Orthopaedics in the developing world: present and future concerns.

Half of the world's population lack access to adequate primary health care, and two thirds lack access to orthopaedic care. Globally, the need for health care outstrips the available resources. This problem is compounded in the developing world by a lack of trained medical personnel, a lack of medical facilities, and, in many regions, an inability to access existing facilities. There is little specific epidemiologic data about the exact burden of musculoskeletal disease in these countries, but most agree that it is reasonable to assume that it will increase. In the least developed and developing nations, problems with access are related to fundamental issues such as infrastructure, physical facilities, equipment, and trained personnel. There are a number of ways in which the orthopaedic community can become involved in ameliorating the burden. Education is the most effective method of providing a sustainable solution. The objective of educational organizations should be to train local health-care workers at all levels in their own environment to provide sustainable and appropriate care so that the programs become self-sufficient and ensure a continued supply of competent medical personnel.

Selected conditions common in the developing world.

Although many esoteric diseases occur in the developing world, the majority of the orthopaedic problems encountered are similar throughout the world. Most are secondary to trauma, infection, or congenital anomalies. The geographic differences in provision of care are related to timing of treatment and available facilities. The information presented in this chapter offers examples of successful treatment regimens from many locations, each with a unique set of resources. Producing successful outcomes in such varying environments requires an understanding of the fundamental pathophysiology of the disease, innovation in the application of basic treatment principles, and adjustment of outcome expectations to seek the best possible functional result using the resources available. These resources will change as socioeconomic conditions change and will drive changes in treatment protocols. An understanding of the pathophysiology and basic treatment principles should drive innovation in these changing times.

A critical role for PU.1 in homing and long-term engraftment by hematopoietic stem cells in the bone marrow.

We have previously demonstrated that PU.1 is required for the production of lymphoid and myeloid, but not of erythroid progenitors in the fetal liver. In this study, competitive reconstitution assays show that E14.5 PU.1(-/-) hematopoietic progenitors (HPC) fail to sustain definitive/adult erythropoiesis or to contribute to the lymphoid and myeloid lineages. PU.1(-/-) HPC are unable to respond synergistically to erythropoietin plus stem cell factor and have reduced expression of c-kit, which may explain the erythroid defect. Fluorescently labeled, PU.1(-/-), AA4.1(+), fetal liver HPC were transferred into irradiated recipients, where they demonstrated a severely impaired ability to home to and colonize the bone marrow. PU.1(-/-) HPC were found to lack integrins alpha(4) (VLA-4/CD49d), alpha(5) (VLA-5/CD49e), and CD11b (alpha(M)). Collectively, this study has shown that PU.1 plays an important role in controlling migration of hematopoietic progenitors to the bone marrow and the establishment of long-term multilineage hematopoiesis.

Normal myeloid development requires both the glutamine-rich transactivation domain and the PEST region of transcription factor PU.1 but not the potent acidic transactivation domain.

Gene targeting of transcription factor PU.1 results in an early block to fetal hematopoiesis, with no detectable lymphoid or myeloid cells produced in mouse embryos. Furthermore, PU.1(-/-) embryonic stem (ES) cells fail to differentiate into Mac-1(+) and F4/80(+) macrophages in vitro. We have previously shown that a PU.1 transgene under the control of its own promoter restores the ability of PU. 1(-/-) ES cells to differentiate into macrophages. In this study, we take advantage of our PU.1(-/-) ES cell rescue system to genetically test which previously identified PU.1 functional domains are necessary for the development of mature macrophages. PU.1 functional domains include multiple N-terminal acidic and glutamine-rich transactivation domains, a PEST domain, several serine phosphorylation sites, and a C-terminal Ets DNA binding domain, all delineated and characterized by using standard biochemical and transactivational assays. By using the production of mature macrophages as a functional readout in our assay system, we have established that the glutamine-rich transactivation domain, a portion of the PEST domain, and the DNA binding domain are required for myelopoiesis. Deletion of three acidic domains, which exhibit potent transactivation potential in vitro, had no effect on the ability of PU.1 to promote macrophage development. Furthermore, mutagenesis of four independent sites of serine phosphorylation also had no effect on myelopoiesis. Collectively, our results indicate that PU.1 interacts with important regulatory proteins during macrophage development via the glutamine-rich and PEST domains. The PU.1(-/-) ES cell rescue system represents a powerful, in vitro strategy to functionally map domains of PU.1 essential for normal hematopoiesis and the generation of mature macrophages.

Role of PU.1 in hematopoiesis.

The ETS-family transcription factor PU.1 is expressed in hematopoietic tissues, with significant levels of expression in the monocytic and B lymphocytic lineages. PU.1 is identical to the Spi-1 proto-oncogene which is associated with the generation of spleen focus-forming virus-induced erythroleukemias. An extensive body of in vitro gene regulatory studies has implicated PU.1 as an important, versatile regulator of B lymphoid- and myeloid-specific genes. The first half of the review is designed to coalesce data generated from studies examining the two PU.1 "knockout" animals, which have prompted a reevaluation of the proposed function of PU.1 during hematopoiesis. During hematopoiesis, PU.1 is required for development along the lymphoid and myeloid lineages but needs to be downregulated during erythropoiesis. These unique functional characteristics of PU.1 will be exemplified by contrasting the function of PU.1 with other transcription factors required during fetal hematopoiesis. The second half of this review will reexamine the functional characteristics of PU.1 deduced from traditional biochemical and transactivation assays in light of recent experiments examining the functional behavior of PU.1 in an embryonic stem cell in vitro differentiation system. Working models of how PU.1 regulates promoter and enhancer regions in the B cell and myeloid lineage will be presented and discussed.

PU.1 functions in a cell-autonomous manner to control the differentiation of multipotential lymphoid-myeloid progenitors.

Transcription factor PU.1 is required for the development of lymphoid and myeloid progenitors during fetal hematopoiesis. By generating chimeric animals using PU.1-/- ES cells or PU.1(-/-) hematopoietic progenitors, we demonstrate that PU.1 functions in an exclusively cell-autonomous manner to regulate the development of the lymphoid-myeloid system. Multipotential lymphoid-myeloid progenitors (AA4.1+, Lin-) are significantly reduced in PU.1(-/-) embryos and fail to differentiate into B lymphoid or myeloid cells in vitro. These results suggest that the lymphoid and myeloid lineages develop in the fetal liver from a common hematopoietic progenitor not shared with erythrocytes and megakaryocytes. Finally, the Ikaros gene is expressed in PU.1 mutant embryos, suggesting that PU.1 and Ikaros are independently required for specification of embryonic lymphoid cell fates.

Patient education and compliance: a pharmacist's perspective.

Pharmacists are becoming more involved with patient education due to the increased emphasis being placed on primary patient care. Existing research in the area of patient education and compliance can provide pharmacists with the knowledge to enhance patient compliance. Changing noncompliant behavior can make a positive impact on patient's treatment plan. Such interventions involve the education of patients, whether it be during an outpatient consultation session or an inpatient education program. Of the five compliance theories identified in the literature, the Communication Model describes the best mechanism for pharmacists to educate their patients. During consultation sessions, essential knowledge and skills can be communicated to the patient that will maximize compliance. Monitoring medication refills is the most accessible method for pharmacists to identify noncompliant behavior. Determining patient noncompliance and making adjustments with patient education tactics will enable pharmacists to expand their professional role while improving patient outcomes.

Characterization of the Epstein-Barr virus-inducible gene encoding the human leukocyte adhesion and activation antigen BLAST-1 (CD48).

BLAST-1 (CD48) (previously referred to as BCM-1 by the Human Gene Nomenclature Committee) is an early-activation-associated membrane glycoprotein expressed on the surface of human leukocytes and induced to a high level following infection of B cells by the Epstein-Barr virus. It is a member of the immunoglobulin superfamily, mediates cell adhesion, and has significant sequence homology to two other adhesion molecules, CD2 and LFA3. Here we report the isolation and characterization of the BLAST-1 gene. The gene is at least 28.6 kb in length, is split into 4 exons, and contains a restriction fragment-length polymorphism. The overall genomic organization is consistent with other members of the immunoglobulin superfamily, in which extracellular immunoglobulinlike domains are encoded by discrete exons. Transcription is initiated at a series of major and minor sites in both normal and tumor-derived lymphoid cells. Appropriately located TATA and CCAAT box sequences were not detected. These characteristics have also been demonstrated for the recently described B-cell-specific genes B29 and CD20. The expression of these genes in B cells may involve the use of multiple promoters and novel transcription initiator-binding proteins. A 1.58-kb genomic DNA fragment, consisting of the 5'-flanking region located immediately upstream of the ATG initiation codon, was able to drive the expression of a reporter gene in an orientation-dependent and tissue-restricted manner.

Use of the uncemented bipolar endoprosthesis for the treatment of steroid-induced osteonecrosis of the hip in renal transplantation patients.

Osteonecrosis of the hip is a well known complication in renal transplantation patients who are treated with corticosteroids for immunosuppression. In a consecutive series of 10 patients with osteonecrosis of the hip, 16 primary uncemented bipolar endoprostheses were inserted between April 1984, and February 1986. The average follow-up period after surgery was 40 months, (range, 24-48 months). All patients developed osteonecrosis of their hips and were operated on within 2 years of their renal transplant. At the time of surgery, all patients were still taking corticosteroids as well as other immunosuppressants. The average age at surgery was 34.6 years (range, 21-48 years). All hips were classified as stage 3 or 4 before operation. The average Harris score at follow-up examination was 94.2 (range, 74-101), with 13 hips rated excellent, 1 hip rated good, and 1 hip rated fair. One patient's hip prosthesis was removed after 17 months secondary to a septic arthritis. This was the only major complication in this series. Pain was improved in all patients. However, postoperative limp and abductor weakness still presented a significant problem. An extensive radiographic evaluation was made on all hips. Eleven observations and measurements were made using radiographs of the pelvis and hip. Vertical subsidence was present in 33% of the hips and averaged 2.2 mm (range, 1-4 mm). No significant radiographic loosening was evident in any hip. Acetabular protrusio was evaluated in all patients, and was found to be less than 4 mm in either the superior or axial direction. Heterotopic ossification was present in 80% of hips, but resulted in loss of motion in only one hip.(ABSTRACT TRUNCATED AT 250 WORDS)

Synovial leukocytosis in infectious arthritis.

The clinical presentation of 41 adult patients with infectious arthritis has been reviewed with special emphasis on initial synovial fluid leukocytosis. Fifty percent of the patients with culture-proven joint-space infections had synovial fluid leukocyte counts below 28,000/mm3. Comparison of this investigation with previous studies of similar magnitude demonstrates a striking difference in the mean and median synovial fluid white cell counts. The population reviewed had a higher incidence of patients with potentially immunocompromising medical conditions than previous reports. Similarities between this and previous reports include predisposing conditions, the spectrum of pathogens cultured, associated clinical findings on admission, hospital course, and mortality. The data presented here document the magnitude of potential overlap between the synovial fluid leukocytosis in infected joints and in joints afflicted with other forms of inflammatory arthropathy. Three patients populations (malignant neoplasms, steroid use, and intravenous drug abuse) with positive cultures from synovial fluid aspirates but initial synovial fluid white cell counts averaging below 50,000 cells/mm3 were identified. Patients with moderate synovial fluid leukocytosis, especially those potentially immunocompromised, must be considered to have infectious arthritis unless other causes of inflammatory arthropathies are demonstrated.

Blast-1 possesses a glycosyl-phosphatidylinositol (GPI) membrane anchor, is related to LFA-3 and OX-45, and maps to chromosome 1q21-23.

Blast-1 is a human activation-associated glycoprotein expressed on the surface of leukocytes. Analysis of a translated sequence from a Blast-1 cDNA reveals a single hydrophobic sequence which could traverse the plasma membrane, but is devoid of charged residues that might represent a cytoplasmic tail. Consistent with this characteristic, Blast-1 is demonstrated here to be anchored to the cell surface through a glycosyl-phosphatidylinositol (GPI)-containing lipid. Comparison of Blast-1 to other GPI-anchored membrane proteins revealed a striking primary and secondary structure similarity with MRC OX45 and the lymphocyte function antigen LFA-3. The degree of overall amino acid sequence homology reveals that OX45 is a rat homologue of Blast-1. The greatest homology to LFA-3 occurs between their NH2-terminal Ig-like domains. Evidence is presented that demonstrates that Blast-1 and LFA-3 possess a disulfide-bonded second domain. These common characteristics demonstrate a structural and evolutionary relationship between Blast-1, OX45, LFA-3, and CD2, which in turn suggests a functional role for Blast-1 in cell-cell interactions in the immune response. The gene for Blast-1 has been localized to chromosome 1 q21-q23, indistinguishable from the CD1 cluster of Ig superfamily genes, raising the possibility that they may be linked.

Volatile hydrocarbons in the dufour's gland of the parasiteNemeritis canescens (Grav.) (Hymenoptera; ichneumonidae).

The Dufour's gland of the parasitic waspNemeritis (= Venturia) canescens (Grav.) was shown by gas chromatography and mass spectrometry to contain a mixture of C21, C23, and C25 saturated and monounsaturated hydrocarbons. The main component (62%) was (Z)-10-tricosene. The biological activity of the components is discussed.