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.

Degeneration of the intervertebral disc with new approaches for treating low back pain.

This review paper discusses the process of disc degeneration and the current understanding of cellular degradation in patients who present with low back pain. The role of surgical treatment for low back pain is analysed with emphasis on the proven value of spinal fusion. The interesting and novel developments of stem cell research in the treatment of low back pain are presented with special emphasis on the importance of the cartilaginous end plate and the role of IL-1 in future treatment modalities.

Osteogenic differentiation of mouse embryonic stem cells: differential gene expression analysis by cDNA microarray and purification of osteoblasts by cadherin-11 magnetically activated cell sorting.

We have previously shown osteogenic differentiation of mouse embryonic stem (ES) cells and temporal enrichment with osteoblastic cells, by stimulation with serum-containing culture medium supplemented with beta-glycerophosphate, ascorbate, and dexamethasone. In our present study we have used similar culture conditions to further investigate osteogenic differentiation of mouse ES cells. Using reverse transcription-polymerase chain reaction (RT-PCR) we demonstrated the expression of genes associated with osteoblast differentiation including the bone matrix protein osteocalcin and the transcription factor Cbfa-1/runx2. Furthermore, results of cDNA microarray analysis, and subsequent RT-PCR analysis of differentiating ES cells after exposure to osteogenic stimuli, revealed a combination of upregulation of genes involved in osteoblast differentiation including osteopontin, HSP-47, and IGF-II coupled with downregulation of genes involved in differentiation of other phenotypes such as the neuroectoderm factor Stra-13. Finally, we have applied magnetically activated cell-sorting methods to ES cell cultures treated with osteogenic stimuli and, using an antibody to cadherin-11, have purified a subpopulation of cells with osteoblastic characteristics.

Differentiation of osteoblasts and in vitro bone formation from murine embryonic stem cells.

Pluripotent embryonic stem (ES) cells have the potential to differentiate to all fetal and adult cell types and might represent a useful cell source for tissue engineering and repair. Here we show that differentiation of ES cells toward the osteoblast lineage can be enhanced by supplementing serum-containing media with ascorbic acid, beta-glycerophosphate, and/or dexamethasone/retinoic acid or by co-culture with fetal murine osteoblasts. ES cell differentiation into osteoblasts was characterized by the formation of discrete mineralized bone nodules that consisted of 50-100 cells within an extracellular matrix of collagen-1 and osteocalcin. Dexamethasone in combination with ascorbic acid and beta-glycerophosphate induced the greatest number of bone nodules and was dependent on time of stimulation with a sevenfold increase when added to ES cultures after, but not before, 14 days. Co-culture with fetal osteoblasts also provided a potent stimulus for osteogenic differentiation inducing a fivefold increase in nodule number relative to ES cells cultured alone. These data demonstrate the application of a quantitative assay for the derivation of osteoblast lineage progenitors from pluripotent ES cells. This could be applied to obtain purified osteoblasts to analyze mechanisms of osteogenesis and for use of ES cells in skeletal tissue repair.

The role of antibiotics in preventing infections following total hip replacement.

The incidence of infection in hip replacement surgery from the MRC trial was less than 1% and it should be the aim of every centre to remain within this range. Some 50,000 total hip replacements are performed in the United Kingdom each year, and even this incidence would produce a significant number of revision arthroplasties. Perhaps the ideal combination of prophylaxis is to use an ultraclean air system together with short-course high-dose antibiotics delivered at the time of surgery. However, probably more important than anything else is the enforcement of a theatre discipline; large numbers of people should be prevented from moving around in the theatre and the theatre should remain a closed system allowing the clean air plenum ventilation to function.

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.

Motion characteristics of the lumbar spine in the normal population.

STUDY DESIGN: The present study investigated the dynamic motion characteristics of the lumbar spine in the normal population using a potentiometric analysis system. OBJECTIVES: To assess the ability of a triaxial potentiometric analysis system to measure dynamic motion in the lumbar spine, and to use this system to form a database of dynamic motion characteristics from which normal parameters of motion and the factors affecting this motion could be defined. SUMMARY OF BACKGROUND DATA: Spinal motion has been studied using a variety of different methods, the majority of which have been limited either in terms of reliability, accuracy, or invasiveness and many have been only of a static nature. There has been no previous study into the normal dynamic motion characteristics of the lumbar spine. METHODS: The accuracy of the system was determined by a series of tests against a calibrated engineering mill, and the reliability of the system was assessed on 10 subjects with repeated measurements over a 3-day period. Values of range of motion and angular velocity were obtained from 203 normal subjects during flexion and extension, lateral flexion, and rotation. RESULTS: The results of the calibration testing revealed excellent accuracy, and it was shown that the system was repeatable. Initial analysis of the results indicated that sex differences did exist with men having 58.4 degrees of flexion and women having 53.4 degrees. Age appeared to have an influence on motion, and a gradual reduction was seen with each decade (P < 0.001), with the 20-29-year age range having 59.5 degrees mean flexion, the 30-39-year group having 58.1 degrees, the 40-49-year group having 53.7 degrees, the 50-60-year group having 57.5 degrees, and the 60-70-year group having 45.9 degrees. Multiple regression techniques revealed that only a few factors are important with respect to motion and that these varied according to the characteristic being defined. CONCLUSIONS: Range of motion tended to be affected by age and sex, whereas velocity was only affected by distance moved, with occupation and body mass index having little or no influence on the motion. The factors identified could only account for a small proportion of the variation seen, suggesting that it is difficult to predict the motion characteristics with any degree of sensitivity.

Global spinal motion in subjects with lumbar spondylolysis and spondylolisthesis: does the grade or type of slip affect global spinal motion?

STUDY DESIGN: This was a prospective pilot study to investigate the global motion characteristics of the spondylolysis and spondylolisthesis populations. OBJECTIVES: The aim of this study is to determine the influence of a spondylolisthesis or a spondylolysis on global spinal motion and to establish whether this is dependent on the cause of the slip or the degree/grade of the slip. SUMMARY OF BACKGROUND DATA: The condition of spondylolisthesis has been extensively discussed in the literature with respect to its etiology and management. However, the mechanics and movement of the spine in relation to pathology and the effect of this condition on function have received scant attention. METHODS: The motion of the lumbar spine was investigated in 31 patients (19 men, 12 women, mean age 47.7 +/- 17.8 years) who were diagnosed as having either a lumbar spondylolysis or a spondylolisthesis. These patients were compared with a preexisting database of 203 normal subjects (100 men, 103 women, mean age 39.8 +/- 13.4 years). Patients were graded according to the type of spondylolisthesis or spondylolysis they had, and the extent of slip was rated using Meyerding's classification (1932) and measured directly using methods of Boxall et al (1979) and Wiltse et al (1983). RESULTS: Direct measurements of the extent of slip using Boxall et al (1979) and Wiltse et al (1983) methods were found to have no significant correlation with the resultant range of motion (ROM) or the speed of movement. This study suggests that motion parameters are influenced by the grade of slip in patients with spondylolisthesis, and the type of spondylolisthesis i.e., whether isthmic or degenerative. In the A-P flexion-extension plane, the results indicate that subjects with a defect only, i.e., a spondylolysis, and thus no slip present with a spinal hypermobility (P < 0.01). Subjects with an isthmic slip tend to be either slightly hypermobile or within the anticipated range of motion, whereas those subjects with a degenerative slip tend to be hypomobile (P < 0.05). Movements into lateral flexion were restricted in both the isthmic and degenerative spondylolisthesis patients, whereas rotation was only influenced by the level at which the defect occurred. In terms of degree of displacement, in higher grades of displacement, there was a trend towards hypermobility. CONCLUSIONS: The findings of this study suggest that the grade and type of spondylolisthesis do influence global motion parameters. This information may be useful in the clinical assessment of this patient group.

Instantaneous center of rotation and instability of the cervical spine. A clinical study.

STUDY DESIGN: This study was designed to investigate flexion and extension of the cervical spine in patients with "instability" of the cervical spine. OBJECTIVES: To establish a new method of calculating the instantaneous center of rotation (ICR) of the skull relative to the thorax and to compare the differences in the ICR between normal volunteers and patients. SUMMARY OF BACKGROUND DATA: "Instability" of the cervical spine commonly is investigated using functional radiographs, which is an unreliable method. Although the ICR was suggested as an objective parameter in measuring spinal "instability," the ICR of the skull relative to the thorax has not been studied before. METHOD: Three groups of subjects (27 normal volunteers, 28 patients with chronic cervical spondylosis, and 17 patients undergoing fusion for cervical disc degeneration) were measured with a CA-6000 system (OSI, CA). The ICR then were calculated and compared at various angles of flexion and extension. RESULTS: The horizontal component of the ICR in the preoperative group was found to have shifted anteriorly from 5 degrees to 25 degrees of flexion (P < 0.05) and at 5 degrees of extension (P < 0.05), compared with that of the healthy subjects. There also was a significant difference in the vertical component of the ICR at 15 degrees of flexion (P < 0.05). However, there were no significant differences in the horizontal and the vertical components of the ICR between the normal and nonoperative groups. CONCLUSION: The ICR in patients with "instability" of the cervical spine was found to have shifted anteriorly; the method described in this study might be useful for identifying patients who suffer from this condition.

Humoral regulation of blood flow in the vertebral endplate.

STUDY DESIGN: Blood flow in the sheep lumbar spine was measured. OBJECTIVES: The effect of vasoactive agents, noradrenaline and acetylcholine, on blood flow adjacent to the disc--bone interface was determined. SUMMARY OF BACKGROUND DATA: The main route for disc nutrition is through the vertebral endplate. Although the vascular anatomy in this region has been well described, its response to neurohumoral influences has not been quantified. METHODS: Blood flow in bone adjacent to the lumbar intervertebral discs was measured using the microsphere technique before and after infusions of noradrenaline and acetylcholine in two groups of five female sheep. Systemic arterial pressure was measured during each infusion. RESULTS: Vertebral bone blood flow was unchanged during noradrenaline infusion, but increased by 60% during acetylcholine infusion. This was associated with a significant decrease in systemic arterial pressure. CONCLUSIONS: These data are consistent with the existence of muscarinic receptors in vessels of the vertebral endplate, which suggests that the vasculature may influence disc nutrition.

The use of 99mc-EHDP as a scanning agent in the detection of metastases from osteosarcoma.

The early detection of metastatic spread in sixteen patients with osteosarcoma has been studied over a twelve month period, comparing the techniques of bone scanning and radiography. In only two patients were we able to demonstrate changes suggestive of pulmonary metastases any earlier with a 99mTc-EHDP scan than with chest radiographs and one of these resolved spontaneously. However, the bone scan did accurately delineate the extent of the primary tumour and may, therefore, be helpful in deciding the level of the amputation and the response of the patient to treatment, particularly now that chemotherapy and immunotherapy are frequently used in the management of the disease.

The extraction from the blood of phosphate compounds by canine bone.

Uptake by bone of 99mTc-labeled pyrophosphate (PPi) and ethane-1-hydroxy-1,1-diphosphonate (EHDP) involves passage through capillaries in the Haversian system, extracellular fluid space, and membrane of osteoblasts before adsorption onto available apatite surfaces. Passage through capillaries was studied by the outflow-dilution technique in a canine tibia model in mongrel dogs. 51Cr-labeled albumin (nondiffusible reference tracer), sucrose (diffusible reference tracer), PPi, and EHDP were injected into the isolated nutrient tibial artery. Blood was collected from the ipsilateral femoral vein every 15 sec for 2 min. Emax, the apparent extraction at the time of the peaks of the dilution curves, is influenced little by back diffusion; for PP, Emax (mean +/- SD) = 0.42 +/- 0.08 (N = 4); for EHDP, Emax = 0.27 +/- 0.05 (N = 10). Net extraction (apparent fractional retention by bone at 2 min) was 0.36 +/- 0.1 for PP. Emax for 85Sr chloride and 18F sodium in our laboratory is 0.69 +/- 0.11 (N = 14) and 0.70 +/- 0.008 (N = 9), respectively. Permeabilities (P) were calculated by PS = -Fs loge (1-Emax), where Fs = plasma flow and S = capillary surface; the ratio of P for EHDP to P for sucrose was 0.71 which is similar to the ratio of diffusion coefficients, 0.78. The data suggest that EHDP and probably also PPi pass through the capillaries by passive diffusion. As expected, the extraction through capillary walls for EHDP and PPi was lower than that for 85Sr and 18F because of their larger molecular size.

Complete brachial plexus lesions: a ten-year follow-up of twenty cases.

Twenty patients with complete brachial plexus lesions were reviewed approximately nine and a half years after injury. Thirteen were amputees and seven had received no surgical treatment. Amputation did not alleviate pain and a prosthesis was frequently of no greater use of the patient than the useless limb it replaced: only two of the thirteen amputees were true prosthetic users and they both had dominant limb involvement, the rest adapting easily to being one-handed. Initial treatment should therefore be conservative, with intensive rehabilitation and retraining. It is recommended that amputation should not be considered until a year after injury and only if the flail limb causes repulsion, prevents sporting activities or if the patient has difficulty in converting to the non-dominant limb. In no instance should smputation be done for relief of pain.

Phosphate compounds in bone scanning.

Bone scanning with radioactive isotopes has been used to study a wide variety of disorders. Recently certain phosphate compounds, labelled with technetium, have been used as bone scanning agents. The comparative merits of three technetium-labelled phosphate compounds currently available for bone scanning--pyrophosphate, tripolyphosphate and ethylhydroxydiphosphonate (EHDP) have been compared in rabbits. Each substance was injected into ten rabbits and blood was withdrawn at regular intervals. The animals were killed at four hours and the blood and tissue samples were assayed for radioactivity. The results show that EHDP has a more rapid blood clearance than the other two agents, with a resultant improvement in the bone to soft-tissue ratio. Of the three substances investigated technetium-labelled EHDP was the best and might allow the technique of scanning to be used on a wide scale for the general study of bone and its pathology.

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.

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.

The role of the tibial nutrient artery. Microsphere estimation of blood flow in the osteotomised canine tibia.

There has been a long-standing debate as to whether medullary or periosteal flow is the dominant vascular supply during the healing of diaphyseal fractures. We used radioactive microspheres to quantify blood flow to the canine tibia two weeks after an osteotomy. There was a significant contribution from the periosteum to the blood supply of healing cortical bone after nutrient artery ligation, with a reversal of flow from a centrifugal to a centripetal direction. Our study has confirmed the qualitative observations of Trueta (1974) regarding the significant recruitment of vessels from surrounding soft tissue during fracture healing. We have not studied the later stages of healing.

The effect of devascularisation upon early bone healing in dynamic external fixation.

We examined the effect of periosteal devascularisation upon the early healing of osteotomies of sheep tibiae held in an instrumented external fixation system with an axial stiffness of 240 N/mm. At 14 days, cortical blood flow measured by the microsphere technique was 19.3 ml/min/100g in the well-vascularised osteotomies, but only 1.7 ml/min/100g in the devascularised osteotomies, despite an increase in medullary flow (p less than 0.0005). Delay in healing of the devascularised osteotomies was suggested by an in vivo monitoring system and confirmed by post-mortem mechanical testing. We suggest that the osteogenic stimulus of dynamic external fixation is dependent on the early restoration of cortical blood flow in devascularised fractures.

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.

Recurrent dislocation of the patella. Histochemical and electromyographic evidence of primary muscle pathology.

The role of muscle function in the aetiology of recurrent dislocation of the patella has been examined. Eleven of the 12 patients we studied had joint hypermobility. Muscle biopsies from eight of nine patients treated by surgery had a predominance of abnormal Type 2C fibres, and three of six patients whose quadriceps muscles were studied by electromyography also had abnormal results. Our preliminary findings suggest that there may be a primary muscular defect in many cases of recurrent dislocation of the patella.