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Biomedical subjects

D G Wright

Publications and source records attributed to D G Wright.

At least 19 recordsLinked to original sources
PubMed1996

Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients.

The morbidity and lethality of AL amyloidosis is caused by the deposition of lg light chains as fibrillar amyloid protein in vital organs, disrupting their function, and not by the generally low burden of clonal plasma cells that produce the paraproteins. Survival of patients with AL amyloidosis is no more than 1 to 2 years from the time of diagnosis with current management approaches. Clearly, more effective therapies are needed for this rapidly lethal disease. Five patients were treated with dose-intensive melphalan and blood stem cell support and followed for a period of 1 year. Patients were diagnosed with AL amyloidosis by tissue biopsy and categorized by performance status and organ involvement. Their plasma cell dyscrasias were evaluated with immunofixation electrophoresis of serum and urine specimens, quantitative serum lgs, and immunohistochemical staining of bone marrow biopsy specimens. After treatment with dose-intensive intravenous melphalan followed by infusion of autologous growth-factor-mobilized blood stem cells, clinical evaluations and plasma cell studies were repeated at 3 and 12 months. Three men and 2 women aged 38 to 53 years were treated. Median performance status (SWOG) was 2 (1 to 3), and clinical presentations included nephrotic syndrome (n = 1), symptomatic cardiomyopathy (n = 1), gastrointestinal involvement with polyneuropathy (n = 2), and hepatomegaly (n = 1). With a median follow-up of 13 months (12 to 17 months), all five patients are well and have shown stable or improved performance status and clinical remission of organ-related dysfunction, including a 50% reduction in daily proteinuria with no change in creatinine, reversal of symptoms of cardiomyopathy and reductions of posterior wall and septal thickening, reversal of polyneuropathy and gastric atony, and resolution of hepatomegaly by computed tomographic scan. In 3 of the 5 patients (60%) at 12 months after treatment, plasma cell dyscrasias could not be detected. Dose-intensive chemotherapy with intravenous melphalan and growth-factor-mobilized blood stem cell support is feasible therapy for patients with AL amyloidosis, even when there is clinical evidence of cardiac involvement. At least some patients with AL amyloidosis achieve complete remission of their plasma cell dyscrasia, improvement in performance status, and clinical remission of organ-specific disease after this form of treatment.

Adult↗
PubMed1996

Pelvic and bladder trauma: a case report and subject review.

Pelvic fracture and bladder rupture resulted in bladder wall entrapment in the fracture site of a patient involved in a severe motor vehicle accident. Although hematuria and bladder rupture are known to occur after fracture of the pelvis, our literature review showed no reports of this type of injury or management. Bladder extravasation was managed with catheter drainage and surgical extraction; viscus repair was performed for the bladder rupture. Fracture healing and bladder continuity resolved uneventfully.

Accidents, Traffic↗
PubMed1996

Efficiency of human HLA-mismatched CD34+ cells from unrelated donors in establishing in vitro hematopoiesis in allogeneic long-term marrow cultures.

We have examined the capacity of highly purified human CD34+ marrow cell isolates from unrelated, HLA-mismatched donors to establish in vitro hematopoiesis on recipient marrow stromal cells in 2-stage hematopoietic long-term marrow cultures (H-LTMC). HLA-typing of both peripheral blood mononuclear cells and CD34+ marrow cells was performed for both HLA class I and HLA class II antigens for eight healthy individuals. Significant antigenic mismatches for these molecules ranged from three to six antigens for each recipient-donor pair. Comparison of MHC antigen expression by peripheral blood cells and CD34+ marrow cell isolates confirmed the presence of identical HLA-A, -B, and -C, and -DR specificities on the surface of these cells. Typing of -DQ specificities, however, was not consistently reactive on CD34+ cells. The > or = 20% plating efficiency of purified CD34+ cells for BFU-E, CFU-GM, and CFU-MIX allowed us to use inoculum doses of 10(3), 10(4), and 10(5) cells to determine the efficiency of allogeneic CD34+ cells in achieving in vitro engraftment and the establishment of hematopoiesis in H-LTMC. Engraftment of adherent BFU-E, CFU-GM, and CFU-MIX was equally efficient for autologous and allogeneic CD34+ cells. In vitro hematopoiesis reflected by the cumulative recoveries of progenitor cells over time was also equivalent for allogeneic and autologous CD34+ cells. These results demonstrate that highly purified, HLA-mismatched CD34+ marrow cells proliferate and establish in vitro hematopoiesis as efficiently as autologous cells in marrow derived stromal cell cultures and confirm that interactions between stromal cells and highly purified CD34+, DR-, and CD34+, DR+ marrow cell isolates are not MHC-restricted.

Antigens, CD34↗
PubMed1995

Collection of mobilized blood progenitor cells for hematopoietic rescue by large-volume leukapheresis.

BACKGROUND: Mobilized blood progenitor cells rapidly reconstitute hematopoiesis in patients after dose-intensive chemotherapy. However, optimal timing and methods of mobilized blood progenitor cell collection have yet to be fully defined. STUDY DESIGN AND METHODS: The utility of large-volume leukapheresis (LVL; > 15 L blood processed) in collecting target doses of mononuclear cells (7 x 10(8)/kg) for use in autologous hematopoietic rescue was investigated. LVL was begun at a standardized interval (14 days) after a course of limited chemotherapy and subsequent daily recombinant human granulocyte-macrophage-colony-stimulating factor administration to mobilize blood progenitor cells into the circulation. With each LVL procedure, mononuclear cells, colony-forming units-granulocyte-macrophage (CFU-GM), burst-forming units-erythroid, mixed colonies, total clonogenic progenitor cells, and CD34+ cells collected per kg of patient weight were counted. After high-dose chemotherapy and infusion of cryopreserved mobilized blood progenitor cells, the days needed for neutrophils to reach levels of > 0.5 x 10(9) per L and for platelets to reach levels of > 20 x 10(9) per L were recorded. RESULTS: In 14 previously treated cancer patients, an average of 28.9 +/- 4.9 L of blood was processed per LVL (n = 35) to collect medians of 2.5 x 10(8) mononuclear cells per kg (range, 1.0-7.4), 14 x 10(4) CFU-GM per kg (0-208), 27 x 10(4) clonogenic progenitor cells per kg (0-370), and 2.8 x 10(6) CD34+ cells per kg (0-112.5). Fifty-seven percent of patients (8/14) required one or two LVL procedures to collect adequate blood progenitor cells (range, 1-4). After dose-intensive chemotherapy, 13 patients received medians of 6.8 x 10(8) mononuclear cells per kg (range, 5.1-9.9), 53 x 10(4) CFU-GM per kg (9-208), and 12 x 10(6) CD34+ cells per kg (3.6-112.5). Rapid hematopoietic reconstitution occurred with 10 days (range, 8-12) and 9 days (6-15), respectively, for neutrophil and platelet recoveries. CONCLUSION: Scheduled LVL, beginning on Day 14 after the administration of granulocyte-macrophage-colony-stimulating factor following chemotherapy, is a convenient and efficient method of collecting blood progenitor cells. The mononuclear cells so obtained effected consistent and rapid hematopoietic reconstitution in a highly reproducible manner in a group of heavily treated patients.

Adult↗
PubMed1995

Osteomyelitis.

The complexities of osteomyelitis make its diagnosis and treatment challenging. Current trends emphasize early diagnosis and aggressive treatment. Imaging has improved, with nuclear scans and magnetic resonance imaging, and technique modifications have enhanced the specificity of these tests. Treatment depends on thorough debridement of necrotic bone and tissue, accurate cultures and administration of culture, and sensitivity-specific antibiotics. Antibiotic delivery has expanded to include effective oral agents and local agents mixed with polymethylmethacrylate or a biodegradable substance. Success rates in treating this disease have improved with the use of a systematic approach, making outcome more predictable.

Adult↗
PubMed1995

Open dislocation of the knee.

Traumatic open dislocation of the knee is an infrequent, severe injury associated with extensive ligamentous damage and a high incidence of vascular and neurologic involvement. Eighteen patients with 19 open knee dislocations were treated at the affiliated hospitals of the University of Pennsylvania and Louisiana State University Medical Center during an 18-year period. Final results included three above-knee amputations, one knee fusion, and one total knee arthroplasty. The 14 knees salvaged had only fair to poor function according to the Hospital for Special Surgery Knee Injury Score at an average follow-up of 36 months after the injury (average score = 29, range - 17 to 37). Nine patients (47%) had concomitant neurologic or vascular injury, and eight patients (42%) had wound healing difficulties. Five complete disruptions of the popliteal artery or posterior tibial artery underwent emergent revascularization, successful in three of the extremities, with the remaining two extremities requiring above-knee amputations. These massive injuries are often limb-threatening despite prompt surgical intervention and early antibiotic therapy. There is a very high incidence of infection and neurologic injury with a guarded prognosis for limb survival and satisfactory function.

Adolescent↗
PubMed1994

Contrasting effects of recombinant human granulocyte-macrophage colony-stimulating factor (CSF) and granulocyte CSF treatment on the cycling of blood elements in childhood-onset cyclic neutropenia.

Recombinant human granulocyte colony-stimulating factor (G-CSF) treatment has been shown to increase average neutrophil counts substantially in patients with childhood-onset cyclic neutropenia (or "cyclic hematopoiesis"), but not to eliminate the cyclic oscillations of neutrophil counts or those of other blood elements (monocytes, platelets, eosinophils, and reticulocytes) that are characteristic of this hematopoietic disorder. Indeed, oscillations of neutrophil counts are amplified during G-CSF treatment. We have compared the effects of recombinant granulocyte-macrophage-CSF (GM-CSF) with those of G-CSF in three patients with this disease (2 men and 1 woman, 17, 30, and 32 years of age). These patients were treated with GM-CSF (2.1 micrograms/kg/day, subcutaneously) for 6 weeks, preceded and followed by 6 to 13 weeks of detailed observation to document changes in the cyclic oscillations of blood neutrophils and other blood elements; two of the patients were subsequently treated with G-CSF (5.0 micrograms/kg/d, subcutaneously) and observed for comparable periods of time. Unlike G-CSF treatment, which increased average neutrophil counts more than 20-fold, GM-CSF increased neutrophil counts only modestly, from 1.6- to 3.9-fold, although eosinophilia of varying prominence was induced in each patient. However, at the same time, GM-CSF treatment dampened or eliminated the multilineage oscillations of circulating blood elements (neutrophils, monocytes, platelets, and/or reticulocytes) in each of the patients. In contrast, G-CSF treatment of the same patients markedly amplified the oscillations of neutrophil counts and caused the cycling of other blood elements (monocytes in particular) to become more distinct. These findings support the conclusion that the distinctive cycling of blood cell production in childhood-onset cyclic neutropenia results from abnormalities in the coordinate regulation of both GM-CSF-responsive, multipotential progenitor cells and G-CSF-responsive, lineage-restricted, neutrophil progenitors.

Adolescent↗
PubMed1994

Characterization of influenza A virus binding sites on human neutrophils.

Exposure of human neutrophils (PMN) to influenza A virus (IAV) triggers discrete responses in these cells that interfere with their normal host defense functions. Because the restricted host range and tissue specificities of many viruses are determined by cell surface molecules acting as virus receptors on target cells, it seemed plausible that IAV might interact with neutrophils via specific plasma membrane glycoproteins that bind to viral hemagglutinin. When the binding of intact IAV (ATCC strain A/PR/8/34 (H1N1)) to PMNs was examined by flow cytometry, virus binding was found to be saturable and to be diminished after extensive desialation of the cells with neuraminidase. Stimulation of PMNs with FMLP (0.1 microM) caused a transient increase in IAV binding that was maximal (> 200%) at 2 min after stimulation. When neutrophil membrane proteins were separated by gel electrophoresis and transferred to nitrocellulose, IAV bound selectively to two polypeptide bands of approximately 125 and 160 kDa. Relative binding to these two bands was modified and ultimately eliminated by treatment of PMN membrane proteins with neuraminidase before electrophoresis and blotting. Intact virus precipitated a limited number of proteins from solubilized PMN plasma membrane preparations, and Abs specific for sialophorin (CD43) recognized virus-precipitated PMN membrane proteins of the same apparent m.w. as those detected in virus-membrane protein blots. These findings indicate that IAV binds to human PMNs through interactions with a limited number of PMN membrane glycoproteins, which include sialophorin (CD43).

Antigens, CD↗
PubMed1994

Involvement of a botulinum toxin-sensitive 22-kDa G protein in stimulated exocytosis of human neutrophils.

Studies of human peripheral blood neutrophils (PMNs) demonstrated that botulinum neurotoxin D (BT-D) ADP-ribosylates a 22-kDa PMN G protein (G22k) and inhibits the exocytosis of both specific and azurophilic granules stimulated by FMLP. Furthermore, this inhibition of PMN exocytosis by BT-D was found to be correlated with the degree of irreversible ADP-ribosylation of G22k by BT-D and to require modification of at least 85% of PMN G22k before significant inhibition of secretion is observed. Although both pertussis toxin and BT-D inhibited exocytosis in FMLP-stimulated PMNs, the inhibitory effects of the two toxins were found to be additive. Pertussis toxin and BT-D also inhibited Ca2+/GTP/GTP gamma S-induced secretion in digitonin-permeabilized PMNs, but there were distinct differences between the inhibitory effects of the two toxins. In contrast to BT-D, the exotoxin botulinum C3 was found to ADP-ribosylate primarily a 24- to 25-kDa PMN protein, and it was not found to inhibit Ca(2+)- and GTP-induced secretion in permeabilized PMNs. Ultrastructural studies of BT-D-treated PMNs showed an accumulation of distinct membrane-bound organelles in the periphery of the cells after FMLP stimulation, suggestive of a toxin-induced block in organelle-plasma membrane fusion. Taken together, these findings indicate that BT-D-sensitive G22k has a functional role in stimulated exocytosis of PMNs.

ADP Ribose Transferases↗
PubMed1994

Magnetic resonance imaging for the diagnosis of osteomyelitis in the diabetic patient with a foot ulcer.

Twenty-seven diabetic patients (12 males and 15 females) with clinically suspected osteomyelitis complicating soft tissue infection of the foot underwent 29 magnetic resonance imaging studies of the suspected lesion. Of these patients, 26 had plain film radiographs, 11 had technetium bone scanning, and 12 had indium-labeled leukocyte scintigraphy performed within 2 weeks of the magnetic resonance imaging. Definitive diagnosis of the presence or absence of osteomyelitis was obtained on the basis of surgical findings, histological evidence, or resolution with nonoperative therapy. Magnetic resonance imaging was 90% accurate (sensitivity 77%, specificity 100%) in the diagnosis of osteomyelitis in this patient population. Technetium bone scan was 45% accurate (sensitivity 100%, specificity 25%); indium-labeled leukocyte scintigraphy was 50% accurate (80% sensitivity, 29% specificity); and plain film roentgenography was 73% accurate (60% sensitivity, 81% specificity). Magnetic resonance imaging is a powerful, noninvasive tool for determining the presence or absence of osteomyelitis in the patient with a diabetic foot ulcer.

Adult↗
PubMed1994

Inhibitory effects of HIV-1-infected stromal cell layers on the production of myeloid progenitor cells in human long-term bone marrow cultures.

This report presents the results of studies using long-term bone marrow cultures (LTBMC) of human bone marrow cells to investigate the effect of HIV-1 on in vitro hematopoiesis. Confluent stromal cell layers established from human bone marrow cells were irradiated to eliminate residual hematopoietic progenitor cells and exposed to HIV-1ADA or to HIV-1IIIB, monocytotropic and lymphocytotropic strains of HIV-1, respectively. A productive infection did not develop in cultures exposed to HIV-1IIIB but did for cultures exposed to HIV-1ADA as there was a progressive increase in HIV-1 p24 antigen. Stromal cell layers infected with HIV-1ADA were also cocultured with autologous CD34+ bone marrow cells. Four days, 1, 2, and 3 weeks later, the number of colony-forming units granulocyte/macrophage (CFU-GM) in non- and HIV-infected LTBMC was determined. The number of CFU-GM increased during the first week in both non- and HIV-infected LTBMC. One week after the coculture of CD34+ cells with stromal cell layers infected with HIV-1ADA, the number of CFU-GM in six out of eight experiments was reduced compared to noninfected control LTBMC. In those six experiments, the number of CFU-GM was 53 +/- 6% standard error of the mean (SEM) of the number in noninfected LTBMC. A reduced number of CFU-GM was observed in the nonadherent fraction of HIV-infected LTBMC for at least 2 weeks. These results demonstrate that some cells in the stromal cell layers of LTBMC were targets for HIV-1 and that HIV-infected stromal cell layers suppressed or delayed the production of CFU-GM.

Antigens, CD↗
PubMed1993

Rapid and reversible tubulin tyrosination in human neutrophils stimulated by the chemotactic peptide, fMet-Leu-Phe.

Neutrophil activation by specific stimuli, such as the oligopeptide chemotactic factor fMet-Leu-Phe (fMLF), is associated with an increased enzymatic addition of tyrosine to tubulin alpha-subunits, as measured by 14C tyrosine uptake. In studies using immunoblots we have found that this increased tyrosine uptake into tubulin in activated neutrophils reflects an increase in the proportion of cellular tubulin that is tyrosinated rather than simply an increase in the turnover of tyrosinated subunits. However, the increased accumulation of tyrosinated tubulin was also found to follow an initial depletion of tyrosinated tubulin and concomitant increase in detyrosinated tubulin between 0 and 60 sec following stimulation of neutrophils with fMLF. Immunogold electron microscopy studies of intact microtubules recovered from activated neutrophils demonstrated that these rapid changes in the relative content of tubulin isoforms in the cells were not associated with the formation or disappearance of microtubule microdomains composed of only one form of tubulin. Previously, we have shown that under conditions of fMLF-stimulated exocytosis there is an increased binding of neutrophil granules to endogenous microtubules. Since neutrophil activation by fMLF is associated with increased tyrosination of alpha-tubulin subunits, we speculated that rapid changes in the levels of tyrosinated tubulin in the microtubules of activated neutrophils might have a role in the regulation of granule-microtubule interactions. When the binding of purified neutrophil granules to reconstituted rat brain microtubules containing approximately 50% tyrosinated tubulin was measured by electron microscopy and compared with granule binding to microtubules that contained no detectable tyrosinated tubulin, granule-microtubule associations were found to be significantly favored by detyrosinated vs. tyrosinated tubulin. These findings indicate that interactions between cytoplasmic granules and microtubules in activated neutrophils may be modulated by rapid changes in the relative content of detyrosinated and tyrosinated tubulin in the microtubule network of the cells.

Amino Acid Sequence↗
PubMed1993

Affinity purification and subcellular localization of kinesin in human neutrophils.

Studies of granule-microtubule interactions in human neutrophils have suggested that mechanochemical ATPases such as kinesin or dynein may play a role in granule mobilization during neutrophil activation by inflammatory signals. In this study we show that proteins extracted from the surface of neutrophil granules, found previously to contain microtubule-dependent ATPase activity, caused microtubules polymerized from phosphocellulose-purified rat brain tubulin to move across glass slides. Antibodies were generated against peptides based on two regions of the amino acid sequence of Drosophila kinesin: the ATPase active site (amino acids 86-99) in the head of the kinesin heavy chain and the tail of the heavy chain (residues 913-933). These antibodies were found to recognize kinesin in rat brain extracts as well as kinesin-like polypeptides in extracts of human neutrophils. Furthermore, when used in immunoaffinity chromatography, these antibodies permitted the isolation of a protein from neutrophil granule extracts that was recognized by Drosophila kinesin antibodies. Subcellular localization by immunofluorescence microscopy showed this protein to be associated principally with the cytoplasmic granules of neutrophils.

Animals↗
PubMed1993

Immediate internal fixation of low-velocity gunshot-related femoral fractures.

Fractures caused by gunshots are increasingly common in urban hospitals and trauma centers. The rising incidence and complexity of these injuries present difficult management problems and health care burdens. In a 3-year period, from 1989 through 1991, 21 patients with femoral shaft fractures from low-velocity bullets were treated with intramedullary fixation within 15 hours of admission. Eighteen patients were available for follow-up. The fractures had healed in all patients. Average hospitalization for an isolated injury was 7 days. There were no complications related to immediate internal fixation. Immediate internal fixation of femoral shaft fractures caused by low-velocity gunshots can be performed in an efficient and cost effective manner.

Adolescent↗