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Michael H. Shirley and Todd E. A. Larson, eds. Splendidly Victorian: Essays in Nineteenth-and Twentieth-Century British History in Honour of Walter L. Arnstein. Burlington, Vt.: Ashgate. 2001. Pp. x, 251. [...]

Background: The role of bone morphogenetic proteins (BMPs) in osseous repair has been demonstrated in numerous animal models. Recombinant human osteogenic protein-1 (rhOP-1 or BMP-7) has now been produced and was evaluated in a clinical trial conducted under a Food and Drug Administration approved Investigational Device Exemption to establish both the safety and efficacy of this BMP in the treatment of tibial nonunions. The study also compared the clinical and radiographic results with this osteogenic molecule and those achieved with fresh autogenous bone.Materials and Methods: One hundred and twenty-two patients (with 124 tibial nonunions) were enrolled in a controlled, prospective, randomized, partially blinded, multi-center clinical trial between February, 1992, and August, 1996, and were followed at frequent intervals over 24 months. Each patient was treated by insertion of an intramedullary rod, accompanied by rhOP-1 in a type I collagen carrier or by fresh bone autograft. Assessment criteria included the severity of pain at the fracture site, the ability to walk with full weight-bearing, the need for surgical re-treatment of the nonunion during the course of this study, plain radiographic evaluation of healing, and physician satisfaction with the clinical course. In addition, adverse events were recorded, and sera were screened for antibodies to OP-1 and type-I collagen at each outpatient visit.Results: At 9 months following the operative procedures (the primary end-point of this study), 81% of the OP-1-treated nonunions (n = 63) and 85% of those receiving autogenous bone (n = 61) were judged by clinical criteria to have been treated successfully (p = 0.524). By radiographic criteria, at this same time point, 75% of those in the OP-1-treated group and 84% of the autograft-treated patients had healed fractures (p = 0.218). These clinical results continued at similar levels of success throughout 2 years of observation, and there was no statistically significant difference in outcome between the two groups of patients at this point (p = 0.939). All patients experienced adverse events. Forty-four percent of patients in each treatment group had serious events, none of which were related to their bone grafts. More than 20% of patients treated with autografts had chronic donor site pain following the procedure.Conclusions: rhOP-1 (BMP-7), implanted with a type I collagen carrier, was a safe and effective treatment for tibial nonunions. This molecule provided clinical and radiographic results comparable with those achieved with bone autograft, without donor site morbidity. [ABSTRACT FROM AUTHOR]

In the 50 years since antimicrobial agents were first introduced, bacteria have acquired a wide variety of mechanisms which have enabled them to resist the effects of these drugs. One way of overcoming this problem is to administer an antibiotic with an agent which counteracts the mechanism of resistance to that antibiotic; an example of such an approach which has already been successfully implemented is the combination of a beta-lactam antibiotic with a beta-lactamase inhibitor. This review describes antibiotic resistance mechanisms which might lend themselves to an inhibitor approach and the potential therapeutic applications of such a strategy. [ABSTRACT FROM AUTHOR]

This paper reviews the techniques and materials (bone graft and bone graft substitutes) that currently are used to treat nonunions and bone defects. The techniques reviewed are intramedullary nailing, plating, distraction osteogenesis, and electric stimulation. Bone graft and bone graft substitutes reviewed are as follows: vascularized bone transfers; autogenous bone graft; autogenous bone marrow; dimineralized bone matrix; growth factors; calcium sulphate; calcium phosphates; and allograft. The goal of management of fractures, nonunions, and segmental bony defects, is the return of function as quickly and completely as possible. Techniques and management strategies constantly are evolving to accomplish this goal. This paper reviews the history, indications, and limitations of bone repair techniques, methods of bone grafting, and materials available as bone graft substitutes.

Hematogenous septic arthritis causes pain and effusion and begins with inoculation of the joint with bacteria from the intravascular space. The degradation of ground substance by enzymes released and activated by the acute inflammatory response, toxins and enzymes produced by the bacteria, and T lymphocytes stimulated during the delayed immune response, leads to destruction of the articular cartilage. Whether a given patient will develop a septic joint or a less severe form of infection is dependent upon characteristics of the bacterial strain and of the individual's host defenses. Management consists of systemic antibiotic therapy and decompression of the joint. Synovectomy, salicylate administration, and continuous passive motion are adjuvant therapies that have not as yet not been proved to be of benefit.

Two patients sustained severe injuries of the foot and ankle, which were managed with Boyd's amputation. A large-pin dynamic external fixator was used to obtain fusion between the calcaneus and distal tibia. Boyd's amputation preserves limb length and prevents posterior migration of the heel pad (both are disadvantages of Syme's amputation). Use of a dynamic external fixator may result in reliable and rapid consolidation of the fusion (thus overcoming the disadvantage associated with Boyd's amputation).

We performed a prospective clinical study and a cadaveric study to evaluate the morbidity associated with harvesting cancellous bone from the distal femoral metaphysis for use in the lower extremity. Thirty patients underwent harvest of distal femoral cancellous bone: 13 for acute trauma and 17 for reconstructive procedures. The distal femoral condyle is approached through a 6-cm midlateral, longitudinal incision. A small cortical window is created, bone graft is harvested, and the cortical window is replaced. All patients were kept nonweight bearing on the extremity for a minimum of 6 weeks. Patients were followed for an average of 10 months (range 3-32 months) and no patient was lost to follow-up before allowing full weight bearing. There were no donor site would or neurovascular problems and no femur fractures. A cadaveric study was also performed in which bone was harvested from the distal femur, the bone was quantified, and the knees were tested in compression (axial loading). The bone-harvested knees failed in the same load range as the contralateral control knees did. The distal femoral metaphysis has many advantages compared with the iliac crest in cases when cancellous bone is needed for the lower extremity. Harvesting distal femoral bone is associated with little morbidity if performed correctly, and if the patient remains nonweight bearing for 6 weeks.

Intracapsular fractures in the geriatric population are the result of progressive osteopenia, resulting in weakening of the bone. Minor trauma results in fracture of the weakened femoral neck. Most commonly, this process occurs in patients whose osteopenia is secondary to senile osteoporosis. The fact that the femur is osteopenic means that fixation may be difficult to achieve. However, reduction is relatively easy to obtain because of the absence of communication and the minimal displacement.

A cDNA library was constructed in lambda gt11 using mRNA from 11-d-old mycelium of Agaricus bisporus. Three clones containing laccase sequence were identified using an affinity-purified anti-laccase antibody. From one of these clones, a 333 bp sequence was used to identify further cDNA clones (including one which is close to full length) and a genomic clone. The coding sequences found were of two similar but not identical versions with differences at 36 out of 520 residues of deduced amino acid sequence. The laccase genes each encode a sequence expressed as a 2.3 kb mRNA, specifying a 520 residue polypeptide including a 19 amino acid residue signal peptide that is absent from the N terminus of the mature (extracellular) protein. The coding sequence of lcc1 is interrupted by 14 short introns. The lcc1 and lcc2 genes are not allelic as they do not segregate in uninucleate spores derived from a four-spored basidium. Comparison of the deduced amino acid sequences with that of the other fungal laccases that have been cloned, and with the very similar ascorbate oxidases from higher plants shows that whilst some sequence is absolutely conserved at and around the amino acid residues involved in copper binding, the overall sequence similarities are low.

Mupirocin resistance in Staphylococcus aureus results from changes in the target enzyme, isoleucyl-tRNA synthetase (IRS). Twelve strains of S. aureus comprising four susceptible (MICs < or = 4 micrograms/ml), four intermediate level-resistant (MICs between 8 and 256 micrograms/ml), and four highly resistant (MICs > or = 512 micrograms/ml) isolates were examined for their IRS content and the presence of a gene known to encode high-level mupirocin resistance. Ion-exchange chromatography of cell extracts showed a single IRS active peak in mupirocin-susceptible strains, with 50% inhibitory concentrations (IC50s) of 0.7 to 3.0 ng of mupirocin per ml. In strains showing intermediate mupirocin resistance, similar single IRS activity peaks were observed, but these were less sensitive to inhibition, and the mupirocin IC50s for them were 19 to 43 ng/ml. Strains that were highly resistant to mupirocin displayed two distinct peaks; one was similar to that found with susceptible strains (IC50, 0.9 to 2.5 ng/ml), but an additional peak with an IC50 of 7,000 to 10,000 ng/ml was also observed. A strain cured of the plasmid encoding high-level mupirocin resistance lacked the resistant IRS peak. Restriction digests, produced by endonuclease NcoI, of total bacterial DNA isolated from the highly resistant strains hybridized with a mupirocin resistance gene probe, whereas DNA isolated from the intermediate level-resistant and susceptible strains did not. These results demonstrate that two different IRS enzymes were present in highly mupirocin-resistant S. aureus strains. In strains expressing intermediate levels of resistance, only a chromosomally encoded IRS which was inhibited less by mupirocin than IRS from fully susceptible strains was detected.

Agaricus bisporus secretes abundant laccase activity into the medium during mycelial growth. SDS-PAGE analysis of extracellular laccase protein, purified from compost extract, showed a predominant band of 65 kDa molecular mass, together with lesser amounts of smaller polypeptides. The main polypeptide was purified electrophoretically. Amino acid sequence analysis of the N-terminal region of the main polypeptide was used to specify the sequence of a 15-residue chemically synthesized peptide (N-terminal peptide). Rabbit antibodies were raised against pure laccase, electrophoretically purified main polypeptide and the synthetic N-terminal peptide. Electrophoretically purified main polypeptide antibody was further purified by affinity chromatography on laccase-CNBr-Sepharose. Western blot analysis showed that the antigenic behaviour of laccase in compost extract, culture filtrate from malt-extract culture, and the purified enzyme from both sources, differed. The patterns of bands revealed are most simply explained by generation of (proteolytically) partially cleaved enzyme molecules in the culture medium, possibly combined with differences in extent of glycosylation. [35S]Methionine incorporation and immunoprecipitation were used to follow laccase synthesis in cultures grown on malt extract. After short-term labelling, a single polypeptide of 68 kDa apparent molecular mass was immunoprecipitated from both mycelial extracts and the culture medium. When poly(A)-containing RNA from malt-extract-grown mycelium was translated in vitro in rabbit reticulocyte lysate, a single polypeptide of about 57 kDa molecular mass was immunoprecipitated, consistent with the previously measured carbohydrate content of 15% for the pure enzyme. After treatment with N-glycanase, the polypeptide showed an increase in mobility during SDS-PAGE consistent with a reduction in molecular mass of about 5 kDa, indicating about equal amounts of N- and O-linked carbohydrate. C-terminal labelling of pure laccase was attempted by transpeptidation with carboxypeptidase Y. Although some minor bands were labelled, the main polypeptide was not, indicating that the C-terminus of the enzyme may be blocked.

Twelve patients with acutely (symptomatic less than ten weeks) infected arthroplasties were treated with minimal debridement and intraarticular antibiotic, amikacin, delivered via an implantable pump. The infection was suppressed in ten cases. Intraarticular levels of amikacin were obtained in eight cases. These levels ranged from greater than 150 micrograms/ml to 1688 micrograms/ml. The systemic level of amikacin remained below 10 micrograms/ml in all but one case. Duration of hospitalization averaged 19 days. There were no significant toxic side effects to amikacin.

The orthopaedic surgeon uses screws for interfragmentary fixation, fastening soft tissue to bone, or holding plates or nails to bone. The most common function of screws is to fix bone to bone. This article reviews the design parameters and types of screws used in orthopaedic surgery.

Antibiotics can be delivered locally via an implantable pump to treat bone and joint infections. This is a completely closed system, and the pump is refilled percutaneously at intervals based on its flow rate. The use of this method is described in three specific clinical situations: (1) resistant osteomyelitis (patients with persistent infections despite previous therapy), (2) acutely infected arthroplasties (symptomatic for less than six weeks), and (3) chronically infected arthroplasties (patients infected more than six weeks). In all three clinical situations, hospitalization time was shortened, and high local and low systemic levels of antibiotic were obtained. There was only one incident of side effects to the antibiotic used. This method has been successful in obtaining long-term suppression of infection in 30 of 42 patients with resistant osteomyelitis, 30 of 37 patients with acutely infected arthroplasties, and seven of ten patients with chronically infected arthroplasties. The complication unique to this method of therapy is pump-site and catheter-site infections. This occurred in three patients with recalcitrant osteomyelitis and three patients with acutely infected arthroplasties.

A 70-year-old woman incurred a stress fracture of the radius following a fracture of the ulna. The patient had osteomalacia secondary to a Billroth II procedure. The primary reasons for the development of osteomalacia following a Billroth II procedure are: decreased transit time through the gut, which causes less Vitamin D and calcium absorption, and bypassing of the duodenum, where calcium absorption is highest. After treatment of the osteomalacia with calcium and Vitamin D, the fracture healed uneventfully. The present case report emphasizes the need to identify and treat diseases associated with fractures. Patients with severe osteomalacia and ulnar shaft fractures should have the forearm immobilized because motion at the fracture site may lead to a stress fracture of the radius.

Osteomyelitis is usually treated with wide surgical debridement and prolonged intravenous antibiotics. The advent of the implantable drug pump has led us to evaluate this therapeutic modality for the treatment of osteomyelitis. We have previously shown that amikacin retains microbiologic activity in an implantable drug pump over a six-week period when incubated at 37 degrees C. We have also demonstrated in rabbits that high local levels and low systemic levels of antibiotic can be achieved using an implantable drug pump as a delivery system and that this method can be used to sterilize infected wounds. This method was applied in the treatment of osteomyelitis in 14 patients whose duration of symptoms ranged from one month to 22 years. In 13 patients, active drainage had been present for more than six months, and all patients had undergone one or more attempts at eradication of their infection. Prior therapy included surgical debridement alone (one patient), one or more attempts at debridement and extended intravenous antibiotic therapy (13 patients), debridement and local flap procedures (four patients), and extended oral antibiotic therapy (two patients). The bones involved were the tibia (six patients), femur (four patients), and elbow, shoulder, hip, and radius (one patient each). Intra-operative cultures indicated that the infecting organism was Staphylococcus aureus alone (seven patients), S. aureus in combination with gram-negative bacteria (five patients), or gram-negative organisms alone (two patients). Debridement and pump implantation were performed in one stage. On an outpatient basis, the pumps were filled with amikacin in a concentration determined by each patient's serum level. Duration of therapy was based upon cessation of drainage and erythrocyte sedimentation rate. During therapy, serum amikacin levels ranged from less than 2.5 micrograms/ml to 8.2 micrograms/ml. The amikacin concentration in the wound drainage was always greater than the upper limits of what could be measured (greater than 55 micrograms/ml to greater than 5,000 micrograms/ml). There were no cases of ototoxicity and one case of minimal renal toxicity (posttreatment creatinine clearance of 66 ml per minute; normal equal to 70 ml per minute). Length of therapy ranged from 32 to 140 days (mean equal to 63 days). Length of hospitalization ranged from five to 52 days (mean equal to 24 days). Drainage in all patients stopped during therapy, but resumed in three patients after pump removal--in two patients, for brief periods of time, and in one patient, it continues. Twelve patients have posttreatment erythrocyte sedimentation rates less than or equal to 20 mm per hour.(ABSTRACT TRUNCATED AT 400 WORDS)

Seven patients with chronic osteomyelitis were treated by surgical debridement. Cefamandole was administered intravenously before surgery. During the debridement, cefamandole concentrations were measured in serum and necrotic bone. Although adequate levels of antibiotic were achieved in the serum, minimal or no concentration of antibiotic was found in the necrotic bone. There was only minimal penetration of cefamandole into necrotic bone.

A totally implantable drug pump was evaluated as a delivery system in the treatment of osteomyelitis. Gentamicin levels in rabbit serum and bone obtained by systemic administration are compared with levels in rabbit serum and bone obtained by local administration via an implantable drug pump. Systemic administration gave mean gentamicin bone levels ranging from less than 1 microgram/gm to 3.6 micrograms/gm, while drug pump administration gave bone levels ranging from 10.8 micrograms/gm to 64.0 micrograms/gm (micrograms = microgram, or 10(-6) gram). To evaluate the drug pump as a mode of therapy, acute staphylococcal osteomyelitis was induced in ten rabbits. Drug pumps filled with amikacin were inserted in five of the infected animals. Three of these were culture-negative at one week. One had a scant growth of Staphylococcus from the pump, and one had scant growth from the pump and the wound. Clinically, none of these five rabbits appeared infected at seven days. The remaining five rabbits were all culture-positive, with heavy growths of staphylococci from their wounds, and clinically, all appeared grossly infected at seven days. These data demonstrate that high local and low systemic levels of antibiotics can be achieved with an implantable drug pump and that this method can sterilize an infected musculoskeletal wound. Therefore, antibiotic administration via an implantable drug pump is an important potential mode of therapy in the treatment of osteomyelitis.

We measured the stability of vancomycin, amikacin, netilmicin, tobramycin, gentamicin, clindamycin, and aztreonam in an implantable drug pump. Two pumps were filled with the antibiotic being tested and were incubated at 37 degrees for 3 weeks. Samples were taken daily. At 3 weeks the pumps were disassembled and examined microscopically for signs of deterioration. If the pumps were intact, bioassays were used to quantitate the biologic activity of each daily antibiotic sample. Vancomycin degraded the pump. Amikacin, netilmicin, tobramycin, gentamicin, clindamycin, and aztreonam had no effect on the pump and maintained their biologic activity over the 3-week period.

1-O-hexadecyl-2-acetyl-sn-3-glycerophosphorylcholine (PAF) was examined as a potential mediator of aggregation induced by thrombin or high concentrations of collagen in indomethacin treated platelet rich plasma by investigating the response to collagen and thrombin of platelets previously desensitized to PAF. No reduction in the response to collagen or thrombin was observed and it was concluded that PAF was not a mediator of non-prostanoid dependent aggregation in platelets exposed to thrombin or collagen.

A case report of a patient with an isolated avulsion of the anterior tubercle of the tibia is presented. This is the origin of anterior tibiofibular ligament, and this injury is the first stage of a supination external rotation injury of the ankle. It can be easily missed and, if not treated properly, can result in an unstable ankle. The patient was not treated initially and the result was an unstable ankle.

Northern blotting is a way of detecting specific RNA sequences, homologous to a hybridization probe, within a complex RNA sample. In this procedure RNA is first separated by electrophoresis under denaturing conditions (see Chapter 1 ), followed by blotting onto a suitable filter. Specific sequences are then detected by hybridization. The RNA species are both immobilized on the filter and denatured so that when the filter is immersed in a solution containing a labeled nucleic acid probe, the probe binds to RNA of complementary base se?quence (hybridizes), specifically labeling the position on the filter that this RNA sequence has been blotted to from the gel. This defines the size of the RNA molecule complementary to the probe and can be used to compare relative amounts of the RNA species in different samples.

Twenty-one patients with osteomyelitis were treated with surgical debridement and local antibiotic therapy. Amikacin (19 patients) or netilmicin (2 patients) was delivered locally via a pump implanted subcutaneously. The outflow catheters were led from the pump subcutaneously to the infected area and placed in the defect created by the surgical debridement. The pump was refilled at intervals, on an outpatient basis. The pump was surgically removed at the conclusion of therapy. Follow-up evaluation was for 12-27 months. The duration of hospitalization was five to 52 days (mean, 23 days). The infusions were sustained for 32-140 days (mean, 63 days). Systemic levels of antibiotics were always below acceptable trough levels. Levels in the wound drainage of the 11 patients who drained after operation were always greater than the upper limit of the assay. Nephrotoxicity and ototoxicity were determined using pre- and posttherapy creatinine clearances and audiograms. Two patients exhibited minimal nephrotoxicity (creatinine clearance of 66 ml/minute and 55 ml/minute; normal, 70 ml/minute). There were no other adverse effects of the antibiotics. Sixteen patients have not drained since removal of the pumps.

Five patients with infected tibial nonunions and segmental defects were treated with the method of Ilizarov: application of circular small-wire fixator, corticotomy and bone transport to fill the segmental defect. Four of the five patients developed regenerate bone at the corticotomy distraction site. The one failure was related to a previous surgery--reamed locked nailing of the tibia. Three of the four patients with regenerate bone required open reduction and internal fixation at the nonunion site following bone transport. Superficial pin tract infections, broken wires and psychological intolerance of the frame were frequent but minor problems.