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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
PubMed1999

Autoantibodies to leukocyte alphaMbeta2 integrin glycoproteins in HIV infection.

HIV infection is often associated with polyclonal B-cell activation, autoantibodies, and clinically evident autoimmune disease. Because neutropenia and anti-neutrophil autoantibodies are common clinical features of HIV disease, we studied a series of HIV+ patients to determine whether anti-alphaMbeta2 integrin (MAC-1) specific anti-neutrophil autoantibodies occur in HIV disease, as we have shown to occur in patients with immune neutropenia not associated with HIV. Two new assays specific for anti-alphaMbeta2 IgG were developed to carry out these studies: an ELISA method using affinity-purified alphaMbeta2 integrin protein, and a flow cytometry method using subclones of the 293 human fetal kidney cell line, stably transfected with cDNAs for the alphaM and/or beta2 integrin subunits. In studies of the sera of 20 untreated HIV+ individuals, anti-alphaMbeta2 activity was detected in 9 (45%) by one or the other of these assays and in 5 (25%) by both assays. Seven of the 20 HIV+ study subjects had unexplained neutropenia, and of these, 6 (86%) were positive for anti-alphaMbeta2 autoantibodies. Our findings indicate that anti-alphaMbeta2 integrin autoantibodies are frequent in HIV+ individuals, particularly when unexplained neutropenia is also present, and raise the possibility that these autoantibodies may have a role in the acquired neutrophil dysfunction and increased risk of nonopportunistic bacterial infections observed in HIV disease.

Autoantibodies↗
PubMed1998

Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients.

AL (amyloid light-chain) amyloidosis is an uncommon plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure and death in a median of 13 months. Autologous stem-cell transplantation is effective therapy for multiple myeloma and therefore, we evaluated its efficacy for AL amyloidosis. Patients with adequate cardiac, pulmonary, and renal function had stem cells mobilized with granulocyte-colony stimulating factor and were treated with dose-intensive intravenous melphalan (200 mg/m2). Response to therapy was determined by survival and improvement of performance status, complete response or persistence of the clonal plasma cell disorder, and change in the function of organs involved with amyloid at baseline. We enrolled 25 patients with a median age of 48 years (range, 29-60), all of whom had biopsy-proven amyloidosis with clonal plasma cell disorders. Twenty-two (88%) were Southwest Oncology Group performance status 1 or 2 within a year of diagnosis, and 16 (64%) had received no prior therapy. Predominant amyloid-related organ involvement was cardiac (n = 8), renal (n = 7), hepatic (n = 6), neuropathic (n = 3), and lymphatic (n = 1). Fifteen patients had one or two organ systems involved, whereas 10 had three or more involved. With a median follow-up of 24 months (12-38), 17 of 25 patients (68%) are alive, and the median survival has not been reached. Thirteen of 21 patients (62%) evaluated 3 months posttransplant had complete responses of their clonal plasma cell disorders. Currently, two thirds of the surviving patients (11 of 17) have experienced improvements of amyloid-related organ involvement in all systems, whereas 4 of 17 have stable disease. The improvement in the median performance status of the 17 survivors at follow-up (0 [range, 0-3]) is statistically significant versus baseline (2 [range, 1-3]; P < . 01). Significant negative prognostic factors with respect to overall survival include amyloid involvement of more than two major organ systems and predominant cardiac involvement. Three patients have experienced relapses of the clonal plasma cell disorder at 12 and 24 months. Dose-intensive therapy should currently be considered as the preferred therapy for patients with AL amyloidosis who meet functional criteria for autologous transplantation.

Adult↗
PubMed1998

Anti-CD34+ Fabs generated against hematopoietic stem cells in HIV-derived combinatorial immunoglobulin library suggest antigen-selected autoantibodies.

Bone marrow suppression associated with HIV infection does not appear to be solely due to direct viral cytopathic effects. Autoantibodies may play a role in myelosuppression, however it is unclear whether autoantibodies produced in HIV infection represent a primary pathogenic process or merely reflect polyclonal B cell activation. To address these questions, we generated combinatorial immunoglobulin libraries using the pComb3 phagemid from an HIV+ individual with evidence of circulating autoantibodies. From one library, three anti-CD34 Fabs were identified using fresh CD34+ cells as antigenic targets by a method of phage subtraction. The anti-CD34 Fabs are specific by immunoblotting and Elisa and are of high affinity, with calculated Kds in the range of 10(-7) -10(-8) M. Nucleic acid sequencing revealed all three to be of the VH3 family and to have lambda light chains with some gene segments expressing little somatic mutation, while other segments were somatically mutated in patterns suggestive of antigen selection. These findings indicate that (1) A subset of HIV-associated anti-CD34 autoantibodies are monospecific and antigen-selected and are not merely a consequence of polyclonal B cell activation and elevated Ig levels in HIV. Autoreactivity in HIV therefore includes both polyspecific, low affinity antibodies as well as monospecific antigen-selected high affinity antibodies. (2) Although bone marrow suppression in HIV is likely to be multifactorial, autoantibodies to hematopoietic stem cells may contribute to its pathogenesis. (3) Library sampling of VH gene family rearrangements shows no evidence for under-representation of the VH3 family in the immune dysregulation of HIV infection. Phage subtraction is corroborated to be an effective means of identifying, cloning, and characterizing antibodies to hematopoietic differentiation antigens.

Antibody Affinity↗
PubMed1998

Mobilized CD34+ cells selected as autografts in patients with primary light-chain amyloidosis: rationale and application.

BACKGROUND: Concern about tumor cell contamination in stem cell preparations has led to the use of CD34+ cell selection as a means of purging. Increasing the number of CD34+ cells per leukapheresis may help to provide an adequate dose of CD34+ cells. STUDY DESIGN AND METHODS: The reverse transcriptase polymerase chain reaction (RT-PCR) was employed to clone overexpressed clonotypic immunoglobulin light-chain variable region genes (Ig VL) from bone marrows of patients with primary light-chain amyloidosis (AL). Patient-specific primers were designed to evaluate stem cell collections for contamination. CD34+ cell selection was performed on components from AL patients who underwent mobilization with granulocyte-colony-stimulating factor (G-CSF) (filgrastim; 16 microg/kg/d for 4 days) and collection by large-volume leukapheresis (LVL;25L) on Days 4 and 5. The selected cells alone were transfused after patients received mephalan (200 mg/m2). RESULTS: Contamination was found in collections from 4 to 7 patients, which provided the rationale for a subsequent trial of CD34+ cell selection. The median number of CD34+ cells per kg collected on Days 4 and 5, and in toto, was 4.0 x 10(6)(1.1-12.7), 7.9 x 10(6)(1.8-12.7), and 10.7 x 10(6)(2.9-25.4), respectively (n = 9 patients). The median yield per selection was 38 percent, with a purity of 85 percent (45-97%), and the viability of CD34+ cells averaged 96.4 +/- 3.6 percent (n = 18 selections). The median number of CD34+ cells infused was 5.9 x 10(6) per kg (2.1-10.1). In comparison with AL patients given unselected autografts, patients receiving selected CD34+ cells experienced similar reconstitution of neutrophils and platelets but slower lymphocyte recovery. CONCLUSION: Patients with AL often have contamination with clonotypic cells in their blood autografts. G-CSF mobilization and LVL provide components that allow the selection of adequate doses of CD34+ cells. The use of CD34+ cells in patients with AL achieves rapid neutrophil and platelet recovery but delayed lymphocyte recovery. CD34+ cell selection is feasible in the treatment of AL, but its effectiveness in purging clonotypic cells remains to be ascertained.

Adult↗
PubMed1997

Endoscopic plantar fascia release: a cross-sectional anatomic study.

Endoscopic plantar fascia release is a new procedure proposed to treat heel pain and plantar fasciitis. The purpose of this study was to assess the structures at risk during plantar fascia release using this method. Ten fresh-frozen cadaver feet were divided into two groups. All specimens underwent cannula placement inferior to the plantar fascia. Five-of the specimens had plantar fascia release using the endoscopic technique. Six of the specimens were then frozen and cut in transverse, sagittal, and coronal sections to visualize the relationship between the cannula and plantar fascia and surrounding structures. Gross dissection was performed on the remaining four specimens. The amount of plantar fascia released, the relationship to the nerve to abductor digiti minimi, and the fascia of the abductor hallucis muscle were assessed. The average distance from the cannula margin to the nerve to the abductor digiti minimi was 6 mm at the medial border of the plantar fascia. The average amount of plantar fascia released was 90%. Although a complete release was attempted, the fascia to the abductor hallucis was not released in any of the specimens. The nerve to the abductor digiti minimi was not damaged in any of the specimens. On coronal sections, the nerve was closer to the cannula and plantar fascia release than previously reported.

Adult↗
PubMed1997

Calcaneal osteomyelitis caused by nail puncture wounds.

Plantar puncture wounds to the foot are a common injury. A small number (1.8%) of these puncture wounds become infected and progress to osteomyelitis. The purpose of this article is to report the cases of six patients who developed osteomyelitis of the calcaneus after a puncture wound to the heel caused by a nail. The characteristics of the patients, the pathogenic organism, and the outcome were studied. Patients who were healthy and had no systemic illness (N = 4) had only one pathogenic organism cultured, whereas patients who had systemic illness (diabetes mellitus, N = 2) had more than one pathogenic organism cultured. The only amputation in this group occurred in a patient with diabetes mellitus. It was concluded that diabetic patients who develop calcaneal osteomyelitis from a nail puncture wound are more likely to have multiple pathogens cultured. Furthermore, if a diabetic neuropathy is also present, the nail puncture wound may be the initial injury leading to a chronic ulceration, increasing the risk of amputation.

Calcaneus↗
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↗