue. Increased eNOS in bone blood vessels is likely to mediate the increased blood flow recognised during fracture healing. eNOS expression in osteocytes may occur in response to changes in either mechanical or local fluid shear stress. The finding that eNOS is increased and iNOS reduced in early healing of fractures may be important in their successful repair.

Spinal motion in lumbar degenerative disc disease.

We have measured the dynamic movement of the lumbar spine in 57 patients with degenerative lumbar disc disease. Each completed a questionnaire which recorded pain and subjective signs and symptoms. From plain lateral radiographs, the subjects were graded using the criteria of Kellgren and Lawrence and those of Lane et al, which are both based on the severity of degenerative changes. Measurements of the height of the disc space and the vertebral height were obtained and expressed as a ratio. We found no relationship between the characteristics of spinal movement and the overall grading of degenerative disc disease with either system. Both were influenced (p < 0.01) by age, walking distance, severity of symptoms, drug intake and frequency of pain. The present systems for grading degenerative disc disease from plain lateral radiographs have limited application.

Tumor necrosis factor-alpha, interleukin-6, and interleukin-8 secretion and the acute-phase response in patients with bacterial and tuberculous osteomyelitis.

Osteomyelitis, or bone infection, is a major worldwide cause of morbidity. Treatment is frequently unsatisfactory, yet little is known about pathogenesis of infection. Plasma tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 concentrations were measured before and after lipopolysaccharide stimulation of whole blood from patients with bacterial and tuberculous osteomyelitis and from controls. Patients with bacterial and tuberculous osteomyelitis mounted an acute-phase response and were anemic and febrile. However, plasma IL-6 concentrations were significantly elevated in only tuberculous osteomyelitis patients (vs. controls, P < .05). IL-6 concentrations correlated with erythrocyte sedimentation rate, C-reactive protein level, and plasma albumin concentration, all acute-phase markers. There were no other correlations between cytokine concentrations and clinical data. Following ex vivo stimulation, TNF, IL-6, and IL-8 were secreted equally by patients and controls. In summary, tuberculous osteomyelitis is characterized by elevated systemic IL-6 concentrations associated with an acute-phase response. For further insight into immunopathology of osteomyelitis, studies on infected bone are required.

Aseptic loosening of total hip replacement. Macrophage expression of inducible nitric oxide synthase and cyclo-oxygenase-2, together with peroxynitrite formation, as a possible mechanism for early prosthesis failure.

Aseptic loosening is a major cause of failure of total hip arthroplasty. The adverse tissue response to prosthetic wear particles, with activation of cytokine and prostanoid production, contributes to bone loss around the implants. We have investigated the possibility that inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) are expressed in macrophages in the pseudomembrane at the bone-implant interface, thereby contributing to the periprosthetic bone resorption. We also assessed whether peroxynitrite, a nitric oxide (NO)-derived oxidant associated with cellular injury, is generated in the membrane. Enzymatic activity of iNOS was measured using the arginine-citrulline assay technique and prostaglandin E2 (PGE2), as an indicator of COX-2 activity, was measured using an enzyme immunoassay. Cellular immunoreactivity for iNOS, nitrotyrosine (a marker of peroxynitrite-induced cellular injury) and COX-2 was assessed by quantitative peroxidase immunocytochemistry while immunofluorescence methods were used for subsequent co-localisation studies with CD68+ macrophages. The presence of calcium-independent iNOS activity and PGE2 production was confirmed in the homogenised interface membrane. Immunocytochemistry showed that periprosthetic CD68+ wear-debris-laden macrophages were the most prominent cell type immunoreactive for iNOS, nitrotyrosine and COX-2. Other periprosthetic inflammatory and resident cell types were also found to immunolocalise nitrotyrosine thereby suggesting peroxynitrite-induced protein nitrosylation and cellular damage not only in NO-producing CD68+ macrophages, but also in their neighbouring cells. These data indicate that both iNOS and COX-2 are expressed by CD68+ macrophages in the interface membrane and peroxynitrite-induced cellular damage is evident in such tissue. If high-output NO and peroxynitrite generation were to cause macrophage cell death, this would result in the release of phagocytosed wear debris into the extracellular matrix. A detrimental cycle of events would then be established with further phagocytosis by newly-recruited inflammatory cells and subsequent NO, peroxynitrite and prostanoid synthesis. Since both NO and PGE2 have been implicated in the induction and maintenance of chronic inflammation with resulting loss of bone, and peroxynitrite in the pathogenesis of disease states, they may be central to the pathogenesis of aseptic loosening.

Sensory and sympathetic innervation of the vertebral endplate in patients with degenerative disc disease.

We obtained intervertebral discs with cartilage endplates and underlying cancellous bone at operation from patients with degenerative disc disease and then used immunohistochemical techniques to localise the nerves and nerve endings in the specimens. We used antibodies for the ubiquitous neuronal protein gene product 9.5 (PGP 9.5). Immunoreactivity to neuropeptide Y was used to identify autonomic nerves and calcitonin gene-related peptide (CGRP) and substance P to identify sensory nerves. Blood vessels were identified by immunoreactivity with platelet-endothelial cell-adhesion molecule (CD31; PECAM). In a control group with no known history of chronic back pain, nerve fibres immunoreactive to PGP 9.5 and neuropeptide Y were most closely related to blood vessels, with occasional substance P and CGRP immunoreactivity. In patients with severe back pain and markedly reduced disc height, proliferation of blood vessels and accompanying nerve fibres was observed in the endplate region and underlying vertebral bodies. Many of these nerves were immunoreactive to substance P or CGRP, and in addition, substance P- and CGRP-immunoreactive nociceptors were seen unrelated to blood vessels. Quantification by image analysis showed a marked increase in CGRP-containing sensory nerve fibres compared with normal control subjects. We speculate that a chemotactic response to products of disc breakdown is responsible for the proliferation of vascularity and CGRP-containing sensory nerves found in the endplate region and vertebral body adjacent to degenerate discs. The neuropeptides substance P and CGRP have potent vasodilatory as well as pain-transmitting effects. The increase in sensory nerve endings suggests increase in blood flow, perhaps as an attempt to augment the nutrition of the degenerate disc. The increase in the density of sensory nerves, and the presence of endplate cartilage defects, strongly suggest that the endplates and vertebral bodies are sources of pain; this may explain the severe pain on movement experienced by some patients with degenerative disc disease.

Once-daily ceftriaxone out-patient therapy for superficial wound infection following major orthopaedic operation.

We undertook a prospective open, non-randomised study to determine the efficacy of out-patient treatment of postoperative superficial wound infection, in patients with orthopaedic implants using single daily IM injection of ceftriaxone and to examine the cost effectiveness when compared with inpatient management. The study comprised of 25 patients who have had primary total hip or knee replacements or Dynamic Hip Screw fixation for an intertrochantric fracture. The superficial wound infections were categorised into mild, moderate and severe according to the classification described in this article and the length of administration of antibiotic varied according to the severity of infection. There were no failures in the study. It was estimated that an overall cost savings of £33.840 could be achieved. We recommend that superficial wound infection in association with major orthopaedic operations using implants can be managed with ceftriaxone as an out-patient.

A new in-vitro model to investigate antibiotic penetration of the intervertebral disc.

We have studied the ability of a range of antibiotics to penetrate intervertebral disc tissue in vitro, using a mouse disc model. Equilibrium concentrations of antibiotics incorporated into the entire disc were determined by bioassay using a microbial growth-inhibition method. Uptake was significantly higher with positively-charged aminoglycosides compared with negatively-charged penicillins and cephalosporins. Uncharged ciprofloxacin showed an intermediate degree of uptake. Our results support the hypothesis that electrostatic interaction between charged antibiotics and negatively-charged glycosaminoglycans in the disc is an important factor in antibiotic penetration, and may explain their differential uptake.

The acute vascular response to intramedullary reaming. Microsphere estimation of blood flow in the intact ovine tibia.

The tibial nutrient artery supplies 62% of cortical blood flow in the diaphysis and normal blood flow is centrifugal (Willans 1987). Intramedullary reaming destroys the nutrient artery and injures the endosteal surface of the cortex. Trueta (1974) suggested that the direction of blood flow can reverse from centrifugal to centripetal after loss of the endosteal supply. We examined this hypothesis by measuring cortical and periosteal blood flow after intramedullary reaming of the tibia in eight sheep, using 57Co radiolabelled microspheres. The unreamed contralateral tibiae served as a control group. Thirty minutes after reaming there was no significant change in cortical blood flow, but a sixfold increase in the periosteal flow. Our study confirms Trueta's hypothesis; after trauma or in other pathological states, flow can become centripetal.

Measurement of serum angiogenic factor in devascularized experimental tibial fractures.

Early recovery of the vasculature is of profound importance in healing fractures, but the exact role of the regenerating endothelium remains controversial. Serum activity of endothelial cell-stimulating angiogenesis factor (ESAF) was measured after tibial osteotomy in two groups of sheep over a period of 42 days. Each osteotomy was held in an instrumented external fixator, and in one group the musculoperiosteal vasculature was excluded from the osteotomy site. In the well-vascularized group (n = 4), ESAF activity was significantly higher 2-5 days after osteotomy, with a peak at 4 days (21.1 +/- 5.4, p < 0.05), and displayed a biphasic pattern of secretion with a second peak at 7 days (24.3 +/- 5.5). In the devascularized group (n = 4) overall activity was lower, with only a single peak occurring at 9 days (17.5 +/- 3.2). These findings were correlated with significant differences in structural properties and on histological examination. The early detection of such regional vascular responses may prove to be of significant clinical value in high-energy trauma, enabling prediction of those fractures at risk of delayed or nonunion.

[Reactivity of cortical bone capillaries. Functional TEM analysis with adrenaline, ATP and insulin]. / Zur Reagibilität von kortikalen Knochenkapillaren. Funktionelle TEM-Analyse mit Adrenalin, ATP und Insulin.

In order to study any morphological effects that vasoactive drugs might exert on cortical bone capillaries, Swiss mice received one intravenous bolus injection each of epinephrine, ATP and insulin. In one control group saline solution was injected and another was not treated. All animals were handled in the same way. A piece of the tibia diaphysis was resected and prepared for transmission electron microscopy (TEM). The lumina and the endothelia of capillaries were submitted to computerized morphometry. Some significant changes were noted: epinephrine increases both the width of the lumen and the endothelium. ATP decreases the endothelium. Insulin (hypoglycaemia?) thickens the endothelium. These finding suggest some physiological hypotheses: the epinephrine-induced widening of the lumen and the thickening of the endothelium might reflect a decreased extravasal space and oedema of cortical bone that might cause the diffusion of minerals to take longer. Intracortical perfusion pressure would then decrease and the bone perfusion rate increase. ATP might reduce the transcapillary diffusion time and increase the extravasal space in cortical bone. Apparently there are specific insulin receptors in cortical bone capillaries.

Primary knee arthroplasty for distal femoral fractures in elderly patients.

We discuss the role of primary knee arthroplasty in supracondylar and intercondylar fractures of the femur in elderly patients with reference to 13 cases. This method of treatment is shown to be effective and to have good results. It is recommended for all type C and some type A supracondylar fractures in old people.