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Biomedical subjects

P S Brown

Publications and source records attributed to P S Brown.

At least 19 recordsLinked to original sources
PubMed2000

Technique of controlled reperfusion of the transplanted lung in humans.

BACKGROUND: Reperfusion injury remains a significant and sometimes fatal problem in clinical lung transplantation. Controlled reperfusion of the transplanted lung using white cell-filtered, nutrient-enriched blood has been shown recently to significantly ameliorate reperfusion damage in a porcine model. We modified this experimental technique and applied it to human lung transplantation. METHODS: Approximately 1,500 mL of arterial blood was slowly collected in a cardiotomy reservoir during the lung implant, and mixed to make a 4:1 solution of blood:modified Buckberg perfusate. This solution was passed through a leukocyte filter and into the transplant pulmonary artery for 10 minutes, at a controlled rate (200 mL/min) and pressure (less than 20 mm Hg), immediately before removal of the vascular clamp. RESULTS: Five patients underwent lung transplantation (1 bilateral, 4 single lung) using this technique. All patients were ventilated on a 40% fraction of inspired oxygen within a few hours and extubated on or before the first postoperative day. CONCLUSIONS: Controlled reperfusion of the transplanted lung with white cell-filtered, nutrient-enriched blood has given excellent functional results in our small initial clinical series.

Humans↗
PubMed2000

Definition of distinct compartments in polarized Madin-Darby canine kidney (MDCK) cells for membrane-volume sorting, polarized sorting and apical recycling.

Previous studies of fibroblasts have demonstrated that recycling of endocytic receptors occurs through a default mechanism of membrane-volume sorting. Epithelial cells require an additional level of polar membrane sorting, but there are conflicting models of polar sorting, some suggesting that it occurs in early endosomes, others suggesting it occurs in a specialized apical recycling endosome (ARE). The relationship between endocytic sorting to the lysosomal, recycling and transcytotic pathways in polarized cells was addressed by characterizing the endocytic itineraries of LDL, transferrin (Tf) and IgA, respectively, in polarized Madin-Darby canine kidney (MDCK) cells. Quantitative analyses of 3-dimensional images of living and fixed polarized cells demonstrate that endocytic sorting occurs sequentially. Initially internalized into lateral sorting endosomes, Tf and IgA are jointly sorted from LDL into apical and medical recycling endosomes, in a manner consistent with default sorting of membrane from volume. While Tf is recycled to the basolateral membrane from recycling endosomes, IgA is sorted to the ARE prior to apical delivery. Quantifications of the efficiency of sorting of IgA from Tf between the recycling endosomes and the ARE match biochemical measurements of transepithelial protein transport, indicating that all polar sorting occurs in this step. Unlike fibroblasts, rab11 is not associated with Tf recycling compartments in either polarized or glass-grown MDCK cells, rather it is associated with the compartments to which IgA is directed after sorting from Tf. These results complicate a suggested homology between the ARE and the fibroblast perinuclear recycling compartment and provide a framework that justifies previous conflicting models of polarized sorting.

Animals↗
PubMed2000

Apical and basolateral endocytic pathways of MDCK cells meet in acidic common endosomes distinct from a nearly-neutral apical recycling endosome.

Quantitative confocal microscopic analyses of living, polarized MDCK cells demonstrate different pH profiles for apical and basolateral endocytic pathways, despite a rapid and extensive intersection between the two. Three-dimensional characterizations of ligand trafficking demonstrate that the apical and basolateral endocytic pathways share early, acidic compartments distributed throughout the medial regions of the cell. Polar sorting for both pathways occurs in these common endosomes as IgA is sorted from transferrin to alkaline transcytotic vesicles. While transferrin is directly recycled from the common endosomes, IgA is transported to a downstream apical compartment that is nearly neutral in pH. By several criteria this compartment appears to be equivalent to the previously described apical recycling endosome. The functional significance of the abrupt increase in lumenal pH that accompanies IgA sorting is not clear, as disrupting endosome acidification has no effect on polar sorting. These studies provide the first detailed characterizations of endosome acidification in intact polarized cells and clarify the relationship between the apical and basolateral endocytic itineraries of polarized MDCK cells. The extensive mixing of apical and basolateral pathways underscores the importance of endocytic sorting in maintaining the polarity of the plasma membrane of MDCK cells.

Animals↗
PubMed1996

Molecular interactions between human B-cell progenitors and the bone marrow microenvironment.

Apoptosis of normal and leukemic immature B-cells in vitro is suppressed when either cell type is grown in direct contact with a feeder layer of bone marrow-derived stromal cells, including fibroblasts, macrophages, endothelial cells, and adipocytes. In this study, our objective was to identify a stromal cell type which is essential for lymphoblast survival and to characterize the molecules involved in lymphoblast adhesion to these cells. In experiments with B-lineage acute lymphoblastic leukemia (ALL) cells (n = 28) and purified CD19(+) cells from normal bone marrow (n = 6) we found that homogeneous populations of bone marrow fibroblasts could sustain survival of normal and leukemic immature B-cells as efficiently as composite bone marrow stromal layers. Electron microscopic studies showed that leukemic lymphoblasts associate with fibroblasts and with the extracellular matrix (ECM) primarily via their specialized cell surface structures. Immunogold labelingsoliduselectron microscopy analysis revealed that the areas of contact between lymphoblasts and fibroblasts contained beta1 integrins (VLA-4 and VLA-5), fibronectin, vascular cell adhesion molecule (VCAM-1), and a cartilage-link protein, CD44. Double immunogold labeling studies disclosed a direct in situ relationship between fibronectin and VLA-4, VLA-5, and CD44. We hypothesize that these molecular interactions either bring lymphoblasts into close physical proximity with other fibroblast-bound or ECM-bound survival factors or provide survival signals themselves.

B-Lymphocytes↗
PubMed1996

Xanthogranulomatous pyelonephritis: report of nonsurgical management of a case and review of the literature.

A case of focal xanthogranulomatous pyelonephritis (XPN) in a child, successfully cured with antibiotics only, is presented, and this report is followed by a review of the literature on XPN in both children and adults. XPN is a rare inflammatory disease of the kidney. Factors strongly implicated in the development of XPN are genitourinary obstruction and urinary tract infection, although other contributing factors have been suggested. The clinical presentation of the disease is remarkably nonspecific and variable; it therefore is frequently misdiagnosed as other, more common diseases that cause focal or diffuse renal masses, including renal neoplasms, abscesses, and tuberculosis. Diagnosis requires acquisition of renal tissue for special pathological staining. The long-standing mainstay of therapy for XPN has been nephrectomy or partial nephrectomy. However, this report and other recent reports of the successful medical management of focal XPN suggest that a trial of antibiotics prior to surgery is warranted in cases of focal XPN.

Adult↗
PubMed1994

A23187 releases bound rather than free calcium from calcium-loaded liposomes.

We have investigated sonication-, osmotic shock-, and A23187-induced calcium and horseradish peroxidase release from phosphatidylcholine liposomes. We report that sonication and osmotic shock both cause release of liposome-entrapped horseradish peroxidase activity, thus, completely releasing the entrapped volume into and mixing it with the external medium. However, we find that neither sonication nor osmotic shock releases significant amounts of calcium from liposomes pre-loaded with calcium, while A23187 causes release of significant amounts of calcium from similarly prepared liposomes. We also find that A23187 can release calcium from liposomes after release of entrapment volume by sonication or osmotic shock. Alteration of the net charge of liposomes by substitution of phosphatidylcholine with phosphatidylserine or stearylamine dramatically changes the amount of calcium associated with calcium-loaded liposomes; sonication or addition of A23187 to liposomes containing significant amounts of PS does not appear to release calcium bound to these vesicles. These results suggest that a large fraction (> 99%) of the calcium associated with liposomes is bound to the membranes of the liposomes and that the calcium released by A23187 is due to release of bound rather than entrapped calcium.

Amines↗
PubMed1994

The popliteal artery as inflow for distal bypass grafting.

OBJECTIVE: To examine the patency and limb salvage characteristics of the popliteal-distal artery saphenous-vein bypass in patients with minimal superficial femoral artery disease. DESIGN: A retrospective review. SETTING: A tertiary care university hospital in the Chicago, Ill, metropolitan area. PATIENTS: Fifty-two popliteal-distal artery saphenous-vein bypasses for occlusive disease were performed in 51 patients between 1980 and 1993. The mean age at operation was 62 years (range, 37 to 85 years); 34 patients (67%) were male, 45 (88%) were smokers, 44 (86%) had diabetes, and 34 (67%) had coronary disease. The primary indications for operation were gangrene (21 patients [41%]), ulcer (15 patients [29%]), and rest pain (16 patients [31%]). INTERVENTION: Bypass of diseased arterial segments was performed using popliteal-distal artery saphenous-vein bypass grafts. The proximal anastomoses were either to the above-knee popliteal artery (50%) or to the below-knee artery (50%), with outflow to tibial (79%) or pedal vessels (21%). MAIN OUTCOME MEASURES: Overall patient survival, limb salvage, and primary and secondary graft patency. RESULTS: Follow-up of graft patency ranged from 1 day to 11 years (mean follow-up, 2.7 years). The perioperative mortality was 2% and life-table survival was 94% at 1 year, 68% at 5 years, and 50% at 10 years. Primary patency was 90% at 1 month, 82% at 1 year, and 75% at 5 years. There were 14 primary graft failures, only two of which could be traced to progression of proximal disease; five failures occurred less than 30 days after operation. Six of these 14 patients contributed to secondary patency that was 96% at 1 month, 90% at 1 year, and 79% at 5 years. Limb salvage was 96% at 1 month, 90% at 1 year, and 87% at 5 years (seven major amputations were required). No significant differences in patency, limb salvage, or survival were observed on comparison of the level of the proximal or distal anastomosis, type of vein graft, or presence of comorbidities. CONCLUSIONS: We conclude that popliteal-distal artery bypass provides excellent patency and limb salvage for patients with severe ischemia. The use of a popliteal artery inflow source is preferable in patients with a paucity of venous segments since progression of proximal disease rarely leads to graft failure.

Adult↗
PubMed1993

Highly localized tracks of human immunodeficiency virus type 1 Nef in the nucleus of cells of a human CD4+ T-cell line.

A human T-cell line constitutively expressing the nef gene from the human immunodeficiency virus type 1 SF2 isolate was used to examine the distribution of the Nef protein in the nucleus. High-resolution immunogold labeling/electron microscopic studies with polyclonal anti-Nef antibodies on nef+ and nef- cells revealed that a small fraction of Nef is in the nucleus and it is localized in specific curvilinear tracks that extend between the nuclear envelope and the nucleoplasm. An examination of the sequence of the SF2 nef gene revealed a putative nuclear targeting sequence that was previously found in several other eukaryotic nucleoplasmic proteins. The nuclear localization of Nef suggests a potential nuclear function for this protein. The presence of Nef in distinct nuclear tracks suggests that Nef is transported along a specific pathway that extends from the nuclear envelope into the nucleoplasm. A previous study [Meier, U. T. & Blobel, G. (1992) Cell 70, 127-138] has shown that the nucleolar protein of rat liver cells (Nopp140) shuttles from the nucleolus to the nuclear envelope on distinct tracks. The present study has suggested that the transport of a nucleoplasmic protein may also occur on distinct nuclear pathways.

Amino Acid Sequence↗
PubMed1993

Relation between choice of prostheses and late outcome in double-valve replacement.

The purpose of this study was to determine if the combination of a mechanical and bioprosthetic valve in the aortic and mitral positions influences late morbidity and mortality when compared with patients who had dual mechanical or dual bioprosthetic valves inserted. We reviewed the course of 89 hospital survivors of combined aortic and mitral valve replacement. The mean postoperative follow-up interval was 6.6 years, with a total follow-up of 583 years (98% complete). At 12 months after operation, mean functional class decreased from 3.1 to 1.7 (p < 0.05) and mean cardiac index increased from 2.1 to 2.5 L.min-1.m-2 (p < 0.05). Actuarial survival for the 89 patients (exclusive of < 30-day or in-hospital mortality, 14%) was 70%, 51%, and 33% at 5, 10, and 15 years. Freedom from reoperation was 93%, 78%, and 68%, and freedom from combined thromboembolism and anticoagulant-related hemorrhage was 82%, 60%, and 50%. These results show that there was no difference in overall survival in patients with dual mechanical valves, dual bioprosthetic valves, or a combination of both types at 15 years. There was, however, a lower reoperation rate in the group with dual mechanical valves as compared with the group with dual bioprosthetic valves (p < 0.05 at 10 years) or with a combination of valves (p < 0.05 at 15 years). The higher the number of mechanical valves the higher the combined risk of thromboembolism and anticoagulant-related hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)

Actuarial Analysis↗
PubMed1993

Late results after triple-valve replacement with various substitute valves.

The purpose of this study was to determine what influence various combinations of mechanical and bioprosthetic valves in the aortic, mitral, and tricuspid positions had on late morbidity and mortality of 40 hospital survivors of triple-valve replacement. At operation the patients ranged in age from 27 to 69 years; 73% were women. The mean postoperative follow-up interval was 8.3 years, with a total follow-up of 331 years (100% complete). At 12 months after operation, functional class decreased from 3.3 to 1.6 (p < 0.05), cardiac index increased from 2.0 to 2.6 L.min-1 x m-2 (p < 0.05), and pulmonary artery pressures decreased from 59/27 to 40/17 mm Hg (p < 0.05). There were no differences in preoperative variables between groups. Actuarial survival for the 40 patients (exclusive of 30-day or in-hospital mortality, which was 31%) was 78% and 74% at 5 and 10 years. At the same milestones, freedom from reoperation was 96% and 54%, freedom from combined thromboembolism and anticoagulant-related hemorrhage was 68% and 56%, and freedom from all late valve-related morbidity and mortality was 64% and 25%. Comparison of the patients with two or more mechanical prostheses with the patients having two or more bioprostheses indicated no significant differences in actuarial freedom from late death, thromboembolic events, or anticoagulant-related hemorrhage. However the actuarial freedom from reoperation in the groups with two or more mechanical valves was lower than that of the groups with two or more bioprosthetic valves (0/10 versus 13/30; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Actuarial Analysis↗
PubMed1993

Vaginal secretions increase the likelihood of intermale aggression in Syrian hamsters.

Although sexually receptive female hamsters prefer dominant males as mating partners, it is not clear what role the female might play facilitating aggressive interactions among males that would lead to the establishment of a status relationship. The ability of vaginal odors to stimulate male aggression was examined by paring randomly chosen males in a neutral arena with vaginal odors either present or absent. Males exhibited significantly more aggression when tested in the scented arena. Vaginal odors are efficient broadcast signals serving to space females, attract males, and to stimulate aggressive interactions among the males while inhibiting aggression towards the female.

Aggression↗
PubMed1992

Acute severe postischemic myocardial depression reversed by triiodothyronine.

The purpose of this study was to determine the effects of triiodothyronine (T3) on postischemic left ventricular performance and high-energy phosphate content in a severe injury model. Isolated working rat hearts (n = 63) received 20 mL of hyperkalemic NIH No. 1 cardioplegia and were subjected to 20 minutes of ischemia at 37 degrees C. Treated hearts were reperfused with T3-supplemented modified Krebs-Henseleit buffer. Control hearts did not receive T3 supplementation. All treated hearts (n = 44) performed work after ischemia, whereas 26% (5/19) of the control hearts were not able to perform any left ventricular work after ischemia. Comparisons with preischemic values demonstrated significant progressive hemodynamic recovery with increasing concentrations of T3 (0, 0.06, 0.15, and 0.60 ng/mL) with concomitant recovery of left ventricular stroke work index (63%, 72%, 89% [p less than 0.05], and 99% [p less than 0.05], respectively). There were corresponding increases in recovery of aortic flow, systolic pressure, cardiac index, and stroke volume index (p less than 0.05). There were no significant changes in coronary sinus flow or heart rate in any group compared with preischemic values. Comparisons of postischemic high-energy phosphate concentrations also demonstrated no change between treated and untreated groups (p greater than 0.05). We conclude that administration of T3 in a severe left ventricular injury model significantly augments rapid ventricular recovery with no change in postischemic high-energy phosphate concentrations.

Acute Disease↗
PubMed1992

Composition of the helical internal components of influenza virus as revealed by immunogold labeling/electron microscopy.

The composition of the large helical internal components of influenza virus was investigated by immunogold labeling/electron microscopy with antibodies to the nucleoprotein (NP), matrix protein (M), and polymerase complex (PB1, PB2, and PA) of the virus. The morphologically intact helices, obtained by air-drying of the virions on the electron microscope grid, showed little or no labeling with any of the above antibodies. However, partial to full degradation of the helix by proteinase K (2 ng/ml) prior to immunogold labeling made the helices accessible to all three antibodies. The results are consistent with a model that the helix represents a polymer of M protein enclosing or containing the influenza ribonucleoprotein(s).

Antibodies, Monoclonal↗
PubMed1991

Anti-Tac-H, a humanized antibody to the interleukin 2 receptor, prolongs primate cardiac allograft survival.

High-affinity interleukin 2 receptors (IL-2Rs) are expressed by T cells activated in response to foreign histocompatibility antigens but not by normal resting T cells. To exploit this difference in IL-2R expression, anti-Tac-M, a murine monoclonal antibody specific for the IL-2R alpha chain, was used to inhibit organ allograft rejection. However, the use of murine anti-Tac as an immunosuppressive agent was limited by neutralization by human anti-murine antibodies and by weak recruitment of effector functions. To circumvent these difficulties, a humanized antibody to the IL-2R, anti-Tac-H, was prepared. This molecule is human with the exception of the hypervariable segments, which are retained from the mouse. In vivo survival of anti-Tac-H is 2.5-fold longer than simultaneously administered anti-Tac-M (terminal t1/2, 103 hr vs. 38 hr). In addition, anti-Tac-H is less immunogenic than anti-Tac-M when administered to cynomolgus monkeys undergoing heterotopic cardiac allografting. Specifically, all monkeys treated with anti-Tac-M developed measurable anti-anti-Tac-M levels by day 15 (mean onset, 11 days). In contrast, none of the animals receiving anti-Tac-H produced measurable antibodies to this monoclonal antibody before day 33. Finally, there was a prolongation of graft survival in the cynomolgus heterotopic cardiac allograft model in animals receiving anti-Tac. In animals that received anti-Tac-M, the allograft survival was prolonged compared to that of the control group (mean survival, 14 +/- 1.98 days compared to 9.2 +/- 0.48 days; P less than 0.025). Graft survival was further prolonged by anti-Tac-H with a mean survival of 20.0 +/- 0.55 days (compared to controls, P less than 0.001; compared to anti-Tac-M, P less than 0.02). There was no toxicity attributable to the administration of either form of anti-Tac. Thus, anti-Tac-H significantly prolonged allograft survival in primates, without toxic side effects, and may be of value as an adjunct to standard immunosuppressive therapy in humans.

Animals↗