Hydrazinonaphthalene and azonaphthalene thrombopoietin mimics are nonpeptidyl promoters of megakaryocytopoiesis.

High-throughput screening for the induction of a luciferase reporter gene in a thrombopoietin (TPO)-responsive cell line resulted in the identification of 4-diazo-3-hydroxy-1-naphthalenesulfonic acids as TPO mimics. Modification of the core structure and adjustment of unwanted functionality resulted in the development of (5-oxo-1,5-dihydropyrazol-4-ylidene)hydrazines which exhibited efficacies equivalent to those of TPO in several cell-based assays designed to measure thrombopoietic activity. Furthermore, these compounds elicited biochemical responses in TPO-receptor-expressing cells similar to those in TPO itself, including kinase activation and protein phosphorylation. Potencies for the best compounds were high for such low molecular weight compounds (MW < 500) with EC(50) values in the region of 1-20 nM.

Sequence and analysis of chromosome 1 of the plant Arabidopsis thaliana.

The genome of the flowering plant Arabidopsis thaliana has five chromosomes. Here we report the sequence of the largest, chromosome 1, in two contigs of around 14.2 and 14.6 megabases. The contigs extend from the telomeres to the centromeric borders, regions rich in transposons, retrotransposons and repetitive elements such as the 180-base-pair repeat. The chromosome represents 25% of the genome and contains about 6,850 open reading frames, 236 transfer RNAs (tRNAs) and 12 small nuclear RNAs. There are two clusters of tRNA genes at different places on the chromosome. One consists of 27 tRNA(Pro) genes and the other contains 27 tandem repeats of tRNA(Tyr)-tRNA(Tyr)-tRNA(Ser) genes. Chromosome 1 contains about 300 gene families with clustered duplications. There are also many repeat elements, representing 8% of the sequence.

Implant salvage in infected total knee arthroplasty.

In a retrospective study of 60 infected total knee arthroplasties (TKAs), attempted implant salvage of 39 knees was performed with surgical debridement and antibiotic therapy. In seven of the 39 knees (17.9%), infection was successfully eradicated, with a mean follow-up examination of 4.1 years. In comparing knees with successful salvage to those with persistent infection, the following factors strongly correlated with successful salvage: (1) short duration of symptoms of infection (less than 2 weeks); (2) susceptible gram-positive organism (Streptococcus or Methicillin-sensitive Staphylococcus aureus); (3) absence of prolonged postoperative drainage or the development of a sinus tract; and (4) no prosthetic loosening or roentgenographic evidence of infection. Only five knees in this series satisfied all these criteria, and in each case, implant salvage with eradication of infection and maintenance of good knee function was achieved. Although a higher salvage rate was obtained with the less-constrained prostheses, an infected hinge prosthesis did not preclude successful implant salvage. No patient with a draining sinus tract (0/17), infection with a virulent organism (0/9), or earlier revision arthroplasty (0/9) had successful salvage of the infected implant. Of the 22 knees with postoperative drainage for longer than two weeks or failure of primary wound healing at the time of TKA, only two were successfully salvaged and both required a local muscle flap. Therefore, early aggressive management of persistently draining wounds after TKA is imperative. In TKA complicated by infection, implant salvage with aggressive surgical debridement and antibiotic therapy should be strongly considered, provided that these strict criteria for attempted salvage are adhered.

Stable and unstable fractures of the femoral shaft.

A retrospective review of 99 cases of stable and unstable femoral shaft fractures treated with Grosse-Kempf intramedullary fixation is presented. Despite minor complications and technical problems, the procedures resulted in union with acceptable alignment in 98% of cases. Details of the complications and technical problems are reviewed. There was no incidence of deep infection despite 16 open fractures. The two cases of nonunion were salvaged with revision internal fixation and bone grafting. Grosse-Kempf interlocking intramedullary fixation is a technically demanding procedure, but offers excellent results in the management of stable and unstable, open and closed fractures of the femoral shaft.

Prosthesis-associated pseudomembrane-induced bone resorption.

A pseudomembranous structure invariably develops at the cement-bone interface of implanted prostheses in association with aseptic loosening. The tissue has histological characteristics of a foreign body reaction presumably initiated by repetitive microtrauma-associated release of methacrylate cement and polyethylene wear debris. Explant cultures of pseudomembrane and synovial tissue derived from osteoarthritic patients undergoing revision for cemented hip implant failure have been shown to produce interleukin-1, tumour necrosis factor and prostaglandin E2, recognized mediators of bone resorption. Further, the conditioned media obtained from pseudomembrane cultures could directly effect bone resorption by inducing 45Ca release from prelabelled limb bone rudiments. Results implicate the prosthesis-associated pseudomembrane in the pathogenesis of the bone resorptive process responsible for prosthesis failure.

Polymethylmethacrylate-induced release of bone-resorbing factors.

A pseudomembranous structure that has the histological characteristics of a foreign-body-like reaction invariably develops at the bone-cement interface in the proximity of resorption of bone around aseptically loosened cemented prostheses. This study was an attempt to implicate polymethylmethacrylate in this resorptive process. Unfractionated peripheral-blood mononuclear cells (consisting of lymphocytes and monocytes) and surface-adherent cells (monocyte-enriched) were prepared from control subjects who did and did not have clinical evidence of osteoarthrosis and from patients who had osteoarthrosis and were having a revision for failure of a cemented hip or knee implant. Cells were cultured for varying periods in the presence and absence of nonpolymerized methacrylate (one to two-micrometer spherules), pulverized polymerized material, or culture chambers that were pre-coated with polymerized cement. Conditioned media that were derived from both methacrylate-stimulated cell populations were shown to contain specific bone-resorbing mediators (interleukin-1, tumor necrosis factor, or prostaglandin E2) and to directly affect bone resorption in 45Ca-labeled murine limb-bone assays.

A comparative study of indium-111 DTPA radionuclide and iothalamate meglumine roentgenographic arthrography in the evaluation of painful total hip arthroplasty.

Fifteen patients with painful total hip prostheses were referred for nuclear medicine and roentgenographic arthrography studies to exclude loosening of the acetabular and/or the femoral component. A new radioisotopic technique suitable for the evaluation of both components was developed using dual-isotope single-photon tomography with 99mtechnetium methylene diphosphonate bone imaging and indium-111 diethylenetriaminepentacetic acid arthrography. Thirteen of the 15 subjects were subsequently treated with additional surgery. The surgical findings were compared with the nuclear medicine and roentgenographic results. The overall diagnostic accuracy of both arthrographic procedures was approximately 80%, but the roentgenographic arthrogram was more sensitive and the radionuclide arthrogram was more specific.

Modulation of cartilage proteoglycan synthesis by osteoarthritic synovium.

Conditioned media derived from explant cultures of human osteoarthritic synovial tissue have been shown to contain preformed and newly synthesized factors of variable molecular weight which are capable on a concentration dependent basis of modulating cartilage proteoglycan metabolism. Anabolic inhibitory and stimulatory activity often appeared to coexist, a reversible down-regulation usually dominating in unfractionated preparations. The size of newly synthesized proteoglycan aggregates and monomers and the length of glycosaminoglycan chains produced in the presence of conditioned media were normal. The pattern of anabolic response did not necessarily correlate with the presence of catabolic inducing activity.

Ischemic necrosis of the femoral head. Treatment by core decompression.

Since 1977, we have performed twenty-one core decompressions in seventeen patients who had stage-I or II ischemic necrosis of the femoral head. The diagnosis was confirmed histologically in all but one patient. After a mean length of follow-up of thirty-nine months, healing was evident in eight hips (40 per cent) but not in the other twelve. All twelve hips required additional surgical treatment; the average length of time before the additional treatment was required was 9.2 months. The results of two intraoperative diagnostic tests (intramedullary pressure and saline stress tests) did not correlate with the results of biopsy. A perioperative fracture through the site of the decompression occurred in one of the twenty-one hips. Given the relatively poor long-term results and the considerable morbidity that was associated with core decompression, this treatment cannot be recommended.

Giant cell tumor of the metatarsal.

The following is a report of a giant cell tumor of a metatarsal, description of treatment, and review of the literature. Giant cell tumors comprise approximately 5-8% of the primary bone tumors. Metatarsal bones are a very rare primary site of involvement. Clinically aggressive or benign behavior cannot be predicted histologically. Treatment should be aggressive, as in this case where en bloc resection and bone graft were performed. Results were excellent with 4 yr follow-up.

Pain clinic #8. Patient-controlled analgesia for postoperative pain in orthopaedic patients.

Patient-controlled analgesia for pain management following orthopaedic surgery was evaluated subjectively by 22 patients and 11 nurses. Half of the patients received morphine and half received meperidine. No difference was found in the amount of drug used between groups. Although pain was never completely relieved, 91% of patients experienced only mild pain or were mildly comfortable with the technique. All patients reported a high satisfaction with patient-controlled analgesia and all nurses ranked the technique as good to excellent. Eight-six percent of patients who had previously used another type of pain management ranked patient-controlled analgesia superior.

Traumatic dislocation of the knee: a report of 30 cases and literature review.

Traumatic dislocation of the knee, an uncommon injury, is sustained as the result of violent trauma. Thirty documented cases of complete traumatic dislocation of the tibia from the femur are identified and retrospectively reviewed. Twenty had adequate documentation with a minimum two-year follow-up to evaluate the results of operative versus nonoperative treatment of this ligamentous injury. Nonoperative treatment can result in a functional knee depending on the patient's demands. However, early operative repair, followed by early limited motion (cast bracing), and aggressive physical therapy to regain motion, are recommended in young active patients. Prolonged immobilization postoperatively should be avoided.

Unstable intertrochanteric fractures of the hip.

In spite of a host of operative techniques and fixation devices, no one method of treatment has gained universal acceptance for the treatment of unstable intertrochanteric hip fractures. Although it is important to determine if a fracture is stable or unstable, stability should be considered a relative term. Degree of stability should be assessed by a careful review of the preoperative radiographs as well as postreduction films and palpation of comminution at surgery. Those fractures with minimal to moderate posteromedial comminution are probably best managed by anatomic reduction and compression hip screw fixation. The collapsing device will allow the fracture to obtain its own stability (Figure 5). However, in severely comminuted fractures the screw may slide completely prior to the stable apposition of cortical surfaces of the proximal and distal fragments. Fixation failure will result in a significant percentage of these fractures unless a stable reduction is obtained surgically. Medial displacement osteotomy, valgus osteotomy, or augmentation with cement should be considered in these high-risk fractures. Regardless of the reduction technique the proximal fragment must be aligned properly with the femoral shaft. If the major fracture fragments are prevented from reaching a stable configuration, fixation failure will likely occur (Figure 6).

Comparison of continuous epidural infusion of a local anesthetic and administration of systemic narcotics in the management of pain after total knee replacement surgery.

Continuous bupivacaine epidural analgesia was compared with conventional methods of systemic analgesic administration in the management of postoperative pain in 30 patients for 3 days following total knee replacement surgery. Patients given continuous epidural analgesia had significantly better pain relief (visual analogue scale, global evaluation), needed significantly fewer supplementary analgesics, and had significantly fewer side effects. In the epidural group, sensory block averaged six dermatomes on day 1 and four dermatomes on day 3. The number of patients with complete (or almost complete) motor block of the lower limbs decreased from eight on day 1 to five on day 3. The mean dosage of bupivacaine decreased from 21.0 +/- 5.7 (SD) mg/hr on day 1 to 15.1 +/- 8.5 mg/hr on day 3. No signs of accumulation of or toxic reactions to bupivacaine were seen.

Histologic assessment of cathepsin D in osteoarthritic cartilage.

The lysosomal endopeptidase cathepsin D is the most abundant proteinase in chondrocytes. Its significance in the pathogenesis of cartilage matrix proteoglycan (PG) degradation in osteoarthritis (OA) is unclear. The extracellular localization of cathepsin D and its potential spatial relationship to areas of PG depletion has been studied in human femoral head OA cartilage. Enzyme was identified by indirect immunofluorescence using rabbit antisera developed against a highly purified cathepsin D preparation. PG distribution was assessed in parallel sections by safranin O staining. Specimens were selected to include regions of cartilage having minimal structural and cellular alterations, severe reduction in thickness, hypocellularity, multicellular chondrocyte clusters and varying degrees of PG loss. Cathepsin D was identified in chondrocytes. When overlying fibrous connective tissue pannus was present, extracellular enzyme was predominantly localized to the cartilage-pannus interface. Cathepsin D could not be demonstrated extracellularly in areas of cartilage that were partially or totally devoid of PG. Chondrocytes in damaged regions, particularly in the superficial and upper transitional zones showing diffuse hypercellularity and/or "brood" clusters, contained increased enzyme staining. Results fail to support a role for cathepsin D in extracellular matrix PG degradation. The potential significance of this enzyme in the pathogenesis of OA would appear relegated to intracellular catabolism. Its intracellular increase at pathologic sites is consistent with enhanced catabolic activity in such regions.

Aseptic loosening in metal-backed acetabular components for total hip replacement. A minimum five-year follow-up.

We reviewed the cases of thirty-six patients who had forty cemented total hip replacements with the Harris metal-backed acetabular component. The operations were done between 1972 and 1977, and the duration of follow-up averaged 7.6 years (range, five to 10.8 years). The average age of the patients was forty-four years (range, sixteen to sixty-two years). Aseptic loosening of the acetabular component occurred in three hips (7.5 per cent), and three more sockets were revised for other reasons. Two of the three sockets with aseptic loosening were in the fifteen patients (seventeen hips) who were forty-five years old or younger. The remaining loose cup was in one of the twenty-one patients (twenty-three hips) who were forty-six years old or older. The reduction in the rate of aseptic loosening of the socket in our series, compared with the higher rates reported in similar long-term studies in which other acetabular components were used, supports the conclusion that there is enhanced longevity of acetabular fixation when a metal-backed acetabular component is used in cemented total hip arthroplasty.