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Biomedical subjects

R W Sanders

Publications and source records attributed to R W Sanders.

At least 19 recordsLinked to original sources
PubMed2003

Inhibiting HIV-1 entry with fusion inhibitors.

In recent years, tremendous progress has been made in understanding the HIV-1 entry process in which the viral and cellular membranes are fused, resulting in the subsequent delivery of the viral genome into the host cell. The mechanistic insight gained from these studies has led to the formulation of exciting new approaches for therapeutic intervention. One of the first and clinically most advanced drugs to emerge from this effort is the fusion inhibitor T20. T20 acts by freezing a transient structural intermediate of the HIV-1 fusion process, thus blocking an essential step in viral entry. With phase III clinical trials already well underway, the success of T20 indicates that targeting of the viral entry process will soon be an important component of antiretroviral therapy. This review addresses this rapidly developing area of HIV research, with a focus on the mechanistic role of fusion inhibitors targeted to the HIV-1 gp41 transmembrane glycoprotein. We will review the results of recent clinical trials with T20 and discuss possible mechanisms of viral escape through the evolution of drug-resistant HIV-1 variants. We will also discuss ongoing research on fusion inhibitor susceptibility testing and the development of new improved fusion inhibitors.

Clinical Trials as Topic↗
PubMed2001

Evolution of AZT resistance in HIV-1: the 41-70 intermediate that is not observed in vivo has a replication defect.

The human immunodeficiency virus type 1 (HIV-1) is notorious for its ability to evolve drug-resistance in patients treated with potent antivirals. Resistance to inhibitors of the viral reverse transcriptase (RT) enzyme is frequently mediated by a single amino acid substitution within RT. Resistance against the nucleoside analogue AZT is remarkable in that multiple amino acid changes accumulate over time to yield virus variants with high-level drug resistance. We now report that in addition to drug-resistance properties, the relative replication capacity of the virus variants affects the evolution of AZT resistance. Some of the typical AZT-resistance mutations have a negative impact on virus replication, and the 41-70 double mutant was found to represent a particularly poor virus. Furthermore, introduction of additional AZT-resistance mutations (41-70-215) leads to nearly complete restoration of virus replication. These results may explain the absence of the 41-70 double mutant in clinical samples and indicate that the evolution of AZT resistance is also influenced by virus replication parameters. Prolonged passage of the replication-impaired 41-70 virus in the absence of AZT yielded several fast-replicating variants. These revertants have compensatory changes in the RT polymerase, some of which have been observed previously in AZT-treated patients. Because we could select for these changes without drug pressure, these changes are likely to improve the RT enzyme function and the HIV-1 replication capacity.

Anti-HIV Agents↗
PubMed2001

A prospective evaluation of the clinical utility of the lower-extremity injury-severity scores.

BACKGROUND: High-energy trauma to the lower extremity presents challenges with regard to reconstruction and rehabilitation. Failed efforts at limb salvage are associated with increased patient mortality and high hospital costs. Lower-extremity injury-severity scoring systems were developed to assist the surgical team with the initial decision to amputate or salvage a limb. The purpose of the present study was to prospectively evaluate the clinical utility of five lower-extremity injury-severity scoring systems. METHODS: Five hundred and fifty-six high-energy lower-extremity injuries were prospectively evaluated with use of five injury-severity scoring systems for lower-extremity trauma designed to assist in the decision-making process for the care of patients with such injuries. Four hundred and seven limbs remained in the salvage pathway six months after the injury. The sensitivity, specificity, and area under the receiver operating characteristic curve were calculated for the Mangled Extremity Severity Score (MESS); the Limb Salvage Index (LSI); the Predictive Salvage Index (PSI); the Nerve Injury, Ischemia, Soft-Tissue Injury, Skeletal Injury, Shock, and Age of Patient Score (NISSSA); and the Hannover Fracture Scale-97 (HFS-97) for ischemic and nonischemic limbs. The scores were analyzed in two ways: including and excluding limbs that required immediate amputation. RESULTS: The analysis did not validate the clinical utility of any of the lower-extremity injury-severity scores. The high specificity of the scores in all of the patient subgroups did confirm that low scores could be used to predict limb-salvage potential. The converse, however, was not true. The low sensitivity of the indices failed to support the validity of the scores as predictors of amputation. CONCLUSIONS: Lower-extremity injury-severity scores at or above the amputation threshold should be cautiously used by a surgeon who must decide the fate of a lower extremity with a high-energy injury.

Adolescent↗
PubMed2000

The effects, risks, and guidelines for radiation use in orthopaedic surgery.

Radiation is used during orthopaedic surgery in more than 15 million studies performed yearly. The biologic effects of radiation have been shown to inhibit mitosis by producing irrepairable deoxyribonucleic acid double strand breaks or create structural changes by damaging the nucleus, thereby producing potential genetic transmissions. Although human cells are thought to be resistant to malignant change and no studies have shown toxic effects resulting from long-term exposure to low-dose radiation, risks still are assumed. To decrease all risks, radiographic units should undergo periodic calibration, surgeons should wear protective devices, increase their working distance from the x-ray beam, and limit their duration of radiation exposure by making certain that they follow the guidelines set forth by the National Council for Radiation Protection and Measurement.

Fluoroscopy↗
PubMed2000

Bohler incision: an extensile anterolateral approach to the foot and ankle.

Incisions in the foot and ankle should allow efficient surgical approaches to the anatomic structures being addressed while preventing chronic neuritic symptoms, extensive scar contractures, soft tissue ischemia or necrosis, and chronic edema. The purpose of this report is to describe the Böhler incision, an extensile approach that provides the surgeon with easy access to the anterior surface of the distal tibia, the anterior talar dome, talar neck, talonavicular, subtalar, and calcaneocuboid joints by allowing direct visualization of these areas. The incision can be extended in both directions, if needed, or it can be used at either end, produces few complications, and closes with a cosmetically acceptable scar that does not produce pressure with shoe wear.

Ankle↗
PubMed2000

Variable-loop-deleted variants of the human immunodeficiency virus type 1 envelope glycoprotein can be stabilized by an intermolecular disulfide bond between the gp120 and gp41 subunits.

We have described an oligomeric gp140 envelope glycoprotein from human immunodeficiency virus type 1 that is stabilized by an intermolecular disulfide bond between gp120 and the gp41 ectodomain, termed SOS gp140 (J. M. Binley, R. W. Sanders, B. Clas, N. Schuelke, A. Master, Y. Guo, F. Kajumo, D. J. Anselma, P. J. Maddon, W. C. Olson, and J. P. Moore, J. Virol. 74:627-643, 2000). In this protein, the protease cleavage site between gp120 and gp41 is fully utilized. Here we report the characterization of gp140 variants that have deletions in the first, second, and/or third variable loop (V1, V2, and V3 loops). The SOS disulfide bond formed efficiently in gp140s containing a single loop deletion or a combination deletion of the V1 and V2 loops. However, deletion of all three variable loops prevented formation of the SOS disulfide bond. Some variable-loop-deleted gp140s were not fully processed to their gp120 and gp41 constituents even when the furin protease was cotransfected. The exposure of the gp120-gp41 cleavage site is probably affected in these proteins, even though the disabling change is in a region of gp120 distal from the cleavage site. Antigenic characterization of the variable-loop-deleted SOS gp140 proteins revealed that deletion of the variable loops uncovers cryptic, conserved neutralization epitopes near the coreceptor-binding site on gp120. These modified, disulfide-stabilized glycoproteins might be useful as immunogens.

Amino Acid Sequence↗
PubMed2000

A recombinant human immunodeficiency virus type 1 envelope glycoprotein complex stabilized by an intermolecular disulfide bond between the gp120 and gp41 subunits is an antigenic mimic of the trimeric virion-associated structure.

The few antibodies that can potently neutralize human immunodeficiency virus type 1 (HIV-1) recognize the limited number of envelope glycoprotein epitopes exposed on infectious virions. These native envelope glycoprotein complexes comprise three gp120 subunits noncovalently and weakly associated with three gp41 moieties. The individual subunits induce neutralizing antibodies inefficiently but raise many nonneutralizing antibodies. Consequently, recombinant envelope glycoproteins do not elicit strong antiviral antibody responses, particularly against primary HIV-1 isolates. To try to develop recombinant proteins that are better antigenic mimics of the native envelope glycoprotein complex, we have introduced a disulfide bond between the C-terminal region of gp120 and the immunodominant segment of the gp41 ectodomain. The resulting gp140 protein is processed efficiently, producing a properly folded envelope glycoprotein complex. The association of gp120 with gp41 is now stabilized by the supplementary intermolecular disulfide bond, which forms with approximately 50% efficiency. The gp140 protein has antigenic properties which resemble those of the virion-associated complex. This type of gp140 protein may be worth evaluating for immunogenicity as a component of a multivalent HIV-1 vaccine.

Amino Acid Sequence↗
PubMed2000

Subtalar arthrodesis for complications of intra-articular calcaneal fractures.

Eighty six subtalar arthrodeses performed between 1985 and 1996 for complications associated with intra-articular calcaneal fractures were retrospectively evaluated. Patients were divided into three Groups: (I) 59 patients with calcaneal malunions (II) 13 patients with failed open reduction and internal fixation, and (III) eight patients undergoing open reductions and primary fusion for highly comminuted fractures. In each scenario, internal fixation was achieved with cancellous lag screws. Bone graft material consisted of either autogenous iliac crest graft, local graft obtained from the lateral wall exostectomy of the malunion, or freeze-dried cancellous allograft. Fusions in Groups II and III were performed in situ. Fusions in Group I were performed either in situ or utilizing a variety of reconstructive procedures depending upon the type of malunion encountered. Eighty three of the 86 fusion attempts were successful following the initial operations for a union rate of 96%. Fusion rates were similar regardless of the graft material used. Complications included four varus malunions, four cases of osteomyelitis, and two cases of reflex sympathetic dystrophy. A statistically significant shorter hospital stay was found for patients not undergoing iliac crest bone graft procedures. Eighty patients with at least two year follow up achieved a mean American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score of 75.0. Scores were similar for all three groups and for the various types of reconstructive procedures used. No correlation was found between postoperative talar declination angle and the AOFAS ankle-hindfoot score. Worker's compensation patients tended to have a poorer clinical outcome.

Adult↗
PubMed2000

Evaluation and treatment of high subtrochanteric femur fractures.

This retrospective study reviews the biomechanical factors and surgical approaches for the treatment of high subtrochanteric femur fractures to determine whether management should be directed toward using an intramedullary or extramedullary device. Results have demonstrated that both plates and intramedullary implants work equally well, with intramedullary implants resulting in significant decreases in surgical times and blood losses. Because intramedullary devices can now be placed through percutaneous trochanteric insertions, they have become more attractive for the management of these injuries. However, intramedullary devices may be difficult to use in fractures presenting with a trochanteric extension, and adjunctive reduction techniques are still required to obtain fracture reductions and prevent varus malunions. When deciding on which technique to use, surgeons should evaluate the fracture pattern and determine whether the implants and techniques that are familiar to them will allow good functional outcomes, high rates of unions, and low rates of complications.

Adolescent↗
PubMed1999

A biomechanical comparison of the antegrade inserted universal femoral nail with the retrograde inserted universal tibial nail for use in femoral shaft fractures.

Femoral shaft fractures with and without bony contact were simulated in cadaver specimens fixed with one of two different types of intramedullary locked nail systems; conventional antegrade nail fixation of the femur with the universal AO femoral nail or retrograde insertion in the femur with the universal tibial nail (a smaller diameter slotted nail) were utilized. Mechanical testing simulated one leg stance, and resultant deformation was measured in bending, torsion, and shortening. In stable fractures, fracture stability was similar to both devices, while in unstable fractures, the larger femoral nail was more stable. Furthermore, the simulation of single leg stance led to a coupled deformation of varus bending, axial shortening, and external rotation, which was dependent on bone geometry.

Adult↗
PubMed1999

Evolution of the human immunodeficiency virus type 1 long terminal repeat promoter by conversion of an NF-kappaB enhancer element into a GABP binding site.

Human immunodeficiency virus type 1 (HIV-1) transcription is regulated by the viral Tat protein and cellular factors, of which the concentration and activity may depend on the cell type. Viral long terminal repeat (LTR) promoter sequences are therefore optimized to suit the specific nuclear environment of the target host cell. In long-term cultures of a Tat-defective, poorly replicating HIV-1 mutant, we selected for a faster-replicating virus with a 1-nucleotide deletion in the upstream copy of two highly conserved NF-kappaB binding sites. The variant enhancer sequence demonstrated a severe loss of NF-kappaB binding in protein binding assays. Interestingly, we observed a new binding activity that is specific for the variant NF-kappaB sequence and is present in the nuclear extract of unstimulated cells that lack NF-kappaB. These results suggest that inactivation of the NF-kappaB site coincides with binding of another transcription factor. Fine mapping of the sequence requirements for binding of this factor revealed a core sequence similar to that of Ets binding sites, and supershift assays with antibodies demonstrated the involvement of the GABP transcription factor. Transient transfection experiments with LTR-chloramphenicol acetyltransferase constructs indicated that the variant LTR promoter is specifically inhibited by GABP in the absence of Tat, but this promoter was dramatically more responsive to Tat than the wild-type LTR. Introduction of this GABP site into the LAI virus yielded a specific gain of fitness in SupT1 cells, which contain little NF-kappaB protein. These results suggest that GABP potentiates Tat-mediated activation of LTR transcription and viral replication in some cell types. Conversion of an NF-kappaB into a GABP binding site is likely to have occurred also during the worldwide spread of HIV-1, as we noticed the same LTR modification in subtype E isolates from Thailand. This typical LTR promoter configuration may provide these viruses with unique biological properties.

Binding Sites↗
PubMed1997

Transolecranon fracture-dislocation of the elbow.

OBJECTIVE: To characterize the prevalence, morphology, and prognosis of anterior (transolecranon) fracture-dislocations of the elbow. DESIGN: Retrospective case series. SETTING: A consecutive series of thirteen patients from a single level-one trauma center, plus four patients from the practices of two of the senior authors. PATIENTS: Three of seventeen patients had simple, oblique fractures of the olecranon, and fourteen had complex, comminuted fractures of the proximal ulna, including fragmentation of the olecranon in seven patients, large coronoid fragments in eight patients, and segmental fractures of the ulna in six patients. Fourteen patients were male and three were female, with an average age of thirty-eight years (range, 18 to 78 years). INTERVENTION: All fractures were treated by open reduction and internal fixation. Two one-third tubular plates had to be revised to 3.5-millimeter dynamic compression plates within six weeks of the initial operation. MAIN OUTCOME MEASURE: Elbow performance rating of Broberg and Morrey. RESULTS: At an average follow-up of twenty-five months, overall outcome was rated as excellent in seven patients, good in eight, and fair in two. Mild posttraumatic arthritis was noted in only two patients. Large coronoid fragments and extensive comminution of the trochlear notch did not preclude a good result provided that stable, anatomic fixation was achieved. CONCLUSIONS: Anterior elbow dislocations occur most often as a fracture-dislocation in which the distal humerus is driven through the olecranon, thereby causing a complex, comminuted fracture of the proximal ulna. This injury is frequently confused with anterior Monteggia lesions by virtue of the readily apparent radiocapitellar dislocation. Stable restoration of the appropriate contour and dimensions of the trochlear notch of the ulna will lead to a good result in most cases.

Adolescent↗
PubMed1994

Accumulation of selenium in a model freshwater microbial food web.

The transfer of selenium between bacteria and the ciliated protozoan, Paramecium putrinum, was examined in laboratory cultures. The population growth of the ciliate was not inhibited in the presence of the highest concentrations of dissolved selenite or selenate tested (10(3) micrograms liter-1). Experiments with radioactive 75selenite or 75selenate indicated that accumulation of selenium by ciliates through time was low when feeding and metabolism were reduced by incubating at 0 degrees C. However, selenium accumulated in ciliate biomass during incubation with dissolved 75Se and bacteria at 24 degrees C and also when bacteria prelabeled with 75Se were offered as food in the absence of dissolved selenium. When 75Se-labeled bacterial food was diluted by the addition of nonradioactive bacteria, the amount of selenite and selenate in ciliates decreased over time, indicating depuration by the ciliates. In longer-term (> 5-day) fed-batch incubations with 75selenite-labeled bacteria, the selenium concentration in ciliates equilibrated at approximately 1.4 micrograms of Se g (dry weight)-1. The selenium content of ciliates was similar to that of their bacterial food on a dry-weight basis. These data indicate that selenium uptake by this ciliate occurred primarily during feeding and that biomagnification of selenium did not occur in this simple food chain.

Animals↗
PubMed1994

Intraarticular "pilon" fracture of the tibia.

Classification and treatment options for the management of tibial pilon fractures are reviewed. For comminuted and/or displaced fractures that require open reduction and internal fixation, a detailed description of the surgical technique, including indirect reduction techniques, is provided. Thirty-four pilon fractures (32 patients) treated during a period of five years (1984-1989) were reviewed. All were high-energy injuries (15 patients with multiple trauma) with Rüedi-Allgöwer Type II in 26 and Type III in eight. Eighteen (56%) were open fractures. Six fractures were treated with external fixation and the remaining 28 with open reduction and internal fixation. The patient follow-up examination period averaged 16.2 months (range, six to 38 months). Thirty (88%) fractures had united by 16 weeks (two delayed unions, one below knee amputation, and one plate breakage). In the 26 Type II fractures, functional grading found 17 excellent (65%) and six (23%) poor results. In the eight Type III fractures, there were four (50%) excellent and three (37%) poor results. Complications included one superficial pin-tract infection and two deep wound infections, both in Grade II open fractures.

Adult↗
PubMed1992

Evaluation of acetabular fractures with two- and three-dimensional CT.

The authors applied a widely used radiographic system of classifying acetabular fractures to axial computed tomographic (CT) scans and three-dimensional reconstructions in over 100 cases. In the classification system, fractures are analyzed according to the extent of involvement of two acetabular columns--the posterior and the anterior. To provide a better understanding of the CT anatomy of the acetabulum, the authors defined the boundaries of the columns on axial CT scans. They illustrated the most common fractures (posterior wall, transverse, transverse with posterior wall, and both columns) with radiographs, axial CT scans, and three-dimensional reconstructions. Axial CT scans readily demonstrated the fractures and presence of intraarticular fragments. Three-dimensional images helped in understanding the precise plane of the fracture, the degree of disruption of the articular surface, and spatial relationships of fragments. Although present three-dimensional CT is not without limitations, the authors believe that the technique is valuable and that, in their experience, it has facilitated preoperative planning.

Acetabulum↗