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Biomedical subjects

M W Flye

Publications and source records attributed to M W Flye.

At least 73 records · Page 4Linked to original sources
PubMed1995

Common variable immunodeficiency in a renal transplant patient with severe recurrent bacterial infection: a case report and review of the literature.

The second reported case of common variable immunodeficiency (acquired agammaglobulinemia) after renal transplantation is presented. Agammaglobulinemia presumably resulted from long-standing immunosuppression. This case and our review of the literature indicate that agammaglobulinemia is a rare event after transplantation but can be treated successfully with intravenous immunoglobulin. Additionally, hypogammaglobulinemia occurs frequently after transplantation and should be monitored and treated in appropriate clinical situations. The treatment of our patient with intravenous immunoglobulin also suggests that patients with common variable immunodeficiency can undergo renal transplantation.

Adolescent↗
PubMed1995

Limb salvage and patency after aortic reconstruction in younger patients.

PURPOSE: The purpose of this report was to compare patient characteristics, treatment, and outcome in younger and older patients with aortoiliac occlusive disease. METHODS: The medical records of 56 patients < or = 50 years of age (Group < or = 50) were retrospectively reviewed and compared to the records of 128 patients > or = 60 years of age (Group > or = 60). All patients were examined and treated between April 1987 and April 1994. Postoperatively, they were enrolled in a vascular laboratory surveillance program to serially monitor the status of the vascular reconstruction. Follow-up averaged more than 3 years in both groups and was available on greater than 90% of patients. RESULTS: Patients in Group < or = 50 had a higher incidence of smoking (68% versus 51%) and a lower incidence of hypertension (29% versus 50%) than patients in group > or = 60 (smoking P = 0.03, hypertension P = 0.007). No other significant differences were noted among cardiovascular risk factors. Preoperative indications for surgery were similar among patients in both groups. An aortoiliac endarterectomy was more commonly used to revascularize the lower extremities in younger patients than in their older counterparts (23% versus 7%, P = 0.002). Graft revisions were more frequently necessary after aortic reconstruction in Group < or = 50 than in Group > or = 60 (29% versus 8%, P = 0.0003); however patency rates computed by life table analysis were not significantly different. The primary patencies for Group < or = 50 and Group > or = 60 at 5 years were 64% and 67%, respectively; their secondary patency rates at 5 years were 84% and 89%, respectively. No significant difference was found in major limb amputation (8% in Group < or = 50 versus 5% in Group > or = 60, P = 0.46). We conclude that aortoiliac reconstruction for occlusive disease can be performed with similar secondary patency and amputation rates in young and old patients. However, close postoperative surveillance and frequent surgical revision are necessary to maintain patency and minimize amputation.

Adult↗
PubMed1995

Administration of anti-CD4 monoclonal antibody with intrathymic injection of alloantigen results in rat cardiac allograft tolerance.

BACKGROUND: We have previously reported the induction of donor-specific tolerance to cardiac allografts after intrathymic injection of alloantigen with simultaneous administration of antilymphocyte serum treatment to eliminate peripheral T cells. The present study determines whether prolongation of a fully major histocompatibility complex-mismatched cardiac allograft is achieved after a single administration of anti-CD4 monoclonal antibody (MoAb) combined with intrathymic injection of alloantigen. METHODS: Male Buffalo rats were given Lewis splenocytes via the intrathymic or intravenous route in combination with a single administration of anti-CD4 monoclonal antibody (OX-38) or anti-CD8 MoAb (OX-8) or both. Heterotopic cardiac transplantation was performed 21 days after intrathymic alloantigen or MoAb pretreatment or both. Fluorescence-activated cell sorter analysis determined changes in lymphocyte compartment T-cell subsets, and in vitro studies examined recipient cellular reactivity. RESULTS: By 21 days after anti-CD4 MoAb treatment earlier nonspecific immunosuppression had resolved with 80% recovery of peripheral CD4+ T cells and restoration of recipient immunocompetence to allow normal rejection of a cardiac allograft. Combined treatment with intrathymic, but not intravenous, alloantigen plus anti-CD4 MoAb induced donor-specific tolerance to subsequent rat cardiac allografts. However, anti-CD8 MoAb combined with intrathymic alloantigen failed to induce tolerance despite a profound depletion of the CD8+ T-cell subset. CONCLUSIONS: Combined treatment of rats with intrathymic donor alloantigen and a single administration of anti-CD4, but not anti-CD8, MoAb significantly prolongs cardiac allograft survival across a fully major histocompatibility complex mismatched strain combination.

Animals↗
PubMed1995

Transabdominal versus retroperitoneal incision for abdominal aortic surgery: report of a prospective randomized trial.

PURPOSE: The purpose of this study was to perform a randomized, prospective trial that compares the transabdominal with the retroperitoneal approach to the aorta for routine infrarenal aortic reconstruction. METHODS: From August 1990 through November 1993, patients undergoing surgery for abdominal aortic aneurysm (AAA) disease or aortoiliac occlusive disease (AIOD) were asked to participate in a randomized trial comparing the transabdominal incision (TAI) to the retroperitoneal incision (RPI) for aortic surgery. One hundred forty-five patients were randomized, with 75 (41 with AAA and 34 with AIOD) in the TAI group and 70 (40 with AAA and 30 with AIOD) in the RPI group. There were no significant differences between the groups in terms of age, sex, postoperative pain control (epidural vs patient-controlled analgesia), or comorbid conditions, except for a higher incidence of chronic obstructive pulmonary disease in the TAI group (21 vs 8 patients). RESULTS: The incidence of intraoperative complications was similar for both groups. After surgery, the incidence of prolonged ileus (p = 0.013) and small bowel obstruction (p = 0.05) was higher in the TAI group. Overall, the RPI group had significantly fewer complications (p < 0.0001). The overall postoperative mortality rate (two deaths) was 1.4%, with both occurring in the TAI group (p = 0.507). The RPI group also had significantly shorter stays in the intensive care unit (p = 0.006), a trend toward shorter hospitalization (p = 0.10), lower total hospital charges (p = 0.019), and lower total hospital costs (p = 0.017). There was no difference in pulmonary complications (p = 0.71). In long-term follow-up (mean 23 months), the RPI group reported more incisional pain (p = 0.056), but no difference was found in incisional hernias or bulges (p = 0.297). CONCLUSIONS: We conclude that the RPI approach for abdominal aortic surgery is associated with fewer postoperative complications, shorter stays in the hospital and intensive care unit, and lower cost. There is, however, an increase in long-term incisional pain. Current methods of postoperative pain control seem to decrease the incidence of pulmonary complications.

Abdomen↗
PubMed1995

Post-treatment management options for patients with lung cancer.

OBJECTIVES: The first objective was to identify variations in patient management practice patterns after potentially curative lung cancer surgery. Patient management practice patterns were expected to range from intensive follow-up to no active surveillance. The second objective was to measure whether intensity of follow-up was related to patient outcomes. METHODS: An 18-month retrospective analysis was conducted of 182 patients with low TNM stage (< or = IIIA) lung cancer who were surgically treated with curative intent over the 11-year period from 1982 through 1992 at the St. Louis Department of Veterans Affairs Medical Center. RESULTS: Patients were followed for a mean of 3.3 years, until death or the end of the study. Analyses of diagnostic test and outpatient visit frequency distributions and cluster analyses facilitated the identification of 62 nonintensively followed patients and 120 intensively followed patients. Both groups were comparable at baseline, and there were no significant differences in patient outcomes attributable to intensity of follow-up. Intensively followed patients did, however, live an average of 192 days longer than nonintensively followed patients. CONCLUSIONS: Significant variations in follow-up practice patterns can exist within a single health care facility. In this analysis, variations in test and visit frequency did not result in statistically significant differences in patient outcomes, though the survival difference between groups suggests that some benefit might exist. Only well-designed prospective trials are likely to answer the question of what constitutes optimal follow-up after potentially curative lung cancer treatment.

Case-Control Studies↗
PubMed1995

Experiments in transgenic mice show that hepatocytes are the source for postnatal liver growth and do not stream.

One hypothesis is that postnatal liver growth involves replication of mature hepatocytes, which have an unlimited proliferative potential. An alternative viewpoint is that only certain periportal cells can replicate extensively and that daughter cells stream slowly from the periportal to the pericentral region of the liver. Transgenic mice expressing the beta-galactosidase (beta-gal) gene from the human alpha 1 antitrypsin promoter were used to examine the proliferative potential of hepatocytes. Surprisingly, only 10% of hepatocytes in two different transgenic lines stain blue with X-gal. In neonatal animals, singlets or doublets of expressing cells are randomly scattered throughout the liver. Although the overall frequency of blue cells is similar in older animals, these cells are present in much larger clusters, suggesting that individual expressing cells have replicated to form a clonally derived cluster. Expression patterns are not altered by the administration of an acute phase stimulus or by the performance a partial hepatectomy, suggesting that the expression state cannot be easily altered, and making it more likely that the expression state is indeed fixed. These results suggest that the clusters of blue cells are clonally derived in the transgenic mice. They argue that the parenchymal hepatocyte is responsible for growth in the postnatal liver and that streaming of liver cells does not occur.

Acute-Phase Proteins↗
PubMed1995

Anomalous ureteral insertion in VATER syndrome complicating renal transplantation.

We report a renal transplantation with uretero-ureterostomy to a normal ureter in a patient with VATER syndrome who had agenesis of the ipsilateral kidney. Anomalous insertion of the native ureter into the ejeculatory duct was subsequently identified when his post-operative course was complicated by an ureteric leak and hydronephrosis. To our knowledge, this anomaly has not been previously reported. Transplant function is now excellent following temporary percutaneous nephrostomy. Contrast delineation of genito-urinary anatomy is recommended, before utilizing existing anatomical structures in the urinary tract, in patients with VATER syndrome.

Abnormalities, Multiple↗
PubMed1995

Donor human leukocyte antigens in the circulation of liver allograft recipients.

Using a solid phase enzyme immunoassay (ELISA) with three different murine monoclonal antibodies (mAb) to HLA (human leukocyte antigens) framework determinants, circulating HLA were detected and quantitated both in normal individuals as well as liver allograft recipients. In normal individuals, the level of circulating HLA remained constant for several months of this study. The quantity of antigens present in the sera was not influenced by the collection procedures. During the immediate post-transplant period there was detectable donor HLA in the recipient's circulation; however, no correlation was noted between graft function and the large quantity of donor HLA present in the sera. Within 5 months after transplantation there was a gradual decrease in the amount of circulating HLA compared to the level seen in normal individuals. These shed donor antigens may play an active role in initiating the development of tolerance to the transplanted organ.

Blood Donors↗
PubMed1995

Beneficial effects of donor-specific transfusions on long-term renal allograft function.

The induction of immunologic unresponsiveness to improve renal allograft survival was attempted in 163 patients by the pretransplant administration of donor-specific whole blood or buffy coat in conjunction with continuous Aza immunosuppression. All donor-recipient combinations were at least one-haplotype disparate, and 21 were two-haplotype disparate. Transient sensitization occurred in 2% and permanent sensitization in 7%. Over a 10-year period, the DST+Aza allograft survival rate is similar to the HLA-identical sibling transplants. The CMV sepsis rate was only 2%, and there were no lymphoproliferative neoplasms. The low rate of sensitization (7%) has permitted almost all patients to undergo eventual renal transplantation from the specific blood donor. This and the low rate of early rejection (3%) argues for a modification of the immunologic response.

Azathioprine↗
PubMed1994

Outcome of Kupffer cell antigen presentation to a cloned murine Th1 lymphocyte depends on the inducibility of nitric oxide synthase by IFN-gamma.

The interaction between lymphocytes and the resident hepatic macrophage, the Kupffer cell (KC), is relevant to the phenomenon of immune tolerance to Ags entering the liver. Tolerance to Ag administered via the portal vein can be prevented by the rare earth lanthanide metal, gadolinium (Gd). Therefore, we studied the ability of OVA-responsive, H-2d-restricted Th1 clones to proliferate in response to KCs from DBA/2J (H-2d) mice that had been injected with either saline (control) or a Gd solution. Whereas control KCs functioned as effective APCs, KCs from Gd-injected mice (GdKC) were incapable of sustaining the proliferative response of the Th1 clone to the 16 mer of OVA (323-339). This lack of proliferation was determined not to be caused by impaired Ag processing, but rather was the result of IFN-gamma-stimulated nitric oxide (NO) release by the APC: 1) In vitro addition of the nitric oxide synthase (NOS) inhibitor NG-methyl-L-arginine (NMMA) restored the ability of the Gd-treated KC to stimulate clone proliferation. 2) Additional of anti-IFN-gamma, but not anti-IL-2 or anti-IL-4, prevented the induction of NOS in the Gd-exposed KC and was associated with clone proliferation. 3) IFN-gamma levels from clone-GdKC-OVA cocultures closely paralleled the nitrite released by GdKCs. 4) Only the addition of rIFN-gamma, and not IL-2 or IL-4, to cultures of purified GdKCs resulted in the release of nitrite. The results of the study suggest an autocrine loop initiated by the interaction of the clone's TCR with the class II MHC molecule presenting processed OVA on the surface of KC. This interaction stimulates the Th1 lymphocyte to release IFN-gamma, which in turn induces NO release by KCs isolated from Gd-injected mice. This release of NO blocks Th1 proliferation. Such a feedback loop may have particular relevance to Ag-specific tolerance, which is not only induced by the administration of Ag into the portal vein, but is also prevented by Gd pretreatment of the recipient animal.

Amino Acid Oxidoreductases↗
PubMed1994

Quantitative evaluation of liver-specific promoters from retroviral vectors after in vivo transduction of hepatocytes.

Hepatic gene therapy could be used to treat a number of inherited blood diseases such as hemophilia or thrombophilia. Although liver-directed retroviral transduction can result in long-term gene expression in vivo, the low level of protein production has limited its clinical application. We reasoned that the insertion of liver-specific promoters into retroviral vectors would increase gene expression in vivo. The 347-bp human alpha 1-antitrypsin (hAAT), the 810-bp murine albumin (mAIb), the 490-bp rat phosphoenolpyruvate carboxykinase (rPECK), and the 596-bp rat liver fatty acid binding protein promoters were inserted into a Moloney murine leukemia retroviral backbone containing the hAAT reporter gene. Vectors that produced appropriately sized RNA and hAAT protein in vitro were tested in vivo by transducing regenerating rat livers. Long-term serum expression of the hAAT reporter gene was normalized to retroviral transduction efficiency as determined by using a polymerase chain reaction-based assay of genomic DNA from transduced rat livers. The hAAT, mAIb, and rPEPCK promoters were, respectively, 35-, 8-, and 0.02-fold as strong as the previously studied constitutive Pol-II promoter. We conclude that the hAAT promoter resulted in the highest expression from a retroviral vector and may result in therapeutically significant expression of other clinically significant blood proteins.

Animals↗
PubMed1994

Immunological tolerance to a defined myelin basic protein antigen administered intrathymically.

To explore the mechanisms responsible for the development of tolerance to allografts after intrathymic (IT) injection of alloantigen, the well-defined model of experimental autoimmune encephalomyelitis (EAE), which mimics the human autoimmune disease multiple sclerosis, was used. This inflammatory neurologic syndrome is initiated by myelin basic protein (MBP)-reactive CD4+ T lymphocytes restricted to self-MHC class II molecules. Naive adult, EAE-susceptible Lewis (RT1(1) rats were treated IT, i.v., or i.p. with a single dose (100 micrograms) of guinea pig-myelin basic protein (GP-MBP 1-176) in PBS plus 1 ml rabbit anti-rat lymphocyte serum i.p. Twenty-one days later, all rats were challenged by intradermal hind footpad injections of 50 micrograms GP-MBP in PBS emulsified in CFA. Only IT, but not i.p. or i.v., administration of GP-MBP plus anti-lymphocyte serum conferred marked resistance to a subsequent systemic challenge of GP-MBP, as demonstrated by the prevention of weight loss and paralysis characteristic of EAE. The IT administration dramatically decreased the size and number of histologic perivascular infiltrates observed per visual field in spinal cord of the tolerant animals and decreased GP-MBP-specific T lymphocyte in vitro proliferation (p < 0.01), whereas proliferation to a nonspecific mitogen (Con A) was not altered. With the addition of rIL-2, the decreased Ag-specific proliferative responses of IT-treated animals increased to control levels. Adoptive transfer of 100 x 10(6) splenocytes from tolerant hosts i.v. to naive syngeneic Lewis rats challenge with 100 micrograms GP-MBP in CFA had no effect on clinical or histologic EAE. Exposure of MBP to maturing thymocytes results in functionally immunounresponsive lymphocytes and prevention of autoimmune EAE.

Animals↗
PubMed1994

Liver-directed gene therapy: quantitative evaluation of promoter elements by using in vivo retroviral transduction.

Liver-directed gene therapy will be applicable to many inherited diseases. Although various protocols have been devised for in vivo delivery of retrovirus, comparison of hepatocyte transduction frequencies has been difficult due to variations in retroviral titer and a paucity of DNA data. We have previously reported an in vivo rat hepatocyte transduction technique which involves 70% hepatectomy followed 24 hr later by portal vein injection of retrovirus during hepatic in-flow occlusion. In this study, we employed this method and concentrated retroviral preparations to achieve transduction of up to 15% of hepatocytes as determined by a quantitative PCR assay. As an initial step toward identifying promoters which lead to high-level long-term expression of retroviral transduced genes, we used our in vivo delivery system to compare the Moloney murine leukemia virus long terminal repeat (LTR) promoter with the promoter for the large subunit of murine RNA polymerase II (Pol-II). Human alpha 1-antitrypsin (hAAT) was used as the reporter gene to facilitate long-term analysis of expression. Serum hAAT levels were higher for the Pol-II promoter (143 ng/ml) than for the LTR promoter (50 ng/ml). This difference was consistent with the higher transduction frequency observed for the Pol-II-hAAT vector. Although serum hAAT expression was sustained for up to 1 year in six of eight Pol-II-hAAT-transduced rats and three of five LTR-hAAT-transduced rats and was proportional to hAAT mRNA level and proviral DNA frequency, in vivo expression was significantly lower than in transduced tissue culture cells. We conclude that a high frequency of in vivo transduction can be achieved by using retroviral vectors and our rapid transduction protocol, but transduced gene expression remains a serious problem. The quantitative assays described herein will facilitate in vivo comparisons of gene regulatory elements.

Animals↗
PubMed1994

Liver-directed gene therapy: evaluation of liver specific promoter elements.

Liver-directed gene therapy could dramatically alter the therapy of many inherited hematologic and metabolic diseases. We have developed a rapid, reliable, low-mortality method for the in vivo delivery in rats of retroviral vectors 24 hr after 70% hepatectomy by intraportal injection during hepatic in-flow occlusion (HIFO). Using the human alpha 1-antitrypsin (hAAT) reporter gene, we found in vivo that up to 10% of hepatocytes integrated the provirus, and serum hAAT protein levels were sustained for up to 1 year. Despite high in vivo transduction efficiencies, gene expression at the mRNA level is disappointingly low compared to in vitro transduced NIH 3T3 or Hepa A1 tissue culture cells. In this report, LNL-6-derived retroviral vectors (RV) were combined with one of two strong, liver-specific promoters, murine albumin or human alpha 1-antitrypsin, an upstream insertion of a trimer of hepatocyte nuclear factor-3 (HNF-3) binding sites, and the hAAT reporter gene. HNF-3 has been demonstrated to increase in vitro transcriptional activity [23]. Twenty-four hours after 70% hepatectomy, 10-fold concentrated (by methotrexate-resistant titer) RV-producing cell supernatant was given intraportally during a 3-min HIFO. Serum hAAT levels as quantitated with a human specific ELISA were sustained for over 40 weeks with all of the liver-specific promoter constructions. However, the hAAT protein production with the murine albumin promoter retroviral constructs decreased with time, but was sustained at levels approximately 80% of the initial serum peak levels with the constructs containing the hAAT promoter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The influence of anesthetic technique on perioperative complications after carotid endarterectomy.

PURPOSE: This study evaluated the influence of anesthetic techniques on perioperative complications after carotid endarterectomy. METHODS: Perioperative complications, the use of a carotid artery shunt, the duration of the operative procedure and postoperative hospital course were retrospectively compared in 584 consecutive patients undergoing 679 carotid endarterectomies with use of either general anesthesia (n = 361) or cervical block regional anesthesia (n = 318). There was no significant difference in the preoperative medical characteristics between the two anesthetic groups. Symptomatic carotid artery disease was the indication for surgery in 247 (68.4%) patients receiving general anesthetics, whereas 180 (56.6%) patients treated with a cervical block anesthetic had a symptomatic carotid artery stenosis (p = 0.02). RESULTS: The perioperative stroke rate and stroke-death rate for the entire series was 2.4% and 3.2%, respectively, and was not significantly different between the anesthetic groups or between patients with symptomatic or asymptomatic disease. A carotid artery shunt was used in 61 (19.2%) patients receiving a cervical block anesthetic and 152 (42.1%) patients treated with a general anesthetic (p < 0.0001). Use of cervical block anesthesia was associated with a significantly shorter operative time, fewer perioperative cardiopulmonary complications, and a shorter postoperative hospitalization when compared with general anesthesia. Multivariate risk factor analysis indicated that age greater than 75 years, operative time greater than 3 hours, and the use of a carotid artery shunt were all independent risk factors for perioperative cardiopulmonary complications. When a carotid artery shunt was not analyzed as a multivariate risk factor, then general anesthesia became a significant risk factor for perioperative cardiopulmonary complications (risk ratio 2.08; p = 0.04). CONCLUSIONS: We conclude that cervical block anesthesia is safer and results in a more efficient use of hospital resources than general anesthesia in the treatment of patients undergoing carotid endarterectomy.

Aged↗