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Biomedical subjects

M R Brown

Publications and source records attributed to M R Brown.

At least 91 records · Page 5Linked to original sources
PubMed1996

Bacterial doubling time modulates the effects of opsonisation and available iron upon interactions between Staphylococcus aureus and human neutrophils.

Staphylococcus aureus was grown exponentially at two doubling times (DT), one related to in vivo (DT 60 min) and one typical of laboratory conditions (DT 24 min), and under iron-poor and iron-rich conditions. Relative to the fast-grown phenotypes, both slow-grown phenotypes exhibited low surface hydrophobicity and low protein A expression, induced poorly in non-opsonised and opsonised chemiluminescence, and survived well in whole blood killing. In particular, slow-grown, iron-poor cocci demonstrated enhanced survival in whole blood killing which correlated with significant reduction in their association with polymorphonuclear leukocytes, compared to the three other phenotypes; iron sufficiency increased the ability to stimulate polymorphonuclear leukocytes irrespective of opsonisation status. Staphylococcal DT may, by influencing surface hydrophobicity, modify interactions with immune system components.

Blood Bactericidal Activity↗
PubMed1996

Measurement of T-cell CD69 expression: a rapid and efficient means to assess mitogen- or antigen-induced proliferative capacity in normals.

We have analyzed the expression of the activation antigen CD69 on normal human T cells by flow cytometry following stimulation with mitogens and recall antigen. These data were compared to parallel studies assessing the proliferative response using the 3H-thymidine (3H-TdR) incorporation assay. Three different mitogens (PHA, ConA, and CD2/CD2R) induced maximal expression of CD69 at 24 h, which remained stable throughout the 72 h culture period. The mitogen-stimulated cells initiated DNA synthesis as determined by the 3H-TdR assay (72 h) while nonstimulated cells failed to upregulate CD69 or incorporate 3H-TdR. We next compared T cell CD69 expression (n = 12) following stimulation with either CD2/CD2R (5 micrograms/ml) or the recall antigen, tetanus toxoid (1:1500). Cell proliferation was determined by the 3H-TdR assay at 72 h (CD2/CD2R) or 120 h (tetanus toxoid). Evaluation of CD69 expression at 6 h predicted CD2/CD2R but not tetanus responder status as defined by 3H-TdR incorporation. However, when 4 known tetanus responders (3H-TdR) were evaluated over time, it was found that at 48 h the fluorescence intensity (of CD69) on tetanus-stimulated CD3+ cells increased markedly compared with nonstimulated cells (range of increase 43-850%). One individual whose cells failed to respond to tetanus toxoid (3H-TdR and CD69) did respond normally to CD2/CD2R. These observations suggest that flow cytometric evaluation of T cell CD69 expression following mitogen (6 h) or antigen (48 h) stimulation may provide an accurate screen of T-cell responsiveness in normals.

Antigens, CD↗
PubMed1996

Autocrine activation of hemopoietic progenitor-derived myelo-monocytic cells by IFN-gamma gene transfer.

Immunomodulatory cytokines have been used with success as adjunctive therapy in genetic disorders such as chronic granulomatous disease and infectious diseases such as leishmaniasis and leprosy. As the first step toward developing novel methods to deliver immunomodulatory cytokines, we used retrovirus-mediated somatic gene transfer techniques to produce IFN-gamma from human peripheral blood CD34+ hemopoietic progenitor (PBHP) cells. After transduction, the PBHP cells were made to differentiate toward myelo-monocytic lineages. Only the PBHP-derived myelo-monocytic cells that were transduced with the IFN-gamma cDNA produced IFN-gamma(4 +/- 1.3 ng of IFN-gamma/10(6) PBHP cells.) Despite a reduction in the proliferation of IFN-gamma-transduced PBHP cells as well as a decrease in erythroid colony formation, there was an enhancement of monocyte differentiation and activation. Monocytes differentiated from the IFN-gamma-transduced PBHP cells demonstrated 1) up-regulation of MHC class I and II Ag expression, 2) increased Fc(gamma)RI expression, and 3) enhanced superoxide production in response to both opsonized zymosan (25-fold) and phorbol ester (3-fold). Furthermore, a functional response to a monocyte-specific chemokine, monocyte chemotactic protein-1 (mobilization of intracellular Ca2+) was seen only in the IFN-gamma-transduced cells. Thus, PBHP cells transduced with IFN-gamma cDNA produce not only biologically active IFN-gamma, but also enhanced monocyte differentiation, resulting in an activated state that includes unique functions, such as responsiveness to monocyte chemotactic protein-1. These transduced activated monocytes may be specifically suited to cellular therapy requiring homing to sites of inflammation where their anti- microbicidal, cytotoxic and APC functions play an important role in host defense against foreign pathogens.

3T3 Cells↗
PubMed1996

Effect of angiotensin II on the renal response to amino acid in rats.

Administration of the nitric oxide (NO) synthase blocker, N(G)-monomethyl L-arginine prevents the increase in glomerular filtration rate (GFR) normally observed with glycine, an effect that is restored by angiotensin II (AII) blockers. These findings suggest that changes in NO and AII dictate the presence or absence of renal vasodilation during amino acid (AA) infusion. We examined the effect of branched-chain (BCAA) and non-branched-chain (NBCAA) AA on GFR, NO, and AII to determine if abnormal NO or AII responses could explain the absence of vasodilation with BCAA. Our findings demonstrated that NBCAA increased GFR and NO and did not modify AII, either plasma (AIIp) or kidney (AIIk) AII. The response with BCAA was strikingly different. L-Valine increased GFR without modifying NO or AII. L-Leucine increased AIIk and NO but did not increase GFR. Administration of AII blockers (captopril or losartan) was associated with an increase in GFR during infusion of leucine. Single nephron studies demonstrated that increased AIIk with L-leucine was associated with decreased absolute proximal reabsorption and probably activation of the tubuloglomerular feedback. An AA-specific increase in AIIk is critical to inhibition of the normal renal response to AA infusion. NO generation is an important mediator but not the sole mechanism that determines the increase in GFR during amino acid infusion.

Amino Acids↗
PubMed1996

Efficacy of subcutaneous silver-impregnated cuffs in preventing central venous catheter infections.

STUDY OBJECTIVES: To determine the efficacy of an attachable subcutaneous silver-impregnated cuff in preventing local central venous catheter (CVC)-related infection and catheter-related sepsis in critically ill surgical patients. DESIGN: A prospective analysis of the use of an attachable subcutaneous silver-impregnated cuff compared with a control group in two consecutive time periods. SETTING: Two surgical ICUs at the Queen's Medical Center at the University of Hawaii Surgical Residency Program, Honolulu. PATIENTS: All surgical ICU patients requiring insertion of central catheters. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULT: Two hundred thirty-five CVCs in 154 patients were prospectively evaluated. Silver-impregnated cuffs were used in the first 100 catheters, but none were used in the remaining 135 catheters. The incidence of catheter-related infection in both groups was 15% and 20%, respectively, not statistically significant. Catheter-related sepsis was 3% in both groups. CONCLUSIONS: The use of an attachable subcutaneous silver-impregnated cuff failed to decrease the incidence of CVC-related infection and sepsis.

APACHE↗
PubMed1996

Shave excision of facial tumors in tuberous sclerosis.

Tuberous sclerosis can manifest itself by multiple facial nodules affecting primarily the nose, cheeks, chin, and the nasolabial folds. A simple tangential (shave) excision of these facial tumors is believed to be adequate treatment for some patients.

Adolescent↗
PubMed1996

Eosinophilia as a marker of adrenal insufficiency in the surgical intensive care unit.

BACKGROUND: Because hemodynamic instability may have several causes in critically ill patients, adrenal insufficiency may not be readily diagnosed. Eosinophilia has been described in patients with chronic adrenal insufficiency but not in critically ill patients. The goal of this study was to determine whether eosinophilia could serve as a marker of adrenal insufficiency in critically ill patients. STUDY DESIGN: During a 1-year period, all surgical patients admitted to the surgical intensive care unit with an eosinophil count greater than 3 percent were prospectively studied. To diagnose adrenal insufficiency, the synthetic corticotropin (cosyntropin) stimulation test was used. RESULTS: Eosinophilia was diagnosed in 31 patients, 7 (23 percent) of whom had adrenal insufficiency. The mean time interval to diagnosis was 13.7 days (range, 4 to 39 days). In 82 percent of the patients treated with hydrocortisone, a response was evidenced within 24 hours of treatment by a decrease in the required inotropic support by more than 50 percent, an increase in the mean arterial blood pressure of more than 25 percent, or both. CONCLUSIONS: New-onset eosinophilia may be a useful marker for adrenal insufficiency. Prompt testing and diagnosis may avoid the occurrence of a treatable, life-threatening condition.

Adrenal Cortex Function Tests↗
PubMed1995

Grasshopper crop and midgut extract effects on plants: an example of reward feedback.

Acid extracts and a resultant fraction from solid-phase extraction (SPE) of Romalea guttata crop and midgut tissues induce sorghum (Sorghum bicolor var. Rio) coleoptile growth in 24-h incubations an average of 49% above untreated controls. When combined with plant auxin, indole-3-acetic acid (IAA), the SPE fraction shows a synergistic reaction, yielding increases in coleoptile growth that average 295% above untreated controls and 8% above IAA standards. The interaction lowered the point of maximum sensitivity of IAA 3 orders of magnitude, resulting in a new IAA physiological set point at 10(-7) g/ml. This synergism suggests that contents in animal regurgitants making their way into plant tissue during feeding may produce a positive feedback in plant growth and development following herbivory. Such a process, also known as reward feedback, may exert major controls on ecosystem-level relationships in nature.

Journal Article↗
PubMed1995

Evidence for a sex-segregated migration in the humpback whale (Megaptera novaeangliae).

Existing population models for humpback whales assume that all individuals within a population undertake the annual migration from feeding areas in high latitudes to breeding areas in tropical waters. An excess of males was recorded in the commercial whaling catches near breeding areas in the southern hemisphere, but no account of this was taken in developing population models, because it was believed that this bias was a result of whalers selecting against females with young calves. Here we demonstrate that the sex ratio of migrating humpback whales near a breeding area is highly skewed towards males. A biopsy study carried out in 1992 throughout the northward and southward migrations revealed a sex ratio of 2.4 males: 1 female in the population of humpback whales migrating along the east Australian coast (n = 180). A reanalysis of the catches made during commercial whaling in this and other areas of the southern hemisphere gave a sex ratio of the same order. The most plausible explanation, supported by some evidence, is that some females remain in the feeding areas throughout winter. The results reported here show that existing management models require major revision to take account of these findings.

Animals↗
PubMed1995

Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy.

BACKGROUND: Inadequate reconstitution of CD4+ T lymphocytes is an important clinical problem complicating chemotherapy, human immunodeficiency virus infection, and bone marrow transplantation, but relatively little is known about how CD4+ T lymphocytes regenerate. There are two main possibilities: bone marrow-derived progenitors could reconstitute the lymphocyte population using a thymus-dependent pathway, or thymus-independent pathways could predominate. Previous studies have suggested that the CD45RA glycoprotein on CD4+ T lymphocytes is a marker for progeny generated by a thymus-dependent pathway. METHODS: We studied 15 patients 1 to 24 years of age who had undergone intensive chemotherapy for cancer. The absolute numbers of CD4+ T lymphocytes in peripheral blood and the expression of CD45 isoforms (CD45RA and CD45RO) on these lymphocytes were studied serially during lymphocyte regeneration after the completion of therapy. Radiographic imaging of the thymus was performed concomitantly. RESULTS: There was an inverse relation between the patients' ages and the CD4+ T-lymphocyte counts six months after therapy was completed (r = -0.92). The CD4+ recovery correlated quantitatively with the appearance of CD45RA+CD4+ T lymphocytes in the blood (r = 0.64). There was a higher proportion of CD45RA+CD4+ T lymphocytes in patients with thymic enlargement after chemotherapy than in patients without such enlargement (two-sided P = 0.015). CONCLUSIONS: Thymus-dependent regeneration of CD4+ T lymphocytes occurs primarily in children, whereas even young adults have deficiencies in this pathway. Our results suggest that rapid T-cell regeneration requires residual thymic function in patients receiving high-dose chemotherapy.

Adolescent↗
PubMed1995

Hemolytic anemia secondary to a porcine mitral prosthetic valve leaflet dissection.

This is a case of a dissecting cusp of a mitral porcine xenograft causing severe hemolytic anemia in the absence of valvular dysfunction and regurgitation. Six months after valve replacement, the patient had no evidence of hemolytic anemia. A cuspal dissection between the atrial and ventricular membranes was found on histologic evaluation.

Aged↗
PubMed1995

Speculations on the influence of infecting phenotype on virulence and antibiotic susceptibility of Legionella pneumophila.

It is not clear how Legionella pneumophila, which is a ubiquitous aquatic organism not possessing a mammalian reservoir, evolved the ability to cause human disease. The unusual ecology of the organism may play an important role in the transmission and virulence of legionella infections. L. pneumophila can infect and kill specific species of free-living amoebae as well as multiplying as an intracellular parasite in human phagocytic cells. In nature L. pneumophila can survive and possibly replicate in free suspension, and grow in biofilms and in protozoa thus leading to diverse phenotypes, potentially with diverse virulence and susceptibility properties. Indeed, recent evidence shows that intra-amoeba growth induces a phenotype that is dramatically different physiologically to that obtained in vitro, with altered virulence and susceptibility properties. Growth in macrophages also has profound effect on the physiological properties of L. pneumophila. Many different stress proteins are expressed by the organism as a result of intra-macrophage growth. A heat shock protein is abundantly synthesised and may be presented on the surface of infected macrophages, which allows them to be targeted by T-lymphocytes for destruction. The difficulties in successfully treating Legionnaires' disease are probably influenced by the intracellular location of L. pneumophila. Retrospective clinical studies show that it is only drugs such as erythromycin, ciprofloxacin and rifampicin, which are capable of accumulating in phagocytic cells, that are efficacious in the treatment of legionnaires' disease. Despite the use of such drugs treatment failures occur, but these do not appear to be associated with the emergence of resistant strains. Studies have shown that although erythromycin and rifampicin can inhibit the multiplication of L. pneumophila in macrophages the organism is not killed and can resume multiplying when the drugs are removed. Thus a competent cell mediated immune response is important in recovery from legionella infections. There is an urgent need for greater understanding of how the changes induced by intracellular growth affect sensitivity to antibiotics and of how the changes induced by intracellular growth affect sensitivity to antibiotics and host defences. Immunocompromised patients, who have the highest mortality rates, are likely to gain the most from progress in the treatment of L. pneumophila infections.

Anti-Bacterial Agents↗
PubMed1995

A simple in vitro model for growth control of bacterial biofilms.

The perfused biofilm fermenter was found to be unsuitable for the long-term culture and growth rate control of Staphylococcus aureus and Pseudomonas aeruginosa biofilms. In a simplified approach, biofilms of these organisms were grown within Sorbarod filter plugs which were perfused with culture medium. Pseudo-steady states were established which were stable over several days at which the growth rate of the biofilm was reproducible, measurable and significantly slower than in broth culture. Environmental scanning electron microscopy of dissected Sorbarods demonstrated an association of cells with the surfaces of individual cellulose fibres, and growth characteristic of biofilms. Relatively high cell numbers recovered from the Sorbarod model facilitated biochemical investigations of biofilm populations and cells released spontaneously from them. SDS-PAGE demonstrated significant differences between the protein profiles of biofilm and eluted populations, which include, in Staph. aureus, the repression of a 48 kDa protein and increased expression of a 21 kDa protein relative to planktonic controls cultured at equivalent growth rates. The paper demonstrates the suitability of the approach for the culture of biofilm samples which are suitable for biochemical analysis.

Bacteriological Techniques↗
PubMed1995

Serum IgG response to Burkholderia cepacia outer membrane antigens in cystic fibrosis: assessment of cross-reactivity with Pseudomonas aeruginosa.

Burkholderia cepacia (Pseudomonas cepacia) is now recognised as an important pathogen in cystic fibrosis patients, and several reports have suggested that sputum-culture-proven colonisation occurs despite the presence of specific antibody. In an attempt to establish the use of antibody studies as diagnostic and prognostic indicators of B. cepacia infection, we have examined the IgG response to B. cepacia outer membrane proteins and lipopolysaccharide in patients also colonised with P. aeruginosa. The B. cepacia strains were grown in a modified iron-depleted chemically defined medium and outer membrane components examined by SDS-PAGE and immunoblotting. IgG antibodies were detected against B. cepacia outer membrane antigens, which were not diminished by extensive preadsorption with P. aeruginosa. The response to B. cepacia O-antigen could be readily removed by adsorption of serum either with B. cepacia whole cells or purified LPS, whereas we were unable to adsorb anti-outer membrane protein antibodies using B. cepacia whole cells. The inability to adsorb anti-outer membrane protein antibodies using B. cepacia whole cells maybe due to non-exposed surface epitopes. Several B. cepacia sputum-culture negative patients colonised with P. aeruginosa had antibodies directed against B. cepacia outer membrane protein. this study suggests that there is a specific anti-B. cepacia LPS IgG response, which is not due to antibodies cross-reactive with P. aeruginosa. Our studies indicate that much of the B. cepacia anti-outer membrane protein response is specific and not attributable to reactivity against co-migrating LPS.

Adolescent↗
PubMed1995

Intraphagocytic growth induces an antibiotic-resistant phenotype of Legionella pneumophila.

The antimicrobial susceptibilities of Legionella pneumophila isolates grown either in U937 human monocytic cells or in Acanthamoeba polyphaga were studied after release from the host cells without further subculture. Time-survival studies showed that exposure of L. pneumophila cells, gown exclusively in vitro, to 5 micrograms of rifampin per ml resulted in at least 99% killing after 6 h and no detectable survivors at 24 h. Similar rates of killing were observed for in vitro-grown cells tested by exposure to ciprofloxacin. Conversely, time-survival studies revealed that macrophage-grown and amoeba-grown cells were ca. 1,000-fold more resistant to the activities of both drugs. Macrophage-grown cells treated with 5 micrograms of rifampin per ml showed 70 and 62% survival after 6 and 24 h, respectively. Intracellularly grown legionellae were also highly resistant to erythromycin (8 microgram/ml). After 24 h of exposure to the drug, there was 70 and 60% survival for amoeba-grown and macrophage-grown legionellae, respectively, whereas in vitro-grown cells showed a 2-log10 reduction in viable count. when intracellularly grown L. pneumophila cells were subcultured in broth for 48 h, they reverted to the phenotype characteristic of in vitro growth. Morphologically, the cells were larger than their intracellularly grown counterparts and resistance characteristics were lost. The susceptibilities of the subcultured cells to all three drugs were similar to those of Legionella cells grown exclusively in vitro. In view of these findings, the successful treatment of Legionnaires disease may be related as much to the resistance phenotype induced by intramacrophage growth as to the ability of the antibiotic to enter phagocytic cells.

Acanthamoeba↗